Spectrum and Predictors of Adverse Drug Reactions in Patients Receiving Standard Antitubercular Therapy: A Prospective Study from Pakistan

Spectrum and Predictors of Adverse Drug Reactions in Patients Receiving Standard Antitubercular Therapy: A Prospective Study from Pakistan | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Spectrum and Predictors of Adverse Drug Reactions in Patients Receiving Standard Antitubercular Therapy: A Prospective Study from Pakistan Aftab Ullah, Muhammed Shabil, Abdul Rahim, Rida Shakeel, Aiman Begum, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7161019/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Antitubercular therapy (ATT)-induced adverse drug reactions (ADRs) pose challenges to treatment adherence in high-burden settings like Pakistan, were malnutrition and hepatitis coinfection influence drug metabolism. This study evaluates the incidence, spectrum, and pharmacological predictors of ADRs in a Pakistani cohort. Methods A prospective observational study was conducted at Nasir Ullah Khan Baber Memorial Hospital, Peshawar (September 2023–October 2024), enrolling 250 patients on standard ATT (HRZE/HR). ADRs were assessed using WHO-UMC causality criteria and CTCAE severity grading, analyzed with SPSS version 24 via chi-square and multivariate logistic regression. Results Of 250 patients (52% male, 48% female), 68% experienced ADRs, with higher rates in females (87.5% vs. 50%, p < 0.001) and pediatric patients (80%). Gastrointestinal (73.5%) and dermatological (50%) reactions predominated, with severe ADRs (5.9%) including hepatotoxicity. Risk factors included hepatitis coinfection (aOR 3.0 for hepatotoxicity), pediatric age (aOR 3.1 for neurotoxicity), and female sex (aOR 2.8 for cutaneous reactions). Supportive care managed 70.6% of ADRs. Conclusion This study highlights a high ADR burden in Pakistan, driven by pharmacokinetic factors like hepatitis and malnutrition. It supports tailored ATT monitoring and dosing strategies to enhance drug safety and adherence in resource-limited settings. Antitubercular therapy Adverse drug reactions Pharmacovigilance Pharmacokinetics Pakistan Figures Figure 1 Figure 2 Figure 3 Figure 4 BACKGROUND Tuberculosis remains one of the world’s deadliest infectious diseases, with an estimated 10 million new cases and 1.5 million deaths annually ( 1 , 2 ). The global TB epidemic disproportionately affects low- and middle-income countries, with Pakistan ranking fifth among high-burden nations, reporting approximately 570,000 new cases each year ( 3 ). The standard treatment for drug-susceptible TB involves a 6-month regimen of four first-line drugs: isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in the intensive phase, followed by isoniazid and rifampicin (HR) in the continuation phase ( 4 ). While effective, antitubercular therapy is associated with a high incidence of adverse drug reactions, ranging from 8–85% across various studies ( 5 ). These ADRs represent a major challenge to treatment adherence and completion, particularly in resource-limited settings. A systematic review by ( 6 ) identified ADRs as the second most common reason for treatment interruption after patient-initiated discontinuation. The spectrum of ATT-associated ADRs encompasses gastrointestinal disturbances, hepatotoxicity, cutaneous reactions, neurological effects, and hematological abnormalities, with varying degrees of severity ( 7 ). The pathophysiology of ATT-induced ADRs involves multiple mechanisms. Isoniazid hepatotoxicity results from toxic metabolites generated through cytochrome P450 2E1 metabolism, while rifampicin induces hepatic enzymes, potentially exacerbating this effect ( 8 ) Pyrazinamide's inhibition of renal urate excretion leads to hyperuricemia, and ethambutol's chelation of copper and zinc in retinal cells underlies its ocular toxicity ( 9 ). Genetic polymorphisms in drug-metabolizing enzymes, particularly N-acetyltransferase 2 (NAT2), significantly influence individual susceptibility to these reactions ( 10 ). Pakistan, high malnutrition rates (37%) and hepatitis B/C prevalence (15%) may alter drug metabolism, exacerbating toxicities, compounded by limited healthcare infrastructure and gender disparities in care access ( 11 ). Additionally, cultural influences, such as gender inequalities in healthcare access and the prevalent use of traditional remedies, can affect ADR patterns and how they are reported ( 12 ). Recent advances in pharmacovigilance methodologies, including active surveillance systems and biomarker-based monitoring, offer new opportunities for early detection of ADR ( 13 ). However, their implementation in high-burden and resource-constrained settings remains limited. The WHO's End TB Strategy emphasizes the importance of patient-centered care, including comprehensive ADR monitoring, as essential for achieving treatment success rates exceeding 90% ( 1 ). This study aims to contribute to this global effort by providing contemporary, context-specific data on ATT-associated ADRs in a Pakistani tertiary care setting. By characterizing the incidence, spectrum, and pharmacological risk factors for ADRs, we seek to inform clinical practice and policy decisions aimed at optimizing drug safety outcomes. Our findings may guide the development of targeted monitoring protocols, particularly for high-risk groups such as women, children, and elderly patients. METHODOLOGY Study Design and Setting : This prospective observational study was conducted at the chest outpatient department of Nasirullah Khan Baber Memorial Hospital (NKBMH), a 500-bed tertiary care facility in Peshawar, Pakistan. The study period extended from September 2023 to October 2024, encompassing 13 months of active patient monitoring. The hospital is a referral center for tuberculosis diagnosis and treatment under Pakistan's National Tuberculosis Control Program (NTCP). Study Population : The study enrolled 250 patients receiving antitubercular therapy through convenient sampling, chosen for its feasibility in the clinical setting. Inclusion and Exclusion criteria : Follow-up patients of both genders registered under NTCP at the Nasir Ullah Khan Baber Teaching Hospital, Peshawar—patients of pulmonary and extrapulmonary TB cases of both new and relapse nature. While newly registered patients were excluded to ensure adequate follow-up duration. Data Collection : An organized, structured proforma (S1) was developed to collect patient data during scheduled follow-up visits systematically. Patients' demographics and clinical characteristics, treatment parameters, and laboratory investigations were recorded from patients' profiles. Patients were actively questioned through both open-ended inquiries and symptom-specific prompts about their potential ADRs. A standardized approach was used to document Patients were actively questioned about potential ADRs through both open-ended inquiries and symptom-specific prompts. A standardized approach was used to document the nature, time of onset, severity, action taken, and outcomes of adverse drug reactions. Casualty Assessment : All reported adverse drug reactions were evaluated for causality using the WHO-UMC causality assessment criteria, which classify ADRs as certain, probable, possible, unlikely, or conditional ( 3 ). Severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Data Analysis: Collected data were entered into Microsoft Excel and analyzed using SPSS version 24 (IBM Corp., Armonk, NY). Descriptive statistics (frequencies, percentages, means) characterized the study population and ADR patterns. Chi-square tests examined associations between categorical variables (e.g., sex, age groups) and ADR occurrence. A p-value < 0.05 was considered statistically significant. Subgroup analyses compared ADR rates between treatment phases (intensive vs. continuation) and patient categories (new vs. relapse cases). RESULTS Demographic and Clinical Characteristics : The cohort consisted of 130 males (52%) and 120 females (48%). The age distribution included 25 pediatricians (10%), 60 young adults (24%), 75 middle-aged (30%), and 90 elderly patients (36%). Disease classification indicated 170 pulmonary TB cases (68%) and 80 extrapulmonary cases (32%), comprising 210 new cases (84%) and 40 relapse cases (16%). See Table 1 for Frequency and distribution of ADRs by patient characteristics Table 1 Baseline Characteristics of Study participants (n = 250) Characteristic n (%) Sex Male 130 (52%) Female 120 (48%) Age group (years) 0–16 25 (10%) 17–30 60 (24%) 31–45 75 (30%) > 45 90 (36%) TB classification Pulmonary TB 170 (68%) Extrapulmonary TB 80 (32%) Patient category New cases 210 (84%) Relapse cases 40 (16%) Frequency and distribution of ADRs by patient characteristics Among 250 patients, 170 (68%) experienced ADRs, showing significant gender variation (males: 65/130, 50% vs females: 105/120, 87.5%; p < 0.001). Age-specific ADR rates were highest in children (20/25, 80%) and lowest in the elderly (55/90, 61.1%). Treatment phase analysis showed intensive phase had 90/120 ADRs (75%) versus 80/130 (61.5%) in the continuation phase (p = 0.021). See Fig. 1 for ADR Prevalence (%). Bar chart showing ADR prevalence (%) by gender, age group, and treatment phase among 250 patients, highlighting pharmacokinetic risk factors (p < 0.001 for gender, p = 0.021 for phase). Spectrum and Severity Grading of Adverse Drug Reactions : Gastrointestinal symptoms predominated (125/170, 73.5%), with abdominal pain being most frequent (80/170, 47.1%). Dermatological reactions occurred in 85/170 patients (50%), including rashes (45, 26.5%) and itching (40, 23.5%). Severity analysis revealed 120 mild (70.6%), 40 moderate (23.5%), and 10 severe cases (5.9%), with hepatotoxicity showing the highest severe proportion (5/10, 50%). See Table 3 for Spectrum and severity grading of reported ADRs and Fig. 2 for Bar graph showing ADR categories (gastrointestinal, dermatological, etc.) and severity (mild, moderate, severe) in 170 patients, linked to drug-specific toxicities. Table 2 Spectrum and severity grading of reported ADRs (N = 170 patients with ADRs) ADR Category Specific ADR n (%) Severity (Mild/Moderate/Severe) Gastrointestinal Abdominal pain 80 (47.1%) 50/25/5 Epigastric distress 30 (17.6%) 20/8/2 Anorexia 15 (8.8%) 10/5/0 Dermatological Rashes 45 (26.5%) 30/12/3 Itching 40 (23.5%) 25/13/2 Neurological Peripheral neuropathy 35 (20.6%) 20/10/5 Hepatic Elevated LFTs 30 (17.6%) 15/10/5 Hepatitis 10 (5.9%) 0/5/5 Metabolic Hyperuricemia 25 (14.7%) 20/5/0 Gout 15 (8.8%) 5/8/2 Hematological Anemia 10 (5.9%) 5/3/2 Thrombocytopenia 5 (2.9%) 0/3/2 Ocular Optic neuritis 10 (5.9%) 0/5/5 Bar graph showing ADR categories (gastrointestinal, dermatological, etc.) and severity (mild, moderate, severe) in 170 patients, linked to drug-specific toxicities. Management And Outcomes Of ADRS : Supportive care alone sufficed for 120 ADRs (70.6%), with 100 improvements (83.3% success rate). Dose adjustment was required for 30 cases (17.6%), showing 25 improvements (83.3% efficacy). Among 20 discontinuations (11.7% total), 15 were temporary, with 12 resolutions (80% success), while 5 permanent discontinuations all showed improvement (100%). See Table 3 for Clinical Management Approaches and Therapeutic Outcomes for ADRs Table 3 Clinical Management Approaches and Therapeutic Outcomes for ADRs Management Strategy n (%) Outcome (Improved/Unchanged/Worsened) Continued ATT with supportive care 120 (70.6%) 100/15/5 Dose adjustment 30 (17.6%) 25/4/1 Temporary discontinuation 15 (8.8%) 12/2/1 Permanent discontinuation 5 (2.9%) 5/0/0 Temporal Pattern of Adverse Drug Reactions : Temporal distribution of adverse drug reactions (ADRs) during antitubercular therapy. The line graph (Fig. 3 ) depicts the number of reported cases (y-axis) for four major ADR categories across weeks 1–8 of treatment (x-axis). Data represents 170 patients experiencing ADRs, and shaded bands represent 95% confidence intervals. The onset timing varied significantly by ADR category (Kruskal-Wallis χ²=28.7, p = 0.001). Gastrointestinal ADRs (n = 125, 47.1% of total) manifested earliest, peaking at week 2 (median onset: day 9), consistent with direct mucosal irritation from first-line agents. Dermatological reactions (n = 85) exhibited a biphasic pattern with initial hypersensitivity responses at week 2 (predominantly maculopapular rash) followed by delayed-type reactions at week 4 (itching/urticaria). Hepatic toxicity (n = 30) showed strong temporal progression (R²=0.89, p < 0.01 by linear regression), with 80% of cases occurring after week 4, aligning with cumulative drug metabolite effects. Neurological manifestations (n = 35, predominantly peripheral neuropathy) demonstrated the latest median onset (day 24, IQR: 18–31), corresponding to reported isoniazid-induced neuronal toxicity timelines. See Fig. 3 showing Temporal distribution of adverse drug reactions (ADRs) during antitubercular therapy Line graph of ADR incidence (y-axis) by category across weeks 1–8 (x-axis) in 170 patients, illustrating pharmacokinetic onset patterns (Kruskal-Wallis χ²=28.7, p = 0.001). Risk Factor Associations for Antitubercular Therapy Adverse Drug Reactions : Heatmap visualization of adjusted odds ratios (scale 1.0–3.0) derived from multivariate logistic regression analysis (N = 250). Color intensity corresponds to association strength between patient factors (y-axis) and ADR categories (x-axis). Multivariate regression revealed distinct risk patterns for antitubercular therapy ADRs, with hepatotoxicity showing the strongest association with hepatitis coinfection (aOR 3.0, 95% CI 2.2–4.1), intensive phase treatment (aOR 2.7, 1.9–3.8), and older age (> 45 years; aOR 2.3, 1.6–3.3). Neurotoxicity was predominantly linked to pediatric age (aOR 3.1, 2.1–4.6) and malnutrition (aOR 2.4, 1.7–3.4), while cutaneous reactions correlated with female sex (aOR 2.8, 2.0-3.9) and intensive phase (aOR 2.1, 1.5-3.0) (all p < 0.01). See Fig. 4 for Stratified Risk Associations Between Patient Characteristics and Antitubercular Therapy-Induced Adverse Drug Reactions Heatmap of adjusted odds ratios (aOR, 1.0–3.0) from logistic regression, linking patient factors (e.g., hepatitis, gender) to ADR categories with pharmacological implications (p < 0.01). DISCUSSION The findings from our cohort of 250 patients provide compelling evidence regarding the safety profile of antitubercular therapy in Pakistan's clinical setting. Several key observations merit particular attention: Our study confirms the significantly higher ADR prevalence among female patients (87.5% vs 50%, p < 0.001), aligning with recent pharmacoepidemiologic studies from South Asia. Reported similar gender differences, attributing them to hormonal modulation of cytochrome P450 enzymes affecting drug metabolism. This biological factor may be compounded by nutritional deficiencies prevalent among Pakistani women, as documented in the National Nutrition Survey ( 14 ), where 52% of reproductive-aged women showed multiple micronutrient deficiencies impacting drug detoxification pathways ( 15 ). The elevated ADR rates in pediatric (80%) and elderly populations (61.1%) corroborate findings from multinational study on age-specific pharmacokinetics of ATT. ( 2 , 16 ) Our data particularly supports their recommendation for weight-based dose adjustments in children, as we observed disproportionate neurotoxicity (20.6% peripheral neuropathy) despite pyridoxine prophylaxis. For elderly patients, the high incidence of hepatotoxicity (17.6% elevated LFTs) mirrors concerns raised regarding age-related decline in hepatic function ( 5 ). The significantly higher ADR incidence during the intensive phase (75% vs 61.5%, p = 0.021) reinforces the hepatotoxic potential of pyrazinamide-containing regimens as described in the WHO 2022 treatment guidelines. ( 3 ) Our findings quantitatively support enhanced monitoring during initial treatment months, with 5.9% of patients developing clinically significant hepatitis requiring temporary discontinuation, suggesting pharmacokinetic accumulation. The predominance of gastrointestinal (47.1%) and dermatological (26.5%) reactions parallels global surveillance data from the WHO Global Tuberculosis Programme (2023) ( 17 ). However, our observed rates exceed those reported in clinical trials, highlighting the importance of real-world pharmacovigilance as emphasized ( 13 ). The successful management of 70.6% ADRs with supportive care alone demonstrates the effectiveness of proactive monitoring strategies advocated by the NTCP Pakistan (2022) guidelines ( 18 , 19 ). These findings have three major practice implications: the need for gender-specific monitoring protocols, particularly for women of reproductive age, mandatory baseline, and periodic hepatic function testing during the intensive phase, and the development of pediatric-friendly formulations to improve dose accuracy and reduce toxicity The 8.8% treatment interruption rate due to ADRs in our study remains lower than the 15–20% range reported in similar low-resource settings ( 5 ), possibly reflecting the hospital's robust patient education program. This suggests enhanced counseling, as recommended in the WHO End TB Strategy ( 1 ), can mitigate ADR-related treatment discontinuation. LIMITATIONS Convenient sampling may introduce selection bias, potentially skewing pharmacokinetic risk estimates. Excluding newly registered patients may miss early ADR patterns. Future studies should use random sampling and pharmacokinetic modeling to validate these findings. CONCLUSION This prospective study of 250 TB patients in Pakistan reveals a 68% ADR incidence, with gastrointestinal (73.5%) and dermatological (50%) reactions predominating, and severe cases (5.9%) including hepatotoxicity. Females (87.5% vs. 50% males, p < 0.001) and pediatric patients (80%) were at higher risk, with hepatitis coinfection (aOR 3.0), pediatric age (aOR 3.1), and female sex (aOR 2.8) as key predictors. In Pakistan’s context, where malnutrition and hepatitis influence drug metabolism, these findings underscore the need for pharmacokinetic-guided monitoring, gender-specific dosing adjustments, and enhanced pharmacovigilance during the intensive ATT phase. These insights support personalized medicine approaches to improve TB treatment safety and adherence. Abbreviations 1. ADR Adverse Drug Reaction 2. ATT Antitubercular Therapy 3. HRZE Isonazid, Rifampicin, Pyrazinamide, Ethambutol 4. HR Isoniazid, Rifampicin (continuation phase regimen) 5. WHO UMC -World Health Organization-Uppsala Monitoring Centre 6. CTCAE Common Terminology Criteria for Adverse Events 7. SPSS Statistical Package for the Social Sciences 8. aOR Adjusted Odds Ratio 9. NTCP National Tuberculosis Control Program (Pakistan) 10. NKBMH Nasirullah Khan Baber Memorial Hospital 11. LFTs Liver Function Tests 12. NAT2 N-Acetyltransferase 2 13. TB Tuberculosis 14. WHO World Health Organization 15. NTCP National Tuberculosis Control Program 16. CI Confidence Interval 17. IQR Interquartile Range Declarations Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Human Ethics and Consent to Participate declarations: The study protocol received ethical approval from the Institutional Review Board of the University of Peshawar (S2). Written informed consent(S2) was obtained from all participants or their legal guardians in the case of minors. Patient confidentiality was maintained through anonymization of data and secure storage practices. IRB Approval for conducting this study by University of Peshawar showing approved patient consent is attached with the manuscript. Questionnaire for this study is also attached. Financial support and Acknowledgment: Open Access funding provided by the Qatar National Library Author Contribution Credit Authorship Contributiont Statement Aftab Ullah : Conceptualization, Writing Original Manuscript, Review Muhammed Shabil: Conceptualization, Writing Original Manuscript, Review Abdul Rahim: Conceptualization, Writing Original Manuscript, Review Rida Shakeel: Writing Original Manuscript, Review & Editing. Aiman Begum: Writing Original Manuscript, Data Collection Uzma bibi: Writing Original Manuscript, Analysis Urooj Khan: Writing Original Manuscript, Table and Figures Javed Iqbal: Writing- review & editing. Acknowledgement Financial support and Acknowledgment: Open Access funding provided by the Qatar National Library Data Availability Ethical Approval : The study protocol received ethical approval from the Institutional Review Board of the University of Peshawar (S2). Written informed consent(S2) was obtained from all participants or their legal guardians in the case of minors. Patient confidentiality was maintained through anonymization of data and secure storage practices. References Global Tuberculosis Report 2023 [Internet]. [cited 2025 Jul 19]. 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Iqbal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBACxmYGNgaGgho5AxCPh3gtBseMidcCBCAtzIkbiNbC3M687cEPA7b07eynEz+8YbCWJ8JhbOWGPQYyuTt7cjdLzmFIN2wgrIXHTILHgC13w4HcDdI8DIcZidIi+ceAOd3g/NvNv4Fa7InSIs1jwJxgcCN3G8iWRCK0sJUbyxgcM9xw4+02yzkG6ckEtRj2H9728E1FjbzB+dzNN95UWNsS1tLAYIDENWAmpIGBARgNyFoYiNAyCkbBKBgFIw4AAFyrOfIn2yeLAAAAAElFTkSuQmCC","orcid":"","institution":"Hamad Medical Corporation","correspondingAuthor":true,"prefix":"","firstName":"Javed","middleName":"","lastName":"Iqbal","suffix":""}],"badges":[],"createdAt":"2025-07-19 00:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7161019/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7161019/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88490076,"identity":"7a879130-4e99-48bd-b77f-68035aee1eb1","added_by":"auto","created_at":"2025-08-07 04:09:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":121187,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrevalence of Adverse Drug Reactions Stratified by Patient Characteristics (Age, Gender, and Treatment Phase)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7161019/v1/a9b9b70b9aa9e01d561ba0e4.png"},{"id":88490078,"identity":"11a3a89b-fadd-4dc7-86e9-935f4e3d1389","added_by":"auto","created_at":"2025-08-07 04:09:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":137761,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSpectrum of severity grading and types of ADRs\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7161019/v1/66254753a3043a25ec83bb9b.png"},{"id":88490079,"identity":"2e948d68-eb59-43ae-b3a6-4de5894fe541","added_by":"auto","created_at":"2025-08-07 04:09:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":420286,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTemporal distribution of adverse drug reactions (ADRs) during antitubercular therapy\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7161019/v1/7d33f7c179324749bb7a2980.png"},{"id":88491138,"identity":"e2764427-6c4a-49c1-a508-9031cf46bf75","added_by":"auto","created_at":"2025-08-07 04:17:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":119055,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStratified Risk Associations Between Patient Characteristics and Antitubercular Therapy-Induced Adverse Drug Reactions\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7161019/v1/86d7f7e37310ea8ed8acc507.png"},{"id":93369773,"identity":"62d5e9e6-7c93-41b1-bd2a-20a839fa6c8d","added_by":"auto","created_at":"2025-10-13 06:17:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2090960,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7161019/v1/6389a04f-b29f-4624-89ac-5b1a937f8b8a.pdf"},{"id":88490074,"identity":"3ea136f9-1bf8-4099-b40a-5c12e29610d6","added_by":"auto","created_at":"2025-08-07 04:09:58","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":17258,"visible":true,"origin":"","legend":"","description":"","filename":"Questionirre.docx","url":"https://assets-eu.researchsquare.com/files/rs-7161019/v1/e52b0946122d9addd08048d7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Spectrum and Predictors of Adverse Drug Reactions in Patients Receiving Standard Antitubercular Therapy: A Prospective Study from Pakistan","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eTuberculosis remains one of the world\u0026rsquo;s deadliest infectious diseases, with an estimated 10\u0026nbsp;million new cases and 1.5\u0026nbsp;million deaths annually (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The global TB epidemic disproportionately affects low- and middle-income countries, with Pakistan ranking fifth among high-burden nations, reporting approximately 570,000 new cases each year (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The standard treatment for drug-susceptible TB involves a 6-month regimen of four first-line drugs: isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in the intensive phase, followed by isoniazid and rifampicin (HR) in the continuation phase (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhile effective, antitubercular therapy is associated with a high incidence of adverse drug reactions, ranging from 8\u0026ndash;85% across various studies (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These ADRs represent a major challenge to treatment adherence and completion, particularly in resource-limited settings. A systematic review by (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) identified ADRs as the second most common reason for treatment interruption after patient-initiated discontinuation. The spectrum of ATT-associated ADRs encompasses gastrointestinal disturbances, hepatotoxicity, cutaneous reactions, neurological effects, and hematological abnormalities, with varying degrees of severity (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe pathophysiology of ATT-induced ADRs involves multiple mechanisms. Isoniazid hepatotoxicity results from toxic metabolites generated through cytochrome P450 2E1 metabolism, while rifampicin induces hepatic enzymes, potentially exacerbating this effect (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Pyrazinamide's inhibition of renal urate excretion leads to hyperuricemia, and ethambutol's chelation of copper and zinc in retinal cells underlies its ocular toxicity (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGenetic polymorphisms in drug-metabolizing enzymes, particularly N-acetyltransferase 2 (NAT2), significantly influence individual susceptibility to these reactions (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePakistan, high malnutrition rates (37%) and hepatitis B/C prevalence (15%) may alter drug metabolism, exacerbating toxicities, compounded by limited healthcare infrastructure and gender disparities in care access (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Additionally, cultural influences, such as gender inequalities in healthcare access and the prevalent use of traditional remedies, can affect ADR patterns and how they are reported (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eRecent advances in pharmacovigilance methodologies, including active surveillance systems and biomarker-based monitoring, offer new opportunities for early detection of ADR (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, their implementation in high-burden and resource-constrained settings remains limited. The WHO's End TB Strategy emphasizes the importance of patient-centered care, including comprehensive ADR monitoring, as essential for achieving treatment success rates exceeding 90% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study aims to contribute to this global effort by providing contemporary, context-specific data on ATT-associated ADRs in a Pakistani tertiary care setting. By characterizing the incidence, spectrum, and pharmacological risk factors for ADRs, we seek to inform clinical practice and policy decisions aimed at optimizing drug safety outcomes. Our findings may guide the development of targeted monitoring protocols, particularly for high-risk groups such as women, children, and elderly patients.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cp\u003e\u003cb\u003eStudy Design and Setting\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e This prospective observational study was conducted at the chest outpatient department of Nasirullah Khan Baber Memorial Hospital (NKBMH), a 500-bed tertiary care facility in Peshawar, Pakistan. The study period extended from September 2023 to October 2024, encompassing 13 months of active patient monitoring. The hospital is a referral center for tuberculosis diagnosis and treatment under Pakistan's National Tuberculosis Control Program (NTCP).\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Population\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe study enrolled 250 patients receiving antitubercular therapy through convenient sampling, chosen for its feasibility in the clinical setting.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInclusion and Exclusion criteria\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eFollow-up patients of both genders registered under NTCP at the Nasir Ullah Khan Baber Teaching Hospital, Peshawar\u0026mdash;patients of pulmonary and extrapulmonary TB cases of both new and relapse nature. While newly registered patients were excluded to ensure adequate follow-up duration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Collection\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAn organized, structured proforma (S1) was developed to collect patient data during scheduled follow-up visits systematically. Patients' demographics and clinical characteristics, treatment parameters, and laboratory investigations were recorded from patients' profiles. Patients were actively questioned through both open-ended inquiries and symptom-specific prompts about their potential ADRs. A standardized approach was used to document Patients were actively questioned about potential ADRs through both open-ended inquiries and symptom-specific prompts. A standardized approach was used to document the nature, time of onset, severity, action taken, and outcomes of adverse drug reactions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCasualty Assessment\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAll reported adverse drug reactions were evaluated for causality using the WHO-UMC causality assessment criteria, which classify ADRs as certain, probable, possible, unlikely, or conditional (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eData Analysis:\u003c/h2\u003e\u003cp\u003eCollected data were entered into Microsoft Excel and analyzed using SPSS version 24 (IBM Corp., Armonk, NY). Descriptive statistics (frequencies, percentages, means) characterized the study population and ADR patterns. Chi-square tests examined associations between categorical variables (e.g., sex, age groups) and ADR occurrence. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Subgroup analyses compared ADR rates between treatment phases (intensive vs. continuation) and patient categories (new vs. relapse cases).\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cb\u003eDemographic and Clinical Characteristics\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe cohort consisted of 130 males (52%) and 120 females (48%). The age distribution included 25 pediatricians (10%), 60 young adults (24%), 75 middle-aged (30%), and 90 elderly patients (36%). Disease classification indicated 170 pulmonary TB cases (68%) and 80 extrapulmonary cases (32%), comprising 210 new cases (84%) and 40 relapse cases (16%). \u003cb\u003eSee\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003efor Frequency and distribution of ADRs by patient characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline Characteristics of Study participants (n\u0026thinsp;=\u0026thinsp;250)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e130 (52%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e120 (48%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge group (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u0026ndash;16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (10%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u0026ndash;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 (24%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e31\u0026ndash;45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75 (30%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90 (36%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTB classification\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePulmonary TB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e170 (68%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExtrapulmonary TB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (32%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient category\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNew cases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e210 (84%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRelapse cases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (16%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eFrequency and distribution of ADRs by patient characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eAmong 250 patients, 170 (68%) experienced ADRs, showing significant gender variation (males: 65/130, 50% vs females: 105/120, 87.5%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Age-specific ADR rates were highest in children (20/25, 80%) and lowest in the elderly (55/90, 61.1%). Treatment phase analysis showed intensive phase had 90/120 ADRs (75%) versus 80/130 (61.5%) in the continuation phase (p\u0026thinsp;=\u0026thinsp;0.021).\u003c/em\u003e \u003cb\u003eSee\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003efor ADR Prevalence (%).\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eBar chart showing ADR prevalence (%) by gender, age group, and treatment phase among 250 patients, highlighting pharmacokinetic risk factors (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for gender, p\u0026thinsp;=\u0026thinsp;0.021 for phase).\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSpectrum and Severity Grading of Adverse Drug Reactions\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eGastrointestinal symptoms predominated (125/170, 73.5%), with abdominal pain being most frequent (80/170, 47.1%). Dermatological reactions occurred in 85/170 patients (50%), including rashes (45, 26.5%) and itching (40, 23.5%). Severity analysis revealed 120 mild (70.6%), 40 moderate (23.5%), and 10 severe cases (5.9%), with hepatotoxicity showing the highest severe proportion (5/10, 50%). \u003cb\u003eSee\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003efor Spectrum and severity grading of reported ADRs and\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003efor Bar graph showing ADR categories (gastrointestinal, dermatological, etc.) and severity (mild, moderate, severe) in 170 patients, linked to drug-specific toxicities.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSpectrum and severity grading of reported ADRs (N\u0026thinsp;=\u0026thinsp;170 patients with ADRs)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADR Category\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpecific ADR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSeverity (Mild/Moderate/Severe)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbdominal pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e80 (47.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50/25/5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEpigastric distress\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30 (17.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20/8/2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnorexia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15 (8.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10/5/0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDermatological\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRashes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e45 (26.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30/12/3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eItching\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e40 (23.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25/13/2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeurological\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePeripheral neuropathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35 (20.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20/10/5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eElevated LFTs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30 (17.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15/10/5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10 (5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/5/5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHyperuricemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e25 (14.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20/5/0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGout\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15 (8.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5/8/2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHematological\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10 (5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5/3/2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (2.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/3/2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOcular\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOptic neuritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10 (5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/5/5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eBar graph showing ADR categories (gastrointestinal, dermatological, etc.) and severity (mild, moderate, severe) in 170 patients, linked to drug-specific toxicities.\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eManagement And Outcomes Of ADRS\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eSupportive care alone sufficed for 120 ADRs (70.6%), with 100 improvements (83.3% success rate). Dose adjustment was required for 30 cases (17.6%), showing 25 improvements (83.3% efficacy). Among 20 discontinuations (11.7% total), 15 were temporary, with 12 resolutions (80% success), while 5 permanent discontinuations all showed improvement (100%). \u003cb\u003eSee\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003efor Clinical Management Approaches and Therapeutic Outcomes for ADRs\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eClinical Management Approaches and Therapeutic Outcomes for ADRs\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eManagement Strategy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOutcome (Improved/Unchanged/Worsened)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eContinued ATT with supportive care\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e120 (70.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100/15/5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDose adjustment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e30 (17.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25/4/1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTemporary discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (8.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12/2/1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePermanent discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (2.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/0/0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTemporal Pattern of Adverse Drug Reactions\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eTemporal distribution of adverse drug reactions (ADRs) during antitubercular therapy. The line graph (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) depicts the number of reported cases (y-axis) for four major ADR categories across weeks 1\u0026ndash;8 of treatment (x-axis). Data represents 170 patients experiencing ADRs, and shaded bands represent 95% confidence intervals. The onset timing varied significantly by ADR category (Kruskal-Wallis χ\u0026sup2;=28.7, p\u0026thinsp;=\u0026thinsp;0.001). Gastrointestinal ADRs (n\u0026thinsp;=\u0026thinsp;125, 47.1% of total) manifested earliest, peaking at week 2 (median onset: day 9), consistent with direct mucosal irritation from first-line agents. Dermatological reactions (n\u0026thinsp;=\u0026thinsp;85) exhibited a biphasic pattern with initial hypersensitivity responses at week 2 (predominantly maculopapular rash) followed by delayed-type reactions at week 4 (itching/urticaria). Hepatic toxicity (n\u0026thinsp;=\u0026thinsp;30) showed strong temporal progression (R\u0026sup2;=0.89, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 by linear regression), with 80% of cases occurring after week 4, aligning with cumulative drug metabolite effects. Neurological manifestations (n\u0026thinsp;=\u0026thinsp;35, predominantly peripheral neuropathy) demonstrated the latest median onset (day 24, IQR: 18\u0026ndash;31), corresponding to reported isoniazid-induced neuronal toxicity timelines. \u003cb\u003eSee\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003eshowing Temporal distribution of adverse drug reactions (ADRs) during antitubercular therapy\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eLine graph of ADR incidence (y-axis) by category across weeks 1\u0026ndash;8 (x-axis) in 170 patients, illustrating pharmacokinetic onset patterns (Kruskal-Wallis χ\u0026sup2;=28.7, p\u0026thinsp;=\u0026thinsp;0.001).\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eRisk Factor Associations for Antitubercular Therapy Adverse Drug Reactions\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eHeatmap visualization of adjusted odds ratios (scale 1.0\u0026ndash;3.0) derived from multivariate logistic regression analysis (N\u0026thinsp;=\u0026thinsp;250). Color intensity corresponds to association strength between patient factors (y-axis) and ADR categories (x-axis). Multivariate regression revealed distinct risk patterns for antitubercular therapy ADRs, with hepatotoxicity showing the strongest association with hepatitis coinfection (aOR 3.0, 95% CI 2.2\u0026ndash;4.1), intensive phase treatment (aOR 2.7, 1.9\u0026ndash;3.8), and older age (\u0026gt;\u0026thinsp;45 years; aOR 2.3, 1.6\u0026ndash;3.3). Neurotoxicity was predominantly linked to pediatric age (aOR 3.1, 2.1\u0026ndash;4.6) and malnutrition (aOR 2.4, 1.7\u0026ndash;3.4), while cutaneous reactions correlated with female sex (aOR 2.8, 2.0-3.9) and intensive phase (aOR 2.1, 1.5-3.0) (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). \u003cb\u003eSee\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e \u003cb\u003efor Stratified Risk Associations Between Patient Characteristics and Antitubercular Therapy-Induced Adverse Drug Reactions\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eHeatmap of adjusted odds ratios (aOR, 1.0\u0026ndash;3.0) from logistic regression, linking patient factors (e.g., hepatitis, gender) to ADR categories with pharmacological implications (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/em\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe findings from our cohort of 250 patients provide compelling evidence regarding the safety profile of antitubercular therapy in Pakistan's clinical setting. Several key observations merit particular attention:\u003c/p\u003e\u003cp\u003eOur study confirms the significantly higher ADR prevalence among female patients (87.5% vs 50%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), aligning with recent pharmacoepidemiologic studies from South Asia. Reported similar gender differences, attributing them to hormonal modulation of cytochrome P450 enzymes affecting drug metabolism. This biological factor may be compounded by nutritional deficiencies prevalent among Pakistani women, as documented in the National Nutrition Survey (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), where 52% of reproductive-aged women showed multiple micronutrient deficiencies impacting drug detoxification pathways (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe elevated ADR rates in pediatric (80%) and elderly populations (61.1%) corroborate findings from multinational study on age-specific pharmacokinetics of ATT. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) Our data particularly supports their recommendation for weight-based dose adjustments in children, as we observed disproportionate neurotoxicity (20.6% peripheral neuropathy) despite pyridoxine prophylaxis. For elderly patients, the high incidence of hepatotoxicity (17.6% elevated LFTs) mirrors concerns raised regarding age-related decline in hepatic function (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e The significantly higher ADR incidence during the intensive phase (75% vs 61.5%, p\u0026thinsp;=\u0026thinsp;0.021) reinforces the hepatotoxic potential of pyrazinamide-containing regimens as described in the WHO 2022 treatment guidelines. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Our findings quantitatively support enhanced monitoring during initial treatment months, with 5.9% of patients developing clinically significant hepatitis requiring temporary discontinuation, suggesting pharmacokinetic accumulation.\u003c/p\u003e\u003cp\u003eThe predominance of gastrointestinal (47.1%) and dermatological (26.5%) reactions parallels global surveillance data from the WHO Global Tuberculosis Programme (2023) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, our observed rates exceed those reported in clinical trials, highlighting the importance of real-world pharmacovigilance as emphasized (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The successful management of 70.6% ADRs with supportive care alone demonstrates the effectiveness of proactive monitoring strategies advocated by the NTCP Pakistan (2022) guidelines (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThese findings have three major practice implications: the need for gender-specific monitoring protocols, particularly for women of reproductive age, mandatory baseline, and periodic hepatic function testing during the intensive phase, and the development of pediatric-friendly formulations to improve dose accuracy and reduce toxicity\u003c/p\u003e\u003cp\u003eThe 8.8% treatment interruption rate due to ADRs in our study remains lower than the 15\u0026ndash;20% range reported in similar low-resource settings (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), possibly reflecting the hospital's robust patient education program. This suggests enhanced counseling, as recommended in the WHO End TB Strategy (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), can mitigate ADR-related treatment discontinuation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLIMITATIONS\u003c/b\u003e\u003c/p\u003e\u003cp\u003eConvenient sampling may introduce selection bias, potentially skewing pharmacokinetic risk estimates. Excluding newly registered patients may miss early ADR patterns. Future studies should use random sampling and pharmacokinetic modeling to validate these findings.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis prospective study of 250 TB patients in Pakistan reveals a 68% ADR incidence, with gastrointestinal (73.5%) and dermatological (50%) reactions predominating, and severe cases (5.9%) including hepatotoxicity. Females (87.5% vs. 50% males, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and pediatric patients (80%) were at higher risk, with hepatitis coinfection (aOR 3.0), pediatric age (aOR 3.1), and female sex (aOR 2.8) as key predictors. In Pakistan\u0026rsquo;s context, where malnutrition and hepatitis influence drug metabolism, these findings underscore the need for pharmacokinetic-guided monitoring, gender-specific dosing adjustments, and enhanced pharmacovigilance during the intensive ATT phase. These insights support personalized medicine approaches to improve TB treatment safety and adherence.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e1. \u003cb\u003eADR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAdverse Drug Reaction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e2. \u003cb\u003eATT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAntitubercular Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e3. \u003cb\u003eHRZE\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIsonazid, Rifampicin, Pyrazinamide, Ethambutol\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e4. \u003cb\u003eHR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIsoniazid, Rifampicin (continuation phase regimen)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e5. \u003cb\u003eWHO\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cb\u003eUMC\u003c/b\u003e-World Health Organization-Uppsala Monitoring Centre\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e6. \u003cb\u003eCTCAE\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e7. \u003cb\u003eSPSS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStatistical Package for the Social Sciences\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e8. \u003cb\u003eaOR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAdjusted Odds Ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e9. \u003cb\u003eNTCP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNational Tuberculosis Control Program (Pakistan)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e10. \u003cb\u003eNKBMH\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNasirullah Khan Baber Memorial Hospital\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e11. \u003cb\u003eLFTs\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLiver Function Tests\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e12. \u003cb\u003eNAT2\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eN-Acetyltransferase 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e13. \u003cb\u003eTB\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTuberculosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e14. \u003cb\u003eWHO\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e15. \u003cb\u003eNTCP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNational Tuberculosis Control Program\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e16. \u003cb\u003eCI\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence Interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e17. \u003cb\u003eIQR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInterquartile Range\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003ch3\u003eHuman Ethics and Consent to Participate declarations:\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThe study protocol received ethical approval from the Institutional Review Board of the University of Peshawar (S2). Written informed consent(S2) was obtained from all participants or their legal guardians in the case of minors. Patient confidentiality was maintained through anonymization of data and secure storage practices. \u003cstrong\u003eIRB Approval for conducting this study by University of Peshawar showing approved patient consent is attached with the manuscript. Questionnaire for this study is also attached.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support and Acknowledgment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOpen Access funding provided by the Qatar National Library\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCredit Authorship Contributiont Statement Aftab Ullah : Conceptualization, Writing Original Manuscript, Review Muhammed Shabil: Conceptualization, Writing Original Manuscript, Review Abdul Rahim: Conceptualization, Writing Original Manuscript, Review Rida Shakeel: Writing Original Manuscript, Review \u0026amp; Editing. Aiman Begum: Writing Original Manuscript, Data Collection Uzma bibi: Writing Original Manuscript, Analysis Urooj Khan: Writing Original Manuscript, Table and Figures Javed Iqbal: Writing- review \u0026amp; editing.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eFinancial support and Acknowledgment: Open Access funding provided by the Qatar National Library\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eEthical Approval : The study protocol received ethical approval from the Institutional Review Board of the University of Peshawar (S2). Written informed consent(S2) was obtained from all participants or their legal guardians in the case of minors. Patient confidentiality was maintained through anonymization of data and secure storage practices.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGlobal Tuberculosis Report 2023 [Internet]. [cited 2025 Jul 19]. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/2019168/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/2019168/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antitubercular therapy, Adverse drug reactions, Pharmacovigilance, Pharmacokinetics, Pakistan","lastPublishedDoi":"10.21203/rs.3.rs-7161019/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7161019/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAntitubercular therapy (ATT)-induced adverse drug reactions (ADRs) pose challenges to treatment adherence in high-burden settings like Pakistan, were malnutrition and hepatitis coinfection influence drug metabolism. This study evaluates the incidence, spectrum, and pharmacological predictors of ADRs in a Pakistani cohort.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA prospective observational study was conducted at Nasir Ullah Khan Baber Memorial Hospital, Peshawar (September 2023\u0026ndash;October 2024), enrolling 250 patients on standard ATT (HRZE/HR). ADRs were assessed using WHO-UMC causality criteria and CTCAE severity grading, analyzed with SPSS version 24 via chi-square and multivariate logistic regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf 250 patients (52% male, 48% female), 68% experienced ADRs, with higher rates in females (87.5% vs. 50%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and pediatric patients (80%). Gastrointestinal (73.5%) and dermatological (50%) reactions predominated, with severe ADRs (5.9%) including hepatotoxicity. Risk factors included hepatitis coinfection (aOR 3.0 for hepatotoxicity), pediatric age (aOR 3.1 for neurotoxicity), and female sex (aOR 2.8 for cutaneous reactions). Supportive care managed 70.6% of ADRs.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study highlights a high ADR burden in Pakistan, driven by pharmacokinetic factors like hepatitis and malnutrition. It supports tailored ATT monitoring and dosing strategies to enhance drug safety and adherence in resource-limited settings.\u003c/p\u003e","manuscriptTitle":"Spectrum and Predictors of Adverse Drug Reactions in Patients Receiving Standard Antitubercular Therapy: A Prospective Study from Pakistan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-07 04:09:53","doi":"10.21203/rs.3.rs-7161019/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ed20600b-4190-41a6-baa2-5154608943dc","owner":[],"postedDate":"August 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T06:09:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-07 04:09:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7161019","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7161019","identity":"rs-7161019","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}