EDITORIAL
INT J TUBERC LUNG DIS 19(5):497–498 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.15.0110
Expanding the evidence base supporting shorter treatment durations for multidrug-resistant tuberculosis IN THE MOST RECENT World Health Organization (WHO) guidelines on the treatment of multidrugresistant tuberculosis (MDR-TB), the recommended duration of treatment is 20 months.1 As such lengthy treatment with second-line drugs is inevitably associated with drug intolerance and toxicity, high treatment costs and patient and provider non-adherence, there has been much enthusiasm for the exploration of short-course treatment regimens to reduce these undesirable outcomes.2 The nine-month standardized Bangladesh regimen for the treatment of MDR-TB, based on the use of high-dose gatifloxacin along with other second-line drugs, clofazimine and high-dose isoniazid, has yielded quite glamorous results.3,4 While this later-generation fluoroquinolone was well tolerated even when given in high doses of up to 800 mg once daily, few corresponding data have demonstrated comparable tolerance of high-dose moxifloxacin and levofloxacin to date.5 In this issue of the Journal, Kuaban and co-workers have demonstrated the efficacy and safety of a similar 12-month standardized regimen using gatifloxacin at the conventional dosage of 400 mg daily.6 These results beg several questions. The first is whether all patients with MDR-TB require the prolonged 20month therapy regimen, as recommended by the WHO. In an earlier retrospective analysis, about 55% of patients with MDR-TB in Hong Kong were adequately treated with individualized regimens not exceeding 15 months in duration.7 The relapse rate in this subset of MDR-TB was comparable with those who received the longer treatment regimen. The patients who benefited from shorter durations of therapy had non-cavitary disease and achieved sputum culture conversion within 3 months of starting treatment. The results of Kuaban et al.6 add to previous results indicating that standardized ‘Bangladesh-like’ regimens of 9–12 months’ duration are highly effective under conditions with minimal bacillary resistance to second-line drugs and a relatively low prevalence (i.e., 6 20%) of human immunodeficiency virus co-infection.3,4,8 It would thus appear that selected patients with MDR-TB could be optimally treated with shorter durations of therapy. Which drugs (and doses) are necessary components of shortened MDR-TB regimens? The importance of high-dose gatifloxacin (or, presumably, another lategeneration fluoroquinolone) in the 9-month Bangladesh regimen was recently established.4 The positive results of Kuaban et al. with standard doses of
gatifloxacin in their 12-month regimen are reassuring,6 but leave open the possibility that higher doses may be needed for shorter treatment durations. Other important questions pertain to the impact of pyrazinamide susceptibility4,9 and the inclusion of clofazimine and isoniazid on the outcomes with these regimens. Finally, could the use of promising new agents such as bedaquiline, delamanid and linezolid further shorten or simplify these regimens or expand their utility to settings with higher rates of resistance to second-line drugs and pyrazinamide? Regardless of the regimen employed, an important prerequisite for effective treatment of MDR-TB is a sound and well-functioning management program, as promulgated by the WHO.1 The use of chest radiography and sputum culture to inform clinical decision-making regarding the duration of therapy is relatively basic and does not create additional monetary and non-monetary demands, even in resource-limited countries and geographical areas. New biomarkers might refine the monitoring of patient treatment response and enable more individualized treatment durations,10 but operational research is required to show their superiority of performance in the field setting. In addition, the costs of implementing these sophisticated monitoring tools can be prohibitive in the majority of settings plagued with a high burden of MDR-TB. ERIC NUERMBERGER* WING-WAI YEW† *Center for Tuberculosis Research, Johns Hopkins University Baltimore, Maryland, USA †Stanley Ho Centre for Emerging Infectious Diseases The Chinese University of Hong Kong Hong Kong, SAR China e-mail: [email protected]
Conflicts of interest: WWY is a consultant to Otsuka Pharmaceutical Co Ltd.
References 1 Falzon D, Jaramillo E, Schunemann H J, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38: 516–528. 2 Chiang C-Y, Van Deun A, Enarson D A. A poor drug-resistant tuberculosis programme is worse than no programme: time for a change. Int J Tuberc Lung Dis 2013; 17: 714–718. 3 Van Deun A, Maaug A K, Salim M A, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-
[A version in French of this article is available from the Editorial Office in Paris and from the Union website www.theunion.org]
498
4
5
6
7
The International Journal of Tuberculosis and Lung Disease
resistant tuberculosis. Am J Respir Crit Care Med 2010; 182: 684–692. Aung K J, Van Deun A, Declercq E, et al. Successful ‘9-month Bangladesh regimen’ for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014; 18: 1180–1187. Yew W-W, Nuermberger E. High-dose fluoroquinolones in short-course regimens for treatment of MDR-TB: the way forward? Int J Tuberc Lung Dis 2013; 17: 853–854. Kuaban C, Noeske J, Rieder H L, A¨ıt-Khaled N, Abena Foe J-L, Tr´ebucq A. High effectiveness of a 12-month regimen for MDRTB patients in Cameroon. Int J Tuberc Lung Dis 2015; 19: 000– 000. [in this issue] Leung E D, Yew W-W, Leung C C, Leung W M, Tam C M.
Shorter treatment duration for selected patients with multidrugresistant tuberculosis. Eur Repir J 2011; 38: 227–230. 8 Piubello A, Harouna S H, Souleymane M B, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis 2014; 18: 1188–1194. 9 Chang K C, Leung C C, Yew W-W, et al. Pyrazinamide may improve fluoroquinolone-based treatment of multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5465–5475. 10 Heyckendorf J, Olaru I D, Ruhwald M, Lange C. Getting personal perspectives on individualized treatment duration in multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2014; 190: 374–383.
INT J TUBERC LUNG DIS 19(5):497–498 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.15.0110
Expanding the evidence base supporting shorter treatment durations for multidrug-resistant tuberculosis IN THE MOST RECENT World Health Organization (WHO) guidelines on the treatment of multidrugresistant tuberculosis (MDR-TB), the recommended duration of treatment is 20 months.1 As such lengthy treatment with second-line drugs is inevitably associated with drug intolerance and toxicity, high treatment costs and patient and provider non-adherence, there has been much enthusiasm for the exploration of short-course treatment regimens to reduce these undesirable outcomes.2 The nine-month standardized Bangladesh regimen for the treatment of MDR-TB, based on the use of high-dose gatifloxacin along with other second-line drugs, clofazimine and high-dose isoniazid, has yielded quite glamorous results.3,4 While this later-generation fluoroquinolone was well tolerated even when given in high doses of up to 800 mg once daily, few corresponding data have demonstrated comparable tolerance of high-dose moxifloxacin and levofloxacin to date.5 In this issue of the Journal, Kuaban and co-workers have demonstrated the efficacy and safety of a similar 12-month standardized regimen using gatifloxacin at the conventional dosage of 400 mg daily.6 These results beg several questions. The first is whether all patients with MDR-TB require the prolonged 20month therapy regimen, as recommended by the WHO. In an earlier retrospective analysis, about 55% of patients with MDR-TB in Hong Kong were adequately treated with individualized regimens not exceeding 15 months in duration.7 The relapse rate in this subset of MDR-TB was comparable with those who received the longer treatment regimen. The patients who benefited from shorter durations of therapy had non-cavitary disease and achieved sputum culture conversion within 3 months of starting treatment. The results of Kuaban et al.6 add to previous results indicating that standardized ‘Bangladesh-like’ regimens of 9–12 months’ duration are highly effective under conditions with minimal bacillary resistance to second-line drugs and a relatively low prevalence (i.e., 6 20%) of human immunodeficiency virus co-infection.3,4,8 It would thus appear that selected patients with MDR-TB could be optimally treated with shorter durations of therapy. Which drugs (and doses) are necessary components of shortened MDR-TB regimens? The importance of high-dose gatifloxacin (or, presumably, another lategeneration fluoroquinolone) in the 9-month Bangladesh regimen was recently established.4 The positive results of Kuaban et al. with standard doses of
gatifloxacin in their 12-month regimen are reassuring,6 but leave open the possibility that higher doses may be needed for shorter treatment durations. Other important questions pertain to the impact of pyrazinamide susceptibility4,9 and the inclusion of clofazimine and isoniazid on the outcomes with these regimens. Finally, could the use of promising new agents such as bedaquiline, delamanid and linezolid further shorten or simplify these regimens or expand their utility to settings with higher rates of resistance to second-line drugs and pyrazinamide? Regardless of the regimen employed, an important prerequisite for effective treatment of MDR-TB is a sound and well-functioning management program, as promulgated by the WHO.1 The use of chest radiography and sputum culture to inform clinical decision-making regarding the duration of therapy is relatively basic and does not create additional monetary and non-monetary demands, even in resource-limited countries and geographical areas. New biomarkers might refine the monitoring of patient treatment response and enable more individualized treatment durations,10 but operational research is required to show their superiority of performance in the field setting. In addition, the costs of implementing these sophisticated monitoring tools can be prohibitive in the majority of settings plagued with a high burden of MDR-TB. ERIC NUERMBERGER* WING-WAI YEW† *Center for Tuberculosis Research, Johns Hopkins University Baltimore, Maryland, USA †Stanley Ho Centre for Emerging Infectious Diseases The Chinese University of Hong Kong Hong Kong, SAR China e-mail: [email protected]
Conflicts of interest: WWY is a consultant to Otsuka Pharmaceutical Co Ltd.
References 1 Falzon D, Jaramillo E, Schunemann H J, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38: 516–528. 2 Chiang C-Y, Van Deun A, Enarson D A. A poor drug-resistant tuberculosis programme is worse than no programme: time for a change. Int J Tuberc Lung Dis 2013; 17: 714–718. 3 Van Deun A, Maaug A K, Salim M A, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-
[A version in French of this article is available from the Editorial Office in Paris and from the Union website www.theunion.org]
498
4
5
6
7
The International Journal of Tuberculosis and Lung Disease
resistant tuberculosis. Am J Respir Crit Care Med 2010; 182: 684–692. Aung K J, Van Deun A, Declercq E, et al. Successful ‘9-month Bangladesh regimen’ for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014; 18: 1180–1187. Yew W-W, Nuermberger E. High-dose fluoroquinolones in short-course regimens for treatment of MDR-TB: the way forward? Int J Tuberc Lung Dis 2013; 17: 853–854. Kuaban C, Noeske J, Rieder H L, A¨ıt-Khaled N, Abena Foe J-L, Tr´ebucq A. High effectiveness of a 12-month regimen for MDRTB patients in Cameroon. Int J Tuberc Lung Dis 2015; 19: 000– 000. [in this issue] Leung E D, Yew W-W, Leung C C, Leung W M, Tam C M.
Shorter treatment duration for selected patients with multidrugresistant tuberculosis. Eur Repir J 2011; 38: 227–230. 8 Piubello A, Harouna S H, Souleymane M B, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis 2014; 18: 1188–1194. 9 Chang K C, Leung C C, Yew W-W, et al. Pyrazinamide may improve fluoroquinolone-based treatment of multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5465–5475. 10 Heyckendorf J, Olaru I D, Ruhwald M, Lange C. Getting personal perspectives on individualized treatment duration in multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2014; 190: 374–383.
