Summary Background Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to ...be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. Methods We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov , number NCT00557245. Findings 4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio HR 0·67, 95% CI 0·39–1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06–0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02–0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. Interpretation These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. Funding Bill & Melinda Gates Foundation and US National Institutes of Health.
Summary Background Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it ...delays HIV-1 disease progression is unknown. We investigated the effect of aciclovir on HIV-1 progression. Methods In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to aciclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per μL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per μL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per μL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00194519. Findings At enrolment, the median CD4 cell count was 462 cells per μL and median HIV-1 plasma RNA was 4·1 log10 copies per μL. Aciclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned aciclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio HR 0·84, 95% CI 0·71–0·98, p=0·03). In those with CD4 counts ≥350 cells per μL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per μL by 19% (0·81, 0·71–0·93, p=0·002) Interpretation The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration. Funding Bill & Melinda Gates Foundation.
Mortality in HIV-infected people after initiation of antiretroviral treatment (ART) in resource-limited settings is an important measure of the effectiveness and comparative effectiveness of the ...global public health response. Substantial loss to follow-up precludes accurate accounting of deaths and limits our understanding of effectiveness. We aimed to provide a better understanding of mortality at scale and, by extension, the effectiveness and comparative effectiveness of public health ART treatment in east Africa.
In 14 clinics in five settings in Kenya, Uganda, and Tanzania, we intensively traced a sample of patients randomly selected using a random number generator, who were infected with HIV and on ART and who were lost to follow-up (>90 days late for last scheduled visit). We incorporated the vital status outcomes for these patients into analyses of the entire clinic population through probability-weighted survival analyses.
We followed 34 277 adults on ART from Mbarara and Kampala in Uganda, Eldoret, and Kisumu in Kenya, and Morogoro in Tanzania. The median age was 35 years (IQR 30-42), 11 628 (34%) were men, and median CD4 count count before therapy was 154 cells per μL (IQR 70-234). 5780 patients (17%) were lost to follow-up, 991 (17%) were selected for tracing between June 10, 2011, and Aug 27, 2012, and vital status was ascertained for 860 (87%). With incorporation of outcomes from the patients lost to follow-up, estimated 3 year mortality increased from 3·9% (95% CI 3·6-4·2) to 12·5% (11·8-13·3). The sample-corrected, unadjusted 3 year mortality across settings was lowest in Mbarara (7·2%) and highest in Morogoro (23·6%). After adjustment for age, sex, CD4 count before therapy, and WHO stage, the sample-corrected hazard ratio comparing the settings with highest and lowest mortalities was 2·2 (95% CI 1·5-3·4) and the risk difference for death at 3 years was 11% (95% CI 5·0-17·7).
A sampling-based approach is widely feasible and important to an understanding of mortality after initiation of ART. After adjustment for measured biological drivers, mortality differs substantially across settings despite delivery of a similar clinical package of treatment. Implementation research to understand the systems, community, and patients' behaviours driving these differences is urgently needed.
The US National Institutes of Health and President's Emergency Fund for AIDS Relief.
Background: Pregnant and postpartum women in high HIV prevalent regions are at increased HIV risk. Oral pre-exposure prophylaxis (PrEP) can decrease HIV incidence reducing infant HIV infections. ...Understanding healthcare worker (HCW) beliefs about PrEP prior to national roll-out is critical to supporting PrEP scale-up. Methods: We conducted 45 semi-structured interviews among a range of HCW cadres with and without PrEP provision experience purposively recruited from four clinics in Kenya to compare their views on prescribing PrEP during pregnancy and postpartum. Interviews were analysed using a conventional content analysis approach to identify key influences on PrEP acceptability and feasibility. Results: All HCWs perceived PrEP as an acceptable and feasible HIV prevention strategy for pregnant and postpartum women. They believed PrEP meets women’s needs as an on-demand, female-controlled prevention strategy that empowers women to take control of their HIV risk. HCWs highlighted their role in PrEP delivery success while acknowledging how their knowledge gaps, concerns and perceived PrEP implementation challenges may hinder optimal PrEP delivery. Conclusion: HCWs supported PrEP provision to pregnant and postpartum women. However, counseling tools to address risk perceptions in this population and strategies to reduce HCW knowledge gaps, concerns and perceived implementation barriers are required.
Adolescent girls and young women (AGYW) are highly affected by the HIV epidemic, yet standard approaches to pre-exposure prophylaxis (PrEP) delivery will not meet their needs. This commentary ...highlights key characteristics of AGYW related to PrEP use and delivery, including typical neurocognitive development, lack of experience with sustained medication use, and the social and connected nature of AGYW’s lives. We then suggest ways for programs to embrace these characteristics, such as presenting PrEP as a lifestyle choice and not a biomedical tool, making access to PrEP simple and easy, and recognizing the many influences AGYW face in taking PrEP. We also suggest ways for programs to identify AGYW at the highest risk of HIV acquisition. Adolescent girls and young women have an important role to play in ending the HIV epidemic and they deserve considerable, tailored investment.
Despite large investments in HIV testing, only an estimated 45% of HIV-infected people in sub-Saharan Africa know their HIV status. Optimum methods for maximising population-level testing remain ...unknown. We sought to show the effectiveness of a hybrid mobile HIV testing approach at achieving population-wide testing coverage.
We enumerated adult (≥15 years) residents of 32 communities in Uganda (n=20) and Kenya (n=12) using a door-to-door census. Stable residence was defined as living in the community for at least 6 months in the past year. In each community, we did 2 week multiple-disease community health campaigns (CHCs) that included HIV testing, counselling, and referral to care if HIV infected; people who did not participate in the CHCs were approached for home-based testing (HBT) for 1-2 months within the 1-6 months after the CHC. We measured population HIV testing coverage and predictors of testing via HBT rather than CHC and non-testing.
From April 2, 2013, to June 8, 2014, 168,772 adult residents were enumerated in the door-to-door census. HIV testing was achieved in 131,307 (89%) of 146,906 adults with stable residence. 13,043 of 136,033 (9·6%, 95% CI 9·4-9·8) adults with and without stable residence had HIV; median CD4 count was 514 cells per μL (IQR 355-703). Among 131,307 adults with stable residence tested, 56,106 (43%) reported no previous testing. Among 13,043 HIV-infected adults, 4932 (38%) were unaware of their status. Among 105,170 CHC attendees with stable residence 104,635 (99%) accepted HIV testing. Of 131,307 adults with stable residence tested, 104,635 (80%; range 60-93% across communities) tested via CHCs. In multivariable analyses of adults with stable residence, predictors of non-testing included being male (risk ratio RR 1·52, 95% CI 1·48-1·56), single marital status (1·70, 1·66-1·75), age 30-39 years (1·58, 1·52-1·65 vs 15-19 years), residence in Kenya (1·46, 1·41-1·50), and migration out of the community for at least 1 month in the past year (1·60, 1·53-1·68). Compared with unemployed people, testing for HIV was more common among farmers (RR 0·73, 95% CI 0·67-0·79) and students (0·73, 0·69-0·77); and compared with people with no education, testing was more common in those with primary education (0·84, 0·80-0·89).
A hybrid, mobile approach of multiple-disease CHCs followed by HBT allowed for flexibility at the community and individual level to help reach testing coverage goals. Men and mobile populations remain challenges for universal testing.
National Institutes of Health and President's Emergency Plan for AIDS Relief.
Universal testing and treatment for HIV has shown promise as an approach to reduce mortality and lower HIV incidence. Evidence on the economic effects of this approach on individuals and households ...in low-resource settings is scarce. We aimed to examine the effect of universal HIV testing and treatment on a range of economic outcomes.
We collected data in household surveys done over a 3-year period in a sample of HIV-positive and HIV-negative adults participating in a cluster-randomised trial of universal HIV testing and treatment in 32 rural communities in Kenya and Uganda. Communities of approximately 10 000 people were pair-matched on the basis of geographical and population characteristics, with the best-matching 16 pairs randomly assigned (1:1) to intervention or control groups. Participants in intervention communities received annual HIV and multidisease testing, universal antiretroviral therapy (ART) eligibility, and patient-centred care. Participants in control communities received baseline testing and medical care according to national guidelines. We analysed employment and health-care utilisation outcomes for working-age adults (age 18–65 years) and education outcomes for school-age children (6–17 years) using data from 3 years after the intervention. This trial is now complete, and is registered with ClinicalTrials.gov, NCT01864603.
Between July 9, 2013, and June 15, 2017, we collected survey data on 8198 working-age adults and 6755 school-age children. Compared with adults living with HIV in control communities, adults living with HIV in intervention communities were more likely to be employed (difference 9·7% 95% CI 2·1 to 18·3), less likely to seek health care (–10·3% –22·0 to 0·1), and less likely to spend money on health care (–12·7% –22·4 to 0·6) 3 years after the intervention. We found no significant differences in outcomes between HIV-negative adults in intervention and control communities. Among children in households with HIV-positive adults, the intervention led to a 7·3% (95% CI 1·0 to 15·1) increase in primary school completion after 3 years in intervention communities compared with control communities.
Universal HIV testing and treatment improved employment outcomes and other indicators of socioeconomic wellbeing for HIV-positive adults and children in their households, but had no effect on HIV-negative adults. Our findings suggest that the considerable investments needed to expand ART access might have substantial short-term and long-term economic returns.
National Institutes of Health.
Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various ...contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy (ART) regimens.
We did this retrospective cohort study of HIV-positive women aged 15-45 years enrolled in 19 HIV care facilities supported by Family AIDS Care and Education Services in western Kenya between Jan 1, 2011, and Dec 31, 2013. Our primary outcome was incident pregnancy diagnosed clinically. The primary exposure was a combination of contraceptive method and efavirenz-based or nevirapine-based ART regimen. We used Poisson models, adjusting for repeated measures, and demographic, behavioural, and clinical factors, to compare pregnancy rates among women receiving different contraceptive and ART combinations.
24,560 women contributed 37,635 years of follow-up with 3337 incident pregnancies. In women using implants, adjusted pregnancy incidence was 1.1 per 100 person-years (95% CI 0.72-1.5) for nevirapine-based ART users and 3.3 per 100 person-years (1.8-4.8) for efavirenz-based ART users (adjusted incidence rate ratio IRR 3.0, 95% CI 1.3-4.6). In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4.5 per 100 person-years (95% CI 3.7-5.2) for nevirapine-based ART users and 5.4 per 100 person-years (4.0-6.8) for efavirenz-based ART users (adjusted IRR 1.2, 95% CI 0.91-1.5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, had 3.1-4.1 higher rates of pregnancy than did those using implants, with 1.6-2.8 higher rates in women using efavirenz-based ART.
Although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than did those using nevirapine-based ART, these women still had lower contraceptive failure rates than did those receiving all other contraceptive methods except for intrauterine devices and permanent methods. Guidelines for contraceptive and ART combinations should balance the failure rates for each contraceptive method and ART regimen combination against the high effectiveness of implants.
None.
As sub-Saharan Africa transitions to a new era of universal antiretroviral therapy (ART), up-to-date assessments of population-level HIV RNA suppression are needed to inform interventions to optimise ...ART delivery. We sought to measure population viral load metrics to assess viral suppression and characterise demographic groups and geographical locations with high-level detectable viraemia in east Africa.
The Sustainable East Africa Research in Community Health (SEARCH) study is a cluster-randomised controlled trial of an HIV test-and-treat strategy in 32 rural communities in Uganda and Kenya, selected on the basis of rural setting, having an approximate population of 10 000 people, and being within the catchment area of a President's Emergency Plan for AIDS Relief-supported HIV clinic. During the baseline population assessment in the SEARCH study, we did baseline HIV testing and HIV RNA measurement. We analysed stable adult (aged ≥15 years) community residents. We defined viral suppression as a viral load of less than 500 copies per mL. To assess geographical sources of transmission risk, we established the proportion of all adults (both HIV positive and HIV negative) with a detectable viral load (local prevalence of viraemia). We defined transmission risk hotspots as geopolitical subunits within communities with an at least 5% local prevalence of viraemia. We also assessed serodiscordant couples, measuring the proportion of HIV-positive partners with detectable viraemia. The SEARCH study is registered with ClinicalTrials.gov, number NCT01864603.
Between April 2, 2013, and June 8, 2014, of 303 461 stable residents, we enumerated 274 040 (90·3%), of whom 132 030 (48·2%) were adults. Of these, 117 711 (89·2%) had their HIV status established, of whom 11 964 (10·2%) were HIV positive. Of these, we measured viral load in 8828 (73·8%) people. Viral suppression occurred in 3427 (81·6%) of 4202 HIV-positive adults on ART and 4490 (50·9%) of 8828 HIV-positive adults. Regional viral suppression among HIV-positive adults occurred in 881 (48·2%) of 1827 people in west Uganda, 516 (45·0%) of 1147 in east Uganda, and 3093 (52·8%) of 5854 in Kenya. Transmission risk hotspots occurred in three of 21 parishes in west Uganda and none in east Uganda and in 24 of 26 Kenya geopolitical subunits. In Uganda, 492 (2·9%) of 16 874 couples were serodiscordant: in 287 (58·3%) of these couples, the HIV-positive partner was viraemic (and in 69 14·0%, viral load was >100 000 copies per mL). In Kenya, 859 (10·0%) of 8616 couples were serodiscordant: in 445 (53·0%) of these couples, the HIV-positive partner was viraemic (and in 129 15%, viral load was >100 000 copies per mL).
Before the start of the SEARCH trial, 51% of east African HIV-positive adults had viral suppression, reflecting ART scale-up efforts to date. Geographical hotspots of potential HIV transmission risk and detectable viraemia among serodiscordant couples warrant intensified interventions.
National Institute of Allergy and Infectious Diseases (National Institutes of Health) and the President's Emergency Plan for AIDS Relief.
Summary Background Male circumcision is a primary HIV-1 prevention intervention for men, but whether the procedure reduces the risk of syphilis among men and their female partners is uncertain. We ...aimed to assess whether male circumcision was associated with incident syphilis in men and in their female partners. Methods In this large prospective cohort study, participants were members of Kenyan and Ugandan HIV-1 serodiscordant heterosexual couples enrolled in a randomised safety and efficacy clinical trial of pre-exposure prophylaxis for HIV-1 prevention (the Partners PrEP Study). Participants attended monthly or quarterly follow-up visits for up to 36 months. Annually, syphilis serology testing was done and male circumcision status was assessed. We used multivariate Andersen-Gill survival methods, adjusted for age, sexual behaviour, and plasma HIV RNA levels of the HIV-infected partner. Findings 4716 HIV-1 serodiscordant couples (38%) with a man with HIV were followed for a median of 2·75 years. At enrolment, 1575 (53%) men with HIV and 560 (32%) men without HIV were circumcised; an additional 69 (4%) men with HIV and 132 (5%) men without HIV were circumcised during study follow-up. 221 incident syphilis infections were reported: 46 (21%) in men with HIV (incidence 1·10 per 100 person-years), 76 (34%) in men without HIV (1·09), 54 (24%) in women with HIV (0·77), and 45 (24%) in women without HIV (1·11). Male circumcision was associated with a 42% reduction in incident syphilis in men (adjusted hazard ratio aHR 0·58, 95% CI 0·37–0·91) including a 62% reduction in men with HIV (0·38, 0·18–0·81), and a non-significant reduction in incident syphilis in men without HIV (0·64, 0·36–1·11). In women, circumcision of their male partners was associated with a 59% reduction in incident syphilis (aHR 0·41, 95% CI 0·25–0·69), including a 75% reduction in women without HIV (0·25, 0·08–0·76) and a 48% reduction in women with HIV (0·52, 0·27–0·97). Interpretation Male circumcision was associated with decreased risk of incident syphilis in men and women. If confirmed, these results suggest that medical male circumcision could substantially reduce incidence of syphilis and its sequelae. Funding Bill & Melinda Gates Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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