Adding CXR to a “Symptom” policy will reduce new INH-R and MDR TB cases; however, because of attrition by requiring CXR, this indirectly increases TB cases and TB deaths because fewer PLWH will benefit from IPT. Attrition must be close to 0% before deaths indirectly caused by a “Symptom+CXR” policy equal those in a “Symptom Only” policy. Although adding CXR also increases costs, a policy that includes intensive tracking efforts to eliminate attrition is not cost-effective by WHO standards at an incremental cost–effectiveness ratio of about $2.8 million per death averted. According to the WHO, ICERs greater than three times the GDP (3 × $6,982 = $20,946 for Botswana in 2008) per disability-adjusted life-year can be considered not cost-effective (37
A rapid point-of-care diagnostic test with high sensitivity and specificity would be highly desirable to improve pre-IPT screening. By producing immediate results, such a hypothetical test would avoid attrition and patient-tracking costs. Ideally the net costs (the costs of screening minus the savings from averted disease and its treatment) of this strategy should be the same or lower than symptom screening alone, which would be the case if the hypothetical test cost is less than or equal to $0.3 per test per patient (data not shown). Until such a test becomes available, our analysis shows that provision of IPT to PLWH in endemic settings should not be hampered by additional screening modalities that would lead to more deaths in PLWH and unacceptably high costs to society. Investigators at Yale University (Ithaca, NY) used a mathematical model to determine the impact on the prevalence of INH-R TB of varying sensitivities of TB detection during screening for IPT (38
). They included transmission of TB within the population and made an extreme assumption that 100% of PLWH with TB disease receiving IPT developed INH-R TB. Their model showed that improving TB screening sensitivity from 60 to 90% did not have a significant impact on INH-R TB transmission rates whereas IPT reduced TB by at least 12 cases per 100,000 PLWH each year. We investigated the consequences of adding CXR to the screening process in terms of cost, deaths, as well as the development of INH-R TB. Both the Yale analysis and ours agree that increasing the sensitivity of screening for TB disease before IPT is not of great societal value.
Our analysis has several important limitations. For a number of model parameters uncertainty existed around their values because of the paucity of published data; nevertheless, our conclusions remained robust in sensitivity and scenario analysis. For example, the outcome of our model is strongly driven by the risk of selecting for INH-R organisms when providing IPT to PLWH with asymptomatic TB disease and abnormal CXR at screening. This risk is not well established. Studies conducted in the precombination chemotherapy era in primarily symptomatic patients with cavitary (i.e., high bacillary load) TB disease showed that 36–68% developed INH-R disease because they were maintained on single-drug therapy for 6–12 months (39
). The screening context of the present analysis is one in which PLWH with TB are asymptomatic, few have cavitary disease (14%, or 3 of 22 in the Botswana Trial; T.S., personal communication), and all are screened monthly for symptoms of TB. Furthermore unpublished data from the Botswana Trial showed that one of seven participants with radiographically evident disease who were taking INH and who developed symptomatic TB disease had INH-R TB (T.S., personal communication). When we varied this parameter to its upper limit (50% which was seen in the pre-DOTS era in symptomatic patients with cavitary TB receiving INH monotherapy) simultaneously with several others in our worst-case scenario, “Symptom+CXR” remained an unacceptable policy because of the increase in deaths due to attrition. Another example is factors that could affect the efficacy of IPT, such as adherence to therapy and the rate of TST positivity, which were not specifically modeled. However, the efficacy of IPT in our model was derived from intent-to-treat analyses, which would incorporate such inefficiencies, and, additionally, we reduced the efficacy of IPT in scenario analysis, which did not affect our major conclusion.
Our model did not incorporate the effects of the transmission of INH-R TB bacilli, which is estimated to be 70% as transmissible as pan-susceptible TB (42
). This concern is unlikely to be of significance because TB transmission would occur not only among about 1.6% of participants with asymptomatic TB disease but also among a similar proportion lost through attrition due to the added requirement of a screening CXR. Furthermore, those enrolled in IPT are monitored monthly for TB symptoms, but those lost to the health care system are more likely to have a prolonged period of transmission before returning to the clinic. Finally, the majority of pulmonary TB in Botswana is smear negative (33
), which presents a lower risk of transmission than smear-positive TB (43
We examined models that included the costs of hospitalization during DOTS (~$400 on average per patient) and the cost–effectiveness rankings were essentially unchanged; hence in this article we present the simpler models without hospitalization costs.
We did not include the effect of ART in reducing TB incidence, even though its beneficial effect is established (20
) and ART is widely available in Botswana (45
). The reasons for not modeling the ART effect include the following: (1
) approximately 70% of Botswana's PLWH do not receive ART because of the eligibility requirement of a CD4+
lymphocyte count below 250 cells/mm (45
), whereas all HIV-infected adults are eligible for IPT; (2
) although there are preliminary data showing the superior efficacy of the combination of ART and IPT (46
), this is not yet well established; and (3
) the results of this analysis will be more generalizable to PLWH in TB-endemic countries that are resource constrained, as ART is not widely available in the majority of such countries whereas a 6-month course of IPT could be more readily available.
Our analysis implies that IPT would exert its greatest benefit when more PLWH receive prophylaxis. Therefore there is a need to increase the awareness for IPT among potential beneficiaries. The Ministry of Health in Botswana could promote awareness of the benefit of IPT among PLWH, as it has so successfully for ART. This source of motivation may also reduce attrition during the screening process and the 6-month follow-up period.