Cost-effectiveness of World Health Organization 2010 guidelines for prevention of mother-to-child HIV transmission in Zimbabwe

Background. In 2010, the World Health Organization (WHO) released revised guidelines for prevention of mother-to-child human immunodeficiency virus (HIV) transmission (PMTCT). We projected clinical impacts, costs, and cost-effectiveness of WHO-recommended PMTCT strategies in Zimbabwe.Methods. We used Zimbabwean data in a validated computer model to simulate a cohort of pregnant, HIV-infected women (mean age, 24 years; mean CD4 count, 451 cells/L; subsequent 18 months of breastfeeding). We simulated guideline-concordant care for 4 PMTCT regimens: single-dose nevirapine (sdNVP); WHO-recommended Option A, WHO-recommended Option B, and Option B+ (lifelong maternal 3-drug antiretroviral therapy regardless of CD4). Outcomes included maternal and infant life expectancy (LE) and lifetime healthcare costs (2008 US dollars [USD]). Incremental cost-effectiveness ratios (ICERs, in USD per year of life saved [YLS]) were calculated from combined (maternal + infant) discounted costs and LE.Results. Replacing sdNVP with Option A increased combined maternal and infant LE from 36.97 to 37.89 years and would reduce lifetime costs from $5760 to $5710 per mother-infant pair. Compared with Option A, Option B further improved LE (38.32 years), and saved money within 4 years after delivery ($5630 per mother-infant pair). Option B+ (LE, 39.04 years; lifetime cost, $6620 per mother-infant pair) improved maternal and infant health, with an ICER of $1370 per YLS compared with Option B.Conclusions. Replacing sdNVP with Option A or Option B will improve maternal and infant outcomes and save money; Option B increases health benefits and decreases costs compared with Option A. Option B+ further improves maternal outcomes, with an ICER (compared with Option B) similar to many current HIV-related healthcare interventions. © 2012 The Author 2012. We used 3 validated, linked computer models for this analysis (Figure ​(Figure1):1): (1) a model of a single pregnancy and delivery (the mother-to-child HIV transmission [MTCT] model [10]); (2) the Cost-effectiveness of Preventing AIDS Complications (CEPAC) model of HIV infection and mortality among breastfed infants (the CEPAC infant model [13, 14]); and (3) the CEPAC-International model of HIV disease progression among postpartum women (the CEPAC adult model [11, 12, 15]). Clinical outcomes of the linked models included infant HIV infection risk at weaning, maternal life expectancy (LE) from delivery, and infant LE from birth. Economic outcomes, from the healthcare system perspective, included ANC costs (through delivery), maternal HIV-related healthcare costs, and infant healthcare costs. Model structure. Three linked models were used for this analysis, as described in the Methods, as well as in the Supplementary Appendix and previous work [10, 14, 15]. The mother-to-child human immunodeficiency virus transmission model includes events during pregnancy and delivery (left panel; Supplementary Figure 1). The Cost-effectiveness of Preventing AIDS Complications (CEPAC) adult model includes events occurring among mothers after delivery (bottom right panel; Supplementary Figure 2A), and the CEPAC infant model includes events for infants after birth (top right panel; Supplementary Figure 2B). Linkages between the models allow a combined analysis in which each woman–infant pair is simulated together from the time of first presentation at antenatal care through pregnancy and delivery, and then each woman and infant are simulated separately throughout their lifetimes. Abbreviations: ANC, antenatal care; ART, 2-drug antiretroviral therapy; ARVs, antiretroviral medications; HIV, human immunodeficiency virus; OI, opportunistic infection; PMTCT, prevention of mother-to-child HIV transmission; sdNVP, single-dose nevirapine. Incremental cost-effectiveness ratios (ICERs), in US dollars per year of life saved (YLS), were calculated from combined projected lifetime healthcare costs (antenatal + maternal + infant) and combined projected life expectancy (maternal + infant) [16], discounted at 3% per year. We used 2 criteria to interpret cost-effectiveness. First, following WHO guidance, an intervention was considered cost-effective if its ICER compared with the next least-expensive alternative was <3 times the 2008 Zimbabwe per capita gross domestic product, or 3 × $400 = $1200 per YLS [17, 18]. Second, we compared results with the recently reported range of ICERs for ART-related interventions in developing countries ($550–$5200 per YLS) [19]. This work was approved by the Partners Healthcare Institutional Review Board, Boston, Massachusetts. The linked models were used to simulate a cohort of pregnant, HIV-infected women in Zimbabwe and their infants. We examined 5 PMTCT regimens: (1) no antenatal ARVs (comparator), (2) sdNVP, (3) WHO Option A, (4) WHO Option B, and (5) Option B+ (Supplementary Table 1). Women were modeled to present to care at 24–28 weeks’ gestation and to breastfeed for 18 months, based on Zimbabwean data [20, 21], with ARV prophylaxis (Options A, B, and B+ ) continued throughout breastfeeding. To demonstrate the impact of guideline-concordant care, all women in the base-case analyses were assumed to be identified as HIV-infected at their first ANC visit. With no ARVs, women received no antiretroviral medications during pregnancy. With sdNVP, women initiated ART in pregnancy if clinical assessment indicated WHO stage 3–4 disease; CD4 testing was not included, reflecting its limited availability in the sdNVP-based National PMTCT Program in 2009. With Options A and B, women received ART during pregnancy if eligible by either CD4 or clinical criteria, and with Option B+, all women received lifelong ART. With all modeled regimens, women who linked to postnatal HIV care were assumed to undergo clinical and CD4 assessment at 6 weeks postpartum and to initiate ART if eligible, regardless of antenatal regimen received. In the base case, we assumed 100% adherence to PMTCT regimens (initiated at 30 weeks’ gestational age), 100% linkage to postnatal care for mothers and infants, and 100% retention in care and ART availability for women and infants meeting WHO ART initiation criteria [22, 23]. In sensitivity analyses, to reflect real-world programs, we examined reduced access to antenatal and postnatal care. The 3 simulation models are described in detail in the Supplementary Appendix and in previous publications [10, 14, 15]. The models were linked so that each mother–infant pair was simulated together from the time of first presentation at ANC through delivery (the MTCT model), and then each woman and infant were simulated separately over their lifetimes after delivery (the CEPAC adult and infant models), as in Figure ​Figure11 and Supplementary Figures 1 and 2. Based on Zimbabwean data, mean age at first ANC visit was 24 years [21]; mean CD4 count was 451 cells/µL (36% of women with CD4 count ≤350 cells/µL) [24]. Because detailed data to inform monthly risks of opportunistic infections (OIs) and HIV-related death in the absence of ART were not available from Zimbabwe, we derived these data from a cohort in South Africa (Supplementary Table 2) [25]. Details of ART initiation and switching, as well as CD4 and HIV RNA changes on ART, are provided in the Supplementary Appendix. Risks of MTCT during pregnancy and breastfeeding were calculated from PMTCT studies among breastfeeding populations in Africa, leading to estimates similar to those derived by the Joint United Nations Programme on HIV/AIDS (Supplementary Appendix) [10, 26]. Data and assumptions to inform infant mortality rates and LE values are shown in Table ​Table11 and detailed in the Supplementary Appendix. Selected Model Input Parameters See Supplementary Table 2 for complete list of parameters. Abbreviations: 3TC, lamivudine; ANC, antenatal care; ART, antiretroviral therapy; ARV, antiretroviral medications; d4T, stavudine; EBF, exclusive breastfeeding (in first 6 months of life, followed by MBF); EFV, efavirenz; FTC, emtricabine; HIV, human immunodeficiency virus; LPV/r, lopinavir/ritonavir; MACS, Multicenter AIDS Cohort Study; MBF, mixed breastfeeding; MOHCW, Zimbabwe Ministry of Health and Child Welfare; NA, not applicable; NVP, nevirapine; PTMCT, prevention of mother-to-child HIV transmission; SD, standard deviation; sdNVP, single-dose nevirapine; TDF, tenofovir; WHO, World Health Organization; ZDV, zidovudine. a ART eligibility was defined as CD4 count of ≤350 cells/µL or WHO stage 3–4 disease. b PMTCT uptake was defined as proportion of HIV-infected, pregnant women accessing PMTCT services by the time of delivery. See Supplementary Appendix text and Supplementary Table 2 for details. c Two months of antentatal drug are assumed in all regimens for the base-case analysis, based on median gestational age at booking in Zimbabwe of 30 weeks. d Total care costs for mothers and infants were calculated by multiplying resource utilization (number of outpatient visits and inpatient days) by an average of WHO-CHOICE estimates of costs for these encounters in 7 sub–Saharan African countries [28]. See Supplementary Appendix for details. e See Supplementary Table 2 for description of assumptions of outpatient healthcare resource utilization. Monthly medication costs were from the Clinton Healthcare Access Initiative [27]. Costs of clinical care were determined by estimating resource utilization (number of inpatient days and outpatient visits) for specified health conditions, then multiplying by the estimated costs of these healthcare encounters in Zimbabwe (Table ​(Table11 and Supplementary Appendix) [28]. For children aged >18 months, monthly utilization estimates (stratified by HIV and ART status) were multiplied by LE to estimate lifetime healthcare costs. Model-derived risks of MTCT, infant mortality, and postpartum maternal OIs were validated against published data, reported previously with extensive sensitivity analyses [10, 14]. For this study, we conducted univariate and multivariate sensitivity analyses on key PMTCT, pediatric, maternal, and cost parameters. We examined the impact of reported rates of PMTCT uptake, defined as the proportion of HIV-infected women receiving PMTCT services and ARVs by delivery (56%, estimated for Zimbabwe in 2009; 80%, the 2009 WHO target goal; 90%, the 2011 WHO target goal; and 95%, reported in neighboring Botswana in 2011) [5, 8, 29]. We varied the availability of CD4 assays from 25% to 100% in Options A, B, and B+; when CD4 count was unavailable in Option A, women were assumed to initiate ART only for WHO stage 3–4 disease. We also examined the impact of reduced pediatric ART availability (36%, estimated for Zimbabwe in 2009) [5] and of reported rates of maternal loss to follow-up (LTFU) from postnatal HIV care (Table ​(Table1)1) [30–32]. We defined a lowest-MTCT risk scenario, using the lowest published risks (best reported effectiveness/efficacy) for each modeled regimen (Table ​(Table1);1); a highest-MTCT risk scenario, combining the highest published risks for each regimen; and a scenario assuming equal MTCT risks with Options A and B. We also used 4 assumptions about LE for HIV-exposed and HIV-infected infants: (1) a high pediatric LE scenario, using the upper bound estimates shown in Table ​Table1,1, (2) a low pediatric LE scenario, using the lower bound estimates, (3) a largest difference scenario (lowest estimates for HIV-infected children; highest estimates for HIV-uninfected children), and (4) a smallest difference scenario (highest estimates for HIV-infected children; lowest estimates for uninfected children). Finally, we investigated potential maternal health impacts of Option B and B+ in 2 ways. First, we varied the efficacy of first-line ART when resumed after ART interruption, reflecting potential interruption-associated drug resistance. Next, we examined the impact of “treatment fatigue” for women who begin ART with CD4 count >350 cells/µL solely for PMTCT, modeled as (1) an increased risk of virologic failure >6 months after ART initiation or (2) a reduction in second-line ART efficacy. Because estimated costs of healthcare in Zimbabwe are markedly lower than in surrounding countries [28], we repeated the analysis using costs from South Africa (Supplementary Table 2) [33]. In the base case, we conservatively assigned lifelong costs of NVP-based ART to HIV-infected infants; in sensitivity analyses, as an upper bound on pediatric ART costs, we assigned the costs of lifelong lopinavir/ritonavir-based ART to sdNVP-exposed, HIV-infected children. Finally, the nondrug costs of providing 3-drug ARV regimens instead of zidovudine alone (e.g., personnel, laboratory costs) have not been reported; we also examined the impact of such implementation costs in the antenatal period.