Delivering preexposure prophylaxis to pregnant and breastfeeding women in Sub-Saharan Africa

Introduction HIV acquisition during pregnancy and postpartum periods remains high despite increased access to and initiation of antiretroviral therapy (ART) in Sub-Saharan Africa [1–5]. There are biological and behavioural factors that drive high HIV incidence during pregnancy and breastfeeding periods such as hormonal changes that alter genital mucosal surfaces, and frequent condomless sex with HIV-infected partners or partners of unknown serostatus [3,6–9]. Maternal seroconversion during pregnancy and breastfeeding contributes significantly toward paediatric HIV infections in Sub-Saharan Africa [3,10]. Oral preexposure prophylaxis (PrEP) efficacy in preventing HIV acquisition has been demonstrated in four randomized control trials among heterosexual men, women, serodiscordant couples, injecting drug users, and MSM when PrEP is used as directed [11–14]. Currently, PrEP is one of the only female-controlled method that is effective for preventing HIV acquisition. However, PrEP trials excluded pregnant women from enrolment, and those who were pregnant during these studies were discontinued from PrEP [11,14]. A recent systematic review demonstrated that PrEP was not associated with increased pregnancy-related adverse events, and no studies have found adverse effects among infants exposed to tenofovir disoproxil fumarate as part of treatment for HIV-infected women during pregnancy [15–19] or breastfeeding [15,20,21]. In addition, our studies in South Africa demonstrated that the use of tenofovir during pregnancy was not associated with adverse events among infants [19,22]. PrEP adherence has been low during clinical trials of women. In the Preexposure Prophylaxis Trial for HIV Prevention among African Women (FEM-PrEP) and Vaginal and Oral Interventions to Control the Epidemic (VOICE) trials, PrEP was not effective at preventing HIV acquisition among women in Eastern and Southern Africa because of low drug exposure (tenofovir was detected in plasma in fewer than one-third of participants) [23–25]. Pregnant and breastfeeding women may have improved initiation and adherence to PrEP because of the desire to prevent vertical HIV transmission. However, future studies need to consider how best to increase adherence. Part of the difficulty in preventing perinatal and postpartum HIV acquisition is that pregnant and breastfeeding women are oftentimes at risk of other health problems in addition to HIV. Prior studies have shown that over half of pregnancies in African women may be unplanned [2,4]. This combined with multiple partners, condomless sex, transactional sex, substance use, sex-based violence, and rape, all compound the challenges of addressing the need for effective female-controlled interventions to prevent HIV, but also to address the complexities of adherence and retention in the face of such clusters of risk. In our view, PrEP is a public health priority in settings of high HIV incidence. This is especially true during periconception, pregnancy, and breastfeeding in South Africa where HIV incidence is high and the probability of vertical transmission is highest when women seroconvert and are viremic. There is an urgent need for operations research to evaluate how best to provide PrEP to pregnant and breastfeeding women in settings of high HIV incidence, including how to ensure optimal adherence. We advocate that the field move beyond clinical trials to focus on operations research to evaluate how best to operationalize PrEP delivery in pregnancy and breastfeeding adolescent girls and women, recognizing the high-risk nature of this group. We review the operational issues that need to be addressed and evaluated to ensure that PrEP delivery is effective at preventing HIV acquisition during pregnancy and lactation in high HIV incidence communities. Integrating preexposure prophylaxis delivery and counselling into antenatal and postnatal care Prior PrEP studies have not included pregnant women; thus, we do not know about how to integrate PrEP delivery and counselling into antenatal and postnatal care. Similar to operational research that helped optimize delivery of ART to pregnant and breastfeeding women [26,27], we need additional studies that operationalize how best to deliver PrEP (e.g. through pharmacies, in community pick-up points, or within clinical visits), monitor PrEP adherence, and counsel pregnant and breastfeeding women to optimize PrEP initiation, retention, and effective use during periods of condomless sex with HIV-infected partners or partners of unknown serostatus. Notably, prevention within serodiscordant couples in an era of multicomponent prevention requires attention to both partners, and development of synergies between ART initiation and retention for HIV-infected partners and PrEP for HIV-negative partners to avoid missing prevention opportunities. Further, integrating PrEP into postnatal care may be more complex, because of the different care providers and locations. For example, postnatal care, well baby visits, and immunization visits may all be separate providers in different locations from antenatal care providers. Operations research studies are urgently required to understand the role of peer educators, counsellors, nurses, and doctors in promoting PrEP use, and ensuring adherence through vulnerable periods of pregnancy and lactation. We hypothesize that mothers’ risk perceptions, risk behaviours, and concerns of protecting her child during and after pregnancy may be powerful drivers of PrEP initiation and adherence, similar to what we have found in prevention of mother to child transmission programs [28]. However, the ongoing concern about taking medication during pregnancy, and beliefs about side-effects among infants, may supersede women's concern about HIV acquisition. In this context, operations research is needed to determine how best to operationalize PrEP delivery to women who need it. Specifically, what cadre of providers should be trained to provide PrEP to pregnant women. Table 1 lists some of the essential operations research questions for optimal PrEP efficacy to prevent maternal HIV acquisition.Table 1: Key operations research questions for optimal preexposure prophylaxis efficacy to prevent maternal HIV acquisition.Optimal preexposure prophylaxis adherence during periconception, pregnancy, and postpartum periods PrEP efficacy requires adherence during periods of sexual activity and adherence requires PrEP access, awareness, and counselling. Currently, a major obstacle in the PrEP field is effective use, especially among women during at-risk periods before periods of sexual activity [23,24,29–32]. Little is known about how to successfully engage and retain women trying to conceive, as well as pregnant and breastfeeding women living in high-burden settings in PrEP care, nor how to effectively support adherence and persistence to PrEP in this population [33]. PrEP adherence in this population must be understood within the context of highly variable risk for HIV infection during pregnancy and breastfeeding [29]. Prevention of mother-to-child transmission may also make women taking PrEP more acceptable to their partner(s), family, as well as health providers. Prior studies demonstrated an association between having perceived HIV risk and improved PrEP adherence [26]. Improving knowledge about the increased risk of HIV acquisition during pregnancy and breastfeeding could possibly contribute to improved PrEP initiation and adherence. Furthermore, provider barriers may include perceptions that PrEP will lead to more risk or more condomless sex. More research is needed on what kinds of messages, and from which types of individuals or providers, are needed to ensure optimal PrEP adherence in periconception, pregnant, and breastfeeding women. Novel approaches are needed to understand and evaluate provider and patient-level barriers to the PrEP cascade in periconception, pregnancy, and lactation periods in high HIV incidence countries. Targeting preexposure prophylaxis to at-risk women in periconception, pregnancy, and postpartum periods Not all HIV-uninfected African pregnant and lactating women will benefit from taking PrEP. The WHO set the threshold of ensuring PrEP availability where HIV incidence is three or more per 1000 person-years [34]. In communities where HIV incidence is lower than three per 1000 person-years, it may make sense to target PrEP delivery to those at highest risk. A recent study, developed a risk score to predict maternal HIV acquisition in Kenya [31]. Risk scores are one method for reaching pregnant women at high risk of HIV acquisition, but, there is a need to identify other ways to reach target populations. For example, a risk score that is dependent on self-reported measures of behaviour may underestimate the true HIV acquisition risk, and not all women have insight into their partners’ risk-taking behaviours. The generalizability of risk prediction method requires careful consideration as part of future operations research to understand the role of targeting PrEP in different contexts [35]. Preexposure prophylaxis for adolescent girls and young women at high risk of HIV acquisition In Sub-Saharan Africa, an estimated 7000 new HIV infections are occurring weekly in adolescent girls and young women [36]. Further, adolescent girls have high pregnancy rates in South Africa. Approximately, 1.6% of 15-year-old, 3.7% of 16-year-old, and 7% of 17-year-old girls were pregnant in 2013 [36]. Prior studies have demonstrated significant challenges providing PrEP to adolescent girls and young women and the issues around providing PrEP to pregnant and postpartum women are unknown, which makes pregnant and postpartum adolescents and young women a particularly vulnerable group [24,37]. Operations research should include adolescent pregnant girls to evaluate predictors of PrEP initiation, retention, and adherence among this particular population which may differ from adult pregnant and breastfeeding women [2]. Including adolescent girls will increase the validity and generalizability of those interventions. Finally, it would be unethical to not provide pregnant and breastfeeding adolescent girls and young women with PrEP and include them in PrEP studies [2]. In conclusion, in light on current knowledge on the safety of PrEP in pregnancy and breastfeeding, and the persistent high HIV incidence during these vulnerable periods, PrEP in pregnancy and breastfeeding is critical to the elimination of maternal to child HIV transmission. There is an urgent need for operations research to evaluate how best to provide PrEP to pregnant and breastfeeding women in settings of high HIV incidence. Specifically, pilots and operations research should focus on evaluating how best to deliver PrEP in periconception, antenatal, and postnatal care, who should be targeted for PrEP delivery (including how best to reach and manage adolescent girls and young women), and how to address the barriers to PrEP effectiveness, and promote optimal adherence given the multifactorial challenges these women face in staying HIV negative. Such studies are required to ensure that when PrEP in pregnancy and breastfeeding programs are rolled out, they are utilizing and adapting the best of current knowledge in the field to ensure optimal impact. Acknowledgements Conflicts of interest There are no conflicts of interest.