Rifapentine 150mg tablets

ObjectivesHigh-dose rifamycin (HDR) regimens have demonstrated significant potential in tuberculosis (TB) treatment. This study aims to evaluate the efficacy and safety profile of different HDR regimens.DesignUsing a systematic review and Bayesian network meta-analysis (NMA).Data sourcesPubMed, Web of Science, Cochrane Library and Embase were searched up to 2 November 2024.Eligibility criteria for selecting studiesRandomised controlled trials that compared the efficacy and safety of HDR regimens (rifampin 15-30 mg/kg/day and rifapentine 7.5-20 mg/kg/day) to standard-dose rifampin in patients with pulmonary drug-susceptible TB were included.Data extraction and synthesisThe risk of bias was assessed using Cochrane tools. We conducted NMA with GEMTC in R. The simulation was performed using the Markov Chain Monte Carlo technique set on four parallel chains, with 20 000 burn-in iterations, 50 000 inference iterations and a thinning factor of n=2.5. To check for model convergence, Gelman and Rubin diagnostic plots and density plots were applied. We assessed heterogeneity using the I² test, evaluated transitivity by comparing effect modifiers across studies and examined consistency via node-splitting analysis. The confidence in network meta-analysis online tool and Cochrane Risk of Bias 2.0 Tool were used to assess evidence certainty and risk of bias, respectively. Higher surface area under the cumulative rank curve scores indicated a higher probability of top-ranking treatments.ResultsOut of 15 766 citations screened, 15 randomised controlled trials were included, encompassing 6456 subjects. The risk of bias was low in 14 studies, with some concerns in one. Patients receiving rifapentine 20 mg/kg/day (risk ratio, 1.09; 95% credible interval, 1.03 to 1.17) had higher culture conversion rates at 8 weeks in solid culture compared with the control. There was no significant difference in primary efficacy within all HDR regimens. Rifapentine 20 mg/kg/day was ranked as the most effective intervention for primary efficacy. No statistical difference in the incidence of serious adverse events was found between all regimens.ConclusionsRifapentine 20 mg/kg/day may be the most effective for achieving the strongest anti-TB activity. All HDR regimens demonstrated good safety.Prospero registration numberCRD42024504575.

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BackgroundGlobally, multiple TB preventive treatment (TPT) regimens are available for Latent Tuberculosis Infection (LTBI) and implementing TPT is essential for achieving TB elimination. Standard treatments for LTBI include 9 and 6-month isoniazid monotherapy (9H and 6H) regimens, recent clinical trials also introduced the shorter once-weekly 3-month isoniazid plus rifapentine (3HP) regimen. To evaluate the clinical effectiveness of 3HP in adults, we performed a comprehensive synthesis on the clinical effectiveness (treatment completion, adverse drug reactions (ADRs) and exploratory analysis of incident active TB) of the 3HP regimen compared with 9H and 6H.MethodsA systematic search was carried out in PubMed, EMBASE, ScienceDirect, and Cochrane Library. An excel data collection tool was used for collecting the required data. Pooled estimates of effectiveness were calculated through random-effects meta-analysis model using odds ratio (OR) and risk ratio (RR) as summary measures. Risk of bias was assessed using the RoB 2.0 and ROBINS-I tools, and publication bias was evaluated. The certainty of the evidence was assessed using the GRADE approach.ResultsTwenty studies met eligibility criteria, of which 5 were trials and 15 were observational studies. Meta-analysis showed that participants receiving the 3HP regimen were nearly three times more likely to complete treatment compared to 9H regimen (OR = 2.81; 95% CI: 2.05-3.86; low certainty) and the OR was 2.91 compared to 6H regimen. The risk of ADRs was 1% higher with 3HP when compared to 9H (RR = 1.01; 95% CI: 0.76-1.33; very low certainty). The pooled RR of adverse events, such as grade 1-2, grade 3-4, grade 5 and hepatotoxicity were 1.38 (95% CI: 0.73-2.59; I2 = 75.9%), 1.19 (95% CI: 0.78-1.82; I2 = 16.6%), 0.77 (95% CI: 0.49-1.22; I2 = 0%) and 0.26 (95% CI: 0.18-0.38; I2 = 17.7%) respectively. Exploratory analysis suggested a lower incidence of active TB with 3HP compared to 9H; however, the difference was not statistically significant (RR = 0.47; 95% CI: 0.16-1.38; moderate certainty).ConclusionThe shorter 3HP regimen is associated with higher treatment completion and lower hepatotoxicity compared to 9H, with evidence on progression to active TB remains exploratory and imprecise. Limited evidence on 6H showed improved treatment completion with 3HP. These findings should be interpreted cautiously as most evidence was derived from heterogeneous observational studies, and the certainty of evidence for main outcomes was low to very low.Clinical trial numberNot applicable.

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Abstract Background A multicountry randomized controlled trial has demonstrated that pan-susceptible pulmonary tuberculosis (TB) can be successfully treated with a 4-month regimen of daily isoniazid, rifapentine, moxifloxacin, and pyrazinamide (HPMZ). We piloted HPMZ in San Francisco (SF) using a modified version of the US Centers for Disease Control and Prevention HPMZ treatment guidelines. Methods In this retrospective cohort, patients consecutively referred to SF TB clinic were evaluated for HPMZ eligibility based on preestablished inclusion/exclusion criteria. All underwent evaluation and management according to national recommendations. We reviewed the medical records of those initiated on HPMZ. Results From August 2021 to December 2023, 30 (18.8%) of 160 patients diagnosed with active TB met HPMZ inclusion criteria; of these, 22 (13.8%) started HPMZ. The median age (range) was 32.5 (14–86) years, 17 (77.3%) were otherwise healthy, and 19 (86.4%) had pulmonary TB, including 7 (36.8%) with cavitary disease. Eighteen (81.8%) patients had an adverse event, with 11 (50%) prematurely discontinuing HPMZ; the most common adverse events were vomiting, elevated transaminases, and rash. To date, 9 (40.9%) have completed treatment, with most achieving criteria for cure. One patient was diagnosed with possible TB recurrence and restarted standard TB treatment. Conclusions Our experience, with half of patients to date prematurely discontinuing HPMZ, illustrates the challenge of extrapolating findings from TB clinical trials commonly conducted in high-incidence, non-US settings to US clinical practice. Further experience may help identify best practices for implementing HPMZ, including identifying predictors of which patients may be most likely to benefit from and tolerate this regimen.

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BackgroundBased on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis.MethodsClo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine-isoniazid-pyrazinamide-ethambutol-clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine-isoniazid-pyrazinamide-clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid-rifampicin-pyrazinamide-ethambutol followed by 18 weeks of rifampicin-isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502.Findings104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82-1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14-45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37-69) in group 1 versus 27% (14-50) in group 2 (p=0·049).InterpretationAlthough the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events.FundingUS National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

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BackgroundTreatment of tuberculosis infection (TBI) is a key pillar of the WHO End TB Strategy. Two short-course rifamycin-based regimens-weekly isoniazid plus rifapentine for 12 weeks (3HP) and daily rifampicin for 16 weeks (4RIF)-are widely recommended; however, they have not previously been directly compared in a randomised controlled trial. We compared treatment completion between 3HP and 4RIF among individuals with TBI.MethodsWe conducted a multicentre, open-label, parallel-group randomised controlled trial across seven tuberculosis clinics in Sydney, Australia, between July 2019 and June 2024. Participants of any age with TBI were randomised 1:1, stratified by site, to receive either weekly 3HP or daily 4RIF. All doses were self-administered. Participants in the 3HP group received weekly SMS adherence reminders; both groups received standard clinic follow-up. The primary outcome was treatment completion, defined as ingestion of ≥90% of prescribed doses. Analyses were conducted on an intention-to-treat basis.ResultsA total of 210 participants were enrolled (106 assigned to 3HP and 104 to 4RIF). Treatment completion was significantly higher in the 3HP group (84.9%) compared with the 4RIF group (65.4%; relative risk 1.30, 95% CI 1.22-1.38; pConclusionWeekly 3HP supported by SMS reminders achieved significantly higher treatment completion than daily 4RIF, with similar safety. These findings support broader implementation of 3HP to optimise adherence and outcomes in TBI programs.

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BackgroundTuberculosis preventive therapy coverage for people with advanced HIV disease (AHD) is poor. Innovative delivery strategies to increase tuberculosis preventive therapy uptake are needed; we sought to evaluate the safety and feasibility of two strategies for ultra-short course tuberculosis preventive therapy with 1 month of daily rifapentine plus isoniazid (1HP).MethodsIn this phase-3, open-label, non-inferiority, randomised controlled strategy trial (ISRCTN 18437550), we recruited consecutive adults (aged ≥18 years) admitted to hospital with AHD receiving treatment for cryptococcal meningitis who were screened for active tuberculosis during their hospitalisation from three tertiary referral hospitals in Uganda (Mulago National Specialised Hospital, Kiruddu National Referral Hospital in Kampala, and Mbarara Regional Referral Hospital). Adults without evidence of tuberculosis disease and meeting all eligibility criteria were approached for consent and inclusion. Patients were excluded if they had evidence of active hepatitis B infection, abnormal liver function tests, had known chronic liver disease, were jaundiced, were pregnant or breastfeeding, or presented with a clinical syndrome which, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. After providing informed consent, we randomly assigned participants (1:1) to inpatient initiation of 1HP before hospital discharge or outpatient initiation at 6 weeks after time of cryptococcal meningitis diagnosis. 1HP was standardised across treatment groups, a 28-day course of 600 mg rifapentine plus 300 mg isoniazid daily with adjunctive pyridoxine (25 mg per day). The 1HP regimen was not dose adjusted on the basis of weight. The primary endpoint was tuberculosis disease-free survival and 1HP treatment completion at 18 weeks, powered for a 15% non-inferiority margin; analysis was by intention to treat.FindingsFrom Jan 24, 2022, to Nov 13, 2024, 419 adults were screened after 210 were found ineligible and four died before random allocation, 205 were randomly allocated (171 in Kampala and 34 in Mbarara, Uganda): 103 to the inpatient group and 102 to the outpatient group. 119 participants (58%) were male and 86 (42%) were female. In the primary adjusted intention-to-treat analysis, 72 participants in the inpatient 1HP group (70%) had tuberculosis disease-free survival and 1HP treatment completion at 18 weeks compared with 63 (62%) in the outpatient 1HP group (adjusted risk difference 7·1%, 90% CI -3·8 to 17·9) confirming non-inferiority. Treatment completion was achieved in 78 (76%) of 103 in the inpatient 1HP group compared to 67 (66%) of 102 in the outpatient 1HP group (site-adjusted risk difference 9·7%, 95% CI -2·4 to 21·8). 170 grade 3 or 4 adverse events occurred in 99 (48%) of 205 participants. Among participants who had taken at least one dose of 1HP the frequency of adverse events across trial groups was similar apart from grade 4 anaemia, which occurred in a higher proportion of participants in the outpatient group (9% vs 2%, p=0·045).Interpretation1HP initiation before hospital discharge was non-inferior to outpatient initiation among adults with AHD and cryptococcosis. These data suggest that following exclusion of active tuberculosis disease, inpatient 1HP initiation is feasible and comparably safe compared with outpatient initiation.FundingThe Wellcome Trust, UK National Institute for Health and Care Research, US National Institutes of Health.

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