Reply to Chang and Leung

Clinical Infectious Diseases, Aug 2010

Surendra K. Sharma, Rohit Singla, Pawan Sarda, Alladi Mohan, Govind Makharia, Arvind Jayaswal, Vishnubhatla Sreenivas, Sarman Singh

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Reply to Chang and Leung

Surendra K. Sharma 2 3 Rohit Singla 2 3 Pawan Sarda 2 3 Alladi Mohan 2 3 4 Govind Makharia 1 2 3 Arvind Jayaswal 0 2 3 Vishnubhatla Sreenivas 2 3 6 Sarman Singh 2 3 5 0 Orthopaedics 1 Gastroenterology 2 Departments of 3 Kwok Chiu Chang and Chi Chiu Leung Tuberculosis and Chest Service, Department of Health , Hong Kong , China 4 Department of Medicine, Sri Venkateswara Institute of Medical Sciences , Tirupati, Andhra Pradesh , India 5 Laboratory Medicine, All India Institute of Medical Sciences , New Delhi 6 Biostatistics CORRESPONDENCE • CID 2010:51 (1 August) • 367 - Potential conflicts of interest. K.C.C. and C.C.L.: no conflicts. 1. Sharma SK, Singla R, Sarda P, et al. Safety of 3 different reintroduction regimens of antitu­ berculosis drugs after development of antitu­ berculosis treatment-induced hepatotoxicity. Clin Infect Dis 2010; 50:833–839. 2. Saukkonen J. Challenges in reintroducing tu­ berculosis medications after hepatotoxicity. Clin Infect Dis 2010; 50:840–842. 3. Tahaog˘lu K, Atac¸ G, Sevim T, et al. The man­ agement of anti-tuberculosis drug-induced he­ patotoxicity. Int J Tuberc Lung Dis 2001; 5: 65–69. 4. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy: clinical profile and reintroduction of therapy. J Clin Gastroen­ terol 1996; 22:211–214. 5. Hong Kong Chest Service/Tuberculosis Re­ search Centre MMRC. A double-blind placebocontrolled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992; 145:36–41. 6. Chang KC, Leung CC, Yew WW, et al. Hepa­ totoxicity of pyrazinamide: cohort and casecontrol analyses. Am J Respir Crit Care Med 2008; 177:1391–1396. Reply to Chang and Leung To the Editor—We thank Chang and Leung [1] for their comments on our ar­ ticle [2]. We agree with their statement that, in the absence of quality trials with sufficient numbers of subjects, the best ap­ proach to reintroducing antituberculosis drugs after hepatotoxicity is still open for debate. We tend to agree with them that the statistical power is inadequate if the noninferiority margin is 8.5%. According to this threshold, 212 subjects would be required per arm, and this would translate to 636 patients with antituberculosis druginduced hepatotoxicity (DIH). It took us 5 years to achieve the sample size of 175 patients with DIH. Here, we would like to point out that directly observed treatment has become an integral part of TB treat­ ment in India, where thrice-weekly, inter­ mittent treatment is administered. Given the low risk of DIH associated with this regimen (authors’ unpublished data) along with the observed exclusion criteria, such a large sample size, would be difficult to attain in a specified time. We fully un­ derstand the limitations of the noninfer­ iority trial design for estimating the sample size and reiterate what we mentioned in the Discussion section of our article: we noted that our study lacked sufficient power to detect a difference between the 3 arms and suggested the need for a mul­ ticenter trial in countries where TB is en­ demic to address this important issue. Chang and Leung [1] mention that the mean pretreatment albumin levels were significantly different between the 3 arms. However, to say that the difference in the risk of recurrent hepatotoxicity among the 3 arms could have been bigger, had the mean pretreatment albumin levels were similar, is a bit far fetched. When we looked for the recurrent hepatotoxicity among the 3 groups, with adjustment for baseline albumin level, the recurrence rates among the 3 groups were still statis­ tically not significant (odds ratio for group 1 vs group 2, 0.50 [95% confidence in­ terval, 0.15–1.65; P p .26]; odds ratio for group 1 vs group 3, 0.39 [95% confidence interval, 0.11–1.39; P p .15). Thus, the postulation that the risk of recurrent he­ patotoxicity among the 3 arms would have been bigger may not be true. We would like to point out here that, although the mean pretreatment serum albumin level ( standard deviation) was higher in arm 1 (4.03 0.66 g/dL) than in arm 2 (3.77 0.60 g/dL) and arm 3 (3.75 0.59 g/dL; P p .03), the values were within the acceptable level for serum albumin (ie, 13.5 g/dL). Furthermore, allocation of pa­ tients to each of the 3 arms was performed randomly with the use of computer-gen­ erated random numbers, blocked in groups of 3 that were kept in sealed opaque envelopes. The envelopes were in the possession of an individual who was not involved in the conduct of study. Each arm had a different reintroduction pro­ tocol for anti-tuberculosis drugs. Because the allocation of the patients to each of the 3 arms was purely by “chance,” and because the mean pretreatment serum al­ bumin level was within the normal range in all the 3 arms, these intergroup differ­ ences occurred purely by chance. Therefore, the issue of the best reintro­ duction regimen is still open for future research. Chang and Leung [1] also sug­ gest that giving full-dose rifampicin and isoniazid together, followed by pyrazin­ amide in escalating doses, may be a rea­ sonable compromise. The idea seems in­ teresting, but the efficacy and safety of this protocol must be established by a pro­ spective study with sufficient power and a large sample size. Acknowledgments Potential conflicts of interest. All authors: no conflicts. 1. Chang KC, Leung CC. The best approach of reintroducing tuberculosis treatment after he­ patotoxicity is still open to debate [letter]. Clin Infect Dis 2010; 51(3):366-367 (in this issue). 2. Sharma SK, Singla R, Sarda P, et al. Safety of 3 different reintroduction regimens of antitu­ berculosis drugs after development of antitu­ berculosis treatment-induced hepatotoxicity. Clin Infect Dis 2010; 50:833–839. Factors Associated with Health Care–Associated 2009 Influenza A (H1N1) Virus Infection among Thai Health Care Workers To the Editor—Unvaccinated health care workers (HCWs) are at risk for oc­ cupational exposure and infection with in­ fluenza and can serve as vectors for health care–associated (HA) influenza transmis­ sion to hospitalized patients [1, 2]. The World Health Organization reported 35,446 laboratory-confirmed cases of pan­ demic 2009 influenza A (H1N1) in Thai­ land by the end of March 2010 [3]. The vaccine for 2009 H1N1 influenza virus was not available in Thailand until 10 February 2010, and exposure of HCWs to patients infected with this virus increased as the pandemic evolved. We conducted a casecontrol study to identify factors associated with HA 2009 H1N1 influenza infection among Thai HCWs in a 500-bed tertiary care medical center during the period from 1 May 2009 through 15 January 2010. Data collected included age, sex, oc­ cupation, hospital units, unit hand hy­ giene compliance rates (before and after patient contact) during the month when index HCWs had confirmed 2009 H1N1 influenza infection, and exposure to pa­ tients with suspected or confirmed 2009 H1N1 influenza regardless of whether a surgical mask was used. Case patients were all HCWs with laboratory-confirmed 2009 H1N1 influenza. For each case, 2 matched controls were randomly selected among HCWs who did not have influenza during the period 2 weeks before and after the case patient’s confirmed infection date and who were assigned to care for patients who were suspected of having 2009 H1N1 influenza. HCWs identified as having influenza-like illness underwent nasopha­ ryngeal swab specimen collection for in­ fluenza testing by means of a rapid influ­ enza diagnostic test (SD Bioline Influenza Antigen A/B; MT Promedt Consulting) and reverse-transcription polymerase chain reaction [4]. Influenza-like illness was defined according to criteria set by the Centers for Diseases Control and Preven­ tion [5]. A suspected case of HA influenza was defined as influenza-like illness if on­ set of illness occurred within 4 days of exposure to a HCW or patient with con­ firmed 2009 H1N1 influenza. A confirmed case of HA influenza was defined as a sus­ pected case that was laboratory confirmed as influenza and did not result from com Reprints or correspondence: Dr Surendra K. Sharma , Dept of Medicine, All India Institute of Medical Sciences, New Dehli , 110029 India ( .in). Clinical Infectious Diseases 2010 ; 51 ( 3 ): 367 - 368 2010 by the Infectious Diseases Society of America. All rights reserved . 1058 - 4838 / 2010 /5103-0022$ 15 .00 DOI: 10.1086/654805


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Surendra K. Sharma, Rohit Singla, Pawan Sarda, Alladi Mohan, Govind Makharia, Arvind Jayaswal, Vishnubhatla Sreenivas, Sarman Singh. Reply to Chang and Leung, Clinical Infectious Diseases, 2010, 367-368, DOI: 10.1086/654805