Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely ...due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation.
Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to <80%. Participants were followed monthly to provide study medication, adherence counseling, and HIV testing. A total of 1,147 HIV-uninfected participants were enrolled: 53% were male, median age was 34 years, and median partnership duration was 8.5 years. Fourteen HIV infections occurred among adherence study participants--all of whom were assigned to placebo (PrEP efficacy = 100%, 95% confidence interval 83.7%-100%, p<0.001). Median adherence was 99.1% (interquartile range IQR 96.9%-100%) by unannounced pill counts and 97.2% (90.6%-100%) by electronic monitoring over 807 person-years. Report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use were associated with <80% adherence; the first 6 months of PrEP use and polygamous marriage were associated with >80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort.
The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Please see later in the article for the Editors' Summary.
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.
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.
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.
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 log(10) 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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Voluntary medical male circumcision (MMC) reduces risk of HIV infection, but uptake remains suboptimal among certain age groups and locations in sub-Saharan Africa. We analysed qualitative data as ...part of the Linkages Study, a randomized controlled trial to evaluate community-based HIV testing and follow-up as interventions promoting linkage to HIV treatment and prevention in Uganda and South Africa. Fifty-two HIV-negative uncircumcised men participated in the qualitative study. They participated in semistructured individual interviews exploring (a) home HTC experience; (b) responses to test results; (c) efforts to access circumcision services; (d) outcomes of efforts; (e) experiences of follow-up support; and (f) local HIV education and support. Interviews were audio-recorded, translated, transcribed, and summarized into “linkage summaries.” Summaries were analysed inductively to identify the following three thematic experiences shaping men’s circumcision choices: (1) intense relief upon receipt of an unanticipated seronegative diagnosis, (2) the role of peer support in overcoming fear, and (3) anticipation of missed economic productivity. Increased attention to the timing of demand creation activities, to who delivers information about the HIV prevention benefits of MMC, and to the importance of missed income during recovery as a barrier to uptake promises to strengthen and sharpen future MMC demand creation strategies.
In this study of 4758 HIV-1–serodiscordant heterosexual couples in Kenya and Uganda, daily antiretroviral prophylaxis (with tenofovir or emtricitabine–tenofovir) in the HIV-1–negative partner ...significantly decreased the risk of HIV infection.
The use of antiretroviral medications for the prevention of HIV type 1 (HIV-1) transmission is a promising strategy for reducing the spread of HIV-1.
1
–
4
Antiretroviral treatment for persons infected with HIV-1 provides important clinical benefits and substantially reduces infectiousness.
5
–
7
Antiretroviral prophylaxis is a potential HIV-1–prevention strategy for those not yet infected with HIV-1, administered either as postexposure prophylaxis after high-risk occupational or nonoccupational exposure or as preexposure prophylaxis in those with ongoing HIV-1 exposure.
8
,
9
The rationale for antiretroviral prophylaxis in persons with ongoing exposure is based on its efficacy in infants exposed to HIV-1 during birth and . . .
BACKGROUND:Intimate partner violence (IPV) is associated with higher HIV incidence, reduced condom use, and poor adherence to antiretroviral therapy and other medications. IPV may also affect ...adherence to pre-exposure prophylaxis (PrEP).
METHODS:We analyzed data from 1785 HIV-uninfected women enrolled in a clinical trial of PrEP among African HIV serodiscordant couples. Experience of verbal, physical, or economic IPV was assessed at monthly visits by face-to-face interviews. Low PrEP adherence was defined as clinic-based pill count coverage <80% or plasma tenofovir levels <40 ng/mL. The association between IPV and low adherence was analyzed using generalized estimating equations, adjusting for potential confounders. In-depth interview transcripts were examined to explain how IPV could impact adherence.
RESULTS:Sixteen percent of women reported IPV during a median of 34.8 months of follow-up (interquartile range 27.0–35.0). Overall, 7% of visits had pill count coverage <80%, and 32% had plasma tenofovir <40 ng/mL. Women reporting IPV in the past 3 months had increased risk of low adherence by pill count (adjusted risk ratio 1.49, 95% confidence interval1.17 to 1.89) and by plasma tenofovir (adjusted risk ratio 1.51, 95% confidence interval1.06 to 2.15). Verbal, economic, and physical IPV were all associated with low adherence. However, the impact of IPV diminished and was not statistically significant 3 months after the reported exposure. In qualitative interviews, women identified several ways in which IPV affected adherence, including stress and forgetting, leaving home without pills, and partners throwing pills away.
CONCLUSIONS:Women who reported recent IPV in the Partners PrEP Study were at increased risk of low PrEP adherence. Strategies to mitigate PrEP nonadherence in the context of IPV should be evaluated.
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.
PDF
