Our cost-effectiveness analysis of treatment strategies provides evidence that DOTS-Plus strategies are likely to be cost-effective in lower-middle-income settings with at least 1% MDR TB. Over a wide range of assumptions, a strategy of testing previously treated patients for MDR TB and then treating them with second-line regimens was found to be cost-effective compared to first-line DOTS alone. In our base case for Peru, we estimate that STR2 would avert 4.8 deaths per 100,000 persons over 30 y, at an incremental cost of $720 per QALY compared to DOTS. A policy of comprehensive DST and individualized treatment for first-line failures (ITR1), the best performing strategy under the cost-effectiveness threshold of the per capita GDP, averted 0.9 additional deaths per 100,000 at an incremental cost of $990 per QALY compared to STR2. A clinical strategy that begins with comprehensive DST for all cases upon diagnosis of TB may be cost-effective in settings with high levels of MDR or where first-line drugs perform especially poorly against MDR TB. The base case incremental cost per QALY gained with this strategy (ITR2 compared to ITR1) was $11,000, but when the prevalence of MDR TB among prevalent TB cases was 10%, the cost per QALY gained for ITR2 dropped to $6,400. Poorer performance of first-line drugs against MDR TB increases the potential gains from immediate diagnosis and treatment of MDR TB. When the effectiveness of a first-line regimen was dropped 20% from the base case assumptions, the ITR2 strategy had a cost per QALY of $5,500.
In our analysis, DOTS-Plus based on standardized second-line regimens administered to previously treated patients presumed to have MDR TB (STR1) was consistently dominated because it provided the same benefit as STR2 at a higher overall cost. This result is largely due to the costs of treating non-MDR cases unnecessarily with second-line therapy. In the base case calibration of our model, on average 54% of cases entering a second round of treatment had MDR TB. This figure is consistent with the outcome of a large retrospective study of laboratory results in Peru that found that 57% of previously treated patients reentering treatment had MDR TB [
DOTS-Plus programs that use standardized regimens typically do not use DST to determine each patient's resistance profile [
], but in a South African DOTS-Plus program, patients suspected of having MDR TB are tested for first-line drug resistance before standardized second-line regimens are administered [
]. Although the STR2 strategy, which mimics the South African program, is an efficient strategy, we found that ITR1 conferred additional benefit at an incremental cost of $990 per QALY, which is still well below the per capita GDP of Peru. In Peru, the difference in MDR TB cure probability between individualized and standardized regimens must be less than 2%, and standardized regimens must be $3,200 less expensive, in order for the incremental cost-effectiveness ratio of ITR1 to be considered beyond the threshold of three times the GDP ($7,080).
The finding that individualized second-line treatment of previously treated cases (ITR1) is highly cost-effective was stable over a wide range of assumptions. The incremental cost per QALY gained for ITR1 remained under $1,900 in all one-way sensitivity analyses. When considering a situation in which several one-way sensitivity analyses were combined into a “worst-case scenario” over a 10-y time horizon with several parameter values simultaneously biased against second-line treatment strategies, STR2 is dominated, but ITR1 still appears quite favorable at $6,400 per QALY as compared to DOTS alone. The incremental cost-effectiveness ratio of the more aggressive individualized treatment strategy (ITR2) compared to ITR1 exceeded the threshold of three times the per capita GDP in the base case, but appeared more favorable when the fraction of MDR TB among prevalent TB cases was higher, and also under the plausible assumption that the cure probability for first-line therapy against MDR TB is 20% lower than assumed in the base case.
Interrupting transmission is a critical component of the overall benefit of treatment. When these community-level benefits were excluded, costs per QALY or per averted death by STR2 and ITR1 approximately doubled. Nonetheless, individualized treatment with second-line drugs remained cost-effective by international standards even without accounting for transmission benefits.
A key uncertainty in our model is the relative fitness of MDR TB strains for transmission. Recent models [
] indicate that over very long time horizons, heterogeneous fitness among MDR strains will lead to the eventual dominance of MDR TB as long as some fraction of MDR strains are as fit as drug-sensitive strains. We assumed that MDR TB was equally transmissible as drug-susceptible TB in our base case, but considered the possibility that it is up to 50% less transmissible. When MDR TB fitness was reduced, DOTS-Plus strategies became somewhat less cost-effective, but remained attractive.
We assumed that second-line therapies were no more effective than DOTS in TB patients without MDR TB. This assumption may underestimate the benefits of DOTS-Plus strategies if second-line drugs confer additional benefits in patients with non-MDR drug resistance.
The analysis reflects the perspective of a public health-care system and includes the costs of medical care only. An analysis from the societal perspective would need to incorporate costs for patient time, transportation, and unpaid caregiver time, but such data were not available and would be unlikely to alter the conclusions.
An analysis by Sterling et al. [
] found that a DOTS-Plus strategy using DST and second-line drugs over a 10-y time period had an incremental cost-effectiveness ratio of $68,860 per averted death compared to a DOTS strategy using first-line drugs only, suggesting that it would be relatively expensive for low- to middle-income countries. However, the study used estimates of the effectiveness of second-line therapy that are lower than current data suggest [
] and assumed that TB incidence and the fraction of MDR TB among new cases would not decline in response to treatment.
Suarez et al. [
] found that the use of second-line drugs in patients failing other therapies had an incremental cost-effectiveness ratio of about $200–$700 per DALY averted (year 2000 US dollars). Our dynamic transmission modeling results corroborate the finding of Suarez et al. [
] that second-line therapy for MDR TB patients is highly cost-effective in Peru.
Like Sterling et al. [
] and Suarez et al. [
], our study suggests that DOTS-Plus is both more effective and more costly than DOTS. Therefore, if DOTS has not been fully implemented and can be expanded within the available infrastructure, it would be more efficient to expand DOTS coverage than to initiate DOTS-Plus. Similarly, an implementation of DOTS-Plus that uses non-surplus resources from an existing DOTS program would also be inefficient. Nevertheless, our results also show that fully implementing DOTS and initiating DOTS-Plus would be a reasonable use of resources in many settings.
We quantified the marginal gains of relatively more aggressive strategies to control MDR TB and found that the relatively high cost of second-line therapy (as compared to first-line therapy) should not be perceived as a barrier to implementation of DOTS-Plus programs. We did not account for start-up costs (e.g., laboratory capacity) required for DST. However, in lower-middle-income countries such as Peru, with about 2,900 MDR TB cases each year [
], even if a lump sum of $5.5 million for start-up costs were added in the first time period to the costs of ITR1, that strategy would still have a cost per QALY less than the per capita GDP.
We found that standardized regimens could be cost-effective when a test for MDR TB is used before enrolling previously treated patients into second-line therapy, suggesting the possible utility of an inexpensive rapid test for MDR such as the Greiss method [
]. We also found that comprehensive DST for previously treated patients followed by individualized treatment for MDR TB cases will likely be cost-effective in a variety of settings, even in countries with severely constrained resources. Furthermore, immediate DST for all detected TB cases and individualized second-line treatment for MDR TB may be cost-effective in middle-income countries with high levels of MDR TB.
The feasibility of delivering effective individualized TB care has been demonstrated in Peru and other countries. Our study finds that the strategy of testing previously treated cases with DST and treating MDR TB with individualized regimens would be cost-effective in Peru under a wide range of alternative assumptions about treatment costs, effectiveness, MDR TB prevalence, and transmission, including a range of assumptions regarding the relative performance of a similar strategy based on standardized regimens. Our study contributes to a growing body of evidence that indicates that national TB programs and nongovernmental organizations should move quickly to implement DOTS-Plus in settings where multiple drug resistance is prevalent.