Current evidence on role of rifabutin on drug resistant TB

1. Rifabutin in Drug Resistant
TB
Dr Gyanshankar Mishra
Associate Professor
Respiratory Medicine
IGGMC Nagpur

2. Rifabutin last appeared in WHO Guidelines
for Programmatic management of drug resistant
Tuberculosis in 2014.

3. Rifabutin was missing in subsequent WHO
Guidelines on drug resistant TB
2016… 2018

4. The issues concerning Use of Rifabutin in Drug
Resistant TB
•Cross resistance of Rifabutin with
Rifampicin
•Efficacy of regimes containing
Rifabutin in Drug Resistant TB

5. How serious is the issue
of cross resistance
between Rifabutin and
Rifampicin?

6. Cross resistance of Rifabutin with Rifampicin
• Of the 62 isolates with rifampin resistance (rifampin MIC>1.0 μg/ml),
12 (19%) would have been considered susceptible to rifabutin using
the conventional agar proportion breakpoint (rifabutin MIC 0.5
μg/ml). Yet another 14 (23%) were within the borderline resistant
range.
• Heysell SK, Ahmed S, Ferdous SS, Khan MSR, Rahman SMM, Gratz J, et al.
Quantitative drug-susceptibility in patients treated for multidrug-resistant
tuberculosis in Bangladesh: implications for regimen choice. PLoS One
[Internet]. 2015 [cited 2018 Nov 25];10(2):e0116795. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25710516

7. Cross resistance of Rifabutin with Rifampicin
• Investigators performed whole genome sequencing of 1005 MTB clinical
isolates and measured minimum inhibitory concentration (MIC) to both
agents (Rifampicin and Rifabutin) on 7H10 agar using the indirect
proportion method. Of the 1005 isolates, 767 were RIF resistant, and of
these, 211 (27%) were sensitive to RFB at the critical concentration of
0.5ug/ml
• ..Thus lack of cross resistance between RIF and RFB occurred in 27% of RR
isolates. RFB resistance among RIF susceptible isolates was very rare and
occurred in only one isolate.
• Farhat MR, Sixsmith J, Calderon R, Hicks N, Fortune S, Murray M. Rifampicin and
rifabutin resistance in 1000 Mycobacterium tuberculosis clinical isolates. bioRxiv
[Internet]. 2018 Sep 25 [cited 2018 Nov 25];425652. Available from:
https://www.biorxiv.org/content/early/2018/09/25/425652

8. Cross resistance of Rifabutin with Rifampicin..
31/102 (30.4 %) isolates were RIFABUTIN
Sensitive and RIFAMPICIN Resistant.

9. Can we know which
Rifampicin Resistant
isolates are Rifabutin
Susceptible?

10. • 112 rpoB polymorphisms (67.9% from literature) were identified from all 2045 RR- TB
patients. 11 polymorphisms were associated with rifabutin susceptibility.
• The 516GTC mutation was the most common.
• At a population level, the 11 polymorphisms associated with rifabutin susceptibility
occurred in 33.2% and 16.6% of all South African and Belgian patients diagnosed with
RR-TB, respectively.
• Identification of the exact rpoB polymorphism leading to the diagnosis of RR-TB has the
potential to allow inclusion of rifabutin in the treatment regimen of a substantial
proportion of RR-TB patients.
• Whitfield MG, Warren RM, Mathys V, Scott L, De Vos E, Stevens W, et al. The potential use of
rifabutin for treatment of patients diagnosed with rifampicin-resistant tuberculosis. J Antimicrob
Chemother [Internet]. 2018 Oct 1 [cited 2018 Nov 25];73(10):2667–74. Available from:
https://academic.oup.com/jac/article/73/10/2667/5049577

11. What is the Efficacy of
regime containing
Rifabutin in Drug
Resistant(RR) TB?

12. • Objective: We investigated the efficacy of rifabutin (RFB)-containing regimens for the treat- ment of RFB-susceptible,
multidrug-resistant tuberculosis (MDR-TB). Methods: From 146 patients diagnosed with MDR-TB between January 2006 and
December 2009 at Asan Medical Center in South Korea, 31 patients (21.2%) were found to have RFB-susceptible MDR-TB. Of
these 31 patients, 14 patients who had been treated with RFB for more than one month were included. Forty-two patients
with RFB-resistant MDR-TB were selected as a control group, and the outcomes of both groups were retrospectively
compared. Results: Of 14 patients with RFB-susceptible MDR-TB, the mean age was 44.4 years and the proportion
of extensively drug-resistant TB (XDR-TB) was 35.7% (5/14). Baseline characteristics and the drug resistance pattern (except RFB) did
not differ between the two groups. Treatment success was achieved in 12 (85.7%) patients in the RFB
group: cure in 10 (71.4%) and treatment completion in two (14.3%). The treatment success rate was 52.4% (22/42) in the control
group (p Z 0.032). Treatment failure was more common in patients of the control group (40.5% vs. 14.3%; p Z 0.106). Conclusions:
RFB is useful as an additional drug in the treatment of MDR-TB in patients with RFB-
susceptible MDR-TB.

13. Objectives: The aim of this study was to evaluate whether rifabutin can improve treatment outcomes in patients with rifabutin-sensitive
MDR-TB. Methods: A retrospective cohort study was performed on 76 patients with rifabutin-sensitive MDR-TB who were treated with or
without rifabutin between 2006 and 2011. Results: Overall, 75% (57/76) of patients achieved favorable outcomes, including cure (53/76,
70%) and treatment completion (4/76, 5%). In contrast, 25% (19/76) had unfavorable treatment outcomes, which included treatment
failure (6/76, 8%), death (2/76, 3%), loss to follow-up (4/76. 5%), and no evaluation due to transfer to other institutions (7/76, 9%).
Rifabutin was given to 52 (68%) of the 76 patients with rifabutin-sensitive MDR-TB. Although
favorable treatment outcomes were more frequent in patients who received rifabutin [81% (42/52)]
than in those who did not receive rifabutin [63% (15/24)], this difference was not statistically significant (P = 0.154).
However, in multivariable regression logistic analysis, use of rifabutin was significantly associated with favorable
treatment outcomes in patients with rifabutin- sensitive MDR-TB (adjusted odds ratio = 9.80, 95% confidence
interval = 1.65–58.37, P = 0.012). Conclusions: These results suggest that the use of rifabutin can improve
treatment outcomes in patients with rifabutin-sensitive MDR-TB.

14. Any Concerns?
• In the previous study by Lee et al. Tolerability and safety of the rifabutin-
containing regimen Of the 52 patients who received a rifabutin-containing
regimen,10 patients (19%) discontinued rifabutin because of
adverse effects that were likely due to rifabutin, including drug-induced
fever (n = 3), gastrointestinal discomfort (n = 2), neutropenia (n = 3),
arthralgia (n = 1), myalgia (n = 1), and itching (n = 1). One patient had both
drug-induced fever and neutropenia.
• Rifabutin lowers the blood levels of bedaquiline (by up to 20%) and
linezolid; however, it does not alter delamanid levels.
• Tiberi S, D’Ambrosio L, Centis R, Migliori GB. Rifabutin: Is it useful in the treatment of
multidrug-resistant tuberculosis? Int J Infect Dis [Internet]. 2017 Dec 1 [cited 2018
Nov 25];65:133–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29122690

15. • Thank You