- Email: [email protected]
Isoniazid-resistant tuberculosis treatment with first-line drugs
Correspondence
2
Food and Agriculture Organization of the United Nations, World Organisation for Animal Health, World Health Organization. Antimicrobial resistance: a manual for developing national action plans. 2016. http://apps.who.int/iris/ bitstream/10665/204 470/1/9789241549530_eng.pdf?ua=1 (accessed Dec 20, 2016).
Outbreak of chikungunya in Pakistan Pakistan, along with other Asian countries, is undergoing substantial climate changes. The summers are getting harsher, whereas the winters are getting milder with every passing year. The rising temperature has nurtured the outbreak of many arboviral illnesses in the region, including malaria and dengue. The deplorable sanitary conditions of most Asian countries further adds fuel to the fire by providing excellent breeding grounds for the arthropod vectors. Chikungunya, another arboviral disease, is now spreading explosively in Karachi, Pakistan (figure). The causal agent of the disease, chikungunya virus, is transmitted through the bites of infected Aedes mosquitoes (Aedes aegypti and Aedes albopictus). The infection is generally symptomatic, and characterised by an abrupt onset of fever followed by severe polyarthralgia. Other common symptoms include rash, headache,
Figure: A public hospital in Karachi inundated with patients with chikungunya
258
nausea, fatigue, and myalgia. Although the illness is self-limiting, joint pain can persist for months and even several years in some cases.1 Additionally, many patients develop neurological, cardiovascular, pulmonary, renal, ocular, and cutaneous sequelae following the acute infection. 2 Regrettably, no vaccines or specific antivirals have been approved for chikungunya fever. Chikungunya virus was found circulating in rodents in Pakistan as early as 1983.3 In fact, a few patients with chikungunya were also reported in Lahore during the 2011 dengue outbreak.4 The current outbreak is said to have started on the second week of November, 2016. Different healthcare authorities in Karachi estimate the total number of patients to be more than 30 000. The National Institutes of Health, Pakistan, and Armed Forces Institute of Pathology, Pakistan, have so far confirmed more than 4000 cases through qualitative RT-PCR. The outbreak is closely tied up with the warm climate and wretched sanitary state of the city. This year, Karachi had a mild winter, with 15oC being the average low temperature documented in December. Chikungunya vectors proliferate prodigiously in mild temperatures. Secondly, the sanitary system of Karachi is deplorable. Open sewers and feculent morasses, which are excellent breeding habitats for mosquitoes, can be found all throughout the city.5 There is an urgent need to rid the city of stagnant water bodies and to raise awareness via campaigns. The city is in dire peril because of the forthcoming summer. Furthermore, Karachi lies on the coast of the Arabian Sea and houses south Asia’s largest cargo port. Hence, there is a serious concern that infection might spread to the neighbouring countries through freight transport. Hence, this momentous issue must be addressed by national and international health-care organisations with haste. Proper epidemic
containment measures along with the investigation of any further complications are urgently required to quell the plague in time. We declare no competing interests. MR, F-t-Z, and SM contributed equally to this letter.
Mahd Rauf, Fatima-tuz-Zahra, Sobia Manzoor*, Azra Mehmood, Shameem Bhatti [email protected] Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan (MF, F-t-Z, SM, SB); and Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan (AM) 1
2
3
4
5
Paul BJ, Pannarkady G, Moni SP, Thachil EJ. Clinical profile and long-term sequelae of chikungunya fever. Indian J Rheumatol 2011; 6: 12–19. Rajapakse S, Rodrigo C, Rajapakse A. Atypical manifestations of chikungunya infection. Trans R Soc Trop Med Hyg 2010; 104: 89–96. Darwish MA, Hoogstraal H, Roberts TJ, Ahmed IP, Omar F. A sero-epidemiological survey for certain arboviruses (Togaviridae) in Pakistan. Trans R Soc Trop Med Hyg 1983; 77: 442–45. Afzal MF, Naqvi SQ , Sultan MA, Hanif A. Chikungunya fever among children presenting with nonspecific febrile illness during an epidemic of dengue fever in Lahore, Pakistan. Merit Res J Med Medical Sci 2015; 3: 69–73. Rahman A, Lee H, Khan MA. Domestic water contamination in rapidly growing megacities of Asia: case of Karachi, Pakistan. Environ Monit Assess 1997; 44: 339–60.
Isoniazid-resistant tuberculosis treatment with first-line drugs We read with interest the systematic review and meta-analysis by Medea Gegia and colleagues1 of use of firstline drugs for isoniazid-monoresistant tuberculosis. Among the main findings, this study revealed that 11% of new patients who received the first-line WHO standard regimen had treatment failure. On the basis of these observations, the authors suggest that standardised empirical treatment of new cases could be contributing substantially to the multidrug-resistant tuberculosis epidemic. However, the authors do not question the reliability of www.thelancet.com/infection Vol 17 March 2017
Correspondence
the initial bacteriological diagnosis that was made for these patients, which supported the clinical decision to initiate standardised first-line treatment. Most studies referenced in the systematic review and meta-analysis used phenotypic drug susceptibility testing methods, which fail to detect a substantial proportion of rifampicin-resistant strains.2 Of the 52 papers cited, only two used molecular methods for establishment of rifampicin resistance. None of the studies included sequencing of the rpoB gene and all were published between 1968 and 2014. Only since 2014 have reports originating from different regions of the world highlighted the fact that several specific mutations were regularly undetected and thus responsible for missed opportunities to diagnose multidrug-resistant tuberculosis. 3–5 To date, the most alarming figures originated from Swaziland, where a third of patients with multidrug-resistant tuberculosis had the rpoB Ile491Phe mutation,6 which is hardly detected by phenotypic drug susceptibility testing methods and missed by commercial molecular assays. In this context, assessment of the efficacy of first-line regimens among patients for whom whether they have isoniazid-monoresistant or undetected multidrug-resistant tuberculosis is of questionable value. In most studies used for this systematic review and metaanalysis, the frequency of negative clinical outcomes is similar to the expected level of detection of multidrug-resistant tuberculosis when suboptimal techniques are used. We would have appreciated this important question being addressed. We declare no competing interests
*Emmanuel Andre, Anandi Martin [email protected] Pôle de Microbiologie Médicale, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels B-1200, Belgium
www.thelancet.com/infection Vol 17 March 2017
1
2
3
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Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis 2016; published online Nov 16. http://dx.doi.org/10.1016/S14733099(16)30407-8. Van Deun A, Aung KJ, Hossain A, de Rijk P, Gumusboga M, Rigouts L, et al. Disputed rpoB mutations can frequently cause important rifampicin resistance among new tuberculosis patients. Int J Tuberc Lung Dis 2015; 19: 185–90. Andres S, Hillemann D, Rusch-Gerdes S, Richter E. Occurrence of rpoB mutations in isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis isolates from Germany. Antimicrob Agents Chemother 2014; 58: 590–92. Ahmad S, Mokaddas E, Al-Mutairi N, Eldeen HS, Mohammadi S. Discordance across phenotypic and molecular methods for drug susceptibility testing of drug-resistant Mycobacterium tuberculosis isolates in a low TB incidence country. PLoS One 2016; 11: e0153563. Shah NS, Grace Lin SY, Barry PM, Cheng YN, Schecter G, Desmond E. Clinical impact on tuberculosis treatment outcomes of discordance between molecular and growth-based assays for rifampin resistance, California 2003–2013. Open Forum Infect Dis 2016; 3: ofw150. Sanchez-Padilla E, Merker M, Beckert P, et al. Detection of drug-resistant tuberculosis by Xpert MTB/RIF in Swaziland. N Engl J Med 2015; 372: 1181–82.
We read with interest the metaanalysis by Medea Gegia and colleagues,1 showing that treatment of isoniazid-resistant tuberculosis by use of WHO’s standard regimen for new cases could result in suboptimal outcomes (high rates of treatment failure and relapse). In such a circumstance, treatment using firstline antituberculosis drugs can be dangerous and can even contribute to the emergence of multidrugresistant tuberculosis, particularly in settings involving a high prevalence of isoniazid resistance. We recently analysed a prospective cohort of 395 patients with isoniazidresistant tuberculosis in Taiwan. 2 All patients with tuberculosis in Taiwan are reported and registered, and they are required to submit at least two sputum samples for smear, mycobacterial culture, and drugsusceptibility tests (for first-line drugs) before treatment, and at 2 and 5 months after treatment begins.
In Taiwan’s national guidelines, the recommended regimen for isoniazid-resistant tuberculosis entails providing at least a three-drug combination (rifampicin, ethambutol, and pyrazinamide with or without isoniazid) on a daily basis for at least 6 months under supervision (the coverage rate for all tuberculosis cases was 93·8% in 2011).3 We found that all patients with relapse had pulmonary cavitary disease. Although the 2-year relapse rate in our cohort2 (1%, 95% CI 0·3–3·0) is much lower than that in the report by Gegia and colleagues1 (10%, 5–15), the presence of pulmonary cavitary lesions in our cohort was significantly associated with a higher relapse rate (4·1% vs 0·0%, p=0·006). In patients with cavitary pulmonary tuberculosis, extending the duration of the rifampicin-containing regimen to at least 7 months was associated with a significantly lower risk of relapse than was the 6-month treatment (2·2% vs 25·0%, p=0·031).2 This finding is consistent with those reported in two reviews by Menzies and Stagg, revealing that extending the duration of the rifampicin-containing regimen could lower the risk of relapse.4,5 WHO has committed to a post-2015 tuberculosis elimination plan. Under this vision, appropriately treating tuberculosis patients who are at a high risk of relapse, especially relapse with acquired resistance, is a tremendous opportunity for control of this disease. Although extending the duration of therapy is challenging in resourcelimited, high-burden countries, it could be an important practice if the toll exerted on individual patients, including household transmission and toxic second-line medications in a so-called retreatment regimen, is considered. It should be even more crucial for high-risk patients such as those with cavitary pulmonary disease. We believe that all patients with isoniazid-resistant pulmonary tuberculosis can be cured, with a less than 5% chance of relapse. We declare no competing interests.
259
2
Food and Agriculture Organization of the United Nations, World Organisation for Animal Health, World Health Organization. Antimicrobial resistance: a manual for developing national action plans. 2016. http://apps.who.int/iris/ bitstream/10665/204 470/1/9789241549530_eng.pdf?ua=1 (accessed Dec 20, 2016).
Outbreak of chikungunya in Pakistan Pakistan, along with other Asian countries, is undergoing substantial climate changes. The summers are getting harsher, whereas the winters are getting milder with every passing year. The rising temperature has nurtured the outbreak of many arboviral illnesses in the region, including malaria and dengue. The deplorable sanitary conditions of most Asian countries further adds fuel to the fire by providing excellent breeding grounds for the arthropod vectors. Chikungunya, another arboviral disease, is now spreading explosively in Karachi, Pakistan (figure). The causal agent of the disease, chikungunya virus, is transmitted through the bites of infected Aedes mosquitoes (Aedes aegypti and Aedes albopictus). The infection is generally symptomatic, and characterised by an abrupt onset of fever followed by severe polyarthralgia. Other common symptoms include rash, headache,
Figure: A public hospital in Karachi inundated with patients with chikungunya
258
nausea, fatigue, and myalgia. Although the illness is self-limiting, joint pain can persist for months and even several years in some cases.1 Additionally, many patients develop neurological, cardiovascular, pulmonary, renal, ocular, and cutaneous sequelae following the acute infection. 2 Regrettably, no vaccines or specific antivirals have been approved for chikungunya fever. Chikungunya virus was found circulating in rodents in Pakistan as early as 1983.3 In fact, a few patients with chikungunya were also reported in Lahore during the 2011 dengue outbreak.4 The current outbreak is said to have started on the second week of November, 2016. Different healthcare authorities in Karachi estimate the total number of patients to be more than 30 000. The National Institutes of Health, Pakistan, and Armed Forces Institute of Pathology, Pakistan, have so far confirmed more than 4000 cases through qualitative RT-PCR. The outbreak is closely tied up with the warm climate and wretched sanitary state of the city. This year, Karachi had a mild winter, with 15oC being the average low temperature documented in December. Chikungunya vectors proliferate prodigiously in mild temperatures. Secondly, the sanitary system of Karachi is deplorable. Open sewers and feculent morasses, which are excellent breeding habitats for mosquitoes, can be found all throughout the city.5 There is an urgent need to rid the city of stagnant water bodies and to raise awareness via campaigns. The city is in dire peril because of the forthcoming summer. Furthermore, Karachi lies on the coast of the Arabian Sea and houses south Asia’s largest cargo port. Hence, there is a serious concern that infection might spread to the neighbouring countries through freight transport. Hence, this momentous issue must be addressed by national and international health-care organisations with haste. Proper epidemic
containment measures along with the investigation of any further complications are urgently required to quell the plague in time. We declare no competing interests. MR, F-t-Z, and SM contributed equally to this letter.
Mahd Rauf, Fatima-tuz-Zahra, Sobia Manzoor*, Azra Mehmood, Shameem Bhatti [email protected] Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan (MF, F-t-Z, SM, SB); and Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan (AM) 1
2
3
4
5
Paul BJ, Pannarkady G, Moni SP, Thachil EJ. Clinical profile and long-term sequelae of chikungunya fever. Indian J Rheumatol 2011; 6: 12–19. Rajapakse S, Rodrigo C, Rajapakse A. Atypical manifestations of chikungunya infection. Trans R Soc Trop Med Hyg 2010; 104: 89–96. Darwish MA, Hoogstraal H, Roberts TJ, Ahmed IP, Omar F. A sero-epidemiological survey for certain arboviruses (Togaviridae) in Pakistan. Trans R Soc Trop Med Hyg 1983; 77: 442–45. Afzal MF, Naqvi SQ , Sultan MA, Hanif A. Chikungunya fever among children presenting with nonspecific febrile illness during an epidemic of dengue fever in Lahore, Pakistan. Merit Res J Med Medical Sci 2015; 3: 69–73. Rahman A, Lee H, Khan MA. Domestic water contamination in rapidly growing megacities of Asia: case of Karachi, Pakistan. Environ Monit Assess 1997; 44: 339–60.
Isoniazid-resistant tuberculosis treatment with first-line drugs We read with interest the systematic review and meta-analysis by Medea Gegia and colleagues1 of use of firstline drugs for isoniazid-monoresistant tuberculosis. Among the main findings, this study revealed that 11% of new patients who received the first-line WHO standard regimen had treatment failure. On the basis of these observations, the authors suggest that standardised empirical treatment of new cases could be contributing substantially to the multidrug-resistant tuberculosis epidemic. However, the authors do not question the reliability of www.thelancet.com/infection Vol 17 March 2017
Correspondence
the initial bacteriological diagnosis that was made for these patients, which supported the clinical decision to initiate standardised first-line treatment. Most studies referenced in the systematic review and meta-analysis used phenotypic drug susceptibility testing methods, which fail to detect a substantial proportion of rifampicin-resistant strains.2 Of the 52 papers cited, only two used molecular methods for establishment of rifampicin resistance. None of the studies included sequencing of the rpoB gene and all were published between 1968 and 2014. Only since 2014 have reports originating from different regions of the world highlighted the fact that several specific mutations were regularly undetected and thus responsible for missed opportunities to diagnose multidrug-resistant tuberculosis. 3–5 To date, the most alarming figures originated from Swaziland, where a third of patients with multidrug-resistant tuberculosis had the rpoB Ile491Phe mutation,6 which is hardly detected by phenotypic drug susceptibility testing methods and missed by commercial molecular assays. In this context, assessment of the efficacy of first-line regimens among patients for whom whether they have isoniazid-monoresistant or undetected multidrug-resistant tuberculosis is of questionable value. In most studies used for this systematic review and metaanalysis, the frequency of negative clinical outcomes is similar to the expected level of detection of multidrug-resistant tuberculosis when suboptimal techniques are used. We would have appreciated this important question being addressed. We declare no competing interests
*Emmanuel Andre, Anandi Martin [email protected] Pôle de Microbiologie Médicale, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels B-1200, Belgium
www.thelancet.com/infection Vol 17 March 2017
1
2
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Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis 2016; published online Nov 16. http://dx.doi.org/10.1016/S14733099(16)30407-8. Van Deun A, Aung KJ, Hossain A, de Rijk P, Gumusboga M, Rigouts L, et al. Disputed rpoB mutations can frequently cause important rifampicin resistance among new tuberculosis patients. Int J Tuberc Lung Dis 2015; 19: 185–90. Andres S, Hillemann D, Rusch-Gerdes S, Richter E. Occurrence of rpoB mutations in isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis isolates from Germany. Antimicrob Agents Chemother 2014; 58: 590–92. Ahmad S, Mokaddas E, Al-Mutairi N, Eldeen HS, Mohammadi S. Discordance across phenotypic and molecular methods for drug susceptibility testing of drug-resistant Mycobacterium tuberculosis isolates in a low TB incidence country. PLoS One 2016; 11: e0153563. Shah NS, Grace Lin SY, Barry PM, Cheng YN, Schecter G, Desmond E. Clinical impact on tuberculosis treatment outcomes of discordance between molecular and growth-based assays for rifampin resistance, California 2003–2013. Open Forum Infect Dis 2016; 3: ofw150. Sanchez-Padilla E, Merker M, Beckert P, et al. Detection of drug-resistant tuberculosis by Xpert MTB/RIF in Swaziland. N Engl J Med 2015; 372: 1181–82.
We read with interest the metaanalysis by Medea Gegia and colleagues,1 showing that treatment of isoniazid-resistant tuberculosis by use of WHO’s standard regimen for new cases could result in suboptimal outcomes (high rates of treatment failure and relapse). In such a circumstance, treatment using firstline antituberculosis drugs can be dangerous and can even contribute to the emergence of multidrugresistant tuberculosis, particularly in settings involving a high prevalence of isoniazid resistance. We recently analysed a prospective cohort of 395 patients with isoniazidresistant tuberculosis in Taiwan. 2 All patients with tuberculosis in Taiwan are reported and registered, and they are required to submit at least two sputum samples for smear, mycobacterial culture, and drugsusceptibility tests (for first-line drugs) before treatment, and at 2 and 5 months after treatment begins.
In Taiwan’s national guidelines, the recommended regimen for isoniazid-resistant tuberculosis entails providing at least a three-drug combination (rifampicin, ethambutol, and pyrazinamide with or without isoniazid) on a daily basis for at least 6 months under supervision (the coverage rate for all tuberculosis cases was 93·8% in 2011).3 We found that all patients with relapse had pulmonary cavitary disease. Although the 2-year relapse rate in our cohort2 (1%, 95% CI 0·3–3·0) is much lower than that in the report by Gegia and colleagues1 (10%, 5–15), the presence of pulmonary cavitary lesions in our cohort was significantly associated with a higher relapse rate (4·1% vs 0·0%, p=0·006). In patients with cavitary pulmonary tuberculosis, extending the duration of the rifampicin-containing regimen to at least 7 months was associated with a significantly lower risk of relapse than was the 6-month treatment (2·2% vs 25·0%, p=0·031).2 This finding is consistent with those reported in two reviews by Menzies and Stagg, revealing that extending the duration of the rifampicin-containing regimen could lower the risk of relapse.4,5 WHO has committed to a post-2015 tuberculosis elimination plan. Under this vision, appropriately treating tuberculosis patients who are at a high risk of relapse, especially relapse with acquired resistance, is a tremendous opportunity for control of this disease. Although extending the duration of therapy is challenging in resourcelimited, high-burden countries, it could be an important practice if the toll exerted on individual patients, including household transmission and toxic second-line medications in a so-called retreatment regimen, is considered. It should be even more crucial for high-risk patients such as those with cavitary pulmonary disease. We believe that all patients with isoniazid-resistant pulmonary tuberculosis can be cured, with a less than 5% chance of relapse. We declare no competing interests.
259