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Introduction: Disengagement from antiretroviral therapy (ART) care is an important reason why people living with HIV do not achieve viral load suppression become unwell., Methods: We searched two databases and conference abstracts from January 2015 to December 2022 for studies which reported reasons for disengagement from ART care. We included quantitative (mainly surveys) and qualitative (in-depth interviews or focus groups) studies conducted after "treat all" or "Option B+" policy adoption. We used an inductive approach to categorize reasons: we report how often reasons were reported in studies and developed a conceptual framework for reasons., Results: We identified 21 studies which reported reasons for disengaging from ART care in the "Treat All" era, mostly in African countries: six studies in the general population of persons living with HIV, nine in pregnant or postpartum women and six in selected populations (one each in people who use drugs, isolated indigenous communities, men, women, adolescents and men who have sex with men). Reasons reported were: side effects or other antiretroviral tablet issues (15 studies); lack of perceived benefit of ART (13 studies); psychological, mental health or drug use (13 studies); concerns about stigma or confidentiality (14 studies); lack of social or family support (12 studies); socio-economic reasons (16 studies); health facility-related reasons (11 studies); and acute proximal events such as unexpected mobility (12 studies). The most common reasons for disengagement were unexpected events, socio-economic reasons, ART side effects or lack of perceived benefit of ART. Conceptually, studies described underlying vulnerability factors (individual, interpersonal, structural and healthcare) but that often unexpected proximal events (e.g. unanticipated mobility) acted as the trigger for disengagement to occur., Discussion: People disengage from ART care for individual, interpersonal, structural and healthcare reasons, and these reasons overlap and interact with each other. While HIV programmes cannot predict and address all events that may lead to disengagement, an approach that recognizes that such shocks will happen could help., Conclusions: Health services should focus on ways to encourage clients to engage with care by making ART services welcoming, person-centred and more flexible alongside offering adherence interventions, such as counselling and peer support., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource-limited settings., Objectives: To determine the accuracy of simple measures of ART adherence (including patient self-report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non-suppressed viral load in people living with HIV and receiving ART treatment., Search Methods: The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African-Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases., Selection Criteria: We included studies of all designs that evaluated a simple measure of adherence (index test) such as self-report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity., Data Collection and Analysis: We screened studies, extracted data, and assessed risk of bias using QUADAS-2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta-analysis or comparison of adherence measures. We explored heterogeneity using pre-defined subgroup analysis., Main Results: We included 51 studies involving children and adults with HIV, mostly living in low- and middle-income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self-report. - Self-report questionnaires (25 studies, 9211 participants; very low-certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%. - Self-report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low-certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%. - Tablet counts (12 studies, 3466 participants; very low-certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%. - Electronic monitoring devices (3 studies, 186 participants; very low-certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%. - Pharmacy records or secondary databases (6 studies, 2254 participants; very low-certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%. - Composite measures (9 studies, 1513 participants; very low-certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%. Across all included studies, the ability of adherence measures to detect viral non-suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision. The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results., Authors' Conclusions: We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non-suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Global HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART., Methods and Findings: We searched databases​ between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults (≥16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97-1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75-1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98-1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63-3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa., Conclusions: Based on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EHG is a member of PLOS Medicine’s editorial board. The other authors have declared that no competing interests exist.

Objective: How clinics structure the delivery of antiretroviral therapy (ART) services may influence patient adherence. We assessed the relationship between models of HIV care delivery and adherence as measured by medication possession ratio (MPR) among treatment-experienced adults in Tanzania, Uganda and Zambia., Methods: Eighteen clinics were grouped into three models of HIV care. Model 1-Traditional and Model 2-Mixed represented task-sharing of clinical services between physicians and clinical officers, distinguished by whether nurses played a role in clinical care; in Model 3-Task-Shifted, clinical officers and nurses shared clinical responsibilities without physicians. We assessed MPR among 3,419 patients and calculated clinic-level MPR summaries. We then calculated the mean differences of percentages and adjusted residual ratio (aRR) of the association between models of care and incomplete adherence, defined as a MPR <90%, adjusting for individual-level characteristics., Results: In the adjusted analysis, patients in Model 1-Traditional were more likely than patients in Model 2-Mixed to have MPR <90% (aRR = 1.60, 95% CI 1-2.48). Patients in Model 1-Traditional were no more likely than patients in Model 3-Task-Shifted to have a MPR <90% (aRR = 1.58, 95% 0.88-2.85). There was no evidence of differences in MPR <90% between Model 2-Mixed and Model 3-Task-Shifted (aRR = 0.99, 95% CI 0.59-1.66)., Conclusion: Non-physician-led ART programmes were associated with adherence levels as good as or better than physician-led ART programmes. Additional research is needed to optimise models of care to support patients on lifelong treatment., (© 2021 John Wiley & Sons Ltd.)

Introduction: Adolescents and young people comprise a growing proportion of new HIV infections globally, yet current approaches do not effectively engage this group, and adolescent HIV-related outcomes are the poorest among all age groups. Providing psychosocial interventions incorporating psychological, social, and/or behavioural approaches offer a potential pathway to improve engagement in care and health and behavioural outcomes among adolescents and young people living with HIV (AYPLHIV)., Methods: A systematic search of all peer-reviewed papers published between January 2000 and July 2020 was conducted through four electronic databases (Cochrane Library, PsycINFO, PubMed and Scopus). We included randomized controlled trials evaluating psychosocial interventions aimed at improving engagement in care and health and behavioural outcomes of AYPLHIV aged 10 to 24 years., Results and Discussion: Thirty relevant studies were identified. Studies took place in the United States (n = 18, 60%), sub-Saharan Africa (Nigeria, South Africa, Uganda, Zambia, Zimbabwe) and Southeast Asia (Thailand). Outcomes of interest included adherence to antiretroviral therapy (ART), ART knowledge, viral load data, sexual risk behaviours, sexual risk knowledge, retention in care and linkage to care. Overall, psychosocial interventions for AYPLHIV showed important, small-to-moderate effects on adherence to ART (SMD = 0.3907, 95% CI: 0.1059 to 0.6754, 21 studies, n = 2647) and viral load (SMD = -0.2607, 95% CI -04518 to -0.0696, 12 studies, n = 1566). The psychosocial interventions reviewed did not demonstrate significant impacts on retention in care (n = 8), sexual risk behaviours and knowledge (n = 13), viral suppression (n = 4), undetectable viral load (n = 5) or linkage to care (n = 1) among AYPLHIV. No studies measured transition to adult services. Effective interventions employed various approaches, including digital and lay health worker delivery, which hold promise for scaling interventions in the context of COVID-19., Conclusions: This review highlights the potential of psychosocial interventions in improving health outcomes in AYPLHIV. However, more research needs to be conducted on interventions that can effectively reduce sexual risk behaviours of AYPLHIV, as well as those that can strengthen engagement in care. Further investment is needed to ensure that these interventions are cost-effective, sustainable and resilient in the face of resource constraints and global challenges such as the COVID-19 pandemic., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants., Setting: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10-12, 2018, in Geneva, Switzerland., Methods: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices., Results: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely-under certain conditions-allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data., Conclusion: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy., Competing Interests: E.J.A. and L.M.M. participated in ViiV Dolutegravir Neural Tube Defect Advisory Board (no honorarium); A.P. has been an advisor to Merck Inc, Gilead Sciences, ViiV, and Janssen; S.K. has received research support from Janssen, Merck, Gilead, and ViiV and provided advice to Merck and ViiV; W.D.F.V. has received drug donations from ViiV and Gilead and participated in the Dolutegravir Neural Tube Defect Advisory Board and received honoraria for talks and board membership for Gilead, Viiv, Mylan, Merk, Adcock-Ingram, Aspen, Abbott, Roche, and J&J; and M.M. has received research support from Merck, Gilead, and ViiV. The other authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The World Health Organization recommends differentiated antiretroviral therapy (ART) delivery with longer visit intervals for clinically stable patients. We examined time trends in visit frequency and associations between criteria for clinical stability and visit frequency in ART programs in Southern Africa., Methods: We included adults on ART from 4 programs with viral-load monitoring, 2 programs with CD4 monitoring, and 4 programs with clinical monitoring of ART. We classified patients as clinically stable based on virological (viral load <1000 copies/mL), immunological (CD4 >200 cells/µL), or clinical (no current tuberculosis) criteria. We used Poisson regression and survival models to examine associations between criteria for clinical stability and the rate of clinic visits., Results: We included 180,837 patients. There were trends toward fewer visits in more recent years and with longer ART duration. In all ART programs, clinically stable patients were seen less frequently than patients receiving failing ART, but the strength of the association varied. Adjusted incidence rate ratios comparing visit rates for stable patients with patients on failing ART were 0.82 (95% confidence interval: 0.73 to 0.90) for patients classified based on the virological criterion, 0.81 (0.69 to 0.93) for patients classified based on the clinical criterion, and 0.90 (0.85 to 0.96) for patients classified based on the immunological criterion for stability., Conclusion: Differences in visit rates between stable patients and patients failing ART were variable and modest overall. Larger differences were seen in programs using virological criteria for clinical stability than in programs using immunological criteria. Greater access to routine viral-load monitoring may increase scale-up of differentiated ART delivery.

Objectives: Renal dysfunction is a significant cause of morbidity and mortality among HIV-positive individuals. This study evaluated renal dysfunction in a cohort of adults who started antiretroviral treatment (ART) regardless of CD4 count at three Department of Health (DOH) clinics included in the HIV Prevention Trials Network 071 (HPTN 071) Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART) trial., Methods: A retrospective cohort analysis of routine data for HIV-positive individuals starting ART between January 2014 and November 2015 was completed. Incident renal dysfunction was defined as an estimated glomerular filtration rate (eEGFR) < 60 mL/min after ART initiation among individuals with a baseline (pre-ART) eGFR ≥ 60 mL/min., Results: Overall, 2423 individuals, with a median baseline CD4 count of 328 cells/μL [interquartile range (IQR) 195-468 cells/μL], were included in the analysis. Forty-seven individuals had a baseline eGFR < 60 mL/min. Among 1634 nonpregnant individuals started on a tenofovir-containing ART regimen and with a baseline eGFR ≥ 60 mL/min, 27 developed an eGFR < 60 mL/min on ART. Regression analysis showed lower odds of baseline eGFR < 60 mL/min at baseline CD4 counts of > 500 cells/μL [adjusted odds ratio (aOR) 0.29; 95% confidence interval (CI) 0.11-0.80], 351-500 cells/μL (aOR 0.22; 95% CI 0.08-0.59) and 201-350 (aOR 0.48; 95% CI: 0.24-0.97) compared with baseline CD4 counts < 200 cells/μL., Conclusions: This study showed low rates of renal dysfunction at baseline and on ART, with lower rates of baseline renal dysfunction among individuals with baseline CD4 counts > 200 cells/μL. Strategies that use baseline characteristics, such as age, to identify individuals at high risk of renal dysfunction on ART for enhanced eGFR monitoring may be effective and should be the subject of future research., (© 2019 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Objectives: To assess adherence outcomes to antiretroviral therapy (ART) of recipients ≥50 years in Soweto, South Africa., Methods: This was a secondary data analysis for a cross-sectional study at two HIV clinics in Soweto. Data on ART adherence and covariates were gathered through structured interviews with HIV 878 persons living with HIV (PLHIV) receiving ART. Logistic regression analysis was used to assess associations., Results: PLHIV ≥50 years (n = 103) were more likely to miss clinic visits during the last six months than PLHIV aged 25-49 (OR 2.15; 95%CI 1.10-4.18). PLHIV ≥50 years with no or primary-level education were less likely to have missed a clinic visit during the last six months than PLHIV with secondary- or tertiary-level education in the same age category (OR 0.3; 95%CI 0.1-1.1), as were PLHIV who did not disclose their status (OR 0.2; 95%CI 0-1.1). There was no evidence of increased risk for non-adherence to ART pills and drug refill visits among older PLHIV., Conclusion: Missing a clinic visit was more common among older PLHIV who were more financially vulnerable. Further studies are needed to verify these findings and identify new risk factors associated with ART adherence., (© 2017 John Wiley & Sons Ltd.)

Background: Recent attention has focused on the question of how quickly antiretroviral therapy (ART) should be started once HIV diagnosis is confirmed. We assessed whether rapid ART initiation improves patient outcomes., Methods: We searched five databases from inception up to August 2017. Rapid ART initiation was defined as initiation within 14 days of HIV diagnosis. Data were pooled using random effects meta-analysis., Results: Across the randomized trials, ART start on the same day increased viral suppression at 12 months [three trials: relative risk (RR) 1.17, 95% confidence interval (CI) 1.07-1.27], retention in care at 12 months (RR 1.11, 95% CI 0.99-1.26), and the likelihood of starting ART within 90 days (four trials: RR 1.35, 95% CI 1.13-1.62) and 12 months after eligibility was established (three trials: RR 1.17, 95% CI 1.07-1.27). There was a nonsignificant trend toward reduced mortality (three trials: RR 0.53, 95% CI 0.24-1.08), as well as reduced loss to follow-up at 12 months (2 trials: RR 0.66, 95% CI 0.42-1.04). In the observational studies, offering accelerated ART initiation resulted in a greater likelihood of having started ART within 3 months (two studies: RR 1.53, 95% CI 1.11-2.10). There was a trend toward an increased risk of being lost to follow-up at 6 months (three studies: RR 1.85, 95% CI 0.96-3.55)., Conclusion: Accelerated ART initiation can lead to improved clinical outcomes and is likely to be of particular benefit in those settings where extensive patient preparation prior to starting ART results in long delays. These findings informed a WHO recommendation supporting accelerated ART initiation, including same day ART start.

Background: Organization of HIV care and treatment services, including clinic staffing and services, may shape clinical and financial outcomes, yet there has been little attempt to describe different models of HIV care in sub-Saharan Africa (SSA). Information about the relative benefits and drawbacks of different models could inform the scale-up of antiretroviral therapy (ART) and associated services in resource-limited settings (RLS), especially in light of expanded client populations with country adoption of WHO's test and treat recommendation., Methods: We characterized task-shifting/task-sharing practices in 19 diverse ART clinics in Tanzania, Uganda, and Zambia and used cluster analysis to identify unique models of service provision. We ran descriptive statistics to explore how the clusters varied by environmental factors and programmatic characteristics. Finally, we employed the Delphi Method to make systematic use of expert opinions to ensure that the cluster variables were meaningful in the context of actual task-shifting of ART services in SSA., Results: The cluster analysis identified three task-shifting/task-sharing models. The main differences across models were the availability of medical doctors, the scope of clinical responsibility assigned to nurses, and the use of lay health care workers. Patterns of healthcare staffing in HIV service delivery were associated with different environmental factors (e.g., health facility levels, urban vs. rural settings) and programme characteristics (e.g., community ART distribution or integrated tuberculosis treatment on-site)., Conclusions: Understanding the relative advantages and disadvantages of different models of care can help national programmes adapt to increased client load, select optimal adherence strategies within decentralized models of care, and identify differentiated models of care for clients to meet the growing needs of long-term ART patients who require more complicated treatment management.

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: In light of recent changes to antiretroviral treatment (ART) guidelines of the World Health Organization and ongoing concerns about adherence with earlier initiation of ART, we conducted a systematic review of published literature to review the association between baseline (pre-ART initiation) CD4 count and ART adherence among adults enrolled in ART programs worldwide., Methods: We performed a systematic search of English language original studies published between January 1, 2004 and September 30, 2015 using Medline, Web of Science, LILACS, AIM, IMEMR, and WPIMR databases. We calculated the odds of being adherent at higher CD4 count compared with lower CD4 count according to study definitions and pooled data using random effects models., Results: Twenty-eight articles were included in the review and 18 in the meta-analysis. The odds of being adherent was marginally lower for patients in the higher CD4 count group (pooled odds ratio, 0.90; 95% confidence interval, 0.84 to 0.96); however, the majority of studies found no difference in the odds of adherence when comparing CD4 count strata. In analyses restricted to comparisons above and below a CD4 count of 500 cells per microliter, there was no difference in adherence (pooled odds ratio, 1.01; 95% confidence interval: 0.97 to 1.05)., Conclusions: This review was unable to find consistent evidence of differences in adherence according to baseline CD4 count. Although this is encouraging for the new recommendations to treat all HIV-positive individuals irrespective of CD4 count, there is a need for additional high-quality studies, particularly among adults initiating ART at higher CD4 cell counts.

Background: New antiretroviral therapy (ART) regimens for HIV could improve clinical outcomes for patients. To inform global guidelines, we aimed to assess the comparative effectiveness of recommended ART regimens for HIV in ART-naive patients., Methods: For this systematic review and network meta-analysis, we searched for randomised clinical trials published up to July 5, 2015, comparing recommended antiretroviral regimens in treatment-naive adults and adolescents (aged 12 years or older) with HIV. We extracted data on trial and patient characteristics, and the following primary outcomes: viral suppression, mortality, AIDS defining illnesses, discontinuations, discontinuations due to adverse events, and serious adverse events. We synthesised data using network meta-analyses in a Bayesian framework and included older treatments, such as indinavir, to serve as connecting nodes. We defined network nodes in terms of specific antivirals rather than specific ART regimens. We categorised backbone regimens and adjusted for them through group-specific meta-regression. We used the GRADE framework to interpret the strength of inference., Findings: We identified 5865 citations through database searches and other sources, of which, 126 articles related to 71 unique trials were included in the network analysis, including 34 032 patients randomly assigned to 161 treatment groups. For viral suppression at 48 weeks, compared with efavirenz, the odds ratio (OR) for viral suppression was 1·87 (95% credible interval [CrI] 1·34-2·64) with dolutegravir and 1·40 (1·02-1·96) with raltegravir; with respect to viral suppression, low-dose efavirenz was similar to all other treatments. Both low-dose efavirenz and integrase strand transfer inhibitors tended to be protective of discontinuations due to adverse events relative to normal-dose efavirenz. The most protective effect relative to efavirenz in network meta-analyses was that of dolutegravir (OR 0·26, 95% CrI 0·14-0·47), followed by low-dose efavirenz (0·39, 0·16-0·92). Owing to insufficient data, we could make no conclusions about serious adverse events. Low event rates also limited the quality of evidence with regard to mortality and AIDS defining illnesses., Interpretation: The efficacy and safety of ART has substantially improved with the introduction of newer drug classes of antiretrovirals that are now available to patients and HIV care providers. Their improved tolerance could be part of a larger solution to improve retention, which is a challenge, particularly in low-income and middle-income country settings., Funding: The World Health Organization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Problem: In Malawi, health-system constraints meant that only a fraction of people infected with human immunodeficiency virus (HIV) and in immediate need of antiretroviral treatment (ART) received treatment., Approach: In 2004, the Malawian Ministry of Health launched plans to scale-up ART nationwide, adhering to the principle of equity to ensure fair geographical access to therapy. A public health approach was used with standardized training and treatment and regular supervision and monitoring of the programme., Local Setting: Before the scale-up, an estimated 930 000 people in Malawi were HIV-infected, with 170 000 in immediate need of ART. About 3000 patients were on ART in nine clinics., Relevant Changes: By December 2015, cumulatively 872 567 patients had been started on ART from 716 clinics, following national treatment protocols and using the standard monitoring system., Lessons Learnt: Strong national leadership allowed the ministry of health to implement a uniform system for scaling-up ART and provided benchmarks for implementation on the ground. New systems of training staff and accrediting health facilities enabled task-sharing and decentralization to peripheral health centres and a standardized approach to starting and monitoring ART. A system of quarterly supervision and monitoring, into which operational research was embedded, ensured stocks of drug supplies at facilities and adherence to national treatment guidelines.

Background: More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance., Methods: We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure., Results: Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely., Conclusions: Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Measurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration., Methods and Findings: Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained., Conclusions: A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.

For more than two decades, CD4 cell count measurements have been central to understanding HIV disease progression, making important clinical decisions, and monitoring the response to antiretroviral therapy (ART). In well resourced settings, the monitoring of patients on ART has been supported by routine virological monitoring. Viral load monitoring was recommended by WHO in 2013 guidelines as the preferred way to monitor people on ART, and efforts are underway to scale up access in resource-limited settings. Recent studies suggest that in situations where viral load is available and patients are virologically suppressed, long-term CD4 monitoring adds little value and stopping CD4 monitoring will have major cost savings. CD4 cell counts will continue to play an important part in initial decisions around ART initiation and clinical management, particularly for patients presenting late to care, and for treatment monitoring where viral load monitoring is restricted. However, in settings where both CD4 cell counts and viral load testing are routinely available, countries should consider reducing the frequency of CD4 cell counts or not doing routine CD4 monitoring for patients who are stable on ART., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Several approaches have been taken to reduce pre-antiretroviral therapy (ART) losses between HIV testing and ART initiation in low- and middle-income countries, but a systematic assessment of the evidence has not yet been undertaken. The aim of this systematic review is to assess the potential for interventions to improve or facilitate linkage to or retention in pre-ART care and initiation of ART in low- and middle-income settings., Methods: An electronic search was conducted on Medline, Embase, Global Health, Web of Science and conference databases to identify studies describing interventions aimed at improving linkage to or retention in pre-ART care or initiation of ART. Additional searches were conducted to identify on-going trials on this topic, and experts in the field were contacted. An assessment of the risk of bias was conducted. Interventions were categorized according to key domains in the existing literature., Results: A total of 11,129 potentially relevant citations were identified, of which 24 were eligible for inclusion, with the majority (n=21) from sub-Saharan Africa. In addition, 15 on-going trials were identified. The most common interventions described under key domains included: health system interventions (i.e. integration in the setting of antenatal care); patient convenience and accessibility (i.e. point-of-care CD4 count (POC) testing with immediate results, home-based ART initiation); behaviour interventions and peer support (i.e. improved communication, patient referral and education) and incentives (i.e. food support). Several interventions showed favourable outcomes: integration of care and peer supporters increased enrolment into HIV care, medical incentives increased pre-ART retention, POC CD4 testing and food incentives increased completion of ART eligibility screening and ART initiation. Most studies focused on the general adult patient population or pregnant women. The majority of published studies were observational cohort studies, subject to an unclear risk of bias., Conclusions: Findings suggest that streamlining services to minimize patient visits, providing adequate medical and peer support, and providing incentives may decrease attrition, but the quality of the current evidence base is low. Few studies have investigated combined interventions, or assessed the impact of interventions across the HIV cascade. RESULTS from on-going trials investigating POC CD4 count testing, patient navigation, rapid ART initiation and mobile phone technology may fill the quality of evidence gap. Further high-quality studies on key population groups are required, with interventions informed by previously reported barriers to care.

Background: Pediatric antiretroviral treatment coverage in resource-limited settings continues to lag behind adults. Task shifting is an effective approach broadly used for adults, which some countries have also adopted for children, but implementation is limited by lack of confidence and skills among nonspecialist staff., Methods: A systematic review was conducted by combining key terms for task shifting, antiretroviral therapy (ART), and children. Five databases and two conferences were searched from inception till August 01, 2013., Results: Eight observational studies provided outcome data for 11,828 children who received ART from nonphysician providers across 10 countries in sub-Saharan Africa. The cumulative pooled proportion of deaths was 3.2% [95% confidence interval (CI): 2.0 to 4.5] at 6 months, 4.6% (95% CI: 2.1 to 7.1) at 12 months, 6.2% (95% CI: 3.7 to 8.8) at 24 months, and 5.9% (95% CI: 3.5 to 8.3) at 36 months. Mortality and loss to follow-up in task-shifting programs were comparable to those reported by programs providing doctor- or specialist-led care., Conclusions: Our review suggests that task shifting of ART care can result in outcomes comparable to routine physician care, and this approach should be considered as part of a strategy to scale-up pediatric treatment. Specialist care will remain important for management of sick patients and complicated cases. Further qualitative research is needed to inform optimal implementation of task shifting for pediatric patients.

Timely linkage to antiretroviral therapy (ART) care is critical for reducing HIV-related morbidity, mortality and transmission. Studies investigating interventions to improve linkage to, and retention in, pre-ART care in sub-Saharan Africa were reviewed. Certain interventions used to overcome economic barriers for ART-patients (i.e. integration of services, medical and food incentives, intensified counselling and peer support) have also shown favourable results in the pre-ART period. A combined package of interventions found to be effective in the pre-ART and ART period might be effective for reducing attrition in both periods. Further operational research in this area is needed to identify local solutions.

In sub-Saharan Africa models of care need to adapt to support continued scale up of antiretroviral therapy (ART) and retain millions in care. Task shifting, coupled with community participation has the potential to address the workforce gap, decongest health services, improve ART coverage, and to sustain retention of patients on ART over the long-term. The evidence supporting different models of community participation for ART care, or community-based ART, in sub-Saharan Africa, was reviewed. In Uganda and Kenya community health workers or volunteers delivered ART at home. In Mozambique people living with HIV/AIDS (PLWHA) self-formed community-based ART groups to deliver ART in the community. These examples of community ART programs made treatment more accessible and affordable. However, to achieve success some major challenges need to be overcome: first, community programs need to be driven, owned by and embedded in the communities. Second, an enabling and supportive environment is needed to ensure that task shifting to lay staff and PLWHA is effective and quality services are provided. Finally, a long term vision and commitment from national governments and international donors is required. Exploration of the cost, effectiveness, and sustainability of the different community-based ART models in different contexts will be needed.

Providing antiretroviral treatment (ART) in humanitarian settings is challenging. Reports suggest that ART provision is feasible, but the evidence base is scarce. We systematically searched three databases for studies reporting ART outcomes among displaced populations in settings of conflict, natural disasters or political instability, and estimated overall mortality using random effects models. Fourteen studies were identified, six in conflict areas, five in areas of post-election violence and three in natural disaster settings. The pooled proportion for mortality was 7.6% (95% CI 5.3-10.0%) at six months and 9.0% (95% CI 5.8-12.2%) at 12 months. Loss-to-follow-up at six months was 6.3% (95% CI 4.3-8.3%) and at 12 months was 8.1% (4.9-11.2%). Adherence was comparable to stable settings. Strategies used to support ART provision included additional drug stocks and establishing peer communication networks. Good clinical outcomes can be achieved with ART in disaster setting, in particular if supported by regional collaboration, standardized drug regimens and contingency planning.

Background: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure., Methods: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance., Results: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01&#95;AE increased the risk of K65R, but only CRF01&#95;AE increased the risk of K65R without Q151M., Conclusions: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Purpose of Review: This review describes the evolution of WHO guidelines for antiretroviral therapy (ART) in HIV-infected individuals, considering the key epidemiological, scientific, programmatic, and political changes over the last decade, and highlights the major trends for the management of the HIV disease in future guidelines revisions., Recent Findings: In the last few years, new evidence has emerged supporting the potential preventive benefit of ART in reducing HIV transmission. This, together with the potential clinical benefits of earlier initiation of therapy, has led to the consideration of the broader strategic use of ART, taking into account the clinical and public health benefit, and programmatic feasibility., Summary: In 2002, WHO established its first guidelines for ART use, primarily focused on a public health approach for resource-limited settings. These recommendations were updated in 2003, 2006, and 2010, incorporating progressive changes reflecting progressive increase in the knowledge of HIV pathogenesis, development of new drugs and diagnostics, and increased experience of HIV treatment and prevention programs. The impact of several international political commitments and scale-up initiatives such as the 3 by 5 Initiative, Universal Access targets, and the Treatment 2.0 Strategy were also important drivers of the global response, increasing the treatment coverage and catalyzing the necessary environment for the establishment of operational and programmatic components for an expanded and sustainable global response to HIV/AIDS.

Global commitments aim to provide antiretroviral therapy (ART) to 15 million people living with HIV by 2015, and recent studies have demonstrated the potential for widespread ART to prevent HIV transmission. Increasingly, countries are adapting their national guidelines to start ART earlier, for both clinical and preventive benefits. To maximize the benefits of ART in resource-limited settings, six key principles need to guide ART choice: simplicity, tolerability and safety, durability, universal applicability, affordability and heat stability. Currently available drugs, combined with those in late-stage clinical development, hold great promise to simplify treatment in the short term. Over the longer-term, newer technologies, such as long-acting formulations and nanotechnology, could radically alter the treatment paradigm. This commentary reviews recommendations made in an expert consultation on treatment scale up in resource-limited settings.

Background: Little is known about the effect of combination antiretroviral therapy (cART) on life expectancy in sub-Saharan Africa., Objective: To estimate life expectancy of patients once they initiate cART in Uganda., Design: Prospective cohort study., Setting: Public sector HIV and AIDS disease-management program in Uganda., Patients: 22 315 eligible patients initiated cART during the study period, of whom 1943 were considered to have died., Measurements: All-cause mortality rates were calculated and abridged life tables were constructed and stratified by sex and baseline CD4 cell count status to estimate life expectancies for patients receiving cART. The average number of years remaining to be lived by patients who received cART at varying age categories was estimated., Results: After adjustment for loss to follow-up, crude mortality rates (deaths per 1000 person-years) ranged from 26.9 (95% CI, 25.4 to 28.5) in women to 43.9 (CI, 40.7 to 47.0) in men. For patients with a baseline CD4 cell count less than 0.050 × 10(9) cells/L, the mortality rate was 67.3 (CI, 62.1 to 72.9) deaths per 1000 person-years, whereas among persons with a baseline CD4 cell count of 0.250 × 10(9) cells/L or more, the mortality rate was 19.1 (CI, 16.0 to 22.7) deaths per 1000 person-years. Life expectancy at age 20 years for the overall cohort was 26.7 (CI, 25.0 to 28.4) additional years and at age 35 years was 27.9 (CI, 26.7 to 29.1) additional years. Life expectancy increased substantially with increasing baseline CD4 cell count. Similar trends are observed for older age groups., Limitations: A small (6.4%) proportion of patients were lost to follow-up, and it was imputed that 30% of these patients had died. Few patients with a CD4 cell count greater than 0.250 × 10(9) cells/L initiated cART., Conclusion: Ugandan patients receiving cART can expect an almost normal life expectancy, although there is considerable variability among subgroups of patients., Primary Funding Source: Canadian Institutes of Health Research.

Background: Adolescents have been identified as a high-risk group for poor adherence to and defaulting from combination antiretroviral therapy (cART) care. However, data on outcomes for adolescents on cART in resource-limited settings remain scarce., Methods: We developed an observational study of patients who started cART at The AIDS Service Organization (TASO) in Uganda between 2004 and 2009. Age was stratified into three groups: children (≤10 years), adolescents (11-19 years), and adults (≥20 years). Kaplan-Meier survival curves were generated to describe time to mortality and loss to follow-up, and Cox regression used to model associations between age and mortality and loss to follow-up. To address loss to follow up, we applied a weighted analysis that assumes 50% of lost patients had died., Findings: A total of 23,367 patients were included in this analysis, including 810 (3.5%) children, 575 (2.5%) adolescents, and 21 982 (94.0%) adults. A lower percentage of children (5.4%) died during their cART treatment compared to adolescents (8.5%) and adults (10%). After adjusting for confounding, other features predicted mortality than age alone. Mortality was higher among males (p<0.001), patients with a low initial CD4 cell count (p<0.001), patients with advanced WHO clinical disease stage (p<0.001), and shorter duration of time receiving cART (p<0.001). The crude mortality rate was lower for children (22.8 per 1000 person-years; 95% CI: 16.1, 29.5), than adolescents (36.5 per 1000 person-years; 95% CI: 26.3, 46.8) and adults (37.5 per 1000 person-years; 95% CI: 35.9, 39.1)., Interpretation: This study is the largest assessment of adolescents receiving cART in Africa. Adolescents did not have cART mortality outcomes different from adults or children.

Objective: Evaluations of CD4 cell count and other prognostic factors on the survival of HIV patients in sub-Saharan Africa are extremely limited. Funders have been reticent to recommend earlier initiation of treatment. We aimed to examine the effect of baseline CD4 cell count on mortality using data from HIV patients receiving combination antiretroviral therapy (cART) in Uganda., Design: Observational study of patients aged at least 14 years enrolled in 10 clinics across Uganda for which The AIDS Support Organization (TASO) has data., Methods: CD4 cell count was stratified into categories (<50, 50-99, 100-149, 150-199, 200-249, 250-299, ≥300 cells/μl) and Cox proportional hazards regression was used to model the associations between CD4 cell count and mortality., Results: A total of 22 315 patients were included. 1498 patients died during follow-up (6.7%) and 1433 (6.4%) of patients were lost to follow-up. Crude mortality rates (CMRs) ranged from 53.8 per 1000 patient-years [95% confidence interval (CI) 48.8-58.8] among those with CD4 cell counts of less than 50, to 15.7, (95% CI 12.1-19.3) among those with at least 300 cells/μl. Relative to a baseline CD4 cell count of less than 50 cells/μl, the risk of mortality was 0.75 (95% CI 0.65-0.88), 0.60 (95% CI 0.51-0.70), 0.43 (0.37-0.50), and 0.41 (0.33-0.51) for those with baseline CD4 cell counts of 50-99, 100-149, 150-249, and ≥250 cells/μl, respectively., Conclusion: Earlier initiation of cART is associated with increased survival benefits over deferred treatment.

Objective: To examine if there is a significant difference in survival between elderly (>50 years) and nonelderly adult patients receiving combination antiretroviral therapy in Uganda between 2004 and 2010., Design: Prospective observational study., Methods: Patients 18-49 years of age (nonelderly) and 50 years of age and older enrolled in the AIDS Support Organization Uganda HIV/AIDS national programme were assessed for time to all-cause mortality. We applied a Weibull multivariable regression., Results: Among the 22 087 patients eligible for analyses, 19 657 (89.0%) were aged between 18 and 49 years and 2430 (11.0%) were aged 50 years or older. These populations differed in terms of the distributions of sex, baseline CD4 cell count and death. The age group 40-44 displayed the lowest crude mortality rate [31.4 deaths per 1000 person-years; 95% confidence interval (CI) 28.1, 34.7) and the age group 60-64 displayed the highest crude mortality rate (58.9 deaths per 1000 person-years; 95% CI 42.2, 75.5). Kaplan-Meier survival estimates indicated that nonelderly patients had better survival than elderly patients (P < 0.001). Adjusted Weibull analysis indicated that elderly age status was importantly associated (adjusted hazard ratio 1.23, 95% CI 1.08-1.42) with mortality, when controlling for sex, baseline CD4 cell count and year of therapy initiation., Conclusion: As antiretroviral treatment cohorts mature, the proportion of patients who are elderly will inevitably increase. Elderly patients may require focused clinical care that extends beyond HIV treatment.

Introduction: Current guidelines contraindicate TDF use when creatinine clearance (CrCl) falls below 50 ml/min. We report prevalence of abnormal renal function at baseline and factors associated with abnormal renal function from a community cohort in Lesotho., Methods: We calculated changes in CrCl from baseline for patients initiated on TDF at 6 and 12 months and the proportion of patients initiated on TDF who developed renal impairment. Screening algorithms were developed using risk factors determined by multivariate analysis., Results: Among 933 adults for whom baseline creatinine was available, 176 (18.9%) presented with a baseline CrCl <50 ml/min. Renal function improved during follow-up. 19 patients who developed renal toxicity during follow up remained on TDF; renal function improved (CrCl≥50 ml/min) in all but 3 of these patients. Among 15 patients with a baseline CrCl <50 ml/min were started in error, none developed severe renal impairment., Conclusion: In this setting TDF-associated renal toxicity is rare and mainly transient. Further studies to assess TDF safety at lower CrCl thresholds are warranted.

Background: Loss to follow-up (LTF) challenges the reporting of antiretroviral treatment (ART) programmes, since it encompasses patients alive but lost to programme and deaths misclassified as LTF. We describe LTF before and after correction for mortality in a primary care ART programme with linkages to the national vital registration system., Methods and Findings: We included 6411 patients enrolled on ART between March 2001 and June 2007. Patients LTF with available civil identification numbers were matched with the national vital registration system to ascertain vital status. Corrected mortality and true LTF were determined by weighting these patients to represent all patients LTF. We used Kaplan-Meier estimates and Cox regression to describe LTF, mortality among those LTF, and true LTF. Of 627 patients LTF, 85 (28.8%) had died within 3 months after their last clinic visits. Respective estimates of LTF before and after correction for mortality were 6.9% (95% confidence interval [CI] 6.2-7.6) and 4.3% (95% CI 3.5-5.3) at one year on ART, and 23.9% (95% CI 21.0-27.2) and 19.7% (95% CI 16.1-23.7) at 5 years. After correction for mortality, the hazard of LTF was reversed from decreasing to increasing with time on ART. Younger age, higher baseline CD4 count, pregnancy and increasing calendar year were associated with higher true LTF. Mortality of patients LTF at 1, 12 and 24 months after their last visits was respectively 23.1%, 30.9% and 43.8%; 78.0% of deaths occurred during the first 3 months after last visit and 45.0% in patients on ART for 0 to 3 months., Conclusions: Mortality of patients LTF was high and occurred early after last clinic visit, especially in patients recently started on ART. Correction for these misclassified deaths revealed that the risk of true LTF increased over time. Research targeting groups at higher risk of LTF (youth, pregnant women and patients with higher CD4 counts) is needed.

Objective: Previous studies have demonstrated a cross-sectional relationship between antiretroviral adherence and HIV virological suppression. We assessed the predictive value of baseline adherence in determining long-term virological failure., Design: We assessed baseline adherence via an adherence questionnaire between administered to all consenting patients attending antiretroviral clinics in Khayelitsha township, South Africa, between May 2002 and March 2004. Virological status was ascertained after five years of follow up and multivariate analysis used to model associations of baseline variables and medication adherence with time to viral suppression or failure., Results: Our adherence cohort comprised 207 patients, among whom 72% were female. Median age was 30 years and median CD4 count at initiation was 55 cells/mm(3). We found no statistically significant differences between baseline characteristics and early adherence groups. Multivariate analysis adjusting for baseline CD4 and age found that patients with suboptimal baseline adherence had a hazard ratio of 2.82 (95% CI 1.19-6.66, p = 0.018) for progression to virological failure compared to those whose baseline adherence was considered optimal., Conclusions: Our longitudinal study provides further confirmation of adherence as a primary determinant of subsequent confirmed virological failure, and serves as a reminder of the importance of initial early investments in adherence counseling and support as an effective way to maximize long-term treatment success.

There has been an historic expectation that delivering combination antiretroviral therapy (cART) to populations affected by violent conflict is untenable due to population movement and separation of drug supplies. There is now emerging evidence that cART provision can be successful in these populations. Using examples from Médecins Sans Frontières experience in a variety of African settings and also local nongovernmental organizations' experiences in northern Uganda, we examine novel approaches that have ensured retention in programs and adequate adherence. Emerging guidelines from United Nations bodies now support the expansion of cART in settings of conflict.

Clinical trials are usually designed to meet registration requirements in developed countries, and do not always address key concerns for use in developing countries. Four late-stage investigational new drugs - rilpivirine, etravirine, raltegravir and maraviroc - show potential to improve antiretroviral therapy. However, a number of issues could limit their use in developing countries, including dose selection, treatment strategy, combination with other drugs, use in specific populations and reliance on expensive tests. Key research questions relevant for developing countries need to be answered early in the drug development process to ensure maximum benefit for the majority.

Health worker shortages are a major bottleneck to scaling up antiretroviral therapy (ART), particularly in rural areas. In Lusikisiki, a rural area of South Africa with a population of 150,000 serviced by 1 hospital and 12 clinics, Médecins Sans Frontières has been supporting a program to deliver human immunodeficiency virus (HIV) services through decentralization to primary health care clinics, task shifting (including nurse-initiated as opposed to physician-initiated treatment), and community support. This approach has allowed for a rapid scale-up of treatment with satisfactory outcomes. Although the general approach in South Africa is to provide ART through hospitals-which seriously limits access for many people, if not the majority of people-1-year outcomes in Lusikisiki are comparable in the clinics and hospital. The greater proximity and acceptability of services at the clinic level has led to a faster enrollment of people into treatment and better retention of patients in treatment (2% vs. 19% lost to follow-up). In all, 2200 people were receiving ART in Lusikisiki in 2006, which represents 95% coverage. Maintaining quality and coverage will require increased resource input from the public sector and full acceptance of creative approaches to implementation, including task shifting and community involvement.