Retention in HIV pre‐exposure prophylaxis (PrEP) care in real‐world settings, outside of controlled trials or demonstration projects, remains poorly understood.We evaluated retention in PrEP care outcomes among men who have sex with men (MSM) and transgender women prescribed PrEP through March 2017 at three clinical sites in the United States (US): Jackson, Mississippi; Providence, Rhode Island; and St. Louis, Missouri. We determined retention rates by attendance of clinical visits every three months, per US Centers for Disease Control and Prevention (CDC) guidelines, as well as by the timing of patients’ actual clinical visits. Multivariable analyses examined demographic and behavioural factors associated with retention.From 2013 to 2015, 282 MSM and transgender women were prescribed PrEP; 82% attended a follow‐up visit. Based on CDC recommendations, 56% of patients were retained in PrEP care at the first follow‐up visit, having attended a visit three months after initiation. However, 76% had a follow‐up visit within eight months. Thirty‐percent were retained at 12 months by CDC criteria, but 62% were retained when using a 16‐month endpoint. Self‐reported adherence was strongly correlated with retention. In multivariable analyses, younger age was associated with decreased odds of retention at initial follow‐up, and completing college was associated with increased odds of retention at 16 months. Eight participants were newly diagnosed with HIV; six were African American, and seven were under 30 years of age.Measuring retention in PrEP care using three‐month follow‐up intervals may underestimate true retention. Nevertheless, retention in PrEP care is suboptimal in real‐world settings and should be the focus of future interventions. MSM have a one in 11 lifetime risk of HIV acquisition in the US. This increases to one in five and one in two for Hispanic/Latino and African American MSM, respectively New frameworks outline opportunities for evaluating patient progression through the continuum of PrEP care. These frameworks measure public health outcomes related to PrEP awareness, linkage to care, initiation, adherence and retention in PrEP care We evaluated initial and long‐term rates of retention in PrEP care at three clinical sites in Providence, Rhode Island; Jackson, Mississippi; and St. Louis, Missouri. We examined demographic and behavioural factors associated with retention in PrEP care using CDC guidelines and compared to actual patient visits for PrEP care at “real‐world” intervals. We also evaluated HIV seroconversions in this group of patients.2In 2013, PrEP implementation programmes were established in Providence, Rhode Island; Jackson, Mississippi; and St. Louis, Missouri. These programmes focused on delivering PrEP care in safety‐net and specialty care settings in three mid‐sized, diverse US cities including a community clinic (Mississippi) and infectious diseases specialty clinics (Missouri and Rhode Island). Individuals were typically provided a 30‐day supply of the medication to be taken daily with two to three refills in accordance with CDC recommendations, but this varied by provider and clinic site and was at times dictated by insurance companies We reviewed clinical records for demographic, behavioural, clinical appointment history and laboratory data on MSM and transgender women prescribed TDF/FTC as PrEP through March 2017. Demographic information collected included age (<30 vs. ≥30 years old), gender (cisgender vs. transgender), race (African American vs. other race), ethnicity (Hispanic/Latino vs. not Hispanic/Latino), income , education (less than college education vs. college education or above) and insurance status. Behavioural data collected included number of sexual partners , gender of sexual partners, condom use  and injection drug use. We also reviewed patient attendance at clinical visits. Adherence was defined as taking four or more daily pills in the previous seven days ever followed up and who reported PrEP adherence of four or more pills per week. Using a similar approach, we also evaluated long‐term retention in care rates.The CDC recommends clinical follow‐up visits every three months Baseline and follow‐up characteristics for the study sample were described with means and standard deviations for continuous variables and proportions for categorical variables for the overall sample as well as by site. We used the chi‐square and Fisher's exact tests for categorical variables and the Kruskal–Wallis test for continuous variables to test for differences in characteristics across sites. We evaluated associations between self‐reported adherence and the number of days from initial PrEP appointments to the first follow‐up visits. To assess variables associated with retention in PrEP care, we built a series of log binomial regression models to determine prevalence ratios (PRs). For each dependent variable, a bivariate log binomial regression model was first built for each independent variable. Second, multivariable log binomial models, including all independent sociodemographic variables, were constructed for each dependent variable. The multivariable log binomial model for long‐term retention also included covariates of initial follow‐up within 120 days and seven‐day adherence at initial follow‐up. Secondary analyses examined retention by age and race within and between sites. All analyses were conducted in R 3.3.5 .All participants provided written informed consent to review of clinical data. The study protocol was approved by institutional review boards at each study site.3Among 317 individuals prescribed PrEP during the study period, 85% were MSM, 8% were women who had sex with men, 4% were men who have sex with both men and women (MSM/F) and 3% were men who had sex with women. The primary analysis was restricted to transgender women (n = 2), persons reporting their gender as “other” (n = 1) and cisgender MSM , of whom 54% were between the ages of 15‐30 years, 29% were African American and 11% were Hispanic/Latino. Twenty‐nine percent of participants reported having an HIV‐positive partner, and 23% reported having more than five male sexual partners in the preceding three months. Among MSM (n = 279), the majority (74%) reported condomless anal sex in the preceding three months , only 72% presented for care within four months; the remaining 28% followed up at a later time. Ninety‐two percent (n = 213) of individuals who followed up at any point during the study period (n = 231) did so within eight months. Among individuals who attended a PrEP follow‐up visit by eight months, self‐reported adherence was 88%. Self‐reported adherence dropped markedly among individuals whose first follow‐up appointment took place after eight months to 33%  were retained in care at their first visit, including 73% in Rhode Island, 69% in Mississippi and 90% in Missouri .When employing retention measures based strictly on CDC guidelines, 30% of all patients n = 282) followed up for long‐term clinical visits within 12 months (±30 days). Given that individuals prescribed PrEP initially presented within a range of eight months, we defined long‐term retention as attending a single visit within an eight month window from 8 to 16 months. When using this cutoff based on patients’ real‐world presentation for long‐term follow‐up visits, 62% of patients presented within 16 months and were considered retained in PrEP care  compared to age 30 years and over, but not with retention at one year Table . Africanp = 0.001). There were no significant differences by age at either time point for Rhode Island and Missouri. Mississippi retained a lower prevalence of African American patients at the initial and long‐term endpoints. At initial follow‐up, 57% of African American individuals in Mississippi were retained in care, compared to 93% of others (p < 0.001). At long‐term follow‐up, 53% of African American individuals were retained compared to 75% of non‐African Americans (p = 0.039). There were no significant race differences in initial and one‐year retention endpoints in Rhode Island or Missouri.Additional analyses examining retention by age and race within each site at eight and 16‐month endpoints indicated that Mississippi individuals had significantly lower prevalence of retention at eight months if under the age of 30, but the difference was not significant at 16 months. In Mississippi, 57% of patients under the age of 30 were initially retained, compared to 90% of patients age 30 or older (p = 0.560). A total of 22 (13.3%) of patients who followed up within 1‐4 months tested positive for a new STI at follow‐up compared to n = 6 (12.8%) of patients who followed up within 5‐8 months (p = 0.930).We also compared patients who had a follow‐up visit within four months of an initial visit to patients who had a follow‐up visit within 5‐8 months of an initial visit on likelihood of an increase in creatinine between initial visit and follow‐up and likelihood of having a new positive STI test between initial visit and follow‐up. There were no significant differences between groups in likelihood of creatinine increase or new STI. Of the 213 patients who had a follow‐up visit, a total of 58 (52.7%) patients who had a follow‐up visit within 1‐4 months showed an increase in creatinine at follow‐up compared to n = 15 (46.9%) of patients who followed up within 5‐8 months (Three percent (n = 8) of individuals prescribed PrEP were newly diagnosed with HIV during the course of the study period . The approximate HIV incidence was 1.14 per 100 person years. Six individuals (75%) who were newly diagnosed were African American, all but one were younger than 30 years old, four (50%) were college educated and four (50%) had an income of <$15,000 per year. All African American patients were younger than 30 years old. Among the eight individuals who were newly HIV diagnosed, four individuals tested positive for HIV at baseline before initiating PrEP and three reported suboptimal adherence. One individual seroconverted at the first follow‐up appointment, suggesting acute HIV infection upon presentation or seroconversion caused by suboptimal medication adherence.4This is among the first studies to evaluate longer term rates of retention in PrEP care at real‐world clinical programmes in the US. We found that individuals prescribed PrEP in settings outside of research presented for care at irregular intervals. Nearly one‐third of individuals presented for follow‐up after four months but were still retained in PrEP care. This can be attributed to several potential reasons. Patients may not present regularly for care, particularly if they are socially disadvantaged, generally healthy and not accustomed to seeking medical care prior to PrEP initiation. Providers may also not be available to see patients at precise three‐month intervals. Otherwise healthy patients may not always prioritize preventive health visits or experience other structural challenges that may delay their presentation to care. We have previously described the study settings and evaluated structural barriers to care that exist at our clinics that specifically highlight insurance‐related and financial challenges Retention in care and self‐reported adherence were highly correlated up until approximately eight months after PrEP initiation. Individuals who returned for their first follow‐up visit within eight months of their initial appointment reported high levels of adherence to PrEP. Adherence was significantly lower in individuals who attended their first follow‐up visit after eight months. This eight‐month drop off is attributed to providers prescribing refills without patients presenting at regular intervals, or even presenting at all, during the early follow‐up period. These phenomena prompted us to develop alternate metrics to more rigorously examine retention in PrEP care. Given that the definition of retention is often defined on more stringent CDC‐based criteria, the approach used in this study allowed an objective measurement of retention in PrEP care based on actual patient visits. This definition was notably more liberal than using a CDC‐based definition and was more inclusive of individuals who actually followed up. This study offers an alternative approach to evaluate retention in PrEP care based on real‐world outcomes. Future studies should evaluate this definition compared to other potential approaches such as those used for retention in HIV care .Long‐term retention in PrEP care was similar across all sites using the alternate, real‐world metric. Using this metric, retention rates declined between initial and long‐term follow‐up (76% and 62% retention respectively). At initial follow‐up as defined by the real‐world metric, a significantly lower prevalence of individuals under 30 years of age were retained in PrEP care compared to older individuals. A significantly greater prevalence of Hispanic individuals were retained in PrEP care in after adjusting for clinical site and demographic factors. Race was not significant after adjusting for clinical site and demographic factors. Finally, three percent of HIV‐negative individuals who were prescribed PrEP at these programmes seroconverted, the majority of whom were young African American MSM. The approximate HIV incidence rate was 1.14 per 100 person years.Notably, younger age was a significant predictor of not being retained in PrEP care at the initial visit, particularly in Mississippi, which had the greatest age discrepancy. This is an unsurprising finding, given that younger age has also been associated with significantly lower PrEP awareness Earlier studies suggest that African Americans may be less likely than other groups to be retained in PrEP care at six‐month time points Three percent of individuals were newly diagnosed with HIV during the study, suggesting that real‐world PrEP programmes are engaging populations that are at risk for HIV. However, the high incidence and suboptimal retention rates underscore the need for further efforts to identify more effective strategies to promote adherence and retention in PrEP care, especially for African Americans. Our HIV diagnosis rate suggests adherence and retention in care may be suboptimal among individuals prescribed PrEP in other US settings. The majority of patients (75%) who were newly HIV diagnosed in this study were young African American MSM. Furthermore, the three percent of individuals who were diagnosed may underrepresent the true number of seroconversions, given that individuals not retained in care may have even higher seroconversion rates.These study findings are subject to several limitations. First, our sample size may have been underpowered to detect associations between race or ethnicity and retention in PrEP care. Given an emerging body of evidence highlighting racial and ethnic disparities across the PrEP care continuum Our findings suggest that using CDC guidelines to measure retention likely underestimates true retention in PrEP care in real‐world settings. Using CDC criteria, many individuals who were ultimately retained in care would have been considered lost to follow‐up. While the majority of patients presented within four months, approximately one‐third of those who ever presented for follow‐up care did so after four months. Our findings suggest there is substantial variability in timing of actual patient visits, and that PrEP programmes may need to develop strategies to prevent gaps in medication adherence when patients present at irregular intervals. These findings are likely generalizable to many other real‐world settings. Further research is needed to determine if these retention patterns have an impact on other outcomes (e.g. other STIs).These findings nevertheless underscore suboptimal retention in PrEP care, and the need for wrap‐around services to promote adherence and retention in care among young and African American MSM. The Ryan White HIV/AIDS Program is the largest funder of HIV care and related wrap‐around services, including services to promote adherence and retention in HIV care 5Retaining individuals at highest risk for HIV transmission in PrEP services is paramount to maximize implementation and achieve the population health goal of reducing HIV incidence. Our results highlight the urgent need for culturally tailored, real‐world interventions to measure and to enhance retention in PrEP care, particularly for young African American MSM.The authors declare that they have no competing interests.PAC, RP, LM, KM and AN conceived of the study. BDLM and JR developed the analytic plan and conducted formal statistical analysis. PAC, CSC, MCM and AN prepared the original manuscript draft; RRP, LM, BDLM, JT, CS and JR contributed to reviewing and editing the manuscript. All authors reviewed and approved the final manuscript.


Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.2011-005973-21EUDRACT number:  Nowadays, late presentation represents one of the major obstacles to HIV eradication. Indeed, after more than 30 years since the beginning of the epidemic, around 40% of new diagnoses worldwide still occur in subjects with less than 200 CD4+/uL ,2. ReasoA prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + DRV/r vs abacavir/lamivudine + RAL in antiretroviral naive HIV+ individuals, HLA B5701 negative, presenting for care with CD4+ cell count < 200/mm3 and a viral load (VL)<500,000 copies/mL. Primary Endpoint: Proportion of patients with undetectable viremia (VL <50 copies/mL) after 48 weeks, secondary Endpoints: Change in CD4+ cell count from baseline through week 48 and time to virological rebound. Abacavir/lamivudine was chosen even if resulted inferior to tenofovir disoproxil fumarate /emtricitabine in the ACTG5202, since no data were available in combination either with raltegravir or darunavir . Conside3, haemoglobin > 9.0 grams/dl (men and women), platelet count ≥ 75,000 cells/mm3, alkaline phosphatase < 3.0 the upper limit of normal, ALT and AST < 3.9 times the upper limit of normal, total bilirubin > 1.5 times the upper limit of normal. Female patients of childbearing potential must be willing to use a reliable form of contraception, which will include a medically approved form of barrier contraception.Males or females antiretroviral-naive aged 19–65 years HIV-1 antibody seropositive, with a CD4+ cell count <200 cells/uL, an HIV RNA level <500,000 copies/mL and able to provide written informed consent. All patients should be HLA B57 or HLA B5701 negative and they should not have resistance to any study drug at randomization. Patients with an opportunistic infection were included as long as this was diagnosed more than 2 weeks prior to screening. Patients must had met the following laboratory criteria: neutrophil count > 1,000 cells/mmPatients with the following characteristics were excluded: a positive HLA B57 or B5701, chronic B hepatitis, the presence of genotypic mutations for any of the study drugs, an opportunistic infection diagnosed less than 2 weeks before screening, an HIV RNA level >500,000 copies/mL, pregnant or breastfeeding, with a current drug, alcohol or substance abuse. Finally, patients receiving any investigational drug or anti-neoplastic radiotherapy/chemotherapy other than local skin radiotherapy within 12 weeks of starting medication were excluded.As this was a non-inferiority trial, we wanted to calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and calculated a 95% confidence interval for this. Non-inferiority of the RAL arm should have been demonstrated if the lower limit of the 95% confidence interval was greater than -12%. In case non-inferiority would have been met, analyses for superiority would have been performed.The planned sample size for this trial was 350 patients. Assuming an underlying response rate of 80% in each of the arms at week 48, this sample size (175 patients per arm) would have provided 80% power to demonstrate non-inferiority of the RAL arm compared to the DRV/r arm  with a non-inferiority margin of 12%. Unfortunately, we could not reach the number of patients planned.Descriptive results are presented as means ± standard deviation (SD), medians with interquartile range (IQR), and percentages with 95% confidence intervals (CI). Inferential statistics using either parametric or non-parametric tests are used, as appropriate. Chi-square or Fisher’s exact test are used to analyze categorical variables. Paired T-test and Wilcoxon signed rank test are used to analyze within participant differences at different time points. Analysis was performed with SPPS for windows 17.0.The study was approved by the ethical committee of the coordinating centers and those of all participant centers.Between February 2012 and February 2016, 53 patients were screened and 46, after having signed the informed consent, were randomly allocated in the two groups (22 with RAL and 24 with DRV/r). 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity .Pneumocystis jirovecii pneumonia (1 in RAL and 3 in DRV/r) and neuro-toxoplasmosis (one in each group). Kaposi Sarcoma, cryptococcal meningitis, lymphoma and wasting syndrome (one each) were diagnosed only in the RAL group, while Cytomegalovirus disseminated disease (2 cases) only in the DRV/r group. Two patients in the DRV/r group were diagnosed with two opportunist infections . Although the median time between HIV diagnosis and cART start was similar between groups (34.5 days for RAL and 53 days for DRV/r), in the latter case, we observed a much greater interquartile range due to a few patients whose therapy was delayed.Baseline characteristics were fairly balanced between groups , althougBeside antiretroviral therapy, due to their advanced status, patients received other concomitant therapies. In the DRV/r group concomitant therapies ranged from 0 to 14, while in the RAL group the range was from 0 to 15. Most commonly used drugs (> 3 patients) were antibiotics (15 cases in each group); antifungals (7 in DRV/r and 5 in RAL); antivirals (6 in DRV/r and 4 in RAL); non -steroids anti-inflammatory drugs (3 in DRV/r and 10 in RAL); steroids (3 in DRV/r and 5 in RAL); vitamins (7 in DRV/r and 8 in RAL); gastro-enteric drugs (5 in DRV/r and 9 in RAL and CNS drugs (5 in DRV/r and 6 in RAL).According to a snapshot algorithm, on the ITT population, after 48 weeks the proportion of treatment success was 77.3% in the RAL group and 66.7% in the DRV/r group. The 95% Confidence interval for the difference between these proportions was from -15.4% to 36.4%. No difference was found considering the rate of suppression below 200 copies/mL. Virologic failure was observed in 22.7% of patients treated with RAL and 29.2% of those receiving DRV/r while only one patient on DRV/r (4.2%) did not have data in window. According to the as treated analysis virologic response was faster in the RAL group being the proportion of subjects below a 50 copies/ml threshold 0f 22% at 4 weeks, 70% at 24 weeks and 94.1% at 48 weeks; the same figures in the DRV/r group were 4.8%; 40% and 84.2%At the end of follow up, the median CD4+ cell count raised to 297 cell/uL (IQR 218–454) in the RAL arm and to 239 cell/uL (IQR 182–458) in the DRV/r group. The increment was slightly higher in the RAL arm (189 vs 112 cells/uL). On the contrary, the median CD8+ cell count raised less in the RAL arm  than in the DRV/r arm . Consequently, these differences influenced the dynamics of the CD4+/CD8+ ratio that increased slightly more in the RAL arm. At baseline the median CD4+/CD8+ ratio was 0.12 (IQR 0.08–0.17) for DRV/r and 0.15 (IQR 0.06–0.22) for RAL while the same values were respectively 0.30 (IQR 0.18–0.37) and 0.34 (IQR 0.19–0.64) at 48 weeks.We did not find clinically significant changes, from baseline to week 48, in hematological exams, hepatic markers, LDH and CPK, nor grade 3–4 laboratory abnormalities for any considered parameter. Renal function remained stable over time with creatinine levels increasing from 0.8 (IQR 0.0.74–0.89) to 0.9 (IQR 0.83–0.96) in the DRV/r arm and from 0.8 (IQR 0.0.68–0.96) to 0.9 (IQR 0.75–0.92) in the RAL arm. Changes in lipids were also small, with limited median increments in total cholesterol, LDL cholesterol and triglycerides. However, especially for LDL cholesterol and triglycerides the increment was slightly more evident in the DRV/r arm . In the Two patients (one in each group) stopped treatment because of adverse events: acute renal failure in the RAL arm and allergic reaction in the DRVr/r group.Beside these two cases, several other patients reported adverse events not leading to treatment discontinuation during the treatment period. In the DRV/r arm 19/24 patients reported between 1 and 7 adverse events, in the RAL arm 11/22 patients reported between 1 and 4 adverse events . Finallyi.e. former drug users and heterosexual contacts, is among the countries with a higher rate of late presentation—around 56% of new diagnosis–.               Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."If this statement is not correct you must amend it as needed.Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.5) Thank you for stating the following in the Competing Interests section:[The authors have declared that no competing interests exists].We note that you received funding from a commercial source: ViiV Healthcare, Merck Sharp & Dohme Corp and Janssen.relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.Please provide an amended Competing Interests Statement that explicitly states these commercial funders, along with any other http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.”  Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: [Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: YesReviewer #3: NoReviewer #4: Partly**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: YesReviewer #3: YesReviewer #4: No**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: YesReviewer #3: YesReviewer #4: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: YesReviewer #3: NoReviewer #4: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: There are only a few randomized clinical trials on antiretroviral head-to-head comparison between protease-inhibitor (PI) versus integrase-inhibitor (INSTI) based combination triple therapy. PRADAR was a multicentre, national , open label study and an attempt to fill this important data gap. The study design radically addressed the open question, whether standard combination ART should better contain an INSTI, or “best practice-PI”. Because the chosen study population was moreover the difficult-to-treat HIV-late presenters, with very low first measured CD4-cell counts (<200/µL), the study finally failed by trying to reach “a bridge too far”. Though the attempt was heroic, this report’s conclusions should not be in vain, as this may guide future RCTs to answer the yet open question.The main problem of this study was the patient recruitment underperformance, reflected by the fact that only 46 individuals were randomized in three years – far from trial’s goal of 350. There are different reasons for this failure: apart from the challenging study population, that may often be deterred from a trial participation due to many reasons, there was another game changer occurring in the middle of the recruitment time – the publication of the START-study, as discussed. All antiretroviral therapy guidelines were subsequently changed to prompt treatment initiation; this diminished indirectly the potential study population.The study addresses a major important study question - better INSTI or PI for late presenters? It anticipated the study question long before other major trials, i.e. currently under investigation (see NCT03696160). Though the report did not fully succeed, it should not hide its’ light under the bushel. Therefore, I consider the report on PRADAR as valuable and worth reading. Nevertheless, I recommend to consider the following minor issues:1. Discussion, page 18/30, line 3, following, you wrote: “Indeed, due to the low number of subjects enrolled it was not possible to perform any comparative analysis between RAL and DRV/r.” – But you have performed comparisons! And you had interesting findings, e.g. on clinical adverse events and cholesterol differences between groups. – Please clarify.2. Discussion, page 19/30, first lines/first para – please consider to discuss the following facts: in NEAT001-randomized clinical trial (NCT01066962), the raltegravir-containing arm did not perform as well as the standard-of-care arm containing darunavir/ritonavir plus two nucleosidal reverse transcriptase inhibitors, in the subgroup of patients with a CD4 cell count <200/µL. Similar findings were detected in patients with another actual dual regimen in naives: NCT02831764 & NCT02831673.3. Discussion, page 19/30, lines 14 & following – see above remarks on START study findings release while PRADAR study recruitment.4. Discussion, page 20/30, second para – you showed differences in week 48-outcomes of complete HIV-RNA suppression (<50 copies/mL) between arms, i.e. the primary end point (94.3 vs. 84.2%). Please consider to argue on the differences concerning the 50 copies/mL-threshold for PI vs. INSTI drug classes and to display as well the results for a 200 copies/mL-threshold, as the ACTG recommended this different limit of detection for studies on protease inhibitors.5. Figure 1, page 27/30: please consider to include the reasons for 7 screening failures.Reviewer #2: Good work by the authors. I agree it is difficult study to recruit to in the current environment. many other options are available and perceived as superior to the combinations you are trying to test.in Your abstract ( in the last line) you stated: the rate of virologic success is similar to that described in the literature and very far from results of the recent trials in naïve patients.this statement needs to be revisited in my view and quantified.in the last line of your introduction: >500000 should be <500000.Reviewer #3: • The paper by Mussini et al. reports on a randomized clinical tria which failed t recruit the goal of 350 patients with advanced HIV infection in order to compare an antiretroviral therapy consititing of either ABC/3TC+DRV/r or ABC/3TC+RAL. In total, onl 46 patients were included, n=22 in the RAL arm and n=24 in the DRV/r arm Thus, the study fails to provide sound and scientifically valid data to make any meaningful conclusions in terms of virological response or other endpoints. Little to nowthing can be said about these combinations for patients presenting late. Same The main conclussion of the authors is that late presenter are frequent but difficult to enroll in clincial trials.• It is unfortunate that the study failed. At the same time, there is no report in the manuscript about how the study team at least tried to increase patient recruitment during study • The time of recruitment is unclear. In the abstract, the authors state 3 years, in the discussion they state that they did nt expect to have such a low number of patients in 5 years.Reviewer #4: A two arm non-inferiority randomized study was conducted to compare 48-week virological response of abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive late presenter HIV patients. The target sample size was 350; although, due to slow accrual only 46 patients were enrolled. At 48 weeks a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r was observed. Too few patients were enrolled to effectively constructed confidence bounds to test non-inferiority.Minor revisions:1- Specify the "parametric or non-parametric tests" that were used.2- Cite the statistical software used for the analysis.3- Table 1: In addition to frequencies, provide corresponding percentages for gender, risk factors and CDC stage. For age, HIV RNA, CD4 and CD8 provide the first and third quartiles.4- Provide confidence intervals for the percentage estimates in the following sentence. “According to a snapshot algorithm, on the ITT population, after 48 weeks the proportion of treatment success was 77.3% in the RAL group and 66.7% in the DRV/r group.”5- Instead of calculating the IQR, provide the first and third quartiles since they are more informative.6- Provide numerical p-values rather than “NS.”7- Include a table summarizing the adverse events by treatment arm. Include percentages corresponding to the frequencies.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  13 Aug 2019Reviewer #1:1. Discussion, page 18/30, line 3, following, you wrote: “Indeed, due to the low number of subjects enrolled it was not possible to perform any comparative analysis between RAL and DRV/r.” – But you have performed comparisons! And you had interesting findings, e.g. on clinical adverse events and cholesterol differences between groups. – Please clarify.Answer: we agree with the reviewer and added a sentence in the discussion.2. Discussion, page 19/30, first lines/first para – please consider to discuss the following facts: in NEAT001-randomized clinical trial (NCT01066962), the raltegravir-containing arm did not perform as well as the standard-of-care arm containing darunavir/ritonavir plus two nucleosidal reverse transcriptase inhibitors, in the subgroup of patients with a CD4 cell count <200/µL. Similar findings were detected in patients with another actual dual regimen in naives: NCT02831764 & NCT02831673.Answer: we agree with the reviewer and added a paragraph in the discussion.3. Discussion, page 19/30, lines 14 & following – see above remarks on START study findings release while PRADAR study recruitment.Answer: we agree with the reviewer and added a sentence in the discussion.4. Discussion, page 20/30, second para – you showed differences in week 48-outcomes of complete HIV-RNA suppression (<50 copies/mL) between arms, i.e. the primary end point (94.3 vs. 84.2%). Please consider to argue on the differences concerning the 50 copies/mL-threshold for PI vs. INSTI drug classes and to display as well the results for a 200 copies/mL-threshold, as the ACTG recommended this different limit of detection for studies on protease inhibitors.Actually, no difference compared to <50 copies/mL was found considering a threshold of 200 copies/mL.5. Figure 1, page 27/30: please consider to include the reasons for 7 screening failures.We added the reason as footnotes to Figure 1.Reviewer #2:1. in Your abstract ( in the last line) you stated: the rate of virologic success is similar to that described in the literature and very far from results of the recent trials in naïve patients. this statement needs to be revisited in my view and quantified.Answer: we agree with the reviewer and changed the last sentence since it was very vague.2. in the last line of your introduction: >500000 should be <500000.Answer: we have corrected the mistake, thanks.Reviewer #3:1. It is unfortunate that the study failed. At the same time, there is no report in the manuscript about how the study team at least tried to increase patient recruitment during study Answer: We thank the reviewer and added a sentence in the discussion.2. The time of recruitment is unclear. In the abstract, the authors state 3 years, in the discussion they state that they did nt expect to have such a low number of patients in 5 years.Answer: we have corrected the mistake, thanks: the correct recruitment duration was 3 years.Reviewer #41- Specify the "parametric or non-parametric tests" that were used.The tests are already specified just one sentence after that reported by the reviewer2- Cite the statistical software used for the analysis.Done3- Table 1: In addition to frequencies, provide corresponding percentages for gender, risk factors and CDC stage. For age, HIV RNA, CD4 and CD8 provide the first and third quartiles.done4- Provide confidence intervals for the percentage estimates in the following sentence. “According to a snapshot algorithm, on the ITT population, after 48 weeks the proportion of treatment success was 77.3% in the RAL group and 66.7% in the DRV/r group.”done5- Instead of calculating the IQR, provide the first and third quartiles since they are more informative.done6- Provide numerical p-values rather than “NS.”done7- Include a table summarizing the adverse events by treatment arm. Include percentages corresponding to the frequencies.doneAttachmentResponse to Review Comments, Cristina Mussini et al..docSubmitted filename: Click here for additional data file. 5 Sep 2019A Prospective Randomized trial on Abacavir/lamivudine plus DArunavir/ritonavir or Raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR Study)PONE-D-19-14981R1Dear Dr. Mussini,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. 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Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact With kind regards,Alan WinstonAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 19 Sep 2019PONE-D-19-14981R1 A Prospective Randomized trial on Abacavir/lamivudine plus DArunavir/ritonavir or Raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR Study) Dear Dr. Mussini:I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. 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An in-depth analysis of nanotechnology applications for the improvement of solubility, distribution, bioavailability and stability of reverse transcriptase inhibitors is reported. Current clinically used nucleoside and non-nucleoside agents, included in combination therapies, were examined in the present survey, as drugs belonging to these classes are the major component of highly active antiretroviral treatments. The inclusion of such agents into supramolecular vesicular systems, such as liposomes, niosomes and lipid solid NPs, overcomes several drawbacks related to the action of these drugs, including drug instability and unfavorable pharmacokinetics. Overall results reported in the literature show that the performances of these drugs could be significantly improved by inclusion into nanosystems.  The human immunodeficiency virus (HIV), belonging to the lentivirus genus of the large family of retroviridae, is the etiological agent of AIDS. The infection causes severe consequences to the immune system including a loss of CD4+T lymphocytes that leads to an increased susceptibility to even fatal opportunistic infections. The identification of various antiretroviral drugs allowed defining efficacious therapeutic regimens for the prevention and treatment of the disease by the combined administration of two, three or more different drugs acting on crucial steps of viral replication. In particular, the targets of conventional drugs are proteins involved in the viral entry or specific enzymes necessary for the virus replication such as protease (PR), reverse transcriptase (RT) and integrase (IN). This approach known as HAART  nowadays represents the most useful therapeutic treatment, even though it is affected by many drawbacks such as lifetime administration with a consequent reduced patients’ compliance, severe side effects, and quick viral outbreak after drug resistance emergence. HAART was demonstrated to be particularly effective in cutting down the overall number of viral particles, but is unable to completely eradicate infection in sanctuary sites, such as the brain, liver and lymphatic system ,2,3,4,5.The above therapeutic strategy is not even capable of stimulating a lasting immune response of memory cells necessary to antagonize the infective agent . Even afIn the light of these findings, the incorporation of new or customary anti-HIV drugs into supramolecular carriers could be particularly effective in suppressing viral replication. This strategy is corroborated by the possibility of encapsulating drugs or genes to not only be delivered next to the infected cells but also to target reservoir tissues to eradicate latent HIV . This in. Furthermore, some nanomaterials possess themselves favorable biological effects. The nanotechnology approach has been advanced for many aspects dealing with HIV infection, namely theranostic, vaccine prophylaxis and gene therapy. This survey however focuses on studies describing NRTI and NNRTI based nanoformulations for prevention or treatment of HIV infection. Although these systems allow a remarkable improvement of the pharmacokinetics and pharmacodynamics of RTI, several drawbacks still need to be overcame. The major advantages and limitations of known nanosystems are listed in Once the supramolecular system reaches the site of action, a controlled drug release provides high local concentration and longer residence time, resulting in an improved antiviral effect . FurtherSeveral of these clinically used drugs show an undesirable stability profile when exposed to stressing conditions either in solution or in solid form ,21. SimiMost of the protocols adopted for studying the drug stability are suggested by the ICH  guidelines . AccordiNiosomal and liposomal vesicles consist of amphiphilic molecules and an aqueous compartment and differ for their structural chemical units. Both systems are very versatile. The hydrophilic drugs can be entrapped in their aqueous core while the lipophilic drugs can be partitioned into the bilayer domains. Liposomes are made of natural phospholipids, resulting in a greater stability, a low production cost and reduced toxicity ,30,31,32More recent SLN have been proposed as alternative formulations for both hydrophilic and hydrophobic drugs. These systems are colloidal carriers based on a solid phase lipid and a surfactant and are characterized by a spherical shape in which the lipid portion is always solid and the surfactant acts as a stabilizing factor ,38,39,40co-glycolide) (PLGA) are reported as ideal delivery systems, showing an improved therapeutic efficacy with lower incidence of side effects oxazin-2 (PPI). These branched three-dimensional polymers were shown to be less toxic than free PPI and could allow the drug to reach monocytes and macrophages, both reservoirs of HIV in the body. In fact, it is known that inhibitors targeting only lymphocytes are ineffective in completely eradicating the infection. These formulations demonstrated to be particularly effective since they are able to promote a significant increase of EFV cellular uptake . The samin silico experiments [Vesicular systems consisting of gold NPs entrapped inside the aqueous core were loaded with EFV in the bilayer membrane. The niosomes so formed were dispersed in carrageenan/hyaluronic acid/poloxamer based thermogel after coating with an opportunely functionalized mannose, in order to combine the action of the protein and the sugar for an effective prophylactic vaginal application. A remarkable inhibition of viral transmission as well as a drastic reduction of side effects was recorded . A soya eriments . The theeriments .in vitro drug release of the NPs, although no detectable degradation was observed for the entrapped drug [Dapivirine (4-((4-(mesitylamino)pyrimidin-2-yl)amino)benzonitrile, DPV) is a new, sparingly soluble NNRTI, under investigation for vaginal application during the prevention of HIV sexual transmission. This compound was shown to be a noncompetitive inhibitor of RT that is particularly useful for topic treatments. In order to improve efficacy, a microbicide film for vaginal delivery was formulated by loading DPV into PLGA NPs and the nanosystems were in turn coupled to a PVA in a cellulose based platform film using solvent casting technique. TDF was also added to the formulation to achieve a synergist antiviral effect. A rapid release of active principles was accordingly recorded suggesting an ideal behavior of such a formulation as prophylactic microbicide ,159. Somped drug . in vitro cells assay and on a macaque cervicovaginal explant model in vivo. The nanoformulation provided a prolonged release by extension of the half-life of drugs, leading to an enhanced synergistic antiviral action [Etravirine (4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethyl-benzonitrile, ETV) is a NNRTI approved in 2008 for monotherapy against HIV, also clinically used in combination with other antiviral agents in antiretroviral treatment-experienced adult patients with onset of resistance. A combination of ETV, maraviroc and raltegravir was loaded into PLGA by emulsion-solvent evaporation technique. The antiviral potency of the resulting NPs was compared to the free triple drug combination in an l action . An innol action . Rilpivirine ((E)-4-((4-((4-(2-cyanovinyl)-2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino) benzonitrile, RPV) is a second-generation NNRTI, approved in 2011, possessing increased potency, longer half-life and lesser side-effects with respect to former non-nucleoside agents, today mainly used in combination with other anti-HIV drugs . RPV metBiodistribution of tri-modal theranostic NPs was studied by single-photon emission computed tomography, magnetic resonance imaging and fluorescence techniques. These devices were prepared by the incorporation of Indium radiolabeled, europium doped cobalt-ferrite particles and RPV loaded into a poly(ε-caprolactone) matrix included into a lipid shell. A sustained drug release and antiretroviral activity were observed in HIV infected macrophages. These multi-functional NPs represent a platform for the monitoring and optimization of the antiretroviral drug pharmacokinetic profile . There is a high level of interest in nanotechnologies for their relevant roles in the design and development of innovative anti-HIV formulations either for oral or topical administration. In the first case, a more specific targeted delivery together with a sustained release represents the major goal in the field. Mucoadhesive performance, prolonged retention time and improved patients’ compliance were desired for vaginal or rectal application of microbicide nanoformulated antiretroviral agents. A large number of diversely assembled nanocarriers loaded with different classes of antiviral drugs were then developed and deeply investigated to improve both pharmacokinetic characteristics and stability behavior. Overall results demonstrated a potential success of such an approach for monotherapy, even though more profitable applications were recorded for the combination therapy, the most diffused method nowadays. In fact, anti-HIV therapeutic regimens today comprise multiple daily doses of more drugs acting at different stages of viral replication, which lead to poor patient compliance. Although the use of protease, integrase and viral entry inhibitors has become customary, NRTIs and NNRTIs remain pivotal tools during the infection management. In the light of these findings, this overview focuses mainly on the application of nanotechnology applied to RTI as vehicles for challenging virus eradication from depot organs and/or as a platform for the design of modern prophylactic devices for stable or stressing conditions.


Pharmacokinetics studies recommend increasing efavirenz dosage in tuberculosis/HIV patients using rifampicin. We aimed to evaluate efficacy and safety of 600 versus 800 mg of efavirenz in tuberculosis/HIV patients using rifampicin. We conducted an open label, multicentre, randomized trial from 2006 to 2012. The primary outcome was the proportion of undetectable viral load (HIV-VL) within six months. Secondary outcomes were time to achieve primary endpoint, trajectories of HIV-VL, proportion of any adverse events (AE), proportion of severe and serious AE (SSAE), and time to treatment interruption due to SSAE. Efavirenz-naïve patients were randomized 30 days after rifampicin-containing regimens initiation to receive 600 (comparison arm) or 800 mg (intervention arm) efavirenz-based regimens and followed-up for 180 days. Sixty-five and 67 participants were respectively included in the comparison and intervention arms with 64.6% (52.5%-65.1%) and 62.7% (50.7%-73.3%) attaining undetectable HIV-VL in six months. Median time to attain undetectable HIV-VL was 70 days in both arms, with HIV-VL overlapping trajectories during follow-up. Cough, acne, and dizziness were more frequent in the intervention arm. SSAE were observed in 19.1% (13.8%-25.8%) and 25.0% (18.9%-33.2%), respectively. Survival curves up to the first SSAE-attributed treatment interruption were similar. None of the differences were statistically significant. Efficacy of efavirenz was similar regardless of dosage. Differences regarding safety occurred as mild and transient events, which did not interfere with treatment. Similar efficacy and safety (SSAE) and lower tolerance (minor AE) in the intervention group favour the use of 600 mg efavirenz in patients using rifampicin. Tuberculosis (TB) in people living with HIV/aids (TB-HIV) is a global public health problem, especially in places with high TB incidence, such as Brazil . The WorEfavirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) which is part of the first-line treatment for HIV infection in Brazil and other TB high-burden countries , 6 becauBecause of this interaction, some authors argue that the EFV dose should be increased from the standard 600 mg to 800 mg daily when used in concomitance with RIF . Moreove Instituto Nacional de Infectologia Evandro Chagas (INI/Fiocruz), Núcleo de Doenças Infecciosas from Universidade Federal do Espírito Santo (NDI/UFES), and Hospital Santa Casa da Misericórdia, in Rio de Janeiro (SCM). Patients were randomized to receive either EFV 600 mg (EFV600 – comparison arm) or EFV 800 mg (EFV800 – intervention arm) daily. The study was open label for safety and tolerance (for patients and physicians), but laboratory technicians, who analysed the main outcomes, did not know the allocation. The protocol was conducted from April 2006 to March 2012.This study consisted of an open label parallel randomized clinical trial for patients with TB-HIV using RIF-containing regimens in three sites in Brazil: Mycobacterium tuberculosis in culture or, when not confirmed by culture, if symptoms subsided after antituberculous therapy provided that other opportunistic diseases were excluded), (d) with life expectancy greater than one year (Karnofsky score ≥ 70%), (e) not using other drugs than RIF with significant EFV interaction, (f) naïve for any NNRTI or protease inhibitor (PI), (g) with no history (current or past) of treatment with more than two nucleoside reverse transcriptase inhibitors (NRTI), and (h) voluntarily signed the informed consent (IC) form.The study population consisted of patients (a) aged 18 years or older, (b) infected with HIV as confirmed by two positive ELISA tests or one ELISA and another confirmatory test or HIV viral load (HIV-VL), (c) diagnosed with TB  antiretroviral (ARV) treatment was not indicated at the time of signing the IC form, (b) they had a history of hypersensitivity, intolerance, or resistance to RIF, (c) they had any psychiatric disorder, (d) one or more of the following laboratory abnormalities were present: liver transaminases ≥ 5-fold the upper level of normality or total bilirubin ≥ 1.5 mg/dL, or (g) they were pregnant.Patients with low adherence to ARV and baseline resistance to RIF or EFV diagnosed during follow-up were excluded from the per protocol analysis but were kept for the intention-to-treat and safety analyses until discontinuation.All participants received first-line TB treatment according to the Brazilian guidelines  for patiAll participants received background optimised ARV therapy, which consisted of two NRTI plus EFV600 or EFV800. The preferred initial NRTI were zidovudine + lamivudine in fixed-dose combination or lamivudine and tenofovir.Patients in the comparison group received one pill of 600 mg EFV, and patients in the intervention group received one 600 mg plus one 200 mg pill. A complementary placebo pill was not available; thus, blinding (patient and physician/nurse) was not possible.Efficacy was evaluated through HIV-VL, safety through severe and serious AE (SSAE), and tolerance through minor AE. The primary endpoint was the proportion of undetectable HIV-VL (<80 copies/ml) on day 180. Secondary endpoints were (a) time to achieve undetectable HIV-VL, (b) HIV-VL (log10) trajectory over time in all trial population and subgroups , (c) proportion of any reported AE, (d) proportion of SSAE, according to WHO Adverse Reaction Terminology (WHO-ART) , and (e)We defined AE as any unwanted medical event that started after the onset of the concomitant use of EFV and RIF, i.e., after randomization. AE were classified according to the AIDS Clinical Trial Group (ACTG) grading .The allocation sequence was computer-generated with simple random numbers and performed by the pharmacy of the coordinating centre, INI/Fiocruz.Timeline of all procedures is represented in The trial baseline visit (D1) was 15 days after the screening visit, i.e., 30 days after TB treatment initiation. Participants were randomized to one of the arms and ARV treatment was started. Blood samples were collected for WBC, liver and renal function tests, CD4+ cell counts, and HIV-VL. Additionally, a rapid pregnancy test in urine was performed among women.Participants returned on days D30, D60, D90, D120, D150, and D180 after the beginning of ARV treatment (D1) for medical evaluation that included anamnesis, physical examination, and a thorough inquiry about AE. In all these visits, blood samples were collected for WBC, liver and renal function tests, CD4+ cell count, and HIV-VL.Sputum smear was collected monthly among patients with pulmonary TB and chest radiographs performed at follow-up visits on D60, D120, and D150. External data monitoring was provided by Fiocruz clinical trial platform.α) was set at 0.95 (z= 1.96), the statistical power (1-β) at 0.80 (z= 0.84). The proportion of undetectable HIV-VL with EFV 600 mg was set at 55%, based on the previous cohort at INI (unpublished data), and the expected response rate to EFV 800 mg was set at 75%, as assessed in HIV clinical trials without TB  in the comparison arm and 160 (49.7% [95% CI 44.3%-55.1%]) in the intervention arm . Most  were immune or infectious events, 52 (16.2%) were neuropsychiatric, 51 (15.8%) were gastrointestinal, 39 (12.1%) were cutaneous, and 21 (6.5%) were liver disorders. Other, less frequent events (less than 10 records each) were blood, cardiovascular, endocrine, hearing, metabolic, musculoskeletal, neoplasms, reproductive, urinary, vascular, and vision disorders.Regarding the specific type of AE, only cough, acne, and dizziness were significantly more frequent in the intervention arm than in the comparison arm .SSAE events were homogeneously distributed between both arms. Most of these events were immune, infectious, and gastrointestinal disorders . The proEarly withdrawal attributable to EA occurred among six participants in the comparison arm and five participants in the intervention arm. The causes of withdrawals in the comparison arm were cutaneous rash and hepatotoxicity, nausea, hepatotoxicity, cutaneous rash plus gastric intolerance, and cutaneous rash and pruritus, while in the intervention arm causes were hallucination plus dizziness, dizziness and insomnia, hepatotoxicity, skin rash and pruritus and rash, with one event each.Temporary or permanent discontinuation of treatment  was required for some SSAE. The hazard of EFV discontinuation due to SSAE was similar in both arms  as was for RIF discontinuation . Confidence bands from Kaplan-Meier curves overlapped throughout the study period, confirming the absence of difference between arms . Five deIn the current trial, designed to detect differences in efficacy and safety of two different EFV dosages when used in association with RIF, no differences between daily doses of 600 mg or 800 mg were found regarding both efficacy  and proportion of SSAE. Likewise, treatment interruption attributable to SSAE (either HIV or TB treatment) was infrequent and similar in both arms. Other endpoints were also similar in both study arms. However, minor AE were more frequent with 800 mg EFV. Altogether, these findings do not support that the dose of EFV should be increased to 800 mg for TB-HIV patients using RIF-containing regimens.The overall absolute effect  of 600 mg EFV was lower in our study than in a trial with non-TB patients in an African country, where 77% had undetectable HIV-VL at 180 days of follow-up , it was Pharmacokinetics studies had shown a decrease in the area under the curve of EFV when used with RIF –10. TherEFV is, in general, a well-tolerated drug used in fixed-dose combination with other ARV agents in most developing countries worldwide . The mosIt is well established that genetics may influence drug metabolism resulting in variable clinical response. Pharmacokinetics and pharmacogenetics analyses have predicted virologic endpoints to EFV in countries with homogeneous black population . The popAnother limitation was the long time to recruit TB-HIV patients and the insufficient recruitment, due to the organization of the Brazilian public health service, since TB as well as HIV patients are assisted in primary care facilities close to their residence. Initially, INI, a tertiary care hospital, was the only recruitment site. To overcome the low recruitment, other sites were invited to join the trial. However, differences between groups were too small and a much larger sample size than calculated would be needed to show any significant difference. Thus, the absence of evidence of efficacy could be due to the reduced power of the study with the current sample. However, trajectories of HIV-VL were absolutely overlapping, and the authors do not believe that increasing the sample size would change the results. The power to detect a significant effect regarding undetectable HIV-VL with the risk ratio actually found (0.97) is indeed very low (2.7%). It would be necessary to include approximately 20,330 participants to detect a 5% significance for this effect, which would be unachievable even in a multicentre trial. Therefore, there was an understanding among authors that reaching the initially planned sample size of 178 would not change the current results interpretation because the low power, subgroup analyses should also be interpreted with caution.Additionally, observation bias cannot be excluded since both patients and physicians were unblinded for the arm. Regarding safety, this bias would result from an excess of reports of SSAE in the intervention arm, which was not observed. Since no differences were found regarding both efficacy and safety (SSAE), bias is unlikely. Finally, the long follow-up period could have resulted in potential external interference not explored in the trial.Our study also has a few strengths. This was a pragmatic trial, sponsored by the Brazilian Ministry of Health, with no influence of private laboratories or other market partners. Thus, findings can be expected to be reproducible in routine conditions. The evidence presented here does not support previous pharmacokinetics suggestions that EFV dose should be increased when prescribed with RIF in TB-HIV patients to increase its efficacy. Although there is no evidence that SSAE and interruption of treatment due to SSAE are more frequent with a higher EFV dose, the slight increase of specific AE among participants taking 800 mg EFV and the lack of difference in efficacy favour the use of 600 mg of EFV even when associated with RIF-containing regimens.


The last evaluation to assess outcomes for patients receiving antiretroviral therapy (ART) through the Zimbabwe public sector was conducted in 2011, covering the 2007–2010 cohorts. The reported retention at 6, 12, 24 and 36 months were 90.7%, 78.1%, 68.8% and 64.4%, respectively. We report findings of a follow-up evaluation for the 2012–2015 cohorts to assess the implementation and impact of recommendations from this prior evaluation.A nationwide retrospective study was conducted in 2016. Multi-stage proportional sampling was used to select health facilities and study participants records. The data extracted from patient manual records included demographic, baseline clinical characteristics and patient outcomes ) at 6, 12, 24 and 36 months. The data were analysed using Stata/IC 14.2. Retention was estimated using survival analysis. The predictors associated with attrition were determined using a multivariate Cox regression model.A total of 3,810 participants were recruited in the study. The median age in years was 35 (IQR: 28–42). Overall, retention increased to 92.4% , 86.5% , 79.2%  and 74.4%  at 6, 12, 24 and 36 months respectively. LTFU accounted for 98% of attrition. Being an adolescent or a young adult (15–24 years) , children (<15years) , receiving care at primary health care facility , having initiated ART between 2014–2015 , having WHO Stage IV  and impaired functional status  predicted attrition.The overall retention was higher in comparison to the previous 2007–2010 evaluation. Further studies to understand why attrition was found to be higher at primary health care facilities are warranted. Implementation of strategies for managing patients with advanced HIV disease, differentiated care for adolescents and young adults and tracking of LTFU clients should be prioritised to further improve retention. Globally by the end of 2018, there were 37.9 million [32.7 million–44.0 million] people living with HIV (PLHIV) with 61% of these residing in Eastern and Southern Africa (ESA) , male sex, younger age and having lower levels of education . Most patients were adults (71.8%), married (55.8%), and had a normal functional status (73.4%). Few (3.1%) were in WHO stage IV, and 27.1% started ART at a primary health care (PHC) facility. At time of ART initiation 5.5% of women were confirmed to be pregnant .Overall, retention at 6, 12, 24 and 36 months was 92.4%, 86.5%, 79.2% and 74.4%, respectively. The maximum follow-up time for the patients who started ART in 2012, 2013, 2014 and 2015 was 40.4, 37.2, 25.2 and 13.4 months respectively . We asseOver 6489 years of patient follow-up; 77.4% were active on treatment, 2.4% transferred out and 20.2% were lost through attrition  The median follow-up time per patient was 1.7 years (IQR 1.1–2.4). The overall attrition rate was 11.8, [95% confidence interval (CI):11.0–12.7] per 100 person years (PY). The other attrition rates are shown in Variables which had p -value < 0.1  were included in multivariable analysis. Sex and level of care were included based on their clinical and biological relevance in HIV retention. In multivariable analysis, being an adolescent or a young adult Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: NoReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: ReviewRetention and predictors of attrition among patients who started antiretroviral therapy in Zimbabwe’s National Antiretroviral Therapy Programme between 2012 and 2015Dear authors,thank you for submitting this interesting paper on factors influencing retention of the ART program in Zimbabwe.I do have the following questions and remarks regarding your methodology and interpretation:Sample size:Your assumptions regarding the sample size does not include the comparison between the retention rates at 12 months between the actual and the former study.Reading the section it seems you need 4000 people to estimate a single rate – but then you should maybe give the broadness of a confidence interval to motivate this sample size.What do you mean by design effect 2.0?Sampling criteria:You sampled from 1.10.2012 to 31.12.2015. The analysis was done in 2016?When I see this information I conclude that in the sub-cohort of those persons starting the ART-Program in 2014/15 there is nobody that can have a retention until 36 months (if starting 2014) and 24 months (if starting in 2015). I don’t find any information at the minimum/maximum length of observation in the (sub-) cohort, could you please add this.Statistical analysis:Line 203-5“Time to attrition was calculated as the time between the date of ART initiation and the date of outcome or last patient clinic visit. Those active on ART and transferred out were censored on the date of data abstraction and the date they were transferred out.”I don’t understand the second sentence. How can you be censored to two dates?- As you don’t have information on the time of censoring you could think of using the AFT-Model (Accelerated-Failure-Time-Modell) instead of the Cox-Model. In the AFT-Model you don’t need a date but a period in which an event/censoring occurs.- Did you check for the proportional hazards assumption of the Cox-Model?- I suggest to look into subgroups of patients conditioning on the time having been in the ART-program:e.g. the retention in those patients already having been in ART for 6 months/for 12 months. Maybe the risk of attritions is time dependent and decreases over time.- Fig 3:In the method section you describe an hierarchical variable selection for a multivariable model. I would have preferred a more knowledge-based model building – if at all. Could you please mention all the variables selected? I guess the reader is supposed to find out in Fig 3 – but I find bivariate p-values <0.1 and no effect estimate of this variable in the multivariable section – for example in the case of marital status. (what does the N.S. – non significant mean in this situation then?).Acutally I don’t think you need the multivariable analysis as you want to describe risk groups for higher attrition. The risk groups are well described already in the bivariable analysis. A multivariable model can be used as a prediction model – but this is not what you wanted or what is wanted in dealing with ART-patients, I guess.In the results section you discuss the single risk factors in comparison to the former analysis – you don’t refer to the a prediction.- Fig 2 and Fig 3https://www.nature.com/articles/d41586-019-00857-9)Please refrain from reporting the p-values besides your main effect :e25239- Please check the syntax of the sentences in lines 283 and 390- Loss-To-Follow-Up not abbreviated correctly all the time – please check!!Reviewer #2: This is a large retrospective study evaluating the risk of LTFU among individuals who started ART between 2012-2015 in Zimbabwe. We commend the efforts of working with program data to produce this manuscript and support it’s publication.I believe this study will benefit from the following comments:-1. The authors should be more specific about the purpose of this study, the comparisons and the hypotheses.2. How would patients who were considered LTFU (>180 days since without a visit) but show up at the clinic over 6 months later were treated in the analysis? I.e. are there some cases that were LFTU based on this criteria but showed up after 6 months has lapsed?3. Could the other program activities (Line 294) explain lower retention in the 2014-2015 cohort compared to 2012-2013? . Did these activities diminish over time? I recall reading that more individuals initiated ART over time so does it mean that although ART was scaled up, the retention was lower. Please correct my misinterpretations and kindly explain these results.4. Discuss program adherence and retention interventions (if any) and consider citing a paper by Coker et al., Curr HIV/AIDS Reports 2015. Socio-Demographic and Adherence Factors Associated with Viral Load Suppression in HIV-Infected Adults Initiating Therapy in Northern Nigeria: A Randomized Controlled Trial of a Peer Support Intervention that highlights that indicate that ART adherence will improve significantly regardless of whether HIV-infected adults received adherence interventions or standard of care services.Please see attachment for additional comments that could not fit in here.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool, AttachmentLetter PLOS_submitted20191017.docSubmitted filename: Click here for additional data file. 7 Dec 2019Dear Editor,Many thanks for the review of “Retention and predictors of attrition among patients who started antiretroviral therapy in Zimbabwe’s National Antiretroviral Therapy Programme between 2012 and 2015". We have carefully read and discussed the recommendations made by the reviewers, and have adapted the paper accordingly.A marked-up copy of the manuscript highlighting changes made to the original version labeled 'Revised Manuscript with Track Changes' and a clean version labeled 'Manuscript' have been uploaded.In this response letter we respond to each point raised by the reviewers. Please find our responses below with revisions or additions to the manuscript in quotes. We shall of course be available to respond to any additional question you may have.Kind regards,Richard Makurumidze, on behalf of the co-authorsAttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 18 Dec 2019Retention and predictors of attrition among patients who started antiretroviral therapy in Zimbabwe’s National Antiretroviral Therapy Programme between 2012 and 2015PONE-D-19-23547R1Dear Dr. Makurumidze,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact With kind regards,Kwasi Torpey, MD PhD MPHAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 23 Dec 2019PONE-D-19-23547R1 Retention and predictors of attrition among patients who started antiretroviral therapy in Zimbabwe’s National Antiretroviral Therapy Programme between 2012 and 2015 Dear Dr. Makurumidze:I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. For any other questions or concerns, please email Thank you for submitting your work to PLOS ONE.With kind regards,PLOS ONE Editorial Office Staffon behalf ofProfessor Kwasi Torpey Academic EditorPLOS ONE


The purpose of this survey was to estimate the prevalence of viral load (VL) suppression and emergence of HIV drug resistance (HIVDR) among individuals receiving antiretroviral therapy (ART) for 36 months or longer in Viet Nam using a nationally representative sampling method.The survey was conducted between May and August 2014 using a two-stage cluster design. Sixteen ART clinics were selected using probability proportional to proxy size sampling, and patients receiving ART for at least 36 months were consecutively enrolled. Epidemiological information and blood specimens were collected for HIV-1 VL and HIVDR testing; HIVDR was defined by the Stanford University HIVDR algorithm.Overall, 365 eligible individuals were recruited with a mean age of 38.2 years; 68.4% were men. The mean time on ART was 75.5 months , and 93.7% of the patients were receiving non-nucleoside reverse transcriptase inhibitor-based regimens. Of the 365 individuals, 345  had VL below 1000 copies/mL and 19  had HIVDR mutations.Our nationally representative survey found a high level of VL suppression and a low prevalence of HIVDR among individuals who received ART for at least 36 months in Viet Nam. Continued surveillance for HIVDR is important for evaluating and improving HIV programs. There were an estimated 250 000 people living with HIV in Viet Nam in 2016.  was first introduced in Viet Nam in the mid-1990s and has been rapidly scaled up since 2005, with a total of 115 927 people receiving ART at the end of 2016.  recommended the prospective cohort studies of patients in conveniently selected sentinel sites to assess the emergence of ADR. ; , which tested specimens from eight outpatient clinics in the north of the country, and the Pasteur Institute in Ho Chi Minh City (PI HCMC), which tested specimens from eight outpatient clinics in the south of the country.HIV-1 RNA viral quantification was conducted using the automated Abbott real-time HIV-1 assay (in NIHE) and the automated Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 assay (in PI HCMC) with detection limits of 20 copies/mL. HIVDR genotypic test was conducted on the pol gene with the ABI 3130XL system using the Big-Dye Terminator v3.1 Cycle Sequencing Kit . HIVDR was interpreted using the HIValg Program on the Stanford University HIV Drug Resistance Database web site.  and statistical analysis was performed using STATA version 11 . Standard descriptive statistics were calculated for categorical and continuous variables. Data analysis for prevalence of VL suppression was conducted in STATA using the survey (svy) suite of commands. Data were weighted by clinic size . .During the enrolment period, a total of 6920 patients were screened at 16 sampled clinics, from which 368 eligible patients were recruited. Three patients were excluded because the duration of ART was less than 36 months; therefore, 365 persons were included in the final analysis. Their baseline characteristics are summarized in Among the 365 participants with VL testing, 345 (95.1%) achieved VL suppression (defined as VL < 1000 copies/mL). The prevalence of VL suppression among individuals on first-line ART was 94.8% (95% CI: 92.1–96.6%)  and among persons with VL > 1000 copies/ml was 94.7% (95% CI: 64.1–99.4%) , K103N , V106I  and G190A . For NRTI resistance, the most common resistance mutations were M184V ; V75M ; and thymidine analogue mutations (TAMs), consisting of T215F/I/Y , K219E/Q , K70R , D67N , M41L  and L210W . There were 45% (9/20) of patients harbouring viruses with three or more TAMs Of the 20 patients failing ART, 75% (15) had mutations that predict resistance to tenofovir, while 85% (17) and 70% (14) had mutations that predict resistance to either lamivudine (3TC) or emtricitabine (FTC) and ZDV, respectively (3 and aOR = 11.4 (95% CI: 2.51–51.9) for CD4 between 100 and 350 cells/µl.This study was the first survey of ADR in Viet Nam following the WHO guidance for ADR surveillance released in 2014, , pre-treatment HIV drug resistance (PDR) and ADR. In a study among 70 newly diagnosed HIV-positive clients aged 18–24 years in Hanoi in 2006, the prevalence of TDR was at a low level , . This study result is also in line with other studies showing that Viet Nam’s programmes are achieving a high level of VL suppression (< 1000 copies/ml) at 12 months as reported from cohort studies (Our study found a strong association between VL and drug-resistance mutations among patients receiving ART for at least 36 months. HIVDR mutations to NNRTI were detected in 19 out of 20 (95%) patients with VL > 1000 copies/ml supporting the notion that a prompt switch to second line therapies is needed in people with detectable virus despite treatment. Because HIVDR is associated with a low level of adherence (more importantly with NNRTI resistance emergence)  were 11.5% (95% CI: 7.8–15.1) at 10–14 months and 10.3% (95% CI: 6.9–13.8) at 22–24 months. The percentages of patients with detectable VL that had drug-resistance mutations were 75.9% at 10–14 months and 86.2% at 22–24 months. , V75M and M184V (NRTI resistance). (The mutation pattern in our study was similar to the results of an ADR survey at three clinics in Ho Chi Minh City in 2009–2010. Among the 22 patients with HIVDR mutations at 12 months, resistance to NRTIs, NNRTIs and to both classes were reported as 4.5%, 9% and 90%, respectively. At 24 months following ART initiation, there were 25 cases with HIVDR mutations: 96% were resistant to both NRTIs and NNRTIs, 0% were resistant to NRTIs alone and 4% were resistant to NNRTIs alone. (In conclusion, this is the first survey to describe nationally representative levels of VL suppression and ADR in adults receiving ART for at least 36 months in Viet Nam. The survey found high levels of VL suppression, low levels of ADR among people on ART and high levels of HIVDR among people failing ART, suggesting that Viet Nam had successfully managed its programme quality to maintain ADR at a low level at the time the survey was conducted in 2014.


HIV related deaths still continue to occur in large numbers in spite of good quality drugs being freely available in India. This study was therefore done to assess the prognostic factors of mortality among people living with HIV (PLHIV) on antiretroviral therapy (ART). This would help in planning strategies for further improving their survival. Record based data from baseline and follow-up visits of a cohort of patients aged above 14 years on ART was retrospectively reviewed over a seven-year period. The Kaplan-Meier models were used to estimate life time survival probability, and Cox proportional hazard regression model was used to determine independent prognostic factors of death, among patients, after initiation of ART. Mean age of the total 285 patients enrolled in this study was 45.8±9.7 years. Mean duration of treatment on ART was 1127±611.8 days. During the follow-up period, 44/285(15.4%) patients died, resulting in incidence density of death rate as 3.12 per 100 person years. Good adherence with treatment was reported by 267(93.7%) patients. Nearly half of the deaths, i.e., 21(47.7%), occurred within three months of them starting ART. The mean survival time after initiation of ART was 2084.0±55.3 days (95% CI is 1975.5-2192.5). The presence of opportunistic infections (OIs) and tuberculosis before and poor/average adherence to ART and alcohol usage after starting ART were independent prognostic factors of mortality among patients. Several prognostic factors influencing mortality among adult HIV patients receiving treatment were identified in this study. Screening efforts is essential in early detection and management of OIs among PLHIV. Good counselling and monitoring is recommended to improve adherence and also to prevent alcohol usage after initiation of ART. Such measures would help in further reducing mortality among HIV patients in the settings. India stands third with respect to HIV epidemic in the world. About 2.1 million people are estimated to be living with HIV in India. The number of deaths due to AIDS related illnesses in India was estimated to be around 62,000 people in the year 2016 The proportion of patients who died in this study was 15.4% in comparison to two other studies done in Ethiopia, where it was reported as 9.4%  and 11.1This study observed that the mean survival time was 46.7 months, among patients with the most recent CD4 count before death, as ≥200 cells per cu.mm. This was more than 44.2 months reported in a study done in Hyderabad, India . This inMajority of deaths in this study occurred within 3 months of starting ART, as also observed in previous studies , 16, 17.In this study, good adherence to ART was reported in 93.7% patients in comparison to 27.4% , 94.2% , and 97.In a study done in Ethiopia, an 8 percentage gain in weight was observed in the first 6 months of treatment . HoweverProgressive change in CD4 count after initiation of ART was noticed in this study. However the increase in median CD4 count level from baseline values over the first 6 months of ART was lesser compared to 76.2% reported in an Ethiopian study .Multivariable analysis in the present study showed that the presence of OIs, including tuberculosis before starting ART, to be associated with greater risk of mortality. Therefore, early identification of OIs will be helpful in identifying patients who need more intense follow-up for treatment of specific OI.Similarly, the presence of tuberculosis infection as an independent prognostic factor of mortality was reported by previous studies , 12, 15.Another important independent prognostic factor of mortality observed in this study was poor/average pattern of adherence to ART, which was also supported by other studies , 22. CarFurther, history of usage of alcohol after starting ART was also an important prognostic factor of mortality. This was probably because it causes poor adherence with treatment. Another Ethiopian study too observed that patients reporting substance usage, with significant independent risk of mortality . AvoidanPrevious studies using Cox regression analysis identified male gender , 23, 24,The proportion of deaths was minimal 4 years after diagnosis of HIV in this study when compared with previous studies. Similarly, the survival probability of patients was better than that reported in other settings, probably due to acceptable level of adherence to treatment and good number of follow-up visits by the patients. The CD4 count and BMI were found to increase among them, as soon as 6 months of treatment. However, majority of deaths were reported within 3 months of starting ART. This could be due to delayed diagnosis of HIV and associated OIs. Added to this, side effects of ART need to be attended to during follow-up visits. Therefore intensive monitoring of HIV patients on ART with various factors identified in multivariable analysis such as presence of OIs before the start of treatment and counselling for the alcoholics and those with poor/average adherence to treatment (probably due to drug side effects) is a must for prolonging the survival of the HIV affected patients in this settings.This study highlights the mortality statistics among PLHIV and the factors influencing it in an urban tertiary care setting of coastal India. It was observed that clinical and simple laboratory data available to health care providers can predict patients on treatment who are at higher risk of mortality. Screening efforts need to be intensified for early detection and management of OIs among HIV infected patients both before and after the start of ART. Other measures like good counselling and periodic monitoring would improve adherence and might also prevent alcohol consumption after treatment with ART. Monitoring and frequency of visits need to be more frequent in the first 3 months of starting ART, during which the proportion of deaths was found to be the most. These measures would help a long way in reducing mortality among PLHIV in the setting.This being a record based study has the limitation of availability of information, as stated in the records. There is also a possibility of deaths in this study which may have occurred due to causes not directly related to HIV/AIDS. The retrospective study design which limits analysis of the role of social and psychological factors and a single centric study which limits generalizability of information are other shortcomings of this research study.