Developing sero-diagnostic tests to facilitate Plasmodium vivax Serological Test-and-Treat approaches: modeling the balance between public health impact and overtreatment

Abstract

Background: Eliminating Plasmodium vivax will require targeting the hidden liver-stage reservoir of hypnozoites. This necessitates new interventions balancing the benefit of reducing vivax transmission against the risk of over-treating some individuals with drugs which may induce haemolysis. By measuring antibodies to a panel of vivax antigens, a strategy of serological-testing-and-treatment (PvSeroTAT) can identify individuals with recent blood-stage infections who are likely to carry hypnozoites and target them for radical cure. This provides a potential solution to selectively treat the vivax reservoir with 8-aminoquinolines.

Methods: PvSeroTAT can identify likely hypnozoite carriers with ~80% sensitivity and specificity. Diagnostic test sensitivities and specificities ranging 50-100% were incorporated into a mathematical model of vivax transmission to explore how they affect the risks and benefits of different PvSeroTAT strategies involving hypnozoiticidal regimens. Risk was measured as the rate of overtreatment and benefit as reduction of community-level vivax transmission.

Results: Across a wide range of combinations of diagnostic sensitivity and specificity, PvSeroTAT was substantially more effective than bloodstage mass screen and treat strategies and only marginally less effective than mass drug administration. The key test characteristic determining of the benefit of PvSeroTAT strategies is diagnostic sensitivity, with higher values leading to more hypnozoite carriers effectively treated and greater reductions in vivax transmission. The key determinant of risk is diagnostic specificity: higher specificity ensures that a lower proportion of uninfected individuals are unnecessarily treated with primaquine. These relationships are maintained in both moderate and low transmission settings (qPCR prevalence 10% and 2%). Increased treatment efficacy and adherence can partially compensate for lower test performance. Multiple rounds of PvSeroTAT with a lower performing test may lead to similar or higher reductions in vivax transmission than fewer rounds with a higher performing test, albeit with higher rate of overtreatment.

Conclusions: At current performance, PvSeroTAT is predicted to be a safe and efficacious option for targeting the hypnozoite reservoir towards vivax elimination. P. vivax sero-diagnostic tests should aim for both high performance and ease of use in the field. The target product profiles informing such development should thus reflect the trade-offs between impact, overtreatment, and ease of programmatic implementation.

Keywords: Modeling; Overtreatment; Plasmodium vivax malaria; Public health interventions; Serological test-and-treat; Test development.

Fig. 1

Modeled P. vivax qPCR prevalence with various implementations of public health interventions in an endemic situation of low transmission. The columns correspond to the different scenarios and rows to the number of intervention rounds, with gray area presenting time of evaluation

Fig. 2

Exploration of the parameter space for the ROC curve of PvSeroTAT in a low transmission setting, with a single round of intervention using a hypothetical optimal hypnozoiticidal drug. A The red square on the full ROC curve represents the parameter space explored as part of the target product profiling. The three triangles correspond to a diagnostic test at 80% sensitivity and specificity (solid color; currently achieved by our antibody panel) as well as two alternatives at 65% and 90% (transparency; tradeoffs between sensitivity and specificity). B Association between impact (prevalence reduction after 6 months) and sensitivity. C Association between overtreatment and specificity. In panels B and C, dots are colored according to the diagnostic criteria not used on the x-axis

Fig. 3

ROC surfaces for A impact and B overtreatment with a hypnozoiticidal drug under the different envisioned scenarios after a single round of PvSeroTAT in a low transmission setting