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4 months of rifampin for latent TB shows promise
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Tuberculosis is a disease that affects millions of individuals globally, killing an estimated 1.3 million people in 2017. Approximately one-quarter of the human population is infected with Mycobacterium tuberculosis. However, not everyone infected will develop active disease. An infected individual may have latent TB infection, or LTBI, if the bacterium remains dormant. Patients with LTBI do not exhibit symptoms and cannot spread the disease to others. If the bacteria overcome the immune system and begin to replicate, LTBI may progress into active TB disease. Without treatment, approximately 5% to 10% of patients will develop active TB.
WHO recommends 6 to 9 months of treatment with isoniazid for LTBI, with longer durations of therapy showing better efficacy. Isoniazid exhibits bactericidal effects by interfering with cell wall synthesis and disrupting the synthesis and metabolism of other substances critical to the cell. This medication has also been associated with hepatotoxic effects and poor adherence rates. For this reason, some health care providers may be hesitant to prescribe isoniazid for the treatment of LTBI. In contrast, several observational studies have shown better tolerability and adherence with short-course rifamycin regimens, and these regimens have been increasing in popularity.
Rifampin
Rifampin is a rifamycin antibiotic that exhibits bactericidal activity against M. tuberculosis. It inhibits DNA-dependent RNA polymerase activity, which prevents bacterial RNA synthesis. It is available orally and intravenously. Oral rifampin is best taken on an empty stomach because oral absorption is reduced by approximately 30% when administered with food. Rifampin widely distributes throughout the body. Because it is a potent inducer of several cytochrome P450 enzymes, rifampin is associated with numerous drug interactions (see Table). Rifampin may also produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum and tears. Baseline and periodic monitoring of liver function is recommended because rifampin has been associated with liver dysfunction. The typical treatment dose for TB is 600 mg as a single daily dose in adults.
Clinical Trials
Trial 1
An open-label, parallel-group, randomized controlled trial conducted in nine countries compared a 4-month regimen of rifampin with a 9-month regimen of isoniazid for LTBI. Adult patients (18 years) were enrolled in the study if they had a positive tuberculin skin test or interferon-gamma release assay results, met criteria for increased risk for reactivation to active TB and were prescribed isoniazid for LTBI. Patients in the experimental group received rifampin 10 mg/kg (maximum dose 600 mg) daily for 4 months, whereas patients in the control group received isoniazid 5 mg/kg (maximum dose 300 mg) daily for 9 months. The primary objective was to compare the rates of confirmed or clinically diagnosed active TB in the two groups during 28 months after randomization. Secondary objectives included a comparison of the rate of confirmed active TB plus clinically diagnosed active TB per 100 person-years, treatment completion rates and adverse events between the two groups.
From 2009 to 2014, a total of 6,012 patients were included in the phase 3, modified, intention-to-treat analysis. The authors also included 847 patients from a previously published phase 2 trial, bringing the total patient population to more than 6,800. The mean age among all participants was 38 years, and 42% were male. Nearly 70% of participants were close contacts of patients with active TB, and only 4% of patients had HIV. Among all participants, confirmed or clinically diagnosed TB occurred in eight and nine patients in the rifampin group and the isoniazid group, respectively. The differences in the rate of confirmed TB was less than 0.01 cases per 100 person-years (95% CI, –0.23 to 0.22). One case of rifampin resistance and one case of isoniazid resistance was observed. The rate of treatment completion was significantly higher with the 4-month rifampin regimen than with the 9-month isoniazid regimen — by 15.6% (95% CI, 13.4-17.8; P < .001). Grade 3 to 5 adverse events judged to be attributed to the trial drug and that led to permanent discontinuation of the drug occurred in 0.9% and 2.3% (95% CI, –2 to –0.8) of patients in the rifampin group and isoniazid group, respectively, with 0.3% and 2% being grade 3 to 4 hepatotoxic events (95% CI, –2.2 to –1.2).
Trial 2
The authors also conducted another trial with a similar design to compare the safety and side effects of the 4-month regimen of rifampin and the 9-month regimen of isoniazid in children, with secondary endpoints of treatment adherence rates and efficacy. This trial enrolled 829 children aged 0 to 17 years, with 128 children aged younger than 5 years and 79 aged younger than 2 years. Children assigned to the isoniazid group (n = 407) received 10 to 15 mg/kg per day, and those assigned to the rifampin group (n = 422) received 10 to 20 mg/kg per day. Both medications were well-tolerated as serious adverse events attributed to the trial drug were not observed in either group. In fact, less than 5% of patients in either group reported minor symptoms attributed to the trial drug during follow-up visits. The rate of treatment completion was significantly higher in the rifampin group than in the isoniazid group (adjusted difference, 13.4%; 95% CI, 7.5-19.3). No cases of active TB were reported in the rifampin group, whereas two cases were reported in the isoniazid group (rate difference, 0.37 cases per 100 person-years; 95% CI, 0.88 to 0.14). Isoniazid resistance occurred in one of the two cases.
Conclusion
Rifampin is a well-tolerated antibiotic that can be considered for the treatment of LTBI. It is associated with numerous drug-drug interactions. Providers should screen for these interactions before initiation of rifampin, and patients should consult with their doctor or pharmacist before starting any over-the-counter medications as well. Rifampin is an attractive option because it is dosed once daily for a shorter duration compared with isoniazid. Overall, the trials mentioned earlier demonstrated that the 4-month regimen of rifampin was noninferior to the 9-month regimen of isoniazid for the prevention of active TB. Consistent with previous observational studies, rifampin was associated with a higher rate of treatment completion and improved safety outcomes. The results from these trials are generalizable to patients from various socioeconomic backgrounds because they were conducted in nine different countries across the world; however, because the trials did not include a large population of HIV-positive patients, the results may not be applicable to this patient population.
- References:
- CDC. Tuberculosis (TB). https://www.cdc.gov/tb/default.htm. Accessed January 20, 2019.
- Diallo T, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1714284.
- Menzies D, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1714283.
- Rifadin [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2010.
- Rifamycins (rifampin, rifabutin, rifapentine). In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2019. www.uptodate.com. Accessed January 21, 2019.
- For more information:
- Khanh-Linh Le, PharmD, is a PGY1 pharmacy resident at Denver Health Medical Center.
- Kati Shihadeh, PharmD, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. She can be reached at katherine.shihadeh@dhha.org.
Disclosures: Le and Shihadeh report no relevant financial disclosures.