Use of combination ART prophylaxis during pregnancy and breastfeeding was associated with a lower rate of infant HIV infection and death when compared to short-course antenatal ZDV and peripartum NVP. Similar trends were observed among infants whose mothers had CD4 cell counts >350 cells/μL. These measureable improvements in infant outcomes support the expansion of ART prophylaxis to all women irrespective of CD4 count, as is recommended in the WHO’s Option B PMTCT policy.
When our study was first designed and implemented in 2009, the standard of care for PMTCT in Zambia focused on the timely triage of HIV-infected pregnant women for HIV treatment. The goal was to urgently identify and initiate treatment for women eligible for ART. In accordance with WHO recommendations at the time, those who did not meet eligibility criteria were initiated on short-course zidovudine and peripartum NVP from 28 weeks gestation onward. Antiretroviral prophylaxis during breastfeeding – to either mother or infant – was not offered. In the ensuing years, however, the science of PMTCT evolved rapidly. Services similar to those provided in our four Kafue pilot sites have been introduced as policy across much of Africa [11
]. In this report, we share our early programmatic experiences and demonstrate the clear benefits to infant health when services are “upgraded” from the previous standard of care (i.e., PMTCT as provided in our control sites) to the current standard of care (i.e., services provided at our intervention sites).
Several clinical trials have demonstrated the efficacy of ART prophylaxis during pregnancy and through breastfeeding [3
]. Universally, these regimens have been shown to reduce mother-to-child HIV transmission; however, study design and primary endpoints have differed from trial to trial. Perhaps most similar to our study is the Kesho Bora study, a randomized controlled trial conducted in Kenya, Burkina Faso, and South Africa. Participants in Kesho Bora were randomized to receive either ART prophylaxis from 28 to 34 weeks gestation through breastfeeding or short-course antenatal ZDV and peripartum NVP. At 12 months postpartum, the risk of HIV infection or death was lower in the intervention group when compared to the control group (5.4% vs. 9.5%; P=0.029), findings that approximate those of our study.
A strength of our study was its focus on field effectiveness, which considered program attrition over time. However, this “real world” perspective also led to analytical challenges as well. For example, women who met immunologic criteria for HIV treatment in the control facilities were immediately referred to the nearest antiretroviral therapy clinic – typically the Kafue District Hospital – prior to 28 weeks gestation. Women in the intervention facilities were not referred in the same manner; in our integrated service model, they could access antiretroviral therapy on site. Because we did not include CD4 eligibility criteria for the study, these differences in patient management led to imbalances between the comparison populations. We attempted to account for these differences in our secondary analysis, which restricted the study population to infants whose mothers had CD4 counts >350 cells/μL. We were reassured to find that results in this sub-analysis were consistent with those of the larger study cohort.
We observed a greater than two-fold hazard for stopping breastfeeding before 12 months in the control group, even after adjusting for baseline participant characteristics. Although we used a core group of study nurses, many factors — including differences in counseling — could have contributed to this incongruity. Breastfeeding cessation may also have been influenced by the perception that ART prophylaxis during breastfeeding imparts additional protection against mother-to-child HIV transmission. If confirmed, this change in maternal infant feeding behavior could present an important collateral benefit of ART prophylaxis.
As part of our analysis, we sought to determine the extent of follow-up losses in our programmatic cohort. We found that at 12 months of age nearly one-fifth of infants had no study outcome and could not be traced. This high percentage is concerning, but in line with other reports. Myer and colleagues showed that 19% of women pregnant at initiation of ART were lost to follow-up after one year [16
]. Similarly, Kaplan and colleagues showed 32% of pregnant women who initiated ART were lost to follow-up after three years [14
]. Among women in the intervention group whose infants were retained in care, only 35% demonstrated optimal adherence to their three-drug regimen as measured by medication possession ratio. This is significantly lower than previous findings in non-pregnant adults on ART, but consistent with studies of pregnant women [15
]. Evidence-based strategies are clearly needed to improve retention and adherence among pregnant and postpartum populations, particularly as Ministries of Health move to Option B or Option “B+” (i.e., initiation of lifelong antiretroviral therapy in pregnancy irrespective of CD4 cell count for PMTCT) [27
]. Since most women in this population will be asymptomatic [10
], there may be less motivation to adhere to long-term treatment once the risk of HIV transmission to the infant has passed.
We note several limitations to the current analysis. First, we were unable gather routine data about reasons behind non-participation in our cohort study. This may have led to unmeasured selection biases between the groups. Second, since neither the participants nor the facilities providing the intervention were randomized, our study data may contain systematic biases. There were several differences between our intervention and comparison groups. Because of the small number of events, particularly in the intervention group, we were unable to perform multivariable analyses. However, the most important potential confounder – maternal CD4 cell count – was examined in greater detail in our secondary analysis through stratification. Third, owing to the swiftly advancing field of PMTCT, the standard of care provided at our control sites is no longer the recommended WHO standard. The lack of antiretroviral coverage during the breastfeeding period, where the majority of infant HIV infections occurred, is most worrisome. Our study was designed to demonstrate the incremental health gains made possible by the implementation of the WHO’s Option B for PMTCT in a field setting.
In summary, our findings demonstrate a significant benefit of maternal ART prophylaxis to HIV-exposed infants. However, patient attrition and poor adherence among those receiving combination regimens in the postpartum period could diminish regimen effectiveness and carry long-term consequences for women on treatment. As country programs seek to implement antiretroviral regimens of longer duration, particularly after delivery, investments are urgently needed to improve timely access to care and retention.