Comparison of the safety and efficacy of a fixed-dose combination regimen and separate formulations for pulmonary tuberculosis treatment

Jiun-Ting Wu, Chien-Tung Chiu, Yu-Feng Wei, Yung-Fa Lai, Jiun-Ting Wu, Chien-Tung Chiu, Yu-Feng Wei, Yung-Fa Lai

Abstract

Objectives: Fixed-dose combination formulations, which simplify the administration of drugs and prevent the development of drug resistance, have been recommended as a standard anti-tuberculosis treatment regimen. However, the composition and dosage recommendations for fixed-dose combination formulations differ from those for separate formulations. Thus, questions about the effectiveness and side effects of combination formulations remain. The aim of this study was to compare the safety and efficacy of these two types of anti-tuberculosis regimens for pulmonary tuberculosis treatment.

Method: A prospective, randomized controlled study was conducted using the directly observed treatment short-course strategy. Patients were randomly allocated to one of two short-course regimens. One year after completing the treatment, these patients' outcomes were analyzed. ClinicalTrials.gov: NCT00979290.

Results: A total of 161 patients were enrolled, 142 of whom were evaluable for safety assessment. The two regimens had a similar incidence of adverse effects. In the per-protocol population, serum bilirubin concentrations at the peak level, at week 4, and at week 8 were significantly higher for the fixed-dose combination formulation than for the separate formulations. All patients had negative sputum cultures at the end of the treatment, and no relapse occurred after one year of follow-up.

Conclusions: In this randomized study, transient higher serum bilirubin levels were noted for the fixed-dose combination regimen compared with the separate formulations during treatment. However, no significant difference in safety or efficacy was found between the groups when the directly observed treatment short-course strategy was used.

Conflict of interest statement

No potential conflict of interest was reported.

Figures

Figure 1
Figure 1
Study profile. ITT=intent-to-treat; PP=per-protocol; NTM=non-tuberculous mycobacteria; FDC=fixed-dose combination; SF=separate formulation

References

    1. World Health Organization. Tuberculosis Programme Treatment of tuberculosis: guidelines for national programmes. 4th ed. WHO/HTM/TB/2009.420. Geneva, Switzerland: WHO; 2009.
    1. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis. 1998;2((1)):10–15.
    1. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of anti-tuberculous medications to prevent drug resistance. Ann Intern Med. 1995;122((12)):951–4. doi: 10.7326/0003-4819-122-12-199506150-00010.
    1. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ. 2001;79((1)):61–8.
    1. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167((4)):603–62. doi: 10.1164/rccm.167.4.603.
    1. Hong Kong Chest Service/British Medical Research Council. Acceptability, compliance, and adverse reactions when isoniazid, rifampin, and pyrazinamide are given as a combined formulation or separately during three-times-weekly anti-tuberculosis chemotherapy. Am Rev Respir Dis. 1989;140((6)):1618–22. doi: 10.1164/ajrccm/140.6.1618.
    1. Blomberg B, Fourie B. Fixed-dose combination drugs for tuberculosis: application in standardised treatment regimens. Drugs. 2003;63((6)):535–53. doi: 10.2165/00003495-200363060-00002.
    1. Lienhardt C, Cook SV, Burgos M, Yorke-Edwards V, Rigouts L, Anyo G, et al. Efficacy and Safety of a 4-Drug Fixed-Dose Combination Regimen Compared With Separate Drugs for Treatment of Pulmonary Tuberculosis. The Study C Randomized Controlled Trial. JAMA. 2011;305((14)):1415–23. doi: 10.1001/jama.2011.436.
    1. Albanna AS, Smith BM, Cowan D, Menzies D. Fixed-dose combination antituberculosis therapy: a systematic review and meta-analysis. Eur Respir J. 2013;42((3)):721–32. doi: 10.1183/09031936.00180612.
    1. Su WJ, Perng RP. Fixed-dose combination chemotherapy (Rifater®/Rifinah®) for active pulmonary tuberculosis in Taiwan: a two-year follow-up. Int J Tuberc Lung Dis. 2002;6((11)):1029–32.
    1. Infectious Diseases Society of the Republic of China; Society of Tuberculosis, Taiwan; Medical Foundation in Memory of Dr. Deh-Lin Cheng; Foundation of Professor Wei-Chuan Hsieh for Infectious Diseases Research and Education; C Y Lee's Research Foundation for Pediatric Infectious Diseases and Vaccines. Guidelines for chemotherapy of tuberculosis in Taiwan. J Microbiol Immunol Infect. 2004;37((6)):382–4.
    1. Taiwan Guidelines for TB Diagnosis and Treatment. (Taiwan): Centers for Disease Control, Department of Health, R.O.C.; (2008). 3rd Ed.
    1. Jiang JR, Yen SY, Wang JY. Increased prevalence of primary drug-resistant pulmonary tuberculosis in immunocompromised patients. Respirology. 2011;16:308–13. doi: 10.1111/res.2011.16.issue-2.
    1. Yu CC, Chang CY, Liu CE, Shih LF, Hsiao JH, Chen CH. Drug Resistance Pattern of Mycobacterium Tuberculosis Complex at a Medical Center in Central Taiwan, 2003–2007. J Microbiol Immunol Infect. 2010;43((3)):285–90. doi: 10.1016/S1684-1182(10)60045-X.
    1. Centers for Disease Control, Republic of China (Taiwan) Department of health, The Executive Tuan, Taiwan. (Available at ) (date of access: May. 3, 2013).
    1. World Health Organization. Laboratory services in tuberculosis control. Part II:microscopy. WHO/TB/98.258. Geneva, Switzerland: WHO; 1998.
    1. Taiwan Centers for Disease Control and Prevention. Nov, 2013. [Promulgated defi nitions of TB]. Taipei, Taiwan: CDC, 2009. . Accessed.
    1. Sun HY, Chen IL, Gau CS, Chang SC, Luh KT. A prospective study of hepatitis during antituberculous treatment in Taiwanese patients and a review of the literature. J Formos Med Assoc. 2009;108((2)):102–11. doi: 10.1016/S0929-6646(09)60040-1.
    1. Zhang L-X, Kan G-Q, Tu D-H, Wan L-Yet, Faruqi AR. Fixed-dose combination chemotherapy versus multiple, single-drug chemotherapy for tuberculosis. Curr Therap Research. 1996;57((11)):849–56. doi: 10.1016/S0011-393X(96)80018-X.
    1. Moulding TS, Le HQ, Rikleen D, Davidson P. Preventing drug-resistant tuberculosis with a fixed dose combination of isoniazid and rifampin. Int J Tuberc Lung Dis. 2004;8((6)):743–8.
    1. Bellabas M, Khaled S, Khaled NA, Boulahbal F, Chaulet P. Therapeutic trial of a combination of isoniazid, rifampicin and pyrazinamide in the first 2 months of treatment of pulmonary tuberculosis. Rev Mal Respir. 1989;6((1)):59–64.
    1. Agounitestane D, Chiheb M, Khaled S, Ait Khaled N, Boulahbal F, Chaulet P. A therapeutic trial of a combination of 3 essential drugs in a short course of chemotherapy in tuberculosis. Results 6months after the end of treatment. Rev Mal Respir. 1990;7((3)):209–13.
    1. Monedero I, Caminero JA. Evidence for promoting fixed-dose combination drugs in tuberculosis treatment and control: a review. Int J Tuberc Lung Dis. 2011;15((4)):433–9. doi: 10.5588/ijtld.09.0439.
    1. Teo SK. Assessment of a combined preparation of isoniazid, rifampicin and pyrazinamide (Rifater®) in the initial phase of chemotherapy in three 6-month regimens for smear-positive pulmonary tuberculosis: a five-year follow-up report. Int J Tuberc Lung Dis. 1999;3((2)):126–32.
    1. Bartacek A, Schutt D, Panosch B, Borek M. Rimstar® 4-FDC Study Group. Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis. Int J Tuberc Lung Dis. 2009;13((6)):760–6.
    1. Girling DJ. Adverse reactions to rifampicin in antituberculosis regimens. J Antimicrob Chemother. 1977;3((2)):115–32.
    1. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest. 1991;99((2)):465–71. doi: 10.1378/chest.99.2.465.
    1. Marra F, Marra CA, Bruchet N, Richardson K, Moadebi S, Elwood RK, et al. Adverse drug reactions associated with first-line anti-tuberculosis drug regimens. Int J Tuberc Lung Dis. 2007;11((8)):868–75.
    1. Laing RO, McGoldrick KM. Tuberculosis drug issues: prices, fixed-dose combinatsion products and second-line drugs. Int J Tuberc Lung Dis. 2000;4((12 Suppl 2)):S194–207.
    1. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet. 2001;358((9285)):912–6. doi: 10.1016/S0140-6736(01)06076-7.
    1. Norval PY, Blomberg B, Kitler ME, Dye C, Spinaci S. Estimate of the globalmarket for rifampicin-containing fixed-dose combination tablets. Int J Tuberc Lung Dis. 1999;3((11 Suppl 3)):S292–300.
    1. Tsai CF, Shiau MY, Chang YH, Wang YL, Huang TL, Liaw YC, et al. Trends of mycobacterial clinical isolates in Taiwan. Trans R Soc Trop Med Hyg. 2011;105((3)):148–52. doi: 10.1016/j.trstmh.2010.11.005.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe