Clinical Consequences of Using an Indeterminate Range for Early Infant Diagnosis of HIV: A Decision Model

Abstract

Background: To minimize false-positive diagnoses of HIV in exposed infants, the World Health Organization recommends confirmatory testing for all infants initiating antiretroviral therapy (ART). In settings where confirmatory testing is not feasible or intermittently performed, clinical decisions may be aided by semi-quantitative cycle thresholds (Cts) that identify positive results most likely to be false-positive.

Methods: We developed a decision analysis model of HIV-exposed infants in sub-Saharan Africa to estimate the clinical consequences of deferring ART for infants with weakly positive ("indeterminate") results. We assessed the degree to which "indeterminate" results may reduce the number of infants starting ART unnecessarily while missing a small number of HIV-infected infants. Our primary outcome was the ratio of averted unnecessary ART regimens to additional HIV-related deaths (due to false-negative diagnosis) at different Ct cutoffs.

Results: The clinical consequences of adopting an indeterminate range varied with the prevalence of HIV and Ct cutoff. Considering a Ct cutoff ≥33, adopting an indeterminate range could prevent a median of 1.4 infants from receiving ART unnecessarily (95% UR: 1.0-2.0) for each additional HIV-related death. This ratio could be improved by prioritizing infants with indeterminate results for confirmatory testing [median 8.8 (95% UR: 6.0-13.3)] and by adopting a higher cutoff [median 82.3 (95% UR: 49.0-155.8) with Ct ≥36].

Conclusions: When implemented in settings where confirmatory testing is not universal, the benefits of classifying weakly positive results as "indeterminate" may outweigh the risks. Accordingly, the World Health Organization has recommended Ct values ≥33 be considered indeterminate for infant HIV diagnosis.

Figure 1.. Test Results and Treatment Decisions for Simulated HIV-Exposed Infants Under Standard of Care and Indeterminate Range Algorithms.

(a) Infants with HIV-infected mothers are assumed to have a given prevalence of HIV. The result of each infant’s initial test is determined by the infant’s HIV status, the sensitivity/specificity of the assay, and (in the Indeterminate Range scenario) the distribution of Ct values among non-negative results. (b) Decreasing Ct values (equivalent to increasing viral loads) are plotted from left to right. The red area represents negative results below the limit of detection of the assay. In the Standard of Care Algorithm (c), any non-negative result (blue area) receives presumptive ART unless (and until) a confirmatory test returns a negative result. In the Indeterminate Range Algorithm (d), Ct values below the threshold (more rapid detection, blue area) trigger presumptive treatment unless (and until) a confirmatory test returns a negative result, whereas Ct values above the threshold (slower detection, purple area) do not receive ART unless a confirmatory test is performed which returns a non-negative result. The key clinical difference between algorithms – care for infants with high Ct results who do not receive confirmatory testing – is outlined with a dotted box. In the scenario under which the indeterminate range is used to prioritize confirmatory testing, all indeterminate results receive confirmatory testing but no frankly positive results (low Ct) receive confirmatory testing (illustrated by solid paths).

Figure 2.. Impact of Prioritizing Infants with Indeterminate Results for Confirmatory Testing.

Clinical outcomes are compared for simulations following the SoC algorithm versus the Indeterminate Range algorithm in which the cutoff for an indeterminate result was varied from a Ct of ≥36 to a Ct of ≥30. Bars represent median estimates (from 10,000 simulations) under the Indeterminate Range algorithm at each cutoff; dotted lines represent the median estimates under the SoC; and arrows and labels indicate the incremental difference between the Indeterminate Range algorithm and SoC. “Unnecessary ART” (in blue) represents the median number of false-positive diagnoses who receive a lifelong indication for ART. “Missed HIV cases” (in green) represents the number of false-negative diagnoses who do not receive presumptive ART. “HIV-Related Deaths” (in purple) represents the number of HIV-infected infants who die before 2 years of age. As lower (more inclusive) Ct values are adopted, more HIV-uninfected infants fall in the indeterminate range, resulting in fewer unnecessary ART regimens but more missed HIV Cases and HIV-Related Deaths.

Figure 3.. Incremental Clinical Consequences following Adoption of an Indeterminate Range.

The ratio of additional unnecessary ART regimens averted to additional excess HIV-related deaths (with both values being measured relative to standard of care, SoC) is plotted for the use of an Indeterminate Range with cutoffs from Ct ≥36 to Ct ≥30. A higher value for this ratio indicates more unnecessary ART regimens averted for each additional death due to missed HIV diagnosis, indicating a more favorable tradeoff for using the indeterminate range. Results from the 15% confirmatory testing scenario are plotted in (a) for HIV prevalence (among tested infants) of 1%, 2.5%, and 5%. Results for the scenario in which all infants with indeterminate results are prioritized for confirmatory testing are plotted in (b). To illustrate the relative scales of (a) and (b), the results of the primary analysis using a cutoff of Ct ≥36 and the bounding box in (a) are reproduced in (b). Points represent median values of 10,000 simulations and error bars represent 95% uncertainty ranges.

Figure 3.. Incremental Clinical Consequences following Adoption of an Indeterminate Range.

The ratio of additional unnecessary ART regimens averted to additional excess HIV-related deaths (with both values being measured relative to standard of care, SoC) is plotted for the use of an Indeterminate Range with cutoffs from Ct ≥36 to Ct ≥30. A higher value for this ratio indicates more unnecessary ART regimens averted for each additional death due to missed HIV diagnosis, indicating a more favorable tradeoff for using the indeterminate range. Results from the 15% confirmatory testing scenario are plotted in (a) for HIV prevalence (among tested infants) of 1%, 2.5%, and 5%. Results for the scenario in which all infants with indeterminate results are prioritized for confirmatory testing are plotted in (b). To illustrate the relative scales of (a) and (b), the results of the primary analysis using a cutoff of Ct ≥36 and the bounding box in (a) are reproduced in (b). Points represent median values of 10,000 simulations and error bars represent 95% uncertainty ranges.