HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial.

BACKGROUND: Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. METHODS: The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (ß2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. INTERPRETATION: Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. FUNDING: Gilead Sciences.

Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

BACKGROUND: There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. METHODS: We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. RESULTS: Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. CONCLUSIONS: No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Gender Affirming Hormones Do Not Affect the Exposure and Efficacy of F/TDF or F/TAF for HIV Preexposure Prophylaxis: A Subgroup Analysis from the DISCOVER Trial.

Purpose: Transgender women are disproportionately affected by HIV and are underutilizing preexposure prophylaxis (PrEP). The lower uptake of PrEP by transgender women may be, in part, owing to the perception that taking PrEP may lower the efficacy of gender-affirming hormone therapy (GAHT) or to provider concerns that GAHT may lower the efficacy of PrEP. Methods: DISCOVER was a randomized, double-blind, noninferiority trial comparing emtricitabine (FTC, F) and tenofovir alafenamide (F/TAF) versus emtricitabine and tenofovir disoproxil fumarate (F/TDF) as PrEP among transgender women and cisgender men who have sex with men (MSM). This nested substudy of the DISCOVER trial compared the exposure of the active intracellular metabolites of FTC and tenofovir (TFV), FTC triphosphate (FTC-TP) and TFV diphosphate (TFV-DP), in peripheral blood mononuclear cells (PBMC) among transgender women receiving GAHT versus MSM within the F/TAF and F/TDF groups. Results: Our results demonstrate that TFV-DP and FTC-TP levels in PBMC were comparable between transgender women on GAHT and MSM receiving F/TAF, and between transgender women on GAHT and MSM receiving F/TDF. TFV-DP concentrations remained above the EC90 of 40 fmol/106 cells across all groups. No clinically significant drug-drug interactions of GAHT were observed with either F/TAF or F/TDF in this subanalysis. Conclusions: These findings are consistent with the clinical pharmacology of GAHT, FTC, TDF, and TAF reported in previous studies, and support the continued use of F/TAF and F/TDF for PrEP in transgender women.Clinicaltrials.gov registration number: NCT02842086.

Proximate and distal factors associated with the stall in the decline of adolescent pregnancy in Uganda.

BACKGROUND: Adolescent pregnancy in Uganda declined from 31% in 2000-01 to 25% in 2006 but thereafter stalled at 25% from 2006 to 2016. This paper investigates the factors associated with the recent stall in the rate of decline of adolescent pregnancy in Uganda. METHODS: We used logistic regression models for 4 years (2000-01, 2006, 2011 and 2016) of data from the Uganda Demographic Health Survey to explore proximate and distal factors of adolescent pregnancy in Uganda. We carried out Blinder-Oaxaca decomposition models to explore the contributions of different factors in explaining the observed decline in adolescent pregnancy between 2001 and 2006, and the subsequent stall between 2006 and 2016. RESULTS: We found that marriage among women aged 15-19 years, and early sexual debut, were strongly associated with adolescent pregnancy. These declined substantially between 2000 and 01 and 2006, leading to a decline in adolescent pregnancy. Their decline was in turn associated with rising levels of female education and household wealth. After 2006, education levels and household wealth gains stalled, with associated stalls in the decline of marriage among women aged 15-19 years and sexual debut, and a stall in the decline of adolescent pregnancy. CONCLUSIONS: The stall in the decline of adolescent pregnancies in Uganda was linked to a stall in the reduction of adolescent marriage, which in turn was associated with limited progress in female educational attainment between 2006 and 2016. We emphasize the need for a renewed focus on girl's education and poverty reduction to reduce adolescent pregnancy in Uganda and subsequently improve health outcomes for adolescent girls.

Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov, number NCT02842086. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07-0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17-0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23-1·26]). Approximately 78-82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p<0·0001). INTERPRETATION: Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. FUNDING: Gilead Sciences.

Burden of non-communicable diseases from infectious causes in 2017: a modelling study.

BACKGROUND: Non-communicable diseases (NCDs) cause a large burden of disease globally. Some infectious diseases cause an increased risk of developing specific NCDs. Although the NCD burden from some infectious causes has been quantified, in this study, we aimed to more comprehensively quantify the global burden of NCDs from infectious causes. METHODS: In this modelling study, we identified NCDs with established infectious risk factors and infectious diseases with long-term non-communicable sequelae, and did narrative reviews between April 11, 2018, and June 10, 2020, to obtain relative risks (RRs) or population attributable fractions (PAFs) from studies quantifying the contribution of infectious causes to NCDs. To determine infection-attributable burden for the year 2017, we applied estimates of PAFs to estimates of disease burden from the Global Burden of Disease Study (GBD) 2017 for pairs of infectious causes and NCDs, or used estimates of attributable burden directly from GBD 2017. Morbidity and mortality burden from these conditions was summarised with age-standardised rates of disability-adjusted life-years (DALYs), for geographical regions as defined by the GBD. Estimates of NCD burden attributable to infectious causes were compared with attributable burden for the groups of risk factors with the highest PAFs from GBD 2017. FINDINGS: Globally, we quantified 130 million DALYs from NCDs attributable to infection, comprising 8·4% of all NCD DALYs. The infection-NCD pairs with the largest burden were gastric cancer due to H pylori (14·6 million DALYs), cirrhosis and other chronic liver diseases due to hepatitis B virus (12·2 million) and hepatitis C virus (10·4 million), liver cancer due to hepatitis B virus (9·4 million), rheumatic heart disease due to streptococcal infection (9·4 million), and cervical cancer due to HPV (8·0 million). Age-standardised rates of infection-attributable NCD burden were highest in Oceania (3564 DALYs per 100 000 of the population) and central sub-Saharan Africa (2988 DALYs per 100 000) followed by the other sub-Saharan African regions, and lowest in Australia and New Zealand (803 DALYs per 100 000) followed by other high-income regions. In sub-Saharan Africa, the proportion of crude NCD burden attributable to infectious causes was 11·7%, which was higher than the proportion of burden attributable to each of several common risk factors of NCDs (tobacco, alcohol use, high systolic blood pressure, dietary risks, high fasting plasma glucose, air pollution, and high LDL cholesterol). In other broad regions, infectious causes ranked between fifth and eighth in terms of crude attributable proportions among the nine risks compared. The age-standardised attributable proportion for infectious risks remained highest in sub-Saharan Africa of the broad regions, but age-standardisation caused infectious risks to fall below dietary risks, high systolic blood pressure, and fasting plasma glucose in ranked attributable proportions within the region. INTERPRETATION: Infectious conditions cause substantial NCD burden with clear regional variation, and estimates of this burden are likely to increase as evidence that can be used for quantification expands. To comprehensively avert NCD burden, particularly in low-income and middle-income countries, the availability, coverage, and quality of cost-effective interventions for key infectious conditions need to be strengthened. Efforts to promote universal health coverage must address infectious risks leading to NCDs, particularly in populations with high rates of these infectious conditions, to reduce existing regional disparities in rates of NCD burden. FUNDING: Leona M and Harry B Helmsley Charitable Trust.

Noncommunicable Disease (NCD) strategic plans in low- and lower-middle income Sub-Saharan Africa: framing and policy response.

BACKGROUND: Global efforts to address NCDs focus primarily on 4-by-4 interventions - interventions to prevent and treat four groups of conditions affecting mainly older adults (some cardiovascular disease and cancers, type 2 diabetes, chronic respiratory disease) and four associated risk factors (alcohol, tobacco, poor diets, and physical inactivity). However, the NCD burden in Sub-Saharan Africa (SSA) is composed of a more diverse set of conditions, driven by a more complex group of risks, and impacting all segments of the population. OBJECTIVE: To document the NCD priorities identified by NCD strategic plans, to characterize the proposed policy response, and to assess the alignment between the two. METHODS: Using a two-part conceptual framework, we undertook a descriptive study to characterize the framing and overall policy response of strategic plans from 24 low- and lower-middle-income countries across SSA. RESULTS: The national situation assessments that ground strategic plans emphasize a diversity of conditions that range in terms of severity and frequency. These assessments also highlight a wide diversity of factors that shape this burden. Most include discussions of a broad range of behavioral, structural, genetic, and infectious risk factors. Plans endorse a more narrow response to this diverse burden, with a focus on primary and secondary prevention that is generally convergent with the objectives established in global policy documents. CONCLUSIONS: Broadly, we observe that plans developed by countries in SSA recognize the heterogeneity of the NCD burden in this region. However, they emphasize interventions that are consistent with global strategies focused on preventing a narrower set of cardiometabolic risk factors and their associated diseases. In comparison, relatively few countries detail plans to prevent, treat, and palliate the full scope of the needs they identify. There is a need for increased support for bottom-up planning efforts to address local priorities.

Cost-effectiveness analysis of integrating screening and treatment of selected non-communicable diseases into HIV/AIDS treatment in Uganda.

INTRODUCTION: Despite growing enthusiasm for integrating treatment of non-communicable diseases (NCDs) into human immunodeficiency virus (HIV) care and treatment services in sub-Saharan Africa, there is little evidence on the potential health and financial consequences of such integration. We aim to study the cost-effectiveness of basic NCD-HIV integration in a Ugandan setting. METHODS: We developed an epidemiologic-cost model to analyze, from the provider perspective, the cost-effectiveness of integrating hypertension, diabetes mellitus (DM) and high cholesterol screening and treatment for people living with HIV (PLWH) receiving antiretroviral therapy (ART) in Uganda. We utilized cardiovascular disease (CVD) risk estimations drawing from the previously established Globorisk model and systematic reviews; HIV and NCD risk factor prevalence from the World Health Organization's STEPwise approach to Surveillance survey and global databases; and cost data from national drug price lists, expert consultation and the literature. Averted CVD cases and corresponding disability-adjusted life years were estimated over 10 subsequent years along with incremental cost-effectiveness of the integration. RESULTS: Integrating services for hypertension, DM, and high cholesterol among ART patients in Uganda was associated with a mean decrease of the 10-year risk of a CVD event: from 8.2 to 6.6% in older PLWH women (absolute risk reduction of 1.6%), and from 10.7 to 9.5% in older PLWH men (absolute risk reduction of 1.2%), respectively. Integration would yield estimated net costs between $1,400 and $3,250 per disability-adjusted life year averted among older ART patients. CONCLUSIONS: Providing services for hypertension, DM and high cholesterol for Ugandan ART patients would reduce the overall CVD risk among these patients; it would amount to about 2.4% of national HIV/AIDS expenditure, and would present a cost-effectiveness comparable to other standalone interventions to address NCDs in low- and middle-income country settings.

Integrating care for non-communicable diseases into routine HIV services: key considerations for policy design in sub-Saharan Africa.

INTRODUCTION: There is great interest for integrating care for non-communicable diseases (NCDs) into routine HIV services in sub-Saharan Africa (SSA) due to the steady rise of the number of people who are ageing with HIV. Suggested health system approaches for intervening on these comorbidities have mostly been normative, with little actionable guidance on implementation, and on the practical, economic and ethical considerations of favouring people living with HIV (PLHIV) versus targeting the general population. We summarize opportunities and challenges related to leveraging HIV treatment platforms to address NCDs among PLHIV. We emphasize key considerations that can guide integrated care in SSA and point to possible interventions for implementation. DISCUSSION: Integrating care offers an opportunity for effective delivery of NCD services to PLHIV, but may be viewed to unfairly ignore the larger number of NCD cases in the general population. Integration can also help maintain the substantial health and economic benefits that have been achieved by the global HIV/AIDS response. Implementing interventions for integrated care will require assessing the prevalence of common NCDs among PLHIV, which can be achieved via increased screening during routine HIV care. Successful integration will also necessitate earmarking funds for NCD interventions in national budgets. CONCLUSIONS: An expanded agenda for addressing HIV-NCD comorbidities in SSA may require adding selected NCDs to conditions that are routinely monitored in PLHIV. Attention should be given to mitigating potential tradeoffs in the quality of HIV services that may result from the extra responsibilities borne by HIV health workers. Integrated care will more likely be effective in the context of concurrent health system reforms that address NCDs in the general population, and with synergies with other HIV investments that have been used to strengthen health systems.

A comparison of all-cause and cause-specific mortality by household socioeconomic status across seven INDEPTH network health and demographic surveillance systems in sub-Saharan Africa.

BACKGROUND: Understanding socioeconomic disparities in all-cause and cause-specific mortality can help inform prevention and treatment strategies. OBJECTIVES: To quantify cause-specific mortality rates by socioeconomic status across seven health and demographic surveillance systems (HDSS) in five countries (Ethiopia, Kenya, Malawi, Mozambique, and Nigeria) in the INDEPTH Network in sub-Saharan Africa. METHODS: We linked demographic residence data with household survey data containing living standards and education information we used to create a poverty index. Person-years lived and deaths between 2003 and 2016 (periods varied by HDSS) were stratified in each HDSS by age, sex, year, and number of deprivations on the poverty index (0-8). Causes of death were assigned to each death using the InterVA-4 model based on responses to verbal autopsy questionnaires. We estimated rate ratios between socioeconomic groups (2-4 and 5-8 deprivations on our poverty index compared to 0-2 deprivations) for specific causes of death and calculated life expectancy for the deprivation groups. RESULTS: Our pooled data contained almost 3.5 million person-years of observation and 25,038 deaths. All-cause mortality rates were higher among people in households with 5-8 deprivations on our poverty index compared to 0-2 deprivations, controlling for age, sex, and year (rate ratios ranged 1.42 to 2.06 across HDSS sites). The poorest group had consistently higher death rates in communicable, maternal, neonatal, and nutritional conditions (rate ratios ranged 1.34-4.05) and for non-communicable diseases in several sites (1.14-1.93). The disparities in mortality between 5-8 deprivation groups and 0-2 deprivation groups led to lower life expectancy in the higher-deprivation groups by six years in all sites and more than 10 years in five sites. CONCLUSIONS: We show large disparities in mortality on the basis of socioeconomic status across seven HDSS in sub-Saharan Africa due to disparities in communicable disease mortality and from non-communicable diseases in some sites. Life expectancy gaps between socioeconomic groups within sites were similar to the gaps between high-income and lower-middle-income countries. Prevention and treatment efforts can benefit from understanding subpopulations facing higher mortality from specific conditions.

Incidence and Risk Factors for Overweight and Obesity after Initiation of Antiretroviral Therapy in Dar es Salaam, Tanzania.

OBJECTIVE: To describe the incidence of and risk factors for overweight and obesity following antiretroviral therapy (ART) initiation. METHODS: We used Cox proportional hazards models to investigate risk factors for incident overweight and obesity in 79 074 individuals aged 15 years or older who initiated ART in Dar es Salaam, Tanzania. RESULTS: Twenty-five percent of the patients became overweight and 10% became obese. The incidence rate of obesity was 3.2 per 100 person-years (95% confidence interval [CI]: 3.1-3.3) in patients who were of normal weight before starting ART and 22.6 per 100 person-years (95% CI: 21.9-23.3) in those who were overweight. Lower CD4 count was associated with a higher risk of overweight and obesity ( P value for trend < .0001). CONCLUSION: There is a high burden of overweight and obesity after starting ART, leading to proportions of these 2 conditions that are similar to those in the general population.

Sexual Relationships Outside Primary Partnerships and Abstinence Are Associated With Lower Adherence and Adherence Gaps: Data From the Partners PrEP Ancillary Adherence Study.

OBJECTIVE: To assess the role of sexual relationships on levels and patterns of adherence to medication for pre-exposure prophylaxis against HIV. METHODS: We enrolled 1147 HIV-negative individuals in long-term serodiscordant relationships at 3 sites in Uganda from the Partners Pre-exposure Prophylaxis Study, a randomized placebo-controlled trial of daily oral tenofovir and emtricitabine/tenofovir. We used generalized estimation equations to assess the effects of sexual relationships on low adherence (<80%) and on gaps in adherence. RESULTS: Fifty-three percent were male, 51% were 18-34 years and 24% were polygamous. Participants who reported sex in the past month with someone other than their primary partner and with <100% condom use were more than twice as likely to have low adherence [adjusted odds ratio (aOR) = 2.48, 95% CI: 1.70 to 3.62] compared with those who had sex with only their primary partners and 100% condom use. Using the same reference group, those who abstained from sex in the previous month had 30% increased odds of low adherence (aOR = 1.30, 95% CI: 1.05 to 1.62) and participants in nonpolygamous marriages who reported sex with both their primary and other partners and <100% condom use were almost twice as likely to be low adherers (aOR = 1.76, 95% CI: 1.01 to 3.08). At least one 72-hour gap in adherence was seen in 598 participants (54.7%); 23.2% had at least one 1-week gap. CONCLUSIONS: Risk of low overall adherence was higher in participants who reported sex outside primary partnerships and suboptimal condom use, as well as in those who abstained from sex. Adherence gaps were common, potentially creating risk for HIV acquisition.

What's love got to do with it? Explaining adherence to oral antiretroviral pre-exposure prophylaxis for HIV-serodiscordant couples.

OBJECTIVE: Adherence may be the "Achilles heel" of pre-exposure prophylaxis (PrEP), a promising biomedical approach to HIV prevention. This article presents an explanation of PrEP adherence for African serodiscordant couples derived from qualitative data. DESIGN: Explaining quantitative findings is one way qualitative investigation contributes to research in medicine and public health. This qualitative interview study was nested in the Partners PrEP Study, a phase III randomized trial evaluating oral tenofovir and emtricitabine/tenofovir PrEP to prevent HIV acquisition by HIV-uninfected partners in serodiscordant heterosexual couples. METHODS: In-depth qualitative interviews were provided by 60 Partners PrEP Study participants in Uganda. Interviews used open-ended questions eliciting information on adherence experiences, barriers, and facilitators. An inductive approach informed by grounded theory methodology was used to analyze study data. RESULTS: The proposed explanation may be summarized as follows. Serodiscordance destabilizes couples, as the HIV-negative partner reacts with anger, fear, and sadness to the implication of infidelity represented by HIV infection. A "discordance dilemma" ensues, as the desire to avoid acquiring HIV and the advantages of preserving the relationship become competing priorities. PrEP is seen as a solution-a means of safeguarding health without ending the relationship. PrEP users benefit from the support of partners, who reinforce adherence. Where discord in the relationship persists, adherence suffers. CONCLUSIONS: PrEP adherence in serodiscordant couples may be understood as a function of the desire to reduce risk although preserving a partnered relationship. PrEP use in stable couples may be associated with improved adherence and thus, greater effectiveness.