Number of infants linked to ART after false-positive diagnosis, per 1,000 ART initiations, by assay specificity and MTCT risk.

<p>Multivariate sensitivity analysis varying specificity of the NAAT and infant HIV prevalence modelled by increasing MTCT risk. The vertical axis shows the number of infants with false-positive diagnosis initiating ART, per 1,000 ART initiations. Groups of coloured bars indicate 3 values for infant HIV prevalence at weaning (12 months of age): purple indicates a low MTCT risk scenario, with 12-month risk of 1.3%; green indicates the base-case value of 4.9%; and blue indicates a high MTCT risk scenario, with risk of 9.6%. Three values of NAAT specificity are shown within each MTCT risk scenario. For each combination of MTCT risk and NAAT specificity, bars indicate those who are truly HIV-uninfected (false-positive diagnosis). The left, dark-coloured bar in each pair reflects the outcome without confirmatory testing, and the right, light-coloured bar reflects the outcome with confirmatory testing. ART, antiretroviral therapy; EID, early infant diagnosis; MTCT, mother-to-child transmission; NAAT, nucleic acid amplification test.</p

Univariate sensitivity analyses examining the impact of variation in individual input parameters on the difference in cost per HIV-exposed infant between the without and with confirmatory testing strategies.

<p>Key parameters varied in sensitivity analyses are shown on the left. Values in parentheses indicate the range examined (from the value leading to the lowest difference in cost to the value leading to the greatest difference, with base-case values after the semicolon). The horizontal axis shows the difference in cost between the 2 strategies: without confirmatory testing minus with confirmatory testing. The bounds of the blue bar indicate the cost differences at the extreme parameter values; longer bars therefore indicate parameters to which the model results were more sensitive. Where confidence intervals were available for the primary data estimates used in the base case, we indicate the bounds of these confidence intervals with brackets overlying the blue bars; the distance between brackets therefore indicates the degree to which the base-case estimates are affected by parameter uncertainty. The blue bar reaches the far left axis (indicating a cost difference of 0) at the threshold value for each parameter where confirmatory testing is no longer cost-saving compared to without confirmatory testing. The grey vertical line indicates the value for each parameter at the base-case result: a savings of US$40 per infant with confirmatory testing. ART, antiretroviral therapy; EID, early infant diagnosis; NAAT, nucleic acid amplification test.</p

Base-case model results: Early infant HIV diagnosis testing at 6 weeks in South Africa with and without confirmatory testing.

<p>Base-case model results: Early infant HIV diagnosis testing at 6 weeks in South Africa with and without confirmatory testing.</p

Selected data parameters for CEPAC–Pediatric model analysis of early infant HIV diagnosis testing in South Africa.

<p>Selected data parameters for CEPAC–Pediatric model analysis of early infant HIV diagnosis testing in South Africa.</p

Total lifetime costs per HIV-exposed infant by EID strategy.

<p>Columns include components of lifetime total costs per HIV-exposed infant tested: routine HIV care, CD4 and HIV viral load monitoring, OIs and end-of-life care, ART, EID costs, and false-positive costs. EID programme costs are shown in blue and comprise 2%–3% of lifetime costs, as shown previously [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002446#pmed.1002446.ref021" target="_blank">21</a>]; false-positive costs are shown in orange and are made up of all component costs acquired for HIV-infected infants other than OI costs. ART, antiretroviral therapy; EID, early infant diagnosis; FP, false-positive; OI, opportunistic infection.</p

Implementation scenario model results: Early infant HIV diagnosis testing at 6 weeks in South Africa with and without confirmatory testing.

<p>Implementation scenario model results: Early infant HIV diagnosis testing at 6 weeks in South Africa with and without confirmatory testing.</p

Selected model input parameters for the base-case analysis (See S1 Table for complete list and ranges evaluated in sensitivity analyses).

<p><b>SD</b>: Standard deviation; <b>ART</b>: antiretroviral therapy; <b>PMTCT</b>: prevention of mother-to-child HIV transmission; <b>AZT</b>: azidothymidine (zidovudine); <b>ARV</b>: antiretroviral; <b>NVP</b>: nevirapine; <b>ABC</b>: abacavir; <b>3TC</b>: lamivudine; <b>LPV/r</b>: lopinavir/ritonavir; <b>TDF</b>: tenofovir; <b>FTC</b>: emtricitabine; <b>EFV</b>: efavirenz; <b>WHO</b>: World Health Organization</p><p><b>a</b>. 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 <i>laboratory</i> CD4 had 100% sensitivity and specificity to detect true CD4 ≤350/μL.</p><p><b>b</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 <i>POC</i> strategy and 3 weeks of AZT and 10 weeks of ART are assumed in the <i>laboratory</i> strategy.</p><p><b>c</b>. Please see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117751#pone.0117751.s004" target="_blank">S1 Table</a> for description of assumptions of outpatient healthcare resource utilization.</p><p>Selected model input parameters for the base-case analysis (See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117751#pone.0117751.s004" target="_blank">S1 Table</a> for complete list and ranges evaluated in sensitivity analyses).</p

Budget impact analysis.

<p>Antenatal and pediatric care costs are shown for the first five years after birth. We include the <i>POC</i> and <i>laboratory</i> base case strategies, as well as the low laboratory access scenario. The arrows indicate the time points at which the upfront higher costs of <i>POC</i> testing are recovered due to savings in pediatric care costs. The open arrow indicates that <i>POC</i> becomes cost-saving compared to “low-access” <i>laboratory</i> testing within six months of delivery; the closed arrow indicates that <i>POC</i> becomes cost-saving compared to the base-case <i>laboratory</i> testing strategy within 36 months after delivery. Costs over the first five years after birth are further detailed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117751#pone.0117751.s007" target="_blank">S4 Table</a>. Maternal costs were nearly equivalent for both strategies, and are not shown. The sharp inflection point in costs at 6 months after delivery represents the cessation of breastfeeding the associated costs for infant nevirapine for postnatal MTCT prophylaxis. <b>Abbreviations</b>: POC: point-of-care testing; ANC: antenatal.</p

Multivariate sensitivity analyses: Cost-effectiveness of POC CD4 testing compared to laboratory testing.

<p>The cost-effectiveness of <i>POC</i> CD4 testing compared to <i>laboratory</i> testing is shown for key combinations of <i>POC</i> CD4 assay cost, <i>POC</i> assay sensitivity, and <i>POC</i> CD4 test and result return rates, defined as the product of (proportion of HIV-identified women undergoing CD4 testing) * (proportion of CD4-tested women receiving CD4 results). <b>Abbreviations</b>: POC: point-of-care testing.</p

Model structure.

<p>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. <b>Abbreviations: ANC</b>: antenatal care; <b>POC</b>: point-of-care testing; <b>ART</b>: three-drug antiretroviral therapy; <b>AZT</b>: zidovudine.</p