Introduction

In 2014, about 1.2 million HIV-positive women were giving birth in the 21 priority countries for prevention of mother-to-child transmission of HIV (PMTCT) in Sub-Saharan Africa, and the number of children newly infected with HIV was still as high as 170.000.[1] Yet, it is beyond doubt that considerable progress has been achieved in PMTCT during the last five years, and UNAIDS has just announced the goal to reach less than 20.000 new infections among children by 2020. [2] The Global Plan towards the elimination of new HIV infections among children targeted a reduction of the final mother-to-child transmission (MTCT) rate to 5% or less among breastfeeding populations, and 2% or less among non-breastfeeding populations. [3] By 2014, the 21 Sub-Saharan African priority countries for PMTCT had in fact achieved an overall transmission rate of 5% after six weeks, but this increased to a final rate of 14% at the end of the breastfeeding period.¹ Hence, breastfeeding still represents the major weakness for successful PMTCT, even though its benefit for the infant´s health in resource-poor settings is uncontroversial. [3–6]

Since 2013, WHO recommends lifelong triple antiretroviral therapy (ART) for all pregnant and breastfeeding women living with HIV regardless of their CD4-cell count and clinical stage, the so-called Option B+, as PMTCT approach wherever this is feasible to implement. [7] According to WHO, when ARVs are taken throughout the breastfeeding period as in Option B+, countries should opt to recommend breastfeeding for the first six months of life, followed by mixing suitable complementary food and continued breastfeeding from month 7–12. [8,9]

When drugs are taken as required, Option B+ allows for achieving lasting viral suppression and reducing emergence of drug resistant viral strains, and the simplified procedures and harmonization of Option B+ with general ART care are assumed to facilitate uptake and long-term adherence. [7] Yet, experiences with this approach have shown that ARV adherence and continuity of care during pregnancy and the early postpartum period are major challenges in the implementation of Option B+. [10–13] Research on later postpartum stages has been limited so far, and there is concern that ARV adherence could even more decline in the later breastfeeding period. A systematic review and meta-analysis studying perinatal adherence before the Option B+ era suggests that sufficient adherence was higher during pregnancy compared to the postpartum period [14], and barriers after delivery, such as the mother´s belief that she is cured or fear of disclosure have been described. [15,16]

Uganda faces an HIV prevalence of 7.4% [17], with a fertility rate of 5.9 births per woman [18] and an estimated number of 120.000 HIV positive pregnant women in 2013 [17]; hence, the country requires continuous engagement in effective implementation of a PMTCT approach. Uganda adopted WHO’s Option B+ strategy as one of the first sub-Saharan African countries. The roll-out began in 2012 and had reached all PMTCT facilities by March 2014. [19] After the fairly rapid nationwide introduction of Option B+, research accompanying the implementation of Option B+ in the postpartum period is rare to date, and to our knowledge, studies on feasibility during an extended breastfeeding period for up to 18 months in Uganda are entirely lacking so far. Therefore, we conducted a longitudinal study in a rural high-prevalence setting in Western Uganda to examine longer-term adherence to Option B+ and associated influencing factors until 18 months postpartum, i.e. until the end of the breastfeeding period.

Methods

Results

Out of 124 HIV-positive women recruited during ANC, eight women (6.5%) were excluded due to abortion, stillbirth or early infant death. Of the remaining 116 women, 67 (58.0%) returned to the involved health facilities after delivery for their 6 weeks-visit and hence formed the cohort of this sub-study. The 67 women had given birth to 68 babies (66 singletons and one set of twins). Out of all enrolled women, 61 (91%) returned at least once in the follow-up period until 18 months postpartum, and 53 (79.1%) attended three or four visits. The number of returning clients and LTFU per visit are displayed in Fig 1.

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Fig 1. Option B+ enrolled women attending postpartum study visits.

https://doi.org/10.1371/journal.pone.0179448.g001

Baseline characteristics

Sociodemographic and clinical characteristics of the study cohort are shown in Table 1. Fourteen women (20.9%) were LTFU within the first six months. Comparing them to participants retained in care for twelve months or longer (n = 53; 79.1%) revealed a significant age difference with women LTFU being significantly younger (mean 22.1 years) than followed-up clients (mean 26.7 years; p = 0.006). Among clients LTFU, 9/14 (64.3%) had disclosed their HIV status to their spouse whereas among the followed-up clients 47/52 (90.4%) had done so (p = 0.029).

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Table 1. Sociodemographic and clinical characteristics of the study cohort.

https://doi.org/10.1371/journal.pone.0179448.t001

Maternal drug adherence

According to the study´s definition of full adherence, three participants (4.5% of all) were adherent until 12 months i.e. during the 6 weeks-6 months interval and during the following 6 months-12 months interval. However, no single client was fulfilling the criteria during the entire follow-up period until 18 months. Analyzing overall adherence and associated factors for every follow-up visit separately, our definition of full adherence applied to 26/51 participants (51.0%) at the 6 weeks-6 months interval, to 8/42 participants (19.0%) at the 6–12 months interval, and to 9/44 participants (20.5%) at the 12–18 months interval (Table 2).

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Table 2. Maternal adherence at different study visits.

https://doi.org/10.1371/journal.pone.0179448.t002

We also analysed the two scales separately that determined our “full adherence” category. Self-rated adherence was high throughout all four study intervals with ≥95% of clients claiming that they had taken all pills. However, drug restock visits, which were part of the PNC routine, were performed less frequently than required: There was no difference between reported drug collection visits and required amount of visits at six months postpartum, but a median of two restock visits was missing for the preceeding time periods at twelve and 18 months postpartum (Table 2). Throughout all study visits, clients median number of drug collections was 11.0 compared to a median of 15.0 required drug collection visits (p = 0.01).

Mothers non-adherent at six months postpartum had a higher median number of previous deliveries (p = 0.015) and higher travel costs to hospital (p = 0.024). Longer intended duration of complementary breastfeeding was associated with full adherence (p = 0.035). However, there was no significant link between actual breastfeeding duration and postpartum adherence. Comparing adherent and non-adherent mothers one year after delivery revealed significantly older age (p = 0.001) and higher number of previous deliveries (p = 0.039) in non-adherent mothers (Table 3). At eighteen months postpartum, none of these differences were found to be significant between the adherent and the non-adherent participants.

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Table 3. Sociodemographic and clinical characteristics by adherence category.

https://doi.org/10.1371/journal.pone.0179448.t003

Discussion

Our longitudinal study in rural Uganda is among the first to observe adherence to Option B+, breastfeeding duration, and MTCT rates from delivery until 18 months postpartum. Overall, we found that despite the relative convenience of simplified procedures in Option B+, no mother from our cohort managed to fully adhere to it until 18 months postpartum. At the six-month postpartum visit, half of all clients fulfilled our definition of adherence, declining to only three clients fully adherent throughout 12 months.

Our finding of suboptimal postpartum adherence coincides with other studies based in sub-Saharan countries. In a recent study conducted in Zambia, Okawa et al. found self-reported adherence to Option B+ in 80% of clients from pregnancy to six weeks postpartum, and a decrease to 70% at 24 weeks postpartum. [13] This is comparable to our finding of high self-reported adherence. Moreover, among previous studies focusing on postpartum Option B+ adherence, follow-up periods are shorter and adherence is often defined as retention in care. Studies conducted before the Option B+ era found comparably low postpartum adherence to PMTCT care. In rural Tanzania, adherence in terms of correct dispensation of drugs after delivery was seen in 78% of participating mother-infant pairs. [21] In a cross-sectional study conducted in South Africa, 86% of participating women who were asked about their postnatal adherence to regular azidothymidine intake reported that they were adherent the last four days prior to the interview. [22] Another study from Uganda found a 38% adherence rate for meeting a scheduled appointment six-weeks postpartum. [23] The design, adherence definition and recommended drug regimens in these studies differed from the conditions in our study, thus, respective adherence levels are not comparable. This represents a general problem in adherence-related research, and further investigations targeting the comparability and also the reliability of various adherence measures would be extremely helpful.

Research on Option B+ adherence during pregnancy usually found better adherence. In an Ethiopian study, 87.1% of participants were reported to be adherent in self-reported drug intake. [10] A Kenyan study revealed predelivery adherence rates of 84% [24], and in Uganda, a median pill count adherence level of 95% was found throughout pregnancy. [11] As a matter of a fact, the relatively high adherence to Option B+ in ANC seems to decline in the postpartum period, particularly in the later breastfeeding stage, as observed in our cohort. We found that from the clients having been enrolled in the larger PMTCT study, only 58% returned after delivery for postnatal care. As our study visits were scheduled in line with routine PNC/drug refill services, LTFU corresponds to poor retention in care in the postpartum period. Future research should focus on how to retain women in PMTCT services at this point of the PMTCT cascade.

Our findings also raise the question how barriers for adherence to Option B+ might be different in the postpartum period compared to the antenatal period. [16] A factor previously suggested, and presumably specific to the postnatal period, is the belief that HIV care for the mother´s own health is irrelevant once the infant is born, especially after a baby is proven to be HIV-negative. [15] Moreover, mothers who do not suffer from clinical symptoms might not feel a strong need to adhere to health care appointments and daily drug intake. Previous research suggests that mothers who initiated ART for PMTCT are more likely to drop out of care after delivery than women starting ART for their own health [12, 25].

According to our findings, adherence was higher in the first six pospartal months compared to later observation periods. This implies that particularly the later part of the breastfeeding period should be in the focus of attention of health care providers regarding adherence motivation to avoid late stage transmission. Phone calls or SMS text messaging have proven to be effective in increasing retention in several studies. [26–28] Furthermore, assignment of community health workers [29], as well as adherence counselling training for health care staff [30] were previously used to increase adherence in pregnancy and early infant diagnosis; these strategies should be adapted to the breastfeeding period. For health service implementers, it is highly relevant to understand in which time interval after delivery it could be especially difficult for mothers to adhere to drug regimens or pick up their drugs from the health facility. This knowledge could lead to specific support activities for specific time intervals e.g., repeated adherence counselling in the later postpartum stage, rendered to Option B+ clients by the health facilities.

Socioeconomic determinants to adherence and retention during the entire PMTCT cascade have been summarized in previous reviews. [16,31,32] We found that postpartum non-adherence until six months after delivery was associated with higher travel costs. Previous research similarly identified structural barriers such as long travel distance to the health facility, often linked with higher travel expenses. [33,34] Another significant influencing factor was found in higher number of previous deliveries, serving as a proxy for the number of children a woman already has at home, hence for the burden of workload she is facing regarding child care. To overcome structural barriers like distance, time and travel funds, health policy makers and governmental institutions should take into consideration how these could be targeted on a lasting basis. Home-based care [35] for those who cannot leave their homes due to child care duties or travel costs might also be an option worthwhile debating.

In our study, three quarters of our participants adhered to the recommended 12-month breastfeeding period with six months of exclusive breastfeeding, demonstrating a broad acceptance of the paradigm shift from abrupt weaning after six months towards a recommended 12-month breastfeeding period for women living with HIV. This is in accordance with findings from Ngoma et al., in which mothers reported a high adherence to breastfeeding recommendations. [36] Mothers’ strong commitment to having a healthy, well-nourished baby [37] could explain the high compliance with breastfeeding recommendations, and represents a factor that interventions for increased PMTCT adherence should focus on. However, continued breastfeeding for 12 months as recommended by WHO is strongly and inevitably linked to the precondition that the mother is under ART/Option B+. [7,8] Without sufficient viral suppression, prolonged breastfeeding could lead to high postnatal vertical transmission rates [38], as in the early times of short-term PMTCT regimens. Our finding that in the Option B+ era, HIV-positive mothers widely apply the recommendation for longer breastfeeding on the one hand, but on the other hand do not adhere to continuous drug intake throughout infant exposure to breastmilk is therefore rather alarming. Health authorities urgently need to focus on strengthening postpartum adherence when deciding that health services should counsel in favor of prolonged breastfeeding, in order to avoid a setback in MTCT rates.

We found no case of vertical transmission in our study cohort. While possibly pointing to a high effectiveness of Option B+ despite suboptimal adherence, such conclusions should be drawn with caution in the light of our relatively small sample size. Apart from that, it is possible that HIV-infected infants were among the cases LTFU, possibly having deceased within the first 18 months of life, and results from our followed-up group could be underestimating true transmission rates. For conclusive appraisals on HIV transmission after 18 months under Option B+, larger cohorts are urgently needed, and following-up the dropout cases would be highly elucidating.

The rather small sample size was also a limitation for our study in terms of not permitting multivariate analysis, which would have strengthened our assessment of factors influencing adherence. Yet, considering the immense scale-up of HIV testing and ART programs in the past years, it has become challenging to obtain large PMTCT cohorts, and related research will have to focus on multicenter studies in order to achieve high patient volumes [11]. At the same time, longitudinal cohorts over a period of 18 months are prone to LTFU, further decreasing the final sample size. The problem of high drop-out rates during follow-up are a common limitation in PMTCT-related research in general [34,39,40]. We tried to mitigate this problem by aligning study visits with routine healthcare visits; yet, dropout rates in the course of the postpartum period were high, and actively following-up on these dropouts was beyond the scope of our study. However, given the scarcity of respective longitudinal studies, we believe that we can still provide meaningful insights in terms of adherence to Option B+ in the postpartum period.

Another limitation of this research is found in the fact that self-reported adherence is prone to social desirability and recall bias and hence to an overestimation of adherence. In our study, we aimed at mitigating those biases by not only relying on self-reported adherence, but combining it with measuring sufficiency of drug restock visits, as well as by creating a nonjudgemental interview setting within the study to facilitate honest reporting. Beyond that, it would give helpful insight on adherence measurement to triangulate self-reported adherence with pill count and plasma drug levels in future research. Finally, we acknowledge that adherence to drug dispensary visits does not necessarily equal drug intake, again underlining the potential risk of overestimating adherence. Still, if true, this only would reinforce our finding of suboptimal adherence.

In conclusion, we identified long-term drug adherence to Option B+ until 18 months postpartum to be suboptimal, pointing at enduring challenges in the implementation of this strategy. Meanwhile, the WHO recommendation for continuous breastfeeding until 12 months and beyond was widely applied by HIV-positive women under Option B+. Low drug adherence clearly compromises the effectiveness of Option B+, and it should be stressed that especially women who prolong the breastfeeding duration for their baby while at the same time not adhering to ARV intake put their infant at high risk for infection. Our findings emphasize a need for postpartum interventions encouraging drug adherence among women taking Option B+, especially in later stages of breastfeeding.

Acknowledgments

We thank all participating women and their infants, as well as midwives, laboratory staff and administration of both, Fort Portal Regional Referral Hospital and the Holy Family Virika Hospital. This work forms part of the doctoral theses of SD, AS, ER, and VB.