RESIST-TB:
A movement to promote and conduct research on the treatment and prevention of drug-resistant tuberculosis, with a commitment to address the substantial existing gaps in our knowledge and to help provide access to an effective cure and prophylaxis of drug-resistant tuberculosis throughout the world.
An Activists Guide to Bedaquiline
Bedaquiline is the first new drug from a new drug class to treat TB that has been approved in the U.S. in over 40 years. Treatment Action Group (TAG) put together an excellent guide that highlights important safety and efficacy data reported thus far, and offers some salient advocacy recommendations going forward. The full guide can be found here.
Mills HL, Cohen T, Colijn C. Sci Transl Med. 2013 Apr 10;5(180):180ra49.
Tuberculosis (TB) control is especially difficult in settings of high HIV prevalence; HIV co-infection erodes host immunity and increases risk of progression to active TB. Studies have demonstrated that a 6-month (or longer) course of monotherapy with isoniazid [isoniazid preventive therapy (IPT)] can reduce this risk. The World Health Organization endorses IPT for symptom-free individuals with HIV/TB co-infection and has recommended expanding IPT to entire communities (community-wide IPT). Although previous reviews have not found a statistically significant elevated risk of isoniazid-resistant TB among individuals previously treated with IPT, community-wide IPT programs may nonetheless generate substantial selective pressure and increase the burden of drug-resistant TB (DRTB). We developed mathematical models to identify the conditions under which community-wide IPT interventions could increase the burden of isoniazid-resistant Mycobacterium tuberculosis, even when we assumed that IPT does not select for resistance among those treated with IPT. We found that in models that included any mechanism of interstrain competition (such as partial immunity conferred by a previous M. tuberculosis infection), community-wide IPT interventions conferred an indirect benefit to drug-resistant strains through selective suppression of drug-sensitive infections.
For whom the bell tolls: isoniazid preventive therapy and tuberculosis drug resistance.
Cobelens FG. Sci Transl Med. 2013 Apr 10;5(180):180.
The expected increase in drug-resistant tuberculosis due to large-scale preventive treatment in people living with HIV calls for reconsidering the "double use" of isoniazid for prophylaxis and curative treatment (Mills et al., this issue).
Serious Treatment Related Adverse Drug Reactions amongst Anti-Retroviral Naïve MDR-TB Patients.
Van der Walt M, Lancaster J, Odendaal R, Davis JG, Shean K, Farley J. PLoS One. 2013;8(4):e58817.
Little is known about the influence of adverse drug reactions (ADRs) on treatment outcomes in South Africa.
We evaluated the impact of severe ADRs among a prospective cohort of MDR-TB patients in South Africa (2000-2004). The HIV-infected study participants were anti-retroviral naïve. Of 2,079 patients enrolled, 1,390 (66.8%) were included in this analysis based on known HIV test results (39.1% HIV-infected). At least one severe ADR was reported in 83 (6.9%) patients with ototoxicity being the most frequent ADR experienced (38.9%). We found that being HIV-infected but antiretroviral naïve did not increase occurrence of SADRs in patients on second-line anti-tuberculosis drugs.
Epidemic spread of multidrug-resistant (MDR) tuberculosis in Johannesburg, South Africa.
Marais Bj BJ, Mlambo CK, Rastogi N, Zozio T, Duse AG, Victor TC, Marais E, Warren RM. J Clin Microbiol. 2013 Apr 3. [Epub ahead of print]
Numerous reports have documented isolated transmission events or clonal "outbreaks" of multidrug-resistant Mycobacterium tuberculosis strains, but knowledge of their epidemic spread remains limited. In this study, we evaluated drug resistance, strain diversity and clustering rates in patients diagnosed with multidrug-resistant (MDR) tuberculosis (TB). Isolates from 434 MDR-TB patients were evaluated, of which 238 (54.8%) were resistant to four first-line drugs (isoniazid, rifampicin, ethambutol and streptomycin). Spoligotyping identified 56 different strains and 28 clusters of variable size (2-71 cases per cluster) with a clustering rate of 87.1%. Ten clusters included 337 (77.6%) of all cases, with strains of the Beijing genotype being most prevalent (16.4%). High levels of clustering among a variety of strains suggest true epidemic spread of MDR-TB in the study setting, emphasizing the urgency of early diagnosis and effective treatment to reduce transmission within this community.
Systematic review of clofazimine for the treatment of drug-resistant tuberculosis [Review article].
Gopal M, Padayatchi N, Metcalfe JZ, O'Donnell MR. Int J Tuberc Lung Dis. 2013 Mar 25. [Epub ahead of print]
Clofazimine (CFZ) is a fat-soluble riminophenazine dye used in the treatment of leprosy worldwide. CFZ has also been used as a Group 5 drug in the treatment of tuberculosis (TB). A large cohort study from Bangladesh published in 2010 described a treatment regimen for multidrug-resistant tuberculosis (MDR-TB) including CFZ as being highly effective against MDR-TB. We searched multiple databases for studies published through February 2012 that reported use of CFZ in MDR- and extensively drug-resistant TB (XDR-TB) treatment regimens. We identified nine observational studies (6 MDR-TB and 3 XDR-TB) including patients with drug-resistant TB treated with CFZ. Overall, 65% (95% confidence interval [95%CI] 54-76) of the patients experienced favorable outcomes, defined as either cure or treatment completion. Using random effects meta-analysis, 65% (95%CI 52-79) of those with MDR-TB and 66% (95%CI 42-89) of those with XDR-TB experienced favorable treatment outcomes. High-quality prospective cohort studies and clinical trials examining the effect of CFZ as part of drug-resistant TB treatment regimens are needed.
Drug-resistant tuberculosis: time for visionary political leadership.
Abubakar I, Zignol M, Falzon D, Raviglione M, Ditiu L, Masham S, Adetifa I, Ford N, Cox H, Lawn SD, Marais BJ, McHugh TD, Mwaba P, Bates M, Lipman M,Zijenah L, Logan S, McNerney R, Zumla A, Sarda K, Nahid P, Hoelscher M, Pletschette M, Memish ZA, Kim P, Hafner R, Cole S, Migliori GB, Maeurer M, Schito M, Zumla A. Lancet Infect Dis. 2013 Mar 22. pii: S1473-3099(13)70030-6.
Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.
Lawn SD, Mwaba P, Bates M, Piatek A, Alexander H, Marais BJ, Cuevas LE, McHugh TD, Zijenah L, Kapata N, Abubakar I, McNerney R, Hoelscher M, Memish ZA, Migliori GB, Kim P, Maeurer M, Schito M, Zumla A. Lancet Infect Dis. 2013 Apr;13(4):349-61.
Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis(MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.
Mills HL, Cohen T, Colijn C. Sci Transl Med. 2013 Apr 10;5(180):180ra49.
Tuberculosis (TB) control is especially difficult in settings of high HIV prevalence; HIV co-infection erodes host immunity and increases risk of progression to active TB. Studies have demonstrated that a 6-month (or longer) course of monotherapy with isoniazid [isoniazid preventive therapy (IPT)] can reduce this risk. The World Health Organization endorses IPT for symptom-free individuals with HIV/TB co-infection and has recommended expanding IPT to entire communities (community-wide IPT). Although previous reviews have not found a statistically significant elevated risk of isoniazid-resistant TB among individuals previously treated with IPT, community-wide IPT programs may nonetheless generate substantial selective pressure and increase the burden of drug-resistant TB (DRTB). We developed mathematical models to identify the conditions under which community-wide IPT interventions could increase the burden of isoniazid-resistant Mycobacterium tuberculosis, even when we assumed that IPT does not select for resistance among those treated with IPT. We found that in models that included any mechanism of interstrain competition (such as partial immunity conferred by a previous M. tuberculosis infection), community-wide IPT interventions conferred an indirect benefit to drug-resistant strains through selective suppression of drug-sensitive infections.
For whom the bell tolls: isoniazid preventive therapy and tuberculosis drug resistance.
Cobelens FG. Sci Transl Med. 2013 Apr 10;5(180):180.
The expected increase in drug-resistant tuberculosis due to large-scale preventive treatment in people living with HIV calls for reconsidering the "double use" of isoniazid for prophylaxis and curative treatment (Mills et al., this issue).
Serious Treatment Related Adverse Drug Reactions amongst Anti-Retroviral Naïve MDR-TB Patients.
Van der Walt M, Lancaster J, Odendaal R, Davis JG, Shean K, Farley J. PLoS One. 2013;8(4):e58817.
Little is known about the influence of adverse drug reactions (ADRs) on treatment outcomes in South Africa.
We evaluated the impact of severe ADRs among a prospective cohort of MDR-TB patients in South Africa (2000-2004). The HIV-infected study participants were anti-retroviral naïve. Of 2,079 patients enrolled, 1,390 (66.8%) were included in this analysis based on known HIV test results (39.1% HIV-infected). At least one severe ADR was reported in 83 (6.9%) patients with ototoxicity being the most frequent ADR experienced (38.9%). We found that being HIV-infected but antiretroviral naïve did not increase occurrence of SADRs in patients on second-line anti-tuberculosis drugs.
Epidemic spread of multidrug-resistant (MDR) tuberculosis in Johannesburg, South Africa.
Marais Bj BJ, Mlambo CK, Rastogi N, Zozio T, Duse AG, Victor TC, Marais E, Warren RM. J Clin Microbiol. 2013 Apr 3. [Epub ahead of print]
Numerous reports have documented isolated transmission events or clonal "outbreaks" of multidrug-resistant Mycobacterium tuberculosis strains, but knowledge of their epidemic spread remains limited. In this study, we evaluated drug resistance, strain diversity and clustering rates in patients diagnosed with multidrug-resistant (MDR) tuberculosis (TB). Isolates from 434 MDR-TB patients were evaluated, of which 238 (54.8%) were resistant to four first-line drugs (isoniazid, rifampicin, ethambutol and streptomycin). Spoligotyping identified 56 different strains and 28 clusters of variable size (2-71 cases per cluster) with a clustering rate of 87.1%. Ten clusters included 337 (77.6%) of all cases, with strains of the Beijing genotype being most prevalent (16.4%). High levels of clustering among a variety of strains suggest true epidemic spread of MDR-TB in the study setting, emphasizing the urgency of early diagnosis and effective treatment to reduce transmission within this community.
Systematic review of clofazimine for the treatment of drug-resistant tuberculosis [Review article].
Gopal M, Padayatchi N, Metcalfe JZ, O'Donnell MR. Int J Tuberc Lung Dis. 2013 Mar 25. [Epub ahead of print]
Clofazimine (CFZ) is a fat-soluble riminophenazine dye used in the treatment of leprosy worldwide. CFZ has also been used as a Group 5 drug in the treatment of tuberculosis (TB). A large cohort study from Bangladesh published in 2010 described a treatment regimen for multidrug-resistant tuberculosis (MDR-TB) including CFZ as being highly effective against MDR-TB. We searched multiple databases for studies published through February 2012 that reported use of CFZ in MDR- and extensively drug-resistant TB (XDR-TB) treatment regimens. We identified nine observational studies (6 MDR-TB and 3 XDR-TB) including patients with drug-resistant TB treated with CFZ. Overall, 65% (95% confidence interval [95%CI] 54-76) of the patients experienced favorable outcomes, defined as either cure or treatment completion. Using random effects meta-analysis, 65% (95%CI 52-79) of those with MDR-TB and 66% (95%CI 42-89) of those with XDR-TB experienced favorable treatment outcomes. High-quality prospective cohort studies and clinical trials examining the effect of CFZ as part of drug-resistant TB treatment regimens are needed.
Drug-resistant tuberculosis: time for visionary political leadership.
Abubakar I, Zignol M, Falzon D, Raviglione M, Ditiu L, Masham S, Adetifa I, Ford N, Cox H, Lawn SD, Marais BJ, McHugh TD, Mwaba P, Bates M, Lipman M,Zijenah L, Logan S, McNerney R, Zumla A, Sarda K, Nahid P, Hoelscher M, Pletschette M, Memish ZA, Kim P, Hafner R, Cole S, Migliori GB, Maeurer M, Schito M, Zumla A. Lancet Infect Dis. 2013 Mar 22. pii: S1473-3099(13)70030-6.
Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.
Lawn SD, Mwaba P, Bates M, Piatek A, Alexander H, Marais BJ, Cuevas LE, McHugh TD, Zijenah L, Kapata N, Abubakar I, McNerney R, Hoelscher M, Memish ZA, Migliori GB, Kim P, Maeurer M, Schito M, Zumla A. Lancet Infect Dis. 2013 Apr;13(4):349-61.
Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis(MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.
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