Population and Procedures
From November 2012 to August 2014, participants were enrolled in the Partners Demonstration Project—a prospective, open-label implementation study that evaluated the delivery of daily oral PrEP integrated in existing antiretroviral treatment (ART) services among high-risk, heterosexual HIV serodiscordant couples in Kenya and Uganda [23, 24]. Four clinical care research sites in Thika and Kisumu, Kenya and in Kampala and Kabwohe, Uganda implemented the study. Couples were eligible for study participation if they were ≥ 18 years of age, sexually active, and planned to remain a couple for ≥ 1 year. Couples were excluded if the partner living with HIV was already using ART based on national clinical guidelines at the time (incorporating CD4 count and clinical conditions).
At enrollment, all couples were counseled on the HIV prevention benefits of early ART and PrEP, and all HIV-uninfected participants were offered PrEP, prescribed as daily co-formulated emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). Couples were scheduled for return visits 1 month after enrollment, 2 months later, and quarterly thereafter. At each visit, HIV-negative partners were tested for HIV according to the national algorithm (a rapid HIV test, confirmed by a different rapid HIV test if positive, with a “tie-breaker” third test if the two rapid test results were inconsistent [25]), provided PrEP refills (as needed), and couples-based HIV prevention counseling including counseling about daily adherence for PrEP. PrEP discontinuation was recommended for the HIV-uninfected partner when the partner living with HIV had used ART for ≥ 6 months (expected to be commensurate with viral suppression) and there were no concerns by either member of the couples about ART adherence or additional sex partners, and the couple did not have immediate plans to become pregnant [23, 24].
Data Collection
Couples were followed for up to 2 years and completed standardized questionnaires at each clinic visit to collect demographic, medical (including ART use by the partner living with HIV), and sexual behavior data. All data were captured on case report forms in face-to-face interviews by experienced quantitative researchers, using the participants’ preferred language (English, Kiswahili [Kenya], Dholuo [Kisumu], Kikuyu [Thika], Luganda [Kampala], Runyankore [Kabowhe]). The paper forms were then faxed and translated by intelligent character recognition software into electronic data via DataFax (DF/Net Research, Inc, Seattle, USA).
Sexual Behavior Outcomes
We measured three sexual behavior outcomes in this study: (i) the number of sex acts with a study partner in the past month, (ii) any condomless sex with a study partner in the past month, and (iii) any sex with a non-study partner in the past month. Sex acts included either vaginal or anal sex. All sexual behavior outcomes were self-reported by the HIV-uninfected study partner. We categorized participants as engaging in any condomless sex if they reported fewer sex acts with a condom than the total number of sex acts with their study partner in the past month.
PrEP Initiation
We measured PrEP initiation, captured on pharmacy records, two different ways for this study: (i) as a binary variable (initiation/no initiation), and (ii) a categorical variable, representing different time periods since initiation. We included six categories in our time since PrEP initiation variable: time prior to PrEP initiation (reference), within 1 month of post PrEP initiation, 1 to 3 months post PrEP initiation, 3 to 6 months post PrEP initiation, 6 to 12 months post PrEP initiation, and more than 12 months post PrEP initiation. We included the categorical measure of time since PrEP initiation to determine whether changes in HIV serodiscordant couples’ sexual behaviors varied with increasing time since PrEP initiation. Adherence to PrEP was measured by electronic medication event monitoring (MEMS) bottle caps given to each participant. MEMS caps recorded a date-time stamp each time the bottle was opened and data were downloaded at each participant visit. We categorized participants as PrEP adherent if they took > 80% of their expected PrEP doses, according to MEMS data [21].
Time-Varying Covariates
At each clinic visit, we measured a number of other variables that are likely to change as time since study enrollment and PrEP initiation progresses, including participants’ pregnancy intentions (trying, not trying, pregnant), recent treatment for a genital infection, and use of hormonal contraception.
Statistical Methods
We used linear probability models with individual fixed effects to measure the association between PrEP initiation and sexual behaviors: (i) number of sex acts with a study partner, (ii) any condomless sex with a study partner, and (iii) any sex with a non-study partner in the past month, as reported by the HIV-negative partner. For the number of sex acts outcomes (count variable), model coefficients are interpreted as mean differences in sex acts following PrEP initiation, while for the any condomless sex and any sex with a non-study partner outcomes (binary variables), coefficients are interpreted as the percentage point changes in the outcomes following PrEP initiation. Based on a priori decisions, we included pregnancy intentions, recent treatment for genital infection, use of hormonal contracetion, and sex with a non-study partner (for outcomes with a study partner only) as time-varying confounders in our models because these may be strongly associated with PrEP use and HIV risk-related sexual behaviors. We also included calendar month of observation in the models to adjust for other community-level changes, such as social marketing campaigns, health system reforms, or general underlying societal trends that may affect all participants. For the models measuring the association between PrEP initiation and any condomless sex, we included the same factors plus the number of sex acts in the past month to control for changes in study couples’ frequency of sex over time.
For these models, we limited the sample population to participants who reported sex with their study partner in the past month—a strong indicator that the couple is still together and PrEP use is warranted, and participants that had more than two PrEP clinic visits—so that differences in sexual behavior following PrEP initiation could be compared. Additionally, in all models, we censored participants at the first visit they reported not using PrEP.
Sensitivity Analyses
We conducted three sensitivity analyses to test the findings from the main analyses. First, to minimize a potential increase in HIV risk-related sexual behaviors associated with perceived viral load suppression among the study partner living with HIV, we censored data for participants whose study partner had been on ART for over 6 months. Second, to isolate the association between PrEP initiation and sexual behaviors among participants who were adherent to PrEP and thus truly protected from HIV infection, we limited the sample to participants who were highly PrEP adherent (with ≥ 80% of expected doses taken based on MEMS data) following PrEP initiation. Third, to disentangle the association between participants’ recent knowledge of their study partners’ HIV-positive status from the association between PrEP initiation on HIV risk-related sexual behaviors, we limited the study sample to participants who learned their study partner was living with HIV more than 3 months prior to enrollment. We used the same individual fixed effects panel estimation described above for both sensitivity analyses.
Sub-group Analyses
We conducted two sub-group analyses, where we measured the association between PrEP initiation and heterosexual HIV serodiscordant couples’ HIV risk-related sexual behaviors by the sex of the HIV-uninfected partner reporting the outcomes (e.g., male or female). It is well established that compared to men in sub-Saharan African settings, women have less ability to negotiate sex, including both the frequency at which sex occurs and condom use during sex [26, 27].
We used Stata 15.1 (Stata Corporation, College Station, Texas) to conduct all analyses.