CONTACT: Lindsay McKenna (Lindsay.McKenna@treatmentactiongroup.org), Erin McConnell (Erin.McConnell@treatmentactiongroup.org)
February 22, 2023 – Treatment Action Group (TAG) welcomes the tuberculosis (TB) data presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI). Highlights include the much-anticipated results of the SimpliciTB trial; additional analyses of the two-month TB treatment regimen studied in the TRUNCATE-TB trial; and the first clinical trial data on sutezolid since 2012. Please find a summary of major findings – and TAG’s analysis, below.
A four-month regimen comprised of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) failed to demonstrate non-inferiority to the 6-month standard of care for drug-sensitive TB (isoniazid, rifampicin, pyrazinamide, ethambutol [HRZE]). The experimental BPaMZ regimen converted TB cultures to negative more quickly (primary endpoint). However, there were more unfavorable outcomes (secondary endpoint) among persons treated with BPaMZ (16.7% vs. 6.9%), driven by withdrawals from treatment due to adverse events (predominantly hepatotoxicity). A similar safety concern was first identified in the STAND trial, which preceded SimpliciTB and evaluated pretomanid, moxifloxacin, and pyrazinamide without bedaquiline (i.e., PaMZ). An exploratory analysis presented by the TB Alliance provides some reassurance that this safety issue is likely more prevalent among regimens that combine pretomanid and pyrazinamide as it was of lower magnitude or not observed as often in studies of the now World Health Organization (WHO) recommended six-month BPaL (bedaquiline, pretomanid, linezolid) regimen for drug-resistant TB. However, even the BPaL regimen has been associated with liver-related adverse events so close monitoring for liver toxicity, especially among people at increased risk, is still needed for pretomanid-containing regimens. In short, the BPaMZ regimen appears to be efficacious at curing TB, but it isn’t as safe or as tolerable as the six-month standard of care – the potential benefits of this shorter regimen for drug-sensitive TB cannot be separated from the greater risk of hepatotoxicity, especially given that safer, efficacious, WHO-recommended, four-month treatment options already exist.
Please note: The SimpliciTB trial included an exploratory cohort of people with drug-resistant TB treated with six months of BPaMZ. Similar to the four-month regimen evaluated in the main part of the trial, 16.5% of participants with drug-resistant TB had an unfavorable outcome, a majority of which were due to withdrawals from treatment because of adverse events. The role of this regimen for drug-resistant TB cannot be easily assessed as the SimpliciTB trial did not include a control arm of participants receiving existing standard of care regimens for drug-resistant TB, which have different safety profiles from the six-month standard of care for drug-sensitive TB (the comparator in the SimpliciTB trial). Without these data, it is difficult to weigh the side effects and risks of the BPaMZ regimen against those that exist for WHO-recommended treatment regimens for drug-resistant TB. This is why TAG and the Global TB Community Advisory Board (TB CAB) advocate for randomized, internal comparisons in clinical trials.
Eristavi M, Variava E, Haraka F, et al. SimpliciTB Results and Hepatic Safety of Pretomanid Regimens +/1 Pyrazinamide [OA-109]. Presented at the 2023 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-02 TB and Hepatitis. 20 Feb 2023; Seattle, Washington.
TAG reported on initial results from the TRUNCATE-TB trial that were presented during the 2022 Union Conference in the 2022 TB Treatment Pipeline Report. TAG and the Global TB CAB also made a joint statement summarizing these and other results from the Union Conference. In short: a two-month regimen comprised of bedaquiline, linezolid, isoniazid, pyrazinamide, and ethambutol—administered within the TRUNCATE-TB strategy—demonstrated non-inferiority to the six-month standard of care (HRZE). The regimens also had comparable safety.
The TRUNCATE-TB strategy accepted that some participants would relapse after taking such a short treatment, so the strategy allowed for re-treatment. All participants received two months of treatment and then were closely monitored for relapse. Participants who relapsed were re-treated with the standard six-month regimen (HRZE). Participants who relapsed but were retreated successfully were categorized as satisfactory outcomes. In the standard treatment group (HRZE), 3.9% of participants had an unsatisfactory outcome vs. 5.8% in the strategy group treated with the two-month bedaquiline- and linezolid-containing regimen (risk difference: 0.8 [CI: -3.4 – 5.1]; within the 12% non-inferiority margin). These findings presented at the Union Conference, and in more detail recently in the New England Journal of Medicine (NEJM), demonstrated proof of concept for the strategy deployed within the trial: there is potential to push treatment shortening for drug-sensitive TB beyond the four-month benchmark set by the rifapentine- and moxifloxacin-containing regimen from Tuberculosis Trials Consortium Study 31 / AIDS Clinical Trials Group Study A5349.
Additional data were presented at CROI, including a statistical probability analysis (referred to as a Bayesian analysis) to assess differences between the six-month standard of care and the two-month regimen without the trial’s retreatment strategy. Instead of categorizing participants that relapsed and were re-treated successfully as satisfactory outcomes, this analysis categorized them as unfavorable outcomes. In this analysis, the proportion of unfavorable outcomes among participants treated with the standard six-month regimen vs. the two-month bedaquiline- and linezolid-containing regimen was 3.9% vs. 13.8%. Most of the unfavorable outcomes were due to relapse (10.6% of people who received the two-month regimen vs. 2.2% of people who received the standard six-month regimen). Although the difference in unfavorable outcomes looks large, the Bayesian analysis suggests that there is a high probability (85% probability) that the difference between the two-month regimen and six-month standard of care regimen is less than 12%. The probability of an unfavorable outcome increased with increased disease burden (evaluated by smear grade, Xpert MTB/RIF burden, and percent of lung affected measured by X-ray).
Overall, these results suggest that the TRUNCATE-TB trial strategy could be effective, and the two-month bedaquiline- and linezolid-containing regimen deployed within the strategy appeared to have reasonable early indicators of safety and efficacy. However, it may be too soon to rewrite WHO and national TB treatment guidelines based on these results. Additional research is needed (1) to further optimize the regimen, (2) to better understand if the risk of relapsing is acceptable to people living with TB, (3) to refine a strategy for identifying people with more severe TB disease burden who might need a longer treatment regimen, and (4) to test the strategy in program settings and a broader population, including among people living with HIV.
Paton N, Cousins C, Lu Q, et al. Efficacy and Safety of 8-wk Tuberculosis Treatment Regimens in the TRUNCATE-TB Trial [OA-113]. Presented at the 2023 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-02 TB and Hepatitis. 20 Feb 2023; Seattle, Washington.
SUDOCU is the first study to provide new clinical data on sutezolid since 2012, when a phase IIa study was completed by the drug’s former sponsor, Pfizer. Sutezolid is a novel oxazolidinone being developed as a possible alternative to linezolid. SUDOCU tested sutezolid administered at different doses (600 mg or 1,200 mg once daily or 600 mg or 800 mg twice daily) in combination with bedaquiline, delamanid, and moxifloxacin for three-months, and found it was safe. There was no treatment attributable neuropathy (nerve pain) or myelosuppression (blood disorders) observed in the study apart from one case of neutropenia (low levels of a type of white blood cell important for fighting certain infections, especially those caused by bacteria) that may have other causes. In terms of efficacy, measured by the decline in bacterial load over 12 weeks, SUDOCU found that sutezolid’s efficacy increased with dose without a plateau in exposure or efficacy or any dose-limiting safety issues observed. As such the investigators were not able to determine a maximum or optimal recommended dose for sutezolid.
Further phase II investigations of sutezolid-containing regimens are being planned by the U.S. government-funded AIDS Clinical Trials Group (ACTG), the Gates Medical Research Institute Project to Accelerate New Treatments for Tuberculosis (PAN-TB) collaboration, and the European and Developing Countries Clinical Trials Partnership (EDCTP) funded PanTB-HM consortium led by the Aurum institute. Sutezolid has potential as a more tolerable alternative oxazolidinone to linezolid, a key component of current treatment regimens for drug-resistant TB that comes with challenging side effects, including neuropathy and myelosuppression.
Heinrich N, Manyama C, Ntinginya NE, et al. PanACEA SUDOCU Comination Dose-Finding Trial Shows Sutezolid is a Safe Oxazolidinone [OA-114]. Presented at the 2023 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-02 TB and Hepatitis. 20 Feb 2023; Seattle, Washington.
Abstracts are forthcoming and will be available at https://www.croiconference.org/search-abstracts/
One Sentence Summaries of Other TB Data Presented at CROI 2023:
Drug-drug interactions, reactions, and data in PHLIV:
- P-755, Effectiveness of Dolutegravir in People on Rifampin-Based Tuberculosis Treatment, which found that giving an additional 50 mg of dolutegravir with the standard combination of tenofovir-lamivudine-doluteagravir was safe and effective in people being treated with rifampicin-based regimens for TB. https://www.croiconference.org/abstract/effectiveness-of-dolutegravir-in-people-on-rifampin-based-tuberculosis-treatment/.
- OA-110, Standard vs Double Dose Dolutegravir in HIV-Associated Tuberculosis: Week 48 Results, which showed that standard doses of dolutegravir are likely sufficient, even when given with rifampicin. Oral Abstract Text Forthcoming at https://www.croiconference.org/search-abstracts/
- P-505, Genetics of HIV and TB Drug Interactions with Levonorgestrel Emergency Contraception, which found that there can be notable drug interactions between TB and HIV drugs and emergency contraception, largely driven by genetic differences in the ways drugs are metabolized, necessitating dose adjustments for emergency contraception when co-administered with efavirenz or rifampicin and isoniazid. https://www.croiconference.org/abstract/genetics-of-hiv-and-tb-drug-interactions-with-levonorgestrel-emergency-contraception/.
- P-751, Twice-Daily Dosing of Atazanavir Safely Overcomes the Interaction with Rifampicin, demonstrated that using a double dose of boosted atazanavir (administered twice a day) could overcome drug-drug interactions with rifampicin. https://www.croiconference.org/abstract/twice-daily-dosing-of-atazanavir-safely-overcomes-the-interaction-with-rifampicin/.
- P-740, TB Outcomes in People Living with HIV: An Integrative Data Analysis of Phase 3 Trials, which found that overall people living with HIV can be effectively treated with shorter, rifapentine- and moxifloxacin-containing regimens but that cisgender males with high baseline bacterial loads might be at risk for worse outcomes. https://www.croiconference.org/abstract/tb-outcomes-in-people-living-with-hiv-an-integrative-data-analysis-of-phase-3-trials/.
- P-741, Adverse Drug Reactions on TB Treatment: A Prediction Model Including HIV and HBA1c, which showed that models which consider baseline co-morbid disease risks (HIV, diabetes) and concomitant medication use can accurately predict who might develop adverse drug reactions. https://www.croiconference.org/abstract/adverse-drug-reactions-on-tb-treatment-a-prediction-model-including-hiv-and-hba1c/.
Models of care:
- OA-111, Increased TB Preventative Therapy Coverage with Integrated Community-Based IPT and ART, which found that integrating IPT with community-based ART delivery was associated with higher rates of IPT uptake and adherence. Oral Abstract Text Forthcoming at https://www.croiconference.org/search-abstracts/
- P-756, Differentiated Service Delivery for People Co-Infected with Drug Resistant TB and HIV, which showed that among people with drug-resistant TB and HIV, adherence support tailored to stage of treatment and to challenges noted with adherence is more person-centered and likely to be more acceptable than giving the same, observation-based adherence support to all. https://www.croiconference.org/abstract/differentiated-service-delivery-for-people-coinfected-with-drug-resistant-tb-and-hiv/.
- P-759, Monocyte-to-Lymphocyte Ratio and Hemoglobin Level to Predict TB After ART Initiation, which found that using routinely collected measures of anemia (hemoglobin) combined with the ratio of monocytes to lymphocytes could help predict increased risk of TB and target TB preventive treatment among people with HIV. https://www.croiconference.org/abstract/monocyte-to-lymphocyte-ratio-and-hemoglobin-level-to-predict-tb-after-art-initiation/.
- P-761, Performance of Urine Xpert Ultra vs Alere LAM for Diagnosing TB in HIV In-patients, which found Ultra more sensitive and specific than LF-LAM, and that combined urine testing on both Xpert Ultra and the LF-LAM was able to identify 75% of people with definite TB disease. https://www.croiconference.org/abstract/performance-of-urine-xpert-ultra-vs-alere-lam-for-diagnosing-tb-in-hiv-in-patients/.
- P-824, Outcomes in Children Living with HIV with Non-Severe Tuberculosis in the SHINE Trial, which showed that children living with HIV could receive the four-month regimen if they met other criteria for non-severe disease, but that sub-optimal viral suppression was seen in the children in the study, especially those on lopinavir/ritonavir.https://www.croiconference.org/abstract/outcomes-in-children-living-with-hiv-with-non-severe-tuberculosis-in-the-shine-trial/.
- P-827, Twice Daily 50 mg Dolutegravir in Tuberculosis-HIV Coinfected Children 20-35 kg, which showed that the twice daily dosing of dolutegravir is well tolerated and effective in children on rifampicin-based TB treatment regimens. https://www.croiconference.org/abstract/twice-daily-50-mg-dolutegravir-in-tuberculosis-hiv-coinfected-children-20-35-kg/.
- P-831, Adequate DTG Exposure in Infants on Rifampicin Treatment Receiving Twice-Daily DTG, which demonstrated that the twice daily dosing of dolutegravir was also well tolerated and effective in infants up to 11 months weighing at least 3 kg on rifampicin-based TB treatment regimens. https://www.croiconference.org/abstract/adequate-dtg-exposure-in-infants-on-rifampicin-treatment-receiving-twice-daily-dtg/.
# # #