Effects of behavioural interventions on postpartum retention and adherence among women with HIV on lifelong ART: the results of a cluster randomized trial in Kenya (the MOTIVATE trial)

Introduction: Retention in HIV care and adherence to antiretroviral therapy (ART) during pregnancy and postpartum for women living with HIV (WLWH) are necessary to optimize health outcomes for women and infants. The objective of this study was to evaluate the impact of two evidenced-based behavioural interventions on postpartum adherence and retention in WLWH in Kenya. Methods: The Mother-Infant Visit Adherence and Treatment Engagement (MOTIVATE) study was a cluster-randomized trial enrolling pregnant WLWH from December 2015 to August 2017. Twenty-four health facilities in southwestern Kenya were randomized to: (1) standard care (control), (2) text-messaging, (3) community-based mentor mothers (cMM) or (4) text-messaging and cMM. Primary outcomes included retention in care and ART adherence at 12 months postpartum. Analyses utilized generalized estimating equations and competing risks regression. Per-protocol analyses examined differences in postpartum retention for women with high versus low levels of exposure to the interventions. Results: We enrolled 1331 pregnant WLWH (mean age 28 years). At 12 months postpartum, 1140 (85.6%) women were retained in care, 96 women (7.2%) were lost-to-follow-up (LTFU) and 95 (7.1%) were discontinued from the study. In intention-to-treat analyses, the relative risk of being retained at 12-months postpartum was not significantly higher in the intervention arms versus the control arm. In time-to-event analysis, the cMM and text arm had significantly lower rates of LTFU (hazard ratio 0.44, p = 0.019). In per-protocol analysis, the relative risk of 12-month postpartum retention was 24–29% higher for women receiving at least 80% of the expected intervention compared to the control arm; text message only risk ratio (RR) 1.24 (95% confidence interval [CI] 1.16–1.32, p<0.001), cMM only RR 1.29 (95% CI 1.21–1.37, p<0.001) and cMM plus text RR 1.29 (1.21–1.37, p<0.001). Women LTFU were younger (p<0.001), less likely to be married (p<0.001) and more likely to be newly diagnosed with HIV during pregnancy (p<0.001). Self-reported ART adherence did not vary by study arm. Conclusions: Behavioural interventions using peer support and text messages did not appear to improve 12-month postpartum retention and adherence in intention-to-treat analyses. Higher levels of exposure to the interventions may be necessary to achieve the desired effects. The MOTIVATE study was a cluster‐randomized, factorial, controlled trial [19]. Twenty‐four Kenyan Ministry of Health facilities were randomized to one of four study arms: (1) standard care (control), (2) text‐messaging only, (3) cMM only or (4) both text‐messaging and cMM. The study was conducted in southwestern Kenyan in Migori, Kisumu and Homabay Counties with adult HIV prevalence ranging from 13.0% to 19.6%, compared to 4.9% nationally [20]. Kenya adopted universal lifelong ART for PWLWH in 2015 [21, 22]. All of the 24 government healthcare facilities participating in the study provided free PMTCT services, including ART (dolutegravir not available), integrated into antenatal and postnatal care through 18 months postpartum along with HIV infant testing and follow up. Clinic visits and ART refills occurred every 1–3 months per Kenyan guidelines and differentiated service delivery models were not in effect. Infant HIV testing occurred at 6 weeks, 6 months and 12 months using HIV PCR and at 18 months using antibody testing. Facilities were purposively selected to represent a distribution of urban and rural, high and lower volume, and geographic locations (e.g. sub‐county). Twenty sites were initially chosen, and four additional sites were added to achieve target enrolment. PWLWH were recruited during routine antenatal clinic visits December 2015 to August 2017 and followed through 1‐year postpartum (March 2019). Inclusion criteria included: women with HIV of at least 18 years of age, mobile phone access (with disclosure of their HIV status to any person sharing the phone), willingness to have home visits (or meetings with a cMM in alternate location) and living within the facility catchment area. After enrolment, women were discontinued from the study if they experienced a miscarriage, stillbirth or other child loss as the study interventions were designed for mother–child pairs. The study interventions and their development during the pre‐trial formative phase have been described in detail elsewhere [11, 13, 19, 23]. In brief, the text messaging intervention was developed based on qualitative formative research and the Health Belief Model [24, 25]. Participants received free tailored text messages delivered by automated texting software. Message content focused on medication and clinic adherence without explicit mention of HIV or ART as well as promotion of maternal and child healthcare services timed to the stage of pregnancy and age of the infant post‐delivery. Messages were sent weekly from study enrolment in pregnancy through 12 months postpartum. Participants were also able to engage by phone without charge with a study nurse. Study staff continuously reviewed texting software logs of all messages sent, delivered (or failed) and received throughout the study. The cMM intervention was adapted from the Kenya Mentor Mother Program and has been previously described [23, 26]. cMMs were WLWH on ART with a recent pregnancy, with a minimum of 8 years of primary education, who had demonstrated good ART adherence and who had disclosed their HIV status. In contrast to traditional mentor mothers who are based at health facilities, cMMs in this study worked from the community and carried out structured home visits. The cMM visit schedule included up to four antenatal visits and nine post‐natal visits designed to maximize retention in PMTCT and other essential health services. cMMs were supervised by study nurses and underwent observed home visits, regular refresher trainings, quarterly evaluations and review of visit logs. Randomization occurred at the facility (cluster) level given concerns for contamination if interventions delivered at the individual level. A participatory open community randomization meeting was held at which a study facility representative chose a sealed opaque envelope with their site's randomization arm. Facilities were stratified by geographic region and each region had at least one site in each of the four study arms. All study data were abstracted by trained data clerks from standardized Kenyan Ministry of Health HIV clinic visit forms and clinic registers (i.e. medical records) at the study facilities into an Open Data Kit (ODK) electronic database with built‐in quality controls. Primary outcome measures were adherence to ART and retention in HIV care at 12 months post‐partum. ART adherence was measured via self‐report, recorded in the woman's medical record during routine visits. Adherence was classified as per Kenya guidelines as good (>95% of pills taken since last clinic visit), fair (85–94%) or poor (<85%). Given >95% of women reported good adherence throughout the study, this was compared versus combined fair or poor adherence. Secondary outcomes included viral suppression and infant outcomes. Viral load was added as a secondary measurement of adherence after routine viral load monitoring was introduced in Kenya after the study launched, and was obtained through health records. Per the Kenya National ART guidelines, viral load was obtained by clinic providers after 6 months of ART for those newly initiating (or at time of pregnancy identification for those already on ART) and every 6 months until cessation of breastfeeding [22]. Those with viral load <1000 copies/ml were considered virally suppressed. Retention in care at 12 months postpartum was defined as the proportion of women who had an HIV care visit within 90 days at 12 months after delivery. Women with documented transfer to another clinic, which required an official transfer letter, were considered retained in care. Women who died, experienced a pregnancy loss or child death, or withdrew were discontinued from the study and their data were used up until study discontinuation. The study was powered based on estimated differences in proportions of maternal ART adherence and retention in the intervention versus the control arms at 12 months postpartum accounting for clustering as previously reported [19, 27]. We estimated a baseline ART adherence rate of 55% based on pre‐universal ART rates found in the literature for pregnant women in SSA at the time of study design [28] and a baseline retention in care rate of 48% based on trial data from a study of service integration conducted in the same region in Kenya [29]. We powered our study to be able to detect a 25% absolute increase due to each intervention individually. To achieve 80% power for both outcomes with a conservative (high) intra‐cluster correlation coefficient of 0.12 and an average of 70 women sampled per community, we calculated 20 sites, 5 in each arm with a target sample size of 1336 women (334 women per arm) would be needed. Descriptive analyses summarized characteristics of participants and assessed frequency distributions of variables. Analyses of primary outcomes of maternal ART adherence and maternal retention in care (dichotomous variables) compared proportions between intervention and control groups using cluster adjusted two‐sided chi square tests. Given the clustered study design, generalized estimating equations (GEEs) were used to test for differences of interest in univariable and multivariable models, adjusted for relevant covariates identified as differing across study arms at baseline with p≤0.05, using a logit link. Secondary outcomes, such as maternal viral load suppression (<1000 copies/ml), were analysed using similar methods, considering the nature of the variable (continuous, dichotomous or time to event). Time to LTFU (defined as no clinic visit ± 90 days at 12 months postpartum) was modelled using competing risks regression analysis accounting for clustering using GEE with resulting in cause‐specific hazard ratios (HRs) and displayed using cumulative incidence plot. Participant or infant/child death or pregnancy loss, as well as transfers out were considered competing events for the LTFU and retention outcomes and were censored at the time of the event. Results were summarized as risk ratios, HRs and mean changes, as appropriate; respective 95% confidence intervals are reported based on the robust variance estimates from the GEE models. Primary analyses were intention‐to‐treat (ITT), while secondary per‐protocol (PP) analyses examined differences in outcomes for women with high (>80% of expected intervention dose received) versus low levels of exposure to the interventions, adjusted for gestational age at enrolment to the study. For the PP analyses, a level of completion of 80% of the intervention received was selected a priori as this was considered by the research team to be the minimal adequate dose of the interventions. Although there is no standard recommended cut‐off in the literature for the dose of multi‐session interventions received to be used in PP analyses, “clinical” judgement of an adequate dose is one accepted approach [30]. All analyses were done using Stata 15 Software [31]. All women enrolled in the study provided written informed consent. The study was approved by the Kenya Medical Research Institute, University of Alabama at Birmingham and the University of Colorado, Denver Institutional Review Boards.