Over the last decade, there have been major advances in the prevention of mother-to-child transmission (PMTCT) of HIV infection across sub-Saharan Africa.1,2 Increasingly complex antiretroviral regimens have been promulgated for prophylaxis along with the expansion of eligibility of pregnant women for triple-drug lifelong antiretroviral therapy (ART).3–5 Yet, implementation of PMTCT services remains suboptimal in many settings, with PMTCT coverage limited by health systems and clinical barriers to ART initiation in pregnancy.6–8
The functional separation of PMTCT and adult ART services within health systems is a potential hurdle to PMTCT implementation.9 In many settings, PMTCT services operate within antenatal care (ANC), separate from ART services, and ART-eligible pregnant women are referred out of ANC for treatment initiation. There is evidence that a substantial proportion of pregnant women do not complete this referral,10,11 and strategies such as use of “patient navigators” have been suggested as an intervention to better link women from ANC/PMTCT services to ART clinics.12,13 Another strategy to overcome this functional separation is the integration of ART services into ANC/PMTCT programs. This approach typically sees providers working in ANC/PMTCT conducting preinitiation assessments (including clinical examination, counseling, and laboratory testing) and initiating ART in eligible pregnant women, eliminating the need for referral from ANC/PMTCT for ART.14–16 However, data are mixed on whether such integration increases antenatal ART initiation in practice.15,17
Specific clinical and immunological eligibility criteria for treatment may introduce further barriers to ART initiation in pregnancy. Historically, guidelines have called for ART initiation in pregnant women based on WHO staging or CD4 cell count thresholds used for nonpregnant adults.18,19 But, as laboratory access is usually required for CD4 cell enumeration, CD4-based criteria for ART eligibility can introduce significant delays related to laboratory logistics.20,21 Provision of point-of-care (POC) CD4 testing is one approach to overcome these logistical barriers and may be particularly helpful in facilitating the rapid identification of ART-eligible pregnant women,22,23 but there are few data on the impact of POC CD4 testing within ANC/PMTCT services. More recently, the 2013 WHO guidelines recommended universal ART for all HIV-infected pregnant women regardless of CD4 cell count or WHO stage, either to be continued for life (“Option B+”) or to be stopped at the end of breastfeeding for women with relatively high CD4 cell counts (“Option B”).5 Although these approaches for universal ART initiation have gained widespread endorsement, there are few data on their practical implementation, and insights into how these compare with approaches to ART initiation in pregnancy that rely on CD4-based eligibility criteria are required.24–26
Many of these strategies to facilitate ART initiation in pregnancy have been discussed individually; however, little is known about the implementation of different interventions in practice. To address this, we examined the evolution of ART services for HIV-infected pregnant women over a 4-year period in Cape Town, South Africa. Specifically, we described how different service delivery models for providing ART to HIV-infected pregnant women influenced the uptake of ART in pregnant women before delivery.
We used routine health care records to construct a retrospective cohort of all HIV-infected pregnant women seeking ANC between January 1, 2010, and December 31, 2013, at a large ANC facility and nearby ART services in the community of Gugulethu in Cape Town, South Africa. The facility serves an estimated population of 350,000, and levels of poverty are high with 60% of the community living in informal housing.
ANC and PMTCT Services
Approximately, 4800 pregnant women seek ANC annually at the facility, which provides basic antenatal and obstetric services with hospital referral available for more complex care. PMTCT services are provided within the antenatal clinic (ANC/PMTCT) based on South African national guidelines. At the first ANC visit, all women receive HIV counseling and testing (HCT) with group and individual pretest counseling and individual posttest counseling. All HIV-infected women receive additional counseling, phlebotomy for CD4 enumeration, and further intervention as appropriate. This ANC service is nested within a community health center that provides a range of primary health care services, including ART, on a campus of adjacent buildings; although the ANC is staffed by nurse-midwives and counselors (with limited support from medical officers and obstetricians), the facility governance and oversight are through the community health center. Levels of ANC coverage in this community are high with >95% of pregnant women attending ANC before delivery. Partner testing is encouraged by the ANC/PMTCT service but was uncommon during the study period; separate HCT services for nonpregnant individuals are widely available in the community, including in the community health center.
Routine ART Services
General adult ART services are provided at a dedicated primary care facility located 100 meters from the ANC/PMTCT facility. The operation and outcomes of the adult ART program have been described previously.27 Briefly, patients identified as ART-eligible based on CD4 cell count or WHO staging are referred to these services for preinitiation assessments that include clinical examination, counseling, and laboratory investigations; ART initiation takes places 2–4 weeks after the review of laboratory testing and completion of adherence counseling. At the start of the study period, there were approximately 3000 adults on ART, and over the 4-year period, an additional 4400 nonpregnant adults and children initiated therapy from the surrounding community.
Models of Care for ART Initiation in Pregnancy
Six service delivery models were examined in sequential phases during the 48-month study period (Table 1).
- During a first preintervention period (January 2010 to October 2010), ANC/PMTCT services referred all eligible pregnant women based on 2006 WHO guidelines to the ART clinic.18 ART eligibility was determined using laboratory-based CD4, and women with CD4 ≤200 cells per microliter were provided with a standardized referral letter and counseling to attend the ART service. Women who completed this referral underwent preinitiation assessment and subsequent ART initiation as described above.
- In a second preintervention period, services (November 2010 to July 2011) followed the same approach, but the CD4 threshold for ART eligibility was increased to CD4 ≤350 cells per microliter.19
- Third, an Enhanced Linkage intervention (August 2011 to January 2012) used lay PMTCT counselors as “patient navigators” to support referrals to the ART service. Lay counselors accompanied eligible women, based on CD4 ≤350 cells per microliter, from the ANC/PMTCT service to the ART clinic, assisting with the appointment process and the first clinic visit while providing PMTCT and ART-related counseling.
- Fourth, an Integrated ART intervention period (January 2012 to August 2012) shifted the site of ART initiation from the ART clinic to the ANC/PMTCT service, removing the need to refer women between services. The Integrated ART service was delivered by ART-trained midwives working in the ANC using clinical and monitoring protocols identical to those used in the ART clinic. Throughout this period, ART eligibility was determined with laboratory-based CD4 ≤350 cells per microliter.
- During the fifth phase, on-site CD4 testing (July 2012 to June 2013) was added to the Integrated ART service using the Alere Pima POC device. Although we found good agreement between POC and laboratory-based testing,28 all specimens tested on the POC machine during this phase were also sent for laboratory testing, and women deemed eligible for ART based on CD4 ≤350 cells per microliter on either platform. The on-site CD4 test resulted in a slightly higher proportion of women being ART-eligible based on CD4 ≤350 cells per microliter compared with the laboratory platform.28 During the on-site CD4 testing phase, approaches to counseling ART-eligible pregnant women emphasized rapid ART initiation.29,30
- Finally, during the sixth phase, Universal ART (July 2013 to December 2013) changes in provincial PMTCT policy to “Option B+” meant that all HIV-infected pregnant women were eligible for lifelong therapy.31 With this shift to universal ART provided as part of PMTCT/ANC, CD4 cell counts were no longer used to determine eligibility but were still performed using laboratory testing to determine nadir CD4.
Following national guidelines, all women initiating ART during the study period received 2 nucleoside reverse transcriptase inhibitors (usually tenofovir and lamivudine) and a non-nucleoside reverse transcriptase inhibitor [nevirapine (NVP) up to 2011 and efavirenz (EFV) thereafter]. Throughout the observation period, both the routine ART service and Integrated ART service used the same clinical and laboratory monitoring protocols, the same laboratory service (with the exception of the POC CD4 technology used during the on-site CD4 phase), and ART and PMTCT counselors were overseen by the same local non-governmental organization. As part of the service delivery models for on-site CD4 testing and Universal ART, there was an effort to expedite ART initiation including minimizing delays to ART initiation due to counseling; however, the counselors working in the service, the patient education materials, and the counseling messages were not changed with the service delivery models.
Data Sources and Measures
Data were drawn from 2 routinely collected data sources. First, the PMTCT register maintained at the ANC was used to extract the number of women making their first ANC visit, consenting to HCT, testing HIV-positive, and CD4 cell counts. Second, records of all patients seen at either the ART service or the PMTCT/ANC service were accessed to abstract the dates of preinitiation assessment and ART initiation, as well as sociodemographic and clinical information. All patient data were deidentified before analysis, and permission to use routine clinical data for the purposes of research was provided by the University of Cape Town Health Research Ethics Committee.
Data were analyzed using Stata version 12.0 (Stata Corporation, College Station, TX). The proportions of women completing different steps within the PMTCT “cascade,” including accepting HCT, testing HIV-positive, with CD4 cell counts results, ART eligibility, and ART initiation were estimated with exact 95% confidence intervals (CI); proportions were compared across service delivery models using χ2 tests. All women who were deemed ART-eligible according to the criteria used in each phase (as listed above) were included in the analyses of ART eligibility; in instances of multiple pregnancies involving the same woman during the 4-year period, analyses of ART eligibility were restricted to the woman's first visit at which she was ART-naive and ART-eligible. Delays between the dates of the first antenatal visit, preinitiation assessment, and ART initiation (for women starting ART) were summarized using medians with interquartile ranges (IQR); comparisons used nonparametric tests for trend.32 We used the product-limit method to estimate the proportion of women initiating ART from the date of the first ANC visit, with censoring at the time of delivery presented as “failure” plots for different periods. Proportional hazards regression was used to compare the frequency of antenatal ART initiation between periods after accounting for covariation in participant demographic and clinical characteristics; results are presented as hazard ratios with 95% CI. Throughout, the primary analyses included all women making their first ANC visit during each intervention period; in sensitivity analyses, we (1) excluded the first 2 months of observation under each service delivery model to allow for transitioning from the previous model and gradual optimization of service routines and then (2) limited analyses to the first 6 months of each period (based on the shortest duration of the observation periods) to limit the possibility of service enhancements that make take place after 6 months of implementation.
Between January 2010 and December 2013, 19,432 women made their first ANC visit and were included in analysis. Table 2 describes the proportion of women engaged in different aspects of ANC/PMTCT and ART care during each service delivery model. Uptake of HCT was high (96%–100%) with the antenatal HIV seroprevalence approximately 30% throughout the study period. Among HIV-infected women, the proportion of women with available CD4 results increased over time but was not significantly different in the Integrated ART service that used laboratory-based testing compared with the same service after the introduction of POC CD4 testing (P = 0.98). The proportion of HIV-infected women who entered ANC already on ART-increased over time, from less than 10% in the first period to more than 40% under universal ART (P < 0.001).
Figure 1 shows the ART initiation “cascade” across service delivery models. The proportion of all HIV-infected pregnant women not already on ART who were identified as eligible increased from 18% during the first phase when eligibility was based on CD4 ≤200 cells per microliter to approximately 40% during subsequent phases when eligibility criteria broadened to CD4 ≤350 cells per microliter to 100% under the Universal ART approach. The absolute numbers of women requiring ART per month increased in parallel.
Among ART-eligible women, the proportions of women undergoing preinitiation assessment and initiating ART before delivery were significantly different across service delivery models (Table 2 and Fig. 1). Compared with the preceding period of separate ART and ANC/PMTCT services, the proportion of ART-eligible women initiating treatment under the enhanced linkage model increased by 27% (from 17% to 44%), and subsequently, the proportion of women initiating ART before delivery in the Integrated ART service model increased a further 34% (from 44% to 78%; P < 0.001 for both comparisons). However, the inclusion of POC CD4 testing in the on-site CD4 testing model did not increase this proportion further (78% vs. 83%, P = 0.64). The highest levels of ART initiation were observed under the Universal ART model with 92% of all HIV-infected women initiating ART during pregnancy and 94% of women with CD4 ≤350 cells per microliter compared with 76%–80% of women initiated under the Integrated ART model using CD4-based eligibility criteria.
In the subset of women initiating ART during pregnancy, the distribution of delays from the time of first ANC attendance to preinitiation assessment and ART initiation are shown in Figure 2. The median delay from first ANC attendance to preinitiation assessment (Fig. 2A) decreased from more than 40 days during the 2 preintervention phases (IQR, 19–80 days), to 17 days (IQR, 11–31 days) in the Integrated ART model, to 0 days (ie, preinitiation assessments were carried out on the same day as the first ANC visit for the majority of women) under both the on-site CD4 testing and Universal ART models (P value for trend, <0.001). In parallel, the median delay from the first ANC attendance to ART initiation decreased from more than 60 days during the preintervention periods (IQR, 34–105 days) to 42 (IQR, 23–76 days), 23 (IQR, 18–42 days), 8 (IQR, 5–23 days), and 0 days under the enhanced linkage, Integrated ART, on-site CD4 testing, and Universal ART models, respectively (P value for trend <0.001). Under the Universal ART model of “Option B+,” 82% of women who initiated ART did so on the date of their first ANC visit.
Figure 3 shows the proportions of women starting ART during pregnancy over time from the first ANC visit under different models of service delivery, including analysis of all HIV-infected women (Fig. 3A), and restricted to women determined to be ART-eligible under the respective service model (Fig. 3B) and women with CD4 cell counts <350 cells per microliter (Fig. 3C). In all analyses, the proportion of women initiating therapy before delivery was the lowest in the preintervention phases, increased under the Integrated ART model and was the highest in the Universal ART model. When the analysis was restricted to women identified as ART-eligible as per the different service delivery models (Fig. 3B), the proportion of women initiating ART before delivery under CD4-based eligibility criteria did not exceed 80% regardless of the model of care. When using an ART initiation CD4 threshold of 350 cells per microliter (Fig. 3C), the proportion of women initiating therapy over time under on-site CD4 testing model was significantly higher than was observed under the Integrated ART model with laboratory-based CD4 cell counts only (log-rank P < 0.001). In sensitivity analyses (see Appendix 1, Supplemental Digital Content, http://links.lww.com/QAI/A653), larger differences were observed between the models when the first 2 months of observation under each model were excluded to allow for service optimization; however, the findings did not vary substantively when analyses were restricted to the first 6 months of each service delivery period.
In proportional hazards regression (Table 3), the differences in ART initiation between service delivery models persisted after adjustment for women's age, gestation in weeks at the start of ANC, and CD4 cell count. Compared with the preintervention model with ART eligibility based on a CD4 ≤350 cells per microliter, women were approximately 7 times more likely to initiate ART before delivery under the Integrated ART model and more than 20 times as likely under the Universal ART model. When the model was restricted to women with CD4 ≤350 cells per microliter, antenatal ART initiation was 30 times more likely under the Universal ART model compared with the preintervention phases (hazard ratios: 32.09; 95% CI: 22.95 to 44.85).
This analysis documents the rapid evolution of services for ART initiation in HIV-infected pregnant women in Cape Town, South Africa. Over 4 years, implementation of new models of service delivery was accompanied by increases in both the numbers of pregnant women who were ART-eligible and the proportion of women starting ART before delivery, as well as significant decreases in the delays to antenatal treatment initiation.
Integration of ART into ANC services has been discussed widely; however, empirical data on the effects of integration on ART initiation are surprisingly mixed.14,15,17 Here, the shift to Integrated ART within ANC services, compared with the preceding period of referral of ART-eligible women from ANC to separate ART facilities, was associated with the single greatest absolute increase in the proportion of ART-eligible women initiating treatment before delivery. Integrated ART services were also associated with significant reductions in the delay from first ANC visit to ART initiation. As with any health service intervention, the effects of integration of ART into ANC services are likely to depend heavily on local contexts. In this setting the system of referral of ART-eligible pregnant women to separate services for treatment initiation was clearly suboptimal, resulting in only 20%–50% of women initiating before delivery.10,33 Although other health systems across sub-Saharan Africa may have stronger ANC-ART referral systems, these data suggest that in settings where referral of pregnant women for ART initiation functions poorly, the integration of services can result in significant advances.
We found that the inclusion of POC CD4 testing did not increase the proportion of women initiating ART before delivery compared with laboratory-based testing systems. However, these observations are from a context of relatively good laboratory access, where more than 80% of women had CD4 counts available through laboratory testing. In settings where laboratory access is limited or nonexistent, POC technologies are likely to play an important role in provision of timely test results. This may be particularly important in settings where CD4 cell counts are used to determine ART eligibility among pregnant women.34,35 In addition, we found that POC testing was associated with a significant reduction in the delays from the first ANC visit to treatment initiation. Minimizing delays to antenatal ART initiation is likely to be associated with improvement in PMTCT outcomes, as increasing the duration of ART received before delivery is associated with significant reductions in vertical transmission risk in utero, intrapartum, and when breastfeeding.36,37
These are the first data from the Western Cape province of South Africa on the implementation of universal ART for all HIV-infected pregnant women. The findings are in broad keeping with previous data on “Option B+” implementation from Malawi,38 demonstrating substantial increases in the initiation of triple-drug regimens during pregnancy when CD4-based ART eligibility criteria are removed. The absolute increases observed here under “Option B+” seem somewhat more modest than those reported from Malawi; however, likely because of the relatively low levels of ART initiation in pregnancy in Malawi before the implementation of “Option B+.”38 Importantly, although the services implemented here called for lifelong ART for all HIV-infected pregnant women regardless of CD4 cell count (“Option B+”), this analysis focused specifically on ART initiation in pregnancy, and the results observed are unlikely to have been substantially different under a policy of universal ART for all pregnant and breastfeeding women to be continued as lifelong treatment only for women with relatively low CD4 cell counts (“Option B”).5 Also, of note, local PMTCT guidelines in this setting call for ongoing use of pre-ART CD4 enumeration in HIV-infected pregnant women despite universal ART eligibility; this approach is believed to be of possible value in clinical management on women on lifelong ART. However, empirical data on the clinical utility and programmatic cost-effectiveness of CD4 cell counts under “Option B+” are sparse, and this aspect of “Option B+” requires further consideration.
These data point to 2 important features of “Option B+” implementation when compared with the preceding policies of CD4-based ART eligibility in pregnant women (“Option A”). First, the removal of CD4-based eligibility criteria is associated with significant increases in antenatal ART initiation in the subgroup of women with low CD4 cell counts who are at greatest risk of vertical transmission as well as morbidity and mortality.39 Here, the proportion of women with CD4 ≤350 cells per microliter who started ART before delivery under “Option A” ranged from 16% in the preintervention period to 80% with the POC CD4 intervention, which may represent the optimal implementation of the WHO's “Option A” approach; under “Option B+,” this increased to 92% of all women.
Second, delays to antenatal ART initiation were largely eliminated by the removal of CD4-based ART eligibility criteria under “Option B+” with approximately 80% of women initiating ART on the day of their first ANC visit. Reducing delays to treatment initiation may have significant transmission benefits by increasing the duration of antenatal ART exposure40; however, the putative advantages of same-day ART initiation must be weighed against the possible limitations of this approach from a patient perspective. Not all women may be willing to start lifelong therapy immediately, and the frequency of same-day initiation has been posited as one reason for the relatively high levels of loss to follow up observed under “Option B+” in Malawi.41 Here, we do not have data on long-term maternal retention on ART under “Option B+” and how same-day treatment initiation may influence adherence, and retention outcomes requires urgent research attention.42,26
This analysis is subjected to several limitations. As routine health systems data, the results are representative of real-world ANC/PMTCT and ART services, but detailed psychosocial and clinical measures are not available. In particular, we do not have data on the non-nucleoside reverse transcriptase inhibitor used in ART regimens. Although the transition from NVP to EFV took place during 2011, we are unable to disaggregate the specific impact of different non-nucleoside reverse transcriptase inhibitors on the timing of antenatal ART initiation. From our experience, the shift to widespread EFV use in pregnancy may have contributed to the reductions in time to ART initiation, as the use of liver function testing before NVP initiation (which was routine in local ART protocols) was removed. In addition, we cannot rule out health system factors influencing ART initiation in pregnancy over time that may have coincided with the service delivery changes described here, although we note that available HIV-related indicators such as HCT uptake within the PMTCT service appeared remarkably constant during the 4-year study period. Similarly, the limited availability of patient-level demographic and psychosocial measures that may influence uptake of ART in pregnancy6 hinders our ability to examine possible residual confounding, whereas the plausibility of patient-level factors changing appreciably over time to explain the observed trends is unclear.
The improvements in service delivery observed in this analysis took place over relatively short periods, with new interventions implemented and optimized within several months of changes in service policy. Although the drivers of this phenomenon require additional attention, we hypothesize that the rapidity of implementation may be attributed to: the combination of a robust underlying service delivery platform in the existing ANC/PMTCT service; a strong local ART service with dedicated providers (including counselors, nurses, and doctors) within the community health center to support integration; and optimization of ART into ANC/PMTCT and focused training and support to nurse-midwives working within the ANC/PMTCT to assist in implementing each change in service delivery. More broadly, the developments documented here took place in the context of an urban South African health service with a high burden of HIV and relatively functional health system; although the findings may be broadly applicable to urban centers across the region, any extrapolation should proceed with caution.
Although this analysis focuses on ART initiation in pregnancy, it is important to note that retaining mothers adherent to ART and preventing mother-to-child transmission are the ultimate goals of effective PMTCT services; understanding how PMTCT policies, most notably universal ART strategies, impact on these outcomes requires further research. In particular, although this analysis focuses on models of service delivery for providing ART during the antenatal period, there has been little attention to optimal models of care for mothers on ART and their infants, and health systems and services that support maternal ART during the postnatal period are required.
In summary, these data demonstrate significant advances in ART initiation during pregnancy over the past 4 years in this setting. Integration of ART into ANC/PMTCT services was associated with substantial increases in antenatal ART initiation. Recent developments calling for universal ART initiation for all HIV-infected pregnant women seem to be associated with significant increases in the proportion of women starting ART before delivery and concomitant decreases in the delays to starting ART. Further investigations are required into how policy developments for ART initiation in pregnancy may influence long-term maternal and child health outcomes, including vertical HIV transmission, maternal ART adherence, and long-term retention in care.
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