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Sub-Saharan Africa carries the highest burden of HIV, with approximately 70% of all people living with HIV (PLWH) globally living in this region. The provision of antiretroviral treatment (ART) significantly affects already overburdened health systems, which need to accommodate large volumes of ART patients while facing a shortage of professional health workers, infrastructure challenges and medical resources. Finding alternative ways to provide routine services to PLWH has become significantly more urgent. Multi-month dispensing (MMD) of ART aims to improve access to treatment for PLWH, while also improving the efficiency of the health system. This study explores the experienced benefits and challenges of community-based MMD in order to make recommendations for future implementation efforts. Twenty focus group discussions were conducted with members of community ART refill groups (CARGs) who received 3-monthly or 6-monthy MMD. Individual interviews were also conducted with health providers. All interviews and focus group discussions took place between April and June 2019 conducted by research nurses in English, Shona or Ndebele. Multiple benefits of community-based MMD were reported, including decreased congestion in health facilities, improved service delivery, decline in staff burnout and increased time availability for CARG members due to less time spent at clinics, improved ART adherence and social support experienced amongst members of CARGs. Identified challenges included the possibility of being exposed to HIV-related stigma when belonging to a CARG, and low levels of medical supplies and ART stock at clinics. Recommendations were made by CARG members and health care workers on how CARGs could be improved and sustained in the future. Results from this study show that the implementation of community-based MMD holds multiple benefits at an individual and health facility level. Future recommendations include evaluating the feasibility of MMD among other vulnerable populations., (© 2022 John Wiley & Sons Ltd.)

Background: Out-of-facility multi-month dispensing (MMD) is a differentiated service delivery model which provides antiretroviral treatment (ART) at intervals of up to 6 monthly in the community. Limited randomized evidence investigating out-of-facility MMD is available. We evaluated participant outcomes and compared out-of-facility MMD models using data from cluster-randomized trials in Southern Africa., Setting: Eight districts in Zimbabwe and Lesotho., Methods: Individual-level participant data from 2 cluster-randomized trials that included stable adults receiving ART at 60 facilities were pooled. Both trials had 3 arms: ART collected 3-monthly at healthcare facilities (3MF, control); ART provided three-monthly in community ART groups (CAGs) (3MC); and ART provided 6-monthly in either CAGs or on an individual provider-patient basis (6MC). Participant retention, viral suppression and incidence of unscheduled facility visits were compared., Results: Ten thousand one hundred thirty-six participants were included, 3817 (37.7%), 2893 (28.5%) and 3426 (33.8%) in arms 3MF, 3MC and 6MC, respectively. After 12 months, retention was non-inferior for 3MC (95.7%) vs. 3MF (95.0%) {adjusted risk difference (aRD) = 0.3 [95% confidence interval (CI): -0.8 to 1.4]}; and 6MC (95.1%) vs. 3MF [aRD = -0.2 (95% CI: -1.4 to 1.0)]. Retention was greater amongst intervention arm participants in CAGs versus 6MC participants not in CAGs, aRD = 1.5% (95% CI: 0.2% to 2.9%). Viral suppression was excellent (≥98%) and unscheduled facility visits were not increased in the intervention arms., Conclusions: Three and 6-monthly out-of-facility MMD was non-inferior versus facility-based care for stable ART patients. Out-of-facility 6-monthly MMD should incorporate small group peer support whenever possible., Clinicaltrial Registration: ClinicalTrials.gov NCT03238846 and NCT03438370., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Differentiated service delivery (DSD) models for HIV treatment decrease health facility visit frequency and limit healthcare facility-based exposure to severe acute respiratory syndrome coronavirus 2. However, two important evidence gaps include understanding DSD effectiveness amongst clients commencing DSD within 12 months of antiretroviral treatment (ART) initiation and amongst clients receiving only single annual clinical consultations. To investigate these, we pooled data from two cluster-randomized trials investigating community-based DSD in Zimbabwe and Lesotho., Methods: Individual-level participant data of newly stable adults enrolled between 6 and 12 months after ART initiation were pooled. Both trials (conducted between August 2017 and July 2019) had three arms: Standard-of-care three-monthly ART provision at healthcare facilities (SoC, control); ART provided three-monthly in community ART groups (CAGs) (3MC) and ART provided six-monthly in either CAGs or at community-distribution points (6MC). Clinical visits were three-monthly in SoC and annually in intervention arms. The primary outcome was retention in care and secondary outcomes were viral suppression (VS) and number of unscheduled facility visits 12 months after enrolment. Individual-level regression analyses were conducted by intention-to-treat specifying for clustering and adjusted for country., Results and Discussion: A total of 599 participants were included; 212 (35.4%), 128 (21.4%) and 259 (43.2%) in SoC, 3MC and 6MC, respectively. Few participants aged <25 years were included (n = 32). After 12 months, 198 (93.4%), 123 (96.1%) and 248 (95.8%) were retained in SoC, 3MC and 6MC, respectively. Retention in 3MC was superior versus SoC, adjusted risk difference (aRD) = 4.6% (95% CI: 0.7%-8.5%). Retention in 6MC was non-inferior versus SoC, aRD = 1.7% (95% CI: -2.5%-5.9%) (prespecified non-inferiority aRD margin -3.25%). VS was similar between arms, 99.3, 98.6 and 98.1% in SoC, 3MC and 6MC, respectively. Adjusted risk ratio's for VS were 0.98 (95% CI: 0.92-1.03) for 3MC versus SoC, and 0.98 (CI: 0.95-1.00) for 6MC versus SoC. Unscheduled clinic visits were not increased in intervention arms: incidence rate ratio = 0.53 (CI: 0.16-1.80) for 3MC versus SoC; and 0.82 (CI: 0.25-2.79) for 6MC versus SoC., Conclusions: Community-based DSD incorporating three- and six-monthly ART refills and single annual clinical visits were at least non-inferior to standard facility-based care amongst newly stable ART clients aged ≥25 years. ClinicalTrials.gov: NCT03238846 & NCT03438370., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Southern Africa remains the epicentre of the human immunodeficiency virus (HIV) epidemic with AIDS the leading cause of death amongst adolescents. Poor policy translation, inadequate programme implementation and fragmentation of services contribute to adolescents' poor access to sexual and reproductive health and rights (SRHR) services. This study assessed an integrated, school-based SRHR and HIV programme, modelled on the South African Integrated School Health Policy in a rural, high HIV-prevalence district. A retrospective cohort study of 1260 high-school learners was undertaken to assess programme uptake, change in HIV knowledge and behaviour and the determinants of barrier-methods use at last sexual intercourse. Programme uptake increased (2%-89%; P�<�0.001) over a 16-month period, teenage-pregnancy rates declined (14%-3%; P�<�0.050) and accurate knowledge about HIV transmission through infected blood improved (78.3%-93.8%; P�<�0.050), a year later. Post-intervention, attending a clinic perceived as adolescent-friendly increased the odds of barrier-methods use during the last sexual encounter (aOR=1.85; 95% CI: 1.31-2.60), whilst being female (aOR=0.69; 95% CI: 0.48-0.99), <15 years (aOR=0.44; 95% CI: 0.24-0.80), or having >5 sexual partners in the last year (aOR=0.59; 95% CI: 0.38-0.91) reduced the odds. This study shows that the unmet SRHR needs of under-served adolescents can be addressed through integrated, school-based SRHR programmes., (� The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The HIV epidemic is strongly gendered. Women and girls are more likely to contract HIV for biological and social reasons in Sub-Saharan Africa and men living with HIV are more likely to be lost to follow-up and die on antiretroviral therapy (ART) than women. Care work is also gendered, with women shouldering the burden of HIV care-related work. This paper considers the potential of male delivered community health work to improve men's HIV-related health outcomes and shift gendered norms related to care work. It describes the experiences and perspectives of eight HIV community health workers and their clients from the Cape Town area, and reviews current evidence on male-focused HIV and sexual and reproductive health services, gender transformation and men and care. Findings suggest that meaningfully involving more men in HIV care work may be a way to shift damaging hegemonic masculine norms related to care and health, and that South Africa's roll-out of National Health Insurance could be an opportunity to do so. Barriers to engaging men in this feminised profession are also explored.

Introduction: Multimonth dispensing (MMD) of antiretroviral treatment (ART) aims to reduce patient-related barriers to access long-term treatment and improve health system efficiency. However, randomized evidence of its clinical effectiveness is lacking. We compared MMD within community ART refill groups (CARGs) vs. standard-of-care facility-based ART delivery in Zimbabwe., Methods: A three-arm, cluster-randomized, pragmatic noninferiority trial was performed. Thirty health care facilities and associated CARGs were allocated to either ART collected three-monthly at facility (3MF, control); ART delivered three-monthly in CARGs (3MC); or ART delivered six-monthly in CARGs (6MC). Stable adults receiving ART ≥six months with baseline viral load (VL) <1000 copies/ml were eligible. Retention in ART care (primary outcome) and viral suppression (VS) 12 months after enrollment were compared, using regression models specified for clustering (ClinicalTrials.gov: NCT03238846)., Results: 4800 participants were recruited, 1919, 1335, and 1546 in arms 3MF, 3MC, and 6MC, respectively. For retention, the prespecified noninferiority limit (-3.25%, risk difference [RD]) was met for comparisons between all arms, 3MC (94.8%) vs. 3MF (93.0%), adjusted RD = 1.1% (95% CI: -0.5% to 2.8%); 6MC (95.5%) vs. 3MF: aRD = 1.2% (95% CI: -1.0% to 3.6%); and 6MC vs. 3MC: aRD = 0.1% (95% CI: -2.4% to 2.6%). VL completion at 12 months was 49%, 45%, and 8% in 3MF, 3MC, and 6MC, respectively. VS in 3MC (99.7%) was high and not different to 3MF (99.1%), relative risk = 1.0 (95% CI: 1.0-1.0). VS was marginally reduced in 6MC (92.9%) vs. 3MF, relative risk = 0.9 (95% CI: 0.9-1.0)., Conclusion: Retention in CARGs receiving three- and six-monthly MMD was noninferior versus standard-of-care facility-based ART delivery. VS in 3MC was high. VS in six-monthly CARGs requires further evaluation.

Background: There have been concerns about reduced adherence and human immunodeficiency virus (HIV) virological suppression (VS) among clinically well people initiating antiretroviral therapy (ART) with high pre-ART CD4 cell counts. We compared virological outcomes by pre-ART CD4 count, where universal ART initiation was provided in the HIV Prevention Trials Network 071 (PopART) trial in South Africa prior to routine national and international implementation., Methods: This prospective cohort study included adults initiating ART at facilities providing universal ART since January 2014. VS (<400 copies/mL), confirmed virological failure (VF) (2 consecutive viral loads >1000 copies/mL), and viral rebound were compared between participants in strata of baseline CD4 cell count., Results: The sample included 1901 participants. VS was ≥94% among participants with baseline CD4 count ≥500 cells/µL at all 6-month intervals to 30 months. The risk of an elevated viral load (≥400 copies/mL) was independently lower among participants with baseline CD4 count ≥500 cells/µL (3.3%) compared to those with CD4 count 200-499 cells/µL (9.2%) between months 18 and 30 (adjusted relative risk, 0.30 [95% confidence interval, .12-.74]; P = .010). The incidence rate of VF was 7.0, 2.0, and 0.5 per 100 person-years among participants with baseline CD4 count <200, 200-499, and ≥500 cells/µL, respectively (P < .0001). VF was independently lower among participants with baseline CD4 count ≥500 cells/µL (adjusted hazard ratio [aHR], 0.23; P = .045) and 3-fold higher among those with baseline CD4 count <200 cells/µL (aHR, 3.49; P < .0001)., Conclusions: Despite previous concerns, participants initiating ART with CD4 counts ≥500 cells/µL had very good virological outcomes, being better than those with CD4 counts 200-499 cells/µL., Clinical Trials Registration: NCT01900977., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction: WHO recommends antiretroviral treatment (ART) for all HIV-positive individuals. This study evaluated the association between baseline CD4 count and attrition in a cohort of HIV positive adults initiating ART at three department of health (DOH) clinics routinely providing ART at baseline CD4 counts >500cells/μL for the HPTN 071 (PopART) trial., Methods: All clients attending the DOH clinics were managed according to standard care guidelines with the exception that those starting ART outside of pertinent local guidelines signed research informed consent. DOH data on all HIV-positive adult clients recorded as having initiated ART between January 2014 and November 2015 at the three study clinics was analysed. Attrition, included clients lost to follow up or died, and was defined as 'being three or more months late for an antiretroviral pharmacy pick-up appointment'. All clients were followed until attrition, transfer out or end May 2016., Results: A total of 2423 clients with a median baseline CD4 count of 328 cells/μL (IQR 195-468) were included of whom 631 (26.0%) experienced attrition and 140 (5.8%) were TFO. Attrition was highest during the first six months of ART (IR 38.3/100 PY; 95% CI 34.8-42.1). Higher attrition was found amongst those with baseline CD4 counts > 500 cells/μL compared to those with baseline CD4 counts of 0-500 cells/μL (aHR 1.26, 95%CI 1.05 to 1.52) This finding was confirmed on subset analyses when restricted to individuals non-pregnant at baseline and when restricted to individuals with follow up of > 12months., Conclusions: Attrition in this study was high, particularly during the first six months of treatment. Attrition was highest amongst clients starting ART at baseline CD4 counts > 500 cells/μL. Strategies to improve retention amongst ART clients, particularly those starting ART at baseline CD4 counts >500cells/μL, need strengthening. Improved monitoring of clients moving in and out of ART care and between clinics will assist in better understanding attrition and ART coverage in high burden countries.

Introduction: Adolescents and youth receiving antiretroviral treatment (ART) in sub-Saharan Africa have high attrition and inadequate ART outcomes, and evaluations of interventions improving ART outcomes amongst adolescents are very limited. Sustainable Development Goal (SDG) target 3c is to substantially increase the health workforce in developing countries. We measured the effectiveness and cost-effectiveness of community-based support (CBS) provided by lay health workers for adolescents and youth receiving ART in South Africa., Methods: A retrospective cohort study including adolescents and youth who initiated ART at 47 facilities. Previously unemployed CBS-workers provided home-based ART-related education, psychosocial support, symptom screening for opportunistic infections and support to access government grants. Outcomes were compared between participants who received CBS plus standard clinic-based care versus participants who received standard care only. Cumulative incidences of all-cause mortality and loss to follow-up (LTFU), adherence measured using medication possession ratios (MPRs), CD4 count slope, and virological suppression were analysed using multivariable Cox, competing-risks regression, generalized estimating equations and mixed-effects models over five years of ART. An expenditure approach was used to determine the incremental cost of CBS to usual care from a provider perspective. Incremental cost-effectiveness ratios were calculated as annual cost per patient-loss (through death or LTFU) averted., Results: Amongst 6706 participants included, 2100 (31.3%) received CBS. Participants who received CBS had reduced mortality, adjusted hazard ratio (aHR) = 0.52 (95% CI: 0.37 to 0.73; p < 0.0001). Cumulative LTFU was 40% lower amongst participants receiving CBS (29.9%) compared to participants without CBS (38.9%), aHR = 0.60 (95% CI: 0.51 to 0.71); p < 0.0001). The effectiveness of CBS in reducing attrition ranged from 42.2% after one year to 35.9% after five years. Virological suppression was similar after three years, but after five years 18.8% CBS participants versus 37.2% non-CBS participants failed to achieve viral suppression, adjusted odds ratio = 0.24 (95% CI: 0.06 to 1.03). There were no significant differences in MPR or CD4 slope. The cost of CBS was US$49.5/patient/year. The incremental cost per patient-loss averted was US$600 and US$776 after one and two years, respectively., Conclusions: CBS for adolescents and youth receiving ART was associated with substantially reduced patient attrition, and is a low-cost intervention with reasonable cost-effectiveness that can aid progress towards several health, economic and equality-related SDG targets., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Background: Sub-Saharan Africa is the world region with the greatest number of people eligible to receive antiretroviral treatment (ART). Less frequent dispensing of ART and community-based ART-delivery models are potential strategies to reduce the load on overburdened healthcare facilities and reduce the barriers for patients to access treatment. However, no large-scale trials have been conducted investigating patient outcomes or evaluating the cost-effectiveness of extended ART-dispensing intervals within community ART-delivery models. This trial will assess the clinical effectiveness, cost-effectiveness and acceptability of providing ART refills on a 3 vs. a 6-monthly basis within community ART-refill groups (CARGs) for stable patients in Zimbabwe., Methods: In this pragmatic, three-arm, parallel, unblinded, cluster-randomized non-inferiority trial, 30 clusters (healthcare facilities and associated CARGs) are allocated using stratified randomization in a 1:1:1 ratio to either (1) ART refills supplied 3-monthly from the health facility (control arm), (2) ART refills supplied 3-monthly within CARGs, or (3) ART refills supplied 6-monthly within CARGs. A CARG consists of 6-12 stable patients who meet in the community to receive ART refills and who provide support to one another. Stable adult ART patients with a baseline viral load < 1000 copies/ml will be invited to participate (1920 participants per arm). The primary outcome is the proportion of participants alive and retained in care 12 months after enrollment. Secondary outcomes (measured at 12 and 24 months) are the proportions achieving virological suppression, average provider cost per participant, provider cost per participant retained, cost per participant retained with virological suppression, and average patient-level costs to access treatment. Qualitative research will assess the acceptability of extended ART-dispensing intervals within CARGs to both providers and patients, and indicators of potential facility-level decongestion due to the interventions will be assessed., Discussion: Cost-effective health system models that sustain high levels of patient retention are urgently needed to accommodate the large numbers of stable ART patients in sub-Saharan Africa. This will be the first trial to evaluate extended ART-dispensing intervals within a community-based ART distribution model, and results are intended to inform national and regional policy regarding their potential benefits to both the healthcare system and patients., Trial Registration: ClinicalTrials.gov, ID: NCT03238846 . Registered on 27 July 2017.

Introduction: Antiretroviral treatment (ART) guidelines recommend life-long ART for all HIV-positive individuals. This study evaluated tuberculosis (TB) incidence on ART in a cohort of HIV-positive individuals starting ART regardless of CD4 count in a programmatic setting at 3 clinics included in the HPTN 071 (PopART) trial in South Africa., Methods: A retrospective cohort analysis of HIV-positive individuals aged ≥18 years starting ART, between January 2014 and November 2015, was conducted. Follow-up was continued until 30 May 2016 or censored on the date of (1) incident TB, (2) loss to follow-up from HIV care or death, or (3) elective transfer out; whichever occurred first., Results: The study included 2423 individuals. Median baseline CD4 count was 328 cells/μL (interquartile range 195-468); TB incidence rate was 4.41/100 person-years (95% confidence interval [CI]: 3.62 to 5.39). The adjusted hazard ratio of incident TB was 0.27 (95% CI: 0.12 to 0.62) when comparing individuals with baseline CD4 >500 and ≤500 cells/μL. Among individuals with baseline CD4 count >500 cells/μL, there were no incident TB cases in the first 3 months of follow-up. Adjusted hazard of incident TB was also higher among men (adjusted hazard ratio 2.16; 95% CI: 1.41 to 3.30)., Conclusions: TB incidence after ART initiation was significantly lower among individuals starting ART at CD4 counts above 500 cells/μL. Scale-up of ART, regardless of CD4 count, has the potential to significantly reduce TB incidence among HIV-positive individuals. However, this needs to be combined with strengthening of other TB prevention strategies that target both HIV-positive and HIV-negative individuals.

Background: Young Southern African women have the highest HIV incidence globally. Pregnancy doubles the risk of HIV acquisition further, and maternal HIV acquisition contributes significantly to the paediatric HIV burden. Little data on combination HIV prevention interventions during pregnancy and lactation are available. We measured HIV incidence amongst pregnant and postpartum women receiving a community-based combination HIV prevention intervention in a high HIV incidence setting in South Africa., Methods: A cohort study that included HIV-uninfected pregnant women was performed. Lay community-based workers provided individualized HIV prevention counselling and performed three-monthly home and clinic-based individual and couples HIV testing. Male partners were referred for circumcision, sexually transmitted infections or HIV treatment as appropriate. Kaplan-Meier analyses and Cox's regression were used to estimate HIV incidence and factors associated with HIV acquisition., Results: The 1356 women included (median age 22.5 years) received 5289 HIV tests. Eleven new HIV infections were detected over 828.3 person-years (PY) of follow-up, with an HIV incidence rate of 1.33 infections/100 PY (95% CI: 0.74-2.40). Antenatally, the HIV incidence rate was 1.49 infections/100 PY (95% CI: 0.64-2.93) and postnatally the HIV incidence rate was 1.03 infections/100 PY (95% CI: 0.33-3.19). 53% of male partners received HIV testing and 66% of eligible partners received referral for circumcision. Women within known serodiscordant couples, and women with newly diagnosed HIV-infected partners, adjusted hazard ratio (aHR) = 32.7 (95% CI: 3.8-282.2) and aHR = 126.4 (95% CI: 33.8-472.2) had substantially increased HIV acquisition, respectively. Women with circumcised partners had a reduced risk of incident HIV infection, aHR = 0.22 (95% CI: 0.03-1.86)., Conclusions: Maternal HIV incidence was substantially lower than previous regional studies. Community-based combination HIV prevention interventions may reduce high maternal HIV incidence in resource-poor settings. Expanded roll-out of home-based couples HIV testing and initiating pre-exposure prophylaxis for pregnant women within serodiscordant couples is needed in Southern Africa.

Retaining high levels of patients in care who are virally suppressed over long treatment periods has been an important challenge for antiretroviral treatment (ART) programmes in sub-Saharan Africa, the region having the highest HIV burden globally. Clinic-linked community-based adherence support (CBAS) programmes provide home-based adherence and psychosocial support for ART patients. However, there is little evidence of their longer-term impact. This study assessed the effectiveness of CBAS after eight years of ART. CBAS workers are lay healthcare personnel providing regular adherence and psychosocial support for ART patients and their households through home visits addressing household challenges affecting adherence. A multicentre cohort study using routinely collected data was undertaken at six public ART sites in a high HIV-prevalence South African district. Patient retention, loss to follow-up (LTFU), viral suppression and CD4 cell restoration were compared between patients with and without CBAS, using competing-risks regression, linear mixed models and log-binomial regression. 3861 patients were included, of whom 1616 (41.9%) received CBAS. Over 14,792 patient-years of observation, the cumulative incidence of LTFU was 37.3% and 46.2% amongst patients with and without CBAS, respectively, following 8 years of ART; adjusted subhazard ratio (CBAS vs. no CBAS) = 0.74 (95% CI: 0.66-0.84; P < .0001). Amongst patients on ART for 6.5-8 years, proportions not achieving viral suppression were 11.4% and 19.4% in patients with and without CBAS, respectively; adjusted risk ratio = 0.47 (95% CI: 0.26-0.86; P = .015). Annual CD4 cell increases from baseline were 62.8 cells/µL/year and 51.5 cells/µL/year amongst patients with and without CBAS, respectively, after 6.5 years or more (P = .034). After adjustment, annual CD4 cell recovery was 15.1 cells/µL/year (95% CI: 2.7-27.6) greater in CBAS patients (P = .017). ART patients who received CBAS had improved long-term patient retention, viral suppression and immunological restoration. CBAS is an intervention that can improve longer-term ART programme outcomes in resource-limited settings.

Background: The severe shortage of pharmacists is an important limitation to providing antiretroviral treatment (ART) in resource-limited countries. Two task-shifting pharmaceutical care models have been developed to address this in South Africa, namely indirectly supervised pharmacist assistant (ISPA) and nurse-managed models. This study compared pharmaceutical care quality, patient clinical outcomes, and provider staff costs between these models., Methods: An analysis of pharmaceutical quality audits, patient clinical data, and staff costing data collected at 7 ISPA and 8 nurse-managed facilities was undertaken. Pharmaceutical audits were conducted by pharmacists using a standardized tool. Routine clinical data were collected prospectively at patient visits, and staff human resources costs were analyzed., Results: Overall pharmaceutical care quality scores were higher at ISPA sites than nurse-managed sites; 88.8% vs. 79.9%, respectively; risk ratio (ISPA vs. nurse) = 1.11 (95% confidence interval: 1.09 to 1.13; P < 0.0001). Mean provider pharmaceutical-related human resources costs per patient visit and per item dispensed were 29% and 49% lower, respectively, at ISPA facilities. At ISPA facilities, patient attrition was observed to be lower and viral suppression higher than at nurse-managed sites., Conclusion: The ISPA model had a higher quality of pharmaceutical care and was less costly to implement. Further expansion of this model or integrating it with nurse-managed ART may enhance the cost-efficient scale-up of ART programs in Sub-Saharan Africa.

Antiretroviral treatment (ART) initiation in HIV-infected pregnant women in sub-Saharan Africa (SSA) remains inadequate, and there is a severe shortage of professional healthcare workers in the region. The effectiveness of community support programmes for HIV-infected pregnant women and their infants in SSA is unclear. This study compared initiation of maternal antiretrovirals and infant outcomes amongst HIV-infected pregnant women and their infants who received and did not receive community-based support (CBS) in a high HIV-prevalence setting in South Africa. A cohort study, including HIV-infected pregnant women and their infants, was conducted at three sentinel surveillance facilities between January 2009 and June 2012, utilising enhanced routine clinical data. Through home visits, CBS workers encouraged uptake of interventions in the ART cascade, provided HIV-related education, ART initiation counselling and psychosocial support. Outcomes were compared using Kaplan-Meier analyses and multivariable Cox and log-binomial regression. Amongst 1105 mother-infant pairs included, 264 (23.9%) received CBS. Amongst women eligible to start ART antenatally, women who received CBS had a reduced risk of not initiating antenatal ART, 5.4% vs. 30.3%; adjusted risk ratio (aRR) = 0.18 (95% CI: 0.08-0.44; P < .0001). Women who received CBS initiated antenatal ART with less delay after the first antenatal visit, median 26 days vs. 39 days; adjusted hazard ratio (aHR) = 1.57 (95% CI: 1.15-2.14; P = .004). Amongst women who initiated antenatal zidovudine (ZDV) to prevent vertical transmission, women who received CBS initiated ZDV with less delay, aHR = 1.52 (95% CI: 1.18-2.01; P = .001). Women who received CBS had a lower risk of stillbirth, 1.5% vs. 5.4%; aRR = 0.24 (95% CI: 0.07-1.00; P = .050). Pregnant women living with HIV who received CBS had improved antenatal triple ART initiation in eligible women, women initiated ART and ZDV with shorter delays, and had a lower risk of stillbirth. CBS is an intervention that shows promise in improving maternal and infant health in high HIV-prevalence settings.

Background: Combination antiretroviral therapy (ART) suppresses viral replication in HIV-infected children. The growth of virologically suppressed children on ART has not been well documented. We aimed to develop dynamic reference curves for weight-for-age Z scores (WAZ) and height-for-age Z scores (HAZ)., Methods: Children aged <11 years at ART initiation with continuously undetectable viral loads (<400 copies/mL) treated at 7 South African ART programs with routine viral load monitoring were included. We used multilevel models to define trajectories of WAZ and HAZ up to 3 years and developed a web application to monitor trajectories in individual children., Results: A total of 4876 children were followed for 7407 person-years. Analyses were stratified by baseline Z scores and age, which were the most important predictors of growth response. The youngest children showed the most pronounced increase in weight and height initially but catch-up growth stagnated after 1-2 years. Three years after starting ART, WAZ ranged from -2.2 [95% prediction interval (PrI), -5.6 to 0.8] in children with baseline age >5 years and Z score less than -3 to 0.0 (95% PrI, -2.7 to 2.4) in children with baseline age <2 years and WAZ greater than -1. For HAZ, the corresponding range was -2.3 (95% PrI, -4.9 to 0.3) in children with baseline age >5 years and Z score less than -3 to 0.3 (95% PrI, -3.1 to 3.4) in children with baseline age 2-5 years and HAZ greater than -1., Conclusions: We have developed an online tool to calculate reference trajectories in fully suppressed children. The web application could help to define "optimal" growth response and identify children with treatment failure.

Introduction: Increasing numbers of patients are starting antiretroviral treatment (ART) at advanced age or reaching advanced age while on ART. We compared baseline characteristics and ART outcomes of older adults (aged ≥55 years) vs. younger adults (aged 25-54 years) in routine care settings in South Africa., Methods: A multicentre cohort study of ART-naïve adults starting ART at 89 public sector facilities was conducted. Mortality, loss to follow-up (LTFU), immunological and virological outcomes until five years of ART were compared using competing-risks regression, generalised estimating equations and mixed-effects models., Results: 4065 older adults and 86,006 younger adults were included. There were more men amongst older adults; 44.7% vs. 33.4%; RR = 1.34 (95% CI: 1.29-1.39). Mortality after starting ART was substantially higher amongst older adults, adjusted sub-hazard ratio (asHR) = 1.44 over 5 years (95% CI: 1.26-1.64), particularly for the period 7-60 months of treatment, asHR = 1.73 (95% CI: 1.44-2.10). LTFU was lower in older adults, asHR = 0.87 (95% CI: 0.78-0.97). Achievement of virological suppression was greater in older adults, adjusted odds ratio = 1.42 (95% CI: 1.23-1.64). The probabilities of viral rebound and confirmed virological failure were both lower in older adults, adjusted hazard ratios = 0.69 (95% CI: 0.56-0.85) and 0.64 (95% CI: 0.47-0.89), respectively. The rate of CD4 cell recovery (amongst patients with continuous viral suppression) was 25 cells/6 months of ART (95% CI: 17.3-33.2) lower in older adults., Conclusions: Although older adults had better virological outcomes and reduced LTFU, their higher mortality and slower immunological recovery warrant consideration of age-specific ART initiation criteria and management strategies.

Adherence to antiretroviral treatment (ART) is a challenge in childhood, and children on ART have reduced virological suppression compared to adults. This study evaluated the effect of community-based adherence support (CBAS) on virological outcomes amongst children receiving ART in four South African provinces. Patient Advocates are lay CBAS workers who provide adherence and psychosocial support for patients, undertaking home visits to address household challenges affecting adherence. Patient Advocates provide counselling for children's carers regarding adherence and psychosocial problems. A multicentre cohort study using routinely collected data was conducted at 57 public ART sites including ART-naive children (<16 years) starting ART. Virological suppression until four years of ART was compared between children who received and did not receive CBAS. Analyses were by intention-to-treat, controlling for confounding using multivariable generalised estimating equations. A total of 4853 children were included, of whom 982 (20.2%) received CBAS. The median baseline age was 6.3 years and the baseline CD4 cell percentage was 12.0%; both were equivalent between the two groups. CBAS children had more advanced baseline clinical disease (62.1% vs. 52.6% World Health Organisation stages III or IV; P < 0.0001). A total of 5908 viral load results were analysed. Virological suppression was 65.6% (95% confidence interval [CI]: 62.7-68.4%) vs. 55.5% (95% CI: 54.1-57.0%) in CBAS and non-CBAS children, respectively, at any time-point on treatment (P < 0.0001). In analyses controlling for baseline clinical, demographic, site-related variables and time on ART, children receiving CBAS were more likely to achieve virological suppression, adjusted odds ratio (aOR) 1.60 (95% CI: 1.35-1.89; P < 0.0001). The effect of CBAS increased in magnitude with increasing durations of ART, and CBAS particularly improved virological suppression in a higher-risk subgroup (children younger than two years, aOR 2.47 [95% CI: 1.59-3.84]). CBAS was associated with improved virological suppression in children receiving ART. Expanded implementation of this low-cost intervention should be considered in resource-poor settings.

There is concern that the expansion of ART (antiretroviral treatment) programmes to incorporate the use of treatment as prevention (TasP) may be associated with low levels of adherence and retention in care, resulting in the increased spread of drug-resistant HIV. We review research published over the past year that reports on interventions to improve adherence and retention in care in Southern Africa, and discuss these in terms of their potential to support the expansion of ART programmes for TasP. We found eight articles published since January 2012, seven of which were from South Africa. The papers describe innovative models for ART care and adherence support, some of which have the potential to facilitate the ongoing scale- up of treatment programmes for increased coverage and TasP. The extent to which interventions from South Africa can be effectively implemented in other, lower-resource Southern African countries is unclear.

Introduction: Current WHO guidelines for developing countries recommend efavirenz (EFV) and nevirapine (NVP) for first-line antiretroviral treatment (ART). This paper compares the effectiveness of EFV and NVP among ART-naive patients initiating treatment at 56 public health facilities in South Africa between January 2004 and December 2007., Methods: Participants were assigned to the EFV or NVP cohorts depending on their baseline ART regimen. Mortality, viral load suppression after 6 months and ART regimen change were compared between the cohorts using Cox proportional hazards models and logistic regression., Results: At initiation, 19 441 (71.1%) patients started EFV and 7909 (28.9%) started NVP treatment. The median follow-up period was 9.5 months (IQR 4.6-17.7). After adjustment, mortality was similar in the two cohorts, (adjusted HR = 1.07, 95% CI 0.89-1.28). Viral load suppression at 6 months was higher in the EFV cohort overall (adjusted odds ratio [AOR] = 1.29, 95% CI 1.05-1.59) and in women aged 16-40 years (AOR = 1.35, 95% CI 1.11-1.63) and women with CD4 counts <25 cells/µL (AOR = 1.95, 95% CI 1.01-3.76). Patients starting on EFV were 47% less likely to change regimen (AOR = 0.53, 95% CI 0.48-0.59)., Discussion: These findings suggest the superior effectiveness of EFV for first-line ART compared with NVP and should be considered during development of future ART guidelines for high-burden regions.

Introduction: A large increase in lay health care workers has occurred in response to shortages of professional health care staff in sub-Saharan African antiretroviral treatment (ART) programs. However, little effectiveness data of the large-scale implementation of these programs is available. We evaluated the effect of a community-based adherence-support (CBAS) program on ART outcomes across 57 South African sites., Methods: CBAS workers provide adherence and psychosocial support for patients and undertake home visits to address household challenges affecting adherence. An observational multicohort study of adults enrolling for ART between 2004 and 2010 was performed. Mortality, loss to follow-up, and virological suppression were compared by intention to treat between patients who received and did not receive CBAS until 5 years of ART, using multiple imputation of missing covariate values., Results: Of the 66,953 patients who were included, 19,668 (29.4%) patients received CBAS and 47,285 (70.6%) patients did not. Complete-case covariate data were available for 54.3% patients. After 5 years, patient retention was 79.1% [95% confidence interval (CI): 77.7% to 80.4%] in CBAS patients versus 73.6% (95% CI: 72.6% to 74.5%) in non-CBAS patients; crude hazard ratio (HR) for attrition was 0.68 (95% CI: 0.65 to 0.72). Mortality and loss to follow-up were independently lower in CBAS patients, adjusted HR (aHR) was 0.65 (95% CI: 0.59 to 0.72) and 0.63 (95% CI: 0.59 to 0.68), respectively. After 6 months of ART, virological suppression was 76.6% (95% CI: 75.8% to 77.5%) in CBAS patients versus 72% (95% CI: 71.3% to 72.5%) in non-CBAS patients (P < 0.0001), adjusted odds ratio was 1.22 (95% CI: 1.14 to 1.30). Improvement in virological suppression occurred progressively for longer durations of ART [adjusted odds ratio was 2.66 (95% CI: 1.61 to 4.40) by 5 years]., Conclusions: Patients receiving CBAS had considerably better ART outcomes. Further scale-up of these programs should be considered in low-income settings.

Background: HIV-positive children in low-income settings face many challenges to adherence to antiretroviral treatment (ART) and have increased mortality on treatment compared to children in developed countries. Adult ART programmes have demonstrated benefit from community support to improve treatment outcomes; however, there are no empirical data on the effectiveness of this intervention in children. This study compared clinical, virological and immunological outcomes between children who received and who did not receive community-based adherence support from patient advocates (PAs) in four South African provinces., Methods: A multicentre cohort study of ART-naïve children was conducted at 47 public ART facilities. Outcome measures were mortality, patient retention, virological suppression and CD4 percentage changes on ART. PAs are lay community health workers who provide adherence and psychosocial support for children's caregivers, and they undertake home visits to ascertain household challenges potentially impacting on adherence in the child. Corrected mortality estimates were calculated, correcting for deaths amongst those lost to follow-up (LTFU) using probability-weighted Kaplan-Meier and Cox functions., Results: Three thousand five hundred and sixty three children were included with a median baseline age of 6.3 years and a median baseline CD4 cell percentage of 12.0%. PA-supported children numbered 323 (9.1%). Baseline clinical status variables were equivalent between the two groups. Amongst children LTFU, 38.7% were known to have died. Patient retention after 3 years of ART was 91.5% (95% CI: 86.8% to 94.7%) vs. 85.6% (95% CI: 83.3% to 87.6%) amongst children with and without PAs, respectively (p = 0.027). Amongst children aged below 2 years at baseline, retention after 3 years was 92.2% (95% CI: 76.7% to 97.6%) vs. 74.2% (95% CI: 65.4% to 81.0%) in children with and without PAs, respectively (p = 0.053). Corrected mortality after 3 years of ART was 3.7% (95% CI: 1.9% to 7.4%) vs. 8.0% (95% CI: 6.5% to 9.8%) amongst children with and without PAs, respectively (p = 0.060). In multivariable analyses, children with PAs had reduced probabilities of both attrition and mortality, adjusted hazard ratio (AHR) 0.57 (95% CI: 0.35 to 0.94) and 0.39 (95% CI: 0.15 to 1.04), respectively., Conclusion: Community-based adherence support is an effective way to improve patient retention amongst children on ART. Expanded implementation of this intervention should be considered in order to reach ART programmatic goals in low-income settings as more children access treatment.

Improving national prevention of mother-to-child (PMTCT) services in South Africa has been challenging. PMTCT outcomes were analysed at 58 primary and secondary level antenatal facilities across seven high HIV-burden sub-districts in three provinces, over an 18 month period during which new South African PMTCT clinical guidelines were implemented and a nurse quality mentor program was expanded. Early infant HIV DNA polymerase chain reaction test positivity reduced by 75.2% from 9.7% (CI: 8.1%-11.5%) to 2.4% (CI: 1.9%-3.1%); p<0.0005. HIV test positivity at 18 months of age decreased by 64.5% from 10.7% (CI: 7.2-15.1%) to 3.8% (CI: 2.4-5.6%); p<0.0005. PMTCT outcomes have improved substantially at these facilities.

Background: Few studies describe temporal trends in pediatric antiretroviral treatment (ART) programs in sub-Saharan Africa. Adult studies show deteriorating patient retention in recent years. We describe temporal trends in baseline characteristics and treatment outcomes amongst ART-naive children between 2004 and 2009 at 30 facilities in 4 South African provinces., Methods: Linear trend in baseline parameters between annual enrolment cohorts was assessed. Corrected mortality estimates were calculated, correcting for deaths amongst those lost to follow-up using probability-weighted Kaplan-Meier functions. On-treatment immunologic changes were modelled using generalized estimating equations., Results: Three thousand and seven children (median age 6.4 years) were included. Monthly enrollment increased from 1.9 children in 2004 to 106 in 2009. Proportions with severe baseline immunodeficiency decreased from 85.5% to 64.5% between 2004/2005 and 2009, P < 0.0005. Proportions with baseline World Health Organization clinical stages III and IV reduced from 72.9% to 49.0% between 2006 and 2009, P < 0.0005. Later calendar cohorts had independently and progressively reduced on-treatment probabilities of severe immunodeficiency despite adjusting for baseline immunological status, adjusted odds ratio: 0.38 [confidence interval (CI): 0.26 to 0.55; P < 0.0005; 2008/2009 compared with 2004/2005]. After 24 months, corrected mortality was 6.1% (CI: 5.1% to 7.3%) and loss to follow-up was 6.8% (CI: 5.7% to 8.2%), with no deterioration amongst more recently enrolled cohorts (P = 0.50 and P = 0.55, respectively). After 4 years, program retention was 84.1% (CI: 80.9% to 86.7%)., Conclusions: Childrens' baseline condition when starting ART has improved considerably. Improving immunological treatment outcomes, the high medium-term patient retention with lack of temporal deterioration despite rapid patient number increases, provide evidence that pediatric ART programs are increasingly effective for those accessing them. However, children must start treatment when younger, following current international guidelines.

Background: A large proportion of the 340,000 HIV-positive children in South Africa live in rural areas, yet there is little sub-Saharan data comparing rural paediatric antiretroviral therapy (ART) programme outcomes with urban facilities. We compared clinical, immunological and virological outcomes between children at seven rural and 37 urban facilities across four provinces in South Africa., Methods: We conducted a retrospective cohort study of routine data of children enrolled on ART between November 2003 and March 2008 in three settings, namely: urban residence and facility attendance (urban group); rural residence and facility attendance (rural group); and rural residents attending urban facilities (rural/urban group). Outcome measures were: death, loss to follow up (LTFU), virological suppression, and changes in CD4 percentage and weight-for-age-z (WAZ) scores. Kaplan-Meier estimates, logrank tests, multivariable Cox regression and generalized estimating equation models were used to compare outcomes between groups., Results: In total, 2332 ART-naïve children were included, (1727, 228 and 377 children in the urban, rural and rural/urban groups, respectively). At presentation, rural group children were older (6.7 vs. 5.6 and 5.8 years), had lower CD4 cell percentages (10.0% vs. 12.8% and 12.7%), lower WAZ scores (-2.06 vs. -1.46 and -1.41) and higher proportions with severe underweight (26% vs.15% and 15%) compared with the urban and rural/urban groups, respectively. Mortality was significantly higher in the rural group and LTFU significantly increased in the rural/urban group. After 24 months of ART, mortality probabilities were 3.4% (CI: 2.4-4.8%), 7.7% (CI: 4.5-13.0%) and 3.1% (CI: 1.7-5.6%) p = 0.0137; LTFU probabilities were 11.5% (CI: 9.3-14.0%), 8.8% (CI: 4.5-16.9%) and 16.6% (CI: 12.4-22.6%), p = 0.0028 in the urban, rural and rural/urban groups, respectively. The rural group had an increased adjusted mortality probability, adjusted hazards ratio 2.41 (CI: 1.25-4.67) and the rural/urban group had an increased adjusted LTFU probability, aHR 2.85 (CI: 1.41-5.79). The rural/urban group had a decreased adjusted probability of virological suppression compared with the urban group at any timepoint on treatment, adjusted odds ratio 0.67 (CI: 0.48-0.93)., Conclusions: Rural HIV-positive children are a vulnerable group, exhibiting delayed access to ART and an increased risk of poor outcomes while on ART. Expansion of rural paediatric ART programmes, with future research exploring improvements to rural health system effectiveness, is required.

Background: There are conflicting reports of antiretroviral therapy (ART) effectiveness comparisons between primary healthcare (PHC) facilities and hospitals in low-income settings. This comparison has not been evaluated on a broad scale in South Africa., Methodology/principal Findings: A retrospective cohort study was conducted including ART-naïve adults from 59 facilities in four provinces in South Africa, enrolled between 2004 and 2007. Kaplan-Meier estimates, competing-risks Cox regression, generalised estimating equation population-averaged models and logistic regression were used to compare death, loss to follow-up (LTFU) and virological suppression (VS) between PHC, district and regional hospitals. 29 203 adults from 47 PHC facilities, nine district hospitals and three regional hospitals were included. Patients at PHC facilities had more advanced WHO stage disease when starting ART. Retention in care was 80.1% (95% CI: 79.3%-80.8%), 71.5% (95% CI: 69.1%-73.8%) and 68.7% (95% CI: 67.0%-69.7%) at PHC, district and regional hospitals respectively, after 24 months of treatment (P<0.0001). In adjusted regression analyses, LTFU was independently increased at regional hospitals (aHR 2.19; 95% CI: 1.94-2.47) and mortality was independently elevated at district hospitals (aHR 1.60; 95% CI: 1.30-1.99) compared to PHC facilities after 12 months of ART. District and regional hospital patients had independently reduced probabilities of VS, aOR 0.76 (95% CI: 0.59-0.97) and 0.64 (95% CI: 0.56-0.75) respectively compared to PHC facilities over 24 months of treatment., Conclusions/significance: ART outcomes were superior at PHC facilities, despite PHC patients having more advanced clinical stage disease when starting ART, suggesting that ART can be adequately provided at this level and supporting the South African government's call for rapid up-scaling of ART at the primary level of care. Further prospective research is required to determine the degree to which outcome differences are attributable to either facility level characteristics or patient co-morbidity at hospital level.

Objective: To assess and compare the activity and safety of capsules containing enteric-coated beadlets of didanosine given once daily with stavudine and nelfinavir with that of a standard reference triple drug regimen of zidovudine plus lamivudine and nelfinavir., Design: Multinational, 49-site, prospective, open-label, randomized, two-arm comparison study., Participants: HIV-infected subjects with limited or no previous antiretroviral therapy who had plasma HIV RNA levels of >or=2000 copies/mL and CD4 cell counts of >or=200/mm3 (511 were randomized to treatment groups, and 352 completed the study)., Interventions: Triple antiretroviral therapy for 48 weeks: didanosine EC (400 mg once daily), stavudine (40 mg twice daily), and nelfinavir (750 mg three times daily) or a twice-daily coformulation of zidovudine (300 mg) plus lamivudine (150 mg) and nelfinavir (750 mg three times daily)., Main Outcome Measure: Proportion of subjects with HIV RNA levels of <400 copies/mL at week 48 based on an "intent-to-treat, missing = treatment failure" analysis., Results: The two treatment groups were similar in the proportion of treatment responders (i.e., HIV RNA level of <400 copies/mL), with 54% of subjects in the didanosine EC and zidovudine plus lamivudine treatment groups responding at week 48. Results of other analyses supported those of the primary analysis. The two study regimens were associated with similar numbers of adverse events., Conclusions: The antiviral efficacy of a triple combination regimen containing once-daily didanosine EC is similar to that of a reference triple combination regimen.

An introduction is presented in which the editor discusses various reports within the issue on topics including the mother-to-child transmission (MTCT) of HIV, the prevention of human immunodeficiency virus (HIV) in children and the prevalence of HIV in Sub-Saharan Africa.

The need to create medical research within a framework that is appropriate to the social, medical, and political context of developing countries is examined through the AIDS pandemic in sub-Saharan Africa. The scale and scope of AIDS in the environment of a developing country presents unique issues that challenge the role and practices of traditional ethics in healthcare research programs. For HIV/AIDS populations in developing countries, medical researchers must incorporate new thinking into traditional biomedical research ethics which will address the role of innovation; access to treatment; the impact of fear, stigma, and denial; concerns around autonomy for vulnerable populations; capacity building; and sustainable care to communities. Describes the philanthropic program "Secure the Future" of Bristol-Myers Squibb.