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Feasibility and cost-effectiveness of standardised second-line drugtreatment for chronic tuberculosis patients: a national cohortstudy in Peru Pedro G Suárez, Katherine Floyd, Jaime Portocarrero, Edith Alarcón, Elisabetta Rapiti, Gilbert Ramos, Cesar Bonilla, Ivan Sabogal, Isabel Aranda, Christopher Dye, Mario Raviglione, Marcos A Espinal IntroductionMultidrug-resistant (MDR) tuberculosis—ie, resistance to Background There are no data on the feasibility and cost- at least rifampicin and isoniazid—is a threat to effectiveness of using second-line drugs to treat patients with tuberculosis control efforts in some countries.1,2 Patients chronic tuberculosis, many of whom are infected with with MDR tuberculosis often do not respond to short- multidrug resistant (MDR) strains of Mycobacterium course chemotherapy with first-line drugs.3 tuberculosis, in low or middle-income countries. treatment with second-line drugs may be needed to curethese individuals and to curtail transmission of such Methods A national programme to treat chronic tuberculosis strains of Mycobacterium tuberculosis. However, data from patients with a directly observed standardised 18-month daily low-income or middle-income countries on the regimen, consisting of kanamycin (3 months only), management of MDR tuberculosis with second-line drugs ciprofloxacin, ethionamide, pyrazinamide, and ethambutol, under programme conditions are not available. As a was established in Peru in 1997. Compliance and treatment result, international public-health institutions, including outcomes were analysed for the cohort started on treatment the WHO, do not have definitive policy recommendations between October, 1997, and March, 1999. Total and average in place; guidelines exist only for specialised centres where costs were assessed. Cost-effectiveness was estimated as resources that permit treatment are available.4 Treatment of MDR tuberculosis is, however, available in more-developed countries.5,6 Findings 466 patients were enrolled; 344 were tested for After results of a survey of drug-resistant tuberculosis drug susceptibility and 298 (87%) had MDR tuberculosis. showed an MDR prevalence of 16% among previously 225 patients (48%) were cured, 57 (12%) died, 131 (28%) did not respond to treatment, and 53 (11%) defaulted. Of the Programme introduced a standardised treatment regimen, 413 (89%) patients who complied with treatment, 225 (55%) including second-line drugs, for patients who had failed to were cured. Among MDR patients, resistance to five or more respond to standard treatment with first-line drugs. Our drugs was significantly associated with an unfavourable aim was to assess the feasibility, effectiveness, outcome (death, non-response to treatment, or default; odds affordability, and cost-effectiveness of implementing such ratio 3·37, 95% CI 1·32–8·60; p=0·01). The programme cost US$0·6 million per year, 8% of the National TuberculosisProgramme budget, and US$2381 per patient for those who completed treatment. The mean cost per DALY gained was $211 ($165 at drug prices projected for 2002). Peru is a middle-income country that had a per capitaGross National Income of US$2390 in 1999.7 The DOTS Interpretation Treating chronic tuberculosis patients with high strategy was introduced in 1991 and is now implemented levels of MDR with second-line drugs can be feasible and in all health facilities.8,9 WHO targets for tuberculosis cost-effective in middle-income countries, provided a strong control (70% case detection and 85% cure rate among tuberculosis control programme is in place. new smear-positive pulmonary cases) have been achievedand sustained, as a result of which the incidence rate is Lancet 2002; 359: 1980–89. Published online May 14, 2002.
http://image.thelancet.com/extras/01art7269web.pdf Before 1997, the treatment policy in Peru was limited to short-course chemotherapy with first-line drugs. All newly-diagnosed tuberculosis cases are administered a treatmentregimen consisting of an intensive phase of isoniazid,rifampicin, ethambutol, and pyrazinamide for 2 months,followed by a continuation phase with rifampicin andisoniazid for 4 months. Patients who do not respond to thetreatment regimen or default with this regimen, or who arecured but later relapse, are given a re-treatment regimen,which involves five drugs in the 3-month intensive phase of National Tuberculosis Control Programme, Ministry of Health, treatment (isoniazid, rifampicin, ethambutol, and pyrazi- Lima, Peru (J Portocarrero MD, G Ramos MD, C Bonilla MD, namide for 3 months; streptomycin for first 2 months I Sabogal MD, I Aranda RN, P G Suárez MD, E Alarcón RN); and only), and a continuation phase with rifampicin, isoniazid, WHO, Geneva, Switzerland (K Floyd PhD, E Rapiti MPH, C Dye Dphil, and ethambutol for 5 months. In both regimens, treatment is administered daily in the intensive phase and twice a Correspondence to: Dr Marcos Espinal, WHO, Stop TB Department, week during the continuation phase. In each instance, treatment is directly observed by health workers, and is THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Participants and treatment regimen method in the network of 1168 laboratories available in Two categories of patient were eligible for the second-line Peru at the time of the study. Quality control for smear drug treatment programme introduced in October, 1997.
microscopy, culture, and drug susceptibility testing is The first consisted of patients who remained sputum- done routinely in Peru.11 In 1999, proficiency testing by smear positive after completing a fully supervised re- the WHO Supranational Reference Laboratory in treatment regimen. These patients are defined as chronic Argentina showed 100% agreement between the two laboratories for identification of susceptibility to subcategories. The first subcategory comprised patients rifampicin, isoniazid, ethambutol, and streptomycin.
who had consecutively failed to respond to the standard Cure was defined as two negative sputum smear treatment and re-treatment regimens with first-line drugs microscopy results or two negative culture results, or under direct observation by a health worker. The second both, at the end of treatment. Patients who did not subcategory included patients who had been declared respond to treatment were those who remained cured in response to the standard treatment regimen with bacteriologically positive at the end of treatment.
first-line drugs, but who later relapsed and failed to Defaulters were patients who did not attend to take their respond to the standard re-treatment regimen. The drugs for 1 month or more at any time after registration. second category consisted of patients defined asexceptions—for example, those whose previous treatment Data management and statistical analysis had not been administered under direct observation, or At enrolment, we obtained data on demographic involved regimens not recommended by the National variables, clinical history, previous treatments for tuberculosis, history of diseases other than tuberculosis, We obtained written informed consent before giving previous imprisonment, and previous hospital admission.
eligible patients a standardised 18-month daily regimen, During treatment, staff recorded each dose of the drugs consisting of kanamycin (1 g injectable), ciprofloxacin administered, any adverse effects and how they were (1 g orally), ethionamide (750 mg orally), pyrazinamide managed, and radiological and bacteriological results.
(1500 mg orally), and ethambutol (1200 mg orally).
Data were collected in pretested standardised forms.
Kanamycin was administered only for the first 3 months.
Before analysis, electronic data were compared with Treatment was provided on an ambulatory basis under 200 patient charts to verify their accuracy. direct observation at a local health clinic.
Data were analysed with SPSS (version 7.5.2).
Univariate analysis included the ␹2 test for the comparison of categorical variables. Crude and adjusted Patients were enrolled between October, 1997, and odds ratios and 95% CIs were calculated by logistic March, 1999, in any of the 6435 health facilities that regression to test for the relation between an unfavourable provided tuberculosis services in Peru. An MDR outcome—ie, death, non-response to treatment, or tuberculosis unit was established as part of the National default—and predictor variables. To adjust for possible Tuberculosis Programme in Lima, to manage the confounding effects, all variables were entered into implementation of the treatment programme. This unit multiple logistic regression models. Variables were was staffed by a coordinator, two physicians, a nurse, and selected for removal according to their biological a data manager, and was in regular contact with the importance and by backward elimination with the tuberculosis coordinators of the 34 health regions of Peru.
A training programme, consisting of two nationalworkshops and several regional workshops, was Cost-effectiveness was assessed from the perspective of An expert committee of 12 lung specialists, public- the public sector in year 2000 prices (in US$) with health specialists, and laboratory specialists was established in Lima to approve or reject requests from programme described above was compared with two the general health facilities to enrol patients. Requests other strategies using second-line drugs. The first was for enrolment followed a standardised approach, which identical to the standardised treatment programme, included submission of the patients’ medical history, except that patients who do not respond to treatment on previous treatments received and outcomes, and the this programme are given the additional option of latest smear microscopy, culture, and drug susceptibility treatment with an individualised regimen, tailored to their test results. Decisions of the committee to approve or drug susceptibility pattern. The second was a new reject access to drugs were by consensus. strategy proposed for national implementation in 2001.
Patients were seen daily by nurses for administration This approach also includes provision of individualised of drugs and monitoring of any adverse effects treatment to patients not responding to the standardised associated with treatment, and monthly by doctors for a second-line drug treatment programme. However, in medical check-up. To discourage defaulting from addition, patients who do not respond to the first-line treatment, the guidelines of Peru’s National treatment regimen are tested for MDR. Those identified Tuberculosis Programme were followed: patients were with MDR tuberculosis are enrolled in the standardised provided, for example, with an appointment card and a second-line drug treatment programme, instead of the weekly food parcel. Baseline and monthly follow-up first-line re-treatment regimen. For each of the three cultures of sputum samples from which to isolate alternative strategies, cost-effectiveness was calculated according to a strategy’s total incremental costs and 75 laboratories that were doing cultures in Peru between effects compared with a situation where second-line drugs 1997 and 1999. Cultures were done on a Löwenstein- are not available and treatment is confined to isoniazid Jensen medium. Drug susceptibility testing of first-line monotherapy—ie, the analysis focused on the increase in drugs was done with the proportion method at the total costs and effects associated with the use of second- National Institute of Health laboratory in Lima.
line drugs. This was justified on the basis that most low- Baseline and monthly follow-up sputum smear income and middle-income countries routinely provide microscopy analyses were done by the Ziehl-Neelsen treatment with first-line drugs through government THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Variable value (distribution Referencewhere applicable)* Cost of individualised treatment Cost of drugs plus other costs per patient treated (US$) Three scenarios assessed: 4, 18, 19, 201) 2500 2) 5000 3) 10 000 General variables related to effectivenessPrevalence of MDR among patients who do not respond to first-line treatment regimen (%) Self-cure rate among chronic patients (%) Treatment outcomes on the re-treatment regimen for patients who do not respond to first treatment regimen Treatment outcomes on the re-treatment regimen for patients who do not respond to first treatment regimen and do not have MDR Treatment outcomes for patients who are treated with the standardised second-line drug regimen immediately after failing to respond to the first regimen and being found to have MDR (ie, the re-treatment regimen is not used) Treatment outcomes for patients treated with individualised treatment regimen after non-response to the standardised second-line drug regimen¶ Long-term death rate from tuberculosis, chronic patients not receiving treatment with second-line drugs (%)Long-term death rate from tuberculosis among patients who do not respond to treatment with second-line drugs (%)Long-term relapse rate among those initially cured with regimens that include second-line drugs (%) Death rate from tuberculosis among patients initially cured with regimens that include second-line drugs, but who later relapse (%)Death rate among patients who default (%) for chronic cases with no access to second-line drugs Average period of survival for patients who die after failing to respond to treatment with first-line drugs,in the absence of treatment with second-line drugs (years) Discount rate for valuing health gains arising in the future (%) Average health gain associated with one averted death (DALYs)** Variables specifically related to effects associated with the impact of treatment on transmissionCase reproduction number for chronic tuberculosis when no treatment with second-line drugs is available††—ie, average number of secondary cases produced by primary case in the next generation.
Case reproduction number for chronic tuberculosis, in the presence of treatment with second-line drugs infectiousness in presence amount of of treatmentϬaverage transmission for chronic tuberculosis when no treatment with second-line drugs is available Total number of secondary cases arising g years in the future, where g=generation time in years and R is the case reproduction numberTotal number of secondary cases arising in the future, where r is the total number of secondary cases arising g years in the future and g is the generation time in years, ie, r=Re–0·03ϫg Average duration of infectiousness, chronic case not treated with second-line drugs (years) Average duration of infectiousness, chronic case treated with second-line drugs whose outcome is re-treatment regimen considered in the analysis Average duration of infectiousness, when final outcome is non-response to treatment (years) treatment from point of entry into the analysis Average duration of infectiousness, non-responders to the treatment regimen who are cured on the re-treatment regimen (years)Average duration of infectiousness, patients who are cured on the standardised second-line drug re-treatment regimen considered in the analysis Average duration of infectiousness, patients who are cured on individualised treatment after not responding to the standardised second-line drug treatment regimen (years) re-treatment and standardised second-line drug regimen considered in the analysis THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Death rate for secondary cases on first-line treatment regimen (%) Death rate for secondary cases on first-line treatment regimen among patients who default from proportion of untreated chronic cases that die Non-response rate for secondary cases on first-line treatment regimen (%) Average cost per patient treated on the first-line treatment regimen for drugs plus all other costs (US$) 322 Average cost per patient treated on the re-treatment regimen for drugs plus all other costs (US$) *Uniform=analysis used values chosen at random between the lower and upper figures specified for the distribution; normal=first number specifies the mean and thesecond number the SD that define the distribution. †Unpublished—details available upon request. ‡Values chosen on the assumption that the cure rate for patientswithout MDR would be higher than the overall cure rate among all patients who do not respond to the first-line treatment regimen. §Values chosen on assumption thatthe cure rate would be slightly higher than for the cohort treated 1997–99, due to earlier use of second-line drugs. ¶Since most data were from industrialised countrysettings, the lower limit for the cure rate was deliberately set as lower than the minimum cure rate reported and approximately equivalent to the cure rate achievedwith the standardised regimen used in Peru 1997–99. The higher rate was set as the proportion of those completing treatment multiplied by 0·8, to reflect the higherlevel of cure among those completing treatment reported in some studies,24 and which seems plausible based on data reported from Lima, Peru.22 ||Assumptionjustified on the basis that patients who default no longer receive treatment, and can therefore be expected to have treatment outcomes similar to those of chronictuberculosis patients with no access to second-line drugs. **Formula for calculating DALYs provided in reference given.28 Use of the formula requires data on theaverage age at onset of disease (30 years), and the average life expectancy at that age (40 years). ††Assumed to be between 0·5 and 1 to be conservative whenassessing cost-effectiveness. A less conservative assumption, which would improve (ie, lower) cost per DALY gained figures, would have been to assume that thecase reproduction number in the absence of treatment with second-line drugs would be equal to 1. ‡‡Value is conservative with respect to effectiveness and cost-effectiveness calculations (ie, value may lead to effectiveness being under-estimated) because the period on treatment is added to the duration of infectiousnessexpected in the absence of treatment. §§Value is conservative with respect to effectiveness and cost-effectiveness calculations (ie, value may lead to effectivenessbeing underestimated) because it is assumed that for those who cure, culture/smear conversion will take the same time as on the standardised second-line regimen,even though an individualised regimen is tailored to a patient’s drug susceptibility pattern.
Table 1: Variables and variable values used to estimate effectiveness and cost-effectiveness services, but they do not routinely provide treatment with reports,11,15,16 patient case notes, and a study of the second-line drugs. The important question for policy- economic impact of tuberculosis in Peru.17 making purposes is, therefore, what are the additional In view of the uncertainty about several measures that costs and effects associated with implementing second-line affect effectiveness, and the cost of individualised treatment in middle-income countries, effectiveness and Treatment costs in the absence of second-line drugs cost-effectiveness were estimated as part of a multivariate were assessed as zero. This was justified in view of the low uncertainty analysis. This analysis involved three main price of isoniazid (US$0.01 per 100 mg dose in Peru) and the possibility that use of health services is infrequent. For First, a spreadsheet model was developed in Microsoft the standardised second-line drug treatment programme Excel (version 7.0), in which treatment paths were defined implemented between 1997 and 2000, two groups of costs for each alternative strategy. The earliest starting point for were considered: the average cost of individual a treatment path was non-response to the first-line components of treatment—eg, drugs, a visit for direct treatment regimen, since this is the earliest point at which observation of treatment (DOT), training—and the patients become eligible for treatment with second-line drugs in the three strategies assessed. However, the Wherever possible, the costs of individual components treatment paths for exceptions and relapse patients who of treatment were calculated with an “ingredients” did not respond to the first-line re-treatment regimen approach—ie, the quantity of resources used was started at a later point, to reflect when they become combined with unit price data. The exceptions were: non- eligible for treatment with second-line drugs and because personnel recurrent inputs, for which there was only treatment before this time is the same in each strategy. expenditure data; and laboratory tests and radiographs, for Second, the number of patients following each treatment which only prices were available. Overhead tuberculosis path, together with the associated costs and effects, was programme costs—eg, supervision and management, defined according to: the variables, variable values and monitoring, and surveillance—were allocated equally distributions, and data sources2–5,9,11,14,18–31 listed in table 1; across all notified tuberculosis patients in Peru. Since staff the costs per patient reported in this article; and the time was judged to broadly indicate overall resource use treatment outcomes associated with the standardised for different types of patient in outpatient health facilities, second-line drug regimen. The high cost scenario for overhead clinic costs were allocated to tuberculosis individualised treatment (US$10 000 per patient for drugs patients in accordance with the fraction of clinic staff time plus all other costs) was based on drug prices reported for spent on their care. Vehicle and equipment costs were low-income and middle-income countries in the absence of annualised using current replacement prices, the concessional prices,20 and allowance for other costs besides assumption of a 5-year life expectancy, and a discount rate drugs—such as those that applied to the standardised of 3% (the currently recommended international rate).14 second-line drug treatment programme already Start-up training costs were annualised over 3 years.
implemented. The intermediate cost scenario for Building costs per year were based on rental values per individualised treatment (US$5000 per patient for drugs month. All local costs were converted into US$ according plus all other costs) was chosen to reflect the cost per to the average exchange rate in 2000 (US$1=Peruvian patient that might apply with both concessional drug prices20 and with allowance for the costs of other inputs The average cost per patient treated was calculated as being higher than those of the standardised second-line the cost of each treatment component multiplied by the drug treatment programme. The low-cost scenario for average number of times this cost was incurred. This individualised treatment represented an optimistic calculation was done overall, and for three groups of situation in which drugs are available at highly concessional patients: those who completed the full course of prices, and the costs of inputs besides drugs are similar to treatment—ie, cures plus non-responders; those who died; those of the standardised second-line drug treatment programme. Normal distributions were used when Sources of data included expenditure records, standard mean (SD) could be calculated. If only range information salary scales, a database maintained by the MDR unit in was available, a uniform distribution across this range was Lima, interviews with the National Tuberculosis Programme staff, National Tuberculosis Programme The third step was to run a Monte Carlo simulation, THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
involving 5000 iterations, with @RISK (version 3.5), to enrolled patients. 11 (2%) of the enrolled patients were estimate means and lower and upper bounds (5th and 95th excluded from our analysis; reasons included use of a non- centiles) for the main outputs of interest. These outputs standardised treatment regimen, and unfinished treatment.
were total costs, total and average (per patient treated) Table 2 shows demographic characteristics according to effects (cures, deaths averted, years of life gained, and entry criteria. Susceptibility test results were available for DALYs gained), and cost-effectiveness ratios (cost per 344 (74%) patients. 335 (97%) individuals were resistant cure, cost per death averted, cost per year of life gained, and to one or more drugs, 298 (87%) had MDR tuberculosis, cost per DALY gained). To facilitate comparison with and 273 (79%) were resistant to three or more drugs.
other health interventions, the cost-effectiveness results During treatment, 242 (52%) individuals had adverse focus on cost per DALY gained figures.
effects (table 3), leading to permanent interruption of oneor more drugs in 24 (5%) patients. An additional 61 (13%) Sensitivity and threshold analysis patients underwent drug adjustments during treatment— A sensitivity analysis was done to assess the effect of including the extension of kanamycin beyond 3 months and reductions in the cost of the standardised second-line drug addition of drugs such as isoniazid, clavulanic acid, and regimen on total costs and cost-effectiveness ratios.
Projected drug prices were provided by WHO. A thresholdanalysis was done to identify the cost per patient at which use of individualised regimens for MDR patients who do Table 4 shows treatment outcomes. Of the 466 patients not respond to the first-line treatment regimen would be as analysed, 225 (48%) were cured. The proportion of cured cost effective as the strategy proposed for national patients increased to 55% (225 of 413) when patients who complied with treatment (cured plus died plus non-responders) were evaluated, and to 63% (225 of 356) when patients who completed chemotherapy (cured plus The sponsors of the study had no role in study design, data non-responders) were evaluated. Of the 225 patients collection, data analysis, data interpretation, or writing of cured, 210 (93%) and 215 (96%) had converted to sputum smear negative status after 3 months and 6 months of treatment, respectively. Comparable figures for culture conversion were 153 (68%) and 193 (86%). Baseline characteristics and monitoring of participants Of the 298 proven MDR tuberculosis cases, 136 (46%) During enrolment, the committee assessed 755 requests to were cured, 96 (32%) did not respond to treatment, treat tuberculosis cases with second-line drugs; 477 (63%) 32 (11%) died, and 34 (11%) defaulted. Of the 264 MDR were accepted. 21 of 34 health departments in Peru tuberculosis patients who complied with treatment, 52% Susceptibility test resultsMDR tuberculosis Data are n (%). *Patients who are sputum positive at the end of a fully supervised re-treatment regimen with first-line drugs.
Table 2: Demographic characteristics and disease-related variables according to enrolment criteria THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Overall programme management, central level Supervision at department and district levels *Patients could have two or more side-effects simultaneously.
Side-effects and changed treatment (eg, added Table 3: Adverse effects in 466 patients who underwent *Patients treated on the standardised second-line drug regimen who died ontreatment received an average of 57 intensive phase doses and 64 were cured. Patients without susceptibility test results continuation phase doses, whereas those who defaulted received an average were less likely to fail treatment than those with MDR of 59 intensive phase doses and 107 continuation phase doses. Average costs (20 of 122, 16%, vs 96 of 298, 32%; p=0.001) and other for patients who died and patients who defaulted were $1026 and $1209,respectively.
patterns of drug resistance (20 of 122, 16%, vs 13 of 37, Table 5: Average cost per patient treated for patients who 35%; p=0·02). There was a significant increasing trend to completed the full course of treatment,* standardised second- fail the second-line drug regimen as the number of drugs line drug treatment programme implemented in Peru to which patients were resistant increased (p=0·02).
Of the 57 patients who died, 34 (60%) were bacteriologically positive at the time of death and 23 (40%) had 3 months or less of treatment. Among resistance to two drugs or less), and not responding to two patients who defaulted from treatment, 27 (51%) were consecutive treatment regimens with first-line drugs (0·61, bacteriologically negative by the time they defaulted.
0·37–0·99; p=0·04; reference group: relapses of the The average duration of treatment before default was treatment regimen who subsequently did not respond to 6 months. Reasons for defaulting included feeling better, the re-treatment regimen with first-line drugs). When moving house, finding a new job, and mismanaged MDR patients were assessed separately, the probability of an unfavourable outcome in the presence of resistance to In multivariate analysis, the final model for explaining five or more drugs increased (3·37, 1·32–8·60; p=0·01). an unfavourable outcome included sex, the number ofdrugs to which patients were resistant, and entry criteria.
An unfavourable outcome—ie, death, non-response, The average cost per patient treated on the standardised default—was significantly associated with two factors: second-line drug treatment programme, for patients that resistance to five or more drugs (odds ratio 2·94, completed the full course of treatment, was US$2381 95%CI 1·26–6·85; p=0·01; reference group: drug (table 5). Drugs, at US$824 per patient, were the greatest NA=not available.*The number of smear and culture negative results declined over time due to the increase in the number of patients in the “defaulted” and “died”categories over time; in addition, not all patients maintained the same bacteriological status throughout treatment. Table 4: Follow-up and treatment outcome in patients who underwent re-treatment with second-line drugs THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Standardised second-line Standardised second-line Standardised plus individualiseddrug treatment individualised treatment 2001†for patients not responding to treatmentwith standardised second-line drug regimen Cost indicatorsTotal annual cost in US$ millions Affordability indicators‡Total annual cost as % National Tuberculosis Programme budgetTotal annual cost as % total cost of tuberculosis control in PeruTotal annual cost as % total Ministry of Health budget Effectiveness indicatorsLong-term cure rate, all patients included in the analysis (%)§ Long-term cure rate, patients treated with second-line drugs (%) Total deaths averted, excluding transmission benefits Total deaths averted, including transmission benefits Deaths averted per patient treated on second-line drugs, excluding transmission benefits¶Deaths averted per patient treated on second-line drugs, Cost-effectiveness indicators||Cost per DALY gained, excluding transmission benefits Cost per DALY gained, including transmission benefits *Year 2000 US$ prices for standardised second-line drug regimen and US$10 000 per patient for individualised treatment; †ie, as for strategy implemented1997–2000, with two modifications: (a) individualised treatment for patients who do not respond to the standardised second-line drug treatment regimen and (b) standardised second-line drug regimen for patients who do not respond to the treatment regimen with first-line drugs and who are diagnosed with MDR.
‡Affordability in relation to National Tuberculosis Programme (NTP) annual budget (approximately US$4 million) based on costs paid for from this budget;estimated annual cost of tuberculosis control US$23·8 million,17 Ministry of Health annual budget US$497 million. §n=500 (ie, treatment non-responders plusrelapses and exceptions); total number treated on second line drugs estimated as 295 per year for the programme implemented 1997–2000, 295 for the strategythat adds individualised treatment for patients not responding to standardised second-line drug treatment regimen, and 404 for the new strategy proposed fornational implementation in 2001. ¶Average figure for proposed strategy is lower because although more deaths are averted in total, more patients are also treatedon second-line drugs. ||Figures are not simply total annual costs divided by total effects, because they also incorporate the costs of treating the secondary casesthat are associated with each strategy. These costs amounted to about US$30 000–125 000, dependent on the strategy; incremental cost-effectiveness ratioswere calculated but are not shown; details available from the authors.
Table 6: Mean cost, affordability, effectiveness, and cost-effectiveness indicators for alternative strategies, highest costscenarios assessed* (5th and 95th centiles) single cost item. Food parcels, DOT visits, consultations depending on whether or not transmission was included in with doctors, and the MDR tuberculosis unit in Lima also the analysis, of increasing the total number of deaths represented large costs. The total annual cost of the averted by 17–42% (table 6). In the highest cost scenario, programme was about US$0·6 million, with costs funded the cost per DALY gained with these two strategies ranged by the National Tuberculosis Programme equivalent to from about US$200 to US$700, with means of US$368 8% of their budget (table 6). An average of 0·49 deaths and US$484 (table 6). However, if the price of the were averted per patient treated when benefits arising from standardised second-line drug regimen fell to levels prevented transmission were included; the figure was 0·36 projected for 2002, and the cost per patient treated with when only deaths averted among treated patients were individualised regimen was less than US$5000, the mean considered. The mean cost per DALY gained, including cost per DALY gained for both strategies would be transmission benefits, was US$211 (range 126–339). At drug prices projected for 2002, the mean cost per DALY The threshold cost at which use of individualised gained fell to US$165 (table 7), and the cost of the regimens for MDR patients who do not respond to the standardised regimen would be reduced even if first-line treatment regimen would be as cost effective as capreomycin was used instead of kanamycin, and ofloxacin the strategy proposed for national implementation in 2001 was used instead of ciprofloxacin (drug cost US$753 vs was US$1500–6000 per patient (figure). US$824 for patients completing treatment).
The total costs of the two alternative strategies with second-line drugs varied considerably. In the highest cost These data from Peru provide evidence with respect to the scenario, in which individualised treatment was assumed feasibility and cost-effectiveness of providing standardised to cost US$10 000 per patient, total annual costs were second-line drug treatment for chronic tuberculosis between US$1·3 million and US$2·0 million, and around patients among whom MDR prevalence is high, under one quarter to one third of the National Tuberculosis programme conditions and on a national basis, in a Programme budget (table 6). At lower estimates of the cost middle-income country. They show that Peru’s National of individualised treatment, and with projected reductions Tuberculosis Programme was able to achieve a in the cost of the standardised second-line drug regimen, compliance rate of nearly 90%, a cure rate of almost 50% total costs fell to around 10–20% of the National among all patients enrolled, and a cure rate of 63% among Tuberculosis Programme budget (table 7). those who completed the full course of treatment. The Compared with the standardised programme, both total programme cost was affordable in the context of the strategies that included individualised treatment were National Tuberculosis Programme’s budget, and the estimated to be capable of raising cure rates and, mean cost per DALY gained was around US$150-200.
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Mean total annual cost in US$ millions (costs funded by NTP Cost per DALY gained (5th and 95th centiles)* Standardised regimen Standardised regimen Standardised regimen Standardised regimen Standardised regimen Standardised regimenat projected prices for at projected prices for at projected prices for at projected prices for at projected prices for at projected prices for 2002, individualised line drug treatment programme imple-mented 1997–2000 line drug treatment programme plus individualised treatment for patients not responding to treatment withstandardised second-line drug regimen individualisedtreatment strategyproposed forimplementationin 2001† NTP=National Tuberculosis Programme. *Includes costs and effects associated with transmission. †ie, as for strategy implemented 1997–2000, with twomodifications: (a) individualised treatment for patients who do not respond to the standardised second-line drug treatment regimen and (b) standardised second-line drug regimen for patients who do not respond to the treatment regimen with first-line drugs and who are diagnosed with MDR.
Table 7: Cost and cost-effectiveness indicators for alternative strategies under different cost assumptions We believe that the feasibility of using second-line tuberculosis unit operating within the overall framework drugs nationwide relied on three key factors. First, the of the National Tuberculosis Programme, facilitating co- new service was built on a tuberculosis control programme that had already achieved WHO’s global Our results are consistent with previous observations tuberculosis control targets with first-line drugs.8,9 that cure rates for patients with chronic disease who Second, there was a special committee to filter requests complete treatment range from around 60% to 80% when for access to second-line drugs, which allowed the second-line drugs are used,24 and with a study of National Tuberculosis Programme to benefit from the treatment outcomes for patients with MDR-tuberculosis best expertise available in the country, and to screen out in the USA.5 They are poorer than figures reported for candidates for whom treatment with first-line drugs was a patients with MDR tuberculosis in the Netherlands and more appropriate option. Third, there was an MDR Canada, but in these studies a large proportion of patients Standardised second-line drug regimen at 2002 projected prices, individualised treatment US$10 000 per patient, including transmission Standardised second-line drug regimen at 2002 projected prices, individualised treatment US$10 000 per patient, excluding transmission Standardised second-line drug regimen at 2002 projected prices, individualised treatment US$5 000 per patient, including transmission Standardised second-line drug regimen at 2002 projected prices, individualised treatment US$5 000 per patient, excluding transmission Standardised second-line drug regimen at 2002 projected prices, individualised treatment US$2 500 per patient, including transmission Standardised second-line drug regimen at 2002 projected prices, individualised treatment US$2 500 per patient, excluding transmission Threshold cost per patient treated (US$) 1000 Threshold costs for individualised treatment of patients with MDR who do not respond to the first-line treatment regimen and arediagnosed with MDR when compared with strategy proposed for national implementation in 2001 THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
had no history of previous treatment.18,23 Cure rates are our assumptions were conservative, and the exclusion of never likely to be as high as those for new drug susceptible costs borne by patients is consistent with the cost, budget, cases—patients have already failed treatment with first- and cost-effectiveness figures with which we compared line drugs, and second-line drugs are less effective and It is noteworthy that 83% of enrolled patients were The data suggest that cure rates with second-line drugs from Lima. There is evidence to suggest that Lima has can be improved in Peru. Half the patients who defaulted high rates of MDR tuberculosis,38 but these data could were bacteriologically negative at the time of default.
indicate selection bias, resulting from the special Individuals who abandoned therapy could be traced by committee’s location in Lima. Moreover, some of the health workers for adjustment of the time and location of patients enrolled in this programme as exceptions had a treatment. Improved training for health workers with history of only one previous treatment, suggesting that respect to management of adverse effects, and they did not meet the inclusion criteria. strengthening the standardised treatment regimen, might The data have important programmatic policy also help. Substitution of capreomycin for kanamycin, implications, and Peru’s National Tuberculosis and ofloxacin for ciprofloxacin could soon be possible Programme adopted three new policies in 2001. First, a with no increase in cost to the National Tuberculosis patient will be declared as not responding to treatment if Programme, and use of cycloserine could be considered they are culture positive after 6 months of treatment (or in the presence of MDR and ethambutol resistance.
150 doses) with a standardised second-line drug regimen.
Further options for increasing cure rates include use of Second, patients who do not respond to the standardised individualised treatment for some patients, and earlier use second-line drug regimen will have access to a second- of second-line drugs. A promising experience with line drug regimen tailored to their drug susceptibility individualised treatment in Northern Lima is already pattern. This regimen will be provided through an underway;33 what remains to be proven is feasibility and international partnership collaboration that will include upgrading the capabilities of the national reference Choice among strategies should also be informed by laboratory to enable testing for susceptibility to second- economic considerations. Cost was a major factor when line drugs. Third, patients who do not respond to the the standardised programme was first implemented in first-line treatment regimen will be treated with the 1997, with the regimen chosen being the most affordable standardised second-line drug regimen if they are in the context of the National Tuberculosis Programme’s diagnosed with MDR—ie, the first-line re-treatment budget. Other options remain more expensive, but are regimen will not be used for these patients.39 To enhance becoming increasingly realistic with substantial access to second-line drugs outside Lima, special reductions in drug prices.20 Treatment of patients with subcommittees to approve or reject requests for access to chronic disease with second-line drugs is, on average, less standardised second-line drug treatment have been cost-effective than the basic DOTS programme, which established in each of the country’s 34 health relies on first-line drugs. The DOTS programme is much more effective in terms of the cure rate8,9 and previous Our findings are probably applicable to middle-income estimates of averted deaths per patient treated,26 and is countries where high cure and compliance rates with first- substantially less expensive. Nevertheless, the cost- line drugs are achieved, prevalence of HIV-1 is low, and effectiveness figures for all the strategies that we assessed ambulatory care is used. Tuberculosis programmes that are much lower than per capita Gross National Income, are not able to manage first-line drugs properly are which is a more general benchmark for assessing whether unlikely to be successful with second-line drugs.
or not an intervention is cost-effective,34,35 and around or Effectiveness in terms of DALYs gained would be lower if below the US$548–822 per DALY gained (converted to rates of HIV-1 infection among tuberculosis patients are year 2000 US$ prices) that was estimated for the “limited high, due to a smaller number of years of life being gained care” component of an essential health package for per death averted. If admission to hospital is relied on, middle-income countries by the World Bank in 1993.36 costs would be higher in both low-income and middle- The figures for the standardised programme implemented 1997–2000 are similar to the US$176 (converted to year Our findings indicate that use of second-line drugs to 2000 US$ prices) per DALY gained that was suggested as treat chronic tuberculosis patients with high levels of a threshold for defining an “attractive” investment in low- MDR can be feasible and cost-effective in middle-income income countries in 1995.37 The threshold should be countries with strong tuberculosis control programmes.
higher in Peru, in view of its middle-income status. Widespread use of second-line drugs in other countries Our study has several limitations. The treatment will depend on efforts to reduce costs and increase access outcome data are not the result of a trial, so we were not under tightly controlled approaches,20 and on success in able to assess efficacy. Although patients are being building strong tuberculosis control programmes.
followed up for 2 or more years to assess the relapse rate,long-term follow up data are not yet available. There were no data with respect to susceptibility to second-line drugs, M Espinal and K Floyd wrote the report; P Suárez, E Alarcón, J Portocarrero, I Sabogal, and M Espinal designed and planned the study; since the necessary infrastructure and logistics had not J Portocarrero was the study coordinator; C Bonilla and G Ramos been developed in Peru during the period of enrolment coordinated doctors at the MDR tuberculosis unit; I Aranda was the head and follow-up. A quarter of the patients enrolled for nurse coordinating patient follow-up and data management; E Rapiti and treatment did not have susceptibility results for first-line M Espinal were responsible for data analysis with respect to feasibilityand treatment outcomes; K Floyd was responsible for cost and cost- drugs. In the cost-effectiveness analysis, we had no data effectiveness analysis; P Suárez and E Alarcón assisted with the collection on the long-term outcomes and costs associated with of cost data; C Dye assisted with the transmission component of the cost- isoniazid monotherapy, or comprehensive and detailed effectiveness analysis; M Raviglione assisted with analysis of treatment cost data for individualised treatment in a low-income or outcomes; and all investigators contributed to the interpretation of thedata and revisions to the report.
middle-income setting. Several assumptions wererequired to estimate effectiveness, and costs from the perspective of patients were not assessed. Nonetheless, THE LANCET • Vol 359 • June 8, 2002 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
21 Lew W. The fate of intractable multidrug resistant tuberculosis cases We thank Antonio Pio, Fabio Luelmo, Thomas Frieden, and under national tuberculosis programme in Korea. Masters thesis, Rajesh Gupta for helpful comments, and the health workers of Peru for London: London School of Hygiene and Tropical Medicine their commitment to the implementation of this project. The work was supported in part by a grant given from the US Agency for International 22 Bayona J, Furin JJ, Palacios E, et al. DOTS-plus in the northern cone of Lima, Peru. International Colloquium of the Institute of TropicalMedicine: Tuberculosis, the real millennium bug—addressing the threat in developing and industrialized countries. Antwerp: Institute ofTropical Medicine, 1999.
Pablos-Méndez A, Raviglione MC, Laszlo A, et al. Global surveillance 23 Avendano M, Goldstein RS. Multidrug-resistant tuberculosis: long- for antituberculosis-drug resistance, 1994-1997. N Engl J Med 1998; term follow-up of 40 non-HIV-infected patients. Can Respir J 2000; 7:
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Espinal MA, Laszlo A, Simonsen L, et al. Global trends in 24 Chaulet P, Raviglione M, Bustreo F. Epidemiology, control and resistance to antituberculosis drugs. N Engl J Med 2001; 344:
treatment of multidrug-resistant tuberculosis. Drugs 1996; 52 (suppl 2):
Espinal MA, Kim SJ, Suarez PG, et al. Standard short-course glu K, Törün T, Sevim T, et al. The treatment of multi chemotherapy for drug-resistant tuberculosis: treatment outcome in drug-resistant tuberculosis in Turkey. N Engl J Med 2001; 345:
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26 De Jonghe E, Murray CJL, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost-effectiveness of chemotherapy for sputum smear-positive Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, pulmonary tuberculosis in Malawi, Mozambique and Tanzania. Horsburgh CR Jr. Treatment of 171 patients with pulmonary Int J Health Plann Mgmt 1994; 9: 151–81.
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28 Murray CJL, Lopez A, eds. The global burden of disease: a comprehensive assessment of mortality and morbidity from diseases, World Bank. Peru data profile, 2001. http://devdata.worldbank.org injuries and risk factors in 1990 and projected to 2020. Cambridge: WHO. Communicable Diseases Programme: global tuberculosis 29 Vynnycky E, Fine PEM. The long-term dynamics of tuberculosis and other diseases with long serial intervals: implications of and Suaréz PG, Watt CJ, Alarcón E, et al. Epidemiological impact of for changing reproduction numbers. Epidemiol Infect 1998; 121: 309–03.
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30 Pathania VS, Trnka L, Krejbich F, Dye C. A cost-benefit analysis of 10 WHO. Global Tuberculosis Programme: treatment of tuberculosis— BCG revaccination in the Czech Republic. Vaccine 1999; 17: 1926–35.
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13 Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-effectiveness 34 Shepard DS, Agness-Soumahoro J, Bail RN, et al. Expenditures on in health and medicine. New York: Oxford University Press, 1996.
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