Twenty-four of 36 participants entered the treatment extension period, and 21 completed week 240. At week 240, a viral load of <50 copies/mL was achieved by 14/32 (43.8%) participants; virologic response by TLOVR was higher in participants with a baseline viral load of ≤100,000 copies/mL (48.0%) versus a viral load of >100,000 copies/mL (28.6%). By FDA Snapshot, a viral load of <50 copies/mL at week 240 was found in 53.1% (17/32) of participants with a baseline viral load of ≤100,000 copies/mL. Higher response was observed in participants with adherence of >95% and a baseline viral load of ≤100,000 copies/mL. Through week 240, 16/32 participants (50.0%) experienced virologic failure, including seven who developed treatment-emergent RPV resistance-associated mutations (RAMs [frequently E138K]): all 7 had ≥1 treatment-emergent NRTI RAM. No serious AEs after week 48, no discontinuations due to AEs between week 48 and week 240, and no new safety signals were observed. RPV did not affect pubertal development or adolescent growth. At the 5-year follow-up, efficacy was low in adolescents, particularly those with poor adherence and/or a high baseline viral load of >100,000 copies/mL. To limit the risk of virologic failure, RPV is restricted to patients with a baseline VL of ≤100,000 copies/mL in most countries. In addition, adequate treatment adherence to RPV treatment is imperative for long-term viral suppression and should be emphasized in the management of adolescents living with HIV. RPV exhibited a favorable long-term safety profile for adolescents living with HIV-1 with adequate adherence. This phase 2 study investigated long-term safety and efficacy of rilpivirine (RPV) plus two investigator-selected nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in HIV-1-infected antiviral therapy-naive adolescents. Participants (≥12 to <18 years of age) were treated with RPV at 25 mg once daily (q.d.) plus 2 NRTIs and entered the treatment extension period for up to 240 weeks, with visits every 3 months. Long-term safety , efficacy (virologic response and outcome for patients with viral loads of <50 and <400 by time to loss of virologic response [TLOVR] and FDA Snapshot methods, as well as CD4 Long-term data on treatment of adolescents living with HIV-1 are limited . InadequRilpivirine (RPV [Edurant]), a nonnucleoside reverse transcriptase inhibitor (NNRTI), was approved (25-mg once-daily [q.d.] tablet) for treatment of HIV-1 treatment-naive adults based on the results of the phase 3 ECHO and THRIVE studies. RPV at 25 mg q.d. demonstrated noninferior efficacy compared with efavirenz (EFV) at 600 mg q.d., both in combination with two nucleoside/nucleotide RTIs (NRTIs) 68.The PAINT study  is a phase 2, open-label study of RPV in HIV-1-infected, ART-naive adolescents ≥12 to <18 years of age (cohort 1) and children ≥6 to <12 years of age (cohort 2). The 48-week analysis of cohort 1 of this study established that the pharmacokinetic (PK), safety, and resistance profile of RPV (25 mg q.d.) in adolescents was comparable to that in adults . Here, wThe study was conducted at 7 sites across South Africa, India, Thailand, the United States, and Uganda, and 4/7 sites (2 sites in South Africa and 1 each in Thailand and Uganda) participated in the post-week 48 treatment extension period. An overall summary of the study design is presented in Per the TLOVR (time to loss of virologic response [VR]) algorithm, VR (<50 copies/mL) was observed in 26/36 (72.2%) patients at week 48 and 14/32 patients (43.8%) at week 240 . ApplyinAt the week 240 analysis, 16/32 patients (50.0%) were considered VF (TLOVR), of whom 4 were never suppressed and 12 were rebounders  ; 2/32 paVF was observed in 12/25 patients (48.0%) with treatment adherence of >95% versus 4/7 patients (57.1%) with <95% treatment adherence. The VF rate with a baseline VL of ≤100,000 copies/mL and treatment adherence of >95% was 9/21 (42.9%), versus 7/11 (63.6%) with a baseline VL of >100,000 copies/mL and treatment adherence of ≤95% (Table S1).Stratified by age group, VF rates in older adolescents (15 to <18 years old) versus younger adolescents (12 to <15 years old) were 8/14 (57.1%) and 8/18 (44.4%), respectively (Table S2).The mean (standard error [SE]) increases from baseline in absolute CD4 count were 201.2 (32.87) cells/μL at week 48 and 113.6 (26.72) cells/μL at week 240 based on the “noncompleter = failure” (NC = F) approach, with 255.1 (36.12) cells/μL at week 48 and 178.0 (37.67) cells/μL at week 240 based on observed case analysis.Mean RPV treatment adherence (based on pill count) through week 240 was 97.52%. Most patients had >95% adherence (28/36 [77.8%]), and 8/36 (22.2%) patients had ≤95% adherence. Overall, treatment adherence was ≥80% in all the patients. However, considerable within-patient fluctuation was observed throughout the study: 7 patients (21.9%) had ≥1 24-week episode with <80% adherence. However, no clear association with VF (TLOVR) was observed. Of note, some patients had >100% compliance at all scheduled visits, which was indicative of poor adherence  patients did not carry treatment-emergent RPV resistance-associated mutations (RAMs), while 7/32 (21.9%) had ≥1 treatment-emergent RPV RAM at the last post-baseline time point with genotypic data in the week 240 analysis compared to 5/36 patients (13.9%) in the week 48 analysis. Three of seven patients with phenotypic data showed reduced susceptibility to RPV at the last post-baseline time point with genotypic data.n = 1) and M184I (n = 2) were observed in combination with RPV RAMs. Three patients had both treatment-emergent RPV RAM E138K and NRTI RAM M184V at the last post-baseline time point with genotypic data.The most frequent treatment-emergent RPV RAM at the last post-baseline time point was E138K (5/15 patients [33.3%]). All 7 patients with RPV RAMs also had at least 1 treatment-emergent NRTI RAM at the last post-baseline time point with genotypic data. The most frequent treatment-emergent NRTI RAM was M184V (4/15 patients [26.7%]). In addition, K65R plus Y115F  were reported in 35/36 patients (97.2%); such events were reported in 22/24 patients (91.7%) after week 48  increases from baseline in height, weight, and body mass index (BMI) were 10.2 (8.04) cm, 15.7 (7.14) kg, and 3.8 (3.58) kg/m week 48 . The mosAEs of special interest were reported in 26/36 patients (72.2%) during the overall treatment phase: 24/36 patients (66.7%) before week 48 and 8/24 patients (33.3%) after week 48. The most frequently reported individual AEs of special interest after week 48 were headache, depression, and dizziness. Increases in QTcB and QTcF of >60 ms from baseline were observed in 1 patient (2.8%) at week 240 and resulted in unconfirmed pathologically prolonged (>500-ms) QTcB and QTcF values , which were not reported as AEs. There were no pregnancies reported during the study.2) at baseline and had a normal or high renal function (90 to 120 mL/min/1.73 m2) at the time of the largest decrease from baseline in GFR. All of these 3 patients used TDF as a concomitant antiretroviral (ARV).Most laboratory abnormalities were grade 1 or grade 2. Between week 48 and week 240, no grade 4 laboratory abnormalities were observed; grade 3 abnormalities in neutrophils and precursors, neutrophils segmented, and hemoglobin were reported in 1 patient each. Mean (SD) increases from baseline in creatinine were 6.6 (7.35) μmol/L at week 48 and 14.3 (12.12) μmol/L at week 240. Although a mean increase from baseline creatinine of 14.3 μmol/L (0.16 mg/mL) was observed at week 240, in only 3 patients was a decrease from baseline glomerular filtration rate (GFR) of more than 30% observed at any time. The 3 patients had a high renal function  basal cortisol levels were 229.3 (73.57) nmol/L at baseline, 261.0 (114.42) nmol/L at week 48, and 237.8 (58.08) nmol/L at week 240. Adrenocorticotropic hormone (ACTH) stimulation test results were normal  in most patients at week 48 (22/29 patients [75.9%]), at week 240 (8/9 patients [88.9%]), and at the last measurement available on treatment (34/36 patients [94.4%]). RPV did not affect pubertal development (assessed by Tanner staging) or growth of adolescents (assessed by CDC growth curves). No AEs related to clinical manifestations of adrenal insufficiency were reported.The long-term efficacy of RPV at 25 mg q.d. in combination with 2 investigator-selected NRTIs in HIV-1 in ART-naive adolescents living with HIV-1 (≥12 to <18 years of age) was evaluated in this 240-week, phase 2 study (PAINT). VR (<50 copies/mL) was achieved in 72.2% of patients at week 48 and 43.8% of patients at week 240 (TLOVR approach). In patients with a baseline VL of ≤ 100,000 copies/mL, VR was achieved in 12/25 patients (48.0%) at week 240 by TLOVR and in 14/25 patients 56%) by FDA Snapshot. At week 48, this VR rate was lower in this study (73%) than in adult RPV studies at week 48 % by FDA . AdolescIn the PAINT study, VR at week 240 was observed in 12/25 (48.0%) of patients with adherence of >95% and in 2/7 (28.6%) patients with adherence of ≤95%. Of note, VR was higher in the subgroup with a baseline plasma viral load of ≤100,000 copies/mL combined with treatment adherence of >95% (11/21 patients [52.4%]), compared to 3/11 patients (27.3%) in the subgroup with a baseline VL of >100,000 copies/mL or treatment adherence of ≤95%. There is limited long-term data on the efficacy of ARVs in treatment-naive adolescents. In a 96-week study, a once-daily regimen of emtricitabine, didanosine, and efavirenz, achieved a VL of <50 copies/mL in 72% of therapy-naive adolescents and children living with HIV-1 who were 3 to 21 years of age . ResultsIt must be acknowledged that pill count is a suboptimal instrument to measure adherence as actual pill intake was not directly observed. Furthermore, other critical factors, such as adherence to RPV intake with food, could have played a vital role. Hence, these limitations must be considered while interpreting the results.The WHO recommends drug optimization for children and adolescents with HIV, phasing out NNRTI-based regimens and replacing them with optimal regimens and formulations as outlined in the 2018 Optimal Formulary and Limited-Use List for Pediatric ARVs . In thosNo safety concerns were noted in this long-term study with RPV in HIV-1-infected, ART-naive adolescents. The data from adolescents confirm the overall favorable safety profile of RPV, consistent with the established safety profile in adults, with no deaths overall, no SAEs, and no AEs leading to treatment discontinuation after week 48 through week 240. During the overall treatment phase, 35 patients (97.2%) experienced ≥1 AE: the most frequent were upper respiratory tract infection (20/32 [55.6%]), influenza (15/32 [41.7%]), cough (10/32 [27.8%]), headache (9/32 [25.0%]), and depression (8/32 [22.2%]). Most AEs  emerged in the first 48 weeks of treatment, and no new safety concerns were observed thereafter.In the PAINT study, the ACTH stimulation results were normal (cortisol levels of ≥500 nmol/L) over 240 weeks of RPV treatment in the majority of patients during the overall treatment phase. Also, pubertal development, as assessed by Tanner staging  and growThe observed RPV resistance data were in line with the phase 3 ECHO and THRIVE studies , 23. TheIn summary, week 240 results from cohort 1 (adolescents) in the PAINT phase 2 study showed that when RPV at 25 mg q.d. was used in combination with 2 investigator-selected NRTIs in treatment-naive adolescents with a baseline VL of ≤100,000 copies/ml, 56% of patients were responders by FDA Snapshot (16/32 participants [50.0%] had virologic failure). Patients with VF and potentially developing RAMs had a tendency to show poor adherence, along with a higher baseline VL. No new safety concerns were observed in this patient population, aside from the known safety profile of RPV in adults. Moreover, pubertal development and growth of adolescents were not affected by long-term treatment with RPV. Study limitations include small sample size, the open-label and nonrandomized design, the absence of a comparator arm, and challenges in accurate measurement of adherence.To limit the risk of virologic failure, in most countries RPV is restricted to patients with a baseline VL of ≤100,000 copies/mL. In addition, adequate treatment adherence is imperative for long-term viral suppression and should be emphasized in the management of adolescents living with HIV.PAINT  is a phase 2, single-arm, open-label, multicenter study of RPV in ART-naive adolescents living with HIV-1 who are ≥12 to <18 years of age (cohort 1) and children ≥6 to <12 years of age (cohort 2). The study consists of a ≤8-week screening period and a 48-week initial treatment period (48 weeks), followed by a 4-year treatment extension period (up to 240 weeks) for participants who are expected to continue experiencing clinical benefit from RPV plus 2 NRTIs at the end of 48 weeks . For cohThis study was conducted in compliance with the Declaration of Helsinki and was consistent with Good Clinical Practices and applicable regulatory requirements. The study protocol and amendments were reviewed by the independent ethics committees or institutional review boards. Written informed consent was obtained from all participants and/or legally acceptable representatives before study enrollment.Adolescents (boys or girls ≥12 to <18 years of age with a body weight of ≥32 kg) with documented HIV-1 infection and who had never been treated with an HIV vaccine/drug were enrolled. Following approval in 2011 of RPV in adults with a viral load of ≤100,000 HIV-1 RNA copies/mL, enrollment in cohort 1 was restricted to screening HIV-1 plasma VLs of ≤100,000 copies/mL. The patients’ VL at screening had to be between ≥500 and ≤100,000 HIV-1 RNA copies/mL. Patients with previously documented HIV-2 infection, with active AIDS, and with documented genotypic evidence of ≥1 NNRTI resistance-associated mutation (RAM) from a predefined list of the following NNRTI RAMs , 25 at sAll patients received RPV 25 mg q.d. plus an investigator-selected background regimen containing 2 NRTIs  in an age-appropriate formulation based on marketing approval or per the local standard of care.+ cell count (absolute and percentage) from baseline up to week 240.The primary efficacy endpoint represented the proportion of patients with confirmed and sustained virologic response (VR [VL of <50 copies/mL]) according to the time to loss of VR (TLOVR) algorithm at week 24 and was presented in a previous publication . The secPlasma VL was assessed at prespecified time points using the Roche Cobas Amplicor HIV-1 Monitor test, version 1.5 , or the Roche Cobas TaqMan HIV-1 test, version 2.0 .Resistance determination was performed at screening, baseline, early withdrawal, and at virologic failure (VF). Viral genotyping and phenotyping were conducted using VircoTYPE and Antivirogram assays or the PhenoSense GT assay. The RPV fold change (FC) in 50% effective concentration values was assessed using a RPV biological cutoff (BCO) of 3.7 in Antivirogram and 2.0 in PhenoSense GT , 28.Safety assessments included adverse events (AEs), serious AEs (SAEs), AEs related to study drug, AEs leading to discontinuations, AEs of interest , and grade 3 to 4 AEs at week 240.Laboratory data were collected for hematology, biochemistry, endocrine assessments, and urinalysis. The basal cortisol was measured in the morning, between 7:30 and 9:30 a.m. Vital and physical signs and electrocardiograms were recorded at predefined time points. Growth and development parameters were measured every 6 months during the treatment extension period. AEs were coded in accordance with Medical Dictionary for Regulatory Activities (MedDRA), version 13.1. The Division of AIDS (DAIDS) severity grading list (December 2004) was used to grade AEs and laboratory abnormalities.Adherence questionnaires were used to assess adherence during the initial 48-week treatment period, and the results were described in the week 48 analysis . After t+ cell count was performed on imputed data using the approach “noncompleter = failure” (NC=F)—i.e., imputed by baseline value after discontinuation (change = 0)—or last observation carried forward (LOCF) otherwise, as well as the observed case. The ITT population for safety analyses consisted of 36 patients for first 48 weeks of treatment, 24 patients between week 48 and week 240, and 36 patients for the overall 240-week treatment phase.The efficacy and safety analyses were performed on the intent-to-treat (ITT) population, defined as the set of all patients who received at least 1 dose of RPV, regardless of their compliance with protocol and adherence to dosing regimen. The ITT population for efficacy analyses consisted of 36 patients prior to week 48 and 32 patients after week 48 (excluding 4 who completed the study at week 48). Change from baseline in CD4


Both PCs and TCs showed similar acute-phase glycoprotein profiles, even when TCs lost the virological control , and the serum acute-phase glycoprotein signature in PCs did not differ from that in HIV-negative subjects . Differences in serum glycoproteins A and B were significant only in ECs compared to HIV-typical progressors (TPs) with < 100 CD4+ T-cells (p < 0.001). 1H-NMR acute-phase glycoprotein profile does not distinguish TCs form PCs before the loss of viral control. ECs maintain a low-grade inflammatory state compared to TPs. PCs revealed a closer serum signature to HIV-negative subjects, reaffirming this phenotype as a closer model of functional control of HIV.Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) who maintain undetectable viral loads (VLs) despite not being on antiretroviral therapy (ART). However, this phenotype is heterogeneous, with some of these subjects losing virological control over time. In this longitudinal retrospective study, serum acute-phase glycoprotein profile assessed by proton nuclear magnetic resonance ( Elite controllers (ECs) are a select group of people living with HIV (PLWH) who maintain a circulating viral load (VL) at undetectable levels without antiretroviral treatment (ART) , 2. ThisAlthough it was once thought that ECs could have a favorable short- and long-term prognosis, recent real-life data have revealed that ECs are at increased risk of several non-AIDS events . Notably1H-NMR serum glycoprotein measurement encompasses the systemic inflammatory process more comprehensively than other individual biomarkers   were incTwenty-two elite controllers (ECs) were selected, defined as subjects who in the absence of prior or current ART since HIV diagnosis and during the 36 months of the follow-up maintained an undetectable VL. Two groups were distinguished: 11 ECs who lost spontaneous viral load control, defined by detection at least two consecutive measurements above 50 HIV-RNA copies/mL within a year (TCs); and 11 ECs who maintained virological control throughout the follow-up (PCs), as previously described .Regarding the glycoprotein profile, repeated analyses were performed during the follow-up in TCs: two years before the loss of virological control, one year before the loss of virological control (T-1), 6 months before the virological control, at the moment when viral load was detected (T0) and subsequently at one year after the spontaneous loss of control (T+1). In PCs, repeated analyses were also performed at least at two different time points, but no differences were found in the glycoprotein profiles during any of the follow-ups. Thus, median values were calculated and identified as T0 for the PC group Figure 1+ T-cells at starting ART) and HIV-typical progressors with non-severe immunosuppression (> 350 CD4+ T-cells at starting ART) , matched by sex and age with ECs . For theing ART) Figure 1ing ART) . Serum gAll the selected patients had be age over 18 years and no had concomitant acute or chronic conditions or was taking drugs  that could eventually modify the inflammatory status when the blood samples were collected.1H-NMR for glycoprotein profiling as previously reported , and graphical representations were generated with GraphPad Prism software .The continuous variables presented a non-normal distribution due to the small sample size. Data are expressed as medians and 25th and 75th percentiles. Categorical variables are expressed as percentages. Differences between two groups were analysed using the nonparametric Mann-Whitney test, and for multiple comparisons one- way ANOVA followed by Bonferroni’s The study and all of the research protocols were conducted in accordance with the recommendations of the Ethical and Scientific Committees, and all of them were approved by the Committee for Ethical Clinical Research by following the rules of Good Clinical Practice from the Institut d’Investigació Sanitària Pere Virgili (CEIM 041/2019). The CEIm IISPV is an independent committee, consisting of health and non-health professionals that supervise the correct compliance to the ethical principles governing clinical trials and research projects that are performed in our region, specifically in terms of methodology, ethics and laws. An informed consent form signed by each participant was obtained in accordance with the Declaration of Helsinki and which includes the allowance to use the samples stored in the Biobank for related biomedical research projects.+ T-cell or CD8+T-cell counts between TCs and PCs. The T0 since HIV diagnosis was not statistically significance between TCs than PCs (P=0.061).A flow chart illustrating patient enrolment and categorization is shown in To predict the loss of control in TCs, serum glycoprotein concentration and H/W ratios analyzed at 24 months, 12 months and 6 months before the loss of control in TCs were compared to T0 values in the PC group. No differences were observed among the groups of studies and thus, we selected data from 12 months before the loss of control (T-1) as the representative value for TCs Table 2.vs. 402.4, respectively, P = 0.044; GlycA, 691.4 vs. 757.5, respectively, P= 0.054; H/W Glyc B, 4.5 vs. 5.1, respectively, P = 0.049; H/W Glyc A, 15.7 vs. 18.7, respectively, P = 0.002). However, when the serum glycoprotein signature in healthy HIV-negative subjects was separately compared to each group of PLWH-EC, only the difference in TCs remained significant compared to the group of healthy HIV-negative subjects , matched by sex and age . PLWH-TP showed higher serum glycoprotein concentrations and H/W ratios than the PLWH-EC group , serum Glyc A and Glyc B concentration and H/W Glyc A and Glyc B ratios resulted significantly higher in TP with < 100 CD4+ T-cells compared to both, PC and TCs , was also evaluated in a longitudinal analysis. VL evolution from TC after one year of loss of control was not significantly different from baseline (T0)  or the decrease in the CD4+ T-cell counts . However, TC showed a slightly decreased acute-phase glycoprotein profile at one year compared to T0, although the results were only significant for serum GlycA concentrations (P = 0.05). In fact, after one year of viral rebound (T+1), the serum glycoprotein profile in TCs (716.7 [671.4-835.5] µmol/L) became more similar to the serum glycoprotein profile of PCs at T0 (746.2 [638.7-887.8] µmol/L), although maintained a sustained low-grade inflammation in PLWH-EC compared to HIV-negative individuals (691.4 [664.8 – 755.5] µmol/L) Figure 3The loss of spontaneous viral control in TC has been extensively investigated. According to different publications, it seems that there is no single mechanism responsible for controlling viral replication. This situation could be associated with genetic factors in the host  , low pol1H-NMR in PLWH-EC. Low-grade inflammation seems to remain present in PLWH-EC and is one of the reasons why the use of antiretrovirals is debated despite spontaneous suppression of the virus. In our previous work, glycoproteins were prognostic of immune recovery in PLWH . In short, as seen in previous publications, a higher level of glycoproteins will be associated with decreased CD4 counts and higher viral load. This outcome is also reflected when separating the TPs into subgroups, in which the subgroup with the best immune status (CD4+ T-cell> 350) presented a glycoprotein profile more similar to the PLWH-EC compared to the group of PLWH-TP with severe immune damage (CD4+ T-cell <100 cells/µL).In the present study, we observed that the glycoprotein profile remained the same between PC and TC individuals prior to the spontaneous loss of viral control. However, a significant association of H/W GlycA was observed with viral load in TCs once they lost viral control (T0). This finding is in line with previous publications  in whichThe main limitation of the study is the small number of subjects in each arm of the study design which probably means there was insufficient power to detect significant predictive value of the GlycA and B measures, since in previous studies they did predict immune recovery . However1H-NMR have been associated, within the same disease, with worse states . The patients/participants provided their written informed consent to participate in this study.All authors contributed to the article and approved the submitted version. The authors contributions are as follows: experimental design  and intellectual guidance . recruitment of subjects (JP and ER-M) and sample procurement (AIM and JM). Data collection (AIM and NA). data analysis and interpretation . manuscript preparation (AIM and JM). AI-M, JM, AC, FV, LM, and AR were responsible for the study design, data analysis, and article development. FV, LM and AR reviewed and edited the manuscript.This research was funded by the Fondo de Investigacion Sanitaria -ISCIII-FEDER ; Programa de Suport als Grups de Recerca AGAUR (2017SGR948); the SPANISH AIDS Research Network -ISCIII-FEDER (Spain) and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII , Madrid, Spain. JM is supported by the Universitat Rovira i Virgili under grant agreement “2019PMF-PIPF-18,” through the call “Martí Franquès Research Fellowship Programme”. FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII. AR is supported by a grant from IISPV through the project “2019/IISPV/05” , by GeSIDA through the “III Premio para Jóvenes Investigadores 2019” and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program.NA is stockowner of Biosfer Teslab, the company that commercializes the glycoprotein profiling described in the present manuscript.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bedaquiline has a black-box warning of the risk of arrhythmias and sudden death. This study aimed to determine the incidence of QTc prolongation and cardiac events in patients receiving bedaquiline for drug-resistant tuberculosis (DR-TB) under programmatic conditions.Retrospective cohort study of patients receiving bedaquiline at a DR-TB hospital in KwaZulu Natal, South Africa from September 2017 to February 2019. The primary outcome, a prolonged QT interval corrected using the Fridericia formula (QTcF), was defined as QTcF >500 ms, QTcF change >60 ms from baseline, or both.P < .001) and an inverse association with HIV-positive status  and hypertension . After prolongation, the QTcF declined to <500 ms, whether drugs were interrupted or not.Among 420 patients , the median QTcF was 406.4  ms at baseline, increasing to 430.5  ms by 3 months and 434.0  ms at 6 months. Eighteen of 420 patients (4.3%) had a QTcF >500 ms and 110 of 420 patients (26.2%) had a QTcF change >60 ms. There were no recorded arrhythmias or cardiac deaths. Odds of prolonged QTcF were increased with concomitant azoles , 2.26–13.91]; We observed a modest prolongation of QTcF, maximal at week 15; there were no recorded arrhythmias or related deaths. A modest QTcF prolongation, maximal at 15 weeks, was observed in patients receiving bedaquiline treatment for drug-resistant tuberculosis under programmatic conditions in KwaZulu-Natal, South Africa. There were no recorded arrhythmias or related deaths. There were an estimated 465 000 incident cases of drug-resistant tuberculosis (DR-TB) in 2019, 14 000 of which were in South Africa . The advP = .02 for difference) [Bedaquiline belongs to a novel class of TB drugs, the diarylquinolines, and is associated with improved outcomes . World Hference) . Althougference) , the Uniference) , 14.In subsequent trials TMC207-C209) and programmatic evaluations, QT prolongation with bedaquiline has been confirmed , 15, 16.07-C209 aSouth African guidelines recommend performing an ECG at baseline, after 2 weeks, 4 weeks then monthly while on bedaquiline, or more frequently if additional QT-prolonging drugs are being taken . If the We report the incidence of QTc prolongation and cardiac events for a large cohort of patients treated with a combination of DR-TB agents including bedaquiline under programmatic conditions in South Africa.This was a retrospective cohort study at a specialist DR-TB hospital in eThekwini District, KwaZulu-Natal, South Africa. Consecutive patients initiating bedaquiline-based DR-TB therapy from September 2017  to February 2019 were identified using both the hospital register and the Electronic Drug-Resistant Tuberculosis Register (EDRWeb). The standard duration of bedaquiline therapy as per South African guidelines was 6 months .Patients were excluded if they were not treated with a bedaquiline-based DR-TB regimen, if they did not have a baseline ECG recorded within the 4 weeks prior to bedaquiline initiation, or if they did not have at least 1 follow-up ECG in the 6 months of bedaquiline treatment. Patients were eligible regardless of their background DR-TB regimen.A standardized data collection tool was developed using Open Data Kit . We collidelines , as a QTWe used Kaplan-Meier methods to estimate retention on bedaquiline treatment for 6 months. Person-time was calculated from the start of bedaquiline therapy until the earliest of stopping bedaquiline (either permanently or an interruption of treatment), death, loss to follow-up, or 183 days on treatment. Patients were censored when transferred out. Patients who were prescribed bedaquiline for <6 months were censored on the date of completion of therapy. Those who were still on treatment at the time of record review were administratively censored on the date of their last record. As a sensitivity analysis, patients who interrupted treatment temporarily were considered to be retained on treatment, and person-time was calculated ignoring the interruption.P < .20 after adjusting for age, sex, and week were included in a multivariable model; those that remained associated at P < .10 were retained. All analyses used Stata version 15 software.We used random effects logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of factors with the primary outcome of QTcF >500 ms or an increase of >60 ms from baseline at each visit. We restricted the analysis to the first 26 weeks of treatment with bedaquiline. We examined the change in QTcF over time using mixed-effects linear regression to account for the correlation of observations within patients. To allow for nonlinear effects of time, visit week was modeled using restricted cubic splines with 4 knots; this approach provides a flexible way to model the shape of the relationship of a continuous covariate with the outcome. We adjusted for age, sex, and visit week as a priori confounders; visit week was modeled using restricted cubic splines. Factors that were associated with the outcome at The study was approved by the research ethics committees of the University of KwaZulu-Natal (BE314/19) and the London School of Hygiene and Tropical Medicine (16481), and by the Department of Health of KwaZulu-Natal (KZ_201906_001). Due to the retrospective nature of this study, the requirement for written informed consent was waived.Among 450 patient records reviewed, 420 were eligible for inclusion. Reasons for exclusion were as follows: no ECG before bedaquiline treatment initiation (n = 23), no baseline ECG within 4 weeks of bedaquiline treatment initiation (n = 6), or no post–bedaquiline initiation ECG (n = 1).3. All 420 patients were prescribed bedaquiline with an optimized background regimen that included clofazimine and levofloxacin. Forty-seven of 420 (11.2%) were on moxifloxacin at the time of baseline ECG measurement; 46 of these were subsequently converted to levofloxacin.Among 420 patients, the median age was 36  years and 66.2% were male . The majMedian time on bedaquiline among the 420 patients was 6.0  months. The Kaplan-Meier estimate for retention on bedaquiline treatment at 6 months, not discounting treatment interruptions, was 84.5% . At compTwo hundred one of 312 (64.4%) patients living with HIV were already on ART prior to DR-TB therapy: this increased to 99% (309/312) during bedaquiline DR-TB therapy treatment. Median time to ART initiation was 24  days after bedaquiline treatment initiation. All ART regimens included 2 nonnucleoside/nucleotide reverse transcriptase inhibitors; the third agent was nevirapine in 208 of 309 (67.3%), lopinavir/ritonavir in 103 (33.3%), atazanavir/ritonavir in 2, and raltegravir and dolutegravir in 1 each.P = .13).The median QTcF interval at baseline was 406.4  ms. Eighteen patients (4.3%) had a recorded QTcF >450 ms at baseline, of whom 6 (33%) had a repeat baseline ECG; QTcF remained >450 ms in all cases. Two patients (11%) had a QTcF >500 ms at baseline, both of whom commenced therapy without a repeat predose ECG. A median of 8 ECGs  per patient were performed during the 6 months after starting bedaquiline. During these 6 months, 18 patients (4.3%) experienced at least 1 episode of QTcF >500 ms (24 episodes), and 110 patients (26.2%) had a change of >60 ms from baseline (253 episodes). Only 2 of these patients were among the 18 patients with QTcF >450 ms at baseline (11%), compared to 27% of patients with baseline QTcF <450 ms  died, none of whom had a recorded QTcF >500 ms and all of whom had ECGs performed at timepoints consistent with the guidance. The cause of death was not recorded in the medical records.No action was taken if there was a QTcF change >60 ms above baseline (253 episodes). The 24 episodes of QTcF >500 ms are outlined in P < .001); median time on azoles was 14  days and there was strong evidence of an inverse association with HIV-positive status  and hypertension  (P = .11). There was no evidence of an association with QTc prolongation in 12 of 420 (2.9%) patients treated concomitantly with bedaquiline and delamanid .We recorded 254 episodes of QTcF >500 ms or change from baseline >60 ms among 111 patients during the 6 months of bedaquiline therapy. The odds of this combined outcome of QTcF prolongation increased over time and were highest after 15 weeks on treatment . In the P = .02) . There wThis study among patients taking bedaquiline under programmatic conditions demonstrated a progressive increase in QTcF from baseline, with a cumulative incidence of QTcF >500 ms or QTcF >60 ms from baseline of 4.3% and 26.2%, respectively, over 6 months of bedaquiline therapy, and maximum odds for the combined outcome at 15 weeks of bedaquiline therapy. However, we found no evidence of clinical adverse events associated with these changes.Under randomized controlled trial conditions and in combination with ofloxacin or levofloxacin, but without concomitant clofazimine, the mean increase in QTc is in the order of 11.9–15 ms, with an incidence of QTcF >500 ms of ≤1% , 12, 20.There are a number of established risk factors that predispose to QTc prolongation, notably female sex, age, electrolyte disturbance, and certain drug classes . In our In our study, in line with guidelines , we obseIn this cohort the QTcF increased most steeply from baseline in the first 4–6 weeks, then continued to increase more slowly until the end of bedaquiline therapy. Similarly, in the C208 licensing trial, the maximal increase in QTcF was observed in weeks 1–8 , 30. NotIn conclusion, among a cohort of patients receiving bedaquiline alongside clofazimine and levofloxacin for treatment of DR-TB in a routine setting in South Africa, we observed a modest prolongation of the QTc interval, with the greatest QTcF increase in the first 4–6 weeks and the highest odds of combined outcome at week 15. We observed no arrhythmias or attributable deaths, adding to data suggesting that bedaquiline is safe under programmatic conditions.Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at


There is a growing number of older people living with HIV (OPLHIV). While a significant proportion of this population are adults growing into old age with HIV, there are also new infections among OPLHIV. There is a lack of data describing the outcomes of OPLHIV who commenced antiretroviral therapy (ART) after the age of 50 years in sub-Saharan Africa. We conducted a cohort study of patients who enrolled in care at Newlands Clinic in Harare, Zimbabwe, at ages ≥50 years between February 2004 and March 2020. We examined demographic characteristics, attrition, viral suppression, immunological and clinical outcomes. Specifically, we described prevalent and incident HIV-related communicable and non-communicable comorbidities. We calculated frequencies, medians, interquartile ranges (IQR), and proportions; and used Cox proportional hazards models to identify risk factors associated with death. We included 420  who commenced ART and were followed up for a median of 5.6 years (IQR 2.4–9.9). Most of the men were married  whereas women were mostly widowed . Forty per cent (n = 167) had WHO stage 3 or 4 conditions at ART baseline. Hypertension prevalence was 15% (n = 61) at baseline, and a further 27% (n = 112) had incident hypertension during follow-up. During follow-up, 300 (71%) were retained in care, 88 (21%) died, 17 (4%) were lost to follow-up, and 15 (4%) were transferred out. Of those in care, 283 (94%) had viral loads <50 copies/ml, and 10 had viral loads >1000 copies/ml. Seven patients (1.7%) were switched to second line ART during follow-up and none were switched to third-line. Higher baseline CD4 T-cell counts were protective against mortality (p = 0.001) while male sex , being unmarried , and being unemployed  were independent independent risk factors of mortality. There was high retention in care and virologic suppression in this cohort of OPLHIV. Hypertension was a common comorbidity. Being unmarried or unemployed were significant predictors of mortality highlighting the importance of sociologic factors among OPLHIV, while better immune competence at ART commencement was protective against mortality. The number of older people living with HIV (OPLHIV) above the age of 50 years continues to grow due to the increased life expectancy of people living with HIV. In 2019, the proportion of OPLHIV among all people living with HIV was estimated to have risen to 21% globally, from 8% in 2000 –5. This OPLHIV have been shown to have better virologic outcomes and adherence to antiretroviral therapy (ART) than younger people, but have higher mortality and slower immune recovery –9. CompoTo our knowledge, there are no studies from Zimbabwe to document outcomes of ART in OPLHIV. However, there are emerging data on ART outcomes of OPLHIV in sub-Saharan Africa , 17. WitIn this study, we present the sex-stratified prevalence of chronic non-communicable diseases, HIV viral suppression, immunological and clinical outcomes of older patients who registered for HIV management at an HIV clinic in Harare, Zimbabwe between February 2004, and March 2020.This study was conducted within the ongoing International epidemiological Databases to Evaluate AIDS Southern Africa (IeDEA) cohort study of patients attending the Newlands Clinic in Harare, Zimbabwe , 23. TheNewlands Clinic is a referral outpatient clinic providing comprehensive HIV care which is supported by the Ruedi Luethy Foundation, a Swiss-based Private Voluntary Organization. Newlands Clinic was established in February 2004 and operates under a Public-Private Partnership with the Ministry of Health and Child Care of Zimbabwe. Apart from providing antiretroviral therapy to people living with HIV, the clinic also provides, among other services, onsite laboratory investigations, psychosocial support, reproductive health services including cervical cancer screening, dental services, food support, and bus fare assistance. The patient population is predominantly from communities with high prevalence of poverty and unemployment in the Greater Harare area. Further details on the clinic’s operations are provided elsewhere . NewlandWe included all patients aged 50 years or more, who were ART naïve at the time of registration, and started ART at the clinic. Patients were followed from the date of ART commencement until they were transferred out, lost to follow up, or died. Follow up of patients still in care was censored on April 30, 2020. We abstracted demographic, clinical and laboratory data from patient records stored in the clinic’s password protected electronic medical record. Abstracted records were anonymized by removing names and assigning sequential numeric identifiers. We defined baseline CD4 count as a CD4 count closest to the date of initiating ART within 90 days before ART commencement. HIV viral load (VL) measurements were available at the clinic from the year 2014 onwards. The most recent CD4 T-cell count and VL were defined as the last measured CD4 T-cell count or viral load for each patient. CD4 T-cell counts were measured using the CyFlow® Counter (Flow cytometer) and CD4 easy count kits. HIV viral loads were measured using the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, version 2.0.Nurses measured blood pressure during routine clinic visits after the patient had been seated for at least 5 minutes, with the arm supported at the level of the heart and elbow flexed slightly. Nurses ensured the arm was not constricted by tight clothing and placed the cuff on naked skin with the centre of the bladder over the brachial artery. Diagnosis of hypertension was made when a patient’s systolic or diastolic blood pressure was above 140mm Hg or above 90mm Hg, respectively, on two or more days. Risk reduction of major adverse cardiovascular events using aspirin was only provided for patients with history of myocardial infarction. Type II diabetes mellitus was diagnosed when a patient had a random plasma glucose > 11mmol/L or a fasting plasma glucose ≥ 7mmol/L. We grouped all forms of chronic arthritis, excluding gouty arthritis and reported them as arthritis.Patients attended clinic visits at varying intervals determined by the doctors. Those with active comorbid conditions were seen more frequently while stable patients were seen less frequently. The longest interval between visits was 90 days. Patients who missed visits were followed up by a phone call which was recorded in the clinic’s database. Patients without an attended visit for more than 90 days were identified using a system generated report and followed up by a phone call, or a home visit if the phone call follow-up was unsuccessful. When the patient could not be contacted through these strategies, they would be recorded as being lost to follow up.We used frequencies, medians, and interquartile ranges to describe the cohort. The Wilcoxon Rank-Sum test was used to assess differences in skewed continuous variables across categories, and ordinary least-squares regression was used to determine a change in continuous variables over time. The square-root of CD4 T-cell counts was used to normalize the data, and regression analysis was used to compare changes in CD4 T-cell counts for each year on ART. The Chi-square test was used to compare categorical variables. We used Cox Proportional Hazards models to assess risk factors of death. Potential risk factors analyzed were sex, age at enrollment, being married, being unemployed, having attended secondary or higher education, year of recruitment, having a WHO clinical stage 3 or 4 condition at ART baseline, baseline CD4 T-cell count and being hypertensive at enrollment. Potential risk factors of death were individually analyzed in univariate analyses. We included all potentially relevant risk factors  in a multivariable Cox Proportional Hazards model to determine independent risk factors of death. In the multivariable model, CD4 counts were grouped as <100 (severely immune-suppressed), 100–199 (moderately immune-suppressed), and ≥200 (relatively immune-competent). We used Stata  for all statistical analyses.During the study period, 420 patients aged 50 years or older were enrolled into care at Newlands Clinic, 241 (57.4%) being female. The median age at ART commencement was 55 years (IQR: 52–59). There was no difference in ART commencement age between males and females (p = 0.241). More men were married  compared to 58 women (24.4%), while 125 (52.5%) women were widowed compared to 15 (8.4%) men. Seventy-eight (45.1%) men were formally employed compared to 61 (26.5%) women, while 161 women (70.0%) were unemployed compared to 75 (43.4%) men. A total of 123 men (68.7%) had secondary or tertiary education compared to 126 (52.3%) women. Most patients (59.9%) were classified in WHO clinical stage 1 or 2 at ART commencement . Three pThe 420 patients were followed up for a total of 2612 person-years. The median duration of follow up was 5.6 years (IQR: 2.4–9.9). At the time of analysis (30 April 2020), 300 (71.4%) patients were still in care. During follow-up, 88 patients died (21.0%), 17 (4.1%) were lost to follow up, and 15 (3.6%) were transferred to other facilities . Among tThe median baseline CD4 at ART commencement was 158 cells/uL (IQR: 86–274). Females had a higher median baseline CD4 count of 171 (IQR: 89–291) compared to males . Overall, baseline CD4 T-cell counts increased by 11.8 cells/uL per year , but the increase among females  was higher than among males  . One hunMost patients  were initiated on a first-line ART regimen containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz or nevirapine) and two nucleo(t)side reverse transcriptase inhibitors (NRTI). The top three starting regimens were tenofovir + lamivudine + efavirenz, stavudine + lamivudine + nevirapine, and zidovudine + lamivudine + nevirapine with 124 (29.5%), 95 (22.6%), and 91 (21.7%) patients, respectively.Overall, 178 (42.4%) patients experienced at least one treatment adverse effect. The antiretrovirals most discontinued due to adverse events were nevirapine, stavudine, zidovudine and tenofovir disoproxil fumarate (TDF). The top five overall adverse effects were peripheral sensory polyneuropathy comprising 46.1% (n = 82) of all adverse effects, renal toxicity , lipodystrophy , zidovudine induced anaemia  and grade 3 or 4 liver toxicity . Stavudine-induced peripheral neuropathy accounted for 34.8% of all adverse events (n = 62).Overall, seven patients experienced treatment failure and were switched to second-line ART comprising of a ritonavir boosted protease inhibitor (atazanavir or lopinavir) and two NRTIs. None of the patients failed second line ART. Among the 300 patients in care at the time of analysis, 283 (94.3%) had suppressed viral loads (<50 copies/ml), while 10 (3.3%) had viral loads >1000 copies/ml and seven (2.3%) had low-level viremia (50–1000 copies/ml). Among those with viral loads >1000 copies/ml, 5/10 had been receiving ART for less than 24 weeks. Among those who died, 28 (31.8%) had been receiving ART for less than 24 weeks.From a median baseline CD4 T-cell count (IQR) of 158 cells/μL (86–274), median CD4 T-cell counts gradually increased from years 1–5 of follow-up to 254 cells/μL (181–399), 305 cells/μL (221–452), 348 cells/μL (249–464), 353 cells/μL (236–465), and 374 cells/μL (273–522) .2, with 22 in CKD stage 3, and four in CKD stage 4. Of these 26 patients with CKD stage 3 or 4, 20 were female. Twenty-four (5.7%) patients, mostly female (18/26) had incident malignancies. Among females, eight were diagnosed with cervical carcinoma in situ III , and five with cervical cancer. Other cancer types among women with one patient each were Kaposi’s sarcoma, non-Hodgkin’s lymphoma, myosarcoma, hepatoma and ocular malignancy not specified. Among males, two patients had Kaposi’s sarcoma, two had multiple myeloma, one had cancer of the penis and another had lymphoma.During follow-up, the most common incident comorbidities were hypertension, arthritis , and chronic kidney disease (CKD) with 112 (26.7%), 83 (19.8%) and 73 (17.4%) new diagnoses, respectively . Among tOverall, 259 (61.7%) of participants had at least one chronic non-communicable disease (NCD) whether prevalent at baseline or diagnosed during follow-up, excluding cervical carcinoma in situ III and vulvar intraepithelial neoplasia III. More females had NCDs  than males  (p < 0.004).Overall, 245 (58.3%) patients were receiving at least one additional chronic disease medicine other than ART . A higher proportion of females 156 (64.7%) were receiving additional chronic disease medicines compared to males (49.7%) (p = 0.002). Sixty-eight (16.2%) patients had more than three additional chronic disease medicines, and 24 (5.7%)  were receiving more than five. The top five most used chronic disease medicines were the antihypertensives hydrochlorothiazide (16.1%), amlodipine (12.6%), nifedipine (12.6%), enalapril (9.7%), and atenolol (8.9%).In the univariate analysis, increasing enrolment age, unemployment, and baseline WHO status 3 or 4 (HR: 2.66 (1.72–4.12), p < 0.001) were significant predictors of death while increasing baseline CD4 T-cell counts were protective. Low CD4 T-cell counts, male sex, being unmarried and being unemployed were independent risk factors of death with male patients being twice as likely to die compared with females . PatientWe present the treatment outcomes of OPLHIV who enrolled into care at Newlands Clinic in Harare, Zimbabwe, between February 2004, and April 2020. In this cohort, most patients were severely immune suppressed at enrolment, with significant differences between males and females in marital status, employment, and education. Hypertension was the most prevalent baseline and incident comorbidity, disproportionately affecting women. At analysis, 71.4% of patients were still in care, while 21% had died and only 4% had been lost to follow-up. ART related adverse effects were common, with 42% experiencing at least one side effect. ART was highly successful, with 94% of patients who had received ART for over six months being virally suppressed at the time of analysis. Over half of the patients (58%) received concomitant chronic disease medicines with their ART, mostly antihypertensives. Low baseline CD4 T-cell counts, being unmarried, being unemployed and being male were independent risk factors of all-cause mortality.To our knowledge, this is the first study profiling outcomes of ART among OPLHIV in Zimbabwe. Our cohort was similar in sex distribution to other African cohorts that are comprised of more women than men –27. MostThis study spans across a long period during which the WHO recommendations on CD4 T-cell count thresholds for ART commencement changed from <200 cells/μL to <350 cells/μL in 2010, then to <500 cells/μL in 2013, and finally “Treat-All” from 2015 , 31. NevRetention in care of 71.4% after a median follow up time of 5.6 years (IQR: 2.4–9.9) was comparable with that of a younger population (74.4%) at 36 months with a median age of 35 years (IQR: 28–42) in the Zimbabwe National ART Program and higher than that observed in a Kenyan cohort study (54%) at 36 months , 34. HowViral suppression was high amongst those patients in care at 94%. While there are conflicting data on viral suppression and immune recovery among older patients initiating ART . PeriphePrevalence of hypertension was high, as was its incidence during follow-up. This is consistent with previously published Zimbabwean data that estimated hypertension prevalence at 30% (95% CI: 19% - 42%) in the general population . The preLower CD4 T-cell counts at ART commencement, being male, unmarried, or unemployed were independent risk factors of all-cause mortality in this cohort. Advanced immunosuppression, depicted by CD4 T-cell counts below 100 cells/μL, is an indicator of late ART initiation or presentation to care and is associated with high mortality across all age groups , 34, 43.The strength of this study is the high quality of the data, which is ensured by routine data quality checks conducted by clinicians and a data quality manager. However, our study was based on routinely collected data, and we note some of the limitations associated with this method. HIV viral load monitoring was introduced in 2014, and analysis of viral suppression outcomes before this period could not be done. Cause of death information was not available in the records of deceased patients presenting a limitation in our analysis of risk factors of mortality. Furthermore, our study spans a 16-year period during which mortality risk factors may have evolved significantly. The outcomes of this cohort may not be generalizable to other facilities that have a less comprehensive approach to ART management than provided by Newlands Clinic or have much higher patient to clinician ratios. However, these outcomes show what can be achieved in the care of OPLHIV.Our study showed high HIV treatment success among OPLHIV, but with a high burden of hypertension, particularly among women. Low CD4 T-cell counts, male sex, being unmarried and being unemployed were independent predictors of mortality, highlighting the importance of social and socioeconomic factors in addition to the well described early ART for longevity among OPLHIV. We recommend psychosocial support programs to augment the “treat-all” approach aimed at providing ART early before severe immune suppression to improve longevity among OPLHIV.S1 Checklist(DOCX)Click here for additional data file. 19 Mar 2021PONE-D-20-32848Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A Cohort StudyPLOS ONEDear Dr. Shamu,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by May 03 2021 11:59PM. 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Note that if your paper is accepted for publication, this checklist will be published as part of your article.3. As part of your revision, please complete and submit a copy of the RECORD checklist, a document that aims to improve reporting and reproducibility of observational studies that use routinely-collected data for purposes of post-publication data analysis and reproducibility: . 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: This well written manuscript describes HIV care and treatment outcomes as well as NCDs in OPLHIV starting HIV treatment aged 50 or older. Generally it is a well organized manuscript with clear methods, appropriate analysis, and sound discussion. I have only minor suggestions/questions for the authors:1) For the definition of hypertension, on "two separate occasions" likely means two different days, as opposed to two measurements on the same day, but recommend clarification.2) Recommend CD4 T cell count to CD4 cell count terminology3) In the abstract, it appears that the number of men and women do not sum to the total studied, but then it becomes clear in the results that the numbers used in the abstract were just referring to the number with a given marital status. Consider showing the denominator of total n men and women in the abstract or another method to clarify.4) In the introduction, it is stated that there is no similar data on OPLHIV in Zimbabwe - here would be a good place to comment briefly on the existence of OPLHIV data elsewhere in SSA, which is addressed in more detail in the discussion.5) Recommend highlighting which were the adverse effects attributable to tenofovir, as this is a component the new standard first line regimen, TLD.6) Would the study have captured aspirin use for risk reduction in those with HTN? Worth a comment, in my view.7) the finding associated with increased risk of mortality and being unmarried merits some additional discussion.Reviewer #2: This cohort study of 420 patients who are living with HIV and over 50 years old presenting for care and started ART at a clinic in Harare, Zimbabwe over a 16 year period. This cohort demonstrates a high mortality rate (21%) despite high rates of viral suppression (94%). High mortality correlated with delayed initiation of ART (WHO stage 3-4 at initiation) (aHR=3.0) and male sex (aHR=2.0) as well as indicators of poverty (unemployment) and being unmarried. I would recommend revising the analysis to include baseline CD4 count rather than WHO stage as a more objective measure of immunosuppression at initiation of ART. This manuscript is well written aside from some minor grammatical errors  and includes interesting data that indicate the importance of considering gender and socioeconomic status when considering management of persons living with HIV who are >50 years old in order to reduce the risk of early mortality. This analysis adds to the evolving literature around aging and HIV and risk factors for mortality.General comments:1) Both male sex and increased years of uncontrolled viral load (low nadir CD4/high WHO stages) are independent risk factors for cardiovascular disease, and a high incidence rate of hypertension in this cohort, especially among female patients, is a notable mortality risk. However, the absence of cause of death data does not allow for further analysis and may reflect limited life expectancy for all adults in Zimbabwe. This should be more clearly indicated as a limitation of the analyses.2) Given the long duration of 14 years over which this cohort was accrued, the authors should discuss the limitations of temporal trends that could have impacted mortality risks between 2004 and 2020.3) Additional analyses may further illuminate the high mortality rate, especially since univariate analysis was not impacted by prevalent hypertension. In addition, differences by sex should be explored further by adjusting for CD4 count at treatment initiation. Longitudinal multivariate analysis of incidence hypertension, chronic kidney disease, malignancy, and TB would be needed to support the conclusions of this manuscript.Specific comments:1) Line 57 –Be more specific about special considerations for HIV care in aging adults living with HIV. Additionally, increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed.2) Lines 58-59 – Your data and the reference above indicate high rates of adherence in this demographic. Would you consider drug interactions altering drug availability or frequent changes in ART regimen to avoid drug interactions leading to disruptions more accurate that poor adherence?3) Line 80- do you mean PLHIV (rather than OPLHIV) or does this clinic only provide care to patients over the age of 50 years old?4) Line 84 – rather than using the term “vulnerable communities,” which implies weakness, UNAIDS terminology guidelines suggest using specific language such as “communities with high prevalence of poverty and unemployment.”5) Line 132 – Clarify elderly, e.g., “420 patients 50 years or older…”6) Line 152 – Given the elevated p-value, it would be appropriate to state that males and females died at a similar rate.7) Line 202- If possible please clarify “cancer of the eye” or replace with “ocular malignancy not specified”8) Risk of death analysis and Table 4a) The baseline CD4 count was removed from the multivariate analysis because of collinearity with WHO stage. I would suggest removing WHO stage which is a more subjective measure than a CD4 count, especially given the apparent difference in CD4 count at initiation by sex  in the last decade.b) Most participants provide multiple measures of blood pressure over time and the incidence of hypertension is quite high. It would be helpful to indicate what proportion of persons reported to have HTN were noted to have elevated BP at multiple visits.c) Incidence of CKD, TB, and malignancy were also quite high. A longitudinal multivariate analysis of incident hypertension, CKD, TB, and malignancy correlation with mortality risk would be informative.9) Lines 235-237, 251 – The authors note several differences between sexes in prevalence of social hardship and hypertension with females disproportionately impacted; however, male patients had a higher mortality rate. This warrants a comment from the authors.10) Line 248 – Please clarify if you are referring to differences between males and females, sex, vs. social roles, genders. The word gender should be replaced with sex in this context.11) Line 262 – Is this an observation from this cohort? Please ensure that these data on difference in baseline CD4 count and delayed treatment by sex are included in your results section. If these data are not available for your cohort, the reference to Western Cape cohort should be limited to the introduction section.12) Line 269 – It is not possible to know if patients who died would have stayed in care if they were still living, and thus your data do not support your claim that older patients are more likely to remain committed to care than younger people, especially when the amount of patient tracking and staff outreach may differ at these different clinics.13) Line 280 – Please comment on the prevalence of peripheral neuropathy and other side effects experienced in your cohort compared to other, younger cohorts.14) Line 301-303 – Please explain your recommendation for enhancing enrollment strategies for males as a mechanism for reducing mortality among men living with HIV. It is curious that males had high rates of viral suppression but also had a high mortality rate. Figure 1 appears to show lower CD4 at initiation of ART, especially after 2011. Do you have additional data to explain higher mortality rate among males? Can risk of mortality among males be explained by CD4 count at initiation of ART?15) Line 303-304 – Did unmarried patients have higher likelihood of failing treatment or uncontrolled viral loads? Please provide further data to explain the correlation between unmarried status and mortality in your cohort.16) Line 320 – Please list all independent predictors of mortality not just WHO stage and unemployment.17) Conclusion. The results mention the impact of TB and CKD but these were not included in your multivariate (or univariate) analyses. Were these predictors of mortality?**********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, AttachmentPONE_review_20210310.docxSubmitted filename: Click here for additional data file. 3 May 2021Response to ReviewersResponses to the Editor1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfResponseWe have ensured that our manuscript is consistent with PLOS ONE’s requirements.2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.ResponseWe have reviewed the reference list and have not found any retracted papers. We have also checked completeness of the references.http://record-statement.org). Please include your completed checklist as a Supporting Information file. Note that if your paper is accepted for publication, this checklist will be published as part of your article.3. As part of your revision, please complete and submit a copy of the RECORD checklist, a document that aims to improve reporting and reproducibility of observational studies that use routinely-collected data for purposes of post-publication data analysis and reproducibility:  For the definition of hypertension, on "two separate occasions" likely means two different days, as opposed to two measurements on the same day, but recommend clarification.ResponseThank you for this comment. We have reviewed the sentence to read “Diagnosis of hypertension was made when a patient’s systolic or diastolic blood pressure was above 140mm Hg or above 90mm Hg, respectively, on two or more days”2) Recommend CD4 T cell count to CD4 cell count terminology.ResponseWe have replaced “CD4 cell count” with CD4 T-cell count.3) In the abstract, it appears that the number of men and women do not sum to the total studied, but then it becomes clear in the results that the numbers used in the abstract were just referring to the number with a given marital status. Consider showing the denominator of total n men and women in the abstract or another method to clarify.ResponseThank you for noting the discrepancy. We have corrected the figures in both the abstract and Table 1. We have added the denominator in the abstract for clarity.4) In the introduction, it is stated that there is no similar data on OPLHIV in Zimbabwe - here would be a good place to comment briefly on the existence of OPLHIV data elsewhere in SSA, which is addressed in more detail in the discussion.ResponseThank you for this comment. We have added a comment on data from the region.5) Recommend highlighting which were the adverse effects attributable to tenofovir, as this is a component the new standard first line regimen, TLD.ResponseIn the absence of definitive diagnoses of renal impairment which often require kidney biopsies, we could not objectively attribute specific adverse effects to TDF. However, as part of routine clinical care, TDF was stopped with presumptive diagnosis of TDF adverse effects.6) Would the study have captured aspirin use for risk reduction in those with HTN? Worth a comment, in my view.ResponseWe have added the statement “Risk reduction of major adverse cardiovascular events using aspirin was only provided for patients with history of myocardial infarction”. These patients are very few.7) The finding associated with increased risk of mortality and being unmarried merits some additional discussion.ResponseWe have added the statement “Older patients with HIV face a number of challenges that may affect their quality of life. Loss of partners and friends may lead to social isolation, depression and poor adherence to medicines”.Reviewer 2General comments:1. Both male sex and increased years of uncontrolled viral load (low nadir CD4/high WHO stages) are independent risk factors for cardiovascular disease, and a high incidence rate of hypertension in this cohort, especially among female patients, is a notable mortality risk. However, the absence of cause of death data does not allow for further analysis and may reflect limited life expectancy for all adults in Zimbabwe. This should be more clearly indicated as a limitation of the analyses.ResponseThank you for this comment. We have added this limitation in the paragraph discussing strengths and weaknesses of the study as highlighted below:“Cause of death information was not available in the records of deceased patients presenting a limitation in our analysis of risk factors of mortality. Furthermore, our study spans a 16-year period during which mortality risk factors may have evolved significantly.”2. Given the long duration of 14 years over which this cohort was accrued, the authors should discuss the limitations of temporal trends that could have impacted mortality risks between 2004 and 2020.ResponseThank you for this comment. We have also added this limitation in the paragraph discussing strengths and weaknesses of the study as highlighted above.3. Additional analyses may further illuminate the high mortality rate, especially since univariate analysis was not impacted by prevalent hypertension. In addition, differences by sex should be explored further by adjusting for CD4 count at treatment initiation. Longitudinal multivariate analysis of incidence hypertension, chronic kidney disease, malignancy, and TB would be needed to support the conclusions of this manuscript.ResponseThank you for this comment. We analysed the mortality differences by sex adjusting for CD4 count alone and the difference was not apparent. However, adjusting for the other confounders showed that indeed sex is an independent risk factor. Instead of performing additional multivariable analyses on hypertension incidence, CKD, malignancy, and TB, we reviewed the conclusion to reflect findings that were observed in the original analysis. The conclusion now reads as follows:“Our study showed high HIV treatment success among OPLHIV, but with a high burden of hypertension, particularly among women. Low CD4 T-cell counts, male sex, being unmarried and being unemployed were independent predictors of mortality, highlighting the importance of social and socioeconomic factors in addition to the well described early ART for longevity among OPLHIV. We recommend psychosocial support programs to augment the “treat-all” approach aimed at providing ART early before severe immune suppression to improve longevity among OPLHIV.”Specific comments:1. Line 57 –Be more specific about special considerations for HIV care in aging adults living with HIV. Additionally, increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed.ResponseThank you for this comment. We have reviewed the sentence as follows, “. Management of OPLHIV requires a multidisciplinary team approach, taking into account the onset of non-communicable diseases, premature ageing, and an increased risk of drug-to-drug interactions and drug toxicities due to polypharmacy”.2. Lines 58-59 – Your data and the reference above indicate high rates of adherence in this demographic. Would you consider drug interactions altering drug availability or frequent changes in ART regimen to avoid drug interactions leading to disruptions more accurate that poor adherence?ResponseWe agree with your comment. We have reconsidered and edited the sentence as follows: “Polypharmacy also complicates selection of ART regimens and the increased chronic pill burden may lead to treatment fatigue”.3. Line 80- do you mean PLHIV (rather than OPLHIV) or does this clinic only provide care to patients over the age of 50 years old?ResponseThank you for noting this error. We have corrected the sentence as follows:“Apart from providing antiretroviral therapy to people living with HIV, the clinic also provides, among other services, onsite laboratory investigations, psychosocial support, reproductive health services including cervical cancer screening, dental services, food support, and bus fare assistance”.4. Line 84 – rather than using the term “vulnerable communities,” which implies weakness, UNAIDS terminology guidelines suggest using specific language such as “communities with high prevalence of poverty and unemployment.”ResponseWe have replaced “vulnerable communities” with the suggested terminology.5. Line 132 – Clarify elderly, e.g., “420 patients 50 years or older…”ResponseWe have removed the term “elderly” from this sentence and it now reads, “During the study period, 420 patients aged 50 years or older were enrolled into care at Newlands Clinic, 241 (57.4%) being female”6. Line 152 – Given the elevated p-value, it would be appropriate to state that males and females died at a similar rate.ResponseThank you for this observation. The sentence now reads, “There was no difference in proportion of males died (23.5%) compared to females (19.1%) (p = 0.276)”.7. Line 202- If possible please clarify “cancer of the eye” or replace with “ocular malignancy not specified”ResponseThank you for the suggestion. We have changed the term as suggested i.e., “ocular malignancy not specified”.8. Risk of death analysis and Table 4a) The baseline CD4 count was removed from the multivariate analysis because of collinearity with WHO stage. I would suggest removing WHO stage which is a more subjective measure than a CD4 count, especially given the apparent difference in CD4 count at initiation by sex  in the last decade.ResponseWe have repeated the analysis with CD4 included and WHO stage excluded from the Cox model. Table 4 is now updated with new results.b) Most participants provide multiple measures of blood pressure over time and the incidence of hypertension is quite high. It would be helpful to indicate what proportion of persons reported to have HTN were noted to have elevated BP at multiple visits.ResponseWe agree that uncontrolled hypertension among hypertensive patients is interesting but would be better addressed as a different study. In the current study, we used the diagnosis variable to determine the burden of hypertension but we did not abstract individual blood pressure measurements from the database. As described in the methods section, a diagnosis of hypertension was made at the clinic when a patient’s systolic or diastolic blood pressure was above 140mm Hg or above 90mm Hg, respectively, on two or more days.c) Incidence of CKD, TB, and malignancy were also quite high. A longitudinal multivariate analysis of incident hypertension, CKD, TB, and malignancy correlation with mortality risk would be informative.ResponseThe authors agree with this comment. However, we feel that in-depth analysis of the various aspects listed above would go beyond the scope of this current study and may be better done as separate studies.9. Lines 235-237, 251 – The authors note several differences between sexes in prevalence of social hardship and hypertension with females disproportionately impacted; however, male patients had a higher mortality rate. This warrants a comment from the authors.ResponseWe have added the following statement in the discussion: “Despite women being disproportionately affected by adverse social factors as well as hypertension, male patients still had a higher mortality risk in keeping with global general population trends”.10. Line 248 – Please clarify if you are referring to differences between males and females, sex, vs. social roles, genders. The word gender should be replaced with sex in this context.ResponseWe have removed the word “gender” from the sentence, and it now reads, “This difference is common in sub-Saharan Africa, where widows are less likely to remarry than widowers.”11. Line 262 – Is this an observation from this cohort? Please ensure that these data on difference in baseline CD4 count and delayed treatment by sex are included in your results section. If these data are not available for your cohort, the reference to Western Cape cohort should be limited to the introduction section.ResponseWe agree with your comment. We have removed this sentence.12. Line 269 – It is not possible to know if patients who died would have stayed in care if they were still living, and thus your data do not support your claim that older patients are more likely to remain committed to care than younger people, especially when the amount of patient tracking and staff outreach may differ at these different clinics.ResponseThank you for this comment. We have edited the sentence to read as, “However, unlike with this larger Zimbabwean study of younger patients wherein 98% of attrition was due to loss to follow-up, 74% of attrition in our cohort was due to death.”13. Line 280 – Please comment on the prevalence of peripheral neuropathy and other side effects experienced in your cohort compared to other, younger cohorts.ResponseWe have added the following sentence in the discussion, “Older age has been shown to be associated with peripheral neuropathy in both HIV infected and uninfected people”.14. Line 301-303 – Please explain your recommendation for enhancing enrollment strategies for males as a mechanism for reducing mortality among men living with HIV. It is curious that males had high rates of viral suppression but also had a high mortality rate. Figure 1 appears to show lower CD4 at initiation of ART, especially after 2011. Do you have additional data to explain higher mortality rate among males? Can risk of mortality among males be explained by CD4 count at initiation of ART?ResponseWe have added Figure 4 which is depicts Kaplan-Meier survival estimates of mortality by baseline CD4 T-cell counts adjusted for sex, employment, and marital status. From the observed curves, we have edited the comment in the discussion as follows: “The observed trend of persistently higher mortality throughout the follow-up period among people who initiated ART with lower CD4 T-cell counts and the lower baseline CD4 T-cell counts among men affirms the need for a shift in the HIV treatment strategy to improve the ART outcomes observed in men starting with enhanced enrolment strategies”.15. Line 303-304 – Did unmarried patients have higher likelihood of failing treatment or uncontrolled viral loads? Please provide further data to explain the correlation between unmarried status and mortality in your cohort.ResponseThis comment has been partly addressed in comment number 7 under Reviewer 1. In addition, we have added the following statements after Table 4:“Increasing baseline CD4 T-cell counts were associated with lower likelihood of failing ART (p = 0.017), whereas being male, unemployed, or unmarried were not associated with failing ART. Among patients still in care, the number of patients with unsuppressed viral loads was too low to assess for association between independent risk factors of death and having unsuppressed viral loads.”16. Line 320 – Please list all independent predictors of mortality not just WHO stage and unemployment.ResponseThank you for the comment. We have added all independent predictors of mortality to the conclusion.17. Conclusion. The results mention the impact of TB and CKD but these were not included in your multivariate (or univariate) analyses. Were these predictors of mortality?ResponseThank you for this comment. The conclusion has been reviewed as shown in the response to comment 3 under general comments.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 18 May 2021PONE-D-20-32848R1Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A Cohort StudyPLOS ONEDear Dr. Shamu,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but requires further clarifying revision. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Jul 02 2021 11:59PM. 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If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.Additional Editor Comments (if provided):(1) Please address the reviewer's comment re line 64 (formerly line 57) that discusses accelerated immune senescence and disease progression in the elderly. The reviewer point outs: "increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed."(2) Table 4 requires further revision to remove reference to WHO staging in favor of baseline CD4 cell count which is more objectively assessed than the former. There also remains a footnote re WHO staging that will need to be removed.[Note: HTML markup is below. Please do not edit.]https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  24 May 2021Thank you for the follow-up response to our re-submission. Below are responses to the two issues raised in the email dated 18 May 2021:Comment 1 Please address the reviewer's comment re line 64 (formerly line 57) that discusses accelerated immune senescence and disease progression in the elderly. The reviewer point outs: "increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed."ResponseWe previously revised the original sentence suggesting increased risk of opportunistic infections (OI) as suggested by the reviewer and removed the OI connotation. The revised sentence reads as follows, “Management of OPLHIV requires a multidisciplinary team approach, taking into account the onset of non-communicable diseases, premature ageing, and an increased risk of drug-to-drug interactions and drug toxicities due to polypharmacy”. To improve clarity, we have revised the preceding sentence as well which now reads, “Compounding the age-related thymic contraction, HIV infection affects both B- and T-cell function leading to accelerated immunosenescence and consequently increased risk of non-AIDS related, age associated comorbidities in elderly patients”, with the relevant references added.Comment 2Table 4 requires further revision to remove reference to WHO staging in favor of baseline CD4 cell count which is more objectively assessed than the former. There also remains a footnote re WHO staging that will need to be removed.ResponseWe have removed the row with WHO stage from Table 4 and indicated the unadjusted hazard ratio in the text. We have also corrected the Table 4 footnote which now reads, “Baseline WHO clinical stage was omitted from multivariable analysis due to collinearity with baseline CD4 T-cell count.”AttachmentResponse to Reviewers.pdfSubmitted filename: Click here for additional data file. 27 May 2021Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A Cohort StudyPONE-D-20-32848R2Dear Dr. Shamu,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. 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For more information, please contact Kind regards,Hyang Nina Kim, M.D., M.Sc.Academic EditorPLOS ONE 1 Jun 2021PONE-D-20-32848R2 Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A cohort study Dear Dr. Shamu:I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Hyang Nina Kim Academic EditorPLOS ONE