Antiretroviral-based HIV-1 prevention strategies – including

1) antiretroviral treatment (ART) to reduce the infectiousness of HIV-1 infected persons and

2) pre-exposure prophylaxis (PrEP) for uninfected persons to prevent HIV-1 acquisition – are among the most promising new approaches for dramatically decreasing HIV-1 spread. A priority population for implementation of ART and PrEP for HIV-1 prevention is HIV-1 serodiscordant couples (i.e., one member is HIV-1 infected and the other uninfected). Stable, heterosexual African HIV-1 serodiscordant couples face high risk of HIV-1 transmission, from within the partnership and from outside partners, and are a priority population for prevention interventions. Importantly, during the past year, both ART (HPTN 052) and PrEP (Partners PrEP Study) have demonstrated high efficacy for HIV-1 protection when used by members of HIV-1 serodiscordant couples. Critical unanswered questions for successful implementation of antiretroviral-based HIV-1 prevention include how to target these strategies to the highest-risk couples and whether HIV-1 infected persons with asymptomatic disease would accept ART to reduce their risk for transmitting HIV-1, at-risk HIV-1 negative persons would use PrEP, and both would sustain high adherence needed for high effectiveness. This protocol describes an open-label prospective study among high-risk African HIV-1 serodiscordant couples to determine user preferences for ART and PrEP and to optimize targeted delivery and sustained use of these interventions.

 

Design: Prospective, observational, open-label cohort study

Up to 24 months of follow-up per couple

Population: Heterosexual HIV-1 serodiscordant couples in Kenya and Uganda who did not participate in the Partners PrEP Study (approximately 1000 couples in total)

Study Sites: Thika, Kenya and Kampala, Uganda Partners PrEP Study sites

Additional sites will be added if funding permits.

Approach: We will enroll couples with characteristics defining higher HIV-1 transmission risk (i.e., to target those for ART/PrEP that are at greatest risk for HIV-1, a public health priority). We will provide or refer HIV-1 infected participants to ART services following national ART initiation guidelines, recognizing that guidelines for ART initiation (including potentially recommending ART for all HIV-1 infected members in serodiscordant relationships) may change during the course of the study. PrEP will be offered to the HIV-1 uninfected partners as a “bridge” to ART initiation and viral suppression in the partnership; uptake and adherence to PrEP will be measured. Specifically, PrEP as a bridge to ART will be done as follows: when the HIV-1 infected partner is not yet taking ART, PrEP will be offered, and if the HIV-1 infected partner initiates ART, PrEP will be discontinued for the HIV-1 uninfected partner six months later (i.e., once viral suppression in the HIV-1 infected partner would be expected to be typically achieved). We will conduct mixed-methods work to understand user preferences, couples decision-making, risk perception, fertility intentions, and barriers to uptake of and adherence to both PrEP and ART. 

 

Specific Aims:

 

Aim 1: We will evaluate the ability to do targeted enrollment of higher-risk HIV-1 serodiscordant couples into a longitudinal HIV-1 prevention study

 

A critical aspect of implementation and cost-effectiveness of antiretroviral-based HIV-1 prevention in HIV-1 serodiscordant couples will be the ability to utilize behavioral, epidemiologic and clinical data to identify those couples who are at highest risk of HIV-1 acquisition. We have developed a risk score using enrollment data from our previous studies of >8500 HIV-1 serodiscordant couples that is able to discriminate couples at highest risk. The score is comprised of a limited set of variables that can be obtained in research and clinical settings: plasma HIV-1 levels in the HIV-1 infected partner, any unprotected sex in the couple in the prior month, number of children in the partnership, age of the HIV-1 uninfected partner, and circumcision status of HIV-1 uninfected male partners.

The primary outcomes of this aim will be the screened to eligible ratio of HIV-1 serodiscordant couples recruited for this open-label study, the proportion of eligible couples who decide to enroll in the cohort, and the costs of screening and targeting high-risk couples.

 

Aim 2: We will assess user preferences among high-risk HIV-1 serodiscordant couples for ART initiation for HIV-1 infected partners and PrEP for HIV-1 uninfected partners.

 

Understanding couples’ preferences for and concerns about antiretroviral-based HIV-1 prevention is of utmost importance at this time when guidelines for use of PrEP and ART are being formulated.

The primary outcomes for this aim will be measured at baseline and quarterly through an interviewer-administered questionnaire. The questionnaire will specifically ask about willingness to use PrEP or ART for HIV-1 prevention and which method the participant would prefer. Reasons for the choice and concerns about both methods will also be collected through mixed-methods approaches.

 

Aim 3: We will ascertain initiation of and adherence to PrEP among HIV-1 uninfected partners, when implemented as a bridge to ART.

 

Adherence to PrEP is critical to its effectiveness. Understanding adherence to PrEP is a priority, particularly when PrEP is delivered outside of a controlled clinical trial setting. For this study, brief adherence counseling, to reflect real-world settings, will be delivered at baseline and then quarterly thereafter. The content of the adherence counseling will be derived from the counseling messages and procedures in the Partners PrEP Study, and informed by the findings from an ancillary adherence study conducted as part of the Partners PrEP Study. We will explore factors that are related to the decision to start and continue to use PrEP.

The primary measures of adherence will be collection of PrEP, clinic-based pill counts of unused study pills as recorded at each follow-up visit, and MEMS cap data on how frequently the pill bottle was opened. Blood samples for detection and quantification of PrEP levels (testing in batch) will be done for those who seroconvert to HIV-1 and a subset who remain HIV-1 uninfected.

Aim 4: We will ascertain initiation of and adherence to ART among HIV-1 infected partners.

 

In addition to providing clinical benefit to HIV-1 infected partners, ART also confers HIV-1 prevention benefits to HIV-1 uninfected partners. However, a substantial proportion of HIV-1 infected persons who are eligible for ART decline or delay initiation, for a number of reasons. In this study, HIV-1 infected partners who become eligible for ART will be actively encouraged to initiate, including counseling to improve their knowledge and understanding of ART and the benefits for themselves and their partner and the importance of strict adherence to ART regimens to achieve viral suppression. We will explore factors that are related to the decision to start and continue to use ART.

The primary measures of ART adherence will be ART initiation at a local ART provider and plasma HIV-1 RNA levels taken every 6 months for HIV-1 infected partners.

 

Aim 5: We will assess factors influencing preferences, uptake and adherence for antiretroviral-based HIV-1 prevention.

 

Understanding factors that influence couples’ preferences and their likelihood to initiate and adherence to PrEP and/or ART in a real-world setting is critical for providers who will counsel HIV-1 serodiscordant couples and make

Partners PrEP Study Demonstration Project 6 Version 2.0, 10 July 2012

recommendations about the HIV-1 prevention practices that are best indicated for couples.

Through interviewer-administered questionnaires, correlates of preferences, uptake and adherence to ART and PrEP will be assessed, including characteristics of sexual risk (i.e., sexual frequency, condom use, whether the HIV-1 uninfected partner reports outside partners), depression and substance use, gender of the HIV-1 uninfected partner, fertility intentions, partnership characteristics (whether the couple is cohabiting, has children, is together throughout follow-up, whether members have other partners, and whether the HIV-1 infected partner initiates ART), and clinical characteristics of the HIV-1 infected partner (e.g., CD4 count, WHO stage).

Aim 6: We will assess the feasibility of PrEP discontinuation in couples in which the HIV-1 infected partner initiates ART

 

ART is life-long, but PrEP need not be. In fact, time-limited use of PrEP for highest-risk persons and periods of time is likely the most cost-effective approach – since ART has substantial prevention benefits, any additional benefit of PrEP would be small for limiting risk within the partnership. Moreover, time-limited use of PrEP – e.g., until the HIV-1 infected partner initiates ART and is on ART for 6 months (the time by which viral suppression is typically achieved) – would limit risk of long-term side effects or toxicity of a daily PrEP medication and potentially improve adherence, since use would be for a defined period of time. Thus, time-limited use of PrEP has the greatest chance of being implemented widely. In couples in which the HIV-1 infected partner initiates ART, we will discontinue PrEP six months later. It is possible that HIV-1 uninfected partners may be reluctant to discontinue PrEP, for example if they do not trust their partner’s motivation to consistently use ART or if the uninfected partner has additional sexual partners. We will explore the ability to discontinue PrEP.

Through interviewer-administered questionnaires, we will assess couples’ attitudes and understanding of PrEP discontinuation.