Timing of antiretroviral therapy for HIV-infected patients with moderate-to-severe Pneumocystis pneumonia: study protocol for a multi-center prospective randomized controlled trial

Timing of antiretroviral therapy for HIV-infected patients with moderate-to-severe Pneumocystis pneumonia: study protocol for a multi-center prospective randomized controlled trial | 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 Study protocol Timing of antiretroviral therapy for HIV-infected patients with moderate-to-severe Pneumocystis pneumonia: study protocol for a multi-center prospective randomized controlled trial Yuanyuan Qin, Yanqiu Lu, Yihong Zhou, Vijay Harypursat, Feng Sun, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-19306/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jun, 2020 Read the published version in Trials → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Pneumocystis pneumonia (PCP) is a common AIDS-related opportunistic infection. Recent reports estimate that more than 400,000 HIV patients develop PCP each year globally. However, the timing of antiretroviral therapy (ART) initiation for HIV infected patients with PCP is still controversial, and the benefits and risks of early initiation of ART are not completely clear. We thus designed this study in order to determine the optimal timing for ART initiation for HIV-positive patients with moderate to severe PCP. Methods: This study will be an open-labelled, multi-center, prospective, randomized controlled trial. A total of 200 subjects will be randomized to an early ART initiation group (≤14 days after PCP diagnosis), and a deferred ART initiation group (>14 days after PCP diagnosis) at a 1:1 ratio. All subjects will be followed up for 48 weeks after starting ART. The primary outcome is incidence of disease progression (including new opportunistic infections and all-cause mortality) at week 48. The secondary endpoints are the changes in CD4 counts from baseline at week 12, week 24 and week 48, the degree of virological suppression (HIV-RNA<50 copies/mL) at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (IRIS), and adverse events(AEs) at each visit. Discussion: We hope that the results of this study will reveal the optimal timing for initiation of ART in HIV-infected patients with moderate to severe PCP. Trial registration: This trial was registered as one of the twelve trials under the name of a general project at chictr.org.cn on February 1, 2019, and the registration number of the general project is ChiCTR1900021195. Infectious Diseases HIV opportunistic infections Pneumocystis pneumonia antiretroviral therapy initiation Figures Figure 1 Background Pneumocystis pneumonia, one of the most common AIDS-defining diseases, is caused by the fungal opportunistic organism, Pneumocystis jirovecii , and has been effectively controlled in AIDS patients by the widespread use of modern ART. However, the incidence of PCP among undiagnosed HIV patients increased from 48% in 2000 to 67% in 2013 [1]. Reports in recent years estimate that more than 400,000 HIV patients develop PCP globally every year [2, 3]. Mortality of PCP ranges from 10% to 30%, and may be even higher if diagnosis is delayed [4-6]. Although efforts for the early diagnosis and treatment of PCP have been made, the proportion of HIV patients with advanced PCP has not decreased in many high-burden countries [7]. Optimal timing for ART initiation in opportunistically infected patients with HIV infection is controversial. One multi-center randomized clinical trial showed that early initiation of ART had a lower rate of AIDS progression and deaths than deferred ART, without increased adverse events and with optimal viral suppression [8]. In the study, results from both overall analysis of all OIs, and subgroup analysis of PCP were consistent [8]. However, in a recent study investigated the timing of initiation of proteinase-inhibitor ART in HIV-patients with acute AIDS-defining events, enrolling a total of 61 subjects {11 patients with toxoplasmosis (TE) and 50 patients with PCP}, researchers found that there were no significant immunological or virological differences between the immediate ART initiation group and the deferred initiation group [7]. From the results of the above studies, it is obvious that the timing for ART initiation in HIV-infected persons with PCP remains controversial, and warrants further investigation. We thus designed the present study in order to determine the optimal timing for ART initiation for HIV-positive patients with moderate to severe PCP. Research objective This study aims to investigate the optimal timing for ART initiation in HIV-infected patients with moderate to severe PCP. Our primary goal is to compare the progression of disease between an early ART initiation group (initiation within 2 weeks of PCP diagnosis), and a deferred ART initiation group (initiation after 2 weeks of PCP diagnosis) at week 48. Our secondary goal is to compare the safety of the timing of ART initiation between the early-ART initiation group and the deferred-ART initiation group during the 48-week period of this study. Our tertiary goal is to determine whether there are differences in the long-term effects of early ART initiation as compared to deferred ART initiation with regard to CD4 cell counts and HIV RNA loads in HIV-infected patients with moderate to severe PCP. Methods Study design This study will be conducted as an open-labelled, multi-center prospective randomized controlled trial. We will recruit 200 subjects from the following 17 hospitals: Chongqing Public Health Medical Center, Beijing You’an Hospital of Capital Medical University, Harbin Medical University, the Second People's Hospital of Tianjin, the First Hospital of Changsha, the Eighth People's Hospital of Guangzhou, Liuzhou General Hospital, the Third People's Hospital of Guilin, the Third People’s Hospital of Shenzhen, Guiyang Public Health Clinical Center, Public Health Clinical Center of Chengdu, Kunming Third People’s Hospital, Yunnan Provincial Infectious Disease Hospital, the Fourth People’s Hospital of Nanning, Guangxi Longtan Hospital, the First Affiliated Hospital of Zhejiang University, and Xixi Hospital of Hangzhou. This protocol has been written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement [9]. The enrolment, intervention and assessment processes are shown in Figure 1. All subjects in each treatment arm of the study will participate voluntarily, after informed consent is obtained. Each individual will be invited to participate in a 48-week follow-up after commencement of ART. Study visits will be scheduled at week 4, week 8, week 12, week 24, week 36, and week 48. Blood and urine samples will be collected for laboratory testing, including haematological analysis, urinalysis, clinical chemistry studies, serum amylase levels, myocardial enzymes, blood gas analysis, 1,3β-D-glucan, lymphocyte subset and quantitative plasma HIV-1 RNA. Other patient samples to be collected during the follow-up period are listed in Table 1. Table 1. Measurement items and point of data capture. Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Baseline Week 4 Week 8 Week 12 Week 24 Week 36 Week 48 Sign consent × Enrolment × Demography × Signs & symptoms × × × × × × × Haematological analysis × × × × × × × Urinalysis × × × × × × × Clinical chemistry studies × × × × × × × Serum Amylase levels × Myocardial enzymes × Blood gas analysis × 1,3β-D-glucan × Urine pregnancy test × Lymphocyte subset × × × × × × Quantitative plasma HIV-1 RNA × × × Chest CT/X-ray × × × × × × × IRIS × × × × × × Drug combination × × × × × × × Adverse events × × × × × × Participants Diagnostic criteria The presumptive diagnosis of moderate to severe PCP will have to meet the following criteria: (1) Progressive exacerbation of dyspnoea; (2) Diffuse “ground-glass” interstitial infiltrates spreading from the hilum in chest radiograph; (3) Alveolar-arterial O2 gradient, (A-a)DO2≥35mmHg, or room air arterial oxygen, PO2＜70mmHg. The definitive diagnosis of PCP requires identification of Pneumocystis cysts or trophozoites via staining, or detection of Pneumocystis DNA via PCR in sputum samples, bronchoalveolar lavage (BAL) fluid, or biopsy samples, in addition to the criteria for the presumptive diagnosis of moderate to severe PCP. We define PCP-IRIS as occurring when the subject experiences a paradoxical exacerbation of either clinical symptoms or radiological signs of PCP after the initiation of ART, despite receiving appropriate drug treatment for PCP. Inclusion criteria Subjects will be included in our study if they satisfy the following criteria: (1) Are aged 18 years or over; (2) Have confirmed diagnosis of HIV-1 infection; (3) Are diagnosed with moderate to severe PCP presumptively or definitively; (4) Have not received any antiretroviral treatment; (5) Be willing to give the informed consent. Exclusion criteria Subjects will be excluded from the study if they: (1) Are allergic or intolerant to any of the prescribed therapeutic drugs; (2) Have hemoglobin (Hb) <60g/L, white blood cell count (WBC) <1.0×10^9/L, neutrophil count (N) <0.5×10^9/L, platelet count (PLT) 2×upper normal limit (UNL), serum creatinine (SCr) >1.5×UNL, aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)/ alkaline phosphatase (ALP) >5 times of UNL, total bilirubin (TB) >2×UNL, serum creatine phosphokinase (CK) >2×UNL; (4) Have unstable concomitant opportunistic infections other than PCP; (5) Have serious heart disease, brain disease, lung disease, kidney disease, tumor disease and other systemic diseases; (6) Are pregnant or breastfeeding women; (7) Have severe mental illness; (8) Are intravenous drug users; (9) Are not of Chinese nationality. Randomization A specific random number sequence will be generated by Medical Research Platform ( http://www.51yyt.org/FrontPage/login.aspx?Inviter= ) for each subject with consent. Once eligibility has been confirmed, the investigators or designers will randomize the subjects into the early ART initiation group or the deferred ART initiation group at a 1:1 ratio. Data collection and quality assurance All of the results will be recorded and double entered independently. All data will be documented on case report forms (CRFs) and immediately recorded in the database through the Medical Research Platform. Missing values will be checked to ensure data completeness as much as possible. Data that are significantly abnormal or outside the clinically acceptable range (laboratory items exceeding 20% of the normal value) must be explained, and the necessary explanation must be given by the physician. Drop-outs and adverse events will be recorded in time, and drugs used for trial will be supplied, stored, distributed, and recycled in accordance with relevant regulations. After the trial is completed, a data management report meeting will be held to guarantee the validity and authenticity of this trial. The data administrator will perform a database lock after the data lock record is signed by the principal investigator, sponsor, statistical analysts and data managers. Intervention All subjects will receive conventional treatment for PCP according to the recommendations of Chinese guidelines for diagnosis and treatment of HIV/AIDS (2018) [10]. TMP-SMZ (trimethoprim-sulfamethoxazole, co-trimoxazole) combined with prednisone will be the preferred regimen. An alternative regimen may be used if the preferred regimen is intolerable, or if the patient is allergic to the preferred regimen. Those who have no obvious improvement after a full course of treatment or deteriorate during the course of treatment will be considered for replacement therapy or extension of treatment. Secondary prophylaxis will be initiated immediately after successful treatment, and maintained until CD4 cell counts are >200 cells/μL for at least six months. Once diagnosed, subjects will be randomly assigned to the early ART initiation (≤14 days after PCP diagnosis) arm or the deferred ART initiation (>14 days after PCP diagnosis) arm based on the random number sequence generated by the Medical Research Platform. As per the local guidelines [10], TDF (300mg/d) +3TC (300mg/d) +EFV (600mg/d) is preferred for ART, and other regimens are optional. Study endpoints The primary endpoint is incidence of disease progression (including new opportunistic infections and all-cause mortality). The secondary endpoints are the changes in CD4 counts from baseline to week 12, week 24 and week 48, virologic suppression (HIV-RNA<50 copies/mL) rate at week 24 and week 48, as well as rates of development of PCP-associated IRIS, and adverse events at each visit, including: (1) grade 3 or 4 adverse events; (2) serious adverse events; (3) adverse events related to discontinuation of medication or regimen change. Sample Size The sample size will be 100 subjects per treatment arm in order to provide at least 80% power, and an overall two-side alpha level of 0.05. We hypothesize that the proposed study will observe a 20% survival benefit in the early initiation arm, and the expected lost-to-follow-up rate will be 15%. Data analysis The primary outcome analysis will be conducted using the Intent-to-Treat Exposed (ITT-E) population, which consists of all randomized patients, whether they are in full compliance with the study protocol or not. ITT-E will be used to assess the primary efficacy endpoints. We also plan to analyse the primary outcome using the per-protocol (PP) analysis set, which excludes subjects who do not follow the treatment regimens. If any data is not recorded, the last observation carried forward (LOCF) method will be used. Baseline will be defined as the date of randomization. We will compare the primary endpoint in the two groups using time-to-event methods with Cox proportional-hazards models. Categorical variables will be analysed using Fisher’s exact test. To explain the competing risk of death, the cumulative incidence function will be used to compare adverse events and IRIS between the two groups [11]. A p -value of <0.05 will be considered to be statistically significant. Ethics and dissemination The study was approved by The Ethics Committee of the Chongqing Public Health Medical Center (2019-003-02-KY), and duly registered at the Chinese Clinical Trial Registry (ChiCTR1900021195). We will share the results through published medical journal articles and at conference presentation after completion of the study. Discussion The decision as to when to initiate ART in patients with moderate-to-severe PCP continues to cause confusion and frustration in clinical practice. On the one hand, patients desperately need suppression of HIV replication, as most are severely immunocompromised due to their high viral loads. The sooner the initiation of ART in these patients, the more favourable the chances of survival they would have, notwithstanding concerns regarding drug toxicity and IRIS. On the other hand, the complications relating to the administration of a multitude of medications intended to treat both PCP and HIV infection to such systemically unwell patients makes it inevitable to have to consider the emergence of IRIS, or the overlapping toxicities of various drugs, and complex drug-drug interactions among various drugs. The earlier that ART is initiated, the higher the risk of subsequently developing IRIS, and of arousing drug toxicities, and of initiating unfavourable drug-drug interactions. Previous studies have investigated the timing of ART initiation in patients with OIs, including PCP. The PISCIS cohort study (conducted from 1998 to 2006) found that patients with AIDS-defining diseases, including those with PCP, were significantly more likely to progress to a new AIDS-defining disease or death if ART initiation was deferred >30 days after HIV infection diagnosis, compared with early ART initiation patients (<30 days after HIV infection diagnosis) [12]. The AIDS Clinical Trials Group (ACTG) reported in 2009 that AIDS progression and death of HIV patients with non-tuberculous OIs are decreased if they initiated ART early (within 14 days of starting acute OI treatment) [8]. Previous studies show that patients with OIs, including PCP, may be able to benefit from early ART initiation. However, a recent study investigating the timing of initiation in HIV-patients with acute AIDS-defining events, enrolling 50 patients with PCP, found that there were no significant differences in safety, efficacy and quality of life between the immediate ART initiation group (initiation within 7 days of PCP diagnosis and treatment) and the deferred initiation group (after the treatment for PCP was over) [7]. The above conflicting studies clearly indicate that the optimal timing for ART initiation in patients with PCP remains controversial, and further investigation of this issue is warranted, especially for those with moderate-to-severe PCP, which is associated with high mortality. Herein, we designed a multi-center prospective randomized controlled trial in China, in which all eligible subjects will be randomized into an early ART initiation group (≤14 days after PCP diagnosis) and a deferred ART initiation group (>14 days after PCP diagnosis). We will collect data of survival, immunological reconstitution, virological suppression, AEs, and IRIS emergence in HIV-infected patients with moderate-to-severe PCP, with the aim to investigate the safety and benefits of early ART. We speculate that subjects in the early ART initiation group will have lower new OI incidence rates and all-cause mortality than those in the deferred ART group. We hope that our results will provide unequivocal clinical evidence as to the optimal timing to initiate ART in HIV-infected patients who are diagnosed with moderate-to-severe PCP. Trial Status This trial is currently in the recruitment phase. Patient recruitment began in March 2019 and is expected to be completed in May 2020. (protocol version 5, 28 August 2019). Abbreviations ACTG: AIDS Clinical Trials Group; AEs: adverse events; AIDS: acquired immune deficiency syndrome; ART: antiretroviral therapy; BAL: bronchoalveolar lavage; CRFs: case report forms; HIV: human immunodeficiency virus; IRIS: inflammatory syndrome; ITT-E: Intent-to-Treat Exposed; LOCF: last observation carried forward; PCP: Pneumocystis pneumonia; PP: per-protocol; SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials; TE: toxoplasmosis; UNL: upper normal limit Declarations Acknowledgements Not applicable. Authors’ contributions Y-YQ and Y-QL conceived and drafted the protocol. VH and Y-KC revised the protocol and contributed to finalizing the manuscript. FS and SY contributed to the design and implementation of the study. LY, X-QH and Y-MZ helped to revise the protocol. Y-HZ and S-QT contributed to the statistical analysis and interpretation. All authors contributed to the refinement of the study protocol, and approved the final manuscript. Funding This study was supported by the National Science and Technology Major Project of China during the 13th Five-year plan period (2018ZX10302104) and Beijing Medical and Health Foundation (YWJKJJHKYJJ-TM19001). The funding bodies have no role in the trial design or interpretation of the data. Availability of data and materials The dataset necessary to interpret the findings are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was approved by The Ethics Committee of Chongqing Public Health Medical Center (No. 2019-003-02-KY). Written informed consent will be obtained from each patient before randomization. All subjects will sign informed consent before enrolment in the study. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Authors details 1 Division of Infectious Diseases, Chongqing Public Health Medical Center, 109 Baoyu Road, Shapingba District, Chongqing, China. References Lopez-Sanchez C, Falco V, Burgos J, Navarro J, Martin MT, Curran A, Miguel L, Ocana I, Ribera E, Crespo M et al : Epidemiology and long-term survival in HIV-infected patients with Pneumocystis jirovecii pneumonia in the HAART era: experience in a university hospital and review of the literature . Medicine (Baltimore) 2015, 94 (12):e681. Armstrong-James D, Meintjes G, Brown GD: A neglected epidemic: fungal infections in HIV/AIDS . Trends Microbiol 2014, 22 (3):120-127. Bongomin F, Gago S, Oladele RO, Denning DW: Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision . J Fungi (Basel) 2017, 3 (4). Limper AH, Adenis A, Le T, Harrison TS: Fungal infections in HIV/AIDS . The Lancet Infectious diseases 2017, 17 (11):e334-e343. Thomas CF, Jr., Limper AH: Pneumocystis pneumonia . N Engl J Med 2004, 350 (24):2487-2498. Thomas CF, Jr., Limper AH: Current insights into the biology and pathogenesis of Pneumocystis pneumonia . Nat Rev Microbiol 2007, 5 (4):298-308. Schafer G, Hoffmann C, Arasteh K, Schurmann D, Stephan C, Jensen B, Stoll M, Bogner JR, Faetkenheuer G, Rockstroh J et al : Immediate versus deferred antiretroviral therapy in HIV-infected patients presenting with acute AIDS-defining events (toxoplasmosis, Pneumocystis jirovecii-pneumonia): a prospective, randomized, open-label multicenter study (IDEAL-study) . AIDS Res Ther 2019, 16 (1):34. Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L: Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial . PloS one 2009, 4 (5):e5575. Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hrobjartsson A, Schulz KF, Parulekar WR et al : SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials . BMJ 2013, 346 :e7586. Aids, Hepatitis C Professional Group SoIDCMA, Chinese Center for Disease C, Prevention: [Chinese guidelines for diagnosis and treatment of HIV/AIDS (2018)] . Zhonghua nei ke za zhi 2018, 57 (12):867-884. Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS: Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda . Clin Infect Dis 2008, 47 (12):1556-1561. Manzardo C, Esteve A, Ortega N, Podzamczer D, Murillas J, Segura F, Force L, Tural C, Vilaro J, Masabeu A et al : Optimal timing for initiation of highly active antiretroviral therapy in treatment-naive human immunodeficiency virus-1-infected individuals presenting with AIDS-defining diseases: the experience of the PISCIS Cohort . Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2013, 19 (7):646-653. 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17:25:59","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":121856,"visible":true,"origin":"","legend":"","description":"","filename":"Additionalfile1SPIRIT2013Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-19306/v1/Additional file 1-SPIRIT 2013 Checklist.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eTiming of antiretroviral therapy for HIV-infected patients with moderate-to-severe \u003cem\u003ePneumocystis\u003c/em\u003e pneumonia: study protocol for a multi-center prospective randomized controlled trial\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003e\u003cem\u003ePneumocystis\u003c/em\u003e pneumonia, one of the most common AIDS-defining diseases, is caused by the fungal opportunistic organism, \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e, and has been effectively controlled in AIDS patients by the widespread use of modern ART. However, the incidence of PCP among undiagnosed HIV patients increased from 48% in 2000 to 67% in 2013 [1]. Reports in recent years estimate that more than 400,000 HIV patients develop PCP globally every year [2, 3]. Mortality of PCP ranges from 10% to 30%, and may be even higher if diagnosis is delayed [4-6]. Although efforts for the early diagnosis and treatment of PCP have been made, the proportion of HIV patients with advanced PCP has not decreased in many high-burden countries [7].\u003c/p\u003e\n\u003cp\u003eOptimal timing for ART initiation in opportunistically infected patients with HIV infection is controversial. One multi-center randomized clinical trial showed that early initiation of ART had a lower rate of AIDS progression and deaths than deferred ART, without increased adverse events and with optimal viral suppression [8]. In the study, results from both overall analysis of all OIs, and subgroup analysis of PCP were consistent [8]. However, in a recent study investigated the timing of initiation of proteinase-inhibitor ART in HIV-patients with acute AIDS-defining events, enrolling a total of 61 subjects {11 patients with toxoplasmosis (TE) and 50 patients with PCP}, researchers found that there were no significant immunological or virological differences between the immediate ART initiation group and the deferred initiation group [7]. From the results of the above studies, it is obvious that the timing for ART initiation in HIV-infected persons with PCP remains controversial, and warrants further investigation. We thus designed the present study in order to determine the optimal timing for ART initiation for HIV-positive patients with moderate to severe PCP.\u003c/p\u003e"},{"header":"Research objective","content":"\u003cp\u003eThis study aims to investigate the optimal timing for ART initiation in HIV-infected patients with moderate to severe PCP.\u003c/p\u003e\n\u003cp\u003eOur primary goal is to compare the progression of disease between an early ART initiation group (initiation within 2 weeks of PCP diagnosis), and a deferred ART initiation group (initiation after 2 weeks of PCP diagnosis) at week 48.\u003c/p\u003e\n\u003cp\u003eOur secondary goal is to compare the safety of the timing of ART initiation between the early-ART initiation group and the deferred-ART initiation group during the 48-week period of this study.\u003c/p\u003e\n\u003cp\u003eOur tertiary goal is to determine whether there are differences in the long-term effects of early ART initiation as compared to deferred ART initiation with regard to CD4 cell counts and HIV RNA loads in HIV-infected patients with moderate to severe PCP.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be conducted as an open-labelled, multi-center prospective randomized controlled trial. We will recruit 200 subjects from the following 17 hospitals: Chongqing Public Health Medical Center, Beijing You\u0026rsquo;an Hospital of Capital Medical University, Harbin Medical University, the Second People's Hospital of Tianjin, the First Hospital of Changsha, the Eighth People's Hospital of Guangzhou, Liuzhou General Hospital, the Third People's Hospital of Guilin, the Third People\u0026rsquo;s Hospital of Shenzhen, Guiyang Public Health Clinical Center, Public Health Clinical Center of Chengdu, Kunming Third People\u0026rsquo;s Hospital, Yunnan Provincial Infectious Disease Hospital, the Fourth People\u0026rsquo;s Hospital of Nanning, Guangxi Longtan Hospital, the First Affiliated Hospital of Zhejiang University, and Xixi Hospital of Hangzhou. This protocol has been written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement [9]. The enrolment, intervention and assessment processes are shown in Figure 1. All subjects in each treatment arm of the study will participate voluntarily, after informed consent is obtained. Each individual will be invited to participate in a 48-week follow-up after commencement of ART. Study visits will be scheduled at week 4, week 8, week 12, week 24, week 36, and week 48. Blood and urine samples will be collected for laboratory testing, including haematological analysis, urinalysis, clinical chemistry studies, serum amylase levels, myocardial enzymes, blood gas analysis, 1,3\u0026beta;-D-glucan, lymphocyte subset and quantitative plasma HIV-1 RNA. Other patient samples to be collected during the follow-up period are listed in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Measurement items and point of data capture.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"#000000\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eVisit 1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eVisit 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eVisit 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eVisit 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003eVisit 5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eVisit 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eVisit 7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eWeek 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eWeek 8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eWeek 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003eWeek 24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eWeek 36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eWeek 48\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eSign consent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eEnrolment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eDemography\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eSigns \u0026amp; symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eHaematological analysis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eUrinalysis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eClinical chemistry studies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eSerum Amylase levels\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eMyocardial enzymes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eBlood gas analysis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e1,3\u0026beta;-D-glucan\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eUrine pregnancy test\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eLymphocyte subset\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eQuantitative plasma HIV-1 RNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eChest CT/X-ray\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eIRIS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eDrug combination\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003eAdverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026times;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"179\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDiagnostic criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe presumptive diagnosis of moderate to severe PCP will have to meet the following criteria:\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(1) Progressive exacerbation of dyspnoea;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(2) Diffuse \u0026ldquo;ground-glass\u0026rdquo; interstitial infiltrates spreading from the hilum in chest radiograph;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(3) Alveolar-arterial O2 gradient, (A-a)DO2\u0026ge;35mmHg, or room air arterial oxygen, PO2＜70mmHg.\u003c/p\u003e\n\u003cp\u003eThe definitive diagnosis of PCP requires identification of \u003cem\u003ePneumocystis\u003c/em\u003e cysts or trophozoites via staining, or detection of \u003cem\u003ePneumocystis\u003c/em\u003e DNA via PCR in sputum samples, bronchoalveolar lavage (BAL) fluid, or biopsy samples, in addition to the criteria for the presumptive diagnosis of moderate to severe PCP.\u003c/p\u003e\n\u003cp\u003eWe define PCP-IRIS as occurring when the subject experiences a paradoxical exacerbation of either clinical symptoms or radiological signs of PCP after the initiation of ART, despite receiving appropriate drug treatment for PCP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubjects will be included in our study if they satisfy the following criteria:\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(1) Are aged 18 years or over;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(2) Have confirmed diagnosis of HIV-1 infection;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(3) Are diagnosed with moderate to severe PCP presumptively or definitively;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(4) Have not received any antiretroviral treatment;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(5) Be willing to give the informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eExclusion criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubjects will be excluded from the study if they:\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(1) Are allergic or intolerant to any of the prescribed therapeutic drugs;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(2) Have hemoglobin (Hb) \u0026lt;60g/L, white blood cell count (WBC) \u0026lt;1.0\u0026times;10^9/L, neutrophil count (N) \u0026lt;0.5\u0026times;10^9/L, platelet count (PLT) \u0026lt;50\u0026times;10^9/L, blood amylase (AMS) \u0026gt;2\u0026times;upper normal limit (UNL), serum creatinine (SCr) \u0026gt;1.5\u0026times;UNL, aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)/ alkaline phosphatase (ALP) \u0026gt;5 times of UNL, total bilirubin (TB) \u0026gt;2\u0026times;UNL, serum creatine phosphokinase (CK) \u0026gt;2\u0026times;UNL;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(4) Have unstable concomitant opportunistic infections other than PCP;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(5) Have serious heart disease, brain disease, lung disease, kidney disease, tumor disease and other systemic diseases;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(6) Are pregnant or breastfeeding women;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(7) Have severe mental illness;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(8) Are intravenous drug users;\u003c/p\u003e\n\u003cp style=\"padding-left: 30px;\"\u003e(9) Are not of Chinese nationality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA specific random number sequence will be generated by Medical Research Platform (\u003ca href=\"http://www.51yyt.org/FrontPage/login.aspx?Inviter=\"\u003ehttp://www.51yyt.org/FrontPage/login.aspx?Inviter=\u003c/a\u003e) for each subject with consent. Once eligibility has been confirmed, the investigators or designers will randomize the subjects into the early ART initiation group or the deferred ART initiation group at a 1:1 ratio.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and quality assurance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll of the results will be recorded and double entered independently. All data will be documented on case report forms (CRFs) and immediately recorded in the database through the Medical Research Platform. Missing values will be checked to ensure data completeness as much as possible. Data that are significantly abnormal or outside the clinically acceptable range (laboratory items exceeding 20% of the normal value) must be explained, and the necessary explanation must be given by the physician. Drop-outs and adverse events will be recorded in time, and drugs used for trial will be supplied, stored, distributed, and recycled in accordance with relevant regulations. After the trial is completed, a data management report meeting will be held to guarantee the validity and authenticity of this trial. The data administrator will perform a database lock after the data lock record is signed by the principal investigator, sponsor, statistical analysts and data managers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll subjects will receive conventional treatment for PCP according to the recommendations of Chinese guidelines for diagnosis and treatment of HIV/AIDS (2018) [10]. TMP-SMZ (trimethoprim-sulfamethoxazole, co-trimoxazole) combined with prednisone will be the preferred regimen. An alternative regimen may be used if the preferred regimen is intolerable, or if the patient is allergic to the preferred regimen. Those who have no obvious improvement after a full course of treatment or deteriorate during the course of treatment will be considered for replacement therapy or extension of treatment. Secondary prophylaxis will be initiated immediately after successful treatment, and maintained until CD4 cell counts are \u0026gt;200 cells/\u0026mu;L for at least six months. Once diagnosed, subjects will be randomly assigned to the early ART initiation (\u0026le;14 days after PCP diagnosis) arm or the deferred ART initiation (\u0026gt;14 days after PCP diagnosis) arm based on the random number sequence generated by the Medical Research Platform. As per the local guidelines [10], TDF (300mg/d) +3TC (300mg/d) +EFV (600mg/d) is preferred for ART, and other regimens are optional.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is incidence of disease progression (including new opportunistic infections and all-cause mortality). The secondary endpoints are the changes in CD4 counts from baseline to week 12, week 24 and week 48, virologic suppression (HIV-RNA\u0026lt;50 copies/mL) rate at week 24 and week 48, as well as rates of development of PCP-associated IRIS, and adverse events at each visit, including: (1) grade 3 or 4 adverse events; (2) serious adverse events; (3) adverse events related to discontinuation of medication or regimen change.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size will be 100 subjects per treatment arm in order to provide at least 80% power, and an overall two-side alpha level of 0.05. We hypothesize that the proposed study will observe a 20% survival benefit in the early initiation arm, and the expected lost-to-follow-up rate will be 15%. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome analysis will be conducted using the Intent-to-Treat Exposed (ITT-E) population, which consists of all randomized patients, whether they are in full compliance with the study protocol or not. ITT-E will be used to assess the primary efficacy endpoints. We also plan to analyse the primary outcome using the per-protocol (PP) analysis set, which excludes subjects who do not follow the treatment regimens. If any data is not recorded, the last observation carried forward (LOCF) method will be used. Baseline will be defined as the date of randomization. We will compare the primary endpoint in the two groups using time-to-event methods with Cox proportional-hazards models. Categorical variables will be analysed using Fisher\u0026rsquo;s exact test. To explain the competing risk of death, the cumulative incidence function will be used to compare adverse events and IRIS between the two groups [11]. A \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;0.05 will be considered to be statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and dissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by The Ethics Committee of the Chongqing Public Health Medical Center (2019-003-02-KY), and duly registered at the Chinese Clinical Trial Registry (ChiCTR1900021195). We will share the results through published medical journal articles and at conference presentation after completion of the study.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe decision as to when to initiate ART in patients with moderate-to-severe PCP continues to cause confusion and frustration in clinical practice. On the one hand, patients desperately need suppression of HIV replication, as most are severely immunocompromised due to their high viral loads. The sooner the initiation of ART in these patients, the more favourable the chances of survival they would have, notwithstanding concerns regarding drug toxicity and IRIS. On the other hand, the complications relating to the administration of a multitude of medications intended to treat both PCP and HIV infection to such systemically unwell patients makes it inevitable to have to consider the emergence of IRIS, or the overlapping toxicities of various drugs, and complex drug-drug interactions among various drugs. The earlier that ART is initiated, the higher the risk of subsequently developing IRIS, and of arousing drug toxicities, and of initiating unfavourable drug-drug interactions.\u003c/p\u003e\n\u003cp\u003ePrevious studies have investigated the timing of ART initiation in patients with OIs, including PCP. The PISCIS cohort study (conducted from 1998 to 2006) found that patients with AIDS-defining diseases, including those with PCP, were significantly more likely to progress to a new AIDS-defining disease or death if ART initiation was deferred \u0026gt;30 days after HIV infection diagnosis, compared with early ART initiation patients (\u0026lt;30 days after HIV infection diagnosis) [12]. The AIDS Clinical Trials Group (ACTG) reported in 2009 that AIDS progression and death of HIV patients with non-tuberculous OIs are decreased if they initiated ART early (within 14 days of starting acute OI treatment) [8]. Previous studies show that patients with OIs, including PCP, may be able to benefit from early ART initiation. However, a recent study investigating the timing of initiation in HIV-patients with acute AIDS-defining events, enrolling 50 patients with PCP, found that there were no significant differences in safety, efficacy and quality of life between the immediate ART initiation group (initiation within 7 days of PCP diagnosis and treatment) and the deferred initiation group (after the treatment for PCP was over) [7]. The above conflicting studies clearly indicate that the optimal timing for ART initiation in patients with PCP remains controversial, and further investigation of this issue is warranted, especially for those with moderate-to-severe PCP, which is associated with high mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHerein, we designed a multi-center prospective randomized controlled trial in China, in which all eligible subjects will be randomized into an early ART initiation group (\u0026le;14 days after PCP diagnosis) and a deferred ART initiation group (\u0026gt;14 days after PCP diagnosis). We will collect data of survival, immunological reconstitution, virological suppression, AEs, and IRIS emergence in HIV-infected patients with moderate-to-severe PCP, with the aim to investigate the safety and benefits of early ART. We speculate that subjects in the early ART initiation group will have lower new OI incidence rates and all-cause mortality than those in the deferred ART group. We hope that our results will provide unequivocal clinical evidence as to the optimal timing to initiate ART in HIV-infected patients who are diagnosed with moderate-to-severe PCP.\u003c/p\u003e"},{"header":"Trial Status","content":"\u003cp\u003eThis trial is currently in the recruitment phase. Patient recruitment began in March 2019 and is expected to be completed in May 2020. (protocol version 5, 28 August 2019).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTG: AIDS Clinical Trials Group; AEs: adverse events; AIDS: acquired immune deficiency syndrome; ART: antiretroviral therapy; BAL: bronchoalveolar lavage; CRFs: case report forms; HIV: human immunodeficiency virus; IRIS: inflammatory syndrome; ITT-E: Intent-to-Treat Exposed; LOCF: last observation carried forward; PCP: \u003cem\u003ePneumocystis\u003c/em\u003e pneumonia; PP: per-protocol; SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials; TE: toxoplasmosis; UNL: upper normal limit\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY-YQ and Y-QL conceived and drafted the protocol. VH and Y-KC revised the protocol and contributed to finalizing the manuscript. FS and SY contributed to the design and implementation of the study. LY, X-QH and Y-MZ helped to revise the protocol. Y-HZ and S-QT contributed to the statistical analysis and interpretation. All authors contributed to the refinement of the study protocol, and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Science and Technology Major Project of China during the 13th Five-year plan period (2018ZX10302104) and Beijing Medical and Health Foundation (YWJKJJHKYJJ-TM19001). The funding bodies have no role in the trial design or interpretation of the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset necessary to interpret the findings are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by The Ethics Committee of Chongqing Public Health Medical Center (No. 2019-003-02-KY). Written informed consent will be obtained from each patient before randomization. All subjects will sign informed consent before enrolment in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDivision of Infectious Diseases, Chongqing Public Health Medical Center, 109 Baoyu Road, Shapingba District, Chongqing, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLopez-Sanchez C, Falco V, Burgos J, Navarro J, Martin MT, Curran A, Miguel L, Ocana I, Ribera E, Crespo M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEpidemiology and long-term survival in HIV-infected patients with Pneumocystis jirovecii pneumonia in the HAART era: experience in a university hospital and review of the literature\u003c/strong\u003e. \u003cem\u003eMedicine (Baltimore) \u003c/em\u003e2015, \u003cstrong\u003e94\u003c/strong\u003e(12):e681.\u003c/li\u003e\n\u003cli\u003eArmstrong-James D, Meintjes G, Brown GD: \u003cstrong\u003eA neglected epidemic: fungal infections in HIV/AIDS\u003c/strong\u003e. \u003cem\u003eTrends Microbiol \u003c/em\u003e2014, \u003cstrong\u003e22\u003c/strong\u003e(3):120-127.\u003c/li\u003e\n\u003cli\u003eBongomin F, Gago S, Oladele RO, Denning DW: \u003cstrong\u003eGlobal and Multi-National Prevalence of Fungal Diseases-Estimate Precision\u003c/strong\u003e. \u003cem\u003eJ Fungi (Basel) \u003c/em\u003e2017, \u003cstrong\u003e3\u003c/strong\u003e(4).\u003c/li\u003e\n\u003cli\u003eLimper AH, Adenis A, Le T, Harrison TS: \u003cstrong\u003eFungal infections in HIV/AIDS\u003c/strong\u003e. \u003cem\u003eThe Lancet Infectious diseases \u003c/em\u003e2017, \u003cstrong\u003e17\u003c/strong\u003e(11):e334-e343.\u003c/li\u003e\n\u003cli\u003eThomas CF, Jr., Limper AH: \u003cstrong\u003ePneumocystis pneumonia\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2004, \u003cstrong\u003e350\u003c/strong\u003e(24):2487-2498.\u003c/li\u003e\n\u003cli\u003eThomas CF, Jr., Limper AH: \u003cstrong\u003eCurrent insights into the biology and pathogenesis of Pneumocystis pneumonia\u003c/strong\u003e. \u003cem\u003eNat Rev Microbiol \u003c/em\u003e2007, \u003cstrong\u003e5\u003c/strong\u003e(4):298-308.\u003c/li\u003e\n\u003cli\u003eSchafer G, Hoffmann C, Arasteh K, Schurmann D, Stephan C, Jensen B, Stoll M, Bogner JR, Faetkenheuer G, Rockstroh J\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eImmediate versus deferred antiretroviral therapy in HIV-infected patients presenting with acute AIDS-defining events (toxoplasmosis, Pneumocystis jirovecii-pneumonia): a prospective, randomized, open-label multicenter study (IDEAL-study)\u003c/strong\u003e. \u003cem\u003eAIDS Res Ther \u003c/em\u003e2019, \u003cstrong\u003e16\u003c/strong\u003e(1):34.\u003c/li\u003e\n\u003cli\u003eZolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L: \u003cstrong\u003eEarly antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial\u003c/strong\u003e. \u003cem\u003ePloS one \u003c/em\u003e2009, \u003cstrong\u003e4\u003c/strong\u003e(5):e5575.\u003c/li\u003e\n\u003cli\u003eChan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hrobjartsson A, Schulz KF, Parulekar WR\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials\u003c/strong\u003e. \u003cem\u003eBMJ \u003c/em\u003e2013, \u003cstrong\u003e346\u003c/strong\u003e:e7586.\u003c/li\u003e\n\u003cli\u003eAids, Hepatitis C Professional Group SoIDCMA, Chinese Center for Disease C, Prevention: \u003cstrong\u003e[Chinese guidelines for diagnosis and treatment of HIV/AIDS (2018)]\u003c/strong\u003e. \u003cem\u003eZhonghua nei ke za zhi \u003c/em\u003e2018, \u003cstrong\u003e57\u003c/strong\u003e(12):867-884.\u003c/li\u003e\n\u003cli\u003eLongley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS: \u003cstrong\u003eDose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda\u003c/strong\u003e. \u003cem\u003eClin Infect Dis \u003c/em\u003e2008, \u003cstrong\u003e47\u003c/strong\u003e(12):1556-1561.\u003c/li\u003e\n\u003cli\u003eManzardo C, Esteve A, Ortega N, Podzamczer D, Murillas J, Segura F, Force L, Tural C, Vilaro J, Masabeu A\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOptimal timing for initiation of highly active antiretroviral therapy in treatment-naive human immunodeficiency virus-1-infected individuals presenting with AIDS-defining diseases: the experience of the PISCIS Cohort\u003c/strong\u003e. \u003cem\u003eClinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases \u003c/em\u003e2013, \u003cstrong\u003e19\u003c/strong\u003e(7):646-653.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HIV, opportunistic infections, Pneumocystis pneumonia, antiretroviral therapy, initiation","lastPublishedDoi":"10.21203/rs.3.rs-19306/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-19306/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u003cem\u003ePneumocystis\u003c/em\u003e pneumonia (PCP) is a common AIDS-related opportunistic infection. Recent reports estimate that more than 400,000 HIV patients develop PCP each year globally. However, the timing of antiretroviral therapy (ART) initiation for HIV infected patients with PCP is still controversial, and the benefits and risks of early initiation of ART are not completely clear. We thus designed this study in order to determine the optimal timing for ART initiation for HIV-positive patients with moderate to severe PCP.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis study will be an open-labelled, multi-center, prospective, randomized controlled trial. A total of 200 subjects will be randomized to an early ART initiation group (≤14 days after PCP diagnosis), and a deferred ART initiation group (\u0026gt;14 days after PCP diagnosis) at a 1:1 ratio. All subjects will be followed up for 48 weeks after starting ART. The primary outcome is incidence of disease progression (including new opportunistic infections and all-cause mortality) at week 48. The secondary endpoints are the changes in CD4 counts from baseline at week 12, week 24 and week 48, the degree of virological suppression (HIV-RNA\u0026lt;50 copies/mL) at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (IRIS), and adverse events(AEs) at each visit.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eWe hope that the results of this study will reveal the optimal timing for initiation of ART in HIV-infected patients with moderate to severe PCP.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e This trial was registered as one of the twelve trials under the name of a general project at chictr.org.cn\u0026nbsp;on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.\u003c/p\u003e","manuscriptTitle":"Timing of antiretroviral therapy for HIV-infected patients with moderate-to-severe Pneumocystis pneumonia: study protocol for a multi-center prospective randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-03-25 17:25:59","doi":"10.21203/rs.3.rs-19306/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-04-26T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n\nComments to Author:\n---\nThe trial protocol is clearly laid out and most components well described. There are two omissions of concern. The primary and secondary endpoints are not clearly defined. and consequently the sample size calculation is not sufficiently detailed, the proposed test is not given, nor is the timing of the test given. The sample size section needs to be re-written to include all components required including what test, when the test will be carried out, if there are any interim looks at the data, noting that the study should be powered on the primary outcome, which is the other description I am no clear on.\n\nThere is no indication if there will be interim looks at the data, and so if there will be any adjustment to the pvalue threshold or for multiple testing in general.\n\nLast observation carried forward is a method for missing data that carries considerable risk of bias, other methods such as multiple imputation could be looked into.\n\nPrimary method of analysis is Cox proportional hazards, but no indication is made if the proportional hazards assumption will be evaluated and how, and generally the analyses methods section is confusing and it is not clear what method will be applied to what outcome and in what order.\n\nOverall the statistical approach seems appropriate however it is lacking in a great amount of detail which is required.* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Acceptable**\n* Quality of figures: **Acceptable**\n* Statistical review: **Yes, and I have assessed the statistics in my report**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"decision","content":"Major revision","date":"2020-04-26T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-07T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-06T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-04-06T12:00:00+00:00","index":1,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n\nComments to Author:\n---\nThis is a review by the SPIRIT protocol editor for Trials.\n\nThis is a reasonably well written protocol for a randomised controlled trial to determine the optimal timing of antiretroviral therapy for HIV-infected patients with moderate-to-severe Pneumocystis pneumonia.\nI suggest you add Randomised controlled trial to the keywords.\n\nI will use the SPIRIT checklist to structure further comments on the manuscript.\n\nSPIRIT checklist - It is not acceptable for Trials journal for the authors to leave any items blank, with N/A for any item in the SPIRIT checklist. Further information giving rationale and why an item is not applicable is required. Please either edit the protocol and insert page numbers in the checklist or insert relevant information in the SPIRIT checklist\n\n* Item 2b. All items from the World Health Organization Trial Registration Data Set. Please state: Please refer to Item 2a and registration in the chictr.org.cn on February 1, 2019, and the registration number ChiCTR1900021195.\n* Item 5d: I could not find this on page 7. Perhaps you could give information on the composition, roles and responsibilities of the coordinating centre and trial steering committee and all groups providing day to day support for the trial. We also need information on who is responsible for all aspects of local organisation including identifying potential recruits and taking consent. Who is supervising the trial and how often they will meet, plus information on the Trial Steering Committee (TSC), and how often they will meet over the course of the trial to oversee conduct and progress. Plus, information and how often the Stakeholder and Public Involvement Group (SPIG) if there is one, and their specific role.\n* Item 10: line 91 diagnostic criteria - do you have a time period for (1) Progressive exacerbation of dyspnoea?\n* Item 14: Sample size - please give further information on your calculations. What software did you use and do you have any references to cite for this study? Any pilots?\n* Item 17a: So is outcome assessment blinded? I am not clear if outcome assessors or data analysts are blinded.\n* Item 17b: N/A is not acceptable please write in the SPIRIT checklist \"the design is open label with only outcome assessors and data assessors being blinded (if correct) so unblinding will not occur\".\n* Item 18b: I could not find the information on page 8/9 but there was reference to loss to follow up. Please complete and detail plans to promote participant retention and compete follow up. Insert information into the protocol with page number in the checklist.\n* Item 21a I could not find this information on page 7. Under this item please state composition of data monitoring committee; summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests. This requires information inserted into the SPIRIT checklist on Data Monitoring committee referring to page X stating that additional information is in the Appendix.\n* Item 24: This information was in line 254 - though you refer to the ethical approval document. Please give details of research ethics committee/institutional review board (REC/IRB) approval.\n* Item 25: This information should be in the protocol not just the ethical approval document. Protocol amendments - please details plans for notifying of any changes to the protocol i.e. notifying sponsor and funder first then the PI will notify the centres and that a copy of the revised protocol will be sent to the PI to add to the Investigator Site File. You may also want to state that any deviations from the Protocol will be fully documented using a breach report form. You can also include you will update the protocol in the clinical trial registry.\n* Item 26b: As the consent form was in Chinese, I could not find the information for this item in the consent form. Please write in the protocol something like this \"On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the Universities taking part in the research or from regulatory authorities, where relevant. This trial collects biological specimens for storage.\"\n* Item 27: Please include this item in the protocol manuscript as the consent form will not be accessible to the readers. Perhaps you could state how you will store information to ensure confidentiality. Verify that data collected during the course of the research will be kept strictly confidential and only accessed by members of the trial team (or individuals from the Sponsor organisation or centre sites where relevant to the trial). Will participants be allocated an individual trial identification number and will participant's details will be stored on a secure database? Who will access rights to the data set? Will anonymised trial data be shared with other researchers to enable international prospective meta-analyses?\n* Item 30: Please include this item in the protocol manuscript as the consent form will not be accessible to the readers. Provisions for post-trial care - you could state \"There is no anticipated harm and compensation for trial participation\" and it would be helpful to know if there will be any provision for post-trial care.\n* Item 32: This item is referred to in Item 26a and has been attached in the original version. As is in Chinese perhaps you can also state \"These are available from the corresponding author on request.\"\n* Item 33: I could not find all the information for this item on page 4. For this SPIRIT item, please add information on plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trials and for future use in ancillary studies.\"\n\nReferences: There was one article that could not be checked, please ensure information as in guidelines below. One article was not validated. https://trialsjournal.biomedcentral.com/submission-guidelines/preparing-your-manuscript/study-protocol/#references\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Acceptable**\n* Quality of figures: **Acceptable**\n* Statistical review: **Yes, but I do not feel adequately qualified to assess the statistics**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"reviewersInvited","content":"","date":"2020-03-29T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-03-26T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-03-24T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-02-26T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d3cebeec-2c8a-4f37-8525-32b6434923d0","owner":[],"postedDate":"March 25th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":74652,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2020-06-28T15:01:27+00:00","versionOfRecord":{"articleIdentity":"rs-19306","link":"https://doi.org/10.1186/s13063-020-04450-8","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2020-06-22 12:00:00","publishedOnDateReadable":"June 22nd, 2020"},"versionCreatedAt":"2020-03-25 17:25:59","video":"","vorDoi":"10.1186/s13063-020-04450-8","vorDoiUrl":"https://doi.org/10.1186/s13063-020-04450-8","workflowStages":[]},"version":"v1","identity":"rs-19306","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-19306","identity":"rs-19306","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}