Archive \ Volume.12 2021 Issue 3

Hepatic Safety of High-Dose Rifampicin for Tuberculosis Treatment in TB/HIV Co-infected Patients: A Randomized Clinical Trial

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High-dose Rifampicin regimens have been shown to be more effective for tuberculosis (TB) treatment in TB/HIV co-infected patients. This study assessed the hepatic safety of a high-dose Rifampicin regimen among TB/HIV co-infected patients. 811 TB/HIV co-infected patients, antiretroviral treatment (ART) naïve, at least 18 years old with a CD4 T-cell count between 50 and 350 cells/mm3 were enrolled. Patients with multidrug-resistant tuberculosis were excluded. Patients had received first-line antituberculosis treatment followed by ART after two weeks (arm A) or two months (arm B). In arm C, they received antituberculosis treatment with a high dose of Rifampicin (15 mg/kg/day instead of 10 mg/kg/day) during the TB intensive phase of treatment and ART after two months. The patients performed transaminases (ALT, AST), γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase (ALP), and total bilirubin blood tests. The study outcomes were an elevation of ALT at least 5 times the Upper Limit of Normal (Primary outcome), an isolated elevation grade 4 of AST, γ-GT, ALP, and/or total bilirubin (Secondary outcomes). The patients included were 53.97% men and 2.44% co-infected hepatitis B or C virus. There were no significant differences between ALT, AST, γ-GT, ALP, and total bilirubin between the standard regimens (Arms A and B) and high dose Rifampicin regimen (Arm C). This study showed that a high-dose Rifampicin regimen for TB treatment in TB/HIV co-infected patients was as safe as that of a standard regimen.

How to cite:
Sanni S, Wachinou AP, Merle CSC, Bekou KW, Esse M, Gossa S, et al. Hepatic Safety of High-Dose Rifampicin for Tuberculosis Treatment in TB/HIV Co-infected Patients: A Randomized Clinical Trial. Arch Pharm Pract. 2021;12(3):66-72.
Sanni, S., Wachinou, A. P., Merle, C. S. C., Bekou, K. W., Esse, M., Gossa, S., Gomina, K., Baba-Moussa, L., & Affolabi, D. (2021). Hepatic Safety of High-Dose Rifampicin for Tuberculosis Treatment in TB/HIV Co-infected Patients: A Randomized Clinical Trial. Archives of Pharmacy Practice, 12(3), 66-72.

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1.        World Health Organisation. Global Tuberculosis Report. Geneva: 2019. doi:10.16309/j.cnki.issn.1007-1776.2003.03.004

2.        Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806-15. doi:10.1038/clpt.2011.58

3.        Wang T, Lin S, Shie S, Chou P, Huang C, Chung F. Clinical Characteristics and Treatment Outcomes of Patients with Low- and High-Concentration Isoniazid- Monoresistant Tuberculosis. 2014;9(1):1-6. doi:10.1371/journal.pone.0086316

4.        Bao Y, Ma X, Rasmussen TP, Zhong XB. Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury. Curr Pharmacol Rep. 2018;4(3):171-81. doi:10.1007/s40495-018-0131-8

5.        Gurumurthy P, Ramachandran G, Kumar AKH, Rajasekaran S, Padmapriyadarsini C, Swaminathan S, et al. Decreased Bioavailability of Rifampin and Other Antituberculosis Drugs in Patients with Advanced Human Immunodeficiency Virus Disease. Society. 2004;48(11):4473-5. doi:10.1128/AAC.48.11.4473

6.        Chigutsa E, Visser ME, Swart EC, Denti P, Pushpakom S, Egan D, et al. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: Dosing implications. Antimicrob Agents Chemother. 2011;55(9):4122-7. doi:10.1128/AAC.01833-10

7.        Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, Salfinger M, et al. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother. 2007;51(11):3781-8. doi:10.1128/AAC.01533-06

8.        Jindani A, Harrison TS, Nunn AJ, Phillips PPJ, Churchyard GJ, Charalambous S, et al. High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis. N Engl J Med. 2014;371:1599-608. doi:10.1056/NEJMoa1314210

9.        Ruslami R, Menzies D. Finding the right dose of rifampicin, and the right dose of optimism. Lancet Infect Dis. 2017;17(1):2-3. doi:10.1016/S1473-3099(16)30315-2

10.      Milstein M, Lecca L, Peloquin C, Mitchison D, Seung K, Pagano M, et al. Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): Study protocol for a randomized controlled trial. BMC Infect Dis. 2016;16(1):1-7. doi:10.1186/s12879-016-1790-x

11.      Steingart KR, Jotblad S, Robsky K, Deck D, Hopewell PC, Huang D, et al. Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review [Review article]. Int J Tuberc Lung Dis. 2011;15(3):305-16.

12.      Boeree MJ, Diacon AH, Dawson R, Narunsky K, Du Bois J, Venter A, et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015;191(9):1058-65. doi:10.1164/rccm.201407-1264OC

13.      Ruslami R, Nijland HMJ, Alisjahbana B, Parwati I, Van Crevel R, Aarnoutse RE. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2007;51(7):2546-51. doi:10.1128/AAC.01550-06

14.      Boeree MJ, Van Balen GP, Aarnoutse RA. High-dose rifampicin: How do we proceed? Int J Tuberc Lung Dis. 2011;15(8):1133. doi:10.5588/ijtld.11.0198

15.      Hu Y, Liu A, Ortega-Muro F, Alameda-Martin L, Mitchison D, Coates A. High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo. Front Microbiol. 2015;6:1-10. doi:10.3389/fmicb.2015.00641

16.      Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017;17(1):39-49. doi:10.1016/S1473-3099(16)30274-2

17.      Onorato L, Gentile V, Russo A, Caprio G Di, Alessio L, Chiodini P, et al. Standard versus high dose of rifampicin in the treatment of pulmonary tuberculosis : a systematic review and meta-analysis. Clin Microbiol Infect. 2021;27(6):830-7.

18.      World Health Organization. Treatment of Tuberculosis Guidelines. Geneva: 2009.

19.      National Institute of Allergy and Infectious Diseases. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. 2014. doi:10.7326/0003-4819-157-11-201212040-00003

20.      WHO. Global Tuberculosis Report 2016. Geneva: 2016. doi:ISBN 978 92 4 156539 4

21.      Petros Z, Kishikawa J, Makonnen E, Yimer G, Habtewold A, Aklillu E. HLA-B*57 allele is associated with concomitant anti-tuberculosis and antiretroviral drugs induced liver toxicity in ethiopians. Front Pharmacol. 2017;8:1-9. doi:10.3389/fphar.2017.00090

22.      Walker L, Yip V, Pirmohamed M. Adverse Drug Reactions. Elsevier Inc.; 2014. doi:10.1016/B978-0-12-386882-4.00020-7

23.      Hassen Ali A, Belachew T, Yami A, Ayen WY. Anti-Tuberculosis Drug Induced Hepatotoxicity among TB/HIV Co-Infected Patients at Jimma University Hospital, Ethiopia: Nested Case-Control Study. PLoS One. 2013;8(5):e64622. doi:10.1371/journal.pone.0064622

24.      Björnsson ES. Hepatotoxicity by drugs: The most common implicated agents. Int J Mol Sci. 2016;17(2):224. doi:10.3390/ijms17020224

25.      Sarges P, Steinberg JM, Lewis JH. Drug-Induced Liver Injury: Highlights from a Review of the 2015 Literature. Drug Saf. 2016;39(9):801-21. doi:10.1007/s40264-016-0427-8

26.      Björnsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol. 2015;89(3):327-34. doi:10.1007/s00204-015-1456-2

27.      Wang P, Pradhan K, Zhong XB, Ma X. Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B. 2016;6(5):384-92. doi:10.1016/j.apsb.2016.07.014

28.      Metushi I, Uetrecht J, Phillips E. Mechanism of isoniazid-induced hepatotoxicity: Then and now. Br J Clin Pharmacol. 2016;81(6):1030-6. doi:10.1111/bcp.12885

29.      Daly AK, Martin Armstrong MP. Pharmacogenetics of Adverse Drug Reactions. Pharmacogenetics Individ. Ther. First Edit, John Wiley & Sons, Inc; 2012. p. 295-321. doi:10.1016/bs.apha.2018.03.002

30.      Kim SH, Kim SH, Lee JH, Lee BH, Kim YS, Park JS, et al. Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs. Tuberculosis. 2012;92(1):100-4. doi:10.1016/

31.      Andrade R, Agundez J, Lucena M, Martinez C, Cueto R, Garcia-Martin E. Pharmacogenomics in Drug Induced Liver Injury. Curr Drug Metab. 2009;10(9):956-70. doi:10.2174/138920009790711805

32.      Yew WW, Chang KC, Chan DP. Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity. Antimicrob Agents Chemother. 2018;62(8):1-11.

33.      Oscanoa T, Moscol S, Amado J. Clinical characteristics of pyrazinamide-associated hepatotoxicity in patients at a hospital in lima, peru. Rev Peru Med Exp Salud Publica. 2020;37(3):516-20.

34.      Kwon BS, Kim Y, Lee SH, Lim SY, Lee YJ, Park JS, et al. The high incidence of severe adverse events due to pyrazinamide in elderly patients with tuberculosis. PLoS One. 2020;15(7 July):1-10.

35.      Waggiallah HA, Eltayeb LB, BinShaya AS, Elmahi OM. A saga of Hepcidin anti-microbial Effectiveness as Iron Acquisitor and Anemia Initiator in Mycobacterium Tuberculosis Infection. J Biochem Techol. 2020;11(2):128-34.

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