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Cost-Effectiveness Analysis of Introduction of Rapid, Alternative Methods to Identify Multidrug-Resistant Tuberculosis in Middle-Income Countries

  1. Carlos Acuna-Villaorduna1,5,
  2. Anna Vassall6,
  3. German Henostroza1,2,
  4. Carlos Seas1,2,
  5. Humberto Guerra1,2,
  6. Lucy Vasquez3,
  7. Nora Morcillo7,
  8. Juan Saravia4,
  9. Richard O'Brien8,
  10. Mark D. Perkins8,
  11. Jane Cunningham9,
  12. Luis Llanos-Zavalaga2, and
  13. Eduardo Gotuzzo1,2
  1. 1Instituto de Medicina Tropical Alexander Von Humboldt, Lima, Peru
  2. 2Universidad Peruana Cayetano Heredia, Lima, Peru
  3. 3Instituto Nacional de Salud, Lima, Peru
  4. 4Direccion de Salud Lima Norte, Lima, Peru
  5. 5Internal Medicine Department, Washington Hospital Center, Washington, DC
  6. 6Royal Tropical Institute, Amsterdam, The Netherlands, Argentina
  7. 7Antonio Cetrangolo Hospital, Buenos Aires, Argentina
  8. 8Foundation for Innovative New Diagnostics, Geneva, Switzerland
  9. 9Tropical Disease Research, World Health Organization, Geneva, Switzerland
  1. Reprints or correspondence: Dr. Carlos Acuna-Villaorduna, Washington Hospital Center, Internal Medicine Dept., Rm. 2A38, 110 Irving St. NW, Washington, DC 20010-3017 (carlosvillaorduna{at}hotmail.com).

  1. Presented in part: 36th Union World Conference in Lung Health, Paris, France, October 2005 (abstract 1825–22).

 
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Abstract

Background. Resistance to commonly used antituberculosis drugs is emerging worldwide. Conventional drug-susceptibility testing (DST) methods are slow and demanding. Alternative, rapid DST methods would permit the early detection of drug resistance and, in turn, arrest tuberculosis transmission.

Methods. A cost-effectiveness analysis of 5 DST methods was performed in the context of a clinical trial that compared rapid with conventional DST methods. The methods under investigation were direct phage-replication assay (FASTPlaque-Response; Biotech), direct amplification and reverse hybridization of the rpoB gene (INNO-LiPA; Innogenetics), indirect colorimetric minimum inhibitory concentration assay (MTT; ICN Biomedicals), and direct proportion method on Löwenstein-Jensen medium. These were compared with the widely used indirect proportion method on Löwenstein-Jensen medium.

Results. All alternative DST methods were found to be cost-effective, compared with other health care interventions. DST methods also generate substantial cost savings in settings of high prevalence of multidrug-resistant tuberculosis. Excluding the effects of transmission, the direct proportion method on Löwenstein-Jensen medium was the most cost-effective alternative DST method for patient groups with prevalences of multidrug-resistant tuberculosis of 2%, 5%, 20%, and 50% (cost in US$2004, $94, $36, $8, and $2 per disability-adjusted life year, respectively).

Conclusion. Alternative, rapid methods for DST are cost-effective and should be considered for use by national tuberculosis programs in middle-income countries.

Resistance to commonly used antituberculosis drugs is emerging worldwide [1–3]. National tuberculosis (TB) control programs require effective strategies to rapidly detect and treat infection with resistant organisms. Guidelines on multidrug-resistant (MDR) TB treatment and affordable drugs are now available [4–9]. However, a consensus on the best strategy for detection of MDR TB in resource-poor settings remains elusive. Conventional drug-susceptibility testing (DST) methods are slow and cumbersome [10, 11]. This limits their availability and allows the transmission of MDR TB to proceed unchecked [12–15]. In contrast, alternative, rapid methods for assessment of in vitro antibiotic susceptibility would permit the prompt detection and treatment of MDR TB.

The indirect proportion method on Löwenstein-Jensen medium (IDLJ) is the most widely used DST method. However, it takes 8–12 weeks to yield results in good circumstances and up to 6 months in field conditions. Morbidity, mortality, and transmission of resistant strains during this period are critical concerns. Recently, several alternative methods for DST have been developed, including colorimetric indicators for early detection of bacterial growth, molecular methods to detect resistance-associated mutations, and phage-replication assays. Several studies have evaluated the performance of these methods, with promising results [16–25]. However, there are no studies that estimate the cost and cost-effectiveness of implementing DST methods in low- or middle-income settings. Therefore, the question of whether DST methods are affordable and cost-effective in the context of the severe resource constraints faced by developing countries remains unanswered.

Peru is a middle-income country [26] with an incidence of pulmonary TB of 178 cases per 100,000 inhabitants. Currently, MDR TB testing is limited to the IDLJ method for those at high risk for MDR TB and those who experience treatment failure after 5 months of treatment [27]. Recently, several alternative methods for detection of MDR TB have been evaluated in a large trial. These included a commercially available line-probe assay (INNO-LiPA; Innogenetics) that detects mutations in the rpoB “hotspot” gene region, which is responsible for >90% of rifampicin resistance [16, 17]; a phage-based assay (FASTPlaque-Response; Biotech) that detects live Mycobacterium tuberculosis in a plaque assay on a lawn of rapidly growing detector cells [18, 19]; a noncommercial colorimetric assay (MTT; ICN Biomedicals) that uses tetrazolium salt, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide, which is a general indicator of cellular growth and viability whose oxidized yellow form becomes purple after reduction to formazan by the dehydrogenases of live bacterial cells [20–22]; and the direct proportion method on Löwenstein-Jensen medium (DLJ), whereby sputum is inoculated directly on Löwenstein-Jensen slants with and without antibiotics after being decontaminated and diagnosis is based on the proportion of mycobacteria growing in a drug-containing Löwenstein-Jensen slant, compared with the growth of the strain in a drug-free slant [25].

We report the costs and cost-effectiveness of introducing these methods in Peru for patient groups with different prevalences of MDR TB. Our results can be used by other national TB control programs in middle-income countries to help assess whether alternative DST methods could rationally be adopted and to estimate the financial impact of doing so.

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Methods

Data on the cost and performance of DST methods were collected from a phase 3 clinical trial conducted in Lima Norte, Peru. This region, 1 of 5 health care jurisdictions in Lima, has a population of 3.3 million inhabitants. The prevalence of MDR TB is 2% among new patients with smear-positive TB and is 50% among those who experience treatment failure [27]. From May 2004 through September 2005, all adults newly diagnosed with smear-positive pulmonary TB from all 37 health care centers in Lima Norte were identified. After informed consent was obtained, at least 1 sample containing 5 mL of sputum was obtained from each patient and was sent for decontamination and DST (3 samples had been taken previously to establish smear-positive TB). IDLJ, INNO-LiPA, MTT, and DLJ were performed at the National Institute of Health laboratory in Lima. FASTPlaque-Response was performed at the Alexander von Humboldt Tropical Medicine Institute laboratory in Lima.

Cost and cost-effectiveness estimates were calculated for patient groups with 2%, 5%, 20%, and 50% prevalence of MDR TB. These rates correspond to those most commonly found in global surveillance of TB drug resistance by the World Health Organization [28]. Costs and health outcomes for each method were calculated and compared with a “do-nothing” scenario in which MDR TB treatment is provided but DST is not available. In this scenario, clinical diagnosis of MDR TB is made on the basis of failure of first-line treatment. It was assumed that patients who experienced failure of first-line treatment would be switched to a standardized MDR TB treatment regimen at 5 months and that 2% of patients would die while waiting for MDR TB treatment. In contrast, it was assumed that a patient with DST results positive for MDR TB would be switched to MDR TB treatment within 7 days. Patient pathways for DST and for clinically defined MDR TB are shown in figure 1.

Figure 1
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Figure 1

Patient pathways for drug-susceptibility testing (DST) methods, compared with clinical diagnosis of multidrug-resistant (MDR) tuberculosis (TB). X values are determined by prevalence of MDR TB. *Treatment failure is defined as the persistence of positive smear results after 5 months of first-line treatment.

Table 1
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Table 1

List of variables and assumptions used in cost-effectiveness analysis.

Table 2
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Table 2

Unit cost per test.

Table 3
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Table 3

Average cost per case detected, excluding the effects of transmission.

Table 4
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Table 4

Average cost per case detected, including the effects of transmission.

Table 5
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Table 5

Costs per disability-adjusted life year (DALY) gained.

The first step in our analysis was to calculate the average cost per case detected for each DST method. This cost includes the unit costs of tests, the cost savings from the reduced duration of first-line treatment that results from increased diagnostic speed, and the costs of mistakenly treating false-positive cases. The cost of false-positive cases was calculated assuming that the corresponding patients would receive a full course of MDR TB treatment.

Unit costs of tests for each DST method were measured using standard methods [29, 30]. Costs were calculated for each test by using a health care services perspective. Costs were measured for IDLJ and all alternative DST methods for detection of resistance to rifampicin and, when appropriate, resistance to rifampicin and isoniazid (i.e., multidrug resistance). All costs were measured from the time of sputum collection until the time of test results. We included all indirect (overhead) and direct (including buildings, equipment, training, transportation, supplies, salaries, and utilities) inputs. Test costs were calculated using the “ingredients” approach. This multiplies the quantity of inputs used by their price. There were 2 exceptions: the cost of sputum collection, which was taken from Suárez et al. [31], and overhead and quality-control costs, which were calculated by allocating the total expenditures to each test on the basis of staff time (e.g., management and/or supervision costs) or, when relevant, building space (e.g., utilities costs).

The quantity of inputs used (e.g., staff time and supplies) was measured by a mixture of observations and recording by laboratory technicians. This was done at the midpoint of the trial. Quantities were based on 20 observations per test method and were verified by examination of protocols, expenditures, and laboratory records. This measurement did not include staff time between tests, the wastage of supplies, and unused equipment capacity. Data on these items were collected through a mixture of observations, interviews, and examination of laboratory records. Costs were then calculated assuming 80% usage of staff and equipment and 5% wastage of medical supplies. Costs of contamination and invalid tests were also included.

Costs are presented using international prices (US$2004). Prices of inputs vary considerably by country, and there are no standard international prices available for many laboratory supplies. We sourced prices from catalogs and Web sites, reviewed by the World Health Organization. The cost of delivering the goods to Lima was included. Local prices were converted to international prices with an exchange rate of 3.5 soles to $1.

The second step was to estimate the average cost per case detected, including the future cost savings associated with the reduced transmission of MDR TB that results from improved diagnostic speed. Estimates of the period of infectiousness assume that DST would occur at 0 months for all patient groups, that patients would remain infectious for the first 2 months of treatment, and that patients with false-negative results would remain infectious for the entire period. The model presented by Bailey et al. [32] was used to estimate the probability of infection and the secondary cases averted during the period of infectiousness. This model excludes further (tertiary) cases generated by secondary cases. Cost savings were calculated by multiplying the number of secondary cases by costs of MDR TB treatment. These future savings were discounted at an annual rate of 3%, as recommended by the Panel on Cost-Effectiveness in Health and Medicine [33–34].

The third step was to estimate the average cost per disability-adjusted life year (DALY) for each test. Estimates of health outcomes and DALYs were based on the deaths averted from early case detection and the corresponding reduced transmission. For those who received treatment, no direct health benefit was assumed for early initiation of treatment, because evidence of this is scanty. Deaths averted from secondary cases were calculated assuming that 30% remain untreated, in line with national case-detection rates. Age at onset of MDR TB, treatment cure rates, and life expectancy were sourced from clinical trial data, data from national TB control programs, and international life tables. As with cost savings from reduced transmission, DALYs calculated exclude the benefits of prevention of further tertiary cases generated by secondary cases.

Data analysis was conducted using Excel (Microsoft). A full list of assumptions, variables, and their sources is presented in table 1. It should be noted that, although IDLJ is widely used as the gold standard for DST in developing countries, there is little evidence to support this use. Therefore, the cost-effectiveness of IDLJ was calculated assuming 98% specificity and 98% sensitivity. A spreadsheet containing all estimates and data analysis can be obtained on request.

Sensitivity analysis was performed to test the robustness of our results. Results were subjected to 1-way, 2-way, and multiway analyses. The effects of changes in prices (±10%), sensitivities (±2%), specificities (±2%), and our efficiency assumptions (±5%) were among the variables tested. Finally, we ran a Monte Carlo simulation involving 10,000 iterations for most variables in our model, including the sensitivities and specificities of tests, period of infectiousness, wastage, self-cure rate, hours of daily contact, number of contacts per patient, and percentage of patients with latent TB who developed active TB. We used @Risk software, version 3.5 (Palisade), to determine the means and upper and lower bounds (95% CI) of the main output of interest (i.e., average cost per DALY gained).

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Results

During the study period, 1120 patients with smear-positive pulmonary TB were enrolled. Of these, 278 were excluded: 35 because of inability to produce sputum and 243 because the sample obtained was later found to be smear negative. A total of 842 patients had confirmed cases of smear-positive and culture-positive pulmonary TB. DST results were available from IDLJ for 804 (95.5%) of the specimens, from FASTPlaque-Response for 607 (72.1%), from INNO-LiPA for 797 (94.7%), from DLJ for 739 (87.8%), and from MTT for 799 (94.9%). FASTPlaque-Response displayed high levels of contamination and indeterminate results. Table 1 shows diagnostic performances, speed of diagnosis, and contamination rates.

Unit costs for each DST method are presented in table 2. The unit cost for all tests, aside from INNO-LiPA, was $25–$42. DLJ had the lowest unit cost ($30.46 to test for MDR TB). INNO-LiPA had the highest unit cost ($111.79 to test for MDR TB). Medical supplies (i.e., kit costs) are the major determinant of costs for the commercial tests. The noncommercial tests (DLJ, IDLJ, and MTT) are more time intensive and, therefore, had a high proportion of overhead and capital costs. Staff costs are high for INNO-LiPA and FASTPlaque-Response because of the time and expertise required. Unit costs for tests of multidrug resistance are slightly higher than those for tests of rifampicin resistance.

The cost of testing for 1000 patients and the average cost per case detected for each DST method, excluding savings from reduced transmission, are presented in table 3. DLJ had the lowest cost per case detected for all prevalence groups ($3913, $1522, $326, and $87 per MDR TB case detected in groups with prevalence of 2%, 5%, 20%, and 50%, respectively). IDLJ ranked second ($4886, $1950, $433, and $129 per MDR TB case detected, respectively), and MTT ranked third ($6146, $2399, $525, and $151 per MDR TB case detected, respectively).

Table 4 presents the cost of testing for 1000 patients and the average cost per case detected for each DST method, including savings from reduced transmission. All tests were cost saving in patient groups with >20% prevalence of MDR TB. For the group with 50% prevalence of MDR TB, all methods generated near-equivalent savings (∼$700 saved per MDR TB case detected). DLJ was the lowest-cost option for the groups with 2% and 5% prevalence of MDR TB ($3031 and $640 per case detected, respectively). IDLJ was the second-lowest-cost option for these groups ($4111 and $1159 per case detected, respectively).

Table 5 presents the average cost per DALY for each DST method. Including the cost savings from reduced transmission, DLJ had the lowest cost per DALY gained for the group with a 2% prevalence of MDR TB ($41 per DALY gained), and MTT had the second lowest cost per DALY gained ($95 per DALY gained). One-way sensitivity analysis showed that our results were robust for all variables tested. The 95% CIs generated by the Monte Carlo analysis showed a significant degree of uncertainty that will affect the cost-effectiveness ranking of different DST methods, particularly for patient groups with a high prevalence of MDR TB.

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Discussion

MDR TB testing is not routinely performed in developing countries, which raises concern about the transmission of resistant strains from unidentified cases. Our study demonstrates that MDR TB testing among patients with smear-positive TB, with IDLJ or other methods, is cost-effective, even in settings with a moderate prevalence of drug resistance.

All the DST methods studied are cost-effective when the average cost per DALY (excluding effects of transmission) is compared with a benchmark of gross national income. For example, the cost-effectiveness of using the least cost-effective alternative, FASTPlaque-Response, in groups with 2% prevalence of MDR TB ($272 per DALY gained) compares favorably with that of providing antiretroviral therapy to patients with TB who are coinfected with HIV ($462 per DALY gained) [35] and that of providing individualized treatment for patients with MDR TB that is not responding to standardized second-line therapy ($368 per DALY gained) [31]. Strikingly, introducing an inexpensive and moderately rapid method such as MTT for populations with high prevalence of MDR TB had cost-effectiveness comparable to that of implementing the directly observed treatment–short course (DOTS) strategy in developing countries ($12 vs. $15 per DALY gained) [36].

Our calculation of cost-effectiveness underestimates both the health benefits and cost savings from early diagnosis. We assumed no benefit for timely treatment, nor benefits for reduced transmission from secondary cases. However, all DST methods yielded cost savings, compared with clinically defined drug resistance, in settings of high-prevalence of MDR TB. DST methods generate substantial savings in diagnostic time that translate into substantial cost savings when transmission is considered, even in a model that includes only household contacts and secondary cases. MDR TB treatment costs have a substantial impact on our estimates of treatment savings. Treatment and hospitalization costs are comparatively low in Peru ($2895 for MDR TB treatment and $75 for first-line treatment) [31]. Thus, the cost savings associated with the reduction of transmission that results from rapid diagnosis may be higher in other settings, particularly where ambulatory care is not well established [37].

Because of high levels of uncertainty found by the Monte Carlo analysis and taking into account that our data are generated from a single clinical trial, our study is only suggestive of the relative cost-effectiveness ranking of different tests. Nevertheless, we found that test costs and costs of false-positive cases substantially affect the cost-effectiveness of DST. DLJ performs well in both aspects, and therefore, DLJ emerged as the most cost-effective DST method. For groups with a higher prevalence of MDR TB, the speed of diagnosis becomes more important; although DLJ still performs well, the difference in cost per DALY between alternative DST methods is reduced.

Our study assumed an accuracy for IDLJ of 98%, as is commonly found for proficiency testing. Under this assumption, our calculations showed that IDLJ may not always be the most cost-effective option for any patient group. In addition, the real-life performance of indirect methods may be much slower than that observed in a clinical trial. DLJ is cheaper than and as effective as IDLJ, it yields results 4 weeks earlier, and it can be implemented in most laboratories. Our study showed that MTT is also lower in cost and is faster than IDLJ, although, in practice, it may lead to emergence of resistance because of its low sensitivity.

The selection of DST method is dependent not solely on cost-effectiveness but also on feasibility. A high TB burden and lack of infrastructure represent significant obstacles to implementing DST methods in developing countries [38]. Therefore, their implementation must be accompanied by a national commitment to improve culture-performing laboratories. Introduction of INNO-LiPA remains a challenge because of the cost and complexity of performing this assay based on standard PCR of processed DNA-extracted sputum. However, DLJ, MTT, and FASTPlaque-Response can be adopted in most laboratories that currently perform conventional culture on Löwenstein-Jensen medium. More research is therefore required to examine further the feasibility, costs, and effectiveness of these methods in other settings.

It should also be noted that, although INNO-LiPA and FASTPlaque-Response appear to be the least cost-effective of the methods studied, their high kit costs had a substantial impact on our results. If national TB control programs were to have access to concessional prices or less expensive versions, this would considerably increase their affordability and cost-effectiveness. Furthermore, a test that is the most cost-effective but not the most effective method should not necessarily be prioritized. The question for policy makers is whether the extra cost (∼$90,000 for FASTPlaque-Response and INNO-LiPA) is justified by the ∼600 DALYs generated (∼20 deaths averted), compared with other uses for their funds.

We present results for different prevalence groups, to assist the generalization of our findings to other settings. Our results are applicable to countries where prevalence of HIV infection is low and ambulatory treatment is available. Effectiveness in terms of DALYs may be higher in countries with a high prevalence of HIV infection, because of a greater number of deaths averted, and in which rapid tests might have a substantial impact on treatment outcomes [39, 40]. In addition, rapid tests may prevent the emergence of extensively drug-resistant TB in settings where quality-assured treatment (i.e., the DOTS strategy) is not provided.

In conclusion, MDR TB has emerged as a major public health threat worldwide. The establishment of the DOTS-Plus and the Green Light Committee has greatly improved the availability of treatment, but delays in the diagnosis of MDR TB remain a major obstacle to its control (L. Castagnini, J. Cunningham, and E. Gotuzzo, unpublished data) [41–44]. Our results indicate that several DST methods are cost-effective, and additional trials should be considered by national TB control programs. However, the feasibility of implementing rapid DST methods and the health benefits that might accrue from their use require further study. Additional data are needed from other populations and settings, particularly those in which HIV infection is prevalent. If interest and effort continue in this area of research, this will positively influence MDR TB policy, patient care, and, ultimately, TB control.

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Acknowledgments

We thank Andrew Ramsay for his painstaking work in reviewing all the input required for each test.

>Financial support. World Health Organization through its Tropical Disease Research program.

>Potential conflicts of interest. R.O. works for the Foundation for Innovative New Diagnostics (FIND), which has a contractual agreement with Biotech, the manufacturer of the FASTPlaque-Response tuberculosis test, that calls for FIND to undertake evaluation and demonstration studies of the test. In turn, Biotech is to provide the test at the lowest possible price to the public health care sector in developing countries. All other authors: no conflicts.

  • Received December 29, 2007.
  • Accepted March 9, 2008.
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  1. Clin Infect Dis. (2008) 47 (4): 487-495. doi: 10.1086/590010
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