Universal HIV testing is now recommended in generalised HIV epidemic settings. Although home-based HIV counselling and testing (HB-HCT) has been shown to be effective in achieving high levels of HIV status awareness, little is still known about the cost implications of universal and repeated HB-HCT. We estimated the costs of repeated HB-HCT and the scale economies that can be obtained when increasing the population coverage of the intervention. We used primary data from the ANRS 12249 Treatment as Prevention (TasP) trial in rural South Africa (2012-2016), whose testing component included six-monthly repeated HB-HCT. We relied on the dynamic system generalised method of moments (GMM) approach to produce unbiased short- and long-run estimates of economies of scale, using the number of contacts made by HIV counsellors for HB-HCT as the scale variable. We also estimated the mediating effect of the contact quality - measured as the proportion of HIV tests performed among all contacts eligible for an HIV test - on scale economies. The mean cost (standard deviation) of universal and repeated HB-HCT was $24.2 (13.7) per contact, $1694.3 (1527.8) per new HIV diagnosis, and $269.2 (279.0) per appropriate referral to HIV care. The GMM estimations revealed the presence of economies of scale, with a 1% increase in the number of contacts for HB-HCT leading to a 0.27% decrease in the mean cost. Our results also suggested a significant long-run relationship between mean cost and scale, with a 1% increase in the scale leading to a 0.36% decrease in mean cost in the long run. Overall, we showed that significant cost savings can be made from increasing population coverage. Nevertheless, there is a risk that this gain is made at the expense of quality: the higher the quality of HB-HCT activities, the lower the economies of scale.

Background: Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC).

Methods: We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR).

Results: Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR.

Conclusions: This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization's recommendation to avoid using NNRTIs in countries where levels of PDR are high.

Prolonged virologic failure on 2nd-line protease inhibitor (PI)-based antiretroviral therapy (ART) without emergence of major protease mutations is well recognized and provides an opportunity to study within-host evolution in long-term viremic individuals. Using next-generation sequencing and in silico haplotype reconstruction, we analyzed whole-genome sequences from longitudinal plasma samples of eight chronically infected HIV-1-positive individuals failing 2nd-line regimens from the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) trial. On nonsuppressive ART, there were large fluctuations in synonymous and nonsynonymous variant frequencies despite stable viremia. Reconstructed haplotypes provided evidence for selective sweeps during periods of partial adherence, and viral haplotype competition, during periods of low drug exposure. Drug resistance mutations in reverse transcriptase (RT) were used as markers of viral haplotypes in the reservoir, and their distribution over time indicated recombination. We independently observed linkage disequilibrium decay, indicative of recombination. These data highlight dramatic changes in virus population structure that occur during stable viremia under nonsuppressive ART.

Introduction
Limited antimicrobial resistance (AMR) surveillance coupled with syndromic management of sexually transmitted infections (STIs) in sub-Saharan Africa (SSA) could be contributing to an increase in AMR in the region. This systematic review aims to synthesise data on the prevalence of AMR in common STIs in SSA and identify some research gaps that exist.

Methods
We searched three electronic databases for studies published between 1 January 2000 and 26 May 2020. We screened the titles and abstracts for studies that potentially contained data on AMR in SSA. Then we reviewed the full text of these studies to identify articles that reported data on the prevalence of AMR in Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) in SSA. We summarised the data using a narrative synthesis.

Results
The 40 included studies reported on AMR data from 7961 NG isolates from 15 countries in SSA and 350 MG specimens from South Africa. All four SSA regions reported very high rates of ciprofloxacin, tetracycline and penicillin resistance in NG. Resistance to cefixime or ceftriaxone was observed in all regions except West Africa. Azithromycin resistance, recommended as part of dual therapy with the ESC for gonorrhoea, was reported in all the regions. Both macrolide and fluoroquinolone-associated resistance were reported in MG in South Africa. Studies investigating AMR in CT and TV were not identified.

Conclusion
There is a need to strengthen AMR surveillance in SSA for prompt investigation and notification of drug resistance in STIs.

The 2015 El Niño-triggered drought in Southern Africa caused widespread economic and livelihood disruption in South Africa, imposing multiple physical and health challenges for rural populations including people living with HIV (PLHIV). We examined the economic, social and demographic impacts of drought drawing on 27 in-depth interviews in two cohorts of PLHIV in Hlabisa, uMkhanyakude district, KwaZulu-Natal. Thematic analysis revealed how drought-enforced soil water depletion, dried-up rivers, and dams culminated in a continuum of events such as loss of livestock, reduced agricultural production, and insufficient access to water and food which was understood to indirectly have a negative impact on HIV treatment adherence. This was mediated through disruptions in incomes, livelihoods and food systems, increased risk to general health, forced mobility and exacerbation of contextual vulnerabilities linked to poverty and unemployment. The systems approach, drawn from interview themes, hypothesises the complex pathways of plausible networks of impacts from drought through varying socioeconomic factors, exacerbating longstanding contextual precarity, and ultimately challenging HIV care utilisation. Understanding the multidimensional relationships between climate change, especially drought, and poor HIV care outcomes through the prism of contextual vulnerabilities is vital for shaping policy interventions.

Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a systems understanding of the nexus between drought and antiretroviral therapy (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/MEDLINE, and PsycINFO suggests that livelihoods and economic conditions, comorbidities and ART regimens, human mobility, and psychobehavioural dispositions and support systems interact in complex ways in the drought–ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions, and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and developing interventions.

Objectives
Population-based universal test and treat (UTT) trials have shown an impact on population-level virological suppression. We followed the ANRS 12249 TasP trial population for 6 years to determine whether the intervention had longer-term survival benefits.

Methods
The TasP trial was a cluster-randomized trial in South Africa from 2012 to 2016. All households were offered 6-monthly home-based HIV testing. Immediate antiretroviral therapy (ART) was offered through trial clinics to all people living with HIV (PLHIV) in intervention clusters and according to national guidelines in control clusters. After the trial, individuals attending the trial clinics were transferred to the public ART programme. Deaths were ascertained through annual demographic surveillance. Random-effects Poisson regression was used to estimate the effect of trial arm on mortality among (i) all PLHIV; (ii) PLHIV aware of their status and not on ART at trial entry; and (iii) PHLIV who started ART during the trial.

Results
Mortality rates among PLHIV were 9.3/1000 and 10.4/1000 person-years in the control and intervention arms, respectively. There was no evidence that the intervention decreased mortality among all PLHIV [adjusted rate ratio (aRR) = 1.10, 95% confidence interval (CI) = 0.85–1.43, p = 0.46] or among PLHIV who were aware of their status but not on ART. Among individuals who initiated ART, the intervention decreased mortality during the trial (aRR = 0.49, 95% CI = 0.28–0.85, p = 0.01), but not after the trial ended.

Conclusions
The ‘treat all’ strategy reduced mortality among individuals who started ART but not among all PLHIV. To achieve maximum benefit of immediate ART, barriers to ART uptake and retention in care need to be addressed.

In 2015, South Africa experienced one of the worst (El Niño-induced) droughts in 35 years. This affected economic activities, individual and community livelihoods and wellbeing especially in rural communities in northern KwaZulu-Natal. Drought’s direct and indirect impacts on public health require urgent institutional responses, especially in South Africa’s stride to eliminate HIV as a public health threat by 2030 in line with the UNAIDS goals. This paper draws on qualitative data from interviews and policy documents to discuss how the devastating effect of the 2015 drought experience in the rural Hlabisa sub-district of uMkhanyakude, a high HIV prevalence area, imposes an imperative for more proactive institutional responses to drought and other climate-related events capable of derailing progress made in South Africa’s HIV/AIDS response. We found that drought had a negative impact on individual and community livelihoods and made it more difficult for people living with HIV to consistently engage with care due to economic losses from deaths of livestock, crop failure, food insecurity, time spent in search of appropriate water sources and forced relocations. It also affected government institutions and their interventions. Interviewed participants’ reflections on drought-related challenges, especially those related to institutional and coordination challenges, showed that although current policy frameworks are robust, their implementation has been stalled due to complex reporting systems, and inadequate interdepartmental collaboration and information sharing. We thus argue that to address the gaps in the institutional responses, there is a need for more inclusive systems of drought-relief implementation, in which government departments, especially at the provincial and district levels, work with national institutions to better share data/information about drought-risks in order to improve preparedness and implementation of effective mitigation measures

We describe the case of a 30-year-old care home employee diagnosed with COVID-19 and acute untreated HIV-1. He was unable to return to work for 119 days due to concerns over transmission risk as his SARS-CoV-2 PCR remained detectable. This highlights the uncertainty in interpreting SARS-CoV-2 PCR results post-infection in acute untreated HIV.

Background
South Africa implemented universal test and treat (UTT) in September 2016 in an effort to encourage earlier initiation of antiretroviral therapy (ART).

Methods
We therefore conducted an interrupted time series (ITS) analysis to assess the impact of UTT on mean CD4 count at ART initiation among adults ≥16 years old attending 17 public sector primary care services in rural South Africa between July 2014 and March 2019.

Results
Among 20,599 individuals (69% women), CD4 counts were available for 74%. Mean CD4 at ART initiation increased from 317.1 cells/μL (95% confidence interval, CI, 308.6 to 325.6)—one to eight months prior to UTT—to 421.0 cells/μL (95% CI 413.0 to 429.0) one to twelve months after UTT, including an immediate increase of 124.2 cells/μL (95% CI 102.2 to 146.1). However, mean CD4 count subsequently fell to 389.5 cells/μL (95% CI 381.8 to 397.1) 13 to 30 months after UTT, but remained above pre-UTT levels. Men initiated ART at lower CD4 counts than women (-118.2 cells/μL, 95% CI -125.5 to -111.0) throughout the study.

Conclusions
Although UTT led to an immediate increase in CD4 count at ART initiation in this rural community, the long-term effects were modest. More efforts are needed to increase initiation of ART early in HIV infection, particularly among men.

Purpose We examine the levels of post-trial responsibility ascribed to different stakeholders, following a community-based clinical trial and how the ‘responsibility’ is understood.

Methods We employed photovoice, unstructured observations and key informant interviews to gain insights into contexts of access to care following transition to the public health system post trial. We used an inductive narrative analysis to explore experiences and understandings of post-trial access (PTA).

Results In their photovoice stories, many participants expressed a sense of abandonment after the trial. This was viewed as a contributing factor to failing to re-engage with care available in the public health system. This led to the experiences of loss as some trial participants defaulted and died. Research investigators, department of health participants and sponsor agreed that PTA was especially important for communities in resource-limited settings. The government has an obligation towards its citizens while researchers have a responsibility to ensure a smooth transition of patients to public clinics. Sponsors have a responsibility to ensure that the trial is conducted in accordance with the protocol and post-trial agreements are in place and adhered to. Research partnerships among stakeholders were affected by power imbalances making it difficult to negotiate and plan for post-trial care responsibilities.

Conclusions The research community still struggles with understanding the scope of PTA responsibilities. Power dynamics between public health actors and research sponsors need to be managed to ensure that government involvement is not tokenistic. The responsibility of trial participants and ethics committees needs to be investigated further.

Introduction
Antiretroviral therapy (ART) has revolutionised the care of HIV-positive individuals resulting in marked decreases in morbidity and mortality, and markedly reduced transmission to sexual partners. However, these benefits can only be realised if individuals are aware of their HIV-positive status, initiated and retained on suppressive lifelong ART. Framed using the socio-ecological model, the present study explores factors contributing to poor ART uptake among community members despite high acceptance of HIV-testing within a Treatment as Prevention (TasP) trial. In this paper we identify barriers and facilitators to treatment across different levels of the socio-ecological framework covering individual, community and health system components.

Methods
This research was embedded within a cluster-randomised trial (ClinicalTrials.gov, number NCT01509508) of HIV treatment as Prevention in rural KwaZulu-Natal, South Africa. Data were collected between January 2013 and July 2014 from resident community members. Ten participants contributed to repeat in-depth interviews whilst 42 participants took part in repeat focus group discussions. Data from individual interviews and focus group discussions were triangulated using community walks to give insights into community members’ perception of the barriers and facilitators of ART uptake. We used thematic analysis guided by a socio-ecological framework to analyse participants’ narratives from both individual interviews and focus group discussions.

Results
Barriers and facilitators operating at the individual, community and health system levels influence ART uptake. Stigma was an over-arching barrier, across all three levels and expressed variably as fear of HIV disclosure, concerns about segregated HIV clinical services and negative community religious perceptions. Other barriers were individual (substance misuse, fear of ART side effects), community (alternative health beliefs). Facilitators cited by participants included individual (expectations of improved health and longer life expectancy following ART, single tablet regimens), community (availability of ART in the community through mobile trial facilities) and health system factors (fast and efficient service provided by friendly staff).

Discussion
We identified multiple barriers to achieving universal ART uptake. To enhance uptake in HIV care services, and achieve the full benefits of ART requires interventions that tackle persistent HIV stigma, and offer people with HIV respectful, convenient and efficient services. These interventions require evaluation in appropriately designed studies.

Objectives
We evaluated whether implementation of lockdown orders in South Africa affected ambulatory clinic visitation in rural Kwa-Zulu Natal (KZN).

Design
Observational cohort

Setting
Data were analysed from 11 primary healthcare clinics in northern KZN.

Participants
A total of 46 523 individuals made 89 476 clinic visits during the observation period.

Exposure of interest
We conducted an interrupted time series analysis to estimate changes in clinic visitation with a focus on transitions from the prelockdown to the level 5, 4 and 3 lockdown periods.

Outcome measures
Daily clinic visitation at ambulatory clinics. In stratified analyses, we assessed visitation for the following subcategories: child health, perinatal care and family planning, HIV services, non-communicable diseases and by age and sex strata.

Results
We found no change in total clinic visits/clinic/day at the time of implementation of the level 5 lockdown (change from 90.3 to 84.6 mean visits/clinic/day, 95% CI −16.5 to 3.1), or at the transitions to less stringent level 4 and 3 lockdown levels. We did detect a >50% reduction in child healthcare visits at the start of the level 5 lockdown from 11.9 to 4.7 visits/day (−7.1 visits/clinic/day, 95% CI −8.9 to 5.3), both for children aged <1 year and 1–5 years, with a gradual return to prelockdown within 3 months after the first lockdown measure. In contrast, we found no drop in clinic visitation in adults at the start of the level 5 lockdown, or related to HIV care (from 37.5 to 45.6, 8.0 visits/clinic/day, 95% CI 2.1 to 13.8).

Conclusions
In rural KZN, we identified a significant, although temporary, reduction in child healthcare visitation but general resilience of adult ambulatory care provision during the first 4 months of the lockdown. Future work should explore the impacts of the circulating epidemic on primary care provision and long-term impacts of reduced child visitation on outcomes in the region.

Background
Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC).

Methods/design
A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures.

Discussion
We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations.

Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. This database is a free password-protected open source database available on www.bioafrica.net.

The ANRS 12249 Treatment-as-Prevention (TasP) cluster-randomized trial in rural South Africa uses a “test and treat” approach. Home-based testing services and antiretroviral treatment initiation satellite clinics were implemented in every cluster as part of the trial. A social science research agenda was nested within TasP with the aim of understanding the social, economic and contextual factors that affect individuals, households, communities and health systems with respect to TasP. Considering the rural nature of the trial setting, we sought to understand community perceptions and experiences of the TasP Trial interventions as seen through the eyes of traditional health practitioners (THPs). A qualitative study design was adopted using four repeat focus group discussions conducted with nine THPs, combined with community walks and photo-voice techniques, over a period of 18 months. A descriptive, interpretive and explanatory approach to analysis was adopted. Findings indicate that THPs engaged with the home-based testing services and HIV clinics established for TasP. Specifically, home-based testing services were perceived as relatively successful in increasing access to HIV testing. A major gap observed by THPs was linkage to HIV clinics. Most of their clients, and some of the THPs themselves, found it difficult to use HIV clinics due to fear of labelling, stigma and discrimination, and the ensuing personal implications of unsolicited disclosure. On the one hand, a growing number of patients diagnosed with HIV have found sanctuary with THPs as alternatives to clinics. On the other hand, THPs in turn have been struggling to channel patients suspected of HIV into clinics through referrals. Therefore, acceptability of the TasP test and treat approach by THPs is a major boost to the intervention, but further success can be achieved through strengthened ties with communities to combat stigma and effectively link patients into HIV care, including partnerships with THPs themselves.

Prompt uptake of antiretroviral treatment (ART) is essential to ensure the success of universal test and treat (UTT) strategies to prevent HIV transmission in high-prevalence settings. We describe ART initiation rates and associated factors within an ongoing UTT cluster-randomized trial in rural South Africa. HIV-positive individuals were offered immediate ART in the intervention arm vs. national guidelines recommended initiation (CD4≤350 cells/mm3) in the control arm. We used data collected up to July 2015 among the ART-eligible individuals linked to TasP clinics before January 2015. ART initiation rates at one (M1), three (M3) and six months (M6) from baseline visit were described by cluster and CD4 count strata (cells/mm3) and other eligibility criteria: ≤100; 100–200; 200–350; CD4>350 with WHO stage 3/4 or pregnancy; CD4>350 without WHO stage 3/4 or pregnancy. A Cox model accounting for covariate effect changes over time was used to assess factors associated with ART initiation. The 514 participants had a median [interquartile range] follow-up duration of 1.08 [0.69; 2.07] months until ART initiation or last visit. ART initiation rates at M1 varied substantially (36.9% in the group CD4>350 without WHO stage 3/4 or pregnancy, and 55.2–71.8% in the three groups with CD4≤350) but less at M6 (from 85.3% in the first group to 96.1–98.3% in the three other groups). Factors associated with lower ART initiation at M1 were a higher CD4 count and attending clinics with both high patient load and higher cluster HIV prevalence. After M1, having a regular partner was the only factor associated with higher likelihood of ART initiation. These findings suggest good ART uptake within a UTT setting, even among individuals with high CD4 count. However, inadequate staffing and healthcare professional practices could result in prioritizing ART initiation in patients with the lowest CD4 counts.

Objective: To explore the impact of expanded eligibility criteria for antiretroviral therapy (ART) on median CD4+ cell count at ART initiation and early mortality on ART.

Methods: Analyses included all adults (16 years) initiated on first-line ART between August 2004 and July 2012. CD4+ cell count threshold 350 cells per microliter for all adults was implemented in August 2011. Early mortality was defined as any death within 91 days of ART initiation. Trends in baseline CD4+ cell count and early mortality were examined by year (August to July) of ART initiation. Competing risks analysis was used to examine early mortality.

Results: A total of 19,080 adults (67.6% female) initiated ART. Median CD4+ cell count at ART initiation was 110-120 cells per microliter over the first 6 years, increasing marginally to 145 cells per microliter in 2010-2011 and more significantly to 199 cells per microliter in 2011-2012. Overall, there were 875 deaths within 91 days of ART initiation; early mortality rate was 19.4 per 100 personyears [95% confidence interval (CI) 18.2 to 20.7]. After adjustment for sex, age, baseline CD4+ cell count, and concurrent tuberculosis (TB), there was a 46% decrease in early mortality for those who initiated ART in 2011-2012 compared with the reference period 2008-2009 (subhazard ratio, 0.54; 95% CI: 0.41 to 0.71).

Conclusions: Since the expansion of eligibility criteria, there is evidence of earlier access to ART and a significant reduction in early mortality rate in this primary health care programme. These findings provide strong support for national ART policies and highlight the importance of earlier ART initiation for achieving reductions in HIV-related mortality. Copyright © 2013 by Lippincott Williams & Wilkins.

Background. Second-line antiretroviral therapy (ART) based on ritonavir-boosted protease inhibitors (bPIs) represents the only available option after first-line failure for the majority of individuals living with human immunodeficiency virus (HIV) worldwide. Maximizing their effectiveness is imperative.

Methods. This cohort study was nested within the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa. We prospectively investigated risk factors for virological failure (VF) of bPI-based ART in the combined study arms. VF was defined by a plasma viral load >1000 copies/mL ≥6 months after initiating bPI-based ART. Cumulative incidence of VF was estimated and competing risk regression was used to derive the subdistribution hazard ratio (SHR) of the associations between VF and patient clinical and demographic factors, taking into account death and loss to follow-up.

Results. One hundred one participants contributed 178.7 person-years of follow-up. Sixty-five percent were female; the median age was 37.4 years. Second-line ART regimens were based on ritonavir-boosted lopinavir, combined with zidovudine or tenofovir plus lamivudine or emtricitabine. The incidence of VF on second-line ART was 12.9 per 100 person-years (n = 23), and prevalence of VF at censoring was 17.8%. Thirteen of these 23 (56.5%) virologic failures resuppressed after a median of 8.0 months (interquartile range, 2.8-16.8 months) in this setting where viral load monitoring was available. Tuberculosis treatment was associated with VF (SHR, 11.50 [95% confidence interval, 3.92-33.74]; P < .001).

Conclusions. Second-line VF was frequent in this setting. Resuppression occurred in more than half of failures, highlighting the value of viral load monitoring of second-line ART. Tuberculosis was associated with VF; therefore, novel approaches to optimize the effectiveness of PI-based ART in high-tuberculosis-burden settings are needed.

Background: The 2015 WHO recommendation of antiretroviral therapy (ART) for all immediately following HIV diagnosis is partially based on the anticipated impact on HIV incidence in the surrounding population. We investigated this approach in a cluster-randomised trial in a high HIV prevalence setting in rural KwaZulu-Natal. We present findings from the first phase of the trial and report on uptake of home-based HIV testing, linkage to care, uptake of ART, and community attitudes about ART.

Methods and Findings: Between 9 March 2012 and 22 May 2014, five clusters in the intervention arm (immediate ART offered to all HIV-positive adults) and five clusters in the control arm (ART offered according to national guidelines, i.e., CD4 count ≤ 350 cells/μl) contributed to the first phase of the trial. Households were visited every 6 mo. Following informed consent and administration of a study questionnaire, each resident adult (≥16 y) was asked for a finger-prick blood sample, which was used to estimate HIV prevalence, and offered a rapid HIV test using a serial HIV testing algorithm. All HIV-positive adults were referred to the trial clinic in their cluster. Those not linked to care 3 mo after identification were contacted by a linkage-to-care team. Study procedures were not blinded. In all, 12,894 adults were registered as eligible for participation (5,790 in intervention arm; 7,104 in control arm), of whom 9,927 (77.0%) were contacted at least once during household visits. HIV status was ever ascertained for a total of 8,233/9,927 (82.9%), including 2,569 ascertained as HIV-positive (942 tested HIV-positive and 1,627 reported a known HIV-positive status). Of the 1,177 HIV-positive individuals not previously in care and followed for at least 6 mo in the trial, 559 (47.5%) visited their cluster trial clinic within 6 mo. In the intervention arm, 89% (194/218) initiated ART within 3 mo of their first clinic visit. In the control arm, 42.3% (83/196) had a CD4 count ≤ 350 cells/μl at first visit, of whom 92.8% initiated ART within 3 mo. Regarding attitudes about ART, 93% (8,802/9,460) of participants agreed with the statement that they would want to start ART as soon as possible if HIV-positive. Estimated baseline HIV prevalence was 30.5% (2,028/6,656) (95% CI 25.0%, 37.0%). HIV prevalence, uptake of home-based HIV testing, linkage to care within 6 mo, and initiation of ART within 3 mo in those with CD4 count ≤ 350 cells/μl did not differ significantly between the intervention and control clusters. Selection bias related to noncontact could not be entirely excluded.

Conclusions: Home-based HIV testing was well received in this rural population, although men were less easily contactable at home; immediate ART was acceptable, with good viral suppression and retention. However, only about half of HIV-positive people accessed care within 6 mo of being identified, with nearly two-thirds accessing care by 12 mo. The observed delay in linkage to care would limit the individual and public health ART benefits of universal testing and treatment in this population. Trial registration: ClinicalTrials.gov NCT01509508

Background. Antiretroviral therapy (ART) was highly efficacious in preventing human immunodeficiency virus (HIV) transmission in stable serodiscordant couples in the HPTN-052 study, a resource-intensive randomized controlled trial with near-perfect ART adherence and mutual HIV status disclosure among all participating couples. However, minimal evidence exists of the effectiveness of ART in preventing HIV acquisition in stable serodiscordant couples in "real-life" population-based settings in hyperendemic communities of sub-Saharan Africa, where health systems are typically resource-poor and overburdened, adherence to ART is often low, and partners commonly do not disclose their HIV status to each other.

Methods. Data arose from a population-based open cohort in KwaZulu-Natal, South Africa. A total of 17 016 HIV-uninfected individuals present between January 2005 and December 2013 were included. Interval-censored time-updated proportional hazards regression was used to assess how the ART status affected HIV transmission risk in stable serodiscordant relationships.

Results. We observed 1619 HIV seroconversions in 17 016 individuals, over 60 349 person-years follow-up time. During the follow-up period, 1846 individuals had an HIV-uninfected and 196 had an HIV-infected stable partner HIV incidence was 3.8/100 person-years (PY) among individuals with an HIV-infected partner (95% confidence interval [CI], 2.3-5.6), 1.4/100 PY (.4-3.5) among those with HIV-infected partners receiving ART, and 5.6/100 PY (3.5-8.4) among those with HIV-infected partners not receiving ART. Use of ART was associated with a 77% decrease in HIV acquisition risk among serodiscordant couples (adjusted hazard ratio, 0.23; 95% CI,. 07-.80).

Conclusions. ART initiation was associated with a very large reduction in HIV acquisition in serodiscordant couples in rural KwaZulu-Natal. However, this "real-life" effect was substantially lower than the effect observed in the HPTN-052 trial. To eliminate HIV transmission in serodiscordant couples, additional prevention interventions are probably needed.

Introduction: We aimed to quantify and identify associated factors of linkage to HIV care following home-based HIV counselling and testing (HBHCT) in the ongoing ANRS 12249 treatment-as-prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa.

Methods: Individuals ]16 years were offered HBHCT; those who were identified HIV positive were referred to cluster-based TasP clinics and offered antiretroviral treatment (ART) immediately (five clusters) or according to national guidelines (five clusters). HIV care was also available in the local Department of Health (DoH) clinics. Linkage to HIV care was defined as TasP or DoH clinic attendance within three months of referral among adults not in HIV care at referral. Associated factors were identified using multivariable logistic regression adjusted for trial arm.

Results: Overall, 1323 HIV-positive adults (72.9% women) not in HIV care at referral were included, of whom 36.9% (n488) linked to care B3 months of referral (similar by sex). In adjusted analyses (n1222), individuals who had never been in HIV care before referral were significantly less likely to link to care than those who had previously been in care (B33% vs. 42%, pB0.001). Linkage to care was lower in students (adjusted odds-ratio [aOR] 0.47; 95% confidence interval [CI] 0.240.92) than in employed adults, in adults who completed secondary school (aOR0.68; CI 0.490.96) or at least some secondary school (aOR0.59; CI 0.410.84) versus 5 primary school, in those who lived at 1 to 2 km (aOR0.58; CI 0.440.78) or 25 km from the nearest TasP clinic (aOR0.57; CI 0.410.77) versus B1 km, and in those who were referred to clinic after ]2 contacts (aOR0.75; CI 0.580.97) versus those referred at the first contact. Linkage to care was higher in adults who reported knowing an HIV-positive family member (aOR1.45; CI 1.121.86) versus not, and in those who said that they would take ART as soon as possible if they were diagnosed HIV positive (aOR2.16; CI 1.134.10) versus not.

Conclusions: Fewer than 40% of HIV-positive adults not in care at referral were linked to HIV care within three months of HBHCT in the TasP trial. Achieving universal test and treat coverage will require innovative interventions to support linkage to HIV care.

Background: The Universal HIV Test and Treat (UTT) strategy represents a challenge for science, but is also a challenge for individuals and societies. Are repeated offers of provider-initiated HIV testing and immediate antiretroviral therapy (ART) socially-acceptable and can these become normalized over time? Can UTT be implemented without potentially adding to individual and community stigma, or threatening individual rights? What are the social, cultural and economic implications of UTT for households and communities? And can UTT be implemented within capacity constraints and other threats to the overall provision of HIV services? The answers to these research questions will be critical for routine implementation of UTT strategies.

Methods/design: A social science research programme is nested within the ANRS 12249 Treatment-as-Prevention (TasP) cluster-randomised trial in rural South Africa. The programme aims to inform understanding of the (i) social, economic and environmental factors affecting uptake of services at each step of the continuum of HIV prevention, treatment and care and (ii) the causal impacts of the TasP intervention package on social and economic factors at the individual, household, community and health system level. We describe a multidisciplinary, multi-level, mixed-method research protocol that includes individual, household, community and clinic surveys, and combines quantitative and qualitative methods.

Discussion: The UTT strategy is changing the overall approach to HIV prevention, treatment and care, and substantial social consequences may be anticipated, such as changes in social representations of HIV transmission, prevention, HIV testing and ART use, as well as changes in individual perceptions and behaviours in terms of uptake and frequency of HIV testing and ART initiation at high CD4. Triangulation of social science studies within the ANRS 12249 TasP trial will provide comprehensive insights into the acceptability and feasibility of the TasP intervention package at individual, community, patient and health system level, to complement the trial's clinical and epidemiological outcomes. It will also increase understanding of the causal impacts of UTT on social and economic outcomes, which will be critical for the long-term sustainability and routine UTT implementation. Trial registration: Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974.

Background: Antiretroviral therapy (ART) suppresses HIV viral load in all body compartments and so limits the risk of HIV transmission. It has been suggested that ART not only contributes to preventing transmission at individual but potentially also at population level. This trial aims to evaluate the effect of ART initiated immediately after identification/diagnosis of HIV-infected individuals, regardless of CD4 count, on HIV incidence in the surrounding population. The primary outcome of the overall trial will be HIV incidence over two years. Secondary outcomes will include i) socio-behavioural outcomes (acceptability of repeat HIV counselling and testing, treatment acceptance and linkage to care, sexual partnerships and quality of life); ii) clinical outcomes (mortality and morbidity, retention into care, adherence to ART, virologic failure and acquired HIV drug resistance), iii) cost-effectiveness of the intervention. The first phase will specifically focus on the trial's secondary outcomes.Methods/design: A cluster-randomised trial in 34 (2 × 17) clusters within a rural area of northern KwaZulu-Natal (South Africa), covering a total population of 34,000 inhabitants aged 16 years and above, of whom an estimated 27,200 would be HIV-uninfected at start of the trial. The first phase of the trial will include ten (2 × 5) clusters. Consecutive rounds of home-based HIV testing will be carried out. HIV-infected participants will be followed in dedicated trial clinics: in intervention clusters, they will be offered immediate ART initiation regardless of CD4 count and clinical stage; in control clusters they will be offered ART according to national treatment eligibility guidelines (CD4 <350 cells/μL, World Health Organisation stage 3 or 4 disease or multidrug-resistant/extensively drug-resistant tuberculosis). Following proof of acceptability and feasibility from the first phase, the trial will be rolled out to further clusters.Discussion: We aim to provide proof-of-principle evidence regarding the effectiveness of Treatment-as-Prevention in reducing HIV incidence at the population level. Data collected from the participants at home and in the clinics will inform understanding of socio-behavioural, economic and clinical impacts of the intervention as well as feasibility and generalizability. © 2013 Iwuji et al.; licensee BioMed Central Ltd.

Introduction
There is limited literature on the appropriateness of viral load (VL) monitoring and management of detectable VL in public health settings in rural South Africa.

Methods
We analysed data captured in the electronic patient register from HIV‐positive patients ≥ 15 years old initiating antiretroviral therapy (ART) in 17 public sector clinics in rural KwaZulu‐Natal, during 2010–2016. We estimated the completion rate for VL monitoring at 6, 12, and 24 months. We described the cascade of care for those with any VL measurement ≥ 1000 HIV‐1 RNA copies/mL after ≥ 20 weeks on ART, including the following proportions: (1) repeat VL within 6 months; (2) re‐suppressed; (3) switched to second‐line regimen.

Results
There were 29 384 individuals who initiated ART during the period [69% female, median age 31 years (interquartile range 25–39)]. Of those in care at 6, 12, and 24 months, 40.7% (9861/24 199), 34% (7765/22 807), and 25.5% (4334/16 965) had a VL test at each recommended time‐point, respectively. The VL results were documented at all recommended time‐points for 12% (2730/22 807) and 6.2% (1054/16 965) of ART‐treated patients for 12 and 24 months, respectively. Only 391 (18.3%) of 2135 individuals with VL ≥ 1000 copies/mL on first‐line ART had a repeat VL documenting re‐suppression or were appropriately changed to second‐line with persistent failure. Completion of the treatment failure cascade occurred a median of 338 days after failure was detected.

Conclusion
We found suboptimal VL monitoring and poor responses to virologic failure in public‐sector ART clinics in rural South Arica. Implications include increased likelihood of morbidity and transmission of drug‐resistant HIV.

Introduction
Achieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population‐based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub‐Saharan Africa (SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90‐90‐90 campaign.

Discussion
These three‐year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community‐based testing approaches) achieved >90% coverage in all studies. (2) When coupled with robust linkage to HIV care, rapid ART start and patient‐centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population‐level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub‐populations and were lower among youth. (3) UTT resulted in marked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universal testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in which mortality was comprehensively measured.

Conclusions
These trials provide strong evidence that UTT inclusive of universal testing increases population‐level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub‐country level as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets.

Purpose of Review
The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of a universal test and treat (UTT) approach on reducing HIV incidence in one of the regions of the world most severely affected by the HIV epidemic—KwaZulu-Natal, South Africa. We summarize key findings from this trial as well as recent findings from controlled studies conducted in the linked population cohort quantifying the long-term effects of expanding ART on directly measured HIV incidence (2004–2017).

Recent Findings
The ANRS TasP trial did not—and could not—demonstrate a reduction in HIV incidence, because the offer of UTT in the intervention communities did not increase ART coverage and population viral suppression compared to the standard of care in the control communities. Ten controlled studies from the linked population cohort—including several quasi-experimental study designs—exploit heterogeneity in ART exposure to show a consistent and substantial impact of expanding provision of ART and population viral suppression on reduction in HIV incidence at the couple, household, community, and population levels.

Summary
In this setting, all of the evidence from large, population-based studies (inclusive of the ANRS TasP trial) is remarkably coherent and consistent—i.e., higher ART coverage and population viral suppression were repeatedly associated with clear, measurable decreases in HIV incidence. Thus, the expanded provision of ART has plausibly contributed in a major way toward the dramatic 43% decline in population-level HIV incidence in this typical rural African population. The outcome of the ANRS TasP trial constitutes a powerful null finding with important insights for overcoming implementation challenges in the population delivery of ART. This finding does not imply lack of ART effectiveness in blocking onward transmission of HIV nor its inability to reduce HIV incidence. Rather, it demonstrates that large increases in ART coverage over current levels will require health systems innovations to attract people living with HIV in early stages of the disease to participate in HIV treatment. Such innovations and new approaches are required for the true potential of UTT to be realized.

Introduction: The universal test-and-treat (UTT) strategy aims to maximize population viral suppression (PVS), that is, the proportion of all people living with HIV (PLHIV) on antiretroviral treatment (ART) and virally suppressed, with the goal of reducing HIV transmission at the population level. This article explores the extent to which temporal changes in PVS explain the observed lack of association between universal treatment and cumulative HIV incidence seen in the ANRS 12249 TasP trial conducted in rural South Africa.
Methods: The TasP cluster-randomized trial (2012 to 2016) implemented six-monthly repeat home-based HIV counselling and testing (RHBCT) and referral of PLHIV to local HIV clinics in 2 9 11 clusters opened sequentially. ART was initiated according to national guidelines in control clusters and regardless of CD4 count in intervention clusters. We measured residency status, HIV status, and HIV care status for each participant on a daily basis. PVS was computed per cluster among all resident PLHIV (≥16, including those not in care) at cluster opening and daily thereafter. We used a mixed linear model to explore time patterns in PVS, adjusting for sociodemographic changes at the cluster level.
Results: 8563 PLHIV were followed. During the course of the trial, PVS increased significantly in both arms (23.5% to 46.2% in intervention, +22.8, p < 0.001; 26.0% to 44.6% in control, +18.6, p < 0.001). That increase was similar in both arms (p = 0.514). In the final adjusted model, PVS increase was most associated with increased RHBCT and the implementation of local trial clinics (measured by time since cluster opening). Contextual changes (measured by calendar time) also contributed slightly. The effect of universal ART (trial arm) was positive but limited.
Conclusions: PVS was improved significantly but similarly in both trial arms, explaining partly the null effect observed in terms of cumulative HIV incidence between arms. The PVS gains due to changes in ART-initiation guidelines alone are relatively small compared to gains obtained by strategies to maximize testing and linkage to care. The achievement of the 90-90-90 targets will not be met if the operational and implementational challenges limiting access to care and treatment, often context-specific, are not properly addressed. Clinical trial number: NCT01509508 (clinicalTrials.gov)/DOH-27-0512-3974 (South African National Clinical Trials Register).

Objectives
The aim of the study was to estimate rates of linkage to HIV care and antiretroviral treatment (ART) initiation after the introduction of home‐based HIV counselling and testing (HBHCT) and telephone‐facilitated support for linkage in rural South Africa.

Methods
A population‐based prospective cohort study was carried out in KwaZulu Natal, South Africa. All residents aged ≥ 15 years were eligible for HBHCT. Those who tested positive and were not in care were referred for ART at one of 11 public‐sector clinics. Individuals who did not attend the clinic within 2 weeks were sent a short message service (SMS) reminder; those who had not attended after a further 2 weeks were telephoned by a nurse counsellor, to discuss concerns and encourage linkage. Kaplan–Meier methods were used to estimate the proportion of newly diagnosed individuals linking to care and initiating ART.

Results
Among 38 827 individuals visited, 26% accepted HBHCT. Uptake was higher in women than in men (30% versus 20%, respectively), but similar in people aged < 30 years and ≥ 30 years (28% versus 26%, respectively). A total of 784 (8%) tested HIV positive, of whom 427 (54%) were newly diagnosed. Within 6 months, 31% of women and 18% of men < 30 years old had linked to care, and 29% and 16%, respectively, had started ART. Among those ≥ 30 years, 41% of women and 38% of men had linked to care within 6 months, and 41% and 35%, respectively, had started ART.

Conclusions
Despite facilitated linkage, rates of timely linkage to care and ART initiation after HBHCT were very low, particularly among young men. Innovations are needed to provide effective HIV care and prevention interventions to young people, and thus maximize the benefits of universal test and treat.

Objective: To study retention in care (RIC) trajectories and associated factors in patients eligible for antiretroviral treatment (ART) in a universal test-and-treat setting (TasP trial, South Africa, 2012-2016).

Design: A cluster-randomized trial whereby individuals identified HIV-positive after home-based testing were invited to initiate ART immediately (intervention) or following national guidelines (control).

Methods: Exiting care was defined as ≥3 months late for a clinic appointment, transferring elsewhere, or death. Group-Based Trajectory Modelling was performed to estimate RIC trajectories over 18 months and associated factors in 777 ART-eligible patients.

Results: Four RIC trajectory groups were identified: i) group 1 “remained” in care (reference, n=554, 71.3%), ii) group 2 exited care then “returned” after (median [interquartile range]) 4 [3-9] months (n=40, 5.2%), iii) group 3 “exited care rapidly” (after 4 [4-6] months, n=98, 12.6%), iv) group 4 “exited care later” (after 11 [9-13] months, n=85, 10.9%). Group 2 patients were less likely to have initiated ART within 1 month and more likely to be male, young (<29 years), without a regular partner and to have a CD4 count >350 cells/mm3. Group 3 patients were more likely to be women without social support, newly diagnosed, young, and less likely to have initiated ART within 1 month. Group 4 patients were more likely to be newly diagnosed and aged ≤39 years.

Conclusions: High CD4 counts at care initiation were not associated with a higher risk of exiting care. Prompt ART initiation and special support for young and newly diagnosed HIV-patients are needed to maximize RIC.

Background
Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial.

Methods
Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation.

Results
PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91–2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12–0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82–1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance.

Conclusions
NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone.

Objectives: The WHO recently recommended the use of a new first-line ART containing dolutegravir. We investigated the efficacy of NRTI backbones (tenofovir or abacavir with a cytosine analogue) in low- and middleincome countries where there is significant prior exposure to antiretrovirals and drug resistance to NRTIs.

Methods: Within the treatment-as-prevention study in South Africa, we selected participants with available nextgeneration sequencing (NGS) data for the HIV-1 pol gene at trial entry; they were either ART initiators (n" 1193) or already established on ART (n" 94). NGS of the HIV-1 pol gene was carried out using MiSeq technology; reverse transcriptase drug resistance mutations (DRMs) were detected at 5% (DRM5%) and 20% (DRM20%) for all 1287 participants. Genotypic susceptibility was assessed using the Stanford HIVDB resistance interpretation algorithm.

Results: NRTI DRM20% and DRM5% were detected among 5/1193 (0.4%) and 9/1193 (0.8%) of ART initiators, respectively. There was tenofovir exposure in 73/94 (77.7%) of those established on ART, with full susceptibility to abacavir in 57/94 (60.6%) and 56/94 (59.6%) for DRM20% and DRM5%, respectively, while 67/94 (71.3%) and 64/94 (68.1%) were fully susceptible to tenofovir, respectively. The differences between tenofovir and abacavir were not statistically significant at the 20% or 5% variant level (P" 0.16 and 0.29, respectively). NGS detection of variants at the 5% level increased detection of K65R in both naive and treated groups. One of 607 integrase sequences carried a DRM20% (Q148R).

Conclusions: Dolutegravir with a cytosine analogue plus tenofovir or abacavir appears to have similar efficacy in South Africans naive to ART. NGS should be considered in HIV drug resistance surveillance.

Introduction
The universal test and treat strategy (UTT) was developed to maximize the proportion of all HIV‐positive individuals on antiretroviral treatment (ART) and virally suppressed, assuming that it will lead to a reduction in HIV incidence at the population level. The evolution over time of the cross‐sectional HIV care cascade is determined by individual longitudinal trajectories through the HIV care continuum and underlying population dynamics. The purpose of this paper is to quantify the contribution of each component of population change (in‐ and out‐migration, HIV seroconversion, ageing into the cohort and definitive exit such as death) on the HIV care cascade in the context of the ANRS 12249 Treatment as Prevention (TasP) cluster‐randomized trial, investigating UTT in rural KwaZulu‐Natal, South Africa, between 2012 and 2016.

Methods
HIV test results and information on clinic visits, ART prescriptions, viral load and CD4 count, migration and deaths were used to calculate residency status, HIV status and HIV care status for each individual on a daily basis. Position within the HIV care continuum was considered as a score ranging from 0 (undiagnosed) to 4 (virally suppressed). We compared the cascade score of each individual joining or leaving the population of resident adults living with HIV with the average score of their cluster at the time of entry or exit. Then, we computed the contribution of each entry or exit on the average cascade score and their annualized total contribution, by component of change.

Results
While the average cascade score increased over time in all clusters, that increase was constrained by population dynamics. Permanent exits and ageing into the people living with HIV cohort had a marginal effect. Both in‐migrants and out‐migrants were less likely to be retained at each step of the HIV care continuum. However, their overall impact on the cross‐sectional cascade was limited as the effect of in‐ and out‐migration balanced each other. The contribution of HIV seroconversions was negative in all clusters.

Conclusions
In a context of high HIV incidence, the continuous flow of newly infected individuals slows down the efforts to increase ART coverage and population viral suppression, ultimately attenuating any population‐level impact on HIV incidence.

Clinical Trial Number
NCT01509508 (clinicalTrials.gov)/DOH‐27‐0512‐3974 (South African National Clinical Trials Register).

Introduction
HIV treatment guidelines now recommend antiretroviral therapy (ART) initiation regardless of CD4 count to maximise benefit both for the individual and society. It is unknown whether the initiation of ART at higher CD4 counts would affect adherence levels. We investigated whether initiating ART at higher CD4 counts was associated with sub-optimal adherence (<95%) during the first 12 months of ART.

Methods
A prospective cohort study nested within a two-arm cluster-randomised trial of universal test and treat implemented March 2012 - June 2016 to measure impact of ART on HIV incidence in rural KwaZulu-Natal. ART was initiated regardless of CD4 count in the intervention arm and according to national guidelines in the control arm. ART adherence was measured monthly using a visual analogue scale (VAS) and pill counts (PC). HIV viral load was measured at ART initiation, 3 and 6 months, and six monthly thereafter. We pooled data from participants in both arms and used random-effects logistic regression models to examine the association between CD4 count at ART initiation and sub-optimal adherence, and assessed if adherence levels were associated with virological suppression.

Results
Among 900 individuals who initiated ART ≥ 12 months before study end, median (IQR) CD4 at ART initiation was 350 cells/mm3 (234, 503); median age was 34.6 years (IQR 27.4-46.4) and 71.7% were female. Adherence was sub-optimal in 14.7% of visits as measured by VAS and 20.7% by PC. In both the crude analyses and after adjusting for potential confounders, adherence was not significantly associated with CD4 count at ART initiation (adjusted OR for linear trend in sub-optimal adherence with every 100 cells/mm3 increase in CD4 count: 1.00, 95% CI 0.95-1.05, for VAS, and 1.03, 95%CI 0.99-1.07, for PC). Virological suppression at 12 months was 97%. Optimal adherence by both measures was significantly associated with virological suppression (p<0.001 for VAS; p=0.006 for PC).

Conclusions
We found no evidence that higher CD4 counts at ART initiation were associated with sub-optimal ART adherence in the first 12 months. Our findings should alleviate concerns about adherence in individuals initiating ART at higher CD4 counts, however long-term outcomes are needed.

Since 2007, the World Health Organization has recommended that in countries with generalized HIV epidemics, HIV testing and counselling should be offered to all adults and adolescents seen in a health facility (1). This recommendation had been policy in Uganda since 2005 (2). However, evidence suggests that translation of this policy to practice in real-world settings has been patchy and that missed opportunities with HIV testing in the inpatient setting are still contributing to HIV related deaths (3,4).

Background
Universal antiretroviral therapy (ART), as per the 2015 WHO recommendations, might reduce population HIV incidence. We investigated the effect of universal test and treat on HIV acquisition at population level in a high prevalence rural region of South Africa.

Methods
We did a phase 4, open-label, cluster randomised trial of 22 communities in rural KwaZulu-Natal, South Africa. We included individuals residing in the communities who were aged 16 years or older. The clusters were composed of aggregated local areas (neighbourhoods) that had been identified in a previous study in the Hlabisa subdistrict. The study statisticians randomly assigned clusters (1:1) with MapInfo Pro (version 11.0) to either the control or intervention communities, stratified on the basis of antenatal HIV prevalence. We offered residents repeated rapid HIV testing during home-based visits every 6 months for about 4 years in four clusters, 3 years in six clusters, and 2 years in 12 clusters (58 cluster-years) and referred HIV-positive participants to trial clinics for ART (fixed-dose combination of tenofovir, emtricitabine, and efavirenz) regardless of CD4 cell count (intervention) or according to national guidelines (initially ≤350 cells per μL and <500 cells per μL from January, 2015; control). Participants and investigators were not masked to treatment allocation. We used dried blood spots once every 6 months provided by participants who were HIV negative at baseline to estimate the primary outcome of HIV incidence with cluster-adjusted Poisson generalised estimated equations in the intention-to-treat population after 58 cluster-years of follow-up. This study is registered with ClinicalTrials.gov, number NCT01509508, and the South African National Clinical Trials Register, number DOH-27-0512-3974.

Findings
Between March 9, 2012, and June 30, 2016, we contacted 26 518 (93%) of 28 419 eligible individuals. Of 17 808 (67%) individuals with a first negative dried blood spot test, 14 223 (80%) had subsequent dried blood spot tests, of whom 503 seroconverted after follow-up of 22 891 person-years. Estimated HIV incidence was 2·11 per 100 person-years (95% CI 1·84–2·39) in the intervention group and 2·27 per 100 person-years (2·00–2·54) in the control group (adjusted hazard ratio 1·01, 95% CI 0·87–1·17; p=0·89). We documented one case of suicidal attempt in a woman following HIV seroconversion. 128 patients on ART had 189 life-threatening or grade 4 clinical events: 69 (4%) of 1652 in the control group and 59 (4%) of 1367 in the intervention group (p=0·83).

Interpretation
The absence of a lowering of HIV incidence in universal test and treat clusters most likely resulted from poor linkage to care. Policy change to HIV universal test and treat without innovation to improve health access is unlikely to reduce HIV incidence.

Introduction: Remarkable strides have been made in controlling the HIV epidemic, although not enough to achieve epidemic control. More recently, interest in biomedical HIV control approaches has increased, but substantial challenges with the HIV cascade of care hinder successful implementation. We summarise all available HIV prevention methods and make recommendations on how to address current challenges.

Discussion: In the early days of the epidemic, behavioural approaches to control the HIV dominated, and the few available evidence-based interventions demonstrated to reduce HIV transmission were applied independently from one another. More recently, it has become clear that combination prevention strategies targeted to high transmission geographies and people at most risk of infections are required to achieve epidemic control. Biomedical strategies such as male medical circumcision and antiretroviral therapy for treatment in HIV-positive individuals and as preexposure prophylaxis in HIV-negative individuals provide immense promise for the future of HIV control. In resourcerich settings, the threat of HIV treatment optimism resulting in increased sexual risk taking has been observed and there are concerns that as ART roll-out matures in resource-poor settings and the benefits of ART become clearly visible, behavioural disinhibition may also become a challenge in those settings. Unfortunately, an efficacious vaccine, a strategy which could potentially halt the HIV epidemic, remains elusive.

Conclusion: Combination HIV prevention offers a logical approach to HIV control, although what and how the available options should be combined is contextual. Therefore, knowledge of the local or national drivers of HIV infection is paramount. Problems with the HIV care continuum remain of concern, hindering progress towards the UNAIDS target of 90-90-90 by 2020. Research is needed on combination interventions that address all the steps of the cascade as the steps are not independent of each other. Until these issues are addressed, HIV elimination may remain an unattainable goal.