In the one-way sensitivity analyses, we varied select variables and examined the total expected cost keeping all other variables constant. As expected, the relative test performance, test costs, and costs associated with adverse pregnancy outcomes were all influential. However, in almost all scenarios the ranges we used for the 1- and 2-way sensitivity analyses showed the screening programs to be cost-saving. When we increased the sensitivity of RPR from 60% to 98%, our results indicated that the RPR strategy was more cost-saving than the Dual-POC strategy when its sensitivity was at ≥85% and the ICS strategy when its sensitivity was at ≥93% (not shown). Figure 2 shows one-way sensitivity analyses results for syphilis prevalence, sensitivity of the Dual-POC test, cost of the Dual-POC test, and the sensitivity of the ICS test. The total cost for all the alternatives increased with syphilis prevalence (Fig. 2A). The Dual-POC strategy was less cost-saving than the onsite RPR strategy when the sensitivity of the Dual-POC test was less than 75%. However, the Dual-POC was the most cost-saving strategy when its sensitivity was ≥97% (Fig. 2B). Over the range of the cost of the Dual-POC test used (i.e., $0.5–$5), it remained more cost-saving than the onsite RPR and lab-based RPR+TPHA strategies (Fig. 2C). Finally, the sensitivity of the ICS test would have to be less than 90% for it to be less cost-saving than the Dual-POC strategy (Fig. 2D).
We evaluated the health and economic outcomes of a new Dual-POC test compared with other diagnostic approaches, by examining expected pregnancy outcomes for 1000 women using conservative assumptions based on the performance characteristics of the test determined during an evaluation at the US CDC, serological profiles, and patient characteristics among antenatal clinic attendees previously reported in studies conducted in southern Africa.13,15,41 The laboratory based RPR+TPHA algorithm prevented 26 adverse pregnancy outcomes; the onsite RPR prevented 28; the Dual-POC prevented 34; and the ICS prevented 37 out of a total of 39 expected adverse pregnancy outcomes when there was no screening program. In terms of costs, the Dual-POC saved more cost than the onsite RPR and RPR+TPHA strategies, while the ICS strategy saved the most cost.
We checked the consistency of the results from our model by comparing our results with 2 recent studies that compared RPR+TPHA, RPR, and ICS for a similar setting.13,15 We found that the relative costs and effectiveness were consistent with their results based on the test performance values used. Additionally, the relative adverse pregnancy outcomes (miscarriage, congenital syphilis, low birth weight, stillbirth, and neonatal death) were consistent with the results reported in previous studies in similar settings.2,13,15
The strengths of this study are that we accounted for previously treated infections in the population that was studied.16,37 Second, we provided detail information on the expected overtreatment rate, which has been ignored (or has not been reported) in previously published studies. Finally, we improved the robustness of the results by conducting a comprehensive sensitivity analyses to account for inconsistencies in the data we used.
Our study has all the limitations associated with models in general: models are simplifications of reality and do not capture all the important characteristics of the events/phenomena being studied. In addition, the values used in our study were estimates obtained from other studies that were not consistent. There was no substantial difference between the total societal costs and total health clinic costs due to lack of reliable societal cost estimates. Another major limitation of our study is the inability to independently assess the Dual-POC. This was because the performance of the Dual-POC was assessed using RPR and TPPA (equivalent to TPHA) tests under ideal laboratory conditions. Also, we ignored ongoing transmission in the population. Nonetheless, to the extent that the screening strategy adopted does not affect the transmission dynamics, we believe that the relative costs and outcomes would not change for the onsite strategies (RPR, ICS, and Dual-POC). We did not account for costs associated with follow-ups, which may include assessment of response to therapy using serial quantitative titers.
The effect of transmission on the RPR+TPHA and No-Program strategies on our final results is difficult to assess because it would require more data and assumptions about mixing patterns and the prevalence among men. Additionally, pregnant women may not be an important source of ongoing transmission, which may limit the importance of this omission. Our assumption of untreated early syphilis (i.e., the exclusion of early and late latent forms of syphilis) in the hypothetical cohort of pregnant women implied that the estimated overall adverse health outcome was relatively higher for each strategy. However, it is difficult to determine how this omission affected the relative costs and effects of the testing strategies assessed in this study. Finally, due to lack of data, we did not include the cost of advanced stages of syphilis for the mothers.
With regard to comparing point-of-care tests to the 2-step algorithm, our results were consistent with previous studies in similar settings.2,13,15 Consistent with results reported by Rydzak and Goldie,15 our results indicated that the screening strategies examined (onsite RPR, ICS, lab-based RPR+TPHA, and onsite Dual-POC) were cost-saving when compared with the No-Program strategy. The cost-savings found in Rydzak and Goldie15 were substantially higher than we found because they accounted for lifetime pregnancies (6 per woman). Although we used a similar time frame and similar cost values as Blandford et al.,13 we included 2 other substantially more expensive adverse pregnancy outcomes (neonatal death and low birth weight) that may result from untreated maternal syphilis which resulted in higher savings for the screening strategies compared with the No-Program strategy.
Although the use of the RPR test may result in a small number of false positives,5 studies have demonstrated that nontreponemal test reactivity has a higher correlation with disease activity than detection of treponemal antibody.42 In addition, nontreponemal tests are more likely to be nonreactive following successful treatment.9 On the other hand, the use of a treponemal ICS test alone will inevitably result in high rates of overtreatment because all treponemal tests detect antibodies that may be present for a lifetime even following provision of adequate treatment.43 As demonstrated by our analyses, even when the specificity of the Dual-POC was as low as 85% (or 30% for previous infections), it resulted in a substantially lower overtreatment rate when compared with the ICS strategy.
Given these limitations of treponemal and nontreponemal tests (when used individually), the Dual-POC can help to detect syphilis cases in resource-poor settings while substantially reducing the rate of overtreatment. Additionally, the Dual-POC test should prove to be a useful screening/confirmatory test for the prevention of congenital disease because further laboratory evaluation indicated that its sensitivity was substantially higher (99.7%) for sera with RPR antibody titers ≥1:8 (during pregnancy, transplacental transmission of syphilis rarely occurs at confirmed maternal RPR titers <1:85,19). Further independent assessment of the Dual-POC should be undertaken to enable wider and more objective comparability, including guidelines on interpretation of results.
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