Elioda Tumwesigye

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

BACKGROUND Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

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.

Characteristics of HIV-1 Serodiscordant Couples Enrolled in a Clinical Trial of Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention

Introduction Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort. Methods HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24–36 months. Results From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758) of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2–8); 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log10 copies/mL (IQR 3.31–4.53) and median CD4 count was 496 cells/µL (IQR 375–662); the majority (64%) had WHO stage 1 HIV-1 disease. Conclusions Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov NCT00557245)

Initiation of antiretroviral therapy and viral suppression after home HIV testing and counselling in KwaZulu-Natal, South Africa, and Mbarara district, Uganda: a prospective, observational intervention study

OBJECTIVE Antiretroviral therapy (ART) significantly decreases HIV-associated morbidity, mortality, and HIV transmission through HIV viral load suppression. In high HIV prevalence settings, outreach strategies are needed to find asymptomatic HIV positive persons, link them to HIV care and ART, and achieve viral suppression. METHODS We conducted a prospective intervention study in two rural communities in KwaZulu-Natal, South Africa, and Mbabara district, Uganda. The intervention included home HIV testing and counseling (HTC), point-of-care CD4 count testing for HIV positive persons, referral to care, and one month then quarterly lay counselor follow-up visits. The outcomes at 12 months were linkage to care, and ART initiation and viral suppression among HIV positive persons eligible for ART (CD4≤350 cells/μL). FINDINGS 3,393 adults were tested for HIV (96% coverage), of whom 635 (19%) were HIV positive. At baseline, 36% of HIV positive persons were newly identified (64% were previously known to be HIV positive) and 40% were taking ART. By month 12, 619 (97%) of HIV positive persons visited an HIV clinic, and of 123 ART eligible participants, 94 (76%) initiated ART by 12 months. Of the 77 participants on ART by month 9, 59 (77%) achieved viral suppression by month 12. Among all HIV positive persons, the proportion with viral suppression (<1,000 copies/mL) increased from 50% to 65% (p=<0.001) at 12 months. INTERPRETATION Community-based HTC in rural South Africa and Uganda achieved high testing coverage and linkage to care. Among those eligible for ART, a high proportion initiated ART and achieved viral suppression, indicating high adherence. Implementation of this HTC approach by existing community health workers in Africa should be evaluated to determine effectiveness and costs.

Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial

Background Antiretroviral pre-exposure prophylaxis (PrEP), using daily oral tenofovir disoproxil fumarate (TDF) or TDF in combination with emtricitabine (FTC/TDF), has been demonstrated to be efficacious for HIV-1 prevention. While the use of multiple antiretroviral agents is essential for effective HIV-1 treatment, multiple agents may not be required for effective prophylaxis. The relative efficacy of single-agent TDF versus combination FTC/TDF PrEP has not been directly assessed.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 trials 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.

Household-Based HIV Counseling and Testing as a Platform for Referral to HIV Care and Medical Male Circumcision in Uganda: A Pilot Evaluation

Background Combination HIV prevention initiatives incorporate evidence-based, biomedical and behavioral interventions appropriate and acceptable to specific populations, aiming to significantly reduce population-level HIV incidence. Knowledge of HIV serostatus is key to linkages to HIV care and prevention. Household-based HIV counseling and testing (HBCT) can achieve high HIV testing rates. We evaluated HBCT as a platform for delivery of combination HIV prevention services in sub-Saharan Africa. Methods We conducted HBCT in a semi-urban area in southwestern Uganda. All adults received standard HIV prevention messaging. Real-time electronic data collection included a brief risk assessment and prevention triage algorithm for referrals of HIV seropositive persons to HIV care and uncircumcised HIV seronegative men with multiple sex partners to male circumcision. Monthly follow-up visits for 3 months were conducted to promote uptake of HIV care and male circumcision. Results 855 households received HBCT; 1587 of 1941 (81.8%) adults were present at the HBCT visit, 1557 (98.1% of those present) were tested and received HIV results, of whom, 46.5% were men. A total of 152 (9.8%) were HIV seropositive, for whom the median CD4 count was 456 cells/µL, and 50.7% were newly-identified as HIV seropositive. Three months after HBCT, 88.5% of HIV seropositive persons had attended an HIV care clinic; among those with CD4 counts <250 cells/µL, 71.4% initiated antiretroviral therapy. Among 123 HIV seronegative men with an HIV+ partner or multiple partners, 62.0% were circumcised by month 3. Conclusions HBCT achieves high levels of knowledge of HIV serostatus and is an effective platform for identifying at-risk persons and achieving higher uptake of HIV prevention and care services through referrals and targeted follow-up than has been accomplished through other single focus strategies.

Effect of home-based HIV counselling and testing on stigma and risky sexual behaviours: serial cross-sectional studies in Uganda

A large, district‐wide, home‐based HIV counselling and testing (HBHCT) programme was implemented in Bushenyi district of Uganda from 2004 to 2007. This programme provided free HBHCT services to all consenting adults of Bushenyi district and had a very high uptake and acceptability. We measured population‐level changes in knowledge of HIV status, stigma and HIV‐risk behaviours before and after HBHCT to assess whether widespread HBHCT had an effect on trends of risky sexual behaviours and on stigma and discrimination towards HIV.

Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda

BACKGROUND Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision. METHODS We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged ≥16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02038582. FINDINGS Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow-up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0·668 for clinic facilitation and p=0·273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1·72, 95% CI 1·36-2·17; p<0·0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1·67, 1·29-2·14; p=0·0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma. INTERPRETATION All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression. FUNDING National Institute of Allergy and Infectious Diseases, National Institutes of Health.

An intervention to support HIV preexposure prophylaxis adherence in HIV-serodiscordant couples in Uganda

Background:Daily preexposure prophylaxis (PrEP) is an effective HIV prevention strategy, but adherence is required for maximum benefit. To date, there are no empirically supported PrEP adherence interventions. This article describes the process of developing a PrEP adherence intervention and presents results on its impact on adherence. Methods:The Partners PrEP Study was a placebo-controlled efficacy trial of daily oral tenofovir and emtricitabine/tenofovir PrEP among uninfected members of HIV-serodiscordant couples. An ancillary adherence study was conducted at 3 study sites in Uganda. Participants with <80% adherence as measured by unannounced pill count received an additional adherence counseling intervention based on Lifesteps, an evidence-based HIV treatment adherence intervention, based on principles of cognitive–behavioral theory. Findings:Of the 1147 HIV-seronegative participants enrolled in the ancillary adherence study, 168 (14.6%) triggered the adherence intervention. Of participants triggering the intervention, 62% were men; median age was 32.5 years. The median number of adherence counseling sessions was 10. Mean adherence during the month before the intervention was 75.7% and increased significantly to 84.1% in the month after the first intervention session (P < 0.001). The most frequently endorsed adherence barriers at session 1 were travel and forgetting. Interpretation:A PrEP adherence intervention was feasible in a clinical trial of PrEP in Uganda and PrEP adherence increased after the intervention. Future research should identify PrEP users with low adherence for enhanced adherence counseling and determine optimal implementation strategies for interventions to maximize PrEP effectiveness.

Delay of Antiretroviral Therapy Initiation is Common in East African HIV-Infected Individuals in Serodiscordant Partnerships

Objective:WHO guidance recommends antiretroviral therapy (ART) initiation for all persons with a known HIV-uninfected partner, as a strategy to prevent HIV transmission. Uptake of ART among HIV-infected partners in serodiscordant partnerships is not known, which we evaluated in African HIV serodiscordant couples. Design:Prospective cohort study. Methods:Among HIV-infected persons from Kenya and Uganda who had a known heterosexual HIV-uninfected partner, we assessed ART initiation in those who became ART eligible under national guidelines during follow-up. Participants received quarterly clinical and semi-annual CD4 monitoring, and active referral for ART upon becoming eligible. Results:Of 1958 HIV-infected ART-eligible partners, 58% were women, and the median age was 34 years. At the first visit when determined to be ART eligible, the median CD4 count was 273 cells per microliter (interquartile range, 221–330), 77% had WHO stage 1 or 2 HIV disease, and 96% were receiving trimethoprim-sulfamethoxazole prophylaxis. The cumulative probabilities of initiating ART at 6, 12, and 24 months after eligibility were 49.9%, 70.0%, and 87.6%, respectively. Younger age [<25 years; adjusted hazard ratio (AHR), 1.39; P = 0.001], higher CD4 count (AHR, 1.95; P < 0.001 for >350 compared with <200 cells/µL), higher education (AHR, 1.25; P < 0.001), and lack of income (AHR, 1.15; P = 0.02) were independent predictors for delay in ART initiation. Conclusions:In the context of close CD4 monitoring, ART counseling, and active linkage to HIV care, a substantial proportion of HIV-infected persons with a known HIV-uninfected partner delayed ART initiation. Strategies to motivate ART initiation are needed, particularly for younger persons with higher CD4 counts.