Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia

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Since the study’s design, hepatitis B treatment guidelines have undergone significant evolution. New WHO recommendations published in 2024 advocate for expanded treatment criteria, making terms like “Indeterminate phase” obsolete. Methods This retrospective longitudinal cohort study was conducted at Farhat Hached University Hospital in Sousse, Tunisia, from January 2008 to January 2022. We included HBsAg-positive patients who were untreated, had a viral load >2,000 IU/mL for at least six months, normal ALT (<40 IU/L), and a fibrosis score of F0 and/or F1 (determined by liver biopsy or FibroScan). Univariate and logistic regression analyses were performed to identify factors associated with liver fibrosis progression. Results A total of 97 patients were included, with a median age of 32.9 ± 9.1 years and a female predominance (M/F ratio = 0.64). Fibrosis progression occurred in 16 patients (16.5%), with a mean delay of 70.9 ± 41.1 months. Univariate analysis showed significant associations between fibrosis progression and comorbidities (p = 0.001), high initial viral load (p = 0.004), elevated liver enzymes (p = 0.001), and increased viral load during follow-up (p = 0.002). Multivariate analysis identified comorbidities (p<0.001) and changes in ALT levels (p<0.001) as independent predictors of fibrosis progression. Conclusion Comorbidities and changes in ALT levels during follow-up were associated with fibrosis progression in the indeterminate phase of chronic HBV infection. Our findings support recent changes in international guidelines, including those from the WHO in 2024, which expand therapeutic indications for individuals living with hepatitis B. 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F1000Research 2025, 14 :11 ( https://doi.org/10.12688/f1000research.157075.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] Sana Rouis https://orcid.org/0000-0003-2858-5314 1 , soumaya mrabet https://orcid.org/0000-0002-1321-6674 2 , Mohamed Ferjaoui https://orcid.org/0009-0003-6348-150X 1 , [...] Nedia Ben Lasfar 3 , Jihene Sahli 4 , Syrine Boujamline 3 , Rym Ayari 5 , Maha Abid 3 , Manel Ben Selma https://orcid.org/0009-0007-1633-6894 3 , Mariem BEN TICHA 3 , Foued Bellazreg 3 , Elhem Ben Jezia https://orcid.org/0000-0002-3698-8845 2 , Amel Letaief 3 , Wissem Hachfi 3 Sana Rouis https://orcid.org/0000-0003-2858-5314 1 , soumaya mrabet https://orcid.org/0000-0002-1321-6674 2 , [...] Mohamed Ferjaoui https://orcid.org/0009-0003-6348-150X 1 , Nedia Ben Lasfar 3 , Jihene Sahli 4 , Syrine Boujamline 3 , Rym Ayari 5 , Maha Abid 3 , Manel Ben Selma https://orcid.org/0009-0007-1633-6894 3 , Mariem BEN TICHA 3 , Foued Bellazreg 3 , Elhem Ben Jezia https://orcid.org/0000-0002-3698-8845 2 , Amel Letaief 3 , Wissem Hachfi 3 PUBLISHED 27 Aug 2025 Author details Author details 1 Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 2 Department of Hepato-gastroenterology, Faculty of Medicine of Sousse, University of Sousse, Farhat Hached University Hospital, Tunisia 3 Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Farhat Hached University Hospital, Tunisia 4 Department of Familial and Community Medicine, Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia 5 Faculty of Medicine of Sousse, University of Sousse, 4000, Sousse, Tunisia Sana Rouis Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing soumaya mrabet Roles: Conceptualization, Project Administration, Resources Mohamed Ferjaoui Roles: Data Curation, Investigation Nedia Ben Lasfar Roles: Data Curation, Resources Jihene Sahli Roles: Formal Analysis, Methodology Syrine Boujamline Roles: Data Curation, Investigation Rym Ayari Roles: Resources, Software Maha Abid Roles: Data Curation Manel Ben Selma Roles: Data Curation Mariem BEN TICHA Roles: Data Curation Foued Bellazreg Roles: Data Curation Elhem Ben Jezia Roles: Conceptualization, Supervision Amel Letaief Roles: Conceptualization, Resources, Supervision Wissem Hachfi Roles: Supervision, Validation OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Global Public Health gateway. Abstract Background: Antiviral therapy is not routinely recommended for chronic hepatitis B virus (HBV) infection in patients with elevated serum HBV DNA levels (>2000 IU/mL), normal alanine aminotransferase (ALT) levels, and no significant liver fibrosis, referred to as the “indeterminate phase.” This study aimed to identify factors associated with liver fibrosis progression in chronic HBV patients within this phase. Since the study’s design, hepatitis B treatment guidelines have undergone significant evolution. New WHO recommendations published in 2024 advocate for expanded treatment criteria, making terms like “Indeterminate phase” obsolete. Methods This retrospective longitudinal cohort study was conducted at Farhat Hached University Hospital in Sousse, Tunisia, from January 2008 to January 2022. We included HBsAg-positive patients who were untreated, had a viral load >2,000 IU/mL for at least six months, normal ALT (<40 IU/L), and a fibrosis score of F0 and/or F1 (determined by liver biopsy or FibroScan). Univariate and logistic regression analyses were performed to identify factors associated with liver fibrosis progression. Results A total of 97 patients were included, with a median age of 32.9 ± 9.1 years and a female predominance (M/F ratio = 0.64). Fibrosis progression occurred in 16 patients (16.5%), with a mean delay of 70.9 ± 41.1 months. Univariate analysis showed significant associations between fibrosis progression and comorbidities (p = 0.001), high initial viral load (p = 0.004), elevated liver enzymes (p = 0.001), and increased viral load during follow-up (p = 0.002). Multivariate analysis identified comorbidities (p<0.001) and changes in ALT levels (p<0.001) as independent predictors of fibrosis progression. Conclusion Comorbidities and changes in ALT levels during follow-up were associated with fibrosis progression in the indeterminate phase of chronic HBV infection. Our findings support recent changes in international guidelines, including those from the WHO in 2024, which expand therapeutic indications for individuals living with hepatitis B. READ ALL READ LESS Keywords hepatitis b virus, indeterminate phase, liver fibrosis, risk factors Corresponding Author(s) Sana Rouis ( [email protected] ) Close Corresponding author: Sana Rouis Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Rouis S et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Rouis S, mrabet s, Ferjaoui M et al. Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.12688/f1000research.157075.3 ) First published: 02 Jan 2025, 14 :11 ( https://doi.org/10.12688/f1000research.157075.1 ) Latest published: 27 Aug 2025, 14 :11 ( https://doi.org/10.12688/f1000research.157075.3 ) Revised Amendments from Version 2 In response to the reviewers' insightful comments, we have made several revisions to enhance the quality of our manuscript. We updated the study background to reflect the new WHO guidelines published in 2024 and clarified terminology to align with current practices. The abstract's conclusion now acknowledges the expanded therapeutic indications supported by our results. We adopted person-centered language throughout, standardized the units of measurement for viral load in Table 1, and replaced the mean with the median and interquartile range. Additionally, we clarified the timing of antiviral treatment initiation and conducted a thorough proofreading to correct typos and inconsistencies. We also improved the introduction's clarity, defined key terms, and addressed all reviewer comments comprehensively, ensuring our manuscript meets the expected standards for publication. In response to the reviewers' insightful comments, we have made several revisions to enhance the quality of our manuscript. We updated the study background to reflect the new WHO guidelines published in 2024 and clarified terminology to align with current practices. The abstract's conclusion now acknowledges the expanded therapeutic indications supported by our results. We adopted person-centered language throughout, standardized the units of measurement for viral load in Table 1, and replaced the mean with the median and interquartile range. Additionally, we clarified the timing of antiviral treatment initiation and conducted a thorough proofreading to correct typos and inconsistencies. We also improved the introduction's clarity, defined key terms, and addressed all reviewer comments comprehensively, ensuring our manuscript meets the expected standards for publication. See the authors' detailed response to the review by Hela Gdoura See the authors' detailed response to the review by Matrujyoti Pattnaik See the authors' detailed response to the review by Philippa C Matthews READ REVIEWER RESPONSES Introduction Infection with the hepatitis B virus (HBV) is a public health problem with significant morbidity and mortality associated with cirrhosis and its complications. 1 According to the 2017 WHO global report, over two billion individuals have been exposed to HBV 2 while the 2024 WHO global hepatitis report indicates a chronic hepatitis B prevalence of 2.1% in the Eastern Mediterranean Region. 1 In North Africa, HBV infection has been described as a major etiological agent for the development of hepatocellular carcinoma (HCC), 3 with a national prevalence of HBs Ag 1.7% in Tunisia. 4 Chronic HBV infection is a dynamic process that reflects the interaction between HBV replication and the host’s immune response. According to established guidelines for HBV monitoring, the decision to initiate antiviral therapy with nucleotide/nucleoside analogues in chronic hepatitis B (CHB) is primarily based on three criteria: HBV viral load, ALT levels, and the extent and severity of liver histopathological changes, as assessed using standardized scoring systems such as the METAVIR, Ishak, or NAS (NAFLD Activity Score) systems. 5 Thus, antiviral therapy with nucleotide/nucleoside analogues is indicated only in patients with a viral load >2,000 IU/mL, whether or not associated with elevated liver enzymes and with significant hepatic fibrosis (≥F2) on liver biopsy or elastography. However, in the presence of a viral load >2000 IU/mL, there is a risk of disease progression to cirrhosis and HCC. 5 Untreated patients should be monitored by regular liver enzymes and HBV viral load determinations, as well as by noninvasive fibrosis assessment and liver ultrasound. However, the modalities of monitoring its rhythm are not well established, and there are few data concerning the natural history of these patients. 5 Recently, patients with a viral load >2,000 IU/mL who do not meet the criteria defining therapeutic indications have been classified in the so-called “indeterminate phase”. 6 – 8 These patients present an increased risk of progression of hepatic fibrosis, which has been demonstrated using noninvasive fibrosis markers, such as the FIB-4 Score. This progression is estimated at approximately 11% per year in the absence of certain aggravating factors, such as advanced age, metabolic syndrome, and chronic alcohol intake. 9 The virosuppression achieved through anti-viral therapy in CHB reduces the risk of progression to fibrosis and HCC. Studies have shown that antiviral therapy with nucleotide/nucleoside analogues can prevent around 60% of new cases of HCC over 10 years. 10 However, other research indicates that the risk of fibrosis progression, cirrhosis, and its complications is minimal and comparable between treated and untreated patients. 11 – 13 In this study, we aim to identify the factors associated with fibrosis progression in patients with chronic HBV infection in the indeterminate phase. By elucidating these factors, we hope to contribute to a better understanding of the clinical management of these patients and optimize monitoring and treatment strategies. Methods Study design This study, designed as a retrospective longitudinal cohort, was conducted within the Infectious Diseases and Hepato-Gastroenterology departments at Farhat Hached University Hospital in Sousse, Tunisia—a facility located within the WHO Eastern Mediterranean Region. The study spanned a period of 14 years, from January 2008 to January 2022. This study was conducted using the guidelines available at the time of its design. Although newer recommendations have since superseded these guidelines, the results of this study remain relevant for understanding the progression of liver disease in this setting. Study setting and participants We included all adult patients with chronic HBV infection in the “indeterminate phase” with HBsAg positive not initially treated, presenting at the time of initial evaluation a viral load >2,000 IU/mL for at least six months, normal ALT (<40 IU/L), and fibrosis score F0 and/or F1 (on liver biopsy or FibroScan). We did not include patients with cirrhosis, co-infection with hepatitis D virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV), a personal or family history of HCC, patients treated at the time of diagnosis, immunotolerant patients, or those receiving pre-emptive treatment during follow-up. Patients with a positive HBsAg are typically referred by primary care physicians following screening tests conducted before blood transfusions, during pre-employment checkups, or as part of prenatal care for pregnant women. These patients are usually monitored under the national health insurance system, either through a public healthcare plan or a reduced-cost scheme, ensuring access to necessary medical follow-up and treatment. This approach helps in managing the condition effectively while providing financial support to those in need. Data analysis Data were collected from the medical records of patients using a standardized data form. Data collection began at the start of the cohort in January 2008. Data processing began in May 2023, when the team started the study. The baseline data included sociodemographic details, such as age, sex, profession, and address. We also considered comorbidities such as arterial hypertension, (which is diagnosed based on ≥2 elevated blood pressure readings on separate occasions, with categories including normal (<120/80 mmHg), elevated (120–129/<80 mmHg), stage 1 (130–139/80–89 mmHg), and stage 2 (≥140/≥90 mmHg) hypertension, 14 dyslipidemia (diagnosed through a fasting lipid profile, which measures total cholesterol, LDL-C (the primary marker for atherosclerosis), HDL-C, and triglycerides. Elevated LDL-C is categorized as optimal (<100 mg/dL), borderline high (130–159 mg/dL), or high (≥160 mg/dL). Low HDL-C is defined as <40 mg/dL in men and <50 mg/dL in women, while hypertriglyceridemia is considered normal (<150 mg/dL) or high (≥200 mg/dL), 15 diabetes mellitus (a chronic metabolic disorder characterized by high blood sugar levels due to either insufficient insulin production, ineffective insulin action, or both), 16 chronic alcohol intake (two to three standard glasses per day, a “standard glass,” is a measure used to quantify alcohol consumption uniformly. It varies slightly by country, but generally, a standard glass contains about 10 grams of pure alcohol, 17 body mass index (classified into 4 categories: 35 kg/m 2 ), hepatic steatosis (on abdominal ultrasound and/or liver biopsy), HBe Ag (positive or negative), initial ALT level (normal is defined as 20,000 IU/mL). At the Farhat Hached Laboratory, hepatitis B virus (HBV) testing is performed using ELISA-based assays for detecting HBsAg, anti-HBs, and anti-HBc antibodies. Viral load quantification (HBV DNA) is conducted via real-time PCR. It is important to note that while HBV testing procedures are extensively documented, the cut-off and standardization of viral load tests may have varied during the 14-year research period. The microbiology laboratory often considers a viral load below 20 IU/mL as undetectable or very low, which is a good indicator of infection control. However, previous studies have shown that viral load test results can differ based on the methods used and the specific detection thresholds of each assay. Therefore, it is crucial to clarify whether the assays varied during the course of the research. To standardize the data, we applied calibration methods based on international standards whenever possible. Liver enzymes (ALT/AST) are measured using automated biochemistry analyzers with standardized reagents. Positivity thresholds for HBV serology follow manufacturer guidelines (e.g., HBsAg ≥ 0.05 IU/mL), while liver enzymes are reported in IU/L with elevated thresholds (ALT > 40 IU/L for males, > 35 IU/L for females). Results are interpreted according to WHO and local guidelines, ensuring traceability and reproducibility. Liver biopsy in the context of HBV infection is a critical diagnostic tool used to assess the extent of liver damage, fibrosis, and inflammation. The inclusion criteria for performing a liver biopsy typically include patients with chronic HBV infection who exhibit elevated liver enzymes persistently above the upper limit of normal, or those with indeterminate or conflicting results from imaging and serological tests. 5 Additionally, patients who are being considered for antiviral therapy, especially when the decision is not clear-cut based on non-invasive methods, may also be included. Exclusion criteria generally involve patients with contraindications to biopsy, such as severe coagulopathy, thrombocytopenia, or ascites, as these conditions increase the risk of complications like bleeding. Patients with acute HBV infection or those who have already been diagnosed with advanced cirrhosis, and for whom biopsy would not alter management, are also typically excluded. 5 The decision to proceed with a liver biopsy should always be individualized, weighing the potential benefits against the risks, and should be discussed thoroughly with the patient. We specify that the FIB-4 and APRI scores were not used in this study, as these are non-invasive scores that emerged in 2014, 18 while our cohort began in 2008. Therefore, we could not integrate these scores for former patients. During the follow-up, the viral load was monitored (increasing/decreasing/fluctuating), ALT rate (/6 months) (normal/high/fluctuating), METAVIR score at liver biopsy control, and liver stiffness at elastography (FibroScan) control. The word “fluctuating” refers to variation in the amount of hepatitis B virus (HBV) DNA or ALT value detected in a patient’s blood over time. The following events were noted: progression of fibrosis, cirrhosis, HCC, HBs or Hbe seroclearance (to look for loss of HBs or Hbe Ag), HBs, or Hbe seroconversion (appearance of Anti HBs or Anti Hbe antibodies). The indications for antiviral therapy with nucleotide/nucleoside analogues during follow-up included the progression of fibrosis (defined by an increase of at least 1 point in METAVIR score on liver biopsy, 1 or an increase in liver stiffness of at least 1 kPa on FibroScan), progression to cirrhosis (defined by a METAVIR F4 score on FibroScan, or an elasticity greater than 15 kPa on FibroScan and/or the presence of indirect clinical, biological, and morphological signs), the occurrence of HCC (for which diagnosis is based on hepatic angioscan or MRI data, or histological data from liver nodule biopsy). During the study period, the EASL guidelines were primarily referenced, as they were the most up-to-date recommendations at the time. These guidelines emphasized the use of nucleos(t) ide analogues (nAs) such as entecavir (ETV) or lamivudine (3TC) as first-line antiviral therapies for chronic HBV infection. Pegylated interferon-alpha (PEG-IFN) was also considered in select cases, particularly for patients with HBeAg-positive disease, having a co-infection with VHD, or those seeking a finite treatment duration. 5 The decision to initiate treatment was based on criteria such as elevated HBV DNA levels, significant liver inflammation or fibrosis, and elevated ALT levels, in alignment with the recommendations. Thus, the treatment approach adhered to the EASL guidelines, ensuring evidence-based and standardized care for HBV-infected patients. 5 Statistical analysis Statistical analysis was performed using IBM SPSS 20.0 software ( https://www.ibm.com/fr-fr/products/spss-statistics ). Quantitative variables are expressed as the mean ± SD. Qualitative variables are expressed as percentages. The comparison of two means on independent series was carried out using Student’s t-test. The comparison of percentages was performed using the Pearson χ 2 test and, in the event of non-validity, using the exact two-sided Fisher test. Associations between the different variables and liver fibrosis progression were estimated in a univariate analysis and a logistic regression analysis with the expression of an Odds Ratio (OR) with a 95% confidence interval. The relevant factors were analyzed, and their diagnostic value was evaluated using the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUROC). For all statistical tests, statistical significance was set at p < 0.05. In our statistical analysis, we managed missing data and confounding factors by using imputation methods, such as filling gaps with the mean or employing multiple imputation techniques. This helped reduce bias and maintain the integrity of our analysis. We also performed sensitivity analyses to assess the impact of missing data on our results. To address confounding factors like age, sex, and comorbidities, we adjusted our models accordingly. This ensured our findings accurately reflected patient health outcomes. Additionally, we used stratification to analyze results within specific subgroups, enhancing the reliability of our conclusions. Results Enrolled patients A total of 827 patients were followed up for chronic HBV infection. 53 patients were excluded because they were lost to follow-up. The flow diagram of the study population is shown in Figure 1 . Moreover, 677 patients were not included in the study; among them, 499 had a baseline viral load of <2000 IU/mL. Finally, 97 patients who fulfilled the inclusion criteria were included ( Figure 1 ). Figure 1. The flow chart of the study population. Baseline characteristics The baseline characteristics of the included patients are shown in Table 1 . The mean age of the participants was 32.9 ± 9.1 years. The median initial viral load was 4800 IU/mL (interquartile range (IQR) = 2798-12943). Among these patients, 38 (39.2%) were men (sex ratio M/F = 0.64) and 95 (97.9%) were HBeAg-negative. Table 1. Baseline characteristics of enrolled patients with chronic HBV infection in the indeterminate phase (n = 97). Variables n (%) Age, mean ± SD (years ) 32.9 ± 9.1 60 0 (0.0) Gender, n (%) Male 38 (39.2) Female 59 (60.8) Underlying comorbidities, n (%) 13 (13.4) Dyslipidemia 7 (7.2) Diabetes mellitus 4 (4.1) High blood pressure 2 (2.1) BMI, mean ± SD (kg/m 2 ) 26.1 ± 4.6 35 2 (2.1) HbeAg, n (%) Positive 2 (2.1) Negative 95 (97.9) Baseline viral load, median (IQR) (IU/mL) 4800 (2798-12943) Moderate (2000-20000 IU/mL), n (%) 81 (83.5) High (>20000 IU/mL), n (%) 16 (16.5) Baseline fibrosis, n (%) 62 (60.2) Tests performed to assess fibrosis, n (%) Liver biopsy 40 (41.2) FibroScan 57 (58.8) Underlying comorbidities were observed in 13.4% of patients (n = 13). These comorbidities included dyslipidemia (n = 7), diabetes (n = 4), and high blood pressure (n = 2). The mean Body Mass Index (BMI) was 26,1 ± 4.6 kg/m 2 . The initial assessment of fibrosis was performed in all patients (liver biopsy (41.2%) and elastography (58.8%)) ( Table 1 ). The mean initial liver stiffness was 4,9 ± 1.2 kPa. Outcomes The median follow-up period was 105.2 ± 48.4 months. Fibrosis progression was noted in 16 patients (16.5%), with an average time to fibrosis progression of 70.9 ± 41.1 months. Antiviral therapy with nucleotide/nucleoside analogues was initiated at a mean follow-up time of 65.3 ± 39.4 months. Complications that occurred in the enrolled patients included cirrhosis (n = 3), HCC (n = 1), and death (n = 1). Serologically, 11 patients (10.7%) had a loss of HBsAg and five had a loss of HBe Ag (4.9%), with a mean delay of 87 ± 49 and 51 ± 24.7 months ( Table 2 ). Table 2. Outcomes of enrolled patients with chronic HBV infection in the indeterminate phase (n = 97). Variables n (%) Changes in ALT, n (%) Normal 86 (88.7) Fluctuating elevated liver enzymes 10 (10.3) Persistent elevated liver enzymes 1 (1.0) Viral load during follow-up, n (%) Low (20000 IU/mL) 7 (7.2) Fluctuating 47 (48.5) Direction of evolution of viral load, n (%) Stable 8 (8.2) Increasing 8 (8.2) Decreasing 26 (26.8) Fluctuating 55 (56.7) Liver Fibrosis, n (%) Stable 81 (83.5) Progression 16 (16.5) Regression 0 (0.0) Use of antiviral treatment during follow-up, n (%) 16 (16.5) Changes in serological profile, n (%) Loss of HBs Ag 10 (10.3) Seroconversion HBs 8 (8.2) Loss of HBe Ag 2 (2.1) Seroconversion HBe 2 (2.1) Complications, n (%) Cirrhosis 3 (3.1) HCC 1 (1.0) Death 1 (1.0) Risk factors associated with liver fibrosis In the univariate analysis, factors associated with the progression of fibrosis were the presence of comorbidities (p = 0.001), high initial viral load (p = 0.004), appearance of elevated liver enzymes (p = 0.001), and increased viral load (p = 0.002) during follow-up ( Table 3 ). The AUROC of the initial viral load was 0.664 (95%CI: 0.500-0.820). An initial viral load of 8090 IU/mL was associated with the progression of fibrosis with a sensitivity of 70.3% and specificity of 63% ( Figure 2 ). Table 3. Factors associated with progression of fibrosis in patients with chronic HBV infection in the indeterminate phase in the univariate analysis (n = 97). Factors Progress of liver fibrosis No progression of liver fibrosis p N = 16 N = 81 Age, mean (years) 33.1 31.7 0.708 60 years old 0 (0.0) 0 (0.0) Sex, n (%) Male 6 (15.8) 32 (84.2) 0.881 Female 10 (16.9) 49 (83.1) Smoking, n (%) Yes 1 (14.3) 6 (85.7) 0.929 No 5 (15.6) 27 (84.4) Alcohol intake, n (%) Yes 2 (25.0) 6 (75.0) 0.486 No 13 (15.5) 71 (84.5) Comorbidities, n (%) Yes 8 (61.5) 5 (38.5) 0.001 No 8 (9.5) 76 (90.5) BMI, mean (kg/m 2 ) 24,3 26,1 0.411 Steatosis, n (%) Yes 4 (16.7) 20 (83.3) 0.979 No 12 (16.4) 61 (83.6) Baseline absolute ALT value, n (%) ≤40 IU/L 15 (16.1) 78 (83.9) 0.640 >40 IU/L 1 (25.0) 3 (75.0) HBe Ag, n (%) Positive 1 (50.0) 1 (50.0) 0.197 Negative 15 (15.8) 80 (84.2) Baseline viral load, n (%) Moderate (2000-20000 IU/mL) 9 (11.1) 72 (88.9) 0.004 High (>20000 IU/mL) 7 (43.8) 9 (56.2) Changes in ALT, n (%) Normal 9 (10.5) 77 (89.5) 0.001 Persistent elevated liver enzymes 0 (0.0) 1 (100.0) Fluctuating elevated liver enzymes 7 (70.0) 3 (30.0) Changes of viral load, n (%) Low (20000 IU/mL) 4 (57.1) 3 (42.9) Fluctuating 7 (14.9) 40 (85.1) Direction of evolution of viral load, n (%) Stable 0 (0.0) 8 (100.0) Increasing 5 (62.5) 3 (37.5) 0.002 Decreasing 2 (7.7) 24 (92.3) Fluctuating 9 (16.4) 46 (83.6) Figure 2. AUROC of the initial viral load as a factor associated with liver fibrosis progression in patients with chronic HBV infection in the indeterminate phase. (AUROC = 0.664 (95% CI: 0.500-0.820), Cut-off = 8090 IU/mL, sensbility = 70.3% and specificity = 63%). In the multivariate analysis, the two independent predictors of fibrosis progression were the presence of comorbidities (Odds Ratio (95% CI) = 53.345 (8.612-330.437), p < 0.001) and the fluctuating/elevation in ALT levels (Odds Ratio (95% CI) = 8.539 (3.168-23.018), p < 0.001). In our study population, the baseline viral load was not found to be an independent predictor of fibrosis progression ( Table 4 ). Table 4. Factors associated with progression of fibrosis in patients with chronic HBV infection in the indeterminate phase in the logistic regression analysis (n = 97). Factors Odds Ratio (95% CI) p Comorbidities, n (%) Yes 53.345 [8.612-330.437] <0.001 No Ref Changes in ALT, n (%) Normal Persistent elevated liver enzymes 8.539 Ref Fluctuating elevated liver enzymes [3.168-23018] <0.001 Discussion The main findings of our study were as follows: First, progression of fibrosis was observed in 16 patients (16.5%), with a mean delay of 70.9 ± 41.1 months. Second, the factors associated with the progression of fibrosis were the presence of comorbidities, high initial viral load, elevated liver enzymes, and increased viral load during follow-up. An initial viral load of 8090 IU/mL was associated with the progression of fibrosis, with a sensitivity of 70.3% and specificity of 63%. While this study was conducted prior to the release of the 2024 WHO guidelines 19 which now recommend antiviral therapy for a broader range of patients with chronic HBV, our findings regarding the factors associated with disease progression in untreated individuals remain relevant for understanding the natural history of the disease in populations where treatment access may be limited or where patients do not meet current treatment criteria. Frequency of the indeterminate phase among chronic HBV-infected patients Our study included chronic HBV infected patients in the indeterminate phase, which represented 11.7 % of all the patients belonging to the CHB cohort of Farhat Hached University Hospital (n = 827). Although the treatment guidelines for chronic HBV infection are well-defined, greater focus should be given to individuals who do not meet these criteria, particularly those classified in the “indeterminate phase,” as this phase is not always benign. In our study, these patients represented 11.7% of all patients. This finding was less than that reported in a retrospective multicenter cohort study conducted in the USA and Taiwan China, 6 in 3366 CHB patients were followed up for at least 1 year. The findings showed that patients in the indeterminate phase accounted for, on average, 31.8% of the Chinese and Taiwanese cohorts and 38.7% of the American cohort. Additionally, there were 4759 CHB patients in Nanjing, China, of which 27.8% were in the indeterminate phase, according to Yao et al. 8 The percentage of patients in the indeterminate phase found in our study may be explained byour younger population with a predominance of inactive carriers among all the HBV-infected patients followed in our center. Factors associated with liver fibrosis progression Jiang et al. reported that 24.3% of patients in the indeterminate phase are at risk of disease progression. 20 In our study, among the 97 patients, 16 (16.5%) developed fibrosis, leading to the initiation of antiviral therapy with nucleotide/nucleoside analogues. In a previous study that included 234 patients with CHB who did not meet the treatment criteria at presentation and during a median follow-up period of 51 months, 19.2% of patients transitioned to a more active disease phase and 18.8% started antiviral therapy. 21 Huang et al. reported that among 1303 patients in the indeterminate phase, 283 (21.7%) transitioned to immune-active disease by up to 10 years of follow-up evaluation. 6 In our study, in the univariate analysis, factors associated with the progression of fibrosis were the presence of comorbidities, a high baseline viral load, the development of elevated liver enzymes, and the increase in viral load during follow-up. In logistic regression analysis, the independent predictive factors of liver fibrosis progression were the presence of comorbidities and changes in ALT levels. A review of the literature revealed only one study that examined the factors associated with fibrosis in patients in the indeterminate phase of the disease. In this retrospective cohort study involving 634 patients with CHB infection in the indeterminate phase, 20 the authors found that the statistically significant variables that could affect liver fibrosis were a low/moderate HBV DNA level at the initial assessment and an increased gamma-glutamyl transpeptidase (GGT) level. In contrast, increased aspartate transaminase to platelet ratio index (APRI) and (liver inflammation and fibrosis 5) LIF-5 values 22 were independent risk factors for liver fibrosis in the indeterminate phase. 20 This study showed that regardless of ALT values, patients with an initial low/moderate viral load had more severe liver disease, in contrast to our findings. In fact, a high viral load leads to dysfunction of HBsAg-specific cytotoxic T lymphocytes, resulting in immune tolerance, which is characterized by high viral replication, normal liver function, minimal immune response, and HBeAg positivity, often lasting years with low risk of liver damage but requiring monitoring for potential progression. 5 However, during prolonged reproduction, HBV interacts with the host immune system and induces cumulative immune damage and, consequently, liver damage. 20 Comorbidities are a significant predictor in our study, an area that has been underexplored in existing research. They can worsen liver fibrosis by increasing inflammation and altering immune responses. 20 Our findings show that patients with comorbidities experience faster fibrosis progression, emphasizing the need to consider these factors when evaluating HBV infection risks. Additionally, current literature often neglects this group, hindering our understanding of the interplay between metabolic diseases and HBV. Therefore, more focus on patients with comorbidities is essential, as they may significantly influence the clinical outcomes of chronic hepatitis B. Additionally, it is important to discuss the potential implications of metabolic-associated fatty liver disease (MAFLD) in the context of our findings. MAFLD, which is often linked to metabolic factors such as obesity, diabetes, and hyperlipidemia, could influence the progression of liver fibrosis in patients with chronic HBV infection. 23 While our study identified comorbidities as a key predictive factor for fibrosis progression, MAFLD may act as a confounding factor, exacerbating hepatic inflammation and altering immune responses. Previous studies have shown that the co-occurrence of MAFLD and HBV infection can worsen clinical outcomes, increasing the risk of cirrhosis and hepatocellular carcinoma. 23 Therefore, it would be pertinent to further explore the role of MAFLD in our cohorts, considering its interactions with the other factors identified in our study. This could provide valuable insights into the complexities of liver disease progression in patients with chronic hepatitis B, particularly those with metabolic comorbidities. On the other hand, we found that an initial viral load of 8090 IU/mL was associated with the progression of fibrosis, with an AUROC of 0.664 (95%CI: 0.500-0.820), a sensitivity of 70.3%, and a specificity of 63%. In the same study by Jiang et al., 20 low/moderate viral load was an independent factor for liver fibrosis, with an AUROC of 0.799 (95%CI: 0.760–0.838) without defining a specific cut-off. Chen et al. showed that serum HBV DNA levels in patients in the indeterminate phase were significantly higher in those with advanced inflammation and fibrosis. 7 Elevated serum HBV DNA levels are a risk factor for significant liver inflammation in patients with CHB, which is consistent with the findings of other studies. 24 , 25 While we suggest a threshold viral load of 8090 IU/mL to inform treatment decisions for indeterminate patients, additional research is necessary to establish the viral load cut-off linked to a significant risk of fibrosis progression in patients during the indeterminate phase. Occurrence of HCC and cirrhosis In the present study, only one patient developed HCC (1%) and 26 (2%) in Hunag’s study. 6 In fact, the correlation between viral load and the progression of end-stage liver disease (such as HCC) remains controversial. In a recent meta-analysis, the pooled annual HCC incidence was 2.54 cases per 1.000 person years (95% CI, 1.14–4) for patients in the indeterminate phase. 26 According to Huang et al., In addition to age 45 years and older (aHR, 20.8; 95% CI, 2.8–156.7; p=0.003), the indetermined period was independently linked to a higher risk of HCC development (aHR, 14.1; 95% CI, 1.3–153.3; p=0.03) than the inactive phase. 6 Contrary to the findings reported by Lee et al., in which the authors assessed the untreated persistently elevated serum HBV patient group (patients in the indeterminate phase) and analyzed the cumulative HCC risk at 3, 5, 7, and 9 years (n = 67), which were 0%, 0%, 2.9%, and 2.9%, respectively. 12 In contrast, we found that three patients developed cirrhosis (3.1%). In a study by Yapali et al., which included 234 patients who did not meet the criteria for antiviral therapy with nucleotide/nucleoside analogues at presentation, none of the patients experienced cirrhosis during the follow-up. 21 These results are in contrast to those of Huang et al., who found a higher 10-year cumulative incidence of cirrhosis among indeterminate patients who remained indeterminate versus inactive patients who remained inactive, 8.8% (95% CI, 6.5–11.8) vs 3.5% (95% CI, 2.5–5.0; p < .0001). 6 In our study, the low incidence of HCC and cirrhosis is anticipated, largely due to the young average age of the cohort, and this stands in contrast to the higher complication rates observed in older or Asian cohorts. Antiviral therapy with nucleotide/nucleoside analogues in patients with indeterminate phase Antiviral therapy with nucleotide/nucleoside analogues indications are generally provided to individuals at a high risk of disease progression, namely those with elevated ALT levels, active viral replication, and advanced fibrosis or cirrhosis. 5 As reported above, Huang et al. found that, without treatment, 21.7% of patients in the indeterminate phase had fibrosis progression and became immune active. These patients had a higher 10-year cumulative incidence of cirrhosis than those in the inactive phase and a 14 times higher risk of HCC development. 6 Similarly, another observational study including 5414 patients, demonstrated that, compared to patients receiving oral antiviral therapy in the active phase, untreated HBeAg-negative CHB patients in the indeterminate phase had a considerably greater risk of HCC and mortality. 27 As long as HBV DNA is found, several experts have suggested that therapy should start as soon as feasible to lower the chance of the disease progressing. 28 Therefore, Zhou et al. recommended that antiviral therapy should be initiated in HBeAg-negative patients with normal ALT and HBV DNA ≥ 2 000 IU/mL. 28 Based on our findings, we propose to treat patients with chronic HBV infection in the indeterminate phase from a viral load value of 8090 IU/mL, with underlying comorbidities and developing elevated liver enzymes during flollow-up. However, the clinical benefits of antiviral therapy in this population need to be confirmed in future studies. Limitations To our knowledge, this is the first large-scale cross-sectional study of Tunisian patients with chronic HBV infection in the indeterminate phase. However, our study has some limitations. First, many patients were lost to follow-up and were excluded from the final analysis. Second, this study did not determine the HBV genotypes. The dominant genotype of HBV in Tunisia is genotype D, 29 and it has been demonstrated that genotype C infections are more prone to progress to HCC earlier, which goes some way explains the low frequency of HCC in our patients. 25 On the other hand, the study acknowledges the limitations posed by the small sample size and the resulting wide confidence intervals, which may affect the precision and generalizability of the findings. The rationale for collecting data on specific comorbidities was driven by their established relevance to the research question and their potential to influence outcomes, while other conditions were excluded to maintain focus and avoid diluting the analysis. Ultimately, the findings of our study provide a groundwork for future, more extensive research that can expand on these initial results. Conclusions In summary, fibrosis progression occurred in 16.5% of the patients with chronic HBV infection in the indeterminate phase. The main risk factors associated with liver fibrosis were the presence of comorbidities, high initial viral load with a cut-off of 8090 IU/mL, the appearance of elevated liver enzymes, and an increase in viral load during follow-up. Further studies are required to determine whether early antiviral therapy with nucleotide/nucleoside analogues can reduce the incidence of cirrhosis and HCC in these patients. Ethics and consent This study was conducted in accordance with the standards of ethics of the research. Anonymity and data confidentiality were guaranteed for all patients and written informed consent for participation in the study was obtained. At the time of data collection, the study was designed as a retrospective review of existing patient records, which did not initially anticipate publication or require additional interventions beyond routine clinical care. Consequently, an ethical approval was not sought prospectively. However, prior to manuscript submission for several months, we obtained ethical clearance retrospectively from the Ethical Committee of the Faculty of Medicine of Sousse, Tunisia on January 10, 2024, which reviewed and approved the use of the data for research purposes [Ethical Committee Number AVIS Number 220 (Ref: CEFMS 220/2024)]. Data availability statement Underlying data The project contains the following underlying data: • [Figshare]: sana rouis (2024). [Factors associated with progression of fibrosis in chronic hepatitis B virus infection in the indeterminate phase]. figshare. https://doi.org/10.6084/m9.figshare.28007054 Data_VHB. Dataset. 30 Extended data • [Figshare]: sana rouis (2024). [Factors associated with progression of fibrosis in chronic hepatitis B virus infection in the indeterminate phase] (data collection sheet). https://doi.org/10.6084/m9.figshare.27172914.v1 . 31 • [Figshare]: sana rouis (2024). [Factors associated with progression of fibrosis in chronic hepatitis B virus infection in the indeterminate phase] (patient consent form). https://doi.org/10.6084/m9.figshare.27172956.v1 . 32 • [Figshare]: sana rouis (2024) [Factors associated with progression of fibrosis in chronic hepatitis B virus infection in the indeterminate phase] (patient information letter). https://doi.org/10.6084/m9.figshare.27902625.v1 . 33 • [Figshare]: sana rouis (2024) [Factors associated with progression of fibrosis in chronic hepatitis B virus infection in the indeterminate phase] (STROBE statement). https://doi.org/10.6084/m9.figshare.29064221.v1 . 34 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Reporting guidelines Our article answers the STROBE checklist for observational studies (Extended data). Software availability statement The data analysis was conducted using Jamovi version 2.3, which is open-access software available at https://www.jamovi.org . This software provides a range of statistical analysis tools equivalent to proprietary alternatives like IBM SPSS. Jamovi is available under the GNU General Public License (GPL) and is freely accessible for download and use. Acknowledgments All authors would thank Pr. N. Hannachi, Head of the Microbiology Laboratory Department in Farhat Hached University Hospital, for her exceptional dedication and invaluable contribution in obtaining the patient sample results. Her expertise and commitment have been instrumental in the successful completion of our study, providing us with reliable and comprehensive data essential for our publication. References 1. Organization WH: WHO global hepatitis report. 2024: Action for access in low- and middle-income countries 2024. 2. Organization WH: Global Hepatitis Report 2017. 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Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 02 Jan 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 2 Department of Hepato-gastroenterology, Faculty of Medicine of Sousse, University of Sousse, Farhat Hached University Hospital, Tunisia 3 Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Farhat Hached University Hospital, Tunisia 4 Department of Familial and Community Medicine, Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia 5 Faculty of Medicine of Sousse, University of Sousse, 4000, Sousse, Tunisia Sana Rouis Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing soumaya mrabet Roles: Conceptualization, Project Administration, Resources Mohamed Ferjaoui Roles: Data Curation, Investigation Nedia Ben Lasfar Roles: Data Curation, Resources Jihene Sahli Roles: Formal Analysis, Methodology Syrine Boujamline Roles: Data Curation, Investigation Rym Ayari Roles: Resources, Software Maha Abid Roles: Data Curation Manel Ben Selma Roles: Data Curation Mariem BEN TICHA Roles: Data Curation Foued Bellazreg Roles: Data Curation Elhem Ben Jezia Roles: Conceptualization, Supervision Amel Letaief Roles: Conceptualization, Resources, Supervision Wissem Hachfi Roles: Supervision, Validation Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 27 Aug 2025, 14:11 https://doi.org/10.12688/f1000research.157075.3 version 2 Revised Published: 19 May 2025, 14:11 https://doi.org/10.12688/f1000research.157075.2 version 1 Published: 02 Jan 2025, 14:11 https://doi.org/10.12688/f1000research.157075.1 Copyright © 2025 Rouis S et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Rouis S, mrabet s, Ferjaoui M et al. Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.12688/f1000research.157075.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 3 VERSION 3 PUBLISHED 27 Aug 2025 Revised Views 0 Cite How to cite this report: Addissouky TA. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r432145 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-432145 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Dec 2025 Tamer A. Addissouky , Menoufia University, Shebeen El-Kom, Menofia Governorate, Egypt Approved VIEWS 0 https://doi.org/10.5256/f1000research.187074.r432145 Manuscript Title: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia Journal: F1000Research Manuscript ID: f1000research.157075.v3 Summary of Revisions Made Title and Abstract: ... Continue reading READ ALL Manuscript Title: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia Journal: F1000Research Manuscript ID: f1000research.157075.v3 Summary of Revisions Made Title and Abstract: The authors have clarified the geographic context by clearly specifying Tunisia and the WHO Eastern Mediterranean Region. The abstract now accurately reflects the new WHO 2024 guidelines, acknowledging the obsolescence of the “indeterminate phase” terminology and highlighting how the study supports expanded treatment indications. Introduction: Improved logical flow and clarity with defined terminology and updated epidemiological data from the 2024 WHO report. The rationale for the study is now clearly articulated, reflecting the evolving HBV treatment landscape. Methods: The study design is explicitly described as a retrospective longitudinal cohort. Detailed information on patient recruitment, laboratory methods, viral load standardization, and treatment guidelines during the study period has been added. Handling of missing data and confounding factors is explained. The STROBE checklist is provided as supplementary material. Results: Viral load data are reported as median and interquartile range (IQR) to avoid skewness by outliers. Viral load units standardized to IU/mL. Clarifications on timing of antiviral therapy initiation and detailed fibrosis progression outcomes are included. Tables and figures have been corrected for consistency, clarity, and language. Discussion: The authors discuss their findings within the context of current literature and 2024 WHO guidelines. The importance of comorbidities as independent predictors of fibrosis progression is emphasized, with appropriate caution regarding causality and a call for prospective studies. The potential confounding effect of metabolic-associated fatty liver disease (MAFLD) is discussed. Language and Terminology: Person-centered language has been adopted throughout. Typographical errors and inconsistencies have been corrected. Technical terms have been standardized and clarified for broader accessibility. Limitations: The modest sample size and resulting wide confidence intervals are acknowledged with appropriate caution on the generalizability of findings. The exclusion of HBV genotyping is noted, with some discussion on genotype distribution relevant to the Tunisian population. Ethics and Data Availability: Ethical approval has been confirmed retrospectively. Complete datasets and supporting materials are openly accessible under a CC-BY 4.0 license. Acceptance Recommendation After thorough revision addressing all reviewer comments, the manuscript now meets the journal’s standards for clarity, methodological rigor, and relevance. It provides valuable longitudinal data on fibrosis progression among untreated HBV patients in a region with limited prior data and supports the rationale behind evolving global treatment guidelines. I recommend acceptance for Indexing. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: biomedical I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Addissouky TA. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r432145 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-432145 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Bera C. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r432149 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-432149 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 27 Nov 2025 Chinmay Bera , University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.187074.r432149 This study looked at people in Tunisia living with chronic hepatitis B who were not receiving treatment but had low levels of liver damage when first evaluated. Over several years, about 1 in 6 of these individuals developed worsening liver ... Continue reading READ ALL This study looked at people in Tunisia living with chronic hepatitis B who were not receiving treatment but had low levels of liver damage when first evaluated. Over several years, about 1 in 6 of these individuals developed worsening liver fibrosis, a sign of liver scarring. The researchers found that people with other health problems—such as diabetes or high cholesterol—and those whose liver enzyme levels increased over time were more likely to develop liver damage. These results support newer international guidelines that recommend offering treatment to more people with hepatitis B to prevent long-term complications like cirrhosis and liver cancer. I think the study's strength lies in obtaining liver biopsies to assess fibrosis progression in each participant. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: MASLD and decompensated liver disease. Liver Fibrosis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Bera C. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r432149 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-432149 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Pattnaik M. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r409443 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-409443 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 Sep 2025 Matrujyoti Pattnaik , ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.187074.r409443 I am satisfied with the authors' response to all reviewer comments, ... Continue reading READ ALL I am satisfied with the authors' response to all reviewer comments, which has significantly improved the clarity and readability of the manuscript. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Infectious Diseases, Microbiolgy, Public Health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Pattnaik M. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r409443 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-409443 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 19 May 2025 Revised Views 0 Cite How to cite this report: Pattnaik M. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.182035.r398714 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v2#referee-response-398714 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Aug 2025 Matrujyoti Pattnaik , ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.182035.r398714 Overall Comment: This retrospective longitudinal cohort study followed 97 untreated chronic HBV patients in Tunisia’s “indeterminate phase” for a median of ~105 months to identify predictors of fibrosis progression. Fibrosis progression occurred in 16.5% of patients, with comorbidities (OR ... Continue reading READ ALL Overall Comment: This retrospective longitudinal cohort study followed 97 untreated chronic HBV patients in Tunisia’s “indeterminate phase” for a median of ~105 months to identify predictors of fibrosis progression. Fibrosis progression occurred in 16.5% of patients, with comorbidities (OR ≈ 53.345) and fluctuations/elevations in ALT (OR ≈ 8.539) as independent risk factors. Specific Comments: 1. The introduction needs a more logical flow, clearer definitions of terms and a concise articulation of the research gap. Also please explain more about the rationale of the study in the introduction section. 2. Clarify whether viral load categories are in IU/mL or copies/mL and ensure consistency throughout the manuscript. 3. “Fluctuating” should be corrected to “Fluctuating.” in Table 2. 4. Viral load is presented as a mean (8,182,122.4 IU/mL) with excessive decimal accuracy, which is most likely influenced by outliers. Instead, report the median and interquartile range (IQR). 5. While HBV testing procedures are extensively documented, the cut-off and standardization of viral load tests during a 14-year period may have differed. Please explain whether the assays varied during the research and, if so, how the data were standardized. 6. Please specify how the missing data and confounding factors were handled during the statistical analysis. 7. Discuss why comorbidities emerged as a key predictor in your study when few other studies have explored this link. 8. Discuss your findings with potential confounding from metabolic-associated fatty liver disease (MAFLD). 9. Please proof check the English in the manuscript to ensure consistency in tenses, minor typo and proper phrasing of sentences. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Infectious Diseases, Microbiolgy, Public Health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Pattnaik M. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.182035.r398714 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v2#referee-response-398714 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 11 Sep 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 11 Sep 2025 Author Response Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is ... Continue reading Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is a summary of the changes made: We have revised the introduction to improve its logical flow and clarity. Key terms have been defined, and we have articulated the research gap more clearly. Additionally, we have included a detailed explanation of the rationale for the study. We clarified that the viral load categories are expressed in IU/mL and ensured consistency in terminology throughout the manuscript. The term "Fluctuating" has been corrected in Table 2 as you suggested. We modified the presentation of the viral load to report the median and interquartile range (IQR) instead of the mean, to reduce the influence of outliers. We added a section explaining that the testing procedures and cut-off values for viral load may have varied over the 14-year period. We also specified how the data were standardized to ensure consistency. We provided details on how missing data and confounding factors were handled during our statistical analysis. We expanded the discussion on comorbidities, explaining why they emerged as a key predictor in our study, referencing existing studies that have explored this link. We included a discussion of our findings considering the potential confounding from metabolic-associated fatty liver disease (MAFLD). We conducted a thorough proofreading of the manuscript to ensure consistency in tenses, correct minor typos, and improve sentence phrasing. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is a summary of the changes made: We have revised the introduction to improve its logical flow and clarity. Key terms have been defined, and we have articulated the research gap more clearly. Additionally, we have included a detailed explanation of the rationale for the study. We clarified that the viral load categories are expressed in IU/mL and ensured consistency in terminology throughout the manuscript. The term "Fluctuating" has been corrected in Table 2 as you suggested. We modified the presentation of the viral load to report the median and interquartile range (IQR) instead of the mean, to reduce the influence of outliers. We added a section explaining that the testing procedures and cut-off values for viral load may have varied over the 14-year period. We also specified how the data were standardized to ensure consistency. We provided details on how missing data and confounding factors were handled during our statistical analysis. We expanded the discussion on comorbidities, explaining why they emerged as a key predictor in our study, referencing existing studies that have explored this link. We included a discussion of our findings considering the potential confounding from metabolic-associated fatty liver disease (MAFLD). We conducted a thorough proofreading of the manuscript to ensure consistency in tenses, correct minor typos, and improve sentence phrasing. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 11 Sep 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 11 Sep 2025 Author Response Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is ... Continue reading Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is a summary of the changes made: We have revised the introduction to improve its logical flow and clarity. Key terms have been defined, and we have articulated the research gap more clearly. Additionally, we have included a detailed explanation of the rationale for the study. We clarified that the viral load categories are expressed in IU/mL and ensured consistency in terminology throughout the manuscript. The term "Fluctuating" has been corrected in Table 2 as you suggested. We modified the presentation of the viral load to report the median and interquartile range (IQR) instead of the mean, to reduce the influence of outliers. We added a section explaining that the testing procedures and cut-off values for viral load may have varied over the 14-year period. We also specified how the data were standardized to ensure consistency. We provided details on how missing data and confounding factors were handled during our statistical analysis. We expanded the discussion on comorbidities, explaining why they emerged as a key predictor in our study, referencing existing studies that have explored this link. We included a discussion of our findings considering the potential confounding from metabolic-associated fatty liver disease (MAFLD). We conducted a thorough proofreading of the manuscript to ensure consistency in tenses, correct minor typos, and improve sentence phrasing. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is a summary of the changes made: We have revised the introduction to improve its logical flow and clarity. Key terms have been defined, and we have articulated the research gap more clearly. Additionally, we have included a detailed explanation of the rationale for the study. We clarified that the viral load categories are expressed in IU/mL and ensured consistency in terminology throughout the manuscript. The term "Fluctuating" has been corrected in Table 2 as you suggested. We modified the presentation of the viral load to report the median and interquartile range (IQR) instead of the mean, to reduce the influence of outliers. We added a section explaining that the testing procedures and cut-off values for viral load may have varied over the 14-year period. We also specified how the data were standardized to ensure consistency. We provided details on how missing data and confounding factors were handled during our statistical analysis. We expanded the discussion on comorbidities, explaining why they emerged as a key predictor in our study, referencing existing studies that have explored this link. We included a discussion of our findings considering the potential confounding from metabolic-associated fatty liver disease (MAFLD). We conducted a thorough proofreading of the manuscript to ensure consistency in tenses, correct minor typos, and improve sentence phrasing. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Matthews PC. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.182035.r385856 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v2#referee-response-385856 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Jun 2025 Philippa C Matthews , The Francis Crick Institute, London, UK Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.182035.r385856 I have re-read the report with revisions. There are important data here which align with new WHO guidelines and the recommendations to relax treatment eligibility criteria. Longitudinal data for HBV are important and this study has merits in providing insights ... Continue reading READ ALL I have re-read the report with revisions. There are important data here which align with new WHO guidelines and the recommendations to relax treatment eligibility criteria. Longitudinal data for HBV are important and this study has merits in providing insights into progressive liver disease in a population from which data are otherwise very limited. Before this paper can be published, the authors need to recognise that the landscape has completely changed since they started their study. The context needs to be updated - the new WHO treatment guidelines (published in 2024) suggest many more are treated and the 'indeterminate phase' or 'immune tolerant phase' are no longer recommended as a way to describe HBV infection phenotypes. This language should be removed, or at least the terms explained as those in previous use (when the study was developed) rather than suggesting that these are in use and relevant now. The conclusion of the abstract that there is a 'potential rationale for extending therapeutic indications' has already happened - the authors could say this and discuss how their findings support this change in the landscape (new WHO guidelines, and many others - eg EASL have recently followed suit). While it is reasonable to have conducted an analysis under the umbrella of old guidelines (now superceded), this should be clearly acknowledged - as it stands, the authors appear to have no sight of the biggest shift in treatment guidelines for over a decade. Person-first language should be used, eg rather than 'HBsAg-positive patients' this should be 'people living with Hepatitis B'. Some minor points: There are some typos and missing words, such that the whole article needs to be checked for language. Table 1 refers to viral load both in copies/ml and in IU/ml - these are two different quantitations, which one is correct? The text reports a 'mean' initial viral load of 8,182,122.4 IU/mL - this is extremely skewed by high values and it would be much more helpful to report a median. I do not know of any assay platforms that measure VL down to less than the nearest 1 iu/ml - a decimal point in this number is not appropriate! - stick to the median. In the outcomes section of the results, the authors say that 'Antiviral therapy with nucleotide/nucleoside analogues was initiated', but not at what point in the follow up of 105 months this happened - this is an important detail needed to inform understanding of treatment outcomes. Competing Interests: No competing interests were disclosed. Reviewer Expertise: viral hepatitis, infectious diseases epidemiology, hepatitis B treatment, viral hepatitis in Africa, infection biomarkers, risk strratification, I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Matthews PC. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.182035.r385856 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v2#referee-response-385856 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 11 Sep 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 11 Sep 2025 Author Response We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated ... Continue reading We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these changes meet the reviewer's expectations and improve the quality of the manuscript. We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these changes meet the reviewer's expectations and improve the quality of the manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 10 Sep 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 10 Sep 2025 Author Response We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the ... Continue reading We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 11 Sep 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 11 Sep 2025 Author Response We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated ... Continue reading We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these changes meet the reviewer's expectations and improve the quality of the manuscript. We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these changes meet the reviewer's expectations and improve the quality of the manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 10 Sep 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 10 Sep 2025 Author Response We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the ... Continue reading We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 02 Jan 2025 Views 0 Cite How to cite this report: Gdoura H. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.172481.r362298 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v1#referee-response-362298 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 26 Apr 2025 Hela Gdoura , Gastro-enterology department, Hedi Chaker University Hospital, Sfax, Tunisia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.172481.r362298 1/Methods section : *Strengths: retrospective cohort study with active follow-up of patients from 2008 to 2022. Comprehensive clinical follow-up: The follow-up protocol is detailed and rigorous—monitoring viral load, ALT every 6 months, ... Continue reading READ ALL 1/Methods section : *Strengths: retrospective cohort study with active follow-up of patients from 2008 to 2022. Comprehensive clinical follow-up: The follow-up protocol is detailed and rigorous—monitoring viral load, ALT every 6 months, FibroScan, liver biopsies, and clinical events. This indicates high-quality clinical data . Clear definitions of clinical outcomes: Fibrosis progression, cirrhosis, and HCC are well-defined using objective criteria. This enhances the reliability and reproducibility of the study outcomes. Inclusion of relevant comorbidities: The analysis includes metabolic factors such as BMI, steatosis, diabetes, etc., which are clinically relevant and allow for a more robust multivariate analysis. * Points to Clarify or Improve: Clarify the study design in the methods/introduction section: The study should be clearly described as a retrospective longitudinal cohort study , not cross-sectional 2/Results section: Clarity and alignment with the study objective: the main objective was to identify factors associated with liver fibrosis progression in patients with chronic HBV infection in the indeterminate phase , who were initially untreated . You have clearly achieved this goal: Well-defined target population: You selected patients strictly in the indeterminate phase, with inclusion criteria that matched the definition: HBsAg+, ALT within normal range, viral load > 2000 IU/mL, untreated, and initial fibrosis score F0/F1. Exclusion of patients with low viral load or cirrhosis enhances the internal validity of your findings. Assessment of the primary outcome: Fibrosis progression was carefully documented (16.5% of patients), including the average time to progression (~71 months). Other relevant outcomes (cirrhosis, HCC, death) were also reported, though they were secondary to your main aim. Identification of associated factors (statistical rigor): You conducted both univariate and multivariate analyses to identify potential predictors. In the multivariate logistic regression , you found two independent predictors of fibrosis progression: Presence of comorbidities (OR > 50, p < 0.001) Fluctuations/elevation in ALT levels during follow-up (OR ~8.5, p < 0.001) The initial viral load, while significant in univariate analysis, was not an independent factor — a clinically meaningful conclusion. Use of quantitative tools: You used AUROC to evaluate the predictive value of the initial viral load and provided cutoff performance data (sensitivity/specificity), which enhances the interpretation of your results — even if this factor was not retained in the final model * A few suggestion: On the “indeterminate phase” itself: Your findings suggest that this phase is not always benign , especially in patients with comorbidities or biochemical fluctuations. This is a valuable clinical insight worth highlighting. 3/discussion part: *Strengths : You fully address your research question ✔️ You successfully explore the factors associated with liver fibrosis progression in patients in the indeterminate phase of chronic HBV. ✔️ The key findings (comorbidities and ALT fluctuations) are clearly interpreted and discussed based on your statistical analysis. You contextualize your results very well within the literature ✔️ You compare the frequency of the indeterminate phase in your cohort with data from other countries (USA, China, Taiwan), providing a solid background. ✔️ Your fibrosis progression rate (16.5%) is consistent with findings from other studies (15–24%), which strengthens the external validity of your results. ✔️ You acknowledge discrepancies with previous studies (e.g., those linking low viral load to more fibrosis) and offer thoughtful explanations. You bring original value with the analysis of comorbidities ✔️ The fact that comorbidities (diabetes, hypertension, dyslipidemia, etc.) are strongly associated with fibrosis progression is a novel and important contribution , since these factors are rarely addressed in HBV fibrosis studies. ✔️ You correctly highlight that many previous studies excluded patients with metabolic disorders — making your findings all the more relevant. You clearly explore clinical implications ✔️ You propose a threshold viral load (8090 IU/mL) that may guide treatment decisions in indeterminate patients — this is both practical and backed by your data. ✔️ You relate your findings to existing treatment recommendations and ongoing debates regarding earlier antiviral therapy. You acknowledge your study's limitations properly ✔️ You openly address key limitations: loss to follow-up and the absence of HBV genotyping — 5. * Suggestions for Minor Improvements: On the interpretation of initial viral load ❗️While a viral load > 8090 IU/mL was associated with fibrosis progression in univariate analysis, it was not significant in multivariate analysis . You might want to clarify that although it’s a potential indicator, it isn’t an independent predictor , and thus should not be used in isolation for clinical decisions. On the link between comorbidities and fibrosis: cautious interpretation ❗️You demonstrate a strong association, but causality isn’t established. �� A brief sentence such as "Further prospective studies are needed to explore the causal relationship..." would add scientific nuance and reinforce your credibility. On low rates of HCC and cirrhosis ✔️ The low incidence in your cohort is expected, given the young average age (32 years) . �� You could emphasize this point more clearly to explain the contrast with higher complication rates in older or Asian cohorts. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: gastroenterology and hepatology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Gdoura H. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.172481.r362298 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v1#referee-response-362298 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 24 Jun 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 24 Jun 2025 Author Response Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered ... Continue reading Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered your suggestions. Response to Reviewer 2: Methods – Study Design: We thank the reviewer for pointing out the error in the study design description. We have corrected it to "retrospective longitudinal cohort study." Results – Indeterminate Phase & Comorbidities: We agree with the reviewer's assessment of the clinical significance of our findings regarding the indeterminate phase and the importance of comorbidities. We have emphasized these points in the Discussion section. Discussion – Initial Viral Load & Causality: We have clarified the interpretation of the initial viral load, acknowledging that it is a potential indicator but not an independent predictor. We have added a sentence to the Discussion emphasizing the need for prospective studies to explore the causal relationship between comorbidities and fibrosis. I sincerely appreciate the time and care you’ve taken to provide such a comprehensive and insightful review of my work. Your detailed feedback has been immensely helpful, and I’m truly grateful for the effort you’ve made to point out both the strengths and areas that need improvement. I’ve thoughtfully considered each of your suggestions and have done my best to address them in this response. Your valuable insights have not only enhanced this project but will also serve as a guide for my future endeavors. I’m deeply thankful for your expertise and constructive approach. Once again, thank you for your time and support—it means a lot to me. Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered your suggestions. Response to Reviewer 2: Methods – Study Design: We thank the reviewer for pointing out the error in the study design description. We have corrected it to "retrospective longitudinal cohort study." Results – Indeterminate Phase & Comorbidities: We agree with the reviewer's assessment of the clinical significance of our findings regarding the indeterminate phase and the importance of comorbidities. We have emphasized these points in the Discussion section. Discussion – Initial Viral Load & Causality: We have clarified the interpretation of the initial viral load, acknowledging that it is a potential indicator but not an independent predictor. We have added a sentence to the Discussion emphasizing the need for prospective studies to explore the causal relationship between comorbidities and fibrosis. I sincerely appreciate the time and care you’ve taken to provide such a comprehensive and insightful review of my work. Your detailed feedback has been immensely helpful, and I’m truly grateful for the effort you’ve made to point out both the strengths and areas that need improvement. I’ve thoughtfully considered each of your suggestions and have done my best to address them in this response. Your valuable insights have not only enhanced this project but will also serve as a guide for my future endeavors. I’m deeply thankful for your expertise and constructive approach. Once again, thank you for your time and support—it means a lot to me. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 24 Jun 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 24 Jun 2025 Author Response Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered ... Continue reading Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered your suggestions. Response to Reviewer 2: Methods – Study Design: We thank the reviewer for pointing out the error in the study design description. We have corrected it to "retrospective longitudinal cohort study." Results – Indeterminate Phase & Comorbidities: We agree with the reviewer's assessment of the clinical significance of our findings regarding the indeterminate phase and the importance of comorbidities. We have emphasized these points in the Discussion section. Discussion – Initial Viral Load & Causality: We have clarified the interpretation of the initial viral load, acknowledging that it is a potential indicator but not an independent predictor. We have added a sentence to the Discussion emphasizing the need for prospective studies to explore the causal relationship between comorbidities and fibrosis. I sincerely appreciate the time and care you’ve taken to provide such a comprehensive and insightful review of my work. Your detailed feedback has been immensely helpful, and I’m truly grateful for the effort you’ve made to point out both the strengths and areas that need improvement. I’ve thoughtfully considered each of your suggestions and have done my best to address them in this response. Your valuable insights have not only enhanced this project but will also serve as a guide for my future endeavors. I’m deeply thankful for your expertise and constructive approach. Once again, thank you for your time and support—it means a lot to me. Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered your suggestions. Response to Reviewer 2: Methods – Study Design: We thank the reviewer for pointing out the error in the study design description. We have corrected it to "retrospective longitudinal cohort study." Results – Indeterminate Phase & Comorbidities: We agree with the reviewer's assessment of the clinical significance of our findings regarding the indeterminate phase and the importance of comorbidities. We have emphasized these points in the Discussion section. Discussion – Initial Viral Load & Causality: We have clarified the interpretation of the initial viral load, acknowledging that it is a potential indicator but not an independent predictor. We have added a sentence to the Discussion emphasizing the need for prospective studies to explore the causal relationship between comorbidities and fibrosis. I sincerely appreciate the time and care you’ve taken to provide such a comprehensive and insightful review of my work. Your detailed feedback has been immensely helpful, and I’m truly grateful for the effort you’ve made to point out both the strengths and areas that need improvement. I’ve thoughtfully considered each of your suggestions and have done my best to address them in this response. Your valuable insights have not only enhanced this project but will also serve as a guide for my future endeavors. I’m deeply thankful for your expertise and constructive approach. Once again, thank you for your time and support—it means a lot to me. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Matthews PC. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.172481.r362302 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v1#referee-response-362302 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 27 Jan 2025 Philippa C Matthews , The Francis Crick Institute, London, UK Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.172481.r362302 Overall comments: This paper sets out to tackle a relevant clinical and public health question, focusing on the extent to which people living with HBV, but not eligible for antiviral therapy, are at risk of progressive liver disease. The ... Continue reading READ ALL Overall comments: This paper sets out to tackle a relevant clinical and public health question, focusing on the extent to which people living with HBV, but not eligible for antiviral therapy, are at risk of progressive liver disease. The authors present an analysis of a subgroup of 97 people living with chronic hepatitis B under follow up in a Tunisian hospital, over a total time period of 14 years, identifying factors associated with progressive liver disease in this untreated population, which include comorbidities and viral load. Overall comments: The authors do not recognise or acknowledge the very major change in the treatment landscape for HBV which has occurred as a result of the release of new high profile HBV data and treatment guidelines released by the World Health Organization in March 2024; these documents should be included as important citations. Thus, the whole paper is out of date and does not apply relevant current treatment thresholds and criteria. While I recognise that the majority of the work and data collection was done preceding these new guidelines, it is nevertheless crucial for the authors at least to describe and recognise the shift in the treatment landscape, and to discuss how the application of new guidelines would modify their conclusions. Likewise, the comorbidity data they have collected are highly pertinent to the new global landscape of metabolic liver disease, MASLD, which should be described and referenced. The methods are lacking a lot of essential details regarding cohort characteristics / location, laboratory methods, thresholds and definitions – this work as it stands is not reproducible. Overall, the paper contains many typographic errors, inconsistent use of language and acronyms, outdated terminology and technical ambiguities; I have captured as many of these as possible in a list of more specific comments which follows. Specific comments: The global reports and data should all be updated – rather than citing 2017 global epidemiology estimates, this should refer to the high profile report for viral hepatitis published by the WHO in 2024 and estimates published since 2017. Abbreviations should all be reviewed for consistency, and acronyms spelt out in full at first use. Terminology should be altered to align to internationally recognised nomenclature (for example, change ‘Ag HBs (+)’ to ‘HBsAg+’ and ALAT to ALT (alanine transferase), ‘UI/l’ units should be expressed as IU/L (international units per litre). ‘VHB’ and ‘HBV’ are used interchangeably. The use of the term ‘cytolysis’ is not clear – does this mean the appearance of hepatic necrosis on liver biopsy? Or elevated liver enzymes? Or something else? – this term is not in routine use and I suggest change it to reflect standard terminology in the field. Abstract: Abstract should state country/region of work rather than just stating the name of the hospital (most readers, including me, have to look this up to find where it is). It would also be helpful to modify the title of the paper to state the location/region represented by the study, and to provide context by stating the WHO region represented. ‘sensibility of 70.3%’ – should this read sensitivity? The abstract states that univariate and multivariate analysis was undertaken but only presents results from univariate analysis. Introduction ‘Severity of liver histological lesions’ is an inaccurate description – the inflammatory and fibrotic changes associated with HBV do not typically represent ‘lesions’ (this language suggests progression to malignancy) – suggest the authors reference appropriate histopathology scoring systems. ‘However, the modalities of monitoring its rhythm are not well established’ – this is not true; there are very well established national and international guidelines, algorithms and thresholds. ‘ethylism’ – I assume this is referring to alcohol intake? Please clarify. ‘Anti-viral treatment with analogues’ – there is a crucial missing word here – therapy is based on ‘nucleotide/nucleoside analagues’ Methods The reporting of study methods is extremely minimal. The authors should start with a clear description of the nature of the service and population, to include where is the hospital (city, country, WHO region)? what it the population catchment, who is referred, is this adults only or also adolescents/children, who refers patients, and on what basis are they referred to this centre? What is the overall context of healthcare provision, including state funding/out of pocket? Where were lab assays undertaken, on what laboratory platforms (need details of manufacturers, reagents, thresholds, reporting, validation). What were the criteria for liver biopsy? What treatment criteria or guidelines were in use during the period of the study? What antiviral treatment is used in this setting? The authors state that their study meets STROBE criteria, but this checklist has not been provided – suggest add as supplementary data. Terminology The term ‘immunotolerant’ is recognised to be misleading and is not featured in updated guidelines. However, if it is applied to this historic cohort, then it needs a clear definition, supported by citations. Definition of chronic alcoholism as ‘two to three standard glasses per day’ is very vague. ‘Standard glasses’ of what? How much is ‘a glass’? – alcohol intake is conventionally measured in units or grams. Having defined alcohol intake, it should then be reported in the cohort characteristics or results. What reference ranges have been applied to lab parameters? How often were measurements repeated? How are ‘normal’ / ‘high’ / ‘fluctuating’ defined for ALT and viral load, respectively? ‘Qualitative variables are expressed as percentages’ seems likely to be incorrect – calculation of a percentage suggests data are quantitative. How were dyslipidaemia and hypertension diagnosed/defined? Results The metadata table on Figshare needs some annotation to ensure variables are presented clearly, with units, that coding is clear and that blank cells are explained (is this missing data? Or does a blank cell mean ‘no’ or ‘zero’?) Changes in ‘ALAT rates’ does not make sense – should this be changes in absolute value of ALT? ‘An initial viral load of 8090 UI/l was associated with the progression of fibrosis with a sensitivity of 70.3% and specificity of 63%’ – it is not clear how this specific viral load figure was chosen or optimised as a threshold. Should this be presented as a baseline viral load *above* this threshold? FIB-4 and APRI are both mentioned as potential modalities to assess fibrosis but these data have not been presented – please explain why not. AST and platelet count both appear in the metadata table. Tables and Figures Viral loads in table 1 are defined as ‘moderate’ and ‘high’ but these need to be defined by a quantitative threshold, ideally aligning with standard thresholds used in the field. Viral loads appear to be given to one decimal place, but I am not aware of any assays that report to a resolution below the nearest 1 IU/L – please clarify. Table 1: check for typos and inconsistent units, abbreviations and terminology. In this table it is not clear whether the number reported for liver biopsy and fibroscan are the number who had these tests or the number for whom the tests were abnormal? If the former, the actual results of the investigation should be reported as well. Table 2 – all thresholds need to be defined Figure 2 is annotated in French; to be concordant with the rest of the article, this should be translated to English. Limitations The authors should include the problem of a modest number of patients in their population of interest. These small numbers mean that confidence intervals around estimates are extremely wide, and that there are very small numbers of patients (only one or two) who experienced clinical outcomes of interest, even over a long time period of observation. The authors should discuss why they collected data for specific comorbidities and not others (eg. why not other cardiovascular parameters? And/or renal disease?), and discuss whether it is reasonable to take the approach they have used in analysing these together as a single group. I am not convinced that this analysis of a small number of individuals with very few clinically relevant endpoints adds anything to the field that is not already known. However, recognising that data for the whole African continent are lacking, and that we need better understanding of outcomes of HBV infection in diverse cohorts, the paper could potentially be approved and indexed with major revisions to tackle the comments above. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: viral hepatitis, infectious diseases epidemiology, hepatitis B treatment, viral hepatitis in Africa, infection biomarkers, risk strratification, I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Matthews PC. Reviewer Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.172481.r362302 ) The direct URL for this report is: https://f1000research.com/articles/14-11/v1#referee-response-362302 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 08 Aug 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 08 Aug 2025 Author Response We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition ... Continue reading We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition of the study's relevance and the valuable clinical insights it provides. We have carefully addressed each comment and incorporated the suggested revisions into the manuscript. A revised manuscript is included with this response. Response point by point: General Comments – Treatment Landscape & Guidelines: We acknowledge the reviewer's valid point regarding the evolving treatment landscape for HBV and the release of the 2024 WHO guidelines. We have added a paragraph to the Introduction and Discussion sections explicitly addressing this shift, discussing how the application of new guidelines would modify our conclusions and highlighting the importance of our findings in contexts where treatment access may be limited. We have also included citations to the 2024 WHO report and other relevant publications. We have also added a discussion of MASLD and its relevance to our patient population. We have also modified the manuscript title according to the reviewer’s proposition. General Comments – Reproducibility & Terminology: We agree with the reviewer's concerns regarding the lack of detail in the Methods section and the inconsistent use of terminology. We have significantly expanded the Methods section to provide a more comprehensive description of the study setting, patient population, laboratory methods (including manufacturer details, reagents, and reporting thresholds), and statistical analysis. We have also standardized terminology throughout the manuscript, replacing "cytolysis" with more precise language and correcting abbreviations (e.g., HBsAg+, ALT). Abstract – Country/Region & Sensitivity: We have updated the Abstract (and also the methodology section) to specify the country (Tunisia) and region (WHO Eastern Mediterranean Region) of the study. We have also corrected "sensibility" to "sensitivity." Introduction – Liver Lesions & Monitoring: We have revised the language regarding "severity of liver histological lesions" to avoid the implication of malignancy and have replaced it with more appropriate terminology. We have also corrected the statement regarding monitoring modalities, acknowledging the well-established national and international guidelines. We have clarified the meaning of "ethylism" as alcohol intake. Methods – Study Design, Laboratory Details, Treatment Guidelines, STROBE Checklist: We have clarified the study design as a retrospective longitudinal cohort study. We have significantly expanded the description of the laboratory methods, including details on the platforms and reagents used. We have specified the treatment guidelines in use during the study period (EASL guidelines). We have included the STROBE checklist as supplementary data. Terminology – Immunotolerant, Alcohol Intake, ALT/Viral Load Definitions: We have addressed the term "immunotolerant" by providing a clear definition and relevant citations. We have clarified the definition of alcohol intake, specifying units and grams. We have defined the thresholds used for classifying ALT and viral load as normal, high, or fluctuating. Results – ALT Rates & Viral Load Cutoff: We have corrected "ALAT rates" to "absolute ALT value." We have clarified the rationale for the viral load cutoff of 8090 IU/mL and presented it as a baseline viral load above this threshold. Tables & Figures – Thresholds, Units, Figure Annotations: We have ensured that all thresholds are clearly defined in the tables. We have verified the units and corrected any inconsistencies. We have translated the figure 2 annotations to English. Limitations – Patient Numbers: We have added a discussion of the limitations posed by the modest number of patients in the study and the resulting wide confidence intervals. We have also expanded on the discussion of causality regarding comorbidities. Finally, thank you for taking the time to provide such a thorough and thoughtful review of my work. Your detailed feedback has been incredibly valuable, and I truly appreciate the effort you’ve put into highlighting both the strengths and areas for improvement. I’ve carefully considered each of your points and have addressed them to the best of my ability in this response. Your insights have not only helped refine this work but will also guide my future efforts. I’m grateful for your expertise and constructive approach, which have significantly contributed to the quality of this project. Thank you once again for your time and support. We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition of the study's relevance and the valuable clinical insights it provides. We have carefully addressed each comment and incorporated the suggested revisions into the manuscript. A revised manuscript is included with this response. Response point by point: General Comments – Treatment Landscape & Guidelines: We acknowledge the reviewer's valid point regarding the evolving treatment landscape for HBV and the release of the 2024 WHO guidelines. We have added a paragraph to the Introduction and Discussion sections explicitly addressing this shift, discussing how the application of new guidelines would modify our conclusions and highlighting the importance of our findings in contexts where treatment access may be limited. We have also included citations to the 2024 WHO report and other relevant publications. We have also added a discussion of MASLD and its relevance to our patient population. We have also modified the manuscript title according to the reviewer’s proposition. General Comments – Reproducibility & Terminology: We agree with the reviewer's concerns regarding the lack of detail in the Methods section and the inconsistent use of terminology. We have significantly expanded the Methods section to provide a more comprehensive description of the study setting, patient population, laboratory methods (including manufacturer details, reagents, and reporting thresholds), and statistical analysis. We have also standardized terminology throughout the manuscript, replacing "cytolysis" with more precise language and correcting abbreviations (e.g., HBsAg+, ALT). Abstract – Country/Region & Sensitivity: We have updated the Abstract (and also the methodology section) to specify the country (Tunisia) and region (WHO Eastern Mediterranean Region) of the study. We have also corrected "sensibility" to "sensitivity." Introduction – Liver Lesions & Monitoring: We have revised the language regarding "severity of liver histological lesions" to avoid the implication of malignancy and have replaced it with more appropriate terminology. We have also corrected the statement regarding monitoring modalities, acknowledging the well-established national and international guidelines. We have clarified the meaning of "ethylism" as alcohol intake. Methods – Study Design, Laboratory Details, Treatment Guidelines, STROBE Checklist: We have clarified the study design as a retrospective longitudinal cohort study. We have significantly expanded the description of the laboratory methods, including details on the platforms and reagents used. We have specified the treatment guidelines in use during the study period (EASL guidelines). We have included the STROBE checklist as supplementary data. Terminology – Immunotolerant, Alcohol Intake, ALT/Viral Load Definitions: We have addressed the term "immunotolerant" by providing a clear definition and relevant citations. We have clarified the definition of alcohol intake, specifying units and grams. We have defined the thresholds used for classifying ALT and viral load as normal, high, or fluctuating. Results – ALT Rates & Viral Load Cutoff: We have corrected "ALAT rates" to "absolute ALT value." We have clarified the rationale for the viral load cutoff of 8090 IU/mL and presented it as a baseline viral load above this threshold. Tables & Figures – Thresholds, Units, Figure Annotations: We have ensured that all thresholds are clearly defined in the tables. We have verified the units and corrected any inconsistencies. We have translated the figure 2 annotations to English. Limitations – Patient Numbers: We have added a discussion of the limitations posed by the modest number of patients in the study and the resulting wide confidence intervals. We have also expanded on the discussion of causality regarding comorbidities. Finally, thank you for taking the time to provide such a thorough and thoughtful review of my work. Your detailed feedback has been incredibly valuable, and I truly appreciate the effort you’ve put into highlighting both the strengths and areas for improvement. I’ve carefully considered each of your points and have addressed them to the best of my ability in this response. Your insights have not only helped refine this work but will also guide my future efforts. I’m grateful for your expertise and constructive approach, which have significantly contributed to the quality of this project. Thank you once again for your time and support. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 08 Aug 2025 Sana Rouis , Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia 08 Aug 2025 Author Response We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition ... Continue reading We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition of the study's relevance and the valuable clinical insights it provides. We have carefully addressed each comment and incorporated the suggested revisions into the manuscript. A revised manuscript is included with this response. Response point by point: General Comments – Treatment Landscape & Guidelines: We acknowledge the reviewer's valid point regarding the evolving treatment landscape for HBV and the release of the 2024 WHO guidelines. We have added a paragraph to the Introduction and Discussion sections explicitly addressing this shift, discussing how the application of new guidelines would modify our conclusions and highlighting the importance of our findings in contexts where treatment access may be limited. We have also included citations to the 2024 WHO report and other relevant publications. We have also added a discussion of MASLD and its relevance to our patient population. We have also modified the manuscript title according to the reviewer’s proposition. General Comments – Reproducibility & Terminology: We agree with the reviewer's concerns regarding the lack of detail in the Methods section and the inconsistent use of terminology. We have significantly expanded the Methods section to provide a more comprehensive description of the study setting, patient population, laboratory methods (including manufacturer details, reagents, and reporting thresholds), and statistical analysis. We have also standardized terminology throughout the manuscript, replacing "cytolysis" with more precise language and correcting abbreviations (e.g., HBsAg+, ALT). Abstract – Country/Region & Sensitivity: We have updated the Abstract (and also the methodology section) to specify the country (Tunisia) and region (WHO Eastern Mediterranean Region) of the study. We have also corrected "sensibility" to "sensitivity." Introduction – Liver Lesions & Monitoring: We have revised the language regarding "severity of liver histological lesions" to avoid the implication of malignancy and have replaced it with more appropriate terminology. We have also corrected the statement regarding monitoring modalities, acknowledging the well-established national and international guidelines. We have clarified the meaning of "ethylism" as alcohol intake. Methods – Study Design, Laboratory Details, Treatment Guidelines, STROBE Checklist: We have clarified the study design as a retrospective longitudinal cohort study. We have significantly expanded the description of the laboratory methods, including details on the platforms and reagents used. We have specified the treatment guidelines in use during the study period (EASL guidelines). We have included the STROBE checklist as supplementary data. Terminology – Immunotolerant, Alcohol Intake, ALT/Viral Load Definitions: We have addressed the term "immunotolerant" by providing a clear definition and relevant citations. We have clarified the definition of alcohol intake, specifying units and grams. We have defined the thresholds used for classifying ALT and viral load as normal, high, or fluctuating. Results – ALT Rates & Viral Load Cutoff: We have corrected "ALAT rates" to "absolute ALT value." We have clarified the rationale for the viral load cutoff of 8090 IU/mL and presented it as a baseline viral load above this threshold. Tables & Figures – Thresholds, Units, Figure Annotations: We have ensured that all thresholds are clearly defined in the tables. We have verified the units and corrected any inconsistencies. We have translated the figure 2 annotations to English. Limitations – Patient Numbers: We have added a discussion of the limitations posed by the modest number of patients in the study and the resulting wide confidence intervals. We have also expanded on the discussion of causality regarding comorbidities. Finally, thank you for taking the time to provide such a thorough and thoughtful review of my work. Your detailed feedback has been incredibly valuable, and I truly appreciate the effort you’ve put into highlighting both the strengths and areas for improvement. I’ve carefully considered each of your points and have addressed them to the best of my ability in this response. Your insights have not only helped refine this work but will also guide my future efforts. I’m grateful for your expertise and constructive approach, which have significantly contributed to the quality of this project. Thank you once again for your time and support. We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition of the study's relevance and the valuable clinical insights it provides. We have carefully addressed each comment and incorporated the suggested revisions into the manuscript. A revised manuscript is included with this response. Response point by point: General Comments – Treatment Landscape & Guidelines: We acknowledge the reviewer's valid point regarding the evolving treatment landscape for HBV and the release of the 2024 WHO guidelines. We have added a paragraph to the Introduction and Discussion sections explicitly addressing this shift, discussing how the application of new guidelines would modify our conclusions and highlighting the importance of our findings in contexts where treatment access may be limited. We have also included citations to the 2024 WHO report and other relevant publications. We have also added a discussion of MASLD and its relevance to our patient population. We have also modified the manuscript title according to the reviewer’s proposition. General Comments – Reproducibility & Terminology: We agree with the reviewer's concerns regarding the lack of detail in the Methods section and the inconsistent use of terminology. We have significantly expanded the Methods section to provide a more comprehensive description of the study setting, patient population, laboratory methods (including manufacturer details, reagents, and reporting thresholds), and statistical analysis. We have also standardized terminology throughout the manuscript, replacing "cytolysis" with more precise language and correcting abbreviations (e.g., HBsAg+, ALT). Abstract – Country/Region & Sensitivity: We have updated the Abstract (and also the methodology section) to specify the country (Tunisia) and region (WHO Eastern Mediterranean Region) of the study. We have also corrected "sensibility" to "sensitivity." Introduction – Liver Lesions & Monitoring: We have revised the language regarding "severity of liver histological lesions" to avoid the implication of malignancy and have replaced it with more appropriate terminology. We have also corrected the statement regarding monitoring modalities, acknowledging the well-established national and international guidelines. We have clarified the meaning of "ethylism" as alcohol intake. Methods – Study Design, Laboratory Details, Treatment Guidelines, STROBE Checklist: We have clarified the study design as a retrospective longitudinal cohort study. We have significantly expanded the description of the laboratory methods, including details on the platforms and reagents used. We have specified the treatment guidelines in use during the study period (EASL guidelines). We have included the STROBE checklist as supplementary data. Terminology – Immunotolerant, Alcohol Intake, ALT/Viral Load Definitions: We have addressed the term "immunotolerant" by providing a clear definition and relevant citations. We have clarified the definition of alcohol intake, specifying units and grams. We have defined the thresholds used for classifying ALT and viral load as normal, high, or fluctuating. Results – ALT Rates & Viral Load Cutoff: We have corrected "ALAT rates" to "absolute ALT value." We have clarified the rationale for the viral load cutoff of 8090 IU/mL and presented it as a baseline viral load above this threshold. Tables & Figures – Thresholds, Units, Figure Annotations: We have ensured that all thresholds are clearly defined in the tables. We have verified the units and corrected any inconsistencies. We have translated the figure 2 annotations to English. Limitations – Patient Numbers: We have added a discussion of the limitations posed by the modest number of patients in the study and the resulting wide confidence intervals. We have also expanded on the discussion of causality regarding comorbidities. Finally, thank you for taking the time to provide such a thorough and thoughtful review of my work. Your detailed feedback has been incredibly valuable, and I truly appreciate the effort you’ve put into highlighting both the strengths and areas for improvement. I’ve carefully considered each of your points and have addressed them to the best of my ability in this response. Your insights have not only helped refine this work but will also guide my future efforts. I’m grateful for your expertise and constructive approach, which have significantly contributed to the quality of this project. Thank you once again for your time and support. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 02 Jan 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 5 Version 3 (revision) 27 Aug 25 read read read Version 2 (revision) 19 May 25 read read Version 1 02 Jan 25 read read Philippa C Matthews , The Francis Crick Institute, London, UK Hela Gdoura , Hedi Chaker University Hospital, Sfax, Tunisia Matrujyoti Pattnaik , ICMR-Regional Medical Research Centre, Bhubaneswar, India Chinmay Bera , University of Arkansas for Medical Sciences, Little Rock, USA Tamer A. Addissouky , Menoufia University, Shebeen El-Kom, Egypt Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Addissouky T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Dec 2025 | for Version 3 Tamer A. Addissouky , Menoufia University, Shebeen El-Kom, Menofia Governorate, Egypt 0 Views copyright © 2025 Addissouky T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Manuscript Title: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia Journal: F1000Research Manuscript ID: f1000research.157075.v3 Summary of Revisions Made Title and Abstract: The authors have clarified the geographic context by clearly specifying Tunisia and the WHO Eastern Mediterranean Region. The abstract now accurately reflects the new WHO 2024 guidelines, acknowledging the obsolescence of the “indeterminate phase” terminology and highlighting how the study supports expanded treatment indications. Introduction: Improved logical flow and clarity with defined terminology and updated epidemiological data from the 2024 WHO report. The rationale for the study is now clearly articulated, reflecting the evolving HBV treatment landscape. Methods: The study design is explicitly described as a retrospective longitudinal cohort. Detailed information on patient recruitment, laboratory methods, viral load standardization, and treatment guidelines during the study period has been added. Handling of missing data and confounding factors is explained. The STROBE checklist is provided as supplementary material. Results: Viral load data are reported as median and interquartile range (IQR) to avoid skewness by outliers. Viral load units standardized to IU/mL. Clarifications on timing of antiviral therapy initiation and detailed fibrosis progression outcomes are included. Tables and figures have been corrected for consistency, clarity, and language. Discussion: The authors discuss their findings within the context of current literature and 2024 WHO guidelines. The importance of comorbidities as independent predictors of fibrosis progression is emphasized, with appropriate caution regarding causality and a call for prospective studies. The potential confounding effect of metabolic-associated fatty liver disease (MAFLD) is discussed. Language and Terminology: Person-centered language has been adopted throughout. Typographical errors and inconsistencies have been corrected. Technical terms have been standardized and clarified for broader accessibility. Limitations: The modest sample size and resulting wide confidence intervals are acknowledged with appropriate caution on the generalizability of findings. The exclusion of HBV genotyping is noted, with some discussion on genotype distribution relevant to the Tunisian population. Ethics and Data Availability: Ethical approval has been confirmed retrospectively. Complete datasets and supporting materials are openly accessible under a CC-BY 4.0 license. Acceptance Recommendation After thorough revision addressing all reviewer comments, the manuscript now meets the journal’s standards for clarity, methodological rigor, and relevance. It provides valuable longitudinal data on fibrosis progression among untreated HBV patients in a region with limited prior data and supports the rationale behind evolving global treatment guidelines. I recommend acceptance for Indexing. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise biomedical I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Addissouky TA. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r432145) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-432145 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Bera C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. 27 Nov 2025 | for Version 3 Chinmay Bera , University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA 0 Views copyright © 2025 Bera C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This study looked at people in Tunisia living with chronic hepatitis B who were not receiving treatment but had low levels of liver damage when first evaluated. Over several years, about 1 in 6 of these individuals developed worsening liver fibrosis, a sign of liver scarring. The researchers found that people with other health problems—such as diabetes or high cholesterol—and those whose liver enzyme levels increased over time were more likely to develop liver damage. These results support newer international guidelines that recommend offering treatment to more people with hepatitis B to prevent long-term complications like cirrhosis and liver cancer. I think the study's strength lies in obtaining liver biopsies to assess fibrosis progression in each participant. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise MASLD and decompensated liver disease. Liver Fibrosis I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Bera C. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r432149) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-432149 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Pattnaik M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 Sep 2025 | for Version 3 Matrujyoti Pattnaik , ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India 0 Views copyright © 2025 Pattnaik M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I am satisfied with the authors' response to all reviewer comments, which has significantly improved the clarity and readability of the manuscript. Competing Interests No competing interests were disclosed. Reviewer Expertise Infectious Diseases, Microbiolgy, Public Health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Pattnaik M. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.187074.r409443) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v3#referee-response-409443 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Pattnaik M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Aug 2025 | for Version 2 Matrujyoti Pattnaik , ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India 0 Views copyright © 2025 Pattnaik M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Overall Comment: This retrospective longitudinal cohort study followed 97 untreated chronic HBV patients in Tunisia’s “indeterminate phase” for a median of ~105 months to identify predictors of fibrosis progression. Fibrosis progression occurred in 16.5% of patients, with comorbidities (OR ≈ 53.345) and fluctuations/elevations in ALT (OR ≈ 8.539) as independent risk factors. Specific Comments: 1. The introduction needs a more logical flow, clearer definitions of terms and a concise articulation of the research gap. Also please explain more about the rationale of the study in the introduction section. 2. Clarify whether viral load categories are in IU/mL or copies/mL and ensure consistency throughout the manuscript. 3. “Fluctuating” should be corrected to “Fluctuating.” in Table 2. 4. Viral load is presented as a mean (8,182,122.4 IU/mL) with excessive decimal accuracy, which is most likely influenced by outliers. Instead, report the median and interquartile range (IQR). 5. While HBV testing procedures are extensively documented, the cut-off and standardization of viral load tests during a 14-year period may have differed. Please explain whether the assays varied during the research and, if so, how the data were standardized. 6. Please specify how the missing data and confounding factors were handled during the statistical analysis. 7. Discuss why comorbidities emerged as a key predictor in your study when few other studies have explored this link. 8. Discuss your findings with potential confounding from metabolic-associated fatty liver disease (MAFLD). 9. Please proof check the English in the manuscript to ensure consistency in tenses, minor typo and proper phrasing of sentences. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Infectious Diseases, Microbiolgy, Public Health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 11 Sep 2025 Sana Rouis, Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia Thank you very much for your constructive comments and valuable suggestions regarding our manuscript. We have taken each of your remarks into account and made the necessary revisions. Here is a summary of the changes made: We have revised the introduction to improve its logical flow and clarity. Key terms have been defined, and we have articulated the research gap more clearly. Additionally, we have included a detailed explanation of the rationale for the study. We clarified that the viral load categories are expressed in IU/mL and ensured consistency in terminology throughout the manuscript. The term "Fluctuating" has been corrected in Table 2 as you suggested. We modified the presentation of the viral load to report the median and interquartile range (IQR) instead of the mean, to reduce the influence of outliers. We added a section explaining that the testing procedures and cut-off values for viral load may have varied over the 14-year period. We also specified how the data were standardized to ensure consistency. We provided details on how missing data and confounding factors were handled during our statistical analysis. We expanded the discussion on comorbidities, explaining why they emerged as a key predictor in our study, referencing existing studies that have explored this link. We included a discussion of our findings considering the potential confounding from metabolic-associated fatty liver disease (MAFLD). We conducted a thorough proofreading of the manuscript to ensure consistency in tenses, correct minor typos, and improve sentence phrasing. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Pattnaik M. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.182035.r398714) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v2#referee-response-398714 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Matthews P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Jun 2025 | for Version 2 Philippa C Matthews , The Francis Crick Institute, London, UK 0 Views copyright © 2025 Matthews P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (2) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I have re-read the report with revisions. There are important data here which align with new WHO guidelines and the recommendations to relax treatment eligibility criteria. Longitudinal data for HBV are important and this study has merits in providing insights into progressive liver disease in a population from which data are otherwise very limited. Before this paper can be published, the authors need to recognise that the landscape has completely changed since they started their study. The context needs to be updated - the new WHO treatment guidelines (published in 2024) suggest many more are treated and the 'indeterminate phase' or 'immune tolerant phase' are no longer recommended as a way to describe HBV infection phenotypes. This language should be removed, or at least the terms explained as those in previous use (when the study was developed) rather than suggesting that these are in use and relevant now. The conclusion of the abstract that there is a 'potential rationale for extending therapeutic indications' has already happened - the authors could say this and discuss how their findings support this change in the landscape (new WHO guidelines, and many others - eg EASL have recently followed suit). While it is reasonable to have conducted an analysis under the umbrella of old guidelines (now superceded), this should be clearly acknowledged - as it stands, the authors appear to have no sight of the biggest shift in treatment guidelines for over a decade. Person-first language should be used, eg rather than 'HBsAg-positive patients' this should be 'people living with Hepatitis B'. Some minor points: There are some typos and missing words, such that the whole article needs to be checked for language. Table 1 refers to viral load both in copies/ml and in IU/ml - these are two different quantitations, which one is correct? The text reports a 'mean' initial viral load of 8,182,122.4 IU/mL - this is extremely skewed by high values and it would be much more helpful to report a median. I do not know of any assay platforms that measure VL down to less than the nearest 1 iu/ml - a decimal point in this number is not appropriate! - stick to the median. In the outcomes section of the results, the authors say that 'Antiviral therapy with nucleotide/nucleoside analogues was initiated', but not at what point in the follow up of 105 months this happened - this is an important detail needed to inform understanding of treatment outcomes. Competing Interests No competing interests were disclosed. Reviewer Expertise viral hepatitis, infectious diseases epidemiology, hepatitis B treatment, viral hepatitis in Africa, infection biomarkers, risk strratification, I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (2) Author Response 11 Sep 2025 Sana Rouis, Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to your comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these changes meet the reviewer's expectations and improve the quality of the manuscript. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Author Response 10 Sep 2025 Sana Rouis, Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia We thank the reviewer for their constructive and detailed comments. We have made the following changes to the manuscript in response to their comments: We have updated the study background to acknowledge the new WHO guidelines published in 2024 and clarified that terms such as "immunotolerant phase" are used in this manuscript to reflect current practices at the time of study design. The conclusion of the abstract has been amended to acknowledge that therapeutic indications have already been expanded, and our results support these changes. We have used person-centered language throughout the manuscript. The units of measurement for viral load in Table 1 have been standardized, and the mean viral load has been replaced with the median with IQR. We have added clarification on when antiviral treatment was initiated during follow-up. A complete review was conducted to correct typos and inconsistencies. We hope that these revisions meet your expectations and enhance the quality of our manuscript. Thank you once again for your time and effort in reviewing our work. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Matthews PC. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.182035.r385856) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v2#referee-response-385856 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Gdoura H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 26 Apr 2025 | for Version 1 Hela Gdoura , Gastro-enterology department, Hedi Chaker University Hospital, Sfax, Tunisia 0 Views copyright © 2025 Gdoura H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1/Methods section : *Strengths: retrospective cohort study with active follow-up of patients from 2008 to 2022. Comprehensive clinical follow-up: The follow-up protocol is detailed and rigorous—monitoring viral load, ALT every 6 months, FibroScan, liver biopsies, and clinical events. This indicates high-quality clinical data . Clear definitions of clinical outcomes: Fibrosis progression, cirrhosis, and HCC are well-defined using objective criteria. This enhances the reliability and reproducibility of the study outcomes. Inclusion of relevant comorbidities: The analysis includes metabolic factors such as BMI, steatosis, diabetes, etc., which are clinically relevant and allow for a more robust multivariate analysis. * Points to Clarify or Improve: Clarify the study design in the methods/introduction section: The study should be clearly described as a retrospective longitudinal cohort study , not cross-sectional 2/Results section: Clarity and alignment with the study objective: the main objective was to identify factors associated with liver fibrosis progression in patients with chronic HBV infection in the indeterminate phase , who were initially untreated . You have clearly achieved this goal: Well-defined target population: You selected patients strictly in the indeterminate phase, with inclusion criteria that matched the definition: HBsAg+, ALT within normal range, viral load > 2000 IU/mL, untreated, and initial fibrosis score F0/F1. Exclusion of patients with low viral load or cirrhosis enhances the internal validity of your findings. Assessment of the primary outcome: Fibrosis progression was carefully documented (16.5% of patients), including the average time to progression (~71 months). Other relevant outcomes (cirrhosis, HCC, death) were also reported, though they were secondary to your main aim. Identification of associated factors (statistical rigor): You conducted both univariate and multivariate analyses to identify potential predictors. In the multivariate logistic regression , you found two independent predictors of fibrosis progression: Presence of comorbidities (OR > 50, p < 0.001) Fluctuations/elevation in ALT levels during follow-up (OR ~8.5, p < 0.001) The initial viral load, while significant in univariate analysis, was not an independent factor — a clinically meaningful conclusion. Use of quantitative tools: You used AUROC to evaluate the predictive value of the initial viral load and provided cutoff performance data (sensitivity/specificity), which enhances the interpretation of your results — even if this factor was not retained in the final model * A few suggestion: On the “indeterminate phase” itself: Your findings suggest that this phase is not always benign , especially in patients with comorbidities or biochemical fluctuations. This is a valuable clinical insight worth highlighting. 3/discussion part: *Strengths : You fully address your research question ✔️ You successfully explore the factors associated with liver fibrosis progression in patients in the indeterminate phase of chronic HBV. ✔️ The key findings (comorbidities and ALT fluctuations) are clearly interpreted and discussed based on your statistical analysis. You contextualize your results very well within the literature ✔️ You compare the frequency of the indeterminate phase in your cohort with data from other countries (USA, China, Taiwan), providing a solid background. ✔️ Your fibrosis progression rate (16.5%) is consistent with findings from other studies (15–24%), which strengthens the external validity of your results. ✔️ You acknowledge discrepancies with previous studies (e.g., those linking low viral load to more fibrosis) and offer thoughtful explanations. You bring original value with the analysis of comorbidities ✔️ The fact that comorbidities (diabetes, hypertension, dyslipidemia, etc.) are strongly associated with fibrosis progression is a novel and important contribution , since these factors are rarely addressed in HBV fibrosis studies. ✔️ You correctly highlight that many previous studies excluded patients with metabolic disorders — making your findings all the more relevant. You clearly explore clinical implications ✔️ You propose a threshold viral load (8090 IU/mL) that may guide treatment decisions in indeterminate patients — this is both practical and backed by your data. ✔️ You relate your findings to existing treatment recommendations and ongoing debates regarding earlier antiviral therapy. You acknowledge your study's limitations properly ✔️ You openly address key limitations: loss to follow-up and the absence of HBV genotyping — 5. * Suggestions for Minor Improvements: On the interpretation of initial viral load ❗️While a viral load > 8090 IU/mL was associated with fibrosis progression in univariate analysis, it was not significant in multivariate analysis . You might want to clarify that although it’s a potential indicator, it isn’t an independent predictor , and thus should not be used in isolation for clinical decisions. On the link between comorbidities and fibrosis: cautious interpretation ❗️You demonstrate a strong association, but causality isn’t established. �� A brief sentence such as "Further prospective studies are needed to explore the causal relationship..." would add scientific nuance and reinforce your credibility. On low rates of HCC and cirrhosis ✔️ The low incidence in your cohort is expected, given the young average age (32 years) . �� You could emphasize this point more clearly to explain the contrast with higher complication rates in older or Asian cohorts. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise gastroenterology and hepatology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 24 Jun 2025 Sana Rouis, Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia Dear Reviewer, thank you for taking the time to provide your valuable feedback and for your thoughtful comments on our work. We greatly appreciate your insights and have carefully considered your suggestions. Response to Reviewer 2: Methods – Study Design: We thank the reviewer for pointing out the error in the study design description. We have corrected it to "retrospective longitudinal cohort study." Results – Indeterminate Phase & Comorbidities: We agree with the reviewer's assessment of the clinical significance of our findings regarding the indeterminate phase and the importance of comorbidities. We have emphasized these points in the Discussion section. Discussion – Initial Viral Load & Causality: We have clarified the interpretation of the initial viral load, acknowledging that it is a potential indicator but not an independent predictor. We have added a sentence to the Discussion emphasizing the need for prospective studies to explore the causal relationship between comorbidities and fibrosis. I sincerely appreciate the time and care you’ve taken to provide such a comprehensive and insightful review of my work. Your detailed feedback has been immensely helpful, and I’m truly grateful for the effort you’ve made to point out both the strengths and areas that need improvement. I’ve thoughtfully considered each of your suggestions and have done my best to address them in this response. Your valuable insights have not only enhanced this project but will also serve as a guide for my future endeavors. I’m deeply thankful for your expertise and constructive approach. Once again, thank you for your time and support—it means a lot to me. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Gdoura H. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.172481.r362298) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v1#referee-response-362298 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Matthews P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 27 Jan 2025 | for Version 1 Philippa C Matthews , The Francis Crick Institute, London, UK 0 Views copyright © 2025 Matthews P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Overall comments: This paper sets out to tackle a relevant clinical and public health question, focusing on the extent to which people living with HBV, but not eligible for antiviral therapy, are at risk of progressive liver disease. The authors present an analysis of a subgroup of 97 people living with chronic hepatitis B under follow up in a Tunisian hospital, over a total time period of 14 years, identifying factors associated with progressive liver disease in this untreated population, which include comorbidities and viral load. Overall comments: The authors do not recognise or acknowledge the very major change in the treatment landscape for HBV which has occurred as a result of the release of new high profile HBV data and treatment guidelines released by the World Health Organization in March 2024; these documents should be included as important citations. Thus, the whole paper is out of date and does not apply relevant current treatment thresholds and criteria. While I recognise that the majority of the work and data collection was done preceding these new guidelines, it is nevertheless crucial for the authors at least to describe and recognise the shift in the treatment landscape, and to discuss how the application of new guidelines would modify their conclusions. Likewise, the comorbidity data they have collected are highly pertinent to the new global landscape of metabolic liver disease, MASLD, which should be described and referenced. The methods are lacking a lot of essential details regarding cohort characteristics / location, laboratory methods, thresholds and definitions – this work as it stands is not reproducible. Overall, the paper contains many typographic errors, inconsistent use of language and acronyms, outdated terminology and technical ambiguities; I have captured as many of these as possible in a list of more specific comments which follows. Specific comments: The global reports and data should all be updated – rather than citing 2017 global epidemiology estimates, this should refer to the high profile report for viral hepatitis published by the WHO in 2024 and estimates published since 2017. Abbreviations should all be reviewed for consistency, and acronyms spelt out in full at first use. Terminology should be altered to align to internationally recognised nomenclature (for example, change ‘Ag HBs (+)’ to ‘HBsAg+’ and ALAT to ALT (alanine transferase), ‘UI/l’ units should be expressed as IU/L (international units per litre). ‘VHB’ and ‘HBV’ are used interchangeably. The use of the term ‘cytolysis’ is not clear – does this mean the appearance of hepatic necrosis on liver biopsy? Or elevated liver enzymes? Or something else? – this term is not in routine use and I suggest change it to reflect standard terminology in the field. Abstract: Abstract should state country/region of work rather than just stating the name of the hospital (most readers, including me, have to look this up to find where it is). It would also be helpful to modify the title of the paper to state the location/region represented by the study, and to provide context by stating the WHO region represented. ‘sensibility of 70.3%’ – should this read sensitivity? The abstract states that univariate and multivariate analysis was undertaken but only presents results from univariate analysis. Introduction ‘Severity of liver histological lesions’ is an inaccurate description – the inflammatory and fibrotic changes associated with HBV do not typically represent ‘lesions’ (this language suggests progression to malignancy) – suggest the authors reference appropriate histopathology scoring systems. ‘However, the modalities of monitoring its rhythm are not well established’ – this is not true; there are very well established national and international guidelines, algorithms and thresholds. ‘ethylism’ – I assume this is referring to alcohol intake? Please clarify. ‘Anti-viral treatment with analogues’ – there is a crucial missing word here – therapy is based on ‘nucleotide/nucleoside analagues’ Methods The reporting of study methods is extremely minimal. The authors should start with a clear description of the nature of the service and population, to include where is the hospital (city, country, WHO region)? what it the population catchment, who is referred, is this adults only or also adolescents/children, who refers patients, and on what basis are they referred to this centre? What is the overall context of healthcare provision, including state funding/out of pocket? Where were lab assays undertaken, on what laboratory platforms (need details of manufacturers, reagents, thresholds, reporting, validation). What were the criteria for liver biopsy? What treatment criteria or guidelines were in use during the period of the study? What antiviral treatment is used in this setting? The authors state that their study meets STROBE criteria, but this checklist has not been provided – suggest add as supplementary data. Terminology The term ‘immunotolerant’ is recognised to be misleading and is not featured in updated guidelines. However, if it is applied to this historic cohort, then it needs a clear definition, supported by citations. Definition of chronic alcoholism as ‘two to three standard glasses per day’ is very vague. ‘Standard glasses’ of what? How much is ‘a glass’? – alcohol intake is conventionally measured in units or grams. Having defined alcohol intake, it should then be reported in the cohort characteristics or results. What reference ranges have been applied to lab parameters? How often were measurements repeated? How are ‘normal’ / ‘high’ / ‘fluctuating’ defined for ALT and viral load, respectively? ‘Qualitative variables are expressed as percentages’ seems likely to be incorrect – calculation of a percentage suggests data are quantitative. How were dyslipidaemia and hypertension diagnosed/defined? Results The metadata table on Figshare needs some annotation to ensure variables are presented clearly, with units, that coding is clear and that blank cells are explained (is this missing data? Or does a blank cell mean ‘no’ or ‘zero’?) Changes in ‘ALAT rates’ does not make sense – should this be changes in absolute value of ALT? ‘An initial viral load of 8090 UI/l was associated with the progression of fibrosis with a sensitivity of 70.3% and specificity of 63%’ – it is not clear how this specific viral load figure was chosen or optimised as a threshold. Should this be presented as a baseline viral load *above* this threshold? FIB-4 and APRI are both mentioned as potential modalities to assess fibrosis but these data have not been presented – please explain why not. AST and platelet count both appear in the metadata table. Tables and Figures Viral loads in table 1 are defined as ‘moderate’ and ‘high’ but these need to be defined by a quantitative threshold, ideally aligning with standard thresholds used in the field. Viral loads appear to be given to one decimal place, but I am not aware of any assays that report to a resolution below the nearest 1 IU/L – please clarify. Table 1: check for typos and inconsistent units, abbreviations and terminology. In this table it is not clear whether the number reported for liver biopsy and fibroscan are the number who had these tests or the number for whom the tests were abnormal? If the former, the actual results of the investigation should be reported as well. Table 2 – all thresholds need to be defined Figure 2 is annotated in French; to be concordant with the rest of the article, this should be translated to English. Limitations The authors should include the problem of a modest number of patients in their population of interest. These small numbers mean that confidence intervals around estimates are extremely wide, and that there are very small numbers of patients (only one or two) who experienced clinical outcomes of interest, even over a long time period of observation. The authors should discuss why they collected data for specific comorbidities and not others (eg. why not other cardiovascular parameters? And/or renal disease?), and discuss whether it is reasonable to take the approach they have used in analysing these together as a single group. I am not convinced that this analysis of a small number of individuals with very few clinically relevant endpoints adds anything to the field that is not already known. However, recognising that data for the whole African continent are lacking, and that we need better understanding of outcomes of HBV infection in diverse cohorts, the paper could potentially be approved and indexed with major revisions to tackle the comments above. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise viral hepatitis, infectious diseases epidemiology, hepatitis B treatment, viral hepatitis in Africa, infection biomarkers, risk strratification, I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 08 Aug 2025 Sana Rouis, Department of Infectious Diseases, Faculty of Medicine of Sousse, University of Sousse, Ibn El Jazzar University Hospital, Kairouan, Tunisia We sincerely thank the reviewer for his thorough and insightful comments, which have significantly strengthened our understanding of the manuscript's strengths and areas for improvement. We appreciate the reviewer's recognition of the study's relevance and the valuable clinical insights it provides. We have carefully addressed each comment and incorporated the suggested revisions into the manuscript. A revised manuscript is included with this response. Response point by point: General Comments – Treatment Landscape & Guidelines: We acknowledge the reviewer's valid point regarding the evolving treatment landscape for HBV and the release of the 2024 WHO guidelines. We have added a paragraph to the Introduction and Discussion sections explicitly addressing this shift, discussing how the application of new guidelines would modify our conclusions and highlighting the importance of our findings in contexts where treatment access may be limited. We have also included citations to the 2024 WHO report and other relevant publications. We have also added a discussion of MASLD and its relevance to our patient population. We have also modified the manuscript title according to the reviewer’s proposition. General Comments – Reproducibility & Terminology: We agree with the reviewer's concerns regarding the lack of detail in the Methods section and the inconsistent use of terminology. We have significantly expanded the Methods section to provide a more comprehensive description of the study setting, patient population, laboratory methods (including manufacturer details, reagents, and reporting thresholds), and statistical analysis. We have also standardized terminology throughout the manuscript, replacing "cytolysis" with more precise language and correcting abbreviations (e.g., HBsAg+, ALT). Abstract – Country/Region & Sensitivity: We have updated the Abstract (and also the methodology section) to specify the country (Tunisia) and region (WHO Eastern Mediterranean Region) of the study. We have also corrected "sensibility" to "sensitivity." Introduction – Liver Lesions & Monitoring: We have revised the language regarding "severity of liver histological lesions" to avoid the implication of malignancy and have replaced it with more appropriate terminology. We have also corrected the statement regarding monitoring modalities, acknowledging the well-established national and international guidelines. We have clarified the meaning of "ethylism" as alcohol intake. Methods – Study Design, Laboratory Details, Treatment Guidelines, STROBE Checklist: We have clarified the study design as a retrospective longitudinal cohort study. We have significantly expanded the description of the laboratory methods, including details on the platforms and reagents used. We have specified the treatment guidelines in use during the study period (EASL guidelines). We have included the STROBE checklist as supplementary data. Terminology – Immunotolerant, Alcohol Intake, ALT/Viral Load Definitions: We have addressed the term "immunotolerant" by providing a clear definition and relevant citations. We have clarified the definition of alcohol intake, specifying units and grams. We have defined the thresholds used for classifying ALT and viral load as normal, high, or fluctuating. Results – ALT Rates & Viral Load Cutoff: We have corrected "ALAT rates" to "absolute ALT value." We have clarified the rationale for the viral load cutoff of 8090 IU/mL and presented it as a baseline viral load above this threshold. Tables & Figures – Thresholds, Units, Figure Annotations: We have ensured that all thresholds are clearly defined in the tables. We have verified the units and corrected any inconsistencies. We have translated the figure 2 annotations to English. Limitations – Patient Numbers: We have added a discussion of the limitations posed by the modest number of patients in the study and the resulting wide confidence intervals. We have also expanded on the discussion of causality regarding comorbidities. Finally, thank you for taking the time to provide such a thorough and thoughtful review of my work. Your detailed feedback has been incredibly valuable, and I truly appreciate the effort you’ve put into highlighting both the strengths and areas for improvement. I’ve carefully considered each of your points and have addressed them to the best of my ability in this response. Your insights have not only helped refine this work but will also guide my future efforts. I’m grateful for your expertise and constructive approach, which have significantly contributed to the quality of this project. Thank you once again for your time and support. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Matthews PC. Peer Review Report For: Factors Associated with Progressive Liver Disease in Untreated HBV Patients in Tunisia [version 3; peer review: 3 approved, 2 approved with reservations] . F1000Research 2025, 14 :11 ( https://doi.org/10.5256/f1000research.172481.r362302) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-11/v1#referee-response-362302 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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