¶ All members of the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB are the authors and are listed in the manuscript byline.
JR is a Consultant for bioMérieux. WWY has been indirectly sponsored to participate in International Conferences by GlaxoSmithKline and Pfizer in the last 3 years. CDM is on the Scientific Advisory Board for Otsuka pharmaceuticals development of OPC67683 (Delaminid), a new anti-TB compound. SK received salary support from the Eli Lilly Foundation as part of funding for the activities of Partners In Health by the Foundation's MDR-TB Partnership. This funder was not involved in the study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication. The Partners In Health project in Tomsk received funding from Mr. Tom White, the Open Society Institute, the Bill and Melinda Gates Foundation, and the Global Fund to fight AIDS, Tuberculosis and Malaria. None of these funders were involved in the study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication. KD is an unpaid, volunteer member of the New Diagnostics Working Group (NDWG), formed of members of the Stop TB Partnership. The Secretariat of the NDWG is hosted by FIND (Foundation for New Innovative Diagnostics). JB was working as consultant for Otsuka Pharmaceutical for the implementation of clinical trial in Peru. JB was co PI of a NIH grant in Peru, Epidemiology of Tuberculosis. MP and GP are members of the Editorial Board of
Performed the experiments. Analyzed the data: SDA DA MA RB MBa JB MCB AB MBu RC EDC CYC HC LD KD NHD DE DF KF JF MLGG NRG RG MGHD THH MDI LGJ SK HRK WJK JLL CL WCMD VL CCL JL DM GBM SM CDM MN PO MP DP SKP GP JMP CPG MIDQ AP VR JR SR HSS KJS LS TSS SSS YS JSO GS MS PT TEP RVA MLV TSV MHV PV JW WWY JJY. Contributed reagents/materials/analysis tools: SDA DA MA RB MBa JB MCB AB MBu RC EDC CYC HC LD KD NHD DE DF KF JF MLGG NRG RG MGHD THH MDI LGJ SK HRK WJK JLL CL WCMD VL CCL JL DM GBM SM CDM MN PO MP DP SKP GP JMP CPG MIDQ AP VR JR SR HSS KJS LS TSS SSS YS JSO GS MS PT TEP RVA MLV TSV MHV PV JW WWY JJY. Wrote the first draft of the manuscript: DM. Contributed to the writing of the manuscript: SDA DA MA RB MBa JB MCB AB MBu RC EDC CYC HC LD KD NHD DE DF KF JF MLGG NRG RG MGHD THH MDI LGJ SK HRK WJK JLL CL WCMD VL CCL JL DM GBM SM CDM MN PO MP DP SKP GP JMP CPG MIDQ AP VR JR SR HSS KJS LS TSS SSS YS JSO GS MS PT TEP RVA MLV TSV MHV PV JW WWY JJY.
Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.
Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]).
In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.
In 2010, 8.8 million people developed tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease.
Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called “individual patient data meta-analysis.” In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB.
The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1–8.5 months and with the total duration of treatment up to 18.6–21.5 months.
These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB.
Please access these Web sites via the online version of this summary at
The World Health Organization provides information on all aspects of
The US Centers for Disease Control and Prevention has information about
The US National Institute of Allergy and Infectious Diseases also has information on all aspects of
MedlinePlus has links to further information about
The
The increasing incidence of multidrug resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampin, is a major concern for TB control programs worldwide. MDR-TB treatment requires prolonged use of multiple second-line anti-TB drugs, which are more expensive and toxic than first-line drugs, yet less efficacious
Three systematic reviews have recently examined determinants of treatment outcomes in MDR-TB
Even in the absence of randomized trials, an individual patient data meta-analysis of observational data offers potential benefits. Detailed patient level information can be used to estimate associations of treatment factors with outcomes, stratified by important covariates, within restricted sub-groups, or adjusted for covariates in meta-regression. We conducted an individual patient data meta-analysis using patient level data combined from different centers, using methods suggested by the Cochrane group
The studies considered for this individual patient data meta-analysis were identified from published original studies included in three recent systematic reviews of MDR-TB treatment outcomes
Letters describing the meta-analysis were communicated to all corresponding authors of eligible studies. The McGill investigators signed formal data sharing agreements with all collaborating investigators regarding sharing of results, publications, and “ownership” of the data. This project was approved by the Research Ethics Board of the Montreal Chest Institute, McGill University Health Centre, and when deemed necessary by local ethics boards of originally approved studies.
Each author provided center-level information such as diagnostic laboratory methods, treatment regimen doses and supervision, and outcome definitions. Regimens were considered individualized if regimens were tailored to individual patients' characteristics such as prior therapy, or drug susceptibility testing (DST) results. Authors also provided de-identified patient level information including age, sex, HIV infection, site of disease, results of chest x-ray, acid fast bacilli (AFB) smear, culture, and DST for first and second-line drugs, drugs used and duration for initial and continuous phases of treatment, surgical resection, and outcomes, including adverse events that required a change in therapy. Treatment outcome definitions provided by each author were compared to the consensus definitions published by Laserson et al.
Authors were contacted to request additional data and clarify variable definitions and coding. Variables from each original dataset were extracted, their meaning and coding verified, then mapped to a common set of variables for all patients. Hence datasets from each center had the same variables for all patients, but each dataset was kept distinct. As a final verification, the clinical characteristics of each study population were compared with the original published papers.
We considered three types of drug-exposure in our meta-analysis: (i) specific drugs administered (grouped as suggested by WHO
We used random effects (random intercept and random slope) multi-variable logistic regression estimated via penalized quasi-likelihood (Proc Glimmix in SAS
Estimates of effect of each treatment parameter for each dataset were adjusted for five covariates: age, gender, HIV co-infection, extent of disease (considered extensive if AFB smear positive, or if AFB smear information was missing, then if there was cavitation on chest x-ray), and past history of TB treatment (a three level variable—no previous TB treatment, previous TB treatment with first-line drugs, and previous treatment with second-line drugs). Analyses were performed in all patients and in subgroups—stratified or restricted by important covariates. We tested for the interaction between previous treatment with second-line TB drugs and the number of drugs and duration of treatment in the intensive and continuation phases, respectively. In secondary analyses we included more than one treatment parameter (up to four drugs at once), and individual drugs with treatment duration. For the multivariable analyses only, missing values of these five clinical covariates were imputed using means of patients at the same center with non-missing information. Sex was missing in three patients, age was missing in 27, HIV was missing in 1,271(14%), history of past TB treatment missing in 443 (5%), history of past second-line drug use 758 (8%), and extent of disease information missing in 174 (2%). We assessed whether findings were altered when missing values were estimated using a different method of probabilistic imputation, in secondary analysis
Additionally, heterogeneity was explored visually using Forest plots of study specific estimates, and estimated quantitatively via the
We identified 67 unique cohorts from the three previous systematic reviews of MDR-TB. Of these, 35 datasets were not used for reasons summarized in
Demographic Characteristics | Data | Data | Data |
Mean age in years (SD) (25 missing) | 38.7 (13.6) | — | — |
Male sex (%) (three missing) | 6,280 (69%) | — | — |
AFB – smear positive ( |
6,012 (66%) | 1,878 (21%) | 1,263 (14%) |
Cavities on x-ray ( |
4,723 (52%) | 2,019 (22%) | 2,411 (26%) |
Extensive disease ( |
6,753 (74%) | 2,226 (24%) | 174 (2%) |
HIV positive ( |
1,077 (12%) | 6,805 (74%) | 1,271 (14%) |
Pulmonary TB only ( |
8,713 (96%) | 232 (2%) | 208 (2%) |
Prior TB therapy (any) | 6,683 (73%) | 2,027 (22%) | 443 (5%) |
Prior therapy with second-line drugs | 942 (10%) | 7,455 (82%) | 756 (8%) |
Ethambutol ( |
2,736 (30%) | 4,065 (44%) | 2,352 (26%) |
Pyrazinamide ( |
2,406 (26%) | 2,443 (27%) | 4,304 (47%) |
Streptomycin ( |
2,454 (27%) | 4,154 (45%) | 2,545 (28%) |
Rifabutin ( |
130 (1.4%) | — | — |
Ethambutol ( |
4,722 (52%) | — | — |
Pyrazinamide ( |
6,571 (72%) | — | — |
Ciprofloxacin ( |
986 (11%) | — | — |
Ofloxacin ( |
6,489 (71%) | — | — |
Later generation quinolones ( |
1,258 (14%) | — | — |
Streptomycin ( |
1,326 (14%) | — | — |
Kanamycin ( |
5,002 (55%) | — | — |
Amikacin ( |
428 (5%) | — | — |
Capreomycin ( |
1,757 (19%) | — | — |
Ethionamide ( |
3,873 (42%) | — | — |
Prothionamide ( |
3,709 (41%) | — | — |
Cycloserine ( |
5,344 (58%) | — | — |
Para-aminosalicylic acid (PAS) ( |
3,196 (33%) | — | — |
One group 5 drug | 2,115 (23%) | — | — |
Two or more group 5 drugs | 594 (7%) | — | — |
Success (cure and treatment completed) | 4,934 (54%) | — | — |
Failure | 645 (7%) | — | — |
Relapse | 87 (1%) | — | — |
Default, transfer out, unknown | 2,095 (23%) | — | — |
Died during MDR-TB treatment | 1,392 (15%) | — | — |
Percentages are of all 9,153 patients. Extensive disease defined as AFB-smear positive, or cavities on chest x-ray if no information about AFB-smear. Prior TB therapy: defined as treatment with any, or second-line TB drugs for 1 mo or more. Later generation quinolones included levofloxacin, moxifloxacin, gatifloxacin, and sparfloxacin. Cycloserine included terizidone—a dimer of D-cycloserine given in some centers. Drugs analysed as group 5 included: amoxicillin-clavulanate, macrolides (azithromycin, roxithromycin, clarithromycin), clofazimine, thiacetazone, imipenem, linezolid, high dose INH, and thioridazine. Relapse ascertained in only 2,261 patients (14 cohorts).
SD, standard deviation.
The included studies originated from 23 countries, from all WHO health regions. Final sample sizes included in the analysis ranged from 18 to 2,174 patients. In the supplement are summarized: study and center characteristics (
Crude treatment success versus failure or relapse or death by study with exact 95% CI, as well as number of subjects with success and number of subjects treated. Fixed and der Simonian and Laird random effects pooled estimates are given (purple dots). Two studies that used only first-line TB drugs are indicated by a red square.
Fixed and der Simonian and Laird random effects pooled estimates are given (purple dots). Two studies that used only first-line TB drugs are indicated by a red square.
As seen in
Drug Used | aOR |
Success Versus Failure/Relapse (95% CI) | aOR |
Success Versus Failure/Relapse/Death (95% CI) | aOR |
Success Versus Failure/Relapse/Death/Default (95% CI) | |||
Pyrazinamide | 3,985 | 1.2 | (0.9–1.7) |
5,096 | 1.3 | (1.1–1.6) |
6,571 | 1.1 | (0.9–1.4) |
Ethambutol | 2,819 | 0.9 | (0.7–1.1) |
3,740 | 0.8 | (0.7–0.9) |
4,719 | 0.9 | (0.8–1.2) |
Kanamycin only | 2,860 | 3,437 | 4,457 | ||||||
Versus no injectable | 1.1 | (0.5–2.3) |
1.3 | (0.7–2.6) |
1.3 | (0.7–2.5) |
|||
Versus capreomycin | 1.3 | (0.7–2.7) |
|||||||
Versus streptomycin | 1.1 | (0.6–2.2) |
1.0 | (0.6–1.6) |
1.0 | (0.8–1.3) |
|||
Amikacin only | 192 | 248 | 307 | ||||||
Versus no injectable | 1.5 | (0.6–4.1) |
1.7 | (0.8–3.3) | 1.3 | (0.5–3.6) |
|||
Capreomycin only | 769 | 940 | 1,127 | ||||||
Versus no injectable | 1.1 | (0.5–2.6) |
1.3 | (0.5–3.7) |
1.1 | (0.4–3.2) |
|||
Later gen. quinolones | 751 | 829 | 974 | ||||||
Versus no quinolones | 2.6 | (0.6,10.5) |
|||||||
Versus ofloxacin | 1.6 | (0.5–5.3) |
|||||||
Versus ciprofloxacin | 0.7 | (0.1,3.8) |
1.5 | (0.5–4.6) |
1.7 | (0.6–4.9) |
|||
Ofloxacin | 3,832 | 4,577 | 6,102 | ||||||
Versus no quinolones | |||||||||
Versus ciprofloxacin | 1.1 | (0.5–2.5) |
1.4 | (0.7–2.6) | 1.3 | (0.7–2.5) |
|||
Ciprofloxacin | 335 | 553 | 644 | ||||||
Versus no quinolones | 1.5 | (0.6–4.1) |
2.0 | (0.8–5.2) | 1.6 | (0.6–4.3) |
|||
Ethionamide/prothionamide | 4,608 | 5,594 | 7,329 | ||||||
Cycloserine/terizidone | 3,547 | 1.1 | (0.8–1.7) |
4,194 | 1.5 | (1.0–2.3) | 5,358 | 1.5 | (0.9–2.2) |
PAS | 2,459 | 1.0 | (0.8–1.3) | 2,860 | 1.0 | (1.0–1.4) |
3,712 | 1.2 | (1.0–1.5) |
Group 5 drugs | |||||||||
Any 1 group 5 versus none | 1,538 | 1,725 | 2,029 | 1.0 | (0.8–1.2) |
||||
2+ group 5 versus one group 5 | 447 | 574 | 654 | ||||||
Amox.-clavulanate only |
232 | 1.0 | (0.4–2.5) |
255 | 1.2 | (0.6–2.6) |
290 | 1.4 | (0.8–2.5) |
Clofazimine only |
651 | 2.7 | (0.6–12.1) |
764 | 2.3 | (0.4–12.4) |
896 | 1.0 | (0.5–2.1) |
Macrolide only |
333 | 396 | 459 | 0.8 | (0.6–1.1) |
||||
Thiacetazone only |
554 | 0.8 | (0.5–1.5) |
576 | 1.0 | (0.6–1.7) |
668 | 1.0 | (0.7–1.4) |
Bold, estimates are significantly different from the reference group.
aOR for use of drug, with non-use as the reference category. Adjusted for age, sex, HIV, past TB treatment, past MDR treatment (treatment for more than 1 mo with two or more second-line drugs), and extent of disease. Missing information was imputed for the following parameters in the following number of patients: Sex was missing in three, age was missing in 27, HIV was missing in 1,271 (14%), history of past TB treatment missing in 443 (5%), history of past second-line drug use 758 (8%), and extent of disease information missing in 174 (2%).
Variance of the random intercepts and slopes low, so heterogeneity not likely to be important.
Variance of the random intercepts and slopes could not be estimated.
Variance of the random intercepts and slopes high, so heterogeneity likely important.
Group 5 individual drugs: Analysis restricted to patients who received only one group 5 drug. Each single drug comparison made between patients who received only that group 5 agent with patients who received any other single group 5 drug. Drugs included in this analysis as group 5 drugs were: amoxicillin-clavulanate, macrolides (azithromycin, roxithromycin, and clarithromycin), clofazimine, thiacetazone, imipenem, linezolid, high dose INH, and thioridazine. Later generation quinolones included levofloxacin, moxifloxacin, gatifloxacin, and sparfloxacin. Cycloserine included terizidone—a dimer of D-cycloserine given in some centers.
Patients with prior treatment with second-line drugs were significantly less likely to have HIV co-infection, but were more likely to have cavitary disease, and strains with resistance to other first-line drugs (
As shown in
All Patients – Success Versus Fail/Relapse | All Patients – Success Versus Fail/Relapse/Death | All Patients – Success Versus Fail/Relapse/Death/Default | ||||
aOR (95% CI) | aOR (95% CI) | aOR (95% CI) | ||||
Initial intensive phase | ||||||
0–2 | 118 | 1.0 (reference) | 277 | 1.0 (reference) | 322 | 1.0 (reference) |
3 | 161 | 1.1 (0.5–2.4) |
250 | 1.7 (1.2–2.5) |
316 | 1.2 (0.8–1.8) |
4 | 468 | 542 | 671 | |||
5 | 814 | 900 | 1,114 | |||
6+ | 811 | 977 | 1,185 | |||
Continuation phase | ||||||
0–2 | 254 | 1.0 (reference) | 531 | 1.0 (reference) | 633 | 1.0 (reference) |
3 | 552 | 635 | 759 | |||
4 | 598 | 663 | 779 | |||
5+ | 560 | 608 | 656 |
Likely effective, drugs to which isolate susceptible in laboratory testing.
Variance of the random intercepts and slopes was low—so heterogeneity not likely to be important.
Variance of the random intercepts and slopes could not be estimated.
All Patients Success Versus Fail/Relapse/Death | No Prior MDR Treatment Success Versus Fail/Relapse/Death | Prior MDR Treatment Success Versus Fail/Relapse/Death | |||||||
aOR | (95% CI) | aOR | (95% CI) | aOR | (95% CI) | ||||
277 | 1.0 | (reference) | 246 | ||||||
250 | |||||||||
542 | 1.4 | (0.5–3.8) | |||||||
900 | |||||||||
531 | 1.0 | (reference) | 467 | 1.0 | (reference) | 32 | 1.0 | (reference) | |
Likely effective, drugs to which isolate susceptible in laboratory testing.
Among those who did not die or default, odds of treatment success increased with longer duration of the initial intensive phase up to the duration of 7.0 to 8.4 mo (
(A) Duration of initial intensive phase in all patients (reference group 1.0–2.5 mo). (B) Duration of initial intensive phase—restricted to patients not previously treated with second-line drugs (reference group 1.0–2.5 mo). (C) Total duration of therapy in all patients (reference group is 6.0–12.5 mo). Patients receiving therapy for less than 6 or more than 36 mo excluded from analysis. Note: For duration of 24.6–27.5 mo the upper limit of the CI was 30.2. This is truncated at 21. (D) Total duration of therapy—analysis restricted to patients not previously treated with second-line drugs (reference group is 6.0–12.5 mo. Patients receiving therapy for less than 6 or more than 36 mo excluded from analysis). Note: For duration of 24.6–27.5 mo, the upper limit of the CI was 56.5. This is truncated at 21.
Duration of Treatment (mo) Intercept | All Patients | No Prior Second-Line Drug Treatment | Prior Second-Line Drug Treatment | |||
aOR (95% CI) | aOR (95% CI) | aOR (95% CI) | ||||
Initial | ||||||
1–2.4 | 308 | 1.0 (reference) | 271 | 1.0 (reference) | 6 | 1.0 (reference) |
2.5–3.9 | 1,406 | 1.3 (0.5–3.2) |
1,298 | 1.5 (0.6–4.2) |
23 | 4.2 (0.5–34.3) |
4.0–5.4 | 481 | 418 | 2.2 (0.8–6.5) |
15 | 10.9 (1.0–117.8) |
|
5.5–6.9 | 377 | 314 | 26 | |||
7.0–8.4 | 172 | 124 | 21 | |||
8.5–20 | 792 | 517 | 228 | |||
Total | ||||||
6.0–12.5 | 778 | 1.0 (reference) | 681 | 1.0 (reference) | 33 | 1.0 (reference) |
12.6–15.5 | 419 | 1.5 (0.6–3.6) |
321 | 1.4 (0.5–4.2) |
34 | 0.4 (0.2–1.1) |
15.6–18.5 | 1,700 | 1,527 | 51 | 2.2 (0.7–6.8) |
||
18.6–21.5 | 655 | 34 | 40 | 1.6 (0.6–4.5) |
||
21.6–24.5 | 553 | 400 | 105 | |||
24.6–27.5 | 313 | 170 | 104 | |||
27.6–30.5 | 160 | 89 | 53 | |||
30.6–36 | 89 | 1.2 (0.2–5.8) |
36 | 2.8 (0.4–19.7) |
38 | 2.0 (0.6–7.3) |
Variance of the random intercepts and slopes high—so heterogeneity likely important. (See
Variance of the random intercepts and slopes low—so heterogeneity not likely to be important. (See also
As a sensitivity analysis, all analyses reported in
To our knowledge this is the largest combined analysis of treatment of MDR-TB, and the first individual patient data meta-analysis of treatment outcomes in drug resistant TB. With the detailed individual clinical information for 9,153 patients it was possible to use stratified, restricted, and/or multivariable analyses to control for differences in treatment regimens, drug resistance patterns, prior treatment histories, and other patient characteristics such as HIV co-infection. Overall treatment results were poor—treatment success was achieved in only slightly more than half of all patients. Treatment success was significantly associated with specific durations, number of likely effective drugs for the initial intensive and continuation phases of therapy, and with use of later generation quinolones (levofloxacin, moxifloxacin, gatifloxacin, and sparfloxacin), ofloxacin or ethionamide/prothionamide. These results helped to inform the forthcoming revised MDR-TB treatment guidelines of WHO, and should be useful in planning therapy for individual patients.
We suggest cautious interpretation of these results in light of a number of important limitations. First, we included only 32 studies out of a possible 67 series that had reported outcomes of MDR-TB treatment and were identified in three systematic reviews. This selection may have introduced some bias, although as seen in
Relapse was ascertained in only 14 studies, which could result in an over-estimate of treatment success. As seen in
This analysis suggests that it would be appropriate to use at least four likely effective drugs in the initial intensive phase and at least three likely effective drugs in the continuation phase. However, it is important to underline that this analysis was restricted to cohorts of patients in whom drug susceptibility testing was routinely performed. These results may not apply when standardized regimens are used without routine drug susceptibility testing. We had to base analysis of likely effective drugs on drug susceptibility testing only, because of limited information on the specific drug regimen for many of the previously treated patients. Hence caution is warranted given the well-known limitations of drug susceptibility testing for many of the drugs used, since prior use of these drugs may increase the likelihood of resistance, even if the laboratory result indicates susceptibility.
The highest odds of success were associated with duration of the initial intensive phase of 7–8.4 mo, and with a total duration of 18–20 mo. However, particular caution should be used for the interpretation of these results. First we did not have data on duration of therapy with individual drugs, only the different phases of treatment. Second, duration of therapy was individualized for most patients, based upon severity of disease, prior therapy, drug resistance patterns, response to therapy, and timing of sputum conversion. Hence duration of treatment may have been prolonged in patients with worse disease—as suggested in
Despite these limitations there were a number of important strengths. A large number of centers, from many different regions of the world, contributed clinical information on a large number of individual patients, allowing a detailed and comprehensive analysis. There was substantial variation in treatment given by different centers, only partially explained by patients' characteristics. In some centers this variation reflected availability of medications, but in other centers this likely reflected individual providers' preferences. This substantial variation in treatment approach would have been much less likely in patients treated at a single center, and enhanced our ability to assess the independent effect of treatment factors on patient outcomes.
This individual patient data meta-analysis of 9,153 patients suggests that treatment of MDR-TB should include a later generation quinolone, and ethionamide or prothionamide. In patients who have not received second-line drugs before, the optimal number of likely effective drugs appears to be at least four in the initial intensive phase, and at least three in the continuation phase. The duration of therapy associated with highest odds of success was 7–8.5 mo for the initial intensive phase, and 25–27 mo for total duration. In view of the serious limitations of this observational data, these findings should be considered to have highlighted several important questions for future clinical trials. These questions include the role and choice of injectables, the optimal duration of an injectable and total therapy, and the potential value of later generation quinolones as well as certain group 4 and group 5 drugs. Randomized trials are urgently needed to address these questions and determine the optimal treatment regimens for MDR-TB patients.
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(a) Overview of settings of 32 studies included in individual patient data meta-analysis of MDR-TB supplemental tables (for on-line supplement—references for included studies are found in main text. (b) Overview of 35 studies excluded from individual patient data meta-analysis of MDR-TB.
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(a) Assessment of potential confounding of clinical characteristics and drug resistance with initial duration (only patients analyzed for success versus fail/relapse). (B) Assessment of potential confounding of clinical characteristics with total duration of therapy (only patients analyzed for success versus fail/relapse).
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The authors also thanks the following individuals for help in the following ways: data gathering in the Philippines by Ruffy Guilatco, Glenn Balane, and Maricar Galipot; data gathering in Toronto: Maja Haslah, and Jane McNamee, facilitation of the study at the US Centers for Disease Control by Philip Lobue; comments on initial analyses and drafts by Karen Shean, Charles Daley, and Fraser Wares; assistance in data management by D. Weissman, Sidney Atwood, Tran Buu, Ed Desmond, Midori Kato-Maeda, Joanne Kirsten, and Grace Lin; secretarial and administrative assistance by Ria Choe and Sandra Ramoutar; statistical and logistic help with South African data from Piet Becker.
acid fast bacilli
adjusted odds ratio
multidrug resistant tuberculosis