CONTACT: Lindsay McKenna (Lindsay.McKenna@treatmentactiongroup.org), Mike Frick (Mike.Frick@treatmentactiongroup.org)
March 14, 2024 – Treatment Action Group (TAG) welcomes the tuberculosis (TB) data presented at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI). The highlights presented here cover the results of several phase II TB prevention and treatment trials. Among these were a study to evaluate a H56:IC31, vaccine candidate for the prevention of TB recurrence and a study to evaluate quabodepistat, a new TB drug with a novel mechanism of action. Please find a summary of major findings – and TAG’s analysis, below.
PREVENTION
DOLPHIN TOO Study of Simultaneous 3HP and Dolutegravir Start (NCT03435146)
DOLPHIN TOO determined that people can safely start HIV treatment with dolutegravir and the TB preventive treatment regimen known as 3HP on the same day. 3HP is a preventive course of two TB drugs—rifapentine and isoniazid—taken once a week for 12 weeks.
We knew from the earlier DOLPHIN study that people already on dolutegravir-based HIV treatment can take 3HP without needing to boost the dose of dolutegravir, which the body clears faster in the presence of rifapentine. The DOLPHIN TOO study shows that the same is true of people starting HIV treatment for the first time (so-called ARV-naive individuals). DOLPHIN TOO looked at safety, dolutegravir drug levels (pharmacokinetics), and HIV viral suppression among 75 participants who started taking either 3HP (n=50) or six months of isoniazid preventive treatment (n=25) on the same day as beginning HIV treatment. Safety and HIV viral suppression outcomes were presented at the 2024 Union World Conference on Lung Health. The pharmacokinetic data were presented at CROI and showed that although rifapentine significantly reduced dolutegravir drug levels , all participants in the 3HP group still had enough dolutegravir in their body to achieve and maintain rapid HIV viral suppression (defined as <50 copies/mL).
These data give HIV programs the greenlight to begin dolutegravir-based antiretroviral treatment simultaneously with 3HP, which should make it easier to prevent TB in one of the groups most at risk of the disease. As the study’s lead investigator, Dr. Ethel Weld of Johns Hopkins University, commented at the end of her presentation: “When we wait to introduce what we know to be one of our most effective TB preventive technologies in precisely the people who are most vulnerable to progression to active disease, we run the risk of introducing a barrier in giving TPT. We shouldn’t be in the business of introducing barriers because they exist and are too many already. We should be in the business of creating ramps and this technology and strategy is just such a ramp.”
The DOLPHIN and DOLPHIN Too studies were supported by the Unitaid-funded IMPAACT4TB consortium.
Weld E, Perez Solans B, Salles I, et al. Simultaneous Initiation in ART-Naive PWH of DTG-Based ART & 3HP Maintains Efficacious DTG Levels [OA-156]. Presented at the 2024 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-08 Hepatitis and Tuberculosis. 5 Mar 2024; Denver, Colorado. Available from: https://www.croiconference.org/abstract/simultaneous-initiation-in-art-naive-pwh-of-dtg-based-art-3hp-maintains-efficacious-dtg-levels/.
H56:IC31 Vaccine for Prevention of Recurrent TB (NCT03512249)
On behalf of the POR TB Consortium, Alvaro Borges from Denmark’s Statens Serum Institut presented results of a phase II study showing that the H56:IC31 TB vaccine candidate did not prevent recurrent TB, defined as either relapse or reinfection, among people who recently finished drug-sensitive TB treatment. H56:IC31 is a subunit vaccine consisting of three TB proteins (H56) with an adjuvant (IC31).
Investigators first shared these disappointing results with scientific and community stakeholders in December 2023. At the time, TAG and the Global TB Community Advisory Board issued a statement commending the study team for sharing results early and reiterated the need to continue research to develop new TB vaccines.
This prevention of recurrence study enrolled 900 HIV-negative people being treated for drug-sensitive TB in South Africa and Tanzania. The primary endpoint was recurrent TB (defined as culture-confirmed pulmonary tuberculosis identified at least 70 days after the second vaccine dose) with secondary endpoints assessing safety and immunogenicity. Investigators observed 23 cases of recurrent TB among participants who received H56:IC31 compared with 14 cases in the placebo group. The majority of excess cases (6 out of 9) were relapses of existing disease (rather than new infections). This difference worked out to an overall estimated vaccine efficacy = -73.8% [95% CI, (-246.9, 9.8)].
In other words, H56:IC31 may have actually increased the risk of relapse, though the reasons for this are unclear. Investigators are now undertaking additional analyses to understand why H56:IC31 appeared to increase the risk of recurrent TB in this population. For example, could unaccounted for differences between people in the vaccine and placebo groups explain the outcome, or was it an effect of the vaccine itself? These are the first efficacy results from a TB vaccine trial designed to evaluate prevention of recurrence and they raise important questions that similar studies—including a prevention-of-recurrence study of a different subunit vaccine called ID93/GLA-SE that is expected to open soon—will need to grapple with; TAG and the Global TB CAB put forward five questions to help guide these discussions.
Borges A, Russel M, Tait D, et al. Efficacy, Safety, and Immunogenicity of H56:IC31 Vaccine for Prevention of Recurrent TB [OA-210]. Presented at the 2024 Conference on Retroviruses and Opportunistic Infections during Special Session: Clinical Late-Breaking Oral Abstract. 6 Mar 2024; Denver, Colorado. Available from: https://www.croiconference.org/abstract/efficacy-safety-and-immunogenicity-of-h56ic31-vaccine-for-prevention-of-recurrent-tb/.
TREATMENT
A Four-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline (Trial 323-201-00006, NCT05221502)
Interim results from a phase IIb/c study of quabodepistat (Q) given in combination with delamanid (D) and bedaquiline (B) found the regimen safe and effective against drug-sensitive TB based on outcomes measured at the end of treatment. Quabodepistat (formerly OPC-167832) is a DprE1 inhibitor sponsored by Otsuka, the drug company also responsible for delamanid. Quabodepistat works by targeting an enzyme (DprE1) involved in cell wall synthesis. Quabodepistat is one of several new TB drugs in development that works by targeting this enzyme. It’s the first new TB drug from a new class to reach this stage of development since bedaquiline and delamanid were in phase IIb over ten years ago.
The results presented at CROI compared the proportion of participants that achieved sputum culture conversion (SCC) by the end of treatment, which lasted four months for participants randomized to receive treatment with QBD and six months for participants randomized to receive treatment with the standard of care (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]). The study team reported that SCC at the end of treatment was achieved by 96% (96/100) of participants in the pooled QBS arms and 91% (19/21) of participants in the HRZE arm. The trial also evaluated three different doses of quabodepistat: 10, 30, and 90 mg. The percentages of participants experiencing at least one grade 3 or higher adverse event (AE) were 15%, 12%, and 11% in the experimental arms with Q dosed at 10, 30, and 90 mg respectively, compared to 5% of participants in the HRZE arm. There were no serious AEs attributed to the study medications. Pharmacokinetic and pharmacodynamic (PK/PD) data collected during the trial will inform dose selection for future trials of quabodepistat-containing regimens.
These interim results are very encouraging, but follow up is ongoing. We will learn more when the study team is able to compare the proportion of participants with favorable longer term clinical outcomes (i.e., relapse free cure 12 months post randomization). Quabodepistat is part of another ongoing phase IIb/c trial led by the Gates Medical Research Institute to evaluate the drug given in combination with bedaquiline, sutezolid (S) and delamanid or pretomanid (4QBDS and 4QBPaS vs 6HRZE). Quabodepistat will likely find a role in TB treatment in the future, but its optimal dose, what other drugs it should be combined with, and for what duration requires further investigation. And we need to see more safety data, especially among people living with HIV (PLHIV), a population that was functionally excluded from the phase IIb/c study of quabodepistat presented at CROI. While the study technically allowed for the inclusion of PLHIV, the initial CD4 cell count cut off criteria was prohibitive to the actual enrollment of PLHIV, and by the time relevant amendments to the protocol were made to address this issue, it was too late.
Dawson R, Diacon AH, Takuva S, et al. A 4-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline for Pulmonary TB: Interim Results [OA-163]. Presented at the 2024 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-08 Hepatitis and Tuberculosis. 5 Mar 2024; Denver, Colorado. Available from: https://www.croiconference.org/abstract/a-4-month-regimen-of-quabodepistat-delamanid-and-bedaquiline-for-pulmonary-tb-interim-results/.
A Three-Month Regimen of Rifapentine, Clofazimine, Ethambutol, and Pyrazinamide (ACTG A5362/CLO-FAST, NCT04311502)
Interim results from a phase IIc study found that a three-month clofazimine (C) – and rifapentine (P) -containing regimen (CPHZE) lacked clinical efficacy compared to the six-month standard of care for drug-sensitive TB (HRZE). The trial was stopped early by an independent data safety monitoring board after an interim look at the data from 58 of a planned 110 participants revealed higher rates of ongoing or recurrent TB among participants taking the investigational regimen.
The results presented at CROI compared the proportion of participants in the experimental vs. the control arm with stable culture conversion after three months of treatment. Based on culture conversion the regimens looked similar (89 % vs. 90 %; adjusted hazard ratio = 1.17 [90% CI, 0.79 to 1.73]). The proportion of participants with an unfavorable outcome, however, looked very different between the two arms of the study, with participants randomized to receive the experimental regimen experiencing a higher proportion of unfavorable outcomes (49% vs. 34%; risk difference = -15% [95% CI, -41% to 11%]). In terms of safety, the proportion of participants experiencing at least one grade 3 or higher adverse event (AE) was also higher in the experimental arm compared to the control (46% vs. 16%; risk difference 30% [90% CI 14-45%]). The difference in safety was driven by changes in creatinine clearance among participants in the experimental arm, an indicator of kidney toxicity that hasn’t been previously observed in association with the use of clofazimine.
Despite compelling data from mice and encouraging rates of culture conversion in humans, the three-month rifapentine- and clofazimine-containing regimen did not prove to be an enduring cure for drug-sensitive TB and has raised some new safety concerns for clofazimine. Follow up and further analysis of data collected in the trial are ongoing– including data collected to measure skin discoloration and evaluate acceptability among participants treated with clofazimine– and should inform other ongoing or planned drug-sensitive treatment-shortening trials that already include or are considering the inclusion of clofazimine.
Metcalfe J, Weir I, Scarsi KK, et al. Provisional Results From a 3-month Clofazimine/Rifapentine-Containing Regimen for Drug-Sensitive TB [OA-164]. Presented at the 2024 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-08 Hepatitis and Tuberculosis. 5 Mar 2024; Denver, Colorado. Available from: https://www.croiconference.org/abstract/provisional-results-from-a-3-month-clofazimine-rifapentine-containing-regimen-for-drug-sensitive-tb/.
Testicular Safety of Pretomanid (PaSEM; NCT04179500)
Reduced fertility has been observed among male rats and mice treated with pretomanid. Results of a long awaited reproductive safety study focused on sperm count in humans was finally presented as a poster during CROI. The study enrolled 26 males from South Africa and Georgia with multidrug-resistant TB who were treated with six-months of pretomanid (in combination with bedaquiline, moxifloxacin, and pyrazinamide). While this was a stand alone study, the same regimen was evaluated in an observational drug-resistant TB cohort enrolled in the SimpliciTB study. (Results from SimpliciTB were presented at CROI in 2023.)
The reproductive safety study measured changes from baseline in total sperm count, sperm concentration, sperm volume, and male reproductive hormones (testosterone, inhibin B, FSH, LH) and found that pretomanid does not have negative effects on the reproductive function of adult males. Both mean total sperm count and concentration increased from baseline when measured at week 26, with 13/22 (59%) participants having greater than 50% increases. Reproductive hormone changes showed improved gonadal status, consistent with the improvements in sperm counts and concentrations observed in the study. This was a single arm study so we don’t know how the observed changes in sperm count and concentration might have compared to those among males treated with pretomanid-sparing regimens. However, hormone levels among males treated with pretomanid-containing vs. pretomanid-sparing regimens have been compared and offer some reassurance that gonadal function appears to improve with health regardless of pretomanid exposure.[1]
The U.S. Food and Drug Administration (FDA) will review these data to determine whether the inclusion of male children in studies of pretomanid in children can proceed. Currently the TB Alliance and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network are limited by the FDA to conducting a single-dose study of pretomanid in female children only (IMPAACT 2034; NCT05586230).
Howell P, Conradie F, Brumskine W, et al. Testicular Safety of a Pretomanid Regimen (BPaMZ) in Men With Pulmonary Drug-Resistant Tuberculosis [Abstract 872]. Presented at the 2024 Conference on Retroviruses and Opportunistic Infections during Poster Session-N1: Pharmacologic and Other Programmatic Insights in Tuberculosis and Cryptococcal Meningitis. 3-6 Mar 2024; Denver, Colorado. Available from: https://www.croiconference.org/abstract/testicular-safety-of-a-pretomanid-regimen-bpamz-in-men-with-pulmonary-drug-resistant-tuberculosis/.
INSIGHT Study of Bictegravir and Rifampicin Interactions (NCT04734652)
The INSIGHT study determined that TB can be safely treated with rifampicin-containing regimens among people living with HIV on bictegravir-based antiretroviral therapy (ART) with bictegravir dosed twice daily during TB treatment.
The INSIGHT study looked at safety, drug levels (pharmacokinetics), and HIV viral suppression among 122 participants randomised 2:1 to receive bictegravir/emtricitabine/tenofovir alafenamide (TAF) or standard of care dolutegravir/lamivudine/tenofovir disoproxil fumarate (TDF). Bictegravir (BIC) and dolutegravir (DTG) were dosed twice daily, until 2 weeks post-TB treatment and once daily thereafter, until 48 weeks. The data presented at CROI showed that participants given bictegravir twice daily during TB treatment were able to achieve and maintain HIV viral suppression (defined as <50 copies/mL).
These data enable TB treatment among people living with HIV on bictegravir-based ART. Bictegravir is an integrase inhibitor that has not yet been recommended by the World Health Organization (WHO) or made available by Gilead in low and middle income countries with high burdens of TB and HIV co-infection. Compared to dolutegravir (the integrase inhibitor recommended as first-line treatment by the WHO and used widely in LMICs), bictegravir has a modestly higher barrier to resistance and is co-formulated with emtricitabine and TAF, which is preferable to TDF for long-term bone and kidney health. Bictegravir is highly potent and binds to integrase for longer making it potentially more forgiving of adherence issues.
Naidoo A, Naidoo K, Letsoalo MP, et al. Efficacy, Safety, and PK of BIC/FTC/TAF in Adults With HIV and Tuberculosis on Rifampicin at Week 24 [OA-211]. Presented at the 2024 Conference on Retroviruses and Opportunistic Infections during Oral Abstracts Session-14 Special Session: Clinical Late-Breaking Oral Abstracts. 3-6 Mar 2024; Denver, Colorado. Available from: https://www.croiconference.org/abstract/efficacy-safety-and-pk-of-bic-ftc-taf-in-adults-with-hiv-and-tuberculosis-on-rifampicin-at-week-24/.
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[1] Boekelheide K, Olugbosi M, Nedelman J, et al. Male reproductive hormones in patients treated with pretomanid. Int J Tuberc Lung Dis. 2022 Jun 1;26(6):558-565. doi: 10.5588/ijtld.21.0654.