Abstract
The recommended 6-month treatment for drug-susceptible tuberculosis (DS-TB) is too long, hence threatening patient adherence, with resulting treatment failure and drug-resistance. Consequently, this complicates efforts towards achieving the TB control and elimination goal. Currently, no new drug is expected in the short term for reducing treatment duration. We hypothesized that optimization of the current treatment regimen with use of high-dose rifampicin (R), above the 10mg/kg current dose, might result in a shorter TB treatment duration (3-4 months). Clinical trials were conducted to investigate two research areas: first, Safety of high-dose R in HIV-negative TB and in HIV-TB coinfected patients; secondly, drug-drug interaction between high-dose R and antiretroviral drugs. A 3rd research area addressed the use of 2 months sputum culture conversion as surrogate marker for treatment efficacy in TB trials.A Phase II, open-label randomized controlled trial (RIFATOX) was conducted with sites in Bolivia, Peru and Uganda. Three hundred HIV-negative smear-positive TB patients were randomised between three regimens differing only by R dose during the first 16 weeks of the standard 24 weeks treatment: R at 10 mg/kg and two high-R doses (15mg/kg or 20mg/kg). Liver function and bacteriological response were monitored. There was no significant increase in hepatotoxicity with high-dose R. Using data from the cohort of patients from the Ugandan site only, we showed that month-2 culture conversion, a commonly used surrogate marker in phase 2 trials was influenced by the culture method used with significantly higher conversion rates noted with solid versus liquid media within patients on high-R dose regimens. We therefore recommend use the same culture method across sites within multi-centric TB trials.We conducted a systematic review to gather existing information on the pharmacokinetics, adverse effects and efficacy of efavirenz (EFV), the most commonly used antiretroviral drug, co-administered with R-based TB regimens among high TB/HIV-burden countries. Twenty-two articles published between 2006 and 2016 were analyzed. With the use of 600mg EFV daily, plasma concentrations on average were above the minimum therapeutic concentrations during R co-administration with good safety and efficacy. No clear relationship between supratherapeutic EFV concentrations and occurrence of neurological and hepatic adverse events was observed.Then, we conducted a phase-2, randomized, open-label pharmacokinetic trial (ANRS12292 RIFAVIRENZ trial) among 97 DS-TB patients and antiretroviral therapy (ART)-naïve Ugandan patients. These were randomized between 3 drug regimens: 2 using R (20mg/Kg) with ART initiation 2-4 weeks later with EFV600mg/day or 800mg/day) and a control regimen using R10mg/kg and EFV600mg/day. At 8 weeks, all patients were switched to standard R and EFV doses. All patients had intensive pharmacokinetic sampling 4 weeks after EFV-R co-administration, and 4 weeks after R discontinuation. Despite a trend of lower EFV concentration when the R dose was doubled, concentrations remained within the therapeutic window. Treatment with high-dose R was well tolerated. Virological efficacy was high during the first 12 weeks on ART but reduced in the R arms after 24 weeks. We conclude that, use of high-dose R at 20mg/Kg is safe and could be evaluated in larger trials towards shortening of treatment for DS-TB patients. Due to late virological failures in patients on R 20 mg/kg and standard EFV dose, comprehensive efforts through additional research are needed to fast-track the inclusion of TB-HIV co-infected patients in phase 3 trials.