|Year : 2021 | Volume
| Issue : 3 | Page : 312-319
Safety and efficacy of high-dose rifampicin in the management of tuberculosis meningitis: Systematic review and meta-analysis
Loveness Charlie1, Solomon Mequante Abay2, Abraham Tesfaye1, Ronald Nachipo Mlera3, Samuel Mwango4, Mary Goretti5
1 Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
2 Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia
3 Department of Professional Practice and Conduct, Nurses and Midwives Council of Malawi, Lilongwe, Malawi, South Africa
4 Center of Excellence for Nutrition, North West University, Potchefstroom Campus, Potchefstroom, South Africa
5 Department of Clinical Pharmacy, Soroti Regional Referral Hospital, Soroti, Uganda
|Date of Submission||26-Jun-2021|
|Date of Acceptance||24-Jul-2021|
|Date of Web Publication||03-Sep-2021|
Centre for Innovative Drug Development and Therapeutic Trials for Africa, College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa
Source of Support: None, Conflict of Interest: None
Background: Mycobacterium tuberculosis (TB) practically affects any part of the body, but when the brain is involved, the consequences are devastating. Tuberculous meningitis (TBM) is the most severe form of drug-susceptible TB, with an estimation of more than 100,000 new cases occurring every year and a high mortality rate globally. The treatment strategy is based on pulmonary TB (PTB) management regimens which consider rifampicin as the backbone. Optimal treatment regimens for PTB may not be the most effective option for TBM due to difference in TB drug penetration across the blood–cerebrospinal fluid barrier, hence the need for other treatment options. This study aims to review the efficacy and safety of higher doses of rifampicin (>10 mg/kg) compared to 10 mg/kg rifampicin as part of standard therapy for the treatment of TBM. Methods: A systematic review and meta-analysis was conducted to assess the efficacy and safety of high-dose rifampicin for TBM. A search was done on PubMed, Google Scholar, and Cochrane library databases without publication date limit to identify studies providing data on the use of high-dose rifampicin for the treatment of TBM. Titles and abstracts were screened for relevance by three reviewers. Two reviewers used a predefined checklist on the inclusion criteria to assess full text for their eligibility in the review. A heterogeneity test was conducted to assess the variations among study outcomes. The risk ratio (RR) with a 95% confidence interval (CI) was calculated as a measure of intervention effect. The study is registered on PROSPERO and the registration number is CRD42020212737. Results: Five Phase 2 trials with a total of 1028 participants were included in this meta-analysis. All the five trials were used to analyze safety data, which found that there was no significant increase in the risk of Grade 3–5 adverse events in high-dose rifampicin (RR = 1.05; 95% CI = 0.95–1.18). Only four of them were included for the analysis of efficacy. The findings indicated that exposure to high-dose rifampicin is not associated with a reduced risk of mortality (RR = 0.95; 95% CI = 0.78–1.16). Conclusions: It can be concluded from this meta-analysis that there is no significant relation of high-dose rifampicin with adverse events and the reduction of mortality in TBM patients. Whether in future optimized TBM treatment regimen will include high-dose rifampicin or not should be determined by a large-scale clinical trial.
Keywords: High-dose rifampicin or rifampin, intensified therapy, systematic review and meta-analysis, tuberculosis meningitis
|How to cite this article:|
Charlie L, Abay SM, Tesfaye A, Mlera RN, Mwango S, Goretti M. Safety and efficacy of high-dose rifampicin in the management of tuberculosis meningitis: Systematic review and meta-analysis. Int J Mycobacteriol 2021;10:312-9
|How to cite this URL:|
Charlie L, Abay SM, Tesfaye A, Mlera RN, Mwango S, Goretti M. Safety and efficacy of high-dose rifampicin in the management of tuberculosis meningitis: Systematic review and meta-analysis. Int J Mycobacteriol [serial online] 2021 [cited 2022 Sep 27];10:312-9. Available from: https://www.ijmyco.org/text.asp?2021/10/3/312/325498
| Introduction|| |
Tuberculosis (TB) is the leading cause of morbidity and mortality worldwide with an estimated 10 million new cases and 1.4 million deaths in 2019. Mycobacterium tuberculosis practically affects any part of the body, but when the brain is involved, the consequences are devastating., Tuberculous meningitis (TBM) is the most severe form of drug-susceptible TB, with an estimation of more than 100,000 new cases occurring every year and a high mortality rate globally.,,
TBM treatment outcomes depend on early diagnosis and appropriate treatment although there is no high-quality evidence to provide guidance when choosing the treatment,, The treatment strategy is based on pulmonary TB (PTB) management regimens which consider rifampicin as the backbone.,,,, Currently, national TB programs are using weight-based World Health Organization (WHO) dosing guidelines that permit the use of rifampicin at 10 mg/kg for treating both pulmonary and TB meningitis even though the standard dose penetrates very poorly into the cerebrospinal fluid (CSF).,,, The choice of the currently recommended rifampicin dose (10 mg/kg) was not based on optimal efficacy but rather driven by cost – rifampicin was prohibitively expensive at the time of its introduction – and fear of toxic effects., Studies have shown that use of suboptimal rifampicin (10 mg/kg) has contributed to a long duration of therapy and poor treatment outcomes (death or/and neurological disability); 19%–28% of human immunodeficiency virus (HIV)-negative patients and 40%–58% of HIV-positive patients die during treatment and half of the survivors suffer neurologic disability.,,
The unique role of rifampicin is the ability to kill two populations of M. tuberculosis: those undergoing rapid metabolism and those in a dormant state but undergoing metabolism for limited periods. The bactericidal and sterilizing effect of rifampicin can be enhanced by increased doses, resulting in significant treatment shortening., A Phase II study suggests that high-dose rifampicin administered intravenously or orally enhances central nervous system penetration and may reduce TBM-associated mortality. A model-based analysis demonstrates that higher rifampicin concentration could significantly increase the bactericidal activity during the first treatment week.,
Due to variable TB drug penetration across the blood–brain barrier and blood–CSF barrier, the optimal treatment regimens for PTB may not be the most effective option for TBM. Improved early treatment outcomes may be achieved by altering drug selection, drug doses, and routes of administration as an effective way of reducing death and disability among TBM patients., Therefore, this study aimed to look at the efficacy and safety of high-dose rifampicin to reduce TBM complications and deaths.
| Methods|| |
The inclusion criteria were determined by the Population, Intervention, Comparator, Outcomes, and Setting as follows:
- The systematic review considered all randomized controlled trials (RCTs) which included bacteriologically and clinically diagnosed TBM patients (adults and children).
- High-dose rifampicin >10 mg/kg with a maximum dose of 50 mg/kg.
- Standard dose rifampicin 10 mg/kg or 600 mg.
- Efficacy and safety.
- Articles written in English without limitation to publication date were also considered.
- Nonneurological studies
- Trials that involve drug administration of fewer than 5 days a week (intermittent) were excluded as these were considered inadequate.
Efficacy was defined as the final treatment outcome/response. Mortality was used to assess efficacy in all the studies. Safety and tolerability end points were classified as severe and mild-to-moderate adverse events based on WHO grading of 1–5, where 1–2 were mild-to-moderate adverse events and 3–5 were severe adverse events – including death. Serious adverse events were defined as any adverse reaction that brought about temporary or permanent discontinuation of high-dose rifampicin, whereas a mild-to-moderate adverse event required only dose adjustment and/or addition of concomitant treatment or just observation.
Search strategy and selection criteria
Data were extracted from PubMed, Google Scholar, and Cochrane's central library electronic databases using the search terms “rifampin” OR “rifampicin” and high dose and TB meningitis. Search terms used and their synonyms were identified using the Medical Subject Headings on PubMed (https://www.ncbi.nlm.nih.gov/pmc): “rifampicin”(MeSH Major Topic) AND (“high”[all fields] AND “dose”[all fields]) AND (“tuberculosis, meningeal”[MeSH Terms] OR (“tuberculosis”[all fields] AND “meningeal”[all fields]) OR “meningeal tuberculosis”[all fields] OR (“TB”[ALL FIELDS] AND “meningitis”[all fields]) OR “TB meningitis”[all fields]).
Without a limitation of the publication date, three investigators independently searched the literature and examined relevant studies for assessment of data on the efficacy and safety of high-dose rifampicin in the treatment of TBM. Reference checking of all the included articles and related systematic reviews and any key papers on Google Scholar was also carried out to identify additional eligible articles. Furthermore, relevant articles were hand-searched from key journals and websites such as https://www.who.int/new-room/fact-sheets/tuberculosis; https://clinicaltrials.gov; American Thoracic Society journals; Infectious Diseases Society of America; https://wellcomeopenresearch.org/ and Web of Science.
The Joanna Briggs Institute critical appraisal checklist for RCTs was used to critically appraise the included studies. The appraisal used a checklist containing items such as randomization of participants; allocation concealment; similarity of treatment arms at baseline; blinding of participants, investigators and outcome assessors; and identical treatment of participants, just to mention a few. A Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flow diagram was used to report the results of all the retrieved studies. The citation manager Zotero v5.0. was used to create a library for this review (https://www.zotero.org).
Titles and abstracts were screened for relevance by three reviewers. Two reviewers used a predefined checklist on the inclusion criteria to assess full text for their eligibility in the review. Any disagreements were discussed and resolved among the reviewers. Both authors independently reported the reasons for the exclusion of any study. Thereafter, the researchers evaluated as full texts the articles previously selected to evaluate them for inclusion.
Data were extracted independently by three investigators (Loveness Charlie, Ronald Mlera, and Samuel Mwango) using a predefined checklist on the inclusion criteria, and differences were resolved by discussion with the third and fourth investigators (Solomon Abbay and Abraham Tesfaye). The reviewers extracted basic study information that included: the first author, publication year and type (full text or abstract), a country in which the study was conducted, title of the article, study design, type of participants (adults or children), sample size, study duration, and participants' HIV status. For the evaluation of efficacy and safety of high-dose rifampicin, the following variables were collected: duration of exposure to high-dose rifampicin, the dosage and route of rifampicin, the final treatment outcome, and adverse events (Grade 1–5). Supplementary data on pharmacokinetics (PK) were also collected.
Assessment of risk of bias in the included articles
Cochrane Collaboration's tool was used for evaluating bias to assess study quality in all the articles that fulfilled the inclusion criteria. The evaluation was conducted independently by two reviewers using the following domains: random sequence generation, randomization, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other possible sources of bias. Any disagreement in the study evaluation was discussed between the reviewers and a third opinion was considered in case of no agreement between the reviewers [Figure 1] and [Figure 2].
Assessment of heterogeneity
The Cochrane Q and I2 statistic was used to measure heterogeneity (the variation in the study outcomes between studies) among the trials. I2 was calculated using the following formula: I2 = 100% × (Q − df)/Q, where Q is Cochran's heterogeneity statistic and df is the degree of freedom. Negative values of I2 are put equal to zero so that I2 lies between 0% and 100%. Q is distributed as a Chi-square statistic with k (number of studies) minus 1 degree of freedom. Q was used in this review because it has low power as a comprehensive test of heterogeneity especially when the number of studies is small, that is, like in our case where only five RCTs were eligible for the meta-analyses. In each analysis, the Chi-square test with a P < 0.05 to indicate statistical significance was used. I2 values between 25% and 49% indicated low heterogeneity, whereas values between 50% and 75% and >75% denoted moderate and high heterogeneity, respectively.
Publication bias was not assessed as tests for funnel plot asymmetry could not be used when there are fewer than ten studies in the meta-analysis because the test power is usually too low to distinguish chance from real asymmetry.
A meta-analysis was performed with the Cochrane Collaboration Review Manager Software (RevMan-computer program. version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane collaboration). Risk ratio (RR) with 95% confidence interval (CI) was performed to evaluate the treatment outcome – mortality and adverse events. For all outcomes (death and side effects), a ratio less than unity indicates an outcome favoring the intervention. Results were considered statistically significant at P < 0.05. Heterogeneity was evaluated by the I2 test and because it was not significant (I2 < 50), the fixed-effects model was used. In pair-wise comparison studies with more than one arm, their results were emerged for easy comparison between the high dose and standard dose. However, if the events in both arms are 0, the RR was not assessed.
| Results|| |
The systematic review identified 56 studies published in the assessed databases. Of these, 43 were excluded for being not being eligible by their title and others were duplicates. Thirteen records were screened. Eight were further excluded for not meeting the eligibility criteria. The remaining seven were fully assessed, of which only five fit the criteria to be included in the systematic review and meta-analysis [Figure 3].
|Figure 3: Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram|
Click here to view
The systematic review included five RCTs with a total of 1028 (540 in high dose and 488 in standard dose) eligible participants.,,,, All the enrolled participants were bacteriologically and clinically diagnosed with TBM. For bacteriologically confirmed cases, CSF was analyzed using culture and GeneXpert platforms. Three trials were conducted in Indonesia, while the other two were from Vietnam and Uganda. The first study from Indonesia was on an intensified regimen containing rifampicin and moxifloxacin for TBM. It assessed the PK, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with TBM in a hospital setting. The study found that intensified treatment given for 2 weeks strongly increased drug exposure, did not increase drug-related adverse events, and improved the survival of patients. On the contrary, a study from Vietnam on intensified anti-TB therapy in adults with TBM focusing on high-dose rifampicin and levofloxacin found that intensified anti-TB treatment was not associated with a higher rate of survival than the rate with standard treatment.
Indonesia conducted another dose-finding study to evaluate high-dose rifampin for TBM. The study found that tripling the standard dose of oral rifampin for 1 month strongly increased the exposure to this pivotal TB drug in plasma and CSF; did not increase the incidence of Grade 3 and 4 adverse events; improved the attainment of previously determined exposure threshold values for lower mortality; and showed a trend for a lower 6-month mortality rate among patients with microbiologically proven (definite) TBM. Another study by Yunivita et al. evaluated the PK and safety/tolerability of higher oral and intravenous doses of rifampicin in adult TBM patients in Indonesia. This study showed that oral administration of 750-mg and 900-mg rifampicin (ca. 17 and 20 mg/kg) daily resulted in geometric mean AUC0–24 values in plasma that are approximately comparable with the geometric mean exposure achieved after 600 mg (ca. 13 mg/kg) rifampicin intravenous (i.v.) during the first days of TBM treatment. Oral and i.v. geometric mean AUC0–24 values differed by no more than 15%.
Because HIV is central to the incidence of TBM in the sub-Saharan Africa, another trial on high-dose oral and intravenous rifampicin for the treatment of TBM has been conducted in Uganda. The majority of the participants (92%) in this study were HIV-positive adults, under half were on antiretroviral therapy, none were virologically suppressed, and the median CD4 count was 50 cells/μL.
All the trials recruited adult patients diagnosed with TBM. Two studies recruited TBM patients of >14 years with an interquartile range (IQR) of 28 (16–64), and another study recruited patients of ≥17 years with an IQR of 33 (17–81) The study from Vietnam had patients of ≥29 years with an IQR of 35 (29–46). Cresswell et al., 2021, in their three-arm trial (i.v. 20 mg/kg, p.o. 35 mg/kg and control arm) included participants with the following age: median (IQR) years 33.5 (25.5–38.5), 32.5 (26.5–38.5), and 34.0 (27–36).
In total, the studies had 657 male and 371 female participants. All the studies reported the HIV status of the recruited participants where out of the 1028 participants, 43.2% were HIV positive. Microbiological examinations were performed for cryptococci in HIV-infected patients.
Regarding disease severity, TBM grading was done using the Glasgow Coma Scale (GCS) where a majority of patients were in Grade 2 counting (525 of 1028) and for Grades 1 and 3, there were 333 and 172, respectively. Characteristics of included studies have been summarized in [Table 1] below.
Risk of bias in the included studies
[Figure 1] and [Figure 4] summarize the risk of bias assessments.
Randomization sequence generation (selection bias)
All the included trials were judged to be low risk for selection bias because they adequately described random sequence generation.
Allocation (selection bias)
Three trials,, were judged to be low risk for selection bias because they adequately described allocation concealment. However, the other two trials, were judged to be unclear for selection bias because the studies did not describe the allocation concealment.
Blinding (performance bias and detection bias)
Two trials,, effectively blinded the participants and outcome assessors (laboratory staff and study physicians). The other three trials,, were open-label trials where participants and outcome assessors were not blinded, but no substantial performance or detection bias was established for them to be judged as high risk. Hence, these three trials were judged to be at low risk for performance and detection bias.
Incomplete outcome data (attrition bias)
All the five trials were judged to be of low risk for attrition bias as there was no evidence of incomplete data.
Selective reporting (reporting bias)
We found evidence of selective reporting in one trial where information of efficacy was not reported.
The overall judgment was “low risk” in all the studies.
Four trials,,, in their individual analysis indicated that high-dose rifampicin reduces mortality in TBM. However, one study demonstrated that results on mortality reduction were not significant. In this meta-analysis, only four trials with a total of 998 participants,,, out of the five included studies were analyzed, as one study did not report on this outcome. In all the studies, much emphasis was on mortality as a measure of treatment efficacy. Short-term mortality (death occurring within 6 months from admission date) was assessed and reported in all the studies. The fixed-effects model was used to calculate the overall RR with 95% CI, considering that no significant heterogeneity (I2 = 39%) was detected. The overall RR was 0.95 [95% CI = 0.78–1.16; [Figure 2]], suggesting that there is no significant difference in mortality when high-dose rifampicin is used to treat patients with TBM. A total of 300 deaths were observed in all the included studies – 150 each in high- and standard-dose rifampicin.
Three trials,, reported adverse events grading from 1 to 4, while two trials, emphasized only on serious adverse events (Grades 3–5). The pooled data on Grade 3–5 adverse events among all trials included in the review suggested that there is no significant difference in the risk of developing serious advents events between the high- and standard-dose rifampicin [RR = 1.05; 95% CI = 0.95–1.18; [Figure 5]]. Serious adverse events identified in the studies were hepatotoxicity – being the most common (RR = 0.98; CI = 0.75–1.29), seizures, and headache. One trial reported a high incidence of consciousness deterioration and other rifampicin-related adverse events with low frequencies were hypersensitivity and anemia.
There were various mild-to-moderate adverse events reported in these three Indonesian trials. Out of the many, the common mild-to-moderate (Grades 1–2) adverse events related to high-dose rifampicin reported in the 150 total participants, included Grade 1–2 hepatotoxicity in 24.7%; nausea in 20%; pruritus in 18%; vomiting in 15.3%; rash in 14.7%; anemia in 13.3%; abdominal discomfort in 10%; and thrombocytopenia in 5.3% of the patients. However, the overall RR = 1.16; CI = 0.89–1.49 indicated no difference associated with 1–2 adverse events between high and standard doses.
| Discussion|| |
This meta-analysis investigated the safety and efficacy outcomes from pooled data of studies which randomize patients to high and standard doses of rifampicin. It has shown no significant difference in mortality and adverse events when high-dose rifampicin is used in patients with TBM.
Regarding mortality, data from five Phase 2 TBM trials investigating intensified and high-dose rifampicin treatment,,,, observed no difference among treatment groups with a RR of 0.95; CI = 0.78–1.16. However, we should consider that only four studies, with a total of 998 patients, reported the outcome, which occurred in a limited number of subjects (15% each in both the high- and standard-dose groups). Similarly, Heemskerk et al. observed no significant effect on mortality when 15 mg/kg was compared to the standard 10 mg/kg dose, with others arguing that the lack of significant improvement was due to the rather limited impact on survival expected with such a modest dose increase (8% for a dose of 750 mg compared to 450 mg). With consideration that death is a relatively rare event during the 6 months of treatment for drug-susceptible PTB, Onorato et al. also found no difference among the treatment groups. Conversely, studies that were conducted in Indonesia demonstrated that higher rifampicin plasma exposure was associated with a lower mortality rate among 148 patients with TBM.,, These data are consistent with a study conducted in Africa where 35-mg/kg oral rifampin dose was associated with an increase in bactericidal activity and the same dose achieved a decrease in time to culture conversion in patients with PTB.
On safety, the pooled analysis showed no relationship between individual rifampicin exposures and adverse events [RR = 1.06; 95% CI = 0.95–1.19; [Figure 6]]. However, we observed high rates of liver-related adverse events (not significant) in those who received the high or standard doses of rifampicin. Similarly, studies in PTB demonstrated that 35–40 mg/kg rifampicin can be administered safely., Recent data from the PanACEA consortium suggest that rifampicin toxicity is largely idiosyncratic and exposure is not a driver of toxicity. This is reassuring given that people with advanced HIV are at increased risk of drug-related toxicity including cutaneous drug reactions, hypersensitivity, liver toxicity, and complications relating to polypharmacy and immune reconstitution., A meta-analysis of rifampicin PK data from 70 studies including 3477 participants confirmed that during the initial days of standard TB treatment, rifampicin total plasma exposure is reduced in People Living with HIV (PLHIV) (mean AUC0–24 was 37.2 h/mg/L in HIV-positive vs. 56.7 h/mg/L in HIV-negative adults, P = 0.003), though this difference diminished at steady state.
High-dose rifampicin may improve the outcomes of TBM – with a total of 30% deaths only in both treatment groups but the desired exposure and necessary dose are unknown. Previous analyses of the trials included in this review found improved survival with high rifampicin dose or exposure.,, Svensson RJ et al. in their meta-analysis evaluating different doses between 450 mg (~10 mg/kg) and 1800 mg (~40 mg/kg) for the probability of attaining early rifampicin exposures found that doses of at least 1350 mg (~30 mg/kg) are needed to give 50% of the maximal effect with high probability, while 1800 mg (~40 mg/kg) would be the recommended dose to achieve the higher target in 95% of patients with TBM.
Early diagnosis and treatment are also crucial aspects in reducing TBM-associated disability and mortality. In this study, a majority of patients were found with Grade 2 meningitis (quantified by GCS score). The severity of the disease may impact patient response to treatment, hence contributing to adverse events and high mortality. A trial also included in this meta-analysis revealed that due to the severely unwell nature of the trial population, Grade 3–5 AEs were experienced by over half (59%, 36/61) of the participants, but were largely complications of the underlying disease process, and events were evenly distributed across arms. This is consistent with the results in a meta-analysis done on treatment outcomes of TBM by Wang et al., 2019. The study found that the risk of death was significantly higher among patients diagnosed in Stage III (65.8%) than in Stage 1 (17.5%) or Stage II (28.5%). Moreover, co-infected patients with HIV were found to have higher mortality (64.8%) than HIV-negative patients (17.5%). However, it cannot be excluded that PK, the safety/tolerability, and the efficacy of high-dose rifampin are different in more severe Grade 3 TBM population.
There were a number of limitations to be considered in this analysis. First, data were combined from five separate studies with slightly different inclusion and exclusion criteria. All the five studies were conducted in developing countries, potentially limiting the global applicability of the results. The length of the high-dose rifampicin treatment varied between the studies (2 or 8 weeks). Furthermore, not all patients had confirmed TBM, and this proportion varied between studies. The route of administration was also different among the studies where others used i.v. rifampicin. Two studies combined high-dose rifampicin with levoflaxin and amoxicillin, disturbing the conclusion of high-dose rifampicin effect on TBM. Hence, the conclusion made from our study is with due consideration of the identified limitations.
Whether in future the optimized TBM treatment regimen will include high-dose rifampicin remains to be concluded. Our meta-analysis study recommends a large-scale trial where a conclusion will be made if an optimized dose of rifampicin can make a difference in reducing mortality among TBM patients. Furthermore, the study recommends trials to investigate the efficacy and tolerability of these higher doses of rifampicin on specific subpopulations, such as HIV-positive subjects and children.
| Conclusion|| |
The present meta-analysis demonstrated that among patients with TBM, a rifampicin dose up to 35 mg/kg is safe and tolerable. However, regarding efficacy, no differences in mortality were observed between high- and standard-dose groups.
Financial support and sponsorship
This study was financially supported by the World Bank through CDT Africa in a form of academic scholarship.
Conflicts of interest
There are no conflicts of interest.
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