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IDCM Issue 13: Drug-Susceptible TB: Updates from WHO's Adult TB Treatment Guidelines
Natasha Chida, MD, MSPH
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Tuberculosis (TB) remains one of the top 10 causes of death worldwide.1 In 2015, 10.4 million people developed active TB, while 1.8 million people died from the infection. TB is also responsible for 35% of deaths among people living with HIV. Given the prevalence of TB, associated mortality, and public health implications of untreated TB, it is important that all medical providers be up to date on the fundamental principles of, and recommendations for, TB treatment. What follows is a review of the 2017 update to the World Health Organization’s (WHO) 2010 guidelines on the treatment of drug-susceptible TB.
Principles of TB Treatment
When reviewing the new guidelines, it is important to remember the treatment of drug-susceptible TB requires multiple drugs; standard therapy consists of rifampin (RIF) isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB).2 This is to both protect against resistance and address varying levels of metabolic activity in tubercle bacilli of active TB infections. For example, INH is highly bactericidal on rapidly growing bacilli, but is less so for slow and intermittently growing bacilli.3 RIF is also highly bactericidal, and, unlike INH, it is effective for both rapid and slow/intermittently growing bacilli. PZA is weakly bactericidal, but is the most effective drug for eliminating the bacilli that are responsible for relapse—those that persist in the low-acid environments of the inflammatory zones of cavity wall, and within the acidic environment of macrophages. EMB acts on rapidly growing bacilli; its primary role is to protect RIF from developing resistance when INH resistance is present and the provider is unaware. If there is no INH resistance, ethambutol doesn’t need to be administered.
Recommended Drugs and Length of Treatment
Background: While most of the tubercle bacilli are killed during the first 8 weeks of TB therapy, some survive longer and are then killed with continued treatment after 8 weeks.4 Length of treatment is thus a critical issue; while months of therapy is difficult for patients, if administered for too short a time, treatment failure and relapse can result. In recent years, there has been interest in the use of fluoroquinolones as potential agents for shortening the course of TB treatment. In the 2010 guidelines, there there were no recommendations about the use of short 4-month fluoroquinolone-containing regimens, due to lack of data.
Update: Since then, 4 trials have been completed examining the use of fluoroquinolones to shorten therapy to 4 months.5-8 The studies showed that these regimens had a non-statistically significant higher rate of culture conversion at 2 months when compared with a standard regimen, but significantly higher rates of relapse at 18 months. There was no difference in adverse events or all-cause TB-related mortality. Therefore, fluoroquinolone-based regimens are not recommended by WHO.
Bottom line: The recommended regimen of drug susceptible TB remains 2 months of RIF, INH, PZA, and EMB (intensive phase), followed by 4 months of RIF and INH (continuation phase).
Background: The previous recommendation was that TB patients receive daily treatment in the intensive phase. The recommendation for the continuation phase was that treatment be administered either daily, or three-times weekly, with preference for daily treatment.
Update: For this update the guideline performed a systematic review of studies evaluating intermittent dosing schedules and of several randomized controlled trials. The review found that patients who received thrice-weekly dosing throughout therapy had a higher risk of treatment failure, relapse, and acquired drug resistance.5,6;9-12 There was also a higher rate of treatment failure and relapse in patients who received thrice weekly dosing only in the continuation phase.
Bottom line: Three-times weekly dosing is not recommended in either the intensive or continuation phase.
Length of Drug-susceptible TB Treatment for Persons Living with HIV
Background: The 2010 WHO guidelines had no recommendation for whether persons living with HIV on antiretroviral therapy (ART) should as a standard receive drug-susceptible TB treatment for more than 6 months.
Update: For this update, a review of the literature found no significant difference with regard to treatment failure or death between 6 and 8 month courses of TB treatment in persons living with HIV. There was a higher rate of relapse with a 6-month regimen in persons living with HIV who were not on ART, but when people were on ART (or were started on ART during TB treatment), there was no difference relapse.13-14 Of note, per this (and several other) guidelines, everyone with TB and HIV should be on ART
Bottom line: Patients living with HIV who have drug-susceptible TB and who receive ART during TB treatment should receive a standard 6 months of therapy, as opposed to 8 months or longer.
ART Initiation in Persons Living with HIV Who Have Active TB Background and Update: Recommendations for ART initiation within 8 weeks of therapy in persons living with HIV with active TB have not changed. The recommendations are based on a review of several randomized controlled trials, which showed an overall mortality benefit to initiation of ART within 8-12 weeks of TB treatment.15 For patients with CD4 counts <50 cc/mm3, initiating ART within 1-4 weeks of TB treatment reduces the risk of developing an AIDS-defining illness and death, although it does increase the risk of TB-IRIS. For patients with CD4 counts >50 cc/mm3 who don’t have severe disease, ART initiation prior to 8-12 weeks did not decrease risk of an AIDS-defining illness or death, and was associated with a lower risk of IRIS. WHO does recommend caution when initiating ART in persons with TB meningitis; in one trial persons with TB meningitis had a significantly higher rate of severe adverse events due to immune reconstitution inflammatory syndrome when initiating ART within 8 weeks of starting TB therapy (without an improvement in outcomes).16
Bottom line: The guidelines recommend initiation of ART for all patients with HIV-associated TB, regardless of CD4 count. TB treatment should be initiated first, then ART within the first 8 weeks of treatment, unless the patient has a CD4 count of <50 cells/mm3; these patients should receive ART within the first 2 weeks of treatment.
Steroid Use in the Treatment of Tuberculous Meningitis and Pericarditis
Background: In 2010 guidelines, there were no recommendations about the use of steroids in the treatment of tuberculous meningitis or pericarditis, due to lack of data.
Update: Since 2010 a systematic review and several randomized controlled trials have showed lower rates of mortality, death, relapse, and disability in persons who received steroids during treatment for TB meningitis.17 Regarding tuberculous pericarditis, the data has been mixed; a systematic review showed a benefit with steroids in the outcomes of death, constrictive pericarditis, and treatment adherence.23 However, the largest study in the review showed no benefit to steroids, although the majority of patients in this study had HIV and most were not on ART.24 It is unclear if immune suppressed patients have a different benefit from steroids in the setting of tuberculous pericarditis.
Bottom line: The guidelines now recommend a 6-8 week dexamethasone or prednisolone taper when treating a patient for tuberculous meningitis. Regarding tuberculous pericarditis, a steroid taper may be considered.
Retreatment of TBBackground: The previous guidelines recommended a standard regimen for patients who were being retreated for TB, labeled “category II.” This regimen included streptomycin with RIF/INH/PZA/EMB for 2 months, followed by 1 month of RIF/INH/PZA/EMB, and then 5 months of RIF/INH/EMB.
Update: A review of the use of the category II regimen was performed and showed that empirical use of the regimen is associated with median treatment success rates of 68% and contributes to the development of drug resistance.2
Bottom line: WHO no longer recommends the category II regimen as the standard therapy for TB retreatment. Instead, drug-susceptibility testing should determine the retreatment regimen.
- Tuberculosis Fact sheet. World Health Organization website. http://www.who.int/mediacentre/factsheets/fs104/en/. Updated March 2017. Accessed 5/15/17
- World Health Organization. Guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 update. Geneva: World Health Organization; 2017. Available at: http://www.who.int/tb/publications/2017/dstb_guidance_2017/en/. Accessed 5/10/17
- Abrex MA, Varella CM, Siqueira HR, Mello FA. Antituberculosis drugs: drug interactions, adverse effects, and use in special situations. Part 1: first-line drugs. J Bras Pneumol. 2010;36(5):626-40. PMID: 21085830
- Centers for Disease Control and Prevention. The Core Curriculum on Tuberculosis: What the Clinician Should Know. http://www.cdc.gov/tb/education/corecurr/. Updated 2013. Accessed 5/10/17
- Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al.; REMoxTB Consortium. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014;371(17):1577-87. PMID: 25196020
- Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, et al.; OFLOTUB/Gatifloxacin for Tuberculosis Project. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014;371(17):1588-98. PMID: 25337748
- Jindani A, Harrison TS, Nunn AJ, Phillips PP, Churchyard GJ, Charalambous S, et al.; RIFAQUIN Trial Team. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014;371(17):1599-608. PMID: 25337749
- Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, Venkatesan P, et al. Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One. 2013;8(7):e67030. PMID: 23843980
- Menzies D, Benedetti A, Paydar A, Martin I, Royce S, Pai M, et al. Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and metaanalysis. PLoS Med. 2009;6(9):e1000146. PMID: 23843980
Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365(16):1471-81. PMID: 22010913
Johnson JL, Hadad DJ, Dietze R, Maciel EL, Sewali B, Gitta P, et al. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med. 2009;180(6):558-63. PMID: 19542476
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. PMID: 21486974
Swaminathan S, Narendran G, Venkatesan P, Iliayas S, Santhanakrishnan R, Menon PA, et al. Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial. Am J Respir Crit Care Med. 2010;181(7):743-51. PMID: 19965813
Khan FA, Minion J, Pai M, Royce S, Burman W, Harries AD, Menzies D. Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis. Clin Infect Dis. 2010;50(9):1288-99. PMID: 20353364
Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, Nachega J. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and meta-analysis. Ann Intern Med. 2015;163:32-9. PMID: 26148280
Torok ME, Bich Yen NT, Hong Chau TT, Hoang Mai HT, Phu NP, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculosis meningitis. Clin Infect Dis. 2011;52(11):1374–83. PMID: 21596680
Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2013;13(3):223-37. PMID: 23369413
Chotmongkol V, Jitpimolmard S, Thavornpitak Y. Corticosteroid in tuberculous meningitis. J Med Assoc Thai. 1996;79(2):83-90. PMID: 8868018
Kumarvelu S, Prasad K, Khosla A, Behari M, Ahuja GK. Randomized controlled trial of dexamethasone in tuberculous meningitis. Tuber Lung Dis. 1994;75(3):203-7. PMID: 7919313
Malhotra HS, Garg RK, Singh MK, Agarwal A, Verma R. Corticosteroids (dexamethasone versus intravenous methylprednisolone) in patients with tuberculous meningitis. Ann Trop Med Parasitol. 2009;103(7):625-34. PMID: 19825284
Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics. 1997;99(2):226-31. PMID: 9024451
Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351(17):1741-51. PMID: 15496623
Mayosi BM, Ntsekhe M, Volmink JA, Commerford PJ. Interventions for treating tuberculous pericarditis. Cochrane Database Syst Rev. 2002;(4):CD000526. PMID: 12519546
Mayosi BM, Ntsekhe M, Bosch J, Pandie S, Jung H, Gumedze F, et al.; IMPI Trial Investigators. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med. 2014;18;371(12):1121-30. PMID: 25178809
Menzies D, Benedetti A, Paydar A, Royce S, Madhukar P, Burman W, et al. Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med. 2009;6(9):e1000150. PMID: 20101802