Safety and Efficacy of High Dose Rifampicin in Tuberculosis (TB)-HIV Co-infected Patients on Efavirenz- or Dolutegravir-based Antiretroviral Therapy

• Status: Unknown status
• Trial end date: 2021-01-31
• Target enrollment: 0
• Participant gender: All

Summary

Higher doses of rifampicin has been associated with a faster drop in bacterial load over time, and shorter treatment regimens with high dose rifampicin are being proposed. Sub-therapeutic rifampicin concentrations are common in TB patients and have been demonstrated in several studies carried out among patients with tuberculosis receiving the standard dose (10mg/kg) of rifampicin. Insufficient exposure to isoniazid and rifampicin, which are the cornerstones of TB treatment, has been associated with drug resistance, treatment failure and delayed bacterial clearance from sputum. Evidence has indicated that the current dose of rifampicin (10mg/kg) is inadequate for many patients. Several studies have suggested that dose escalation (to 20-35mg/kg) is safe, and that higher doses (35mg/kg) may accelerate clearance of TB bacteria from the sputum of infected individuals and achievement of target concentrations.15,16 However, these studies have almost entirely been conducted among HIV negative TB patients, or TB-HIV co-infected patients without severe immunosuppression who are not yet receiving antiretroviral therapy (ART). TB-HIV co-infected patients on multiple additional drugs, including ART, are at increased risk of drug-drug interactions and drug related toxicities, including hepatotoxicity. Increasing the dose of rifampicin is a promising approach; however, there is paucity of data on the safety of higher doses of rifampicin in HIV infected patients on ART, and almost no information on the enzyme induction effect of high dose rifampicin on Efavirenz (EFV) and Dolutegravir (DTG). In this study, the investigators will not only evaluate for the enzyme induction effect of 35mg/kg of rifampicin on the most widely used first-line antiretrovirals, but will also look at the safety of these combinations in a population in which there is still scarce safety data. The aim of this study is to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz and dolutegravir in TB-HIV co-infected patients.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Makerere University
• Treatments: Anti-Retroviral Agents; Dolutegravir; Efavirenz; Rifampin

Criteria

Inclusion Criteria:

• Evidence of a personally signed and dated informed consent document.

• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

• Age of ≥18 years

• Confirmed HIV-1 infection

• Already started on EFV-based or DTG-based ART or planned to start on ART

• Diagnosed with tuberculosis and due to initiate rifampicin-containing therapy

Exclusion Criteria:

• Rifampicin resistant TB identified by baseline Xpert Mycobacterium Tuberculous (MTB)/ Rifampicin (RIF)

• Pregnant women or women planning to get pregnant during TB treatment

• Women of reproductive age on DTG who decline the use of effective contraception methods (in particular: intrauterine device or condoms)

• Decompensated liver disease and/or aminotransferases >5x upper limit of normal (ULN)

• Glomerular filtration rate < 50 ml/min