The risk of HIV-infected tuberculin reactors developing TB is taken from the results of the placebo arms of four clinical trials conducted in developing countries. These studies reported annual TB infection rates of 3.4% to 10.0% [18,19,25,26]. The median rate, 6.7%, was used as the annual risk of active TB in patients not taking preventive therapy.
Effectiveness of preventive therapy regimens
The effectiveness of preventive therapy was taken from the results of clinical trials performed in East Africa and Haiti. Whalen et al. conducted a large study in Uganda of several short-course regimens. Among subjects randomized to 6months of daily INH, the annual TB infection rate was 1.08%, a risk reduction of 67% relative to placebo . This finding is consistent with the results of studies in Kenya and Zambia [25,26]. Whalen et al. also studied a regimen of 3months of daily INH and RIF, and found an annual TB infection rate of 1.32%, a risk reduction of 60% relative to placebo .
Halsey et al. studied the effectiveness of a 2-month regimen of twice-weekly RIF and PZA in a clinical trial in Haiti. The comparison group took 6months of twice-weekly INH. The annual TB infection rate in the RIF and PZA group was 1.8%, not significantly different from the rate of 1.7% in the INH group . Because this trial did not include a placebo group, the base case rate with no preventive therapy, 6.7%, was used to calculate the effectiveness of the RIF and PZA regimen relative to taking no preventive therapy.
Because the duration of effectiveness has not been studied, the base case analysis used the assumption that preventive therapy maintains full effectiveness for 3years from the start of therapy, with declining effectiveness to zero after 5years.
Adverse events were classified by the clinical trials as mild, moderate and severe and included symptoms of rash, pruritus, gastrointestinal distress, arthralgias and evidence of clinical hepatitis. Neither the Ugandan study nor the Haitian study reported cases of severe or fatal hepatitis. The rates of adverse events for the 6-month INH regimen and the 3-month INH and RIF regimen were taken from the Ugandan study by using the incremental increase in rates relative to the rate found in the placebo group . Although no cases of severe or fatal INH-associated hepatotoxicity were reported, we used a rate of 0.001% per year [27,28]. The rate of adverse events for the 2-month RIF and PZA regimen was taken from the Haitian study, which found a 1% to 3% incidence of abnormal laboratory values during the first 8weeks of RIF and PZA therapy, but no serious adverse events or discontinuation of treatment occurred .
The clinical trials of preventive therapy were not designed to demonstrate survival differences between groups, although the trial by Pape et al. did find a survival benefit from 12months of INH preventive therapy  and the trial by Whalen et al.  found a non-significant trend toward improved survival. Three epidemiologic studies compared survival of HIV-infected persons with and without an episode of active TB [10-12]. Braun et al. retrospectively studied women of childbearing age in Kinshasa . The mortality rate among 19 women with pulmonary TB, 26%, was significantly higher than the rate for the 224 women who did not have TB, 10%. Whalen et al. retrospectively studied patients in four USA medical centers, matching cases and controls by CD4 count. The two groups were similar in age, sex, race, history of previous opportunistic infection, and use of antiretroviral therapy. The 1-year mortality rate in patients with a prior diagnosis of active TB, 35%, was significantly greater than the rate in patients without a history of TB, 10% . Leroy et al. performed a large, community-based prospective study (the Aquitaine Cohort) in France, which also matched cases and controls by HIV disease stage. Annual mortality rates were significantly higher in the TB patients than in the controls, 40.7% versus 26.4% . The effect of TB on long-term mortality of HIV-infected people remains a subject of controversy in the literature. With an understanding of the limitations of these studies and specifically the applicability of the USA-based study to sub-Saharan Africa, we have used the annual mortality rates found in the Whalen et al. study  as the base case assumption. The sensitivity analysis uses the mortality rates found in the other studies.
Saunderson  used financial reports from Kagando Hospital, Uganda and the Uganda National Tuberculosis/Leprosy Programme to determine the current costs of TB treatment. The total per patient cost of $113.51 (adjusted to 1997 US$ values) includes the costs of hospital overheads, medical and support staff training, diagnosis of tuberculosis, inpatient and outpatient treatment, antituberculosis drugs, and health education and counseling. The costs assume that sputum-positive patients would be admitted to the tuberculosis ward for 8weeks of intensive therapy, after which they would be referred to a nearby clinic for the 10-month continuation phase of treatment. The cost of treating other opportunistic infections is assumed to be similar among treatment groups and is not included in this analysis. Social, or indirect costs, include the costs of transport, lodging, and food for the patient and an accompanying relative during the diagnosis and treatment of the disease. Also included in social costs are the costs associated with time away from normal activities . Social costs alone were estimated to be $274.66. Total direct and indirect costs were $388.17.
The costs of the three preventive therapy regimens were estimated using the cost data included in studies by Saunderson in Uganda , and Aisu et al. in Uganda  and Foster et al. in Zambia . In an operational assessment of an existing preventive therapy program, Aisu et al. reported the cost of 6months of daily INH preventive therapy to be $22.95 (adjusted to 1997 US$ values) per person successfully completing the regimen. Included in this total are the costs of the initial tuberculin skin test, screening (chest X-ray and sputum smears) for active tuberculosis, a 6-month supply of INH, and personnel and administration of the program . The costs of HIV screening and counseling are not included in this total. Using the program and screening costs reported by Aisu et al. and the unit costs of antituberculosis medications reported by Saunderson, the cost per person was calculated to be $36.67 for 3-months daily INH and RIF and $44.00 for twice-weekly RIF and PZA. Costs of home visits for patients who miss follow-up appointments were included and total per patient costs were calculated using the compliance rates reported in the respective clinical trials. The total cost of the 2-month RIF and PZA regimen also includes directly observed therapy and monthly nutritional supplements for patients .
The costs of treating adverse events from preventive therapy were derived from a study by Masobe et al.  in South Africa, which reported the cost of managing INH-induced hepatitis as $247. This cost was reduced by a factor of 4.9 to $50.22 to reflect the different costs and availability of medical resources in Uganda. The multiplier, 4.9, was determined by relative TB treatment costs in South Africa and Uganda [29,32]. Using cost data from Masobe et al., we estimated the cost of mild adverse events, primarily skin lesions, to be $6.30 per person affected .
Quality of life
Our study applies quality of life values to each transition state in the model. Estimates are derived from a study by Holtgrave et al. which calculated median self-reported quality of life values from six USA studies . Quality of life values assigned were: 0.65 for patients without a prior episode of TB, 0.62 during and after an episode of TB, 0.5 for 1week during a mild adverse drug reaction and 0.25 for 3weeks until recovery or death during a severe adverse drug reaction.
The final cost scenario in this study calculates the TB medical care and social costs for cohort members and their contacts outside the original cohort who become infected and develop TB (secondary cases). Several epidemiological studies have addressed the number of secondary infections for each active case, reporting a range of 4 to 12 infections [32,34,35]. We assumed that each active case infects 4.7 others, a conservative estimate based on the study by Masobe et al.  which used epidemiological data from South Africa. We assumed that among the secondary cases, 10% are HIV-infected, 47% are children, and 3% are elderly [36,37] and that HIV-infected secondary cases have the same TB activation rates and survival as in the base case analysis. For HIV-uninfected people who are newly infected with M. tuberculosis, we assumed that the rate of active TB is 4% in the first 2years and 0.1% each year thereafter . Using data from a Ugandan cohort survival study, we estimated life expectancies to be 53years for children, 25years for adults, and 5years for elderly adults . We calculated the annual mortality rate for the exposed persons based on these life expectancies .
Our model calculates that HIV-infected tuberculin reactors who do not take preventive therapy will have an average life expectancy of 7.79years and a quality-adjusted life expectancy of 3.09QALYs (with future health events discounted at 3% per year). A cohort of 100,000 people will experience 38,126 TB cases over their cumulative lifetimes (Table 3). If the cohort takes the 6-month INH preventive therapy regimen, average life expectancy increases to 8.37years, quality-adjusted life expectancy increases to 3.20QALYs, and the number of TB cases decreases to 30,020 per 100,000. The outcomes calculated with the other preventive therapy regimens, shown in Table 3, are not substantially different than with the 6-month INH regimen.
Cohort members who do not take preventive therapy incur an average cost of $25.30 in TB medical care costs (with future dollars discounted at 3% per year) as a result of the active TB cases of some members (Table 4). Those who take the 6-month INH regimen incur costs of $38.31, which includes the cost of the preventive therapy regimen and the cost to treat adverse reactions of preventive therapy. The cost to increase quality-adjusted life expectancy by 1QALY is therefore calculated to be $114. The total cost of TB medical care with the other regimens is higher, primarily because of the higher cost of those drugs. As a result, the 3-month INH and RIF regimen costs $275 per QALY saved and the 2-month RIF and PZA regimen costs $260 per QALY saved.
Inclusion of social costs in the analysis makes the 6-month INH regimen less costly than having no preventive therapy (Table 4). The other two regimens result in greater costs than the option of no preventive therapy.
The numbers of secondary cases that result from the cohort‚s active TB cases are shown in Table 5. A cohort of 100,000 HIV-infected tuberculin reactors can expect 38,126 primary cases and 19,667 secondary cases of TB as a result of transmission from cohort members, and TB medical care and social costs for the primary and secondary cases average $111.88 per cohort member, when no preventive therapy regimen is used. All three preventive therapy regimens yield fewer primary and secondary cases and incur smaller costs. The regimen that results in the lowest total costs is the 6-month INH regimen.
The difference in costs of the preventive therapy regimens relative to no preventive therapy are shown in Table 6. Considering the costs of preventive therapy, the costs of treating adverse reactions to preventive therapy, and the medical care costs of treating tuberculosis, the preventive therapy regimens cost $13.01 to $32.55 per person. When social costs are included, the 6-month INH regimen results in savings of $12.72 per person whereas the other two regimens result in costs of $4.37 to $5.08 per person relative to no preventive therapy. When the cost of secondary cases is included, the three regimens result in savings of $5.11 to $24.16 per person, with the greatest saving being for the 6-month INH regimen.
Variations of each assumption through the full range shown in Table 1, including making the assumption that preventive therapy is effective for only 1.5years, did not result in any preventive therapy regimen reducing life expectancy relative to not taking preventive therapy. The combination of the most pessimistic assumptions regarding preventive therapy (the extreme of the ranges shown in Table 1) also did not result in any preventive therapy regimen reducing life expectancy. If the cost of preventive therapy is one-half the costs listed in Table 2, preventive therapy becomes very cost-effective: it costs $13 to $95 to extend life by 1QALY and, if social costs or secondary cases are included, preventive therapy saves money. If preventive therapy costs twice the costs listed in Table 2, it costs $315 to $636 to extend life by 1QALY and, if social costs and secondary cases are included, the only regimen that saves money is the 6-month INH regimen. Varying the cost of treating TB from one-half to twice the costs listed in Table 2 has a similar effect on the cost-effectiveness ratios: preventive therapy costs from $21 to $322 to extend life by 1QALY through the full range. If the cost of treating TB is twice the cost listed in Table 2, all three regimens result in substantial savings. If the cost of treating TB is one-half the cost listed in Table 2, the only regimen that results in medical care cost savings is the 6-month INH regimen. Even if both the cost of preventive therapy is one-half the base case cost and the cost of treating TB is twice the base case cost, the 6-month INH regimen results in medical care cost savings (without considering social costs and secondary cases).
If the number of secondary cases per active case is 2 instead of 4.7, preventive therapy is less cost-effective: the 6-month INH regimen and the 2-month RIF and PZA regimen save less money but the 3-month INH and RIF regimen actually costs money to save QALYs. The 3-month INH and RIF regimen saves money if the number of secondary cases per active case is 2.4 or more. If the number of secondary cases per active case is 10, preventive therapy results in substantial medical care cost savings: $17 to $37 per person.
If future costs and health events are discounted at 10% instead of 3%, preventive therapy is less cost-effective: it costs $393 to $889 to extend life by 1QALY and, if social costs or secondary cases are included, the only regimen that saves money is the 6-month INH regimen.
Using a Markov model, the results of recent clinical trials, and cost data from sub-Saharan Africa, we calculated the cost-effectiveness of tuberculosis preventive therapy for HIV-infected persons in Uganda. Life expectancy and quality-adjusted life expectancy are increased and the incidence of TB is reduced as a result of preventive therapy. The cost for these benefits ranges from $114 to $275 per QALY saved. If social costs are included with the cost of TB medical care, the 6-month INH regimen saves money. The regimen costs $22.95 per person and, by reducing the likelihood of developing TB relative to not taking preventive therapy, recovers the investment and saves an additional $12.72 per person. If social costs and secondary case costs are included, all three regimens result in savings in medical care costs, ranging from $5.11 to $24.16 per person. Wide variations in the assumptions made have little impact on these findings. However, the 6-month INH preventive therapy regimen would have to be less than half its current cost and treatment of active TB would have to be more than twice its current cost for preventive therapy to save costs in TB medical care, if social costs and secondary case costs are ignored.
Few other studies have evaluated the cost-effectiveness of tuberculosis preventive therapy in the setting of a developing country. A cost-effectiveness analysis of 6months daily INH preventive therapy for HIV-infected patients in Zambia also found that when only the cost of TB treatment was included, monetary benefits did not exceed costs. But when the cost of patients‚ lost wages was included, benefits exceeded costs by a ratio of 1.86 . This model calculated that if the secondary cases prevented increased to five from their base case assumption of two, INH preventive therapy would be cost-effective even when only direct costs are included. An economic assessment of INH chemoprophylaxis for dually infected people in South Africa reported savings in health-care costs when secondary infections were included together with just direct costs .
Our study has several important limitations. First, we considered only TB medical care costs and did not include other medical care costs, such as HIV-related illness costs. Several observational studies have shown that HIV-infected people have a higher incidence of opportunistic infections after an episode of active TB [11,12]. If this analysis had included the cost of treating HIV-related illness in addition to treating active TB, preventive therapy would have been even more cost-effective. Secondly, this study does not include the costs of the initial HIV screening program. We assumed that patients would be referred for preventive therapy from a voluntary testing and counseling center, however, in areas where HIV testing is not available, additional costs of HIV testing and counseling would be required to facilitate this proposed program. In addition, this analysis assumes an independent preventive therapy program and does not address how integration of preventive therapy into existing national TB control programs would affect costs, follow-up, and compliance. Thirdly, this analysis used the lowest cost of TB treatment cited  which biased the analysis against choosing preventive therapy. The literature cites a wide range of TB treatment costs in Africa for TB treatment regimens that range from primarily inpatient to almost exclusively outpatient; all of these reported costs are higher than that used in this model [29,31,34]. Fourthly, our analysis of secondary case costs depends on a rate of spread that is uncertain, with a wide range cited in published studies [32,34,35]. We found that even the most expensive regimen, 2months of RIF and PZA, will result in reduced TB medical care and social costs if the rate of spread is 2.4 or more secondary infections for each active case. A fifth limitation is that the duration of preventive therapy effectiveness is unknown. However, our model shows that even if preventive therapy has no effect at 2years after treatment, it remains an effective means to extend life expectancy and reduce the incidence of TB.
It is important to note that this study is strongly grounded in the assumption that TB preventive therapy will ultimately prolong life. We acknowledge that the data on this subject remain controversial and that no single study has shown a survival benefit. However, the meta-analysis found a significant increase in survival for tuberculin-positive subjects. Therefore we have restricted this model to a population of HIV-infected patients with positive tuberculin skin tests.
The addition of TB preventive therapy to the case-finding and treatment strategy currently in use in sub-Saharan Africa will result in saving money. As with any disease prevention strategy, a significant initial investment is required, but this investment is recovered and savings are seen when social and secondary case costs are considered. In countries such as Uganda where medical care costs are significantly shouldered by the patient and the patient‚s family, it is important to give appropriate weight to social costs in any health-care cost-effectiveness analysis. Prevention of secondary cases and financial savings are seen with an estimate of secondary cases lower than that commonly reported in the literature.
Feasibility studies of tuberculosis preventive therapy caution that screening, follow-up for test results, and adherence to therapy remain significant problems. However, this study uses the compliance data reported in similar settings and still found preventive therapy to be cost-effective. Drug resistance from poor preventive therapy adherence was not a problem in the clinical trials but remains an important concern .
Our study provides further rationale for the institution of tuberculosis preventive therapy in sub-Saharan Africa and other developing countries. There is now substantial evidence that TB preventive therapy is effective and may prolong life; this study reinforces that TB preventive therapy will also save money. We therefore strongly recommend that TB preventive therapy be provided for HIV-infected tuberculin reactors in developing countries.
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Keywords:© 1999 Lippincott Williams & Wilkins, Inc.
Africa; cost-effectiveness analysis; decision analysis; developing countries; economics; isoniazid; prevention; pyrazinamide; rifampin; tuberculosis; Uganda