As integrase inhibitors become available in low‐ and middle‐income countries (LMICs), they offer the potential to expand extremely limited treatment options available to children and adolescents. In LMICs, only small numbers have used raltegravir, primarily as part of third‐line regimens. Using data from the IeDEA global consortium, we aimed to describe the characteristics of children on raltegravir‐containing regimens and their outcomes.We included data from 1994 to 2017 from children (age <18 years), from East and Southern Africa, Asia and South America, who received cART regimens containing raltegravir for ≥90 days. We describe their characteristics at raltegravir start, and their immunological and virological outcomes.In total, 62 children were included, with median age at raltegravir initiation of 14.3 years (IQR 11.2 to 15.8) and median CD4 count of 276 cells/µL (IQR 68 to 494). Among 40 (65%) with drug resistance testing prior to raltegravir, 71% were resistant to at least one protease inhibitor (PI), and 32% had high‐level resistance to at least one drug class. Most  received raltegravir as part of third‐line cART following PI‐based regimens, and were on regimens containing four or more drugs .By database closure, median duration on raltegravir was 2.0 years (IQR 0.8 to 3.0), 1 (1.6%) patient had died, 6 (9.7%) were lost to follow‐up and 21 (34%) had discontinued raltegravir. Among 15 patients reporting reasons for stopping raltegravir, six discontinued because it was no longer available. Within one year of starting raltegravir, among 53 patients with VL measures, 40 (75%) had VL < 1000 copies/mL, and among 54 with a reported CD4 count, 45 (83%) and 36 (67%) were ≥350 and ≥500 cells/µL, respectively, with median CD4 count increasing to 517.5 cells/µL (IQR 288 to 810).Among children in LMICs, the initial use of raltegravir has been primarily for post PI‐based cART. We found good virological and immunological outcomes despite frequent prior triple‐class failure and high levels of drug resistance. Both access to raltegravir and long‐term adherence to regimens with large pill‐burdens remain challenging. Policies which promote earlier access to new drugs and simplify daily regimens for children and adolescents in LMICs are needed. With more children initiating cART as infants when protease inhibitor (PI)‐based regimens are recommended, and with an increasing number of older children surviving longer on cART, there is a growing need for third‐line and salvage options following PI‐failure.New generation PIs, such as ritonavir‐boosted darunavir (DRV/r), as well as the integrase inhibitors (INSTIs) dolutegravir and raltegravir are slowly becoming available to children in LMICs, although their high costs greatly inhibits access. While dolutegravir offers the promise of a lower burden of treatment failure if used in first‐line and is a robust second‐ or third‐line option, it is currently not registered widely for children <6 years old or those <20 kg, whereas raltegravir is approved for use from birth. The 2019 World Health Organization (WHO) policy brief for first‐ and second‐line cART recommends raltegravir‐based regimens as an alternative first‐line for infants and children for whom approved dolutegravir dosing is not available, and as an alternative second‐line option, following failure of PI‐based cART [Whilst raltegravir has been studied as a second‐line option in LMICs in adults , pharmac22.1Children and adolescents living with HIV with a record of being on raltegravir <18 years were eligible for inclusion. We excluded those with <90 days on raltegravir. Data from the previously described IeDEA multi‐regional collaboration of HIV cohort studies  were obt2.2We described the demographic, clinical, immunological and virological characteristics of patients at raltegravir initiation as well as their prior treatment history. We defined third‐line/salvage regimens as any regimen following exposure to PI‐based cART. We summarized the resistance profile of patients with genotypic resistance testing prior to raltegravir initiation, using the Stanford University HIV genotypic resistance interpretation , 9. We dWe described the immunological and virological outcomes for all patients and for those on raltegravir‐based third‐line regimens. Outcomes are reported at six months and one year from raltegravir initiation using the last available CD4 count or viral load (VL) measure in that time period. All analyses were performed in Stata version 15.0 .33.1We identified 80 children on raltegravir, 11 were excluded because they received raltegravir for <90 days, and seven because they were on a clinical trial. Characteristics at cART and raltegravir initiation of the 62 patients included in our study are summarized in Table Among 50 patients with recorded CD4 count at raltegravir start, the median was 276 cells/µL (IQR 68 to 494), 23 (46%) were <200 and 16 (32%) were <100.3.2Prior to initiating raltegravir‐based regimens, 40 patients  had undergone resistance testing, of whom 38 had data on PI resistance, 39 on nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI resistance, and two on INSTI resistance.Both patients with INSTI resistance data were susceptible to all drugs in the class. Figure Among the 38 with PI resistance data, one patient was susceptible to all PIs, 20 (53%) had high‐level resistance to lopinavir/ritonavir (LPV/r) and 23 (61%) had high or intermediate resistance to both atazanavir and LPV/r. Of the 27 (71%) with high‐level resistance to at least one PI, seven were also highly resistant to all NRTIs and four highly resistant to all NNRTIs. Ten (26%) patients had low‐level, three (8%) intermediate and two (5%) high‐level resistance to DRV/r. The two patients with high‐level resistance to DRV/r had high‐level resistance to all other PIs and were resistant to all NNRTIs.The most commonly reported PI drug resistant mutations are shown in Figure 3.3At database closure, the median duration on raltegravir was 2.0 years (IQR 0.8 to 3.0), 1 (1.6%) patient had died, 6 (9.7%) were lost to follow‐up, and 21 (34%) had discontinued raltegravir. Among the 15 patients with recorded reasons for raltegravir discontinuation, six stopped because it was no longer available (2 from each of the African and Asia‐Pacific regions), four because of treatment failure , three due to side effects or drug‐specific toxicity, one related to patient decision and one to switch to more effective treatment. Among the six who stopped because of lack of availability, two were placed on dolutegravir and the remaining four returned to PI‐based regimens.Treatment outcomes for all patients and those on raltegravir as part of third‐line regimens are summarized in Table 3.4Among 53 patients with VL measures within 1 year of starting raltegravir, 40 (75%) were <1000 copies/mL and 37 (70%) were <400. Among the 11 who failed to suppress and with VL > 1000 on initiating raltegravir, seven (64%) experienced reductions in VL, with median reduction 5.2 log (IQR 3.9 to 5.4), and four (36%) had increasing VL. Similar rates of virological suppression were experienced by those initiating raltegravir as part of third‐line regimens  and 36 (67%) were ≥350 and ≥500 cells/µL, respectively, with median CD4 count increasing by 242 to 517.5 (IQR 288 to 810). Within 1 year on raltegravir, among 36 patients who started with CD4 < 500, median CD4 count increased from 70 (IQR 22 to 210) to 285 (IQR 106 to 382); 15 (42%) recovered to CD4 ≥ 500 and 23 (64%) had CD4 ≥ 350. However, three (8%) experienced declining CD4, with declines of between 3 and 264. All 11 patients with CD4 ≥ 500 at raltegravir start maintained CD4 ≥ 500 within one year. For those on third‐line, although the median CD4 count at raltegravir start and within one year was lower, there was a similar increase of 286 in median CD4 count to 496 (IQR 288 to 869) (Table This study represents the largest reported cohort of children receiving raltegravir as part of routine care in LMICs. Raltegravir was primarily used following failure of PI‐based regimens, initiated during adolescence, after long durations on cART, with almost half of children being immunocompromised. Despite high levels of drug resistance to other classes prior to raltegravir, there were good virological outcomes with three‐quarters of patients suppressing within one year. Median CD4 count substantially increased and most patients experienced immune recovery or maintained CD4 ≥ 500 cells/µL. Notably, three‐quarters of patients received raltegravir as part of regimens containing four or more drugs. This large pill‐burden and the fact that raltegravir is taken twice daily, possibly contributed to difficulties with long‐term adherence, with close to 20% of patients experiencing viral rebound following suppression. This is concerning and raises the questions of whether poor adherence to raltegravir could compromise future use of dolutegravir. Moreover, many of those stopping raltegravir did so due to lack of availability, demonstrating local challenges to sustaining access to less commonly used antiretrovirals.The most recent WHO guidelines recommend INSTI‐based second‐line for children and infants following failure of first‐line PI‐based cART. Our study provides some of the initial evidence of the use of raltegravir for this purpose, with a third of patients having had prior exposure to only PI‐based cART. Our results show that raltegravir provided effective treatment for children with few alternatives. Half our patients had prior treatment with both NNRTI‐ and PI‐based cART. Almost a quarter had exposure to RTV‐only based cART, now known to select for major PI resistance mutations . High leWhile there are studies on the use of INSTIs and third‐line regimens among children and adolescents in LMICs, they have included only small numbers of patients. A study of 12 heavily pre‐treated French adolescents who were treated with raltegravir, DRV/r or etravirine and a Spanish study of 23 multidrug‐resistant paediatric patients who received etravirine both reported good virological outcomes with few side effects , 12. TwoOur study is limited by the use of routinely collected data for a small number of children from different regions where eligibility criteria for raltegravir, and prior drug resistance testing varied. We did not have data on drug formulations, adherence to raltegravir or on measures taken to address adherence barriers across the different regions.4Among adolescents and children in LMICs, raltegravir provided a much‐needed treatment option for children failing PI‐based first‐ and second‐line cART. We found good virological and immunological outcomes despite frequent prior triple‐class failure and high levels of drug resistance, but accessing this drug remains challenging and pill burden was high. Policies which promote earlier access to new drugs for children and adolescents in LMICs to improve treatment outcomes and simplify daily regimens are needed.The authors declare that they have no competing interests.GP undertook the data compilation and analysis, generated the tables and figures, interpreted the results, wrote all drafts and finalized the manuscript. TP, CM, KW‐K, RH, JP, DM, RS, AS, HR, BM and M‐AD managed the cohort and transferred routinely collected data. All authors were involved in designing the study and reviewed the final manuscript.


K65R was the most common minority mutation, of 95.1% (58/61) and 93.1% (54/58) in CRF07_BC and CRF08_BC, respectively, when compared with 5.7% (2/35) in CRF01_AE (p < 0.001). In 49 patients that followed-up a median 10 months later, HIV drug resistance mutations at >20% frequency such as K103N, M184VI and P225H still existed, but with decreased frequencies. The prevalence of HIV drug resistance in ART interruption was higher than 15% in the survey. Next-generation sequencing was able to detect more minority drug resistance variants than Sanger. There was a sharp increase in minority drug resistance variants when the detection threshold was below 5%.Patients with antiretroviral therapy interruption have a high risk of virological failure when re-initiating antiretroviral therapy (ART), especially those with HIV drug resistance. Next-generation sequencing may provide close scrutiny on their minority drug resistance variant. A cross-sectional study was conducted in patients with ART interruption in five regions in China in 2016. Through Sanger and next-generation sequencing in parallel, HIV drug resistance was genotyped on their plasma samples. Rates of HIV drug resistance were compared by the McNemar tests. In total, 174 patients were included in this study, with a median 12 (interquartile range (IQR), 6–24) months of ART interruption. Most (86.2%) of them had received efavirenz (EFV)/nevirapine (NVP)-based first-line therapy for a median 16  months before ART interruption. Sixty-one (35.1%) patients had CRF07_BC HIV-1 strains, 58 (33.3%) CRF08_BC and 35 (20.1%) CRF01_AE. Thirty-four (19.5%) of the 174 patients were detected to harbor HIV drug-resistant variants on Sanger sequencing. Thirty-six (20.7%), 37 (21.3%), 42 (24.1%), 79 (45.4%) and 139 (79.9) patients were identified to have HIV drug resistance by next-generation sequencing at 20% (v.s. Sanger,  By the l counts , a highel counts  and are The emergence of HIV drug resistance (HIVDR) results from the low fidelity of HIV reverse transcriptase, the rapid replication of the virus and the selective pressure of antiretroviral drugs . It willHIVDR assays are usually carried out using Sanger sequencing (SS), which can detect minority variants at a 15%–20% frequency in HIV viral populations (quasi species) within patients , with inIn this study, we conducted a cross-sectional survey among patients under ART interruption, and compared the mutation detection between NGS and SS using plasma samples from patients with ART interruption, to provide more information about detecting low-frequency drug resistance mutations and further assistance in implementing ultrasensitive HIVDR surveillance in routine assays and to guide the choice of treatment regimen.+ T cell count of <200 cells/mm3 at investigation. A total of 150 (86.2%) patients had received non-nucleotide reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral regimens (stavudine (d4T)/azidothymidine (AZT)/tenofovir (TDF) + lamivudine (3TC) + efavirenz (EFV)/nevirapine (NVP)) before ART interruption. The median duration of treatment before ART interruption was 16 (interquartile range (IQR): 7–26) months, while the median duration of ART interruption was 12 (IQR: 6–24) months at survey.A total of 174 patients were included in the survey in 2016 . Only 60pol region by Sanger sequencing (p < 0.001). Other low-frequency NRTI-related mutations were K70QE, F77L, T215AI and K219QE. M46LI was the common low-frequency PI-related mutation, with frequencies ranging from 1% to 13%. Other PI-related mutations such as L10F, I47V, I50V, F53L, I54VT and N83D have the mutation frequency of about 2%.Drug resistance mutations (DRMs) were detected at 12 positions in the partial quencing , includip < 0.05). For PI and NRTI, the prevalence of HIVDR was the same at 0.6%, identified by SS and NGS at the 15% detection threshold. However, NGS at the 1% and 2% thresholds identified more NRTI-related drug resistance variants  than SS. Compared with NGS, a slightly lower percentage of HIVDR was found by SS for NNRTI-related drug resistance  of the patients were shown to have drug resistance variants. With NGS, the rate of resistance was the same; 20.7% (36/174) at the detection thresholds 20% and 15%. It climbed up to 21.3% (37/174), 24.1% (42/174), 45.4% (79/174) and 79.9% (139/174) at thresholds 10%, 5%, 2% and 1%, respectively. Compared with SS, NGS got significantly higher rates of drug resistance at the 1%, 2% and 5% thresholds , 265 cell/mm3 (IQR: 172–378) and 222 cell/mm3 (IQR: 82–302), respectively (p < 0.05). In addition, their median viral loads were 4.6 log10 copies/mL (4.0–4.9), 4.3 log10 copies/mL (IQR: 3.6–4.7) and 4.0 log10 copies/mL (IQR: 3.6–4.4), respectively (p < 0.05). In addition, there was a statistically significant difference in the viral loads between patients with high-frequency variants and patients without variants . At baseline, mutations with a frequency of 20% and above were NRTI-related, such as M184VI , and NNRTI-related like K103N , E138AG , V179D  and P225H . Although these variants still existed at follow-up, the frequencies of the mutations M184VI, K103N and P225H decreased over time, and most of them remained at frequencies of more than 20%. However, the frequency of K103N in one patient (GX064) had dropped from 43.7% to 15.3%, and the mutation K103N in another patient (CQ046) with a frequency of 36.9% disappeared . Within In this study, a cross-sectional survey was conducted among 174 patients with ART interruption in five areas more heavily affected by HIV/AIDS in China. The prevalence of HIVDR was 19.5% at Sanger sequencing, which was obviously higher than a pretreatment HIVDR survey conducted among ART naïve patients in 2017 . A crossIt was unexpected to get higher rates of HIVDR at NGS than through Sanger sequencing. However, the increase in HIVDR was not statistically significant until the detection threshold was lowered to 5%. Moreover, DRMs detected in protease would have limited impacts on such PIs as Lopinavir/r (LPV/r) in second-line regimens. Four DRMs including D30N (1), M46I (2) and N88D (1) were detected in protease in four participants at a 5%–15% frequency, in addition to one Q58E at a frequency above 90%. The former two confer high or intermediate resistance to Nelfinavir, which is seldomly used at present. N88D and Q58E are PI accessary resistance mutations. There were slight increases in NRTI and NNRTI resistance at the threshold of 5%, when compared with the threshold of 20% or SS, which was consistent with other previous studies ,30.Despite the same primer sets for reverse transcription and PCR amplification, there were three NNRTI DRMs in three patients with frequencies between 23% and 44% detected by NGS, not SS. These discrepancies were more likely to be PCR resampling produced at the first several rounds of amplification, and less likely to be the artifacts during NGS sequencing, as NGS artifacts had a <1% frequency and were randomly distributed. Compared with that at the threshold of 5%, the rates of HIVDR were almost doubled when the threshold decreased to 2%, and tripled when down to 1%, as very-low-frequency DRMs were dramatically increased between 1% and 5%. The minority mutations detected by NGS may have resulted from apolipoprotein B mRNA editing catalytic polypeptide (APOBEC)-mediated G-to-A hypermutation such as E138K, M184I and G190E in RT or spontaneous mutation during viral replication, or from PCR error, which was introduced by error-prone reverse transcriptase or PCR enzymes . The shaThe most common NNRTI DRM above a 5% frequency was K103N (14.4%) in RT, which is consistent with the ART history of EFV/NVP-based first-line therapy. In NRTI DRMs, K65R was the highest (1.2%) at a >5% frequency, which was similar to other research results ,38. In a+ T cell counts. After the interruption of antiretroviral therapy, the CD4+ T cell count drops rapidly in the first few months, then declines slowly [+ T cell count between patients with and without HIVDR variants [+ T cell counts among the three groups. After the interruption of ART, the viral load level increased exponentially, reaching a peak of 106 copies/mL. Then, the viral load usually drops to 103–105 copies/mL within a few weeks, which can remain relatively stable for many years [3 copies/mL, and there were statistical differences in the viral loads among the three groups.The disease progression in patients with HIV is usually monitored by measuring their CD4s slowly ,41. A prvariants . In thisny years . In thisGenerally speaking, the drug resistance rate will decrease over time in patients after ART interruption. This trend is mainly due to the fact that, in the absence of drug selection pressure, wild-type strains with high viral fitness replace resistant strains to become the main strains in patients . CompareThere are limitations to this study. Firstly, the number of participants was limited. The findings could not be simply extrapolated to other patients with ART interruption. However, the fall or rise in DRMs would be similar to the other settings without ART. The minority DRMs detected by NGS were consistent with other pre-treatment surveys. Secondly, the participants in this study mainly used NNRTI-based first-line regimens before ART interruption. Thus, the findings were not able to reflect the situations with the interruption of ART on PI or integrase inhibitors. Thirdly, the rate of follow-up was low, as patients with ART interruption also dropped out of the HIV care program and were reluctant to keep the follow-up appointments.In conclusion, patients with ART interruption had higher HIVDR, especially to EFV/NVP. NGS is able to detect more DRMs in such patients than SS, but largely at frequencies of less than 5%. Studies have shown that the drug resistance reports based on a 5% threshold can predict the failure of ART ,45. Due We conducted a cross-sectional study among adult patients with ART interruption between 1 January and 31 December 2016, in four provinces and one municipality of China, including Guangxi, Henan, Sichuan, Yunnan and Chongqing, where in China the HIV epidemic was more concentrated, as described previously . Inclusipol gene region using an in-house method [Viral RNA was extracted using the QIAamp viral RNA mini kit , following the manufacturer’s protocol. Extracted RNA was used for amplification of the PR region (4–99 amino acids) and the partial RT region (1–251 amino acids) of the HIV-1 e method . Brieflyhttps://recall.bccfe.ca/who_qc/, accessed on 23 September 2019) and through constructing Neighbor joining phylogenetic trees using MEGA (version 6.06). HIV-1 subtypes were determined using reference sequences from HIV Databases  through phylogenetic trees. The drug resistance mutations were identified and interpreted using the HIVdb version 8.9-1 .The amplified products were sequenced using Sanger sequencer ABI 3730 . Obtained raw sequences were edited and assembled using Sequencher . The secondary peak threshold was set to 20%. The edited sequence was aligned with the HXB2 reference sequence through BioEdit . Sample contamination and other sequence quality controls were monitored using the WHO HIVDR QC tool  according to HyDRA Web User Guide [Second-round amplicons were cleaned using KAPA PureBeads  and quantified using the Qubit dsDNA HS assay kit . Sequencing libraries were prepared using the 96-sample KAPA HyperPlus Kit . The samples were pooled in each run with a 40% Phix control library  to increase the diversity of libraries and then sequenced on the Illumina Miseq system  using a er Guide , producip values of <0.05 were considered statistically significant.DRMs were identified according to the 2019 International Antiviral Society (IAS) list. HIV drug resistance was defined as low-, intermediate- or high-levels of drug resistance according to the HIVdb algorithm 8.9-1. HIV drug resistance was determined based on NGS with detection thresholds of 20%, 15%, 10%, 5%, 2% and 1%, and was compared with that detected based on Sanger sequencing by the McNemar test, respectively. Quantitative data are presented as medians and were analyzed by the Kruskal–Wallis test. All data were analyzed using the Statistical Analysis System version 9.4 . Two-sided


In accordance with international guidance for tuberculosis (TB) prevention, the Tanzanian Ministry of Health recommends isoniazid preventive therapy (IPT) for children aged 12 months and older who are living with HIV. Concerns about tolerability, adherence, and potential mistreatment of undiagnosed TB with monotherapy have limited uptake of IPT globally, especially among children, in whom diagnostic confirmation is challenging. We assessed IPT implementation and adherence at a pediatric HIV clinic in Tanzania.In this prospective cohort study, eligible children living with HIV aged 1–15 years receiving care at the DarDar Pediatric Program in Dar es Salaam who screened negative for TB disease were offered a 6-month regimen of daily isoniazid. Patients could choose to receive IPT via facility- or community-based care. Parents/caregivers and children provided informed consent and verbal assent respectively. Isoniazid was dispensed with the child’s antiretroviral therapy every 1–3 months. IPT adherence and treatment completion was determined by pill counts, appointment attendance, and self-report. Patients underwent TB symptom screening at every visit.n = 43, 65.1%) and the median age was 11 years . 63 (95.5%) participants chose the facility-based model; due to the small number of participants who chose the community-based model, valid comparisons between the two groups could not be made. Forty-nine participants (74.2%) completed IPT within 10 months. Among the remaining 17, 11 had IPT discontinued by their provider due to adverse drug reactions, 5 lacked documentation of completion, and 1 had unknown outcomes due to missing paperwork. Of those who completed IPT, the average monthly adherence was 98.0%. None of the participants were diagnosed with TB while taking IPT or during a median of 4 months of follow-up.We enrolled 66 children between July and December 2017. No patients/caregivers declined IPT. Most participants were female (High adherence and treatment completion rates can be achieved when IPT is integrated into routine, self-selected facility-based pediatric HIV care. Improved record-keeping may yield even higher completion rates. IPT was well tolerated and no cases of TB were detected. IPT for children living with HIV is feasible and should be implemented throughout Tanzania. Tuberculosis (TB) represents an enormous global disease burden, especially for people living with human immunodeficiency virus (HIV) , 2. RateConsequently, the World Health Organization (WHO) has recommended expanded delivery of isoniazid preventive therapy (IPT) to reach those at greatest risk for progressing to TB disease , includiDespite international endorsement , IPT enrTanzania is one of the 30 high burden countries for TB and TB/HIV co-disease; an estimated 40,000 Tanzanians developed HIV-associated TB in 2018 . While tWe conducted a prospective cohort study of patient-selected IPT delivery models at the DarDar Pediatric Program clinic (DPP) in Dar es Salaam. The clinic provides routine outpatient HIV care for children aged 15 and below together with their parents/caretakers who may also be living with HIV. DPP is located in the Dar es Salaam city center and serves a mixed urban and rural population, with a total patient enrollment of approximately 285 children and 162 parents/caretakers.The DPP clinical staff identified a convenience sample of children living with HIV who were eligible for IPT according to national guidelines during the study enrollment period. Specifically, eligible patients were 1) HIV-infected, 2) between the ages of 1 and 15 years, 3) enrolled in care at DPP, 4) ruled out for TB disease by using the National Tuberculosis and Leprosy Program (NTLP) symptom screen tool, 5) without contraindications to IPT as per national guidelines (e.g. severe liver disease or known adverse reaction to isoniazid), and 6) not planning to move outside of Tanzania in the next 6-months. Per NTLP guidance, only children who had signs or symptoms for TB based on the symptom screening tool were required to undergo a chest x-ray and sputum testing. If a child had a negative chest x-ray and sputum testing, they were eligible to participate in the study. Sputum testing involved AFB smear, culture, and Xpert MTB/RIF. The study nurses obtained verbal informed consent in Kiswahili using a standardized form, which included counseling on the risks and benefits of IPT. Informed consent was obtained from parent/caregivers. Children who were able to  provided verbal assent to a nurse who used age-adjusted language and questions to gauge the child’s understanding. The parent/caregiver, in conjunction with the child (when they were old enough to participate in the decision-making), then selected their IPT delivery model and were dispensed isoniazid (INH) (dosed at 10-15 mg/kg up to a maximum of 300 mg/day). Most children received a 1- or 2-month supply of INH, based on the timing of their next scheduled appointment for ART.Children (and their parent/caregiver) were offered a choice of either facility- or community-based IPT delivery models. In the facility-based model, TB screening, adherence assessment, and INH refills were coordinated with the child’s routine ART refill appointments at the clinic, typically in monthly or bimonthly intervals. Roundtrip travel to the clinic via public transportation was reimbursed for all children and their parents/caregivers regardless of study involvement. One clinician and two nurses performed the screening, adherence assessment, refills, and follow-up of patients. In the community-based model, nurses performed the same functions in the child’s home and dispensed both their INH and ART refills. Patients could switch models at any time during the study and were reminded of this at each follow-up appointment.IPT refill intervals followed the child’s pre-existing ART refill schedule. The study nurses attempted to contact by telephone any study participant who missed an appointment as per routine clinic practice. Adherence was assessed at each visit and IPT completion was documented after the final IPT refill. Average monthly adherence was determined via pill counts. Follow-up visits were attended by the child and parent/caregiver, the child alone, or the parent/caregiver alone. Regardless of who attended the follow-up appointment, INH pill bottles were examined for adherence assessment. INH and ART refills were provided at each follow-up visit. In addition, participants were screened at every appointment for TB disease using the NTLP-recommended symptom screen. If any TB signs or symptoms were present, a chest x-ray and sputum for AFB smear, culture, and Xpert MTB/RIF would be performed. Participants with confirmed TB disease were referred to a separate TB clinic for treatment; if TB was excluded, the child resumed IPT.The primary outcome was IPT completion, defined as completing a 6-month course of INH within 10 months. When exact treatment completion dates were not documented, the completion date was estimated by adding the days of IPT remaining (as indicated by the number of pills that the patient had remaining) at the time of their last IPT appointment. The secondary outcome was adherence, defined as the percentage of prescribed INH taken. Adherence was measured using a combination of pill counts at follow-up appointments, appointment adherence, and patient self-reporting. Pill counts were obtained at each follow up visit and used to calculate monthly adherence. Appointment adherence was used to supplement pill counts by calculating how many INH pills should be left given the interval between appointments. Rarely, participants provided additional information to explain why the pill count and appointment attendance might not accurately reflect their adherence, such as when they lost or dropped pills, to allow our study team to make corrective calculations to their adherence.One clinic physician and two nurses were trained in IPT administration. The study team conducted staff training through didactic lectures, discussion, and role-play. Training sessions focused on 1) review of the national IPT policy, 2) review of the benefits of IPT, 3) results from the IPT program evaluation, 4) patient motivational interviewing techniques and shared decision-making, 5) overview of the project using the approved standard operating procedures, and 6) transfer of data collection tools.Study data were collected using standard paper registers. Basic demographics, method of IPT delivery, reasons for choosing that delivery method, pill counts, dates of IPT initiation and refills, adverse reactions, deviations from prescribed treatment, and patient-initiated switches from the initially-selected delivery model were all recorded. Qualitative data notes, such as reason for choosing a delivery model, were documented by the study staff on the register and later categorized as: general preference (reason not specified), confidentiality/stigma concerns, ease, perceived better treatment support, and other. These data were transferred to a password-protected Microsoft Excel 2010 spreadsheet on password-protected study laptops. Data were exported to JMP v13 for final analysis. All data were validated by comparison between paper and electronic entries. Descriptive analyses using means/medians and proportions were conducted for continuous and categorical data respectively. Adherence was calculated at the first follow-up and for all subsequent visits with available data.The study protocol was approved by the National Institute for Medical Research in Dar es Salaam, Tanzania; Muhimbili University of Health and Allied Sciences (MUHAS) Institutional Review Board in Dar es Salaam, Tanzania; and the Dartmouth Committee for the Protection of Human Subjects in Hanover, NH, USA.n = 43, 65.1%) and all were on ART. The median age was 11 years (interquartile range [IQR] 8–13). Most children did not have a history of TB  and 33 (50.0%) were at WHO clinical stage III for HIV at initiation. Detailed participant characteristics are shown in Table We enrolled 66 eligible children between July and December of 2017, and the last child finished IPT in July 2018. Although not formally documented, the clinic nurses reported that out of the 66 children approached, all accepted IPT. Most participants were female  as their main reason for choosing the facility-based model, specifically because they feared that the community-based model would inadvertently disclose their HIV status to their neighbors. Other reasons for choosing the facility-based model included ease  as visits to the facility for HIV-related care were already integrated into their routine, and a general preference to maintain their routine . Most participants  retained their initially chosen model throughout the study. Of the 5 participants who switched models, 3 (60%) switched once after the first IPT visit, and 2 (40%) switched multiple times throughout the study. Of the 5 participants who switched their models (either once or many times), 3 (60.0%) initiated the study by selecting the facility-based model and 2 (40.0%) initiated with the community-outreach model.The facility-based model was selected by 63 (95.5%) participants at IPT initiation. Table . Most ciForty-nine (74.2%) participants were confirmed to have completed IPT. Of those that completed IPT, pill count data showed a 98% average monthly adherence. Only one child had an adherence of less than 70%, and 33 (50%) had adherence rates between 93 and 100%. The recorded monthly adherence of 98% is well above the 80% standard threshold for adherence. The estimated mean time to complete IPT was 27.6 weeks (6.4 months) among the 35 participants for whom a precise completion date could be determined. Incomplete record keeping meant that not all participants had an exact date of IPT completion. All participants who completed their IPT did so within 10 months of initiation, and no participants missed more than 90 days of IPT doses. Data on IPT adherence and treatment completion are shown in Table n = 2), vomiting (n = 2), numbness (n = 3), oral ulcers (n = 1) and rashes (n = 1). No cases of TB were suspected or confirmed among participants while on IPT or during a median of four additional months of follow up.Among the 17 (25.8%) children who were not included in the adherence analysis, 5 (29.4%) were lacking IPT completion documentation in their medical records, 11 (64.7%) discontinued treatment, and 1 (5.9%) had an unknown outcome due to missing paperwork. Inconsistent documentation practices and patients forgetting to bring their pill bottles for adherence review (pill counts) resulted in incomplete IPT documentation that prevented adherence determinations in some cases. Among the 11 participants who discontinued IPT, 7 (63.6%) did so at the recommendation of the physician due to one or more adverse reactions including joint pain  are believed by the clinic staff who administer their HIV care to have completed IPT but simply lacked official documentation. Among these 5, the mean estimated IPT completion date was 6.5 months after initiation. Thus, it is likely that these five children completed their IPT within the 10-month limit, even if their files did not specify an end date. Using these estimated completion dates, a total of 81.8% (54/66) completed their IPT within the specified timeframe.Where data were available, adherence was very high (98% monthly average). The fact that this study examined an “ART-established” cohort of participants  likely contributed to the excellent adherence as participants were habituated to taking daily medication. Our study parallels other similar findings in IPT adherence. Previous studies have found high adherence to IPT amongst pediatric populations living with HIV, suggesting that IPT is a feasible intervention for wider implementation , 26. Thin = 11) of children stopped IPT, primarily due to minor adverse reaction. Shorter regimens to treat latent TB infection have been shown to be as effective as IPT, with high adherence, and potentially better tolerability, including 3 months of daily INH and rifampin, 3 months once-weekly INH and rifapentine, and 4 months of daily rifampin [Concerns regarding breakthrough TB disease in the pediatric population were not borne out in this study. There were no cases of breakthrough TB and no presentations that warranted further evaluation with bacteriological investigation. The lack of breakthrough TB supports the use of the NTLP-recommended symptom screen to determine patient eligibility for IPT. INH was well tolerated by the majority of the study population. 16.7% . Similar difficulties in record keeping for IPT delivery have been documented in other similar studies in the region . NonetheOur study demonstrates that high adherence and treatment completion rates can be achieved when IPT is integrated into pediatric HIV care and when patients and their parent/caregiver are involved in choosing delivery methods that best fit their needs. Improved record-keeping and patient pill bottle presentation at appointments may yield even higher completion rates. There were no detected cases of TB. For children living with HIV, IPT can be implemented effectively and should be recommended throughout Tanzania.Our study demonstrates IPT feasibility and high completion rates among children living with HIV in Tanzania. When flexible delivery models and shared decision making are included in standard care, high adherence and treatment completion rates of IPT can be achieved. Coordinating IPT and ART is an effective way to minimize patient visit burden and streamline care delivery. There were no cases of TB were detected during or after the study. Improved record-keeping may yield even higher completion rates. IPT should be implemented into routine pediatric HIV within Tanzania.


This study aimed to determine the incidence and factors associated with treatment failure among HIV infected adolescent and adult patients on second-line antiretroviral therapy (ART) in public hospitals of Northern Ethiopia.A retrospective study was conducted from September 1, 2007 to July 30, 2017 on 227 patients. The data were extracted using a retrieval checklist from the patient’s charts. The incidence rate of treatment failure was calculated using Kaplan–Meier methods and Cox proportional hazard model was used to assess factors associated with treatment failure.3 , TB co-morbidity (AHR = 3.39 95%CI = 1.91–6.01) and poor adherence level  at the start of second line ART were significantly associated with second-line ART failure.The study subjects were followed for a total observation of 788.58 person-years with a median follow-up period of 35 (IQR: 17–60) months after switching to second-line ART. About 57 (25.11%) patients developed treatment failure, out of which, 32 (56.14%) occurred during the first two years. The overall incidence of second-line treatment failure was 72.3 per 1000 person years (95%CI: 55.75–93.71) of observation. The Kaplan–Meier estimates of cumulative treatment failure after 1, 2, and around 10 years of follow-up were 12.31% (95%CI: 8.60–17.45%), 14.99% (95%CI: 10.82%-20.57%), and 48.67% (95%CI: 32.45–67.81%) respectively. Age >45 years AHR = 3.33, 95%CI = 1.33–8.31), WHO stage IV , CD4 count <100 cells/mm3, TB co-morbidity, age >45 years, and being in WHO stage IV. Therefore, intensive counseling and adherence support should be given along with strong TB screening. Moreover, the government of Ethiopia should consider endorsing third-line ART drugs after careful cost–benefit analysis.Incidence of second-line ART treatment failure in the first 2 years of follow-up was high. The rate of second-line ART failure was higher in patients who started second-line ART with poor drug adherence, CD4 count <100 cells/mm Out of the 37.9 million people living with HIV globally, 23.3 million were on treatment, more than three times as many as in 2010 . AlthougEthiopia is among the high burden countries, with a prevalence of 1% and the 2018 estimate showed that about 690000 people were living with HIV/AIDS, 23000 new infections and 11000 people died from AIDS-related illness. Since 2010 the number of new HIV infections and deaths has decreased from 29000 to 23000 and from 20000 to 11000 respectively in 2018. About 66% of the adults and adolescents aged 15 years and above were on ART treatment in Ethiopia in 2018 .The recommended first-line ART regimen in 2014 consists of nucleoside reverse transcriptase inhibitor (NRTI) backbone with one of the non-nucleoside reverse transcriptase inhibitor (NNRTI). Once-daily regimens comprising NRTI backbone (TDF + 3TC) and one NNRTI (EFV) are maintained as the preferred choices in adults, adolescents and children older than ten years. Boosted protease inhibitor (PI) + two NRTI combinations is recommended as the preferred strategy for second-line ART for adults, adolescents and also for children when NNRTI containing regimens were used in first-line ART . The secEven though ART reduces morbidity and mortality, non-adherence, drug resistance, and treatment failure are becoming a significant challenge to achieve better treatment outcomes. Antiretroviral treatment failure can be clinical, immunological or virological, which occurs when the ART regimen is unable to control viral replication . The WHOEven though second-line ART was introduced in Ethiopia ten years prior, few studies have reported about the treatment outcome of second-line therapy. Although there were studies on treatment failure focusing on viral suppression and immunological failure on the failure of ART users , 15, nonA retrospective study was conducted from September 1, 2007 to July 30, 2017 in public hospitals of North Ethiopia , Mekelle hospital and Quiha hospital) in Mekelle city, Tigray region, Northern Ethiopia. Mekelle is the capital city of Tigray Regional State which is situated 780 km away from the capital city of Ethiopia, Addis Ababa. The selected hospitals had the highest number of clients on second-line ART in the Tigray region. Since the start of ART, 9919 patients were enrolled on ART (204 on second-line ART) in Mekelle hospital. Quha hospital enrolled 796 patients on ART (27 on second-line ART) and Ayder comprehensive specialized hospital enrolled 1640 patients on ART (94 on second-line ART).All HIV infected patients who were switched to second-line ART from September 1, 2007 to July 30, 2017 in the selected hospitals of Northern Ethiopia.The disaggregation of PEPFAR was used and patients 15 years old and above who were on second-line ART for at least 6 months before treatment failure was diagnosed.Patients who were on care until January 31, 2018.Patients who were on second-line ART but with unknown second-line start date and incomplete data on the basic variables were excluded from the study.The sample size required for Cox proportional hazard (PH) regression was calculated by using STATA statistical package, Version 14.0. Based on a previous study, assumptions of hazard-ratio (2.1) associated with second-line treatment failure, with a probability of event 0.423 , variabiThere were 325 patients on second-line regimen in the selected hospitals. In total 227 patients  who fulfilled the inclusion criteria were included in the study .New or recurrent clinical event indicating severe immunodeficiency  and severe bacterial infections) after 6 months of effective treatment.3.CD4 count falls to the baseline (or below) or persistent CD4 levels below 100 cells/mmPlasma VL level above 1000 viral copies/ mlHIV/AIDS related death in patients who were on second-line ARTPatients who were transferred out, dropped out and any event out of the event of interest was considered as a censored.Includes clinical failure, immunological failure, virological failure and HIV/AIDS related death in patients who were on second-line ART. If a patient developed at least one of these four outcomes, he/she was considered as having treatment failure.Drug adherence of <85% or ≥6 ART drug doses missed out of 30 doses or >9 ART drug doses missed out of 60 doses.Drug adherence of 85–94% or 3–5 missed drug doses out of 30 doses or 3–9 missed drug doses out of 60 doses.Drug adherence of 95% and above or ≤2 missed drug doses out of 30 doses or <3 missed drug doses out of 60 doses.The independent variables of the study were selected from the health facilities’ ART follow-up clinic registration books, ART follow-up and patients’ charts.The dependent variable was treatment failure to second-line ART which was defined as immunological failure, clinical failure, virological failure or HIV related death while on second-line ART. If a patient developed one of the four outcomes, he/she was considered to have a treatment failure –18.The independent variables were: age, CD4 count, and WHO clinical stage at the start of second-line ART. Additionally: sex, educational level, marital status, religion, residence, TB co-morbidity, number of first-line regimen changes, type of first-line regimen prior to switch, duration on first-line ART, second-line ART regimen and adherence level.3 after at least 6 months on second-line ART. Virological failure was identified if plasma VL was above 1000 copies/ ml after at least 6 months on second-line ART. Finally, death was considered if the recorded death was due to HIV/AIDS in patients who were on second-line ART. The dependent variable was a binary outcome which was event (treatment failure) and censored (no treatment failure).The outcome of this study, i.e. treatment failure was assessed from the time of second-line ART initiation to immunological failure, clinical failure virological failure or HIV related death, which ever occurred first. Clinical failure was considered if a new or recurrent clinical event indicating severe immunodeficiency ) after 6 months of effective treatment occurred. Immunological failure was considered if the CD4 count falls to the baseline (or below) or persistent CD4 levels below 100 cells/mmSecondary data were used for this study. The data was collected from the health facilities’ ART follow-up clinic charts and registration books, and patient cards by using retrieval check list The checklist was developed in English. Data were collected from the registration books and patient cards by four trained ART nurses who were in the ART clinics of the selected hospitals. The data collection procedure was closely supervised for assuring the quality of the data. The collected data were checked out for completeness, accuracy and clarity by taking samples.After the data were checked for its completeness and cleanness, it was entered and analyzed using STATA statistical software package, version 14.0. The frequency distribution of the variables was presented using tables. The incidence of treatment failure and cumulative probability of failure was calculated using Kaplan–Meier methods . The facThe multivariable Cox regression model development involved a series of backward selection procedure. Step by step exclusion of variables with large p-value was performed . All posThe Cox proportional assumption was tested based on Schoenfeld residuals . Since the p-value of the global test was 0.1578 (> 0.05), the proportionality assumption of Cox PH model was met . The fitEthical clearance and approval was obtained from Mekelle University, College of Health Sciences, Research and Community Service Ethical Review Committee. Permission letter was obtained from Tigray regional health bureau and the respective hospitals. Nurses from the ART clinics of the selected hospitals were the data collectors to maintain privacy of the patients. The medical registration number (MRN) and unique ART number were used as unique identifiers. The data was not accessible by any other third party other than the study team. Informed consent was waived by the ethical review committee.Almost half of the study participants, 118 (52%) were females. The median age of the patients at the start of second-line ART was 36 (inter quartile range (IQR): 30–43) years. Around half, 117 (51.5%) of the patients were married. Whereas, 51 (22.5%) and 35 (15.4%) were unmarried and divorced respectively. Most, 189 (83.3%) of the patients were urban dwellers. About, 52 (22.9%) of the patients had no formal education. The median duration of first-line ART before switching to second-line was 50 (IQR: 27–80) months. With regard to the number of regimen changes during first-line ART, 116 (51.1%) of the patients had no regimen change, 84 (37%) had regimen change once and 27 (11.9%) had regimen change twice. The frequently prescribed first-line NRTI backbones to patients at the initiation of second-line ART were: 113 (49.8%) on tenofovir disoproxil fumarate (TDF) + lamivudine (3TC), 82 (36.1%) on azidothymidine (AZT) + (3TC) and 28 (12.3%) were on stavudine (d4t) + (3TC) based regiments.3 at the start of second-line ART. At the start of second-line ART, 93 (41%) of the patients were in WHO clinical stage I or II, 85 (37.4%) were in WHO clinical stage III and 49 (21.6%) were in WHO clinical stage IV. With regard to the adherence level at the start of second-line ART, 193 (85%) of the patients had good or fair adherence level (One hundred and seventy two (75.8%) of the patients were started on lopinavir (LP/r) boosted protease inhibitor second-line regimen and 55 (24.2%) received atazanavir (ATV/r) based regimen. Most of the patients, 198 (87.2%) had no TB. One hundred and sixty six patients (73.1%) had a CD4 count below 100 cells/mmce level .(95% CI: 40.60–88.90).The median follow-up period on the patients was 35 (IQR: 17–60) months after switching to second-line ART with a total observation period of 788.58 person-years (PYs). A total of 57 patients developed a treatment failure, of which 32 (56.1%) occurred during the first two years of follow-up. Clinical failure, virological failure, HIV related death and immunological failure was used to diagnose 22, 14, 11 and 10 patients respectively. The overall incidence of second-line treatment failure was 72.3 per 1000 PYs (95% CI: 55.75–93.71) of observation. The incidence of treatment failure in the first two years of follow-up was 85.8 per 1000 PYs (95% CI: 60.70–121.30) but after two years, it was 60.10 per 1000 PYs 3 compared to patients who were started at CD4 count ≥100 cells/mm3 (90.1 vs. 26.90 per 1000 PYs).Different rates of treatment failure were observed across different categories of variables. The rate of treatment failure was higher in patients who started second-line ART at age greater than 45 years compared to patients aged 15 to 29 years (136 vs. 37.6 per 1000 PYs). Higher incidence of treatment failure was observed in patients with TB co-morbidity compared to those without TB (258.10 vs. 52.03 per 1000 PYs). The rate of treatment failure was higher in patients who started on second-line ART at CD4 count <100 cells/mmThe incidence of treatment failure of patients in WHO clinical stage IV was higher compared to patients in WHO stage I or II at the initiation of second-line ART (142.01 vs. 38.2 per 1000 PYs). The incidence of treatment failure in patients with good/ fair and poor adherence levels were 62.4/1000 and 140.1/1000 PYs respectively .The Kaplan–Meier estimates of cumulative treatment failure after 1, 2, 5 and around 10 years of follow-up were: 12.31% (95% CI: 8.60–17.45%), 14.99% (95% CI: 10.82%-20.57%), 28.65% (95% CI: 22.15%-36.58%) and 48.67% (95% CI: 32.45–67.81%) respectively . The Kap3, WHO stage IV, and poor adherence at the start of second-line ART  more likely to develop treatment failure compared to patients in the age group of 15–29 years after adjusting for the effect of WHO stage, TB status, CD4 count and adherence. Patients who started second-line ART with advanced WHO stage (stage IV) had 3.6 times  higher likelihood of treatment failure compared to patients who started second-line ART at early WHO stages (stage I or II) keeping the other variables  constant.3 at the start of second-line ART was 3.8 times  higher compared to patients who started second-line ART at CD4 count of 100 cells/mm3 or above after controlling for the effect of age, TB status, WHO stage and adherence. Patients who started second-line ART with TB co-morbidity had 3.4 times  higher likelihood of treatment failure compared to patients without TB keeping the other variables constant. Patients with poor adherence level at start of second-line ART were 3.6 times  more likely to develop treatment failure compared to patients who had good/fair adherence level after adjusting for the effect of age, TB status, CD4 count and WHO stage Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig(PDF)Click here for additional data file.S4 Fig(PDF)Click here for additional data file.S5 Fig(PDF)Click here for additional data file.S6 Fig(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


HIV treatment and care services were scaled up in 2007 in India with objective to increase HIV-care coverage. CD4 count based criteria was mainly used for treatment initiation with increasing threshold in later years. Therefore, this paper aimed to evaluate the survival by varying CD4 criteria for antiretroviral treatment (ART) initiation among of HIV-positive patients, and independent factors associated with the mortality.This retrospective cohort study included 127 949 HIV-positive patients aged ≥15 years, who initiated ART between 2007 and 2013 in Andhra Pradesh state, India. The patient’s demographic and clinical characteristics were extracted from the patient’s health records from electronic Computerized Management Information System Software (CMIS). Incidence of mortality/100 person-years was calculated for CD4 and treatment initiation categories. Kaplan-Meier and multivariable Cox-regression analyses were used to explore the association.3) was 8.5/100 person-years compared to 6.4/100 person-years at risk for the period 2012 onwards (CD4 ≤ 350 cells/mm3). Earlier thresholds for treatment initiation showed higher risk of mortality (2007-08 (CD4 ≤ 200 cells/mm3), adjusted hazard ratio (HR): 1.86, 95% confidence interval (CI): 1.68-2.07; 2009-11 (CD4 ≤ 250 cells/mm3), HR = 1.67, 95% CI = 1.51-1.85) compared to 2012 onwards (CD4 ≤ 350 cells/mm3) criteria for treatment initiation.Median CD4 count was 172 (inter-quartile range (IQR) = 102-240) at the time of treatment initiation, and 19.3% of them had ≤ 100 CD4 count. Incidence of mortality for the period 2007-08 (CD4 ≤ 200 cells/mmIncreasing CD4 threshold for treatment initiation over time was independently associated with lower risk of mortality. More efforts are required to detect and treat early, monitoring of follow-ups, promote health education to improve ART adherence, and provide supportive environment that encourages HIV-infected patients to disclose their HIV status in confidence. India formed an AIDS Task Force under the Indian Council of Medical Research (ICMR) to respond HIV/AIDS challenge after the detection of first AIDS case in 1986 . India l3 or HIV clinical stage III/IV irrespective of CD4 count, including coinfections such as tuberculosis) for ART initiation was adapted [3 and to ≤ 350 cells/mm3 in 2012, as recommended by the Joint United Nations Programme on HIV/AIDS (UNAIDS) [3, regardless of WHO clinical stage [3 for initiating ART, and 7% moved the CD4 threshold to >500 cells/mm3 by June 2014 [3 in almost all settings [The ART services were scaled up at national level in 2007 with objective to increase HIV-care coverage. A new treatment criterion (CD4 count ≤ 200 cells/mm adapted . The CD4(UNAIDS) . Additioal stage -10. Addial stage . The WHOsettings ,14. Despsettings ,15. The settings ,12-17.Several single centre-based studies have been conducted in India to look for demographic and clinical factors  associated with the early mortality -21. HoweThis retrospective analysis included all registered adult (aged ≥ 15 years) HIV/AIDS patients, who initiated ART treatment between January 2007 and December 2013 in undivided Andhra Pradesh state. The patient’s demographic and clinical characteristics were extracted from the patient’s health records from electronic Computerized Management Information System Software (CMIS). We excluded data from the analysis if the patient initiated their treatment elsewhere and registered in Andhra Pradesh, pre-ART cases, ART initiation date was missing, ART started in Andhra Pradesh but later transferred out to other states, and if the status was unknown at the end of the study period.2 and population density of 308/km2, literacy rate of 67% , and the sex ratio of 993 females per 1000 males. Administratively, Andhra Pradesh was divided into 23 districts that further divided into 1127 revenue divisions. The state has a vast network of public health facilities, including 20 district hospitals, 56 area hospitals, 117 community health centres, 10 specialty hospitals, and 25 civil dispensaries [Andhra Pradesh  is one of the highly populated southern region state in India. According to the national Census 2011, Andhra Pradesh had 84.6 million population, with a total area of 275 045 kmensaries .As of December 2014, the state had 1869 integrated and counselling testing centres (ICTCs), including prevention of parent-to-child treatment (PPTCT) centres, 286 government recognized blood banks, and 274 sexually transmitted disease (STD) clinics . There wOnce an HIV-positive individual reached to an ART centre with an ICTC report, s/he were registered in the pre-ART register for HIV care. Furthermore, demographic details and other relevant information were also recorded in the patient treatment record  and a Green Book was issued. Patients were advised to enrol at the nearest ART centre to their current place of residence to ensure proper adherence to treatment. S/he was re-counselled for implications of being HIV-positive, availability of treatment, positive living, nutrition, and positive prevention, etc. The early testing of their spouse/partner and children was encouraged. Recently detected persons were kept under the supervision of a care coordinator to determine whether a HIV-positive person was treated in the same manner as any other patients at the centre, without any discrimination. Furthermore, the patient was referred to a concerned doctor who conduct a detailed medical examination for WHO clinical staging, opportunistic infections (OIs) and other relevant clinical examinations. Based on the clinical findings, the HIV treatment was initiated as per the NACO guidelines described in the Table S1 in the The primary event of interest was the death of the patients. The date of death for all HIV-infected patients who died from all causes during the study period while on antiretroviral treatment was recorded. Patients missing their follow-up visits for more than three months were counted as lost to follow-up, and the date of the last registered follow-up visit was recorded as the date of follow-up loss. ART for HIV-infected patient who were transferred to another ART centre were recorded as transferred-out cases, and their dates of transfer-out were also recorded. Similarly, patients received medical advice was recorded as on medical advice and their dates of medical advice were also recorded .3 in 2007-2008, ≤ 250 cells/mm3 in 2009-2011 and ≤ 350 from 2012 onwards). The HIV surveillance program-related information included date of ART initiation, follow-up status, and last date of ART centre visit. Clinical characteristics at the time of ART initiation included bodyweight , WHO clinical stage , and CD4 count . We presented missing data as a separate category in each variable and did not impute any value to figure out their characteristics. Imputation was not considered sensible in this case as data were unlikely to be missing at random.Patients’ baseline demographic, program-related information and clinical characteristics data were collected. Baseline demographic characteristics included, age , sex , education , marital status (single/married), and employment (employed or not employed). Time-period was divided according to the CD4 criteria for treatment initiation  or median with interquartile range (IQR) were used to present quantitative data. Mortality density per 100 person-years was calculated for various CD4 categories and ART criteria years. The Kaplan-Meier (KM) method was used to estimate survival after ART initiation, and the log-rank test was used to determine statistical differences between survival rates in subgroups of the variable ,25. UnivIndividual level anonymised PLHIV data access permission was granted by NACO for undivided Andhra Pradesh under a data sharing scheme with national data analysis plan (NDAP) at phase I for policy making in high prevalent states (vide letter No. z-19019/1/2013-NACO(SIMU)). Data were made available to the first author for his PhD research by NACO for secondary data analysis, and it has been approved by the internal ethics committee. Individual consent was taken the affiliated organisations of NACO during the data collection and therefore, no additional consent was required in this study.P < 0.01) to 6.9% in 2012 onwards. The median age was 34 years, 45.9% females, 45.7% had formal education, 59.4% were employed and 68% were married. The median CD4 count was 172 (IQR 102-240) cells/mm3 at the time of ART initiation that consistently increased over time  of adult HIV-positive patients on ART are summarised in 3 treatment initiation criteria in 2012 onwards compared to 59.8% survival with CD4 count ≤ 200 cells/mm3 criteria in 2007-08  and (HR range = 0.64-1.73) 2009-11 to explored the trend of risk in different CD4 levels compared to 2012 onwards category. This analysis clearly indicated higher risk of mortality within the first year of treatment start was associated with older treatment initiation criteria (on average 60% higher risk to 2007-08 and 22% higher risk to 2009-11 compared to 2012 onwards).The effect of varying CD4 cell count categories on the risk of dying in first year of treatment initiation over time is presented in 3 increased to 9-fold , compared to the patients with CD4 count >500 cells/mm3.The unadjusted and adjusted analysis showed the associated predictors of mortality within the first year of treatment initiation among adult HIV-infected patients in 3), and 11.0/100 person-years for 2009-11 period (CD4 ≤ 250 cells/mm3) – compared to 2012 onwards (CD4 ≤ 350 cells/mm3) criteria. Further, the overall excess risk of death was 84%  for 2007-08 period (CD4 ≤ 200 cells/mm3), and 61%  for 2009-11 period (CD4 ≤ 250 cells/mm3) compared to 2012 onwards (CD4 ≤ 350 cells/mm3) criteria. These findings are in agreement with other studies published from resource-limited settings [The ART scaling-up service has resulted greater coverage of HIV-patients at the early stages. Our findings clearly indicate higher incidence of mortality for earlier treatment initiation criteria – 8.5/100 persons-years for 2007-08 period  of these patients had both CD4 cell count ≤ 200 cells/mmr Indian ,16,18,19r Indian ,33-36 str Indian .3. A study in Hong Kong showed 2.69-fold risk of death when they start treatment with a CD4 count <100 cells/mm3 during the follow-up period [3 had about 5-fold higher mortality than did those with ≥ 500 cells/mm3 [The CD4 count is an established indicator of the disease severity that directly related to the functional and immune status of a patient, and risk of early mortality among those with lower CD4 counts . Our anap period . Additioells/mm3 . The CD4ells/mm3 ,36,39 buells/mm3 . This maMales were more at risk for HIV-infection who probably acquired it from the high-risk population  and transmit to their female partner(s). Our findings are similar with other studies from under-developed nations ,42, but The leading causes of HIV-related deaths are mainly due to immune reconstitution syndrome and opportunistic infections. According to a recent report, patients who start their HIV-treatment at late clinical stages (such as III/IV) are at an increased risk of dying . Late prThere were several limitations in this study, and results may carefully be interpreted in the light of these limitations. The electronic database did not have information on causes of death, details of treatment regimen, incomplete data in several important variables, and opportunistic infections. Although these details were routinely entered in the ART registers. Several important variables such as haemoglobin, height and other clinical information were dropped from the analysis due to incomplete information in the electronic database. Additionally, lost to follow-up cases were intractable for outcome assessment and may have been at increased risk of dying. This study was retrospectively conducted; therefore, limitations of retrospective studies were also included in this study.3 in 200708, and ≤ 250 cells/mm3 in 2009-11) for treatment initiation compared to ≤ 350 cells/mm3 from 2012 onwards criteria. It indicates the requirement of more efficient and inclusive HIV programme to respond to the HIV epidemic in the state and country at large. As majority of the HIV-patients were died within the first year of treatment initiation, indicating more efforts are required to detect early, emphasis on regular follow-ups, promote health education to improve ART adherence, and provide supportive environment that encourages HIV-infected patients to disclose their HIV status in confidence.In conclusion, this study compared the effect varying CD4 criteria for treatment initiation with mortality over time in Andhra Pradesh, India. Increased risk of mortality was found to be associated with the earlier CD4 cut-offs (≤ 200 cells/mm


Sub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).We report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with multi-drug resistance to darunavir/r and dolutegravir. Genotypic resistance testing (GRT) and viral tropism were performed during monitoring time points. The patient initiated ART in August 2007. At the time point of the first (29.04.2010), second (01.12.2017) and third (08.08.2019) GRT, prior ART exposure included 3TC, d4T, NVP and EFV; additionally TDF, DRV/r and RAL; and additionally ABC and DTG respectively. First GRT revealed mutations associated with resistance only to first-generation Non-nucleoside reverse transcriptase inhibitors (NNRTI). Second GRT revealed mutations associated with high-level resistance to all NRTIs, first generation NNRTIs, all ritonavir boosted protease inhibitors (PI/r), and all INSTI, while viral tropism (using geno2pheno) revealed a CCR5-tropic virus with a false positive rate (FPR) of 60.9% suggesting effectiveness of maraviroc (MRV). The third GRT showed high-level resistance to NRTI, NNRTI, all PI and all INSTI, with additional mutations (H221HY for NNRTI and S147G for INSTI), and a CCR5-tropic virus with a slightly reduced FPR (57.0%). Without any locally available active therapeutic option, the patient has been on a maintenance therapy with “DRV/r (600mg x 2/day)+TDF+3TC” and patient/family-centered adherence has been reinforced. Since the first viral load (VL) measurement in 2010, the patient has had 12 VL tests with the VL ranging from 4.97 Log to 6.44 Log copies/mL and the CD4 count never exceeded 200 cells/μL.As African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection  of dolutegravir-resistance, supporting case surveillance. Management of treatment-experienced HIV-patients remains very challenging in resource-limited settings where drug options are limited, poor adherence is frequent, and treatment monitoring  remains sub-optimal , 2. ART This is a 65 years old married man, infected with HIV-1 CRF18_cpx. Therapeutic history, VL, CD4 cell counts and genotypic profiles are summarised in Fig. 3). Prior to ART re-initiation in 2010, genotypic resistance testing (GRT) results, interpreted throughout using Stanford HIVDB (http://www.hivdb.stanford.edu) and International AIDS Society mutations list, showed the presence of one resistance associated mutation (RAM) to NRTI (V75I), two non-NRTI RAMs . With this mutational profile, the patient was recommended PI/r + 2NRTI but we have no precision on antiretrovirals used thereafter. From 2011 to 2012, the patient was diagnosed co-infected with pulmonary tuberculosis and treated accordingly, classified as WHO clinical stage 3. After completing anti-tuberculosis treatment in 2012, he was lost to follow-up (duration unclear) and later returned for clinical consultation. Following clinical assessment, he received a regimen consisting of super-boosted ritonavir with darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF) +3TC (unclear start date) till November 2017, a period during which adherence was suboptimal (assessed by self-reporting). While completing anti-tuberculosis treatment the patient discontinued HIV-treatment. Following clinical assessment, he was re-initiated with a regimen consisting of ritonavir boosted darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF) +3TC (unclear start date) till November 2017; a period during which adherence was suboptimal. A second GRT was performed and the resulting mutational profile suggested DRV/r(600 mg × 2/day) + DTG(50 mg × 2/day), possibly associated with ritonavir-boosted atazanavir (ATV/r) for its potential capacity to enhance DTG concentrations (https://www.hiv-druginteractions.org/drug_queries/326049/drug_query_interactions) as an optimal regimen. However, the patient was prescribed DRV/r(600 mg × 2/day) + DTG(50 mg × 1/day) + TDF + 3TC from November 2017 to May 2019. In May 2019, the patient was empirically switched to DRV/r(600 mg × 2/day) + DTG(50 mg × 1/day) + abacavir (ABC) +3TC. Then, ABC was changed to TDF until August 2019 when the third GRT was performed.The patient was diagnosed with HIV in 2002 and has been on ART for 14 years (since 2006). His initial ART regimen was stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP) from August 2006 to August 2007. NVP was subsequently replaced by efavirenz (EFV) from August 2007 to August 2009. From August 2009, the patient voluntarily stopped treatment and returned to the clinic in 2010 for consultation. In 2010, the patient had a high VL  and very-low CD4 cell count  at three different time points [Following GRTs performed on HIV-1 “e points , 11, phyThe first GRT  covered the protease (PR) and reverse transcriptase (RT) regions, with high-level resistance to first-generation NNRTI  and no major-RAM to NRTI and PI/r.The second GRT  covered PR and RT regions. Detected RAMs were M41L, K70Q, V75I, Q151M, M184V and T215F for NRTI; K103N and V108I for NNRTI; and L10F, K20I, M36I, M46I, I47V, I54L, L63H, L76V, V82S and L89I for PI/r. These mutations revealed high-level resistance to all NRTIs, first generation NNRTIs (EFV and NVP) and to all PI/r, including DRV/r. Another GRT, covering HIV-1 integrase (IN) region, performed on the sample plasma aliquot, revealed major RAMs, L74I, E138KQ, G140A, Q148R, and E157Q, to integrase strand transfer inhibitors (INSTI) including raltegravir, dolutegravir, bictegravir and elvitegravir. Viral tropism revealed a CCR5-tropic virus, defined by a false positive rate (FPR) of 60.9%, suggesting eligibility for maraviroc (MRV).The third GRT , encompassing PR, RT and IN regions, showed high-level resistance to NRTI, NNRTI, PI and all INSTI. Additional RAMs were H221HY for NNRTI and S147G for INSTI. Viral tropism was also re-performed and demonstrated CCR5-tropic virus with a slightly reduced FPR (57.0%). Pending access to required innovative regimen, a salvage therapy guided by GRT was recommended, consisting of either “DRV/r(600mg x 2/day), saquinavir/r, TDF+3TC”, or “3TC-monotherapy” which maintains M184V and as such limits the viral replicative fitness. None of the recommendations; in November 2019, VL appeared relatively stable (5.54 Log copies/mL) under “DRV/r(600mg x 2/day)+TDF+3TC” and with an active family-centered adherence monitoring. Following intensified/close adherence strategy implemented, the patient is compliant to treatment but the latest plasma viral load remains high, with a slight increment , which confirms the need of innovative drugs and close case surveillance, including MRV that is not locally available [3 is attribuable to the use of more potent antiretrovirals), high-VL since ART-initiation, and advanced-age (i.e. > 60 years) are risk-factors that might have contributed to ART-failure [https://www.hiv-druginteractions.org/drug_queries/326049/drug_query_interactions). Also, as patients on DTG-containing regimens with high baseline VL  might experience challenges in viral suppression, close monitoring as well as specific case surveillance should be required even in resource-limited settings like Cameroon [To the best of our knowledge, this is the very first clinical case in West and Central Africa of complete four-class multidrug resistance to all antiretrovirals available in resource-limited settings with complete loss of DRV/r and DTG efficacies. Of note, previous report from Cameroon showed a case of successful raltegravir-containing ART for managing a case of multidrug-class-resistance . Thus, p-failure –16. Addi-failure . The cas-failure , 12–15. Cameroon .In the era of transition to DTG-based regimens in resource-limited settings, this clinical case highlights the need for routine ADR population-based surveys to understand the extent of HIVDR to INSTI. Importantly, optimised care/treatment on DTG-containing regimen, alongside adherence support and close VL monitoring, would sustain the efficacy of this therapeutic option. Finally, individual case surveillance after failure to third-line requires genotyping and policies for access to newer drugs in resource-limited settings with similar ART landscapes.


The antiretroviral therapy (ART) adherence club (AC) model has supported clinically stable HIV patients’ retention with group ART refills and psychosocial support. Reducing visit frequency by increasing ART refills to six months could further benefit patients and unburden health systems. We conducted a pragmatic non‐inferiority cluster randomized trial comparing standard of care (SoC) ACs and six‐month refill intervention ACs in a primary care facility in Khayelitsha, South Africa.Existing community‐based and facility‐based ACs were randomized to either SoC or intervention ACs. SoC ACs met five times annually, receiving two‐month refills with a four‐month refill over year‐end. Blood was drawn at one AC visit with a clinical assessment at the next. Intervention ACs met twice annually receiving six‐month refills, with an individual blood collection visit before the annual clinical assessment AC visit. The first study visits were in October and November 2017 and participants followed for 27 months. We report retention in care, viral load completion and viral suppression (<400 copies/mL) 24 months after enrolment and calculated intention‐to‐treat risk differences for the primary outcomes using generalized estimating equations specifying for clustering by AC.Of 2150 participants included in the trial, 977 were assigned to the intervention arm (40 ACs) and 1173 to the SoC (48 ACs). Patient characteristics at enrolment were similar across groups. Retention in care at 24 months was similarly high in both arms: 93.6% (1098/1173) in SoC and 92.6% (905/977) in the intervention arm, with a risk difference of −1.0% (95% CI: −3.2 to 1.3). The intervention arm had higher viral load completion (90.8% (999/1173) versus 85.1% (887/977)) and suppression (87.3% (969 /1173) versus 82.6% (853/977)) at 24 months, with a risk difference for completion of 5.5% (95% CI: 1.5 to 9.5) and suppression of 4.6% (95% CI: 0.2 to 9.0).Intervention AC patients receiving six‐month ART refills showed non‐inferior retention in care, viral load completion and viral load suppression to those in SoC ACs, adding to a growing literature showing good outcomes with extended ART dispensing intervals. With approximately 7.6 million people living with HIV in the country, this represents 65.8% ART coverage .DSD for HIV treatment focuses on the ART delivery component of the HIV care cascade adapting service delivery for clinically stable patients including through less frequent facility visits enabled by longer drug refills. In sub‐Saharan Africa, countries have implemented DSD models for HIV treatment including individual models, both facility‐based and out‐of‐facility, as well as group models that are either client‐led or managed by healthcare workers , 5. ART There is a need to continually investigate the adaptations of differentiated ART delivery models to further increase convenience and access for patients as well as efficiency for healthcare systems. Reducing the frequency of AC visits by increasing the amount of ART dispensed at each refill could convenience further. Such an adaption could reduce costs for patients and increase nurse capacity for those still needing to start ART or requiring more intensive clinical care , 16.The World Health Organization’s (WHO) 2016 ART guidelines already recommend 3‐ to 6‐month ART refills for clinically stable patients . This isWe conducted a study of six‐month ART refills within the widely endorsed and implemented AC DSD model. We describe 24‐month results from this cluster‐randomized non‐inferiority trial investigating the hypothesis that extended ART dispensing intervals among existing AC patients will result in non‐inferior retention in care and viral load (VL) outcomes.22.1The study took place at the Western Cape Provincial Department of Health (WCDoH)‐run Ubuntu ART clinic at the Site B Community Health Center in Khayelitsha, a peri‐urban area in Cape Town, South Africa, home to approximately 500 000 people , 34. The2.2This was a pragmatic, unblinded, cluster‐randomized, non‐inferiority trial comparing six‐month to two‐month ART dispensing intervals in ACs over two years.Participants eligible for AC enrolment were >18 years; not pregnant, not experiencing an opportunistic infection, on ART for more than six months with one VL below 400 copies/ml, able to provide consent, and already in an existing AC .Randomize package in Stata, ensuring balance between community and facility ACs in each arm, by a team member not involved in recruitment or enrolment. The number of ACs assigned to the intervention arm was limited by ART drug costs funded by the study. Study staff drew an envelope containing the randomization outcome at the post‐consent AC meeting and if once again ≥90% of members voted for continued study participation, the AC was enrolled in the study. Further detail can be found in the published protocol [Recruitment for the trial began in February 2017 and the first study visits were AC visits in October‐November 2017. When ≥90% of AC members present voted to participate in the study, the AC was eligible for inclusion. Members were individually consented and offered to transfer to another club if they did not wish to participate. Eligible and consenting ACs were randomized 45:55 to the intervention or standard of care (SoC) using the protocol .2.3The SoC (two‐monthly refills) and the intervention (six‐monthly refills) ACs are described in Table 2.3.1The WCDoH ACs, previously described , 38, met2.3.2Intervention ACs met twice a year and were dispensed six months of ART. One of these visits included a clinical consultation. Intervention patients were given a VL appointment date and allowed to come anytime two to six weeks before their clinical consultation AC visit. Those who did not come for their VL appointment had their VL taken at their clinical consultation AC visit and those with high VLs were recalled. Intervention ACs facilitators remained the same as before the study. VLs and clinical consultations were undertaken by a study nurse.Figure 2.4Retention data were collected from routine AC registers completed by facilitators and VL data from laboratory data. A study data capturer captured visit and laboratory data into REDCap , 39.2.5The primary outcomes were 24‐month retention in care, VL completion and suppression. Secondary outcomes were 24‐month retention in ACs, and 12‐month retention in care and VL completion and suppression.We also reported reasons for referral from AC to clinic care and the timing of blood draws in relation to clinical consultations to investigate operational concerns regarding the availability of VL results at the annual clinical consultation.2.6“Retention in care” at 24 months was defined as any ART collection (AC or clinic visit) at 24 months or within three months thereafter. If the last documented AC or clinic attendance was 12 months or more after the participant’s first study visit, they were considered retained in care at 12 months.“Retention in AC care” was defined as attending the scheduled AC 24‐month visit. AC patients who missed an AC visit by more than five days but were allowed to return to the AC were not considered retained.“VL completion” was defined as having a VL result within 12 months of the first study visit (12‐month VL completion) or between 12 and 24 months of the first study visit (24‐month VL completion).“VL suppression” was defined as a VL below 400 copies/mL.2.7Retention and VL outcomes were calculated as a proportion of total participants enrolled . VL completion and suppression were also presented as a proportion of those enrolled, excluding those transferring to another clinic , and VL suppression as a proportion of those with VL completed.Risk differences were calculated using binomial generalized estimating equations, using robust standard errors and specifying clustering by AC. Outcomes were not adjusted for baseline characteristics, but sensitivity analyses were conducted for patients initiating ART in the previous three years, and stratifying by documented VL suppression at baseline and facility versus community ACs. All analysis was conducted using Stata 15 .2.8The pre‐specified non‐inferiority limit was 5% . ITT sam2.9Ethics approval was granted by the University of Cape Town (HREC 652/2016), Médecins Sans Frontières Ethics Review Board (protocol #1639) and WCDoH (WC_2016RP41_532). The trial was registered retrospectively with the Pan African Clinical Trial Registry (PACTR201810631281009) on 10 October 2018.33.1All 90 sampled ACs were eligible for study inclusion. After randomization, two ACs withdrew from the SoC: one did not have enough members present to vote for continued participation (most had sent buddies to collect treatment), and in the other <90% of members present voted for continued participation. No individual AC members asked to be transferred out of a participating AC. In total, 40 ACs were assigned to the intervention (n = 977 patients) and 48 ACs were assigned to the SoC (n = 1173) Figure .3.2A total of 2150 patients were enrolled in the trial and characteristics were similar in the two arms. There were fewer men than women in both arms (23.7% in SoC and 21.8% in intervention). Participants were on ART for a median of 7.3 years (interquartile range (IQR): 4.7 to 10.2 years) at study start and had a median age of 41.4 years (IQR 36.5 to 47.2 years). The majority (86.9%) were on a fixed‐dose regimen and had a suppressed VL (95.1%) in the 18 months prior to enrolment : −3.2 to 1.3) at 24 months. Over 24 months, 117 were lost to follow‐up, and 27 transferred out. There was no significant difference in retention, death, transfers or loss to follow‐up at 12 or 24 months. The exception was retention in AC care at 24 months where a greater proportion of participants were still in intervention ACs (75.0%) compared to SoC ACs (64.1%), with a risk difference of 10.7% (95% CI: 5.1 to 16.4%) (Table The majority (65.7%) of patients not retained in AC care at 24 months were late for their visit Table  and therIn the ITT analysis, VL completion and suppression were higher in the intervention arm at both 12 months and 24 months. VL completion was 98% versus 94% at 12 months  and 90.8 versus 85.2% at 24 months  in the intervention compared to the control. Similarly, the risk difference in VL suppression was 5.1% (95% CI 1.3 to 8.9%) at 12 months and 4.6% (95% CI 0.2 to 9.0%) at 24 months. In the mITT analysis, the intervention arm still compared favourably to the SoC. VL suppression as a proportion of those with a VL completed did not differ between the intervention and control ACs Table .Among those who were on ART for less than three years at study start (9.9% of the sample), ITT 24‐month retention in care was substantively lower in the intervention arm . During the second year of the study, intervention arm patients were more likely to have VL results available for their clinical visit (86.4% vs. 81.8%) Table .4In this cluster‐randomized trial of extended ART dispensing intervals, AC patients receiving six‐month ART refills showed non‐inferior 24‐month retention in care, VL completion and VL suppression to those in SoC ACs.This is the first study reporting 24‐month outcomes. Our outcomes are consistent with interim 12‐month outcomes in two recently published cluster randomized trials in Zimbabwe  and LesoIn this study, retention in care and viral suppression were, unsurprisingly, high overall with both arms achieving greater than 92% 24‐month retention and viral suppression among those with complete VLs. Patients were treatment experienced, with a median time on ART of over seven years. In addition, all of the patients were required to be clinically stable to enrol in ACs. Patients’ continued retention and viral suppression were expected but it is reassuring that extending their refill length and reducing the frequency of their group AC meetings, thereby reducing interactions with the health system and their peers, did not impact their 24‐month outcomes.Retention at 24 months was similar to community adherence clubs in Kwa‐Zulu Natal reporting 94.9% 12 to 24 month retention , 42. TweVL completion was high in the first 12 months, and lower in the second year of the study (85.2% in SoC and 90.8% in intervention), but still equivalent or better than published data on similar AC cohorts  , 44, 45 4% to 97%Our results add to the growing literature showing good retention and clinical outcomes associated with extended ART dispensing intervals , 47, 48.Reducing the frequency of AC visits ostensibly reduces the opportunity for peer and facilitator support, which patients have described as an important component of the AC model , 13. ParSouth Africa’s DSD policy to date has been conservative towards empowering stable ART patients with a choice to extend their refills. At a time when most sub‐Saharan African countries had moved to a minimum of three‐monthly ART refills, South Africa continued to limit refill length to two months. In 2020, the updated DSD policy shifted to three‐monthly but, in practice, remained constrained by the Central Chronic Medication Dispensing and Distribution (CCMDD), the main DSD drug supply system, continuing to only enable two‐monthly refills. This policy remained unchanged in South Africa’s guidance during COVID‐19 . Now witThis study had a number of limitations. First, we included some participants without documentation of recent viral suppression. However, the sensitivity analyses suggest this did not impact on the results. Second, AC patients who missed a scheduled visit by more than five days were not always referred back to mainstream care at their clinic but were allowed to continue their care within their AC. For purposes of the analysis, we treated these patients as not retained in AC care, but their continued care within the AC model may have supported their overall retention. As there was a higher proportion of these patients in SoC ACs, this may have benefitted retention for the SoC arm, but may have reduced SoC viral suppression. Third, during the first year of the study a once‐off non‐routine four‐month ART refill period was provided to all SoC AC patients in anticipation of a potential Cape Town water crisis , 52, in 5This study demonstrated that patients receiving their care through DSD models, who want less frequent visits and longer multi‐month dispensing, can be safely transitioned to six‐monthly visits and ART refills without compromising their longer term retention and viral suppression outcomes.The authors have no competing interests to declare.LW and AG conceptualized the study. TC and KL managed and curated data and TC performed the analysis. LW and RG were responsible for funding acquisition. TC, LW, AG, CMK and CO contributed to methodology. CMK, TM, KL and NZ ran the study. TC and LW drafted the initial manuscript. All authors reviewed and approved the final manuscript.AC, adherence club; ART, anti‐retroviral therapy; DSD, differentiated service delivery; GEE, generalized estimating equations; ICC, intra‐cluster correlation; IQR, interquartile range; MSF, Médecins Sans Frontières; PEPFAR, U.S. President's Emergency Plan for AIDS Relief; RD, risk difference; SoC, standard of care; SOP, standard operation procedure; VL, viral load; WCDoH, Western Cape Provincial Department of Health.Figure S1. Intention to treatrist differences (95% CI).Click here for additional data file.Table S1. Study power estimates for a range of intervention effects and intra‐cluster correlation using actual sample size, cluster size and retention in care estimates of the SoC armTable S2. Reasons for not being retained in AC careTable S3. Sensitivity analyses of retention at 12 and 24 monthsTable S4. Sensitivity analyses of viral load completion suppressionTable S5. Timing of blood draws for routine viral load monitoringClick here for additional data file.