The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis

Abstract

Background: The specificity of nucleic acid amplification tests (NAATs) used for early infant diagnosis (EID) of HIV infection is <100%, leading some HIV-uninfected infants to be incorrectly identified as HIV-infected. The World Health Organization recommends that infants undergo a second NAAT to confirm any positive test result, but implementation is limited. Our objective was to determine the impact and cost-effectiveness of confirmatory HIV testing for EID programmes in South Africa.

Method and findings: Using the Cost-effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, we simulated EID testing at age 6 weeks for HIV-exposed infants without and with confirmatory testing. We assumed a NAAT cost of US$25, NAAT specificity of 99.6%, NAAT sensitivity of 100% for infants infected in pregnancy or at least 4 weeks prior to testing, and a mother-to-child transmission (MTCT) rate at 12 months of 4.9%; we simulated guideline-concordant rates of testing uptake, result return, and antiretroviral therapy (ART) initiation (100%). After diagnosis, infants were linked to and retained in care for 10 years (false-positive) or lifelong (true-positive). All parameters were varied widely in sensitivity analyses. Outcomes included number of infants with false-positive diagnoses linked to ART per 1,000 ART initiations, life expectancy (LE, in years) and per-person lifetime HIV-related healthcare costs. Both without and with confirmatory testing, LE was 26.2 years for HIV-infected infants and 61.4 years for all HIV-exposed infants; clinical outcomes for truly infected infants did not differ by strategy. Without confirmatory testing, 128/1,000 ART initiations were false-positive diagnoses; with confirmatory testing, 1/1,000 ART initiations were false-positive diagnoses. Because confirmatory testing averted costly HIV care and ART in truly HIV-uninfected infants, it was cost-saving: total cost US$1,790/infant tested, compared to US$1,830/infant tested without confirmatory testing. Confirmatory testing remained cost-saving unless NAAT cost exceeded US$400 or the HIV-uninfected status of infants incorrectly identified as infected was ascertained and ART stopped within 3 months of starting. Limitations include uncertainty in the data used in the model, which we examined with sensitivity and uncertainty analyses. We also excluded clinical harms to HIV-uninfected infants incorrectly treated with ART after false-positive diagnosis (e.g., medication toxicities); including these outcomes would further increase the value of confirmatory testing.

Conclusions: Without confirmatory testing, in settings with MTCT rates similar to that of South Africa, more than 10% of infants who initiate ART may reflect false-positive diagnoses. Confirmatory testing prevents inappropriate HIV diagnosis, is cost-saving, and should be adopted in all EID programmes.

Fig 1. Total lifetime costs per HIV-exposed infant by EID strategy.

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 [21]; 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.

Fig 2. 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.

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.

Fig 3. Number of infants linked to ART after false-positive diagnosis, per 1,000 ART initiations, by assay specificity.

(A) Univariate sensitivity analysis varying NAAT specificity without and with confirmatory testing for 6-week EID testing. The vertical axis depicts the number of infants with a false-positive diagnosis who initiate ART, per 1,000 ART initiations. The horizontal axis depicts the specificity of the NAAT. (B) The inset panel depicts results at higher specificity values, as reported for most NAATs (Table 1). ART, antiretroviral therapy; EID, early infant diagnosis; NAAT, nucleic acid amplification test.

Fig 4. Number of infants linked to ART after false-positive diagnosis, per 1,000 ART initiations, by assay specificity and MTCT risk.

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.