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Espinal MA, Kim SJ, Suarez PG, et al. Standard Short-Course Chemotherapy for Drug-Resistant Tuberculosis: Treatment Outcomes in 6 Countries. JAMA. 2000;283(19):2537–2545. doi:10.1001/jama.283.19.2537
Context No large-scale study has investigated the impact of multidrug-resistant
tuberculosis (TB) on the outcome of standard short-course chemotherapy under
routine countrywide TB control program conditions in the World Health Organization's
(WHO) directly observed treatment short-course strategy for TB control.
Objective To assess the results of treatment with first-line drugs for patients
enrolled in the WHO and the International Union Against Tuberculosis and Lung
Disease's global project on drug-resistance surveillance.
Design and Setting Retrospective cohort study of patients with TB in the Dominican Republic,
Hong Kong Special Administrative Region (People's Republic of China), Italy,
Ivanovo Oblast (Russian Federation), the Republic of Korea, and Peru.
Patients New and retreatment TB cases who received short-course chemotherapy
with isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin
between 1994 and 1996.
Main Outcome Measure Treatment response according to WHO treatment outcome categories (cured;
died; completed, defaulted, or failed treatment; or transferred).
Results Of the 6402 culture-positive TB cases evaluated, 5526 (86%) were new
cases and 876 (14%) were retreatment cases. A total of 1148 (20.8%) new cases
and 390 (44.5%) retreatment cases were drug resistant, including 184 and 169
cases of multidrug-resistant TB, respectively. Of the new cases 4585 (83%)
were treated successfully, 138 (2%) died, and 151 (3%) experienced short-course
chemotherapy failure. Overall, treatment failure (relative risk [RR], 15.4;
95% confidence interval [CI], 10.6-22.4; P<.001)
and mortality (RR, 3.73; 95% CI, 2.13-6.53; P<.001)
were higher among new multidrug-resistant TB cases than among new susceptible
cases. Even in settings using 100% direct observation, cases with multidrug
resistance had a significantly higher failure rate than those who were susceptible
(9/94 [10%] vs 8/1410 [0.7%]; RR, 16.9; 95% CI, 6.6-42.7; P<.001). Treatment failure was also higher among patients with any
rifampicin resistance (n=115) other than multidrug resistance (RR, 5.48; 95%
CI, 3.04-9.87; P<.001), any isoniazid resistance
(n=457) other than multidrug resistance (RR, 3.06; 95% CI, 1.85-5.05; P<.001), and among patients with TB resistant to rifampicin
only (n=76) (RR, 5.47; 95% CI, 2.68-11.2; P<.001).
Of the retreatment cases, 497 (57%) were treated successfully, 51 (6%) died,
and 124 (14%) failed short-course chemotherapy treatment. Failure rates among
retreatment cases were higher in those with multidrug-resistant TB, with any
isoniazid resistance other than multidrug resistance, and in cases with TB
resistant to isoniazid only.
Conclusions These data suggest that standard short-course chemotherapy, based on
first-line drugs, is an inadequate treatment for some patients with drug-resistant
TB. Although the directly observed treatment short-course strategy is the
basis of good TB control, the strategy should be modified in some settings
to identify drug-resistant cases sooner, and to make use of second-line drugs
in appropriate treatment regimens.
The World Health Organization (WHO) tuberculosis (TB) control strategy,
directly observed treatment short-course (DOTS), consists of 5 components,
including the administration of standardized short-course chemotherapy (SCC)
regimens with first-line drugs (isoniazid, rifampicin, pyrazinamide, and streptomycin
or ethambutol or both) under direct observation, at least in the intensive
treatment phase, regardless of patient drug-susceptibility pattern.1 This strategy, which is considered by the World Bank
as one of the most cost-effective interventions in human health,2
has now been adopted by 119 countries worldwide.3
A recent study revealed that TB cases with multidrug-resistance to isoniazid
and rifampicin are a major problem in some countries.4
Patients carrying multidrug-resistant strains of Mycobacterium
tuberculosis might be at greater risk of experiencing SCC failure and
of disseminating multidrug-resistant strains in the community. Thus, the current
recommended treatment strategy might need to be adapted to manage multidrug-resistant
TB at the program level in middle- and low-income countries, in which 95%
of the TB burden exists. No data are available on the response of patients
with TB who have multidrug resistance to SCC with first-line drugs under routine
countrywide control program conditions. Currently, the only available data
are from patients treated in limited or special settings5,6
or in clinical trials.7 In these trials, higher
efficacy of SCC rifampicin-containing regimens was shown in patients with
resistance to isoniazid or streptomycin or both compared with the conventional
12-month regimens based on p-aminosalicylic acid
In several of the countries that participated in the WHO and the International
Union Against Tuberculosis and Lung Disease's (WHO/IUATLD's) project of drug-resistance
surveillance (DRS), the techniques used for culture of M tuberculosis and drug susceptibility testing (DST) (Löwenstein-Jensen
and proportion methods) required up to 3 to 4 months to produce results.8 Furthermore, in many of these countries, second-line
drugs to manage multidrug-resistant TB are not widely available because of
high costs.9,10 In addition, most
of the surveys, done for epidemiological reasons, were unlinked to clinical
management of individual patients. Patients enrolled in these projects who
failed treatment were therefore unlikely to be switched from the standard
treatment regimens to second-line drugs. As a result, the WHO/IUATLD DRS project
offers a unique opportunity to assess outcomes in patients with drug-resistant
strains who were treated with first-line drugs throughout the entire duration
of treatment under routine program conditions.
This is a retrospective cohort study of patients enrolled in the WHO/IUATLD
global project on DRS in the Dominican Republic, Hong Kong Special Administrative
Region (People's Republic of China), Italy, Ivanovo Oblast (Russian Federation),
the Republic of Korea, and Peru. These countries were selected by 2 main criteria:
the existence of a large number of cases of multidrug-resistant TB detected
by DRS studies and the availability of treatment results that could be linked
with DRS results. The methods of the WHO/IUATLD global project on DRS have
been previously published.4 Briefly, surveys
of drug-resistant TB in each of the above settings took place between 1994
The investigations strictly followed 3 methodological principles to
gather comparable data: (1) surveys and surveillance were representative of
the TB population of the country or area surveyed; (2) differentiation between
new and retreatment TB cases based on history of prior treatment by interviews
and review of medical records or both was ensured; and (3) DST followed recommended
techniques. The DST was performed at each country's national reference laboratory
and a network of international reference laboratories validated results. Since
1994, these laboratories have participated in a quality assurance exercise
to maintain high levels of proficiency testing.11
The Republic of Korea, Hong Kong, and Ivanovo Oblast surveyed all TB cases;
the Dominican Republic and Peru used proportionate cluster sampling. In Italy,
50% of all eligible health institutions were sampled.
Following the national policy of these countries or areas, patients
received routine treatment with SCC regimens. New cases received an initial
phase of treatment with 4 drugs (isoniazid, rifampicin, pyrazinamide, and
either ethambutol or streptomycin) for 2 months, followed by a continuation
phase with rifampicin and isoniazid for 4 months (standard regimen among new
cases). Retreatment cases (relapses, failures, and defaulters [patients who
did not collect drugs for at least 2 months] returning for treatment) received
an initial phase of treatment with 5 drugs (isoniazid, rifampicin, streptomycin,
ethambutol, and pyrazinamide; streptomycin for first 2 months only) for 3
months, followed by a continuation phase with rifampicin, isoniazid, and ethambutol
for 5 months (standard retreatment regimen). These regimens are administered
daily in all participating countries; however, the continuation phase is given
twice a week in Peru and 3 times a week in Ivanovo Oblast and in the Dominican
Republic. Health care workers administered treatment ensuring direct observation
when applicable. At the time of the surveys, the DOTS strategy was used for
100% of the patient population in Peru, 50% in the Republic of Korea, and
21% in Italy.12 Ivanovo Oblast started DOTS
about the same time DRS was launched. Hong Kong and the Dominican Republic
were not using DOTS because 1 or more components of the strategy were not
in place. In particular, the Dominican Republic did not use direct observation
and Hong Kong did not use the recommended recording and reporting system.
However, in Hong Kong, treatment was administered using direct observation
to all TB patients.
Monitoring of treatment outcome and the change from treatment to retreatment
regimens in participating countries were based on the results of sputum smear
microscopy.1 In Italy and Hong Kong, where
sputum culture and DST are available, change of regimens also follow the drug
susceptibility pattern. Six standard and mutually exclusive categories were
used to define treatment outcomes.13 These
are cure, treatment completed, death, failure, default, and transfer-out.
Documented treatment success is obtained by adding the percentage of cured
cases (negative sputum smear microscopy at the end of treatment) and the percentage
of cases who completed treatment (no sputum smear microscopy at the end of
treatment with no or only 1 negative sputum smear result at the end of the
intensive phase). Treatment failures were patients who maintained smear-positive
status at 5 months after the start of treatment. Defaulters were patients
who did not collect drugs for 2 months or more at any time after registration.
Transferred out was used for patients transferred to another reporting unit
and for whom results were not known. Under routine circumstances, change from
a standard 4-drug treatment regimen to a standard 5-drug regimen, including
the same 4 drugs used previously, takes place when the patient is declared
a treatment failure, or when he/she returns after defaulting or relapsing.
Report of smear microscopy results follows WHO/IUATLD recommendations. Smear
microscopy quality assurance programs are in place in the participating countries.
Data on previous human immunodeficiency virus (HIV) testing were collected.
Patients enrolled in the global project of DRS were asked if they were tested
for HIV in the past. The provision of such information was entirely voluntary
and patients may have chosen not to disclose it.
Treatment outcomes were recorded on standardized registry forms supplied
to each treatment unit by the national TB program or corresponding entities
of the participating countries. These forms, which are part of the routine
recording and reporting system recommended by the WHO, were returned to a
national TB program central unit in which the data were checked and entered.
Study coordinators linked treatment outcome information with the DRS database.
In each country, data were checked twice for completeness and consistency
and all errors or discrepancies corrected.
Epi Info (version 6.04b, Centers for Disease Control and Prevention,
Atlanta, Ga) and SPSS (version 7.5.2, SPSS Inc, Chicago, Ill) statistical
software were used for analysis. Univariate analyses included χ2 with continuity correction factor and Fisher exact test for the comparison
of categorical variables. To assess the association of the different patterns
of drug resistance with treatment outcomes and to account for the effect of
each country, we performed stratified analysis considering participating countries
as strata. The Mantel-Haenszel weighted relative risk (RR) and the Greenland-Robins
95% confidence intervals (CIs) for stratified analysis are reported accordingly.
Information on treatment outcomes for the 6 participating countries
was available for 6402 (54%) of 11,764 patients enrolled for DST in the DRS.
Of the 5362 patients enrolled for DST without available treatment outcomes,
4411 (82%) were from Hong Kong. The lowest coverage was in Hong Kong (15%
[796/5207 patients]), followed by Italy (67% [545/807 patients]). Hong Kong
did not implement the reporting system recommended by the WHO and the Italian
survey did not cover the entire country. The Dominican Republic (89% [373/420
patients]), Peru (88% [1732/1959 patients]), Ivanovo Oblast in Russia (91%
[637/697 patients]), and the Republic of Korea (87% [2319/2675 patients])
had high coverage. Of the 6402 patients with information available, 5526 (86%)
were new cases and 876 (14%) were retreatment cases. The mean (SD) age of
the patients was 37 (14) years and 4107 were men (64%).
Of the 5526 new cases, 4585 (83%) were successfully treated, 138 (2%)
died, and 151 (3%) experienced SCC failure (Table 1). Results regarding different patterns of resistance are
shown in Table 2. Mantel-Haenszel
weighted RRs for drug-resistant cases vs drug-susceptible cases for 3 categories
of treatment outcome are presented in Table
3. According to the susceptibility pattern, treatment failure was
significantly more likely among resistant cases than among susceptible cases
(RR, 5.35; 95% CI, 3.87-7.40; P<.001). Patients
with multidrug-resistant TB were more likely to experience treatment failure
(RR, 15.4; 95% CI, 10.6-22.4; P<.001) and to die
(RR, 3.73; 95% CI, 2.13-6.53; P<.001) than were
patients with TB strains considered susceptible. This relationship was statistically
significant in all countries with strains studied. Analysis of settings with
100% direct observation (Peru and Hong Kong) showed a significantly higher
failure rate in cases with multidrug resistance compared with susceptible
cases (10% [9/94] vs 0.7% [8/1410]; RR, 16.9; 95% CI, 6.6-42.7; P<.001). Similar results were obtained in settings with limited
or no direct observation (33% [30/90] vs 2% [68/2968]; RR, 14.5; 95% CI, 10-21.2; P<.001).
When multidrug-resistant TB cases were excluded from analysis, drug-resistant
cases (all types combined) were still more likely to fail (RR, 3.27; 95% CI,
2.20-4.87; P<.001) and less likely to respond
to SCC than were susceptible cases (RR, 0.95; 95% CI, 0.92-0.99; P=.009). The risk of treatment failure was greater among cases with
any rifampicin resistance (RR, 5.48; 95% CI, 3.04-9.87; P<.001) or any isoniazid resistance (RR, 3.06; 95% CI, 1.85-5.05; P<.001) other than multidrug-resistant TB. These associations
held when Ivanovo Oblast and the Dominican Republic were excluded from analysis.
No differences, however, were observed for any streptomycin and ethambutol
resistance combined in the absence of multidrug resistance (P=.67).
Among all single drug-resistant cases together, the likelihood of failing
was greater among resistant cases (13% [17/135]) than among susceptible cases
(2% [76/4378]; RR, 2.66; 95% CI, 1.63-4.35; P<.001).
Single rifampicin resistance was significantly associated with treatment failure
(RR, 5.47; 95% CI, 2.68-11.2; P<.001). While the
association was of borderline statistical significance with regard to single
isoniazid resistance (P=.05), no differences were
observed for single ethambutol (P=.93) or streptomycin
(P=.13) resistance. Mortality and treatment success
rates among cases with single-drug resistance were not different from those
of susceptible cases. On the other hand, an approximately linear increase
in the likelihood of treatment failures was observed as the number of drugs
to which the strains were resistant increased (χ2 for trend,
Information on previous HIV testing was available for 816 patients,
of whom 46 were HIV-positive (9 in Peru, 6 in the Dominican Republic, 30 in
Italy, and 1 in Hong Kong). Of these patients, 29 had susceptible strains
(26 treatment successes, 2 failures, and 1 default) and 17 had resistant strains,
of whom 5 had multidrug-resistant TB (4 failures and 1 default), 10 had single
resistance to isoniazid (7 treatment successes, 1 failed, 1 died, and 1 transferred),
1 had single resistance to rifampicin (treatment success), and 1 had single
resistance to ethambutol (defaulted).
Of the retreatment patients (Table
3, Table 4, and Table 5), 497 (57%) successfully responded
to SCC, 51 (6%) died, and 124 (14%) failed. Mortality (RR, 2.49; 95% CI, 1.44-4.49; P=.003) and treatment failure (RR, 3.26; 95% CI, 2.26-4.69; P<.001) were higher among resistant retreatment cases
than among susceptible ones.
Among multidrug-resistant TB retreatment cases, the likelihood of failing
(RR, 5.05; 95% CI, 3.36-7.60; P<.001) and dying
(RR, 3.19; 95% CI, 1.67-6.09; P≤.001) were higher,
whereas the likelihood of success was lower (RR, 0.45; 95% CI, 0.35-0.58; P<.001), than among susceptible cases. Retreatment cases
with any isoniazid resistance other than multidrug resistance were more likely
to fail (RR, 2.08; 95% CI, 1.30-3.35; P=.004) than
susceptible cases. Retreatment cases with single resistance were more likely
to fail (RR, 1.85; 95% CI, 1.13-3.04; P=.03) than
susceptible cases. As with new cases, an approximately linear increase in
the likelihood of treatment failures was observed as the number of drugs to
which the strains were resistant increased (χ2 for trend, 89.4; P<.001).
This study is the first, to our knowledge, to assess the impact of anti-TB
drug resistance on the outcome of SCC administered under countrywide routine
control program conditions. The results quantify the degree to which isoniazid
and rifampicin resistance and multidrug-resistant TB are obstacles to the
success of the WHO-recommended SCC. While 85% of new cases with susceptible
TB successfully responded to SCC with first-line drugs, confirming its effectiveness
in field conditions, new cases with multidrug-resistant TB, with any rifampicin
resistance other than multidrug-resistant TB, and with any isoniazid resistance
other than multidrug-resistant TB had a significantly higher failure rate.
Rifampicin resistance was the only type of monoresistance strongly associated
with treatment failure among new cases. Data available under clinical trial
conditions suggested a poor response of SCC in patients with rifampicin resistance.7 The implications of our findings would support the
restriction of rifampicin use to protect the efficacy of this drug. Rifampicin
is the most potent first-line anti-TB drug; thus, it should be used under
strict direct observation.
The high mortality (9%) and failure (21%) rates of new cases illustrate
the negative impact of multidrug-resistant TB on treatment outcomes. Even
in the presence of 100% direct observation, treatment success of multidrug-resistant
TB cases was only 58% in Peru and 60% in Hong Kong. Although these rates were
slightly higher than those in other areas such as Ivanovo Oblast, Italy, and
the Dominican Republic, the fact that only a little more than half of the
multidrug-resistant cases in Peru and Hong Kong successfully responded to
SSC with first-line drugs is worrisome. It is likely that the remainder of
the patients would keep spreading multidrug-resistant strains in the community
or would die later due to a lack of proper treatment.
These findings suggest that in settings with high rates of multidrug-resistant
TB, the current WHO policy of administration of the 5 first-line drugs as
standard retreatment regimens needs to be revised according to the availability
of resources and DST, the prevalence of multidrug-resistant TB, and the prevailing
quality of TB control. In every country facing the problem of multidrug-resistant
TB, the first priority is to establish best-practice SCC. In countries with
high prevalence of multidrug-resistant TB in which DST is not widely available,
a redefinition of the time frame to consider failure of SCC in retreatment
patients and addition of a multidrug-resistant TB-specific treatment option
are warranted. The current recommendation is to treat new TB cases that fail
first-line treatment at 5 months with a first-line 8-month retreatment regimen.1 However, administration of an 8-month retreatment
regimen, which includes 4 drugs already used in the previous regimen, may
result in the administration of monotherapy in a patient who already failed
standard treatment and is likely to harbor multidrug-resistant strains. As
shown by these data, 67% of the susceptible retreatment cases still responded
to the standard retreatment regimen. Thus, 1 option is an earlier decision
to treat with a multidrug-resistant TB retreatment regimen. Available evidence
suggests that the results of smear microscopy at 3 months of treatment correlate
well with the treatment outcome.14 Therefore,
in high multidrug-resistant TB prevalence settings, patients could be classified
as failures if sputum smear conversion is not achieved after 3 months of a
standard retreatment regimen. These patients who are likely to harbor drug-resistant
strains can be treated with a multidrug-resistant TB retreatment regimen on
the assumption that this is the main cause of failure. Data from Peru suggest
that 90% of retreatment cases failing the standard retreatment regimen have
While routine DST may not be affordable in many countries with high
prevalences of multidrug-resistant TB, its use in selected patients should
be considered to recognize multidrug-resistant TB earlier and begin effective
treatment. This approach should result in reduction of transmission and, ultimately,
multidrug-resistant TB incidence. Available evidence suggests that multidrug-resistant
TB responds fairly well (eg, cure rate >80%) to longer regimens (18-24 months)
with second-line drugs,16,17 although
other data have shown a low-response rate.18
To address multidrug-resistant TB effectively in resource-limited settings,
formal clinical trials of longer treatment regimens will be needed, as well
as the assessment of the feasibility and cost-effectiveness of using second-line
drugs at a programmatic level.
Our findings also indicate that strains of M tuberculosis with certain patterns of resistance do respond to first-line drugs.
Treatment failure was no more likely in new cases monoresistant to isoniazid,
streptomycin, or ethambutol, or with any streptomycin and ethambutol resistance
than for susceptible cases. The same was true for retreatment cases resistant
to rifampicin other than multidrug-resistant TB, or to streptomycin and ethambutol
resistance. While the lack of statistical significance in some of these comparisons
may be attributable to small numbers of cases, similar results have been reported
in clinical trials.7 Such findings were attributed
to the excellent sterilizing activity of both rifampicin and pyrazinamide
and to the ability of rifampicin to help prevent the emergence of drug resistance
during treatment.7 Other factors playing a
role include the natural history of the disease,19,20
limitations in the clinical predictive value of in vitro susceptibility testing,7 and the administration of regimens containing 4 or
5 first-line drugs.
In settings in which the national TB program struggles to perform adequately,
such as in Ivanovo Oblast in Russia and in the Dominican Republic, low rates
of treatment success in both susceptible and resistant cases were observed.
Furthermore, the proportion of defaults among newly susceptible (10% and 21%)
and newly resistant (13% and 19%) TB cases in these 2 settings were the highest
of the 6 participating countries. The DOTS program in Ivanovo Oblast is relatively
new and faces major difficulties because of the nature of an important fraction
of the patient population (eg, alcoholism, ex-prisoners, and long-term TB
cases).21 In the Dominican Republic, the DOTS
strategy was not in place at the time of the study.22
Our study has several limitations. First, we cannot rule out the possibility
of misclassification of retreatment cases as new cases, and of treatment outcomes
in some countries, especially in those settings in which program activities
are not well organized. Second, treatment outcome results were available for
a limited number of patients enrolled for DST in Hong Kong and, to a lesser
extent, in Italy. Treatment outcome data for patients with TB are not collected
on a routine basis in Hong Kong and Italy. Because these 2 settings have second-line
drugs available, the likely effect of the missing cases would be an underestimation
of the treatment failures among drug-resistance cases. Failing patients may
be switched earlier to second-line drugs based on the susceptibility pattern
before they are declared treatment failures. An underestimation of the failure
rates, however, would only suggest a more severe problem. Third, an underestimation
of the failure rates is also possible if smear microscopy is used as the criterion
standard to assess treatment outcomes, as our study did. While quality assurance
programs are in place in the participating countries, the quality of smear
microscopy is unknown in settings in which a high number of patients completed
treatment without bacteriological confirmation. Ideally, assessment of treatment
outcomes should be based on sputum culture to increase sensitivity; however,
culture is not widely available in developing countries. The reliability of
smear microscopy to assess response to therapy in patients with drug-resistant
TB has not been determined. Fourth, due to the nature of the study, which
assessed results at the end of treatment but could not provide longer follow-up
information, we were not able to evaluate relapse rates among successfully
treated drug-resistant cases. It is possible that presumptively "cured" cases
could have presented as relapses a few weeks or months after the study ended.
In such cases, treatment success would have been overestimated. Finally, the
number of HIV-positive patients available was too small to evaluate the relationship
of drug resistance and HIV. Unfortunately, the global project on DRS, from
which the samples studied in this investigation were generated, does not include
a formal component for HIV testing in patients enrolled for DST.
These potential limitations notwithstanding, 5 major findings of our
study are worth emphasizing. First, we have confirmed that cases with drug-susceptible
strains of M tuberculosis respond better to SCC than
cases with resistant strains. Second, multidrug-resistant TB cases have the
highest rates of death and treatment failure in both new and retreatment cases.
Third, any isoniazid resistance other than multidrug resistance is associated
with lower treatment success and higher failure rate in both new and retreatment
cases. Fourth, resistance to rifampicin alone is associated with a higher
treatment failure rate among new cases. Finally, treatment failure increases
steadily as the number of drugs to which the strains were resistant increased.
To allow TB case management in countries with high prevalence of multidrug-resistant
TB, the DOTS strategy should be adapted. Treatment regimens with second-line
drugs should be incorporated as an option for use, provided that high cure
rate and low defaulting rate of new cases are guaranteed. In addition, reassessment
of the recommended standard retreatment regimen with 5 first-line drugs also
should be considered, especially for new cases failing the standard treatment
regimen with 4 first-line drugs. Moreover, DST should be implemented at least
for patients failing the standard treatment regimen with first-line drugs.
The introduction of feasible and inexpensive rapid testing for rifampicin
resistance also should be explored. If DST is not possible, smear microscopy
could still be used to change to a multidrug-resistant TB retreatment regimen.
The best way to prevent the development of multidrug-resistant TB is
to encourage countries to adopt DOTS and to provide standard SCC to new patients
who will be the source of multidrug-resistant TB if not treated properly.
Rifampicin, in particular, needs to be administered under strict supervision.
Otherwise, therapy should be based on the administration of an 8-month treatment
regimen for new cases of TB, in which the unsupervised continuation phase
does not include rifampicin. Regimens including isoniazid and ethambutol in
the continuation phase have been shown to achieve high cure rates.23,24 Finally, our results also suggest
that any good TB control strategy should allow for the use of second-line
drugs provided all possible measures are taken to ensure strict adherence
to treatment, thus preventing the development of further drug resistance.
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