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The PROMISE trial enrolled asymptomatic HIV-infected pregnant and postpartum women not eligible for antiretroviral treatment (ART) per local guidelines and randomly assigned proven antiretroviral strategies to assess relative efficacy for perinatal prevention plus maternal/infant safety and maternal health. The START study subsequently demonstrated clear benefit in initiating ART regardless of CD4 count. Active PROMISE participants were informed of results and women not receiving ART were strongly recommended to immediately initiate treatment to optimize their own health. We recorded their decision and the primary reason given for accepting or rejecting the universal ART offer after receiving the START information. One-third of participants did not initiate ART after the initial session, wanting more time to consider. Six sessions were required to attain 95% uptake. The slow uptake of universal ART highlights the need to prepare individuals and sensitize communities regarding the personal and population benefits of the “Treat All” strategy.
PROMISE was conducted at 70 research sites in 15 countries within sub-Saharan Africa, Asia and the Americas. A total of 5400 asymptomatic HIV-infected pregnant women with high CD4 counts (above 350 cells/mm3 or the treatment threshold at that time) were assigned to different ARV strategies and followed for HIV disease progression, vertical transmission and safety. In settings where maternal ART and replacement feeding was standard, eligible women were randomized within 6 weeks of delivery to continue or stop ART and remain in follow-up for intense monitoring of HIV disease progression and adverse events in a protocol named 1077HS (for HAART standard) [8]. In settings where maternal ART was not standard for the prevention of vertical transmission, separate protocols were conducted—1077FF and 1077BF—in formula feeding and breastfeeding settings, respectively. Within 1077FF/BF, pregnant women were randomized to triple ART or prophylaxis with zidovudine throughout pregnancy and delivery in the Antepartum Component plus single dose nevirapine at delivery followed by a 2 week “tail” of tenofovir/emtricitabine [9]. Women who did not access HIV services in pregnancy could join the study around the time of delivery. Eligible mothers were randomized after delivery in the Postpartum Component to receive or not receive maternal ART. Once the period of risk for vertical transmission was over—at delivery for 1077FF and after weaning or after 18 months of study intervention, whichever came first, for 1077BF—women receiving ART were randomized in the Maternal Health Component to continue or stop ART. Enrolled women who were not eligible for subsequent randomizations were followed in an observational cohort through study completion. Participants were followed at least quarterly to monitor clinical, immunological and virologic status. Women randomly assigned to not take ART started ART once country criteria for treatment initiation were met. Women remained in PROMISE follow-up regardless of ART status. Figure 1 illustrates the timeline of events surrounding the action taken in response to the release of the START study results. The PROMISE study team directed sites to actively contact participants to return to the clinic to receive important information that could influence their decision to remain in follow-up. The rate of return was tracked at each site to ensure a timely response. The study team provided a structured script of simple talking points developed with input from the community and sites, although not formally piloted. After covering the essential elements of the START study population and findings, the script included a recommendation that all women in PROMISE take ART, seeing the START study had showed that it is better to start ART before a decline in CD4 count. Timeline of events in the PROMISE study and concurrent ARV guidelines When the participants returned to the study clinic, trained staff revisited the content of the PROMISE informed consent discussion with the women, emphasizing the study rationale, randomizations and role of the CD4 count in determining eligibility for initiating ART for the purposes of maternal treatment. The START study talking points were then delivered in a language chosen by the participant. Women already receiving ART were told that they would remain on ART and in follow-up through scheduled study exit in September 2016. Women not on ART were strongly advised to accept the offer to immediately initiate ART as the best antiretroviral strategy to preserve their own health. Participants were informed that remaining in follow-up was not dependent on being on ART; their willingness to continue participation was their choice. A discussion followed to verify comprehension of the implications for the individual study participant and address any questions raised. The comprehension discussion lead into an individual counselling session which followed the site’s routine counselling procedures. The approach adopted by the numerous counsellors across the different sites was not standardized due to the rapid nature of the action taken, and sessions were not audio-recorded. Women were encouraged to give their personal interpretation of the START results and to explore their reaction to the strong recommendation for all women with HIV to take ART in a free-ranging discussion. They could take as much time as they needed in the session to work out their feelings about continued study participation and, if relevant, to decide whether they wanted to accept or decline the offer of universal ART. For participants advised to initiate universal ART because of the START results, counsellors probed each woman to give her reasons for accepting or rejecting the offer, then to select her primary reason for doing so. The study physician subsequently completed the routine study review and linkage with appropriate treatment services for those initiating ART. Participants who chose not to initiate universal ART at the initial session repeated the process at subsequent visits scheduled quarterly until ART initiation or through study exit. After the counselling sessions, counsellors completed a structured data form to capture the information delivery process and decisions made. They categorized the responses into pre-set closed options derived from study team discussions with the community representatives and sites. They recorded additional detail as open text comments. Sites submitted data forms to a centralized database for analysis. These data forms were also completed at subsequent sessions for those participants who initially declined universal ART. Open text comments were subsequently categorized by two researchers following a code book developed by consensus through discussion of themes emerging from the line list of comments. These data analyses were based on women in follow-up off ART at the time of this action and with at least one counselling session. Frequencies, means, and percentiles were used for descriptive purposes. T-tests compared the mean difference between groups. The cumulative probability of remaining off ART over time was estimated using the Kaplan–Meier method. Sensitivity analyses were performed by using the antiretroviral drug record in place of the counselling form, with the conclusion that the analysis is robust to missing counselling session forms (data not shown). Analyses were performed using SAS version 9.4. P-values less than 0.05 were considered to be statistically significant. Based on these data generated from a large, multi-site clinical trial population with prior access to intense HIV disease monitoring and extensive counselling services, we report the uptake of universal ART over time by women not receiving ART at the time the START study results were communicated. We describe the primary reasons women gave in support of the decisions they made.
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