Impact of maternal ART on mother-to-child transmission (MTCT) of HIV at six weeks postpartum in Rwanda

The global community has committed to the elimination of mother-to-child transmission of HIV (EMTCT) by 2015 and keeping their mothers alive, with targets of < 5% transmission (< 2% for early postnatal) and antiretroviral therapy (ART) coverage of at least 90% [1‐4] Measuring impact of EMTCT programs is necessary to track acheivements towards this goal.

Rwanda is located in Eastern Africa, with 10.5 million inhabitants. HIV prevalence in 2017 was estimated at 3.1% in the general population and 3.8% among women age 15–49 years. [5] The national EMTCT program started in 2001, and a national EMTCT scale-up plan (2007–2012) articulated a strategy to deliver comprehensive EMTCT interventions within maternal and child health services. [6] The EMTCT program reached 87% of health facilities by 2012. All services were generally provided in the same health facility, though not necessarily in the same service point within the facility.

In November 2010, Rwanda EMTCT program adopted antiretroviral treatment (ART) for all pregnant and breastfeeding women (2010 WHO recommendation Option B). [7] Starting April 2012, the EMTCT program extended ART for all pregnant women beyond the breastfeeding period to life-long therapy (also known as Option B+). [7] From 2010 the EMTCT program included infant antiretroviral prophylaxis from birth to age 4–6 weeks. Table 1 compares Option A, B and B+. [7] Chi et.al. [8] reviewed updated literature in 2013 and confirmed the benefits of of all three options, however they note in their conclusion that “To better understand the downstream impact of the Option B+ approach, ‘real world’ program data are needed and must be carefully evaluated.” [8, pg 129] This report provides ‘real world’ data from the early Rwanda experience using Option B/B+.

This is the first report from a nationally representative study on the early (6–10 postnatal weeks) effectiveness of universal (Option B or B+) perinatal maternal ART on mother-to-child transmission of HIV to measure progress towards EMTCT targets in sub-Saharan Africa. The only other published national early EMTCT effectiveness studies have been from South Africa, [9, 10] which were done when South Africa was using WHO Option A and showed a 6 week transmission of 3.5% [7]. Other published early effectiveness studies of Option B or B+ have been only regional, not national studies with 10% MTCT found in Kenya [11] and 6.7% in Zimbabwe. [12, 13] Finally, one paper has been published on the national 18-month effectiveness of the Zimbabwe EMTCT program during the transition from Option A to Option B. [14] Therefore, this study adds substantially to the current available literature on national effectiveness of Option B or B+ at 6–10 postnatal weeks.

A cross-sectional facility-based survey was conducted amongst mother/caregiver-infant pairs attending their 1st Diptheria-Tetanus-Pertussis (DTP1) immunization at six weeks postnatal. This study was conducted in public and faith-based primary health care facilities offering immunizations in all four Rwanda provinces and Kigali City. Health centers with and without an EMTCT program were selected in order to determine the national maternal and child HIV transmission rate. Routine data showed DTP1 coverage was 98.8%. [15] Facilities with high immunization coverage have been recognized for providing unique opportunities for cost-effectively measuring EMTCT program impact on early MTCT for EMTCT program evaluation. [16, 17] This methodology was first used by Rollins [18] and colleagues, and later was proven to be effective for measuring MTCT in South African. [9], The Rwanda EMTCT Evaluation protocol was adapted from the South African EMTCT Evaluation protocol and approved  by the National Institute of Statistics of Rwanda and by Rwanda’s National Ethics Committee.

Data collection was from July 2011 to June 2012. The sample realized was 1639 (82% of desired sample size). There was slightly lower sample realisation for Rural EMTCT facilities (892/1191, 75%), higher than expected sample realization for Urban EMTCT (655/234, 280%) and substantially lower sample realisation for Non-EMTCT sites (92/575, 16%). The sampling frame was adhered to for selected health facilities and allocated time spent was completed according to protocol, but the realization of participants was different from expected. This differential in expected participants experienced per strata was considered due to natural experience of women accessing EMTCT and accounted for during weighting at analysis stage.

A total of 22,305 infants were screened (using a combination of: maternal interview, maternal HIV rapid testing for mothers who reported HIV status unknown, or HIV-negative mother in a discordant couple relationship). 2066 were identified as HIV-exposed infants and a DBS sample taken. Of these, 1828 met enrollment eligibility criteria, consented to study participation and were interviewed. 189 DBS were rejected by the lab or had indeterminant results, leaving 1639 subjects with both interview questionnaire completed and DNA PCR result available for analysis (Fig. 2).

The average age of the mothers was 29.5 years (SE 0.17) and the majority (72.5%) had primary school education. The majority were married (31.3%) or cohabitating (47.9%). The main building material of the floor was natural/other (68.1%), source of drinking water was a public tap (49.2%), use of a pit latrine (97.5%), and use of firewood/straw/dung/other as primary cooking fuel (72.5%). Almost one in five mothers (18.9%) reflected some food insecurity (i.e. ran out of food in the past year) and the majority had fewer assets (61.5% had 1–3 assets such as a radio, phone, etc.). Just under half of the mothers were employed (47.2%). The majority (81.1%) were multiparas and half (50.0%) had planned pregnancies.

Figure 3 shows results for EMTCT service indicators coverage in HIV-positive mothers and HIV-exposed infants. In all health centers, most of the key EMTCT indicators such as HIV testing, CD4 count, and maternal ART during pregnancy were above 90%. Referral to ART clinic, disclosure of HIV status and infant feeding counseling were below 90% but above 80%. 97.4% (95.8–98.4) of infants received antiretroviral prophylaxis. 91.1% (88.7–93.0) of HIV-positive mothers were on ART during pregnancy and 90.4% (87.9–92.3) of both mothers and infants received antiretroviral treatment/ prophylaxis per protocol. Exclusive breastfeeding in the last/previous 7 days was 88.1% (85.6–90.3) and coverage of maternal ART at six weeks was 85.6% (82.9–88.0).

In univariable analyses, socio-demographic factors significantly increasing the risk of MTCT (Table 2) included younger maternal age, marital status and having a flush toilet. Cohabitating was a protective factor reducing the risk of MTCT.

Multiple EMTCT and maternal and child health service factors were significantly associated with MTCT risk (Table 3) reflecting the impact of missed opportunities in the EMTCT cascade even in the context of high EMTCT service coverage. HIV-exposed infants of mothers who were not referred to the ART clinic, or started ART during pregnancy or after delivery compared to starting before pregnancy, were risk factors for MTCT. HIV-exposed infants whose mothers tested HIV-negative or were not tested during pregnancy or not taking ART during pregnancy were at increased risk of MTCT, as was starting infant antiretroviral prophylaxis after 72 h and incomplete antiretroviral treatment/prophylaxis (lack of anitretrovirals in either mother or baby or both), however these variables did not reach statistical significance (p < 0.05). Lack of infant feeding counseling or disclosure of HIV status also increased MTCT risk. Late attendance at antenatal care (3rd trimester) by the mother was a risk factor. Not testing women for syphilis during antenatal care was a risk factor for MTCT, but this variable did not reach statistical significance (p < 0.05).

Three multivariate models were created to assess independent effects on MTCT. Variables in univariable analysis (Tables 2 and 3) with a p-value < 0.10 were included in the first two multivariable models. The third model combined significant variables from these intial two models for a final model examining both socio-demographic and EMTCT service factors. A backward step-wise approach was used to generate the final model (Table 4). Due to concerns about statistical power as a result of small number of events (n = 26) and potential co-linearity between certain variables (e.g. referral for maternal ART and receipt of maternal ART, measures of maternal and infant antiretroviral treatment/prophylaxis) only the following variables were included in the full model: Maternal HIV testing status; Mother ART clinic referral; Infant Feeding Counseling; HIV Status Disclosure; Late Antenatal Care – 3rd Trimester; Syphilis testing during pregnancy; Delivery attendant; Preterm delivery; Both Mother and Baby getting antiretroviral treatment/prophylaxis; Timing of maternal ART initiation; Timing of infant Nevirapine initiation.

A large number of risk factors remained significant in the final model. Receipt of maternal ART and infant antiretroviral prophylaxis according to Rwanda EMTCT protocol was a highly significant protective factor against MTCT (OR 0.01; 95%CI 0.001–0.17), while variables suggesting inadequate antiretroviral treatment/prophylaxis were all significant risk factors (No referral for ART, started of ART after delivery, and start of infant Nevirapine after 72 h). Maternal age older than 25 years was protective (OR 0.33; 95%CI 0.14–0.78). Factors suggesting higher socio-demographic status were risk factors for MTCT (flush toilet, mother self-employed (borderline significant). No disclosure of HIV status, no syphilis testing during pregnancy and preterm birth were also significant risk factors.

The Rwanda rate of early transmission of HIV from mother-to-child of 1.58% (95% CI 1.05–2.38%) showed a reduction from the 2.6% at 6 weeks reported by routine service delivery data in 2008, though this earlier data from the routine EID program may have reflected selection bias. [21] It also compares favourably to 3.5% documented in South Africa which was using a combination of dual-therapy and maternal ART (WHO Option A). [9] Compared to regional studies of Option B or B+, this rate compares favorably to 10% MTCT found in Kenya and 6.7% in Zimbabwe. [12, 13] The Rwanda national target is 2% at 18 months.

The coverage in the EMTCT Cascade is seen to be high with all indicators above 80% and many over 90%. (Fig. 3) The primary indicator for EMTCT program coverage is mothers who received ART during pregnancy, this showed a coverage of 91.1%, which is just above the Rwanda 2012 national target of 90%. [6] When both mothers and infants are considered 90.4% of mothers and babies received the recommended antiretroviral treatment/prophylaxis. Over 90% coverage of recommended antiretroviral treatment/prophylaxis during pregnancy is also consistent with UNAIDS targets for global elimination of MTCT, however the drop to 85.6% at 6–10 weeks is a concern as it is below the UNAIDS target for ART during breastfeeding of 90%. [10] The coverage figures for mothers and babies combined compare favorably to other studies, such as 65% in Zimbabwe, [13] 26% in rural Kenya, [11]. These figures also suggest approximately 10% missed opportunities for antiretroviral therapy/prophylaxis per Rwandan protocol in mother-baby pairs. These missed opportunities represented a significant risk for increased MTCT (Table 4), which is consistent with other reports in the literature [9‐11].

Several socio-demographic factors showed in univariable analysis to increase MTCT risk, however, only flush toilet and mother self-employed remained significant or borderline significant, respectively, in final multivariable analysis (Table 4). This finding suggests that higher socio-economic mothers seem more at risk of MTCT. Bucagu et al. [22] did not find any association of socio-economic status to MTCT in one health center in Rwanda, however this report was limited in scope and size. While some studies suggest the poor face more barriers to access EMTCT services [23, 24], the findings in this study are consistent with findings from a Nigerian study [25] which found that higher income mothers were less likely to access EMTCT services. Further studies on the relationship of socio-economic status, utilization of EMTCT services and MTCT in Rwanda are needed to allow better targeting of services across populations.

Teen and young mothers (< 25 years old) also showed a higher risk for mother-to-child transmission in the final multivariable analyses. This result is consistent with the Bucagu study which found a small but non-significant increased risk for women age less than 24 [22] and is also consistent with the Nigeria study which found a strong association between teenage mothers and MTCT risk [25]. Younger mothers are theorized to utilize EMTCT services less than older women [25] so this issue is important in the context of the Rwandan EMTCT program.

Lack of disclosure of HIV status showed an almost 7-fold increase in MTCT in the multivariable analysis. More than half (53–65%) of people in the Rwanda DHS indicated an accepting attitude towards persons with HIV/AIDS, [15] and a study of Rwandans with HIV showed limited perceived discrimination [26]. However, lack of disclosure and stigma may impact on both treatment adherence and safe infant feeding. Stigma and disclosure to family and friends of HIV status have consistently been seen to impact EMTCT care and treatment adherence in the literature [22, 26‐29].

Two antenatal care variables were significant risk factors for MTCT, antenatal care started after 27 weeks gestation and no maternal syphilis test during pregnancy. Not having a syphilis test remained significant in the final model. This association was also seen in a South African cohort study, which theorized that syphilis testing may be a marker for quality of antenatal care [30]. More recent policy analyses suggest the need for integration across HIV and Syphillis elimination programs to improve antenatal quality of care [31]. Preterm birth was a risk factor for MTCT which is consistent with the literature [30].

Limitations of the current design must be recognized. The data were facility-based using infants presenting for immunization. In their 2012 publication ‘A short guide on methods: measuring the impact of national EMTCT programmes: towards the elimination of new HIV infections in children by 2015 and keeping their mothers alive, WHO recognizes this methodology as one of several available to assess EMTCT impact. [17] This document notes the following pros and cons for this method: “in settings with high immunization coverage, real time data can be captured to inform population-level transmission and early infant HIV infection; relatively quick to undertake and can be repeated to provide trend data, especially if a modest amount of additional data is collected at the same time; also provides results for infants of mothers who did not attend antenatal clinic or receive EMTCT care; however this design  misses children who have died before immunization” [17,pg9].

In Rwanda the 6 week immunization visit has high attendance nationally (98.8%) meeting the condition for high immunisaiton coverage as suggested by WHO. In addition, the socio-demographic factors in this study were similar to those in the Rwanda DHS completed the year prior to the study. [15] Identification and referral of eligible infants to the clinic was also done during the immunization outreach strategy program in villages to maximize the chance of having all eligible infants. Infants who did not come for immunization, had severe illness or had already died by 6 weeks of age were not included in the sample suggesting a possible under-estimation of prevalence. Also, there were differences in the expected sample size per sampling strata (e.g. urban/rural and EMTCT/Non-EMTCT). These differentials may have existed as there were fewer Non-EMTCT sites due to rapid EMTCT program scale-up, and clients may have traveled to urban areas and EMTCT clinic sites in expection of more comprehensive services. These differences across strata were accounted for by weighting during statistical analyses. There is always potential for recall bias, however the relatively short recall period of 6 weeks minimizes this potential bias. Social desirability bias and fear of disclosure and stigma may cause mothers to either over or under-report participation in the EMTCT program. Confidentiality was assured and discussed as part of the informed consent process and a private place was secured for conducting interviews. In addition, data collectors were routine clinic nurses who had full access to maternal and newborn records to identify possible HIV-exposed infants. Established sensitivity and specificity of the HIV testing were operational, but should have been minimized through proper handling of specimens and assurance of laboratory quality control. The study did not include a measure of daily adherence to ART only regimen. In addition, national averages could hide subnational disparities not addressed in this study and suggest a need for further investigations on equity in the EMTCT program.

The low rate of MTCT of 1.58% achieved in Rwanda is a clear indication that new HIV infections in children can reach elimination targets. To reduce the the MTCT rate futher, the program must begin to address existing missed opportunities, particularly with regard to coverage of maternal ART and infant antiretroviral prophylaxis. Integration of EMTCT within the maternal and child health care platform [32], enhanced early treatment with ART and retention in care, starting antenatal care early and continuing antenatal care are some of the strategies to minimize the risks of missed opportunities. In addition, young, single mothers appear to be at higher risk suggesting the need for targeting this population.