Point-of-care CD4 testing to inform selection of antiretroviral medications in South African antenatal clinics: A cost-effectiveness analysis

Background Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays. Methods We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO “Option A”): antenatal zidovudine (CD4 ≤350/μL) or ART (CD4>350/μL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/lifeyear saved). Results In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs. Conclusions In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection. This work was approved by the Partners Healthcare Human Subjects Committee, Boston, MA, USA and the University of Cape Town IRB, Cape Town, South Africa. Participants at the study site in South Africa provided written informed consent for this work. In 2012, a point-of-care CD4 assay was introduced and evaluated in the Gugulethu Midwife Obstetric Unit (MOU), an antenatal clinic near Cape Town, South Africa (Appendix) [15]. We used data from this evaluation, with published clinical and cost data, to simulate a cohort of pregnant women identified as HIV-infected in antenatal care and their infants [13,14,21–24]. We linked three validated computer models: 1) a decision analytic model simulating a cohort of women through a single pregnancy and delivery (the “MTCT model”) [25–27]; 2) a Monte Carlo model of HIV disease among postpartum women (the Cost-effectiveness of Preventing AIDS Complications-International or “CEPAC-Adult model”) [28,29]; and 3) a Monte Carlo model of perinatal and postpartum HIV infection among HIV-exposed infants (the “CEPAC-Pediatric model”) [26,30]. Together, these three models simulate each mother-infant pair from the time of presentation to antenatal care (ANC) through the lifetimes of both mother and infant. We projected short- and long-term clinical and economic impacts for two CD4 testing strategies: flow cytometry performed in a central laboratory (“laboratory”), and point-of-care testing performed in the antenatal clinic (“POC”). Clinical outcomes included MTCT risk at birth and weaning, pediatric life expectancy from birth, maternal life expectancy from presentation to care, and combined (maternal+pediatric) life expectancy. Economic outcomes, from the healthcare system perspective, included ANC costs, lifetime maternal HIV-related healthcare costs, lifetime pediatric healthcare costs, and 1–5-year maternal and pediatric health care costs (2013 USD). We calculated incremental cost-effectiveness ratios (ICERs) in $/life-year (LY): difference in combined healthcare costs (antenatal+maternal+pediatric costs) between the two strategies divided by difference in combined projected life expectancy (maternal+pediatric life expectancy). For ICERs, all outcomes were discounted at 3%/year [31]. We considered a strategy to be “very cost-effective,” compared to the alternative strategy, if its ICER was <1x South African per-capita gross domestic product (GDP: $6,600 in 2013)/LY, “cost-effective” if the ICER was <3x GDP/LY, and “cost-saving” if it led to greater combined life expectancy and lower combined costs [32,33]. We projected outcomes for a cohort of HIV-infected, ART-naïve pregnant women and their infants in South Africa (Table 1), following a positive HIV test at the first ANC visit [13]. In laboratory, CD4 specimens were shipped to the national laboratory for flow cytometry, with results returned to patients at a second visit three weeks later. In POC, CD4 testing and result-return both occurred during the first ANC visit. SD: Standard deviation; ART: antiretroviral therapy; PMTCT: prevention of mother-to-child HIV transmission; AZT: azidothymidine (zidovudine); ARV: antiretroviral; NVP: nevirapine; ABC: abacavir; 3TC: lamivudine; LPV/r: lopinavir/ritonavir; TDF: tenofovir; FTC: emtricitabine; EFV: efavirenz; WHO: World Health Organization a. Sensitivity and specificity were modeled with regard to true CD4 value of ≤350/μL (sensitivity: assay reports CD4 ≤350/μL when true CD4 is ≤350/μL; specificity: assay reports CD4 >350/μL when true CD4 is >350/μL). To be conservative with regard to the benefit of POC, we assumed in the base case that laboratory CD4 had 100% sensitivity and specificity to detect true CD4 ≤350/μL. b. In the base-case analysis, 13 weeks of antentatal AZT for non-ART eligible women are assumed in both strategies, based on median gestational age at booking in South Africa of 26 weeks. For ART-eligible women, 13 weeks of ART are assumed in the POC strategy and 3 weeks of AZT and 10 weeks of ART are assumed in the laboratory strategy. c. Please see S1 Table for description of assumptions of outpatient healthcare resource utilization. We simulated South African PMTCT guidelines at the time of the study, which reflected WHO Option A (lifelong maternal three-drug ART if CD4 ≤350/μL or WHO Stage 3–4 disease; maternal zidovudine (AZT) in pregnancy, then daily infant nevirapine (NVP) throughout breastfeeding if CD4 >350/μL; Fig. 1) [3,5]. In the antenatal period, we therefore modeled provision of AZT to women who were awaiting CD4 results (laboratory), who never received CD4 results (either strategy), or who received results indicating CD4>350/μL (either strategy). We modeled provision of antenatal three-drug ART to women who received results indicating CD4 ≤350/μL or who had evidence of WHO Stage 3–4 disease (either strategy). As a result, the model permits women with CD4 <350/μL to “incorrectly” receive AZT instead of ART, and thus have higher MTCT risks (Table 1), in order to incorporate the critical role of CD4 testing in selecting antenatal ARV regimens. This figure shows the modeled sequence of events during antenatal care that determine a mother’s prescribed PMTCT drug regimen. During the first visit, all women receive an HIV test and HIV test results. In the current analysis, all women who are HIV-infected are assumed to have positive HIV test results and enter the MTCT model, at which point they are assigned a probability of undergoing a CD4 test and, if tested, a probability of receiving their CD4 test results. Women are also modeled to be eligible for ART (true CD4 ≤350/μL) or non-eligible for ART (true CD4 >350/μL) based on 2010 WHO guidelines. The sensitivity and specificity of the CD4 assays are reflected in assigned probabilities that the CD4 test will indicate women to be eligible or non-eligible for ART. The observed CD4 results then determine whether women receive AZT or ART for PMTCT. Transmission probabilities and maternal outcomes depend on true CD4 count and PMTCT regimen received. Abbreviations: ANC: antenatal care; POC: point-of-care testing; ART: three-drug antiretroviral therapy; AZT: zidovudine. In the absence of data on infant feeding practices under recent South African guidelines, we modeled six months of breastfeeding for all infants [6]. After delivery, modeled women in both strategies linked to postnatal care, including routine laboratory-based CD4 monitoring. Women with initial or current CD4 ≤350/μL continued lifelong ART, and those with initial and current CD4 >350/μL stopped maternal AZT and provided daily nevirapine syrup to their infants until weaning [3,5]. To isolate the impact of the CD4 testing strategies, in the base case, we varied only CD4 testing rates, CD4 result-return rates, and CD4 assay costs. We otherwise assumed guideline-concordant care based on receipt of CD4 results: all women were accurately identified as HIV-infected, all mothers and infants adhered to prescribed PMTCT regimens, and all mothers and infants linked to postnatal HIV-related care, received ART if eligible after delivery, and were retained in care. To be conservative with regard to the benefit of POC, we assumed in the base case that laboratory CD4 had 100% sensitivity and specificity to detect true CD4 ≤350/μL, and that POC had 93% sensitivity and 86% specificity to detect true CD4 ≤350/μL (Table 1) [18]. We varied all of these assumptions in sensitivity analyses. We linked three computer models to simulate mother-infant pairs through pregnancy, breastfeeding, and the lifetimes of both mothers and infants (S1 Appendix; S1–S2 Figs.) [25–29,34]. At the time of presentation to ANC, mother-infant pairs enter the MTCT model, in which they face probabilities of key clinical events during pregnancy and delivery. MTCT model outcomes are assessed after delivery, and include maternal and infant vital status, infant HIV infection, and costs accrued during pregnancy and delivery. From delivery through death, clinical and economic outcomes are simulated for mothers in the CEPAC-Adult model and for infants in the CEPAC-Pediatric model. In these models, individuals are subject to monthly risks of clinical events, including opportunistic infections, response to ART, medication toxicities, and mortality, and the costs associated with these events (Appendix). We simulated the cohort of women seeking care at the Gugulethu MOU, with median age of 26 years and median gestational age at first visit of 26 weeks (Table 1, S1 Table) [13]. Monthly risks for opportunistic infections (OIs) and HIV-related death in the absence of ART were from Cape Town (adults) and from the International Epidemiologic Database for the Evaluation of AIDS (IeDEA; children) [30,35,36]. First-line ART was tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV) for women and abacavir/lamivudine/lopinavir/ritonavir (ABC/3TC/LPV/r) for HIV-infected children [3,37–39]. Further details of ART initiation, CD4 and RNA responses to ART, and switching to second-line ART regimens are provided in the Appendix [40–44]. Modeled MTCT risks during pregnancy and breastfeeding, which substantially impact projected pediatric life expectancy, were the average values from published clinical studies in African breastfeeding populations, stratified by maternal CD4 count and ARV regimen received (Table 1, S1 Table, S1 Appendix) [26]. In sensitivity analyses, we also examined the impact of the highest and lowest published transmission risks for each regimen and CD4 stratum (S1 Appendix). We defined two key parameters for each CD4 testing strategy: the proportion of HIV-infected women undergoing CD4 testing, and the proportion of CD4-tested women receiving CD4 results and initiating three-drug ART if CD4 ≤350/μL (result-return, Table 1; result-return rates below 100% reflect the proportion of women lost to follow-up before receiving CD4 results). For the laboratory strategy, data for testing (96%) and result-return (87%) were from the Cape Town MOU [45]. For the POC testing strategy, data for testing (99%) and result-return (95%) were from the pilot study of POC CD4 measurement at the MOU [45]. Based on MOU data, we modeled a 3-week interval between CD4 testing and CD4 result-return for the laboratory strategy [14]. POC CD4 assay costs (base case: $26) were derived according to Larson et al., substituting healthcare worker time observations from the MOU and local salary data in place of the Larson estimates (Table 1, S1 Table) [21]. Laboratory-based CD4 assay costs (base case: $14) were from published data [22]. During pregnancy, we included the costs of routine antenatal care and delivery (Appendix). After delivery, we included maternal and pediatric costs for routine HIV-related healthcare, acute care for opportunistic infections, ART, laboratory monitoring, and care in the final month of life (Appendix) [22,35,46,47]. All costs were in 2013 US dollars. In previous work, we validated model-projected MTCT risk, pediatric survival, pediatric HIV-free survival, and maternal postpartum OI rates against published data, and we reported extensive sensitivity analyses on clinical, cost, and access-to-care parameters [25–28]. For this analysis, we examined additional variations in test sensitivity, specificity, testing rates, and result-return rates for the POC strategy, as well as antenatal and postnatal loss to follow-up (LTFU) rates, breastfeeding duration, healthcare and medication costs, MTCT risks, and the discount rate for both POC and laboratory strategies (S1 Table). We also examined both decreased POC CD4 costs, reflecting new POC assays in development, and increased POC CD4 costs, to incorporate possible costs not captured in the base-case estimate, for example: additional healthcare worker time to process CD4 specimens, undergo training, or conduct quality control activities; or reduction in staff capacity to perform other patient-related activities [21,48–50]. Finally, we conducted multiway sensitivity analyses, varying POC assay cost, sensitivity, testing rates, and result return rates simultaneously. In many settings, access to laboratory-based CD4 testing is more limited than in Cape Town, an urban area close to central laboratory facilities. We therefore examined a second, “low laboratory access scenario,” in which POC CD4 testing was introduced into a setting with a laboratory test rate (30%) and result-return rate (50%) based on UNAIDS data for low/middle-income countries [51]. To inform short-term budgets, we projected not only lifetime outcomes, but also outcomes over a 5-year horizon. Outcomes included ANC costs, pediatric costs, total costs, and yearly pediatric survival rates for both laboratory and POC strategies. Because variations in access to laboratory-based CD4 testing had the greatest impact on lifetime cost projections, we repeated the budget impact analysis in the “low laboratory access” scenario.