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Efficacy & safety of high-dose rifampicin in pulmonary tuberculosis: A systematic review & meta-analysis
For correspondence: Dr Leeberk Raja Inbaraj, Department of Clinical Research, ICMR- National Institute for Research in Tuberculosis, Chennai 600 031, Tamil Nadu, India e-mail: leeberk2003@gmail.com
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Received: ,
Accepted: ,
Abstract
Background & objectives
Evidence suggests that higher doses of rifampicin aid in faster culture conversion, but its effects on unfavourable outcomes are unclear. We aimed to synthesise evidence on the efficacy and safety of high-dose rifampicin (>15 mg/kg) containing anti-tuberculosis regimen compared to a regimen with standard dose of rifampicin in adults with pulmonary tuberculosis.
Methods
We searched for studies from MEDLINE, Embase, Web of Science, Google Scholar, and the Cochrane Library without geographical restriction. We included randomised controlled trials that evaluated high-dose rifampicin (>15 mg/kg for 8 wk) with a six-month duration. Our outcomes of interest were sputum conversion at eight wk, mortality, treatment failure at six months, Grade 3 and Grade 4 hepatotoxicity, and adverse events leading to treatment discontinuation. Two authors independently screened titles, abstracts, and full texts and extracted data. We performed a meta-analysis using the RevMan web software as per the Cochrane Handbook for Systematic Reviews of Interventions.
Results
Out of 3950 articles screened, we included nine for meta-analysis. High-dose rifampicin (≥15 mg/kg) showed little benefit compared to the standard dose for sputum conversion at eight wk [(83% vs. 78%, Relative risk (RR) 1.05 (95% confidence interval (CI): 1.0-1.09), Number needed to treat (NNT)-24)] and this benefit was higher as the rifampicin dose increased [20-30 mg RR: 1.07 (95% CI 1.02-1.14), NNT-17]; >30 mg RR: 1.12 (95% CI 1.04 -1.20) NNT-9]. However, treatment failure and mortality showed no benefit with high-dose rifampicin. Grade 3 and 4 hepatotoxicity and treatment discontinuation due to toxicity had a dose-response relationship and were significantly higher in the more than 30 mg/kg group [RR: 4.01 (95%CI 1.75-9.19), Number needed to harm -20].
Interpretation & conclusions
High doses of rifampicin (≥15 mg/kg) increased the rate of sputum culture conversion after two months of the intensive phase. There was no difference in mortality and treatment failure between high-dose rifampicin and standard arms. In the subgroup analysis, the 20-30 mg/kg dose exhibited a beneficial effect in sputum conversion with no significant risk of hepatotoxicity and adverse drug reactions (ADR) leading to treatment discontinuation. This dose could be administered with close monitoring of adverse events and hepatotoxicity. There is an urgent need for adequately powered trials that assess long-term treatment outcomes, including recurrence.
Keywords
Culture conversion
high-dose rifampicin
pulmonary tuberculosis
rifampicin
safety and efficacy
Tuberculosis (TB) is curable but still remains the most common cause of death due to infectious diseases, with an estimated 1.3 million deaths globally in 20221. Since 1994, the first line of TB treatment has been chemotherapy combined with isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z). The first three drugs have been part of the World Health Organization (WHO)-recommended TB treatment regimens since the 1980s2,3. Rifampicin was added to the already discovered drugs, such as isoniazid and Ethambutol, in the 1970s. Eventually, the introduction of pyrazinamide replacing streptomycin in the 1980s was a major event in designing the short-course chemotherapy of six to eight months of treatment duration4. Rifampicin plays an important role in TB treatment regimens, because of its potent bactericidal and sterilising capacity, and also as a potential treatment shortening agent5.
Contemporarily, the standard of care for pulmonary TB is HRZE for eight wk, followed by HR for the next 24 wk. Longer durations and adverse events that impact drug compliance may lead to unfavourable TB treatment outcomes6. Currently, Rifampicin is given at a dose of 10 mg/kg as per the WHO recommendation7. Pharmacokinetic studies have shown that conventional dosage (10 mg/kg) of rifampicin is associated with sub-therapeutic concentration, which affects the TB treatment outcomes and contributes to the emergence of multidrug-resistant TB8,9. Hence, there is a need for modification of the existing dosage for better treatment outcomes and to achieve early culture conversion. Many trials in recent years have proven that high-dose rifampicin was efficacious and safe, but also cost-effective in the treatment of pulmonary TB10-14. Even though high-dose rifampicin is found beneficial, the impact of higher doses on treatment outcomes and long-term recurrence-free survival is unclear.
According to a systematic review and meta-analysis that informed WHO recommendations, higher doses of rifampicin may reduce treatment failure rates, recurrence, and all-cause mortality due to tuberculosis; however, the evidence for these outcomes is unclear or low15. Steingart et al16, in their systematic review, concluded that high-dose rifampicin at 900 mg had an increased culture conversion rate. A systematic review done by Onorato et al17 demonstrated that patients on high-dose rifampicin, particularly on more than 20 mg/kg, had a significantly higher proportion of culture conversion. In contrast, they found no differences in treatment failure, adverse events, and mortality. There have been a few new trials evaluating high-dose rifampicin in pulmonary TB, and there is a need to update the current evidence. Hence, we performed this systematic review to synthesise evidence on the efficacy and safety of high-dose rifampicin (>15 mg/kg) containing anti-TB regimen compared to a regimen with standard dose (10 mg/kg) in adults with pulmonary tuberculosis.
Materials & Methods
Protocol and registration
We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024570926).
Inclusion criteria
We included randomised control trials (RCTs) that fulfilled the PICO criteria. Our inclusion criteria were adults (≥18 yr) with pulmonary TB who were on daily anti-TB regimens with or without comorbid illnesses, either managed as inpatients or outpatients. We included trials where participants received a high-dose of rifampicin (≥15 mg/kg) for eight wk along with other first-line anti-tuberculosis medicines (ethambutol, pyrazinamide, isoniazid) in the intervention group, while the control group received a conventional dose of rifampicin (10 mg/kg). Our outcomes of interest were sputum conversion at eight weeks, mortality rates, Grade 3 or 4 hepatotoxicity, adverse drug reactions (ADR) leading to treatment discontinuation, and treatment failure. We excluded case reviews, ecological studies, case-control, cross-sectional, and other study designs. We included studies published in any language and from any country.
Definition of the outcomes
Our primary outcome was sputum conversion either by microscopy or culture at the end of eight wk. Secondary outcomes were mortality until the last follow up, Grade 3 or 4 hepatotoxicity during treatment, adverse drug reactions leading to treatment discontinuation, and treatment failure at six months.
Sputum conversion
Sputum culture conversion from a positive to negative result at the end of eight weeks of anti-TB treatment, confirmed by at least two consecutive liquid or solid culture methods.
Treatment failure
Sputum smear or culture positive within the last month of treatment.
Mortality
Death from any cause before the initiation, during the course of treatment, or during follow up.
Grade 3 and Grade 4 hepatotoxicity
An abnormal liver function test graded as 3 or 4 by standard criteria.
ADR leading to treatment discontinuation
Adverse events resulting in discontinuation of study medication at any time during the treatment.
Data source & search strategy
We performed the search between May 19-20, 2024 through OVID in the following databases: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) in Cochrane Library. We remained restricted to articles published after 1990 as the international guidelines recommended the combination regimen of the current standard of care for drug-susceptible tuberculosis as the first-line regimen from 1990 till 202418. The search strategies (Supplementary Material 1) were developed based on our PICO (participants, intervention, comparator, and outcome). We used search terms such as ‘tuberculosis’, ‘TB’, ‘pulmonary tuberculosis’, PTB, rifampicin, and high-dose rifampicin, and used the MeSH explode option in the OVID database. The search results from the different individual databases were downloaded as an “RIS” file and exported into Rayyan software for removing duplicates before title and abstract screening. We also manually searched the reference list of the selected articles for additional studies missed during the initial electronic search. The bibliographies of all full-text articles and previous systematic reviews were also examined for potential articles.
Data collection
Study selection
Titles/abstracts provided by the search expert (MKS) were imported into the Rayyan software, and duplicates were excluded. Two independent reviewers (AB/JA) screened the titles and abstracts using the above mentioned PICO criteria and shortlisted potential publications for detailed assessment. Two reviewers (AB/JA) further analysed the shortlisted articles independently and documented specific reasons for exclusion. The discrepancies between the two reviewers were resolved by a third investigator (LR). All decisions made during the selection process were recorded and presented in a PRISMA flow diagram (Fig. 1).
- PRISMA flow diagram.
Data extraction & Risk of bias assessment
Two independent reviewers (KB/JA) planned to extract the data from the included studies into a data extraction form. We used the Cochrane Risk of Bias (RoB) V.2.0 scale to assess bias in the included articles19. JA and AB assessed the articles, and LR played the role of arbitrator in resolving the discrepancies. All the outcomes were binary, and we recorded the number of events and total participants for the outcomes. RoB-2 consists of five domains that assess bias: arising from the randomisation process, due to deviation from intended intervention, due to missing outcome data, measurement of the outcome, and selection of the reported results. Each study was assigned a judgement of high risk of bias, some concerns of bias, and low risk of bias.
Statistical analysis
We performed analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions using RevMan web online software. We calculated pooled risk ratios (RR) using the Mantel-Haenszel method and fixed effect models, as we assumed the effect size would be similar across the studies. We used intention-to-treat or modified intention-to-treat analysis. We assessed the heterogeneity of treatment effects between trials using the I2 statistic and visual examination to quantify the statistical heterogeneity. We also performed a subgroup analysis according to the dose of rifampicin (<20, 20-30, and >30 mg/kg). We reported a pooled risk ratio with a 95% Confidence interval (CI), and a P< 0.05 was considered significant. We assessed the certainty of the evidence using the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for reviews of interventional studies, and we made judgments separately for all the outcomes using GRADEpro GDT online software20,21.
Results
Results of the search
We obtained 3909 articles across all databases and screened 3300 after de-duplication. We excluded 3279 and screened 21 full texts. As mentioned above, two review authors screened these full-text articles, and a third author resolved any discrepancies between them. We finally included nine studies for meta-analysis (Fig. 1). We described the reasons for exclusion in supplementary material 2.
Characteristics of the included studies and intervention
The characteristics of the nine included studies are described in table I. All included studies were individual randomised controlled trials, and three were multi-country trials13,22,23. The sample size ranged from 65 to 701, with a median of 300 (IQR: 165-194). Three studies used a two-month intensive phase with four drugs followed by four months of continuation phase with two drugs (3HRZE+4HR)12,23,24. Two trials administered two months of intensive phase with four drugs, followed by four months of continuation phase with three drugs (2HRZE+4HRE)14,25. In one study, participants received five months of HRE during the continuation phase (2HRZE+5HRE)26. In the intervention arm, Jindani et al13 administered a four-month regimen (2HRZE/2HR), while Boere et al11 administered 3HRZE followed by 3HR. Both used 2HRZE followed by 4HR in the control arm11,22. The trials of Jindani et al13,22 reported a 16-wk exposure to high-dose rifampicin, whereas Boere et al11 reported a 12-wk exposure. All other studies administered high-dose rifampicin for eight wk. The high-dose rifampicin dose had a range of 15 to 35 mg/kg. Five studies included individuals living with HIV (PLHIV)11,12,23,25,26, while Sanni et al23 and Atwine et al26 exclusively included PLHIV. All of the studies reported outcomes by intention-to-treat analysis, except for Arantouse et al25, which did not specify the type of analysis.
| High dose group | Standard dose group | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Author & yr | Country | N | Regimen | Dose (mg/kg) | Duration of Rif exposure (wk) | N | Age (yr), median (IQR) | Males, n (%) | HIV, n (%) | Regimen | N | Age (yr), median (IQR) | Males, n (%) | HIV, n (%) |
| Jindani et al13, 2016 |
Bolivia, Nepal, Uganda |
300 |
2EHRZ/4HR 2EHRZ/4HR |
15 20 |
16 | R15: 100 R20: 100 |
27.5 (16-67) 30 (19-66) |
139 (69.5) | 0 | 2HRZE+ 4HR | 100 | 28.5 (18-67) | 66 (66) | 0 |
| Arantouse et al25, 2017 | Tanzania | 150 | 2HRZE+4HRE |
16 21 |
8 | R16:50 R21:50 |
33.0 33.5 |
46 (92) 45 (90) |
5 (10) 6 (12) |
2HRZE+4HRE | 50 | 35 (28-41) | 44 (88) | 4 (12) |
| Boeree et al11, 2017 | Tanzania | 186 | 3HRZE+3 HR | 35 | 12 | R35:63 | 33 (23-40) | 126 (68.8) | 10 (5.5) | 2HRZE+4HR | 123 | 34 (26-41) | 94 (76) | 9 (7) |
| Velasquez et al12, 2017 | Peru | 180 | 2HRZE+4HR |
15 20 |
8 | R15:60 R20:60 |
25 (20-25) 27 (22-37) |
75 (60.8) | 3 (2.5) | 2HRZE+4HR | 60 | 24 (21-37) | 39 (65) | 2 (3.3) |
| Atwine et al26, 2019 | Uganda | 65 | 2HRZE+5HRE | 20 | 8 | 32 | 33.4 (28.0-36.6) | 22 (71.0) | 32 (100) | 2HRZE+5HRE | 33 | 34.1 (29.6-38.1) | 22 (71) | 33 (100) |
| Maug et al24, 2020 | Bangladesh | 701 | 2HRZE+4HR | 20 | 8 | R20:353 | 45 (28-55) | 260 (74) | 0 | 2HRZE+4HR | 348 | 42 (28-55) | 251 (72.7) | 0 |
| Sanni et al23, 2021 | Benin | 517 | 2HRZE+4HR | 15 | 8 | R15:259 | 36.5+/-10.1 | 146 (56.6) | 100 | 2HRZE+4HR | 258 | 35.9+/-9.7 | 141 (54.4) | 259 (100) |
| Jindani et al22, 2023 | Multi country | 672 | 2HRZE/2HR |
23 34 |
16 |
R23- 223 R34- 225 |
29 (22-36) 28 (23-43 |
151 146 |
0 | 2HRZE+4HR | 224 | 29 (23-38) | 137 | 0 |
| Bhavani et al14, 2024 | India | 323 | 2HRZE+4HRE |
25 35 |
8 | R25:112 R35:106 |
33.5 35.5 |
82 75 |
0 | 2HRZE+4HRE | 105 | 35.9 | 76 (69.7) | 0 |
Outcome measures
Four studies11,14,25,26 used both solid cultures using Lowenstein–Jensen (LJ) medium and liquid cultures using Mycobacteria Growth Indicator Tube (MGIT), whereas three12,13,24 used MGIT. Jindani et al22 used Lowenstein–Jensen and Ogawa culture. Sanni et al23 did not specify the culture method used to evaluate the sputum conversion.
Regarding adverse events reporting, five studies13,14,22,23,26 used the Division of AIDS (DAIDS)for grading the adverse events27 while two studies11,25 referred to Common Terminology Criteria for Adverse Events (CTCAE)28. Velasquez et al12 used the Division of Microbiology and Infectious Diseases adult toxicity table by the National Institute of Allergy and Infectious Diseases29. Maug et al24 also graded based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for human use (ICH) guidelines for good clinical practice30.
Assessment of risk of bias
Figure 2 illustrates the methodological quality assessment of the included studies. The risk of bias was assessed as low across all domains for five of the nine studies. The other four studies presented an unclear risk of bias in selective reporting, as we were uncertain whether the analyses followed a pre-specified analysis plan. Nevertheless, the overall risk of bias for all the included studies was assessed as low.
- Risk of bias summary.
Findings
Sputum conversion
We included nine studies for the meta-analysis of sputum conversion at eight wk. High dose rifampicin group had better sputum culture conversion (83.6%) compared to the control group (77.8%) with a pooled relative risk (RR) of 1.05 (95% CI: 1-1.09; P=0.03; moderate certainty of evidence) (Fig. 3A; Table II). We observed a moderate heterogeneity with I2 of 52 per cent (P=0.04). We estimated a number needed to treat (NNT) of 24 for sputum conversion with high-dose rifampicin (Table III). We estimated a comparable pooled RR of 1.07 (95% CI: 1.02-1.14, P=0.01; NNT=17) and 1.12 (95% CI: 1.04-1.20, P=0.002; NNT=9) for dosages of 20-30 mg/kg and >30 mg/kg of rifampicin, respectively (Supplementary Fig. 1A-C). However, a dosage of less than 20 mg/kg of rifampicin did not show any significant difference (RR0.96; 95% CI: 0.91-1.02, P=0.21; NNT=30) (Supplementary Fig. 1A).
| Outcome | Patients (studies), N |
Relative effect (95% CI) |
Absolute effects (95% CI) | NNT/NNH | Difference* | Certainty of evidence | ||
|---|---|---|---|---|---|---|---|---|
| Standard dose | High dose rifampicin (overall) | Difference* | ||||||
| Sputum conversion at 8 weeks |
2594 (8 RCTs) |
RR=1.05 (1.00 to 1.09) |
78 per 100 |
82 per 100 (84 to 91) |
4 more per 100 (from 0 fewer to 7 more) |
24 |
4.2% more (0 fewer to 7.5 more) |
⨁⨁⨁◯ Moderate |
| Grade 3 & Grade 4 toxicity |
2577 (8 RCTs) |
RR=1.17 (0.87 to 1.57) |
6 per 100 |
7 per 100 (5 to 10) |
1 more per 100 (from 1 fewer to 3 more) |
66 |
1.0% more (0.8 fewer to 3.5 more) |
⨁⨁◯◯ Low |
| Mortality |
2902 (8 RCTs) |
RR=0.83 (0.55 to 1.26) |
4 per 100 |
3 per 100 (2 to 4) |
1 fewer per 100 (from 2 fewer to 1 more) |
125 |
0.6% fewer (1.6 fewer to 0.9 more) |
⨁⨁◯◯ Low |
| Treatment failure |
2334 (6 RCTs) |
RR=0.78 (0.46 to 1.32) |
3 per 100 |
2 per 100 (0 to 1) |
1 fewer per 100 (from 1 fewer to 1 fewer) |
142 |
0.1% fewer (0.3 fewer to 0.2 more) |
⨁⨁◯◯ Low |
| Treatment discontinuation |
1612 (6 RCTs) |
RR=2.01 (1.90 to 3.40) |
3 per 100 |
5 per 100 (5 to 9) |
3 more per 100 (from 2 more to 6 more) |
33 |
2.7% more (2.4 more to 6.3 more) |
⨁⨁⨁⨁ High |
CI, confidence interval; RR, risk ratio; NNT, number needed to treat; NNH, number needed to harm; RCT, randomised controlled trials
| Outcome | High dose rifampicin (<20 mg/kg) | High dose rifampicin (20-30 mg/kg) | High dose rifampicin (>30 mg/kg) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Participants (studies) | Relative effect (95% CI) | NNT/NNH | Participants (studies) | Relative effect (95% CI) | NNT/NNH | Participants (studies) | Relative risk (95% CI) | NNT/NNH | |
| Sputum conversion at 8 wk | 916 (4 RCTs) | RR=0.96 (0.91 to 1.02) | 30 | 1027 (6 RCTs) | RR=1.07 (1.02 to 1.14) | 17 | 747 (3 RCTs) | RR=1.12 (1.04 to 1.20) | 9 |
| Grade 3 & Grade 4 toxicity | 420 (3 RCTs) | RR=0.91 (0.54 to 1.55) | 100 | 1850 (7 RCTs) | RR=0.96 (0.69 to 1.34) | 500 | 846 (3 RCTs) | RR=3.11 (1.68 to 5.75) | 15 |
| Mortality | 817 (3 RCTs) | RR=0.95 (0.55 to 1.66) | 500 | 1718 (6 RCTs) | RR=0.81 (0.43 to 1.51) | 200 | 846 (3 RCTs) | RR=0.72 (0.26 to 1.99) | 200 |
| Treatment failure | 637 (2 RCTs) | RR=0.70 (0.27 to 1.81) | 111 | 1465 (5 RCTs) | RR=0.78 (0.40 to 1.52) | 166 | 584 (2 RCTs) | RR=0.54 (0.15 to 1.95) | 91 |
| Treatment discontinuation | 320 (2 RCTs) | RR=1.35 (0.59 to 3.09) | 53 | 974 (5 RCTs) | RR=1.48 (0.78 to 2.81) | 71 | 770 (3 RCTs) | RR=4.01 (1.75 to 9.19) | 20 |
- Forest plot analysis of (A) High dose rifampicin vs. standard dose: sputum conversion at eight wk. (B) High dose rifampicin vs. standard dose: grade 3 and 4 hepatotoxicity. (C) High dose vs. standard dose: mortality.
Grade 3 and 4 hepatotoxicity
High dose rifampicin group had a higher incidence of grade 3 or 4 hepatoxicity (7.6% vs. 6.1%) compared to the standard dose (RR1.17; 95% CI: 0.87-1.57; low certainty of evidence) with no statistically significant difference (P=0.3; Fig. 3B). The Number needed to harm (NNH) was 66. We observed a dose-dependent relationship on the hepatotoxicity as the pooled RR was higher as the dose increased from <20 mg/kg (RR0.9; 95% CI: 0.54 -1.55, P=0.74; NNH=100) to >30 mg/kg (RR3.11; 95% CI: 1.68-5.75, P=0.0003; NNH=15) (Supplementary Fig. 2A-C).
Mortality
Eight studies reported mortality as an outcome, and the pooled RR was not statistically significantly different between the two arms (RR0.83; 95% CI: 0.55 -1.26, P=0.38; NNH=125; low certainty of evidence; Fig. 3C). Similar results were observed even in the subgroup analysis across different doses of rifampicin. High dose rifampicin was not found to be beneficial in reducing the mortality even at the doses of 20-30 mg/kg (RR 0.81; 95% CI: 0.43-1.51, NNH=200) and more than 30 mg/kg (RR 0.72;95% CI: 0.26-1.99, NNT=200; Supplementary Fig. 3A-C).
Treatment failure
Of the 1348 participants in the high dose rifampicin group, 24 (1.78%) had treatment failure, while 25 of the 986 (2.5%) in the standard dose group with no significant difference (RR0.76; 95% CI: 0.46-1.32, P=0.35; NNH=142; low certainty of evidence; Fig. 4A). The subgroup analysis of different doses of high dose rifampicin revealed no beneficial effect. (<20 mg/kg, RR 0.7; 95% CI: 0.27- 1.8, NNH=111; 20-30 mg/kg, RR 0.78; 95% CI: 0.40 -1.52, NNH=166 ;>30 mg/kg, RR 0.54; 95% CI: 0.15 -1.95, NNH=91; Supplementary Fig. 4A-C).
- Forest plot analysis of (A) High dose rifampicin vs. standard dose: Treatment failure. (B) High dose rifampicin vs. standard dose: ADR leading to discontinuation of the treatment.
ADR leading to discontinuation of treatment
The incidence of ADR leading to treatment discontinuation was higher among the participants who received high-dose rifampicin (5.5% vs. 2.6%) and the pooled RR was significantly greater (RR: 2.01; 95% CI:1.19-3.4, P=0.009; NNH=33; high certainty of evidence; Fig. 4B). The pooled risk RR increased for treatment discontinuation as the dose of the rifampicin increased (<20 mg/kg, RR 1.35; 95% CI: 0.59-3.09, NNH=53; 20-30 mg/kg, RR 1.48; 95%CI: 0.78-2.81, NNH=71; >30mg/kg, RR 4.01; 95% CI: 1.75-9.19, NNH=20). We also observed a similar phenomenon in grade 3 and 4 hepatotoxicity (Supplementary Fig. 5 A-C).
Publication bias
We did not detect publication bias for all the outcomes, and funnel plots are shown in supplementary figure 6 A-E.
Discussion
Early sputum conversion is a valuable tool widely used as a surrogate marker for treatment response and those who are at risk for relapse in pulmonary TB. Rifamycins are crucial drugs in the anti-TB regimen, which sterilise the lesions and aid in recurrence-free cure. Although most of our included studies did not assess relapse or recurrence after treatment, the ability of high-dose rifampicin to achieve early sputum conversion and eliminate the persistent bacteria that cause relapse could potentially lead to recurrence-free survival31-33. Early bacterial clearance is also of public health importance as this could potentially reduce disease transmission in the community. Of the nine included studies, five showed a significant sputum conversion rate with high-dose rifampicin11,13,14,22,26,27.These five studies used rifampicin doses ranging from 20 to 35 mg/kg. We also observed that the studies, which used lower doses of rifampicin (15 to 21 mg/kg) did not show significant benefit with sputum conversion individually as well as in the meta-analysis (RR 0.96; 95% CI:0.91-1.02)12,23,25. Pharmacokinetic studies have shown that patients treated with higher doses of rifampicin achieve adequate serum drug concentrations, which is vital for early bacterial clearance, and the therapeutic concentration in those who receive less than 20 mg probably did not result in sputum culture conversion12,34. We found high-dose rifampicin efficacious, leading to a higher sputum conversion rate at eight wk. Our findings corroborate with a systematic review done by Onorato et al17, which showed an increased sputum conversion rate (83.7% vs. 80.6%) among the participants in the high-dose rifampicin arm (RR 1.06) from five included studies17. The authors reported that the sputum conversion was better in participants receiving less than 20 mg/kg17. However, we estimated a significant benefit in the higher doses above 30 mg/kg (RR 1.12; 95% CI: 1.04 - 1.2), followed by the 20-30 mg/kg group (RR 1.07; 95% CI: 1.02-1.14).
Though high-dose rifampicin had a significant efficacy in increasing sputum conversion rate, it was not effective in reducing the treatment failure (RR 0.78; 95% CI: 0.46 -1.32). While six studies contributed to this outcome, only one study, which used 20 mg/kg of rifampicin, showed significant benefit with high-dose rifampicin (RR 1.48; 95 CI: 0.61 to 3.58)24. One of the major concerns regarding increasing the dose of rifampicin and rolling it out in the TB programme is that rifampicin causes drug-induced liver injury (DILI). Our analyses suggest that there was a dose-dependent relationship for the hepatotoxicity grades 3 and 4 and adverse drug reactions resulting in the discontinuation of the treatment. It should be noted that the hepatotoxicity was not very significant in the group receiving less than 20 mg/kg or 20 to 30 mg/kg. In addition, we also observed that the pooled RR was not significant even in these doses for ADR leading to treatment discontinuation. Onorato et al17 did not observe a dose-dependent relationship17. However, the authors reported significant hepatoxicity even in the arm that received a low dose (<20 mg/kg) of rifampicin (RR 1.19; 95% CI: 0.59 to 2.39). While Onorato et al17 included four studies contributing to the assessment of hepatoxicity in <20 mg/kg arm, we included only three trials with 817 participants. A systematic review16, which informed the WHO recommendation, showed that higher doses of rifampicin up to 20 mg/kg may not increase incidences of DILI, thrombocytopenia, or hypersensitivity syndromes, and the evidence on the safety of doses at 30 mg/kg and 35 mg/kg is uncertain16.
We observed no mortality benefit with high-dose rifampicin (RR 0.83; 95% CI: 0.55- 1.26) between the two arms (2.6% vs. 3.5%). A previous systematic review also showed no difference between the two arms in reducing mortality in pulmonary TB17. However, high-dose rifampicin has been beneficial in reducing mortality in TB meningitis (TBM), as shown in several trials35,36. Haigh and colleagues’ systematic review which informed the WHO guidelines included trials on pulmonary TB and TBM and concluded that high dose rifampicin at a dose of 15 mg/kg (RR0.80; 95% CI: 0.47 - 1.37), or 20/mg (RR 0.93; 95% CI: 0.47 -1.81) probably reduces all-cause mortality slightly16.These findings are similar to ours, although we included clinical trials conducted only among patients with pulmonary TB. A model-based study suggested that a high dose of rifampicin exposure substantially reduced death among 144 patients with TBM37. Our findings substantiate the evidence currently available in the literature that the role of high-dose rifampicin in reducing mortality in pulmonary TB is still unclear.
Heterogeneity was limited in our analyses. Meta-analysis of two outcomes (sputum conversion and hepatotoxicity) had moderate heterogeneity, while all other analyses showed no or low heterogeneity. The possible reason for the heterogeneity in sputum conversion could be variation among the study population. Five studies included PLHIV, of which two included exclusively the PLHIV population. One of these two studies did not show a beneficial effect, as HIV infection is known to be associated with longer duration of sputum conversion compared to HIV negative individuals38,39. In addition, only three studies used the MGIT culture method, while four used the solid culture method. The sensitivity of MGIT is significantly higher than that of LJ culture, which could be one reason for the heterogeneity between the studies40. Regarding hepatotoxicity, the studies in our review used various criteria for grading the assessments. However, the variations between these criteria were minor, and most studies used DAIDS grading. Most of the studies used a flat dose of rifampicin irrespective of the patient’s weight. We calculated the dose for each study using the median weight of the participants. However, Kannabiran et al14 used a weight-based high-dose rifampicin. This could have resulted in the heterogeneity between the studies. It is also important to note that five of the included studies were conducted among participants from African countries. The tolerability of rifampicin could also vary between different ethnic groups41.
This systematic review has several strengths, with well-defined PICO and a large number of participants contributing to the meta-analysis for the primary (2594 participants) and secondary outcomes. The outcomes were based on objective assessments with low possibilities for bias. The majority of the included studies were methodologically robust, well-conducted trials and had a low risk of bias in RoB-2. The primary author was not involved in assessing methodological quality, as one of her studies was included in this review. We also had a few limitations. Of the nine included studies, only six reported treatment failure and ADR leading to discontinuation of the treatment. Five studies with a very small number of PLHIV were included in our meta-analysis. Hence, the applicability of these findings to the PLHIV is uncertain.
Overall, high doses of rifampicin (>15 mg/kg) increased the rate of sputum culture conversion after two months of the intensive phase. In the subgroup analysis, the 20-30 mg/kg dose showed a beneficial effect in sputum conversion with no significant risk of hepatotoxicity and ADR leading to treatment discontinuation. High-dose rifampicin of >30 mg/kg was found to have a considerable incidence of grade 3 and 4 hepatotoxicity and an increased incidence of ADR, leading to treatment discontinuation events with a dose-dependent relationship. There was no difference in mortality and treatment failure between high-dose rifampicin and standard arms. In conclusion, a 20-30 mg/kg dose of rifampicin may benefit the patients by providing faster sputum conversion and relapse-free survival, and this could be administered with close monitoring of adverse events and hepatotoxicity. Future trials should focus on evaluating recurrence and relapse after the completion of the treatment.
Acknowledgment
Authors acknowledge and thank Dr Rajiv Bahl, Director General, Indian Council of Medical Research & Secretary, Department of Health Research for his inputs and critical comments on the analysis and interpretation of the findings. Authors also acknowledge Dr Manoj Murhekar, Director (Addl. Charge), ICMR- National Institute for Research in Tuberculosis, Chennai for his guidance and support. We are thankful to Dr Nivedita Gupta, Head, Communicable Diseases, ICMR Headquarters for inputs and suggestions on this review.
Financial support & sponsorship
None.
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
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