March 22, 2022 —Treatment Action Group welcomes the tuberculosis (TB) data reported at the 2022 Conference on Retroviruses and Opportunistic Infections (CROI). Please see a summary of major findings — and TAG’s take on them — below.
TB-PRACTECAL found that 6-month regimens containing a backbone of bedaquiline, pretomanid, and linezolid (BPaL) are effective and relatively safe for the treatment of adults with multidrug-resistant TB. These regimens are shorter and contain fewer drugs than the existing 9-12 month all-oral standard of care for MDR-TB.
ACTG A5375 determined that a double-dose of emergency contraception (levonorgestrel, commonly referred to as Plan B) is required when taken by people receiving rifampicin-based treatment for drug-sensitive TB. The double-dose is required to overcome drug-drug interactions between the two medicines. This means that people in treatment for drug-sensitive TB have a safe and effective option for emergency contraception.
ACTG A5372 determined that dolutegravir taken twice daily by people living with HIV receiving the 1HP regimen for TB prevention (1 month of daily rifapentine and isoniazid) is safe and maintains dolutegravir concentrations at adequate levels in the presence of rifapentine. This means people living with HIV and taking dolutegravir ART can safely and effectively prevent TB at the same time.
TB-PRACTECAL: a phase II/III multi-arm, randomized, controlled, open label trial to evaluate the safety and efficacy of three 6-month all-oral regimens for the treatment of multidrug-resistant TB.
Abstract available from: https://www.croiconference.org/abstract/tb-practecal-results-24-week-all-oral-regimens-for-rifampicin-resistant-tuberculosis/.
The biggest TB study to report results at CROI this year compared three different 6-month, BPaL-based regimens to both long and short regimens, some of which included injectable drugs and others that did not. These regimens in the control arm were composed according to the World Health Organization (WHO) standard of care, which changed over the course of the study (between 2017 and 2021).
The big difference between what TAG reported on TB-PRACTECAL in its 2021 TB Treatment Pipeline Report and what was reported at CROI this year is the inclusion of 72-week outcomes data among the participants randomized to receive BPaL and BPaLC (BPaL plus clofazimine). At the 2021 Union Conference, Médecins Sans Frontières (MSF) presented 72-week outcomes data among participants randomized to receive BPaLM (BPaL plus moxifloxacin) compared to the control.
In the modified intention to treat (mITT) analysis presented at CROI, MSF reported that the percentage of unfavorable outcomes were 48.5% for the control, 23.3% for BPaL, 18.8% for BPaLC, and 11.3% for BPaLM. In terms of safety, MSF reported that 58.9% of control group participants experienced at least one grade 3 and/or serious adverse event, compared to 21.7%, 31.9%, and 19.4% in the BPaL, BPaLC, and BPaLM arms respectively. All three experimental arms achieved non-inferiority against the control, with BPaLM achieving the greatest risk difference compared to the control (-37.2% [-∞ to -21.6%] risk of unfavorable outcome).
These findings are based on data available for 286 participants that have reached the primary endpoint out of 552 people total that were randomized to participate in the trial. The final participant enrolled in the study won’t complete their last visit until August 2022, but the WHO has already convened a Guideline Development Group to review these and other available BPaL data.
Differences in BPaL’s performance in TB-PRACTECAL (76.7% favorable outcomes) compared to in Nix-TB and ZeNix (90% and 89.3% favorable outcomes, respectively) – two other studies that evaluated BPaL, including to improve the regimen’s tolerability by optimizing the dose and duration of linezolid– need to be explored, especially as the WHO may be considering an expanded recommendation to the BPaL regimen in response to findings from the ZeNix trial and experiences from operational research programs.
ACTG A5375: a phase II PK study of levonorgestrel emergency contraception in combination with rifampicin-containing drug-sensitive TB treatment.
ACTG study A5375 found that taking a double-dose of emergency contraception with levonorgestrel (Plan B) while on drug-sensitive TB treatment with rifampicin is enough to overcome the rifampicin-related drug-drug interaction that compromises the efficacy of a single dose of levonorgestrel. The study found that women being treated for TB with rifampicin should take 3.0 mg of levonorgestrel instead of the standard 1.5 mg. This is necessary because levonorgestrel is metabolized by the same liver enzyme that rifampicin induces. Without dose adjustment, rifampicin would reduce total levonorgestrel exposures by 57%.
This study builds on primary investigator Rosie Mngqbisa’s previous work to define drug-drug interactions between rifampicin and hormone-based contraceptives. An earlier ACTG study (A5338) had determined that shortening the dosing interval of Depo Provera/DMPA (e.g., to every 8 weeks instead of every 12) while receiving rifampicin-based TB treatment was enough to overcome the risk of contraceptive failure. We do not yet have clinical trial data on rifapentine-based TB treatment or rifapentine- or rifampicin-based TB preventive treatment given with levonorgestrel or DMPA. But based on the results of A5375 and A5338, it is safe to assume that similar adjustments will be needed when these regimens are taken at the same time as either levonorgestrel or DMPA.
ACTG A5372: a phase II PK study of drug-drug interactions between rifapentine and dolutegravir in people living with HIV taking 1HP TB preventive treatment.
ACTG study A5372 examined the effect of 1HP TB preventive treatment (one month of daily rifapentine and isoniazid) on dolutegravir concentrations in antiretroviral treatment (ART). This is the first clinical trial data of 1HP with dolutegravir-based ART; the earlier DOLPHIN study showed that the 3HP regimen was safe to take with dolutegravir and without the need to adjust dolutegravir doses to overcome rifapentine’s induction of the liver enzyme that processes dolutegravir. Because 1HP is dosed daily, instead of weekly like 3HP, it was necessary to conduct a similar study of 1HP and dolutegravir.
The good news is that there is some slack in dolutegravir dosing, as the dose used clinically (50 mg) performed similarly to a much lower 10 mg dose in the efficacy trial of dolutegravir (SPRING-1). This means dolutegravir concentrations can lose some ground to rifapentine without compromising efficacy, but the question is whether 1HP stays within this bound. The results reported from A5372 are from the first stage of this study in which 25 participants took 1HP with dolutegravir dosed at 50 mg taken twice a day (instead of the standard 50 mg taken once a day). Dolutegravir trough concentrations were higher at twice daily dosing with 1HP than with standard dolutegravir dosed once daily without 1HP. Trough concentrations did decrease over the month 1HP was taken as the rifapentine induction effect on the liver enzyme that metabolized dolutegravir revved up over time. But all trough concentrations remained above the target.
Stopping here would be fine, but would mean doubling the dolutegravir dose when taken with 1HP, which would increase the cost of preventive TB treatment with this regimen and also be an inconvenience for people (more pills to take each day). So based on these results, the study will likely progress to its second stage to evaluate whether a single dose of dolutegravir holds up when taken with 1HP.