CONTACT: Erin McConnell (Erin.McConnell@treatmentactiongroup.org)

March 12, 2026 – Treatment Action Group (TAG) welcomes the wealth of tuberculosis (TB) treatment data presented at the 2026 Conference on Retroviruses and Opportunities Infections (CROI) in Denver, CO, from 22–25 February 2026. Highlights include results from several studies that answered questions on how to give 3HP and 1HP with the HIV medicine dolutegravir (including data for children and pregnant persons); insights into a targeted linezolid dosing strategy; and preclinical data on long-acting pretomanid and TBAJ-876 (sorfequiline). A plenary session on the last day of the conference focused on the major progress made in closing TB treatment and diagnostic evidence gaps for children and the importance of including children and mothers early in clinical research.

Closing Knowledge Gaps in TB Preventive Treatment

CROI 2026 featured results from several long-awaited studies filling gaps in our knowledge of short-course TB preventive treatment (TPT) for children, pregnant people, and people living with HIV (PLHIV). Studies presented focused on the compatibility of co-administering the rifapentine-containing regimens 1HP and 3HP with dolutegravir-based antiretroviral therapy (ART). Rifapentine speeds up the rate that dolutegravir is processed in the body, creating the risk of sub-therapeutic drug levels and reduced anti-HIV efficacy — necessitating the series of safety and pharmacokinetic studies whose results were presented this year, many of which were funded by Unitaid and supported by the IMPAACT4TB consortium.

CROI 2026 brought two exciting additions to the DOLPHIN study findings shared at previous CROIs. DOLPHIN and DOLPHIN TOO studies previously showed that adults can safely remain on dolutegravir-based HIV treatment while taking 3HP without needing to increase the dolutegravir dosage, and that people can start dolutegravir and 3HP on the same day. Findings presented this year from DOLPHIN-Moms and DOLPHIN-Kids show that 3HP and dolutegravir are also safe to use together in children living with HIV and in pregnant persons with good adherence support.

DOLPHIN-Moms (NCT05122026) investigated the safety, tolerability, and pharmacokinetics of rifapentine-based TPT given with dolutegravir in 215 pregnant women living with HIV in their second or third trimesters in South Africa. Investigators measured concentrations of dolutegravir (pharmacokinetics, PK) when taken twice daily with 1HP or 3HP and later dolutegravir taken once daily with 3HP. PK data showed that dolutegravir taken once daily with 3HP had similar concentrations as in non-pregnant adults and over 90% of participants maintained viral suppression with an excellent safety profile. Findings demonstrate that twice-daily dolutegravir dosing is safe and compatible with either 1HP or 3HP and that once-daily dolutegravir is sufficient to maintain viral suppression while on 3HP during pregnancy with strong adherence counseling.

DOLPHIN-Kids (NCT05122767) investigated safety, dolutegravir pharmacokinetics, and HIV viral suppression in 65 South African children (3 months to 18 years) living with HIV on 3HP and twice-daily (stage 1) or once-daily (stage 2) dolutegravir-based HIV treatment. Stage 1 results of twice-daily dolutegravir and 3HP have been previously reported; data presented at CROI this year from stage 2 demonstrated that there were no severe adverse events among participants on once-daily dolutegravir and 3HP with no discontinued treatment. Most participants (95%) maintained viral suppression (<50 copies/mL) throughout the study and all participants were virologically suppressed at study completion. The pharmacokinetic results align with previous findings that rifapentine lowers dolutegravir levels, but both once-daily and twice-daily dolutegravir provided levels compatible with maintaining viral suppression. While the study collected data for children under two years of age, it was unable to collect data for the smallest children under 10 kg, so further studies are needed in this group.

CROI also welcomed the results from two pragmatic trials exploring 1HP and 3HP in PLHIV in real world settings. Investigators in Thailand compared the safety and efficacy of 1HP and 3HP in 1500 adults living with HIV on efavirenz- or dolutegravir-based HIV treatment (NCT03785106). Investigators tracked the incidence of active TB disease and mortality (primary endpoint) alongside HIV virological suppression (<50 copies/mL), adverse and serious adverse events, hepatoxicity, and treatment discontinuation (secondary endpoints). There were just two TB cases and three deaths by the end of the study across 1HP and 3HP arms, regardless of HIV treatment regimens. Only 1.4% of all participants discontinued treatment due to adverse events.

While studies reported previously and above have shown there is no need for dolutegravir dose adjustment while on 3HP, previously presented data from this study in Thailand suggest that this is also true for the 1HP regimen. The ability to give 1HP without dolutegravir dose adjustment would make it a convenient alternative to 3HP for PLHIV. The Thai National TB Program is planning national scale up of 1HP with dolutegravir (once daily) with studies of real-world effectiveness, resistance development, and cost-effectiveness. Evidence from the Thai national roll out of 1HP carries potential to expand acceptability of 1HP with dolutegravir for high TB and HIV burden national programs and contexts.

The One-to-Three Trial (NCT05118490) investigated 1HP and 3HP in real world settings for PLHIV. The study compared treatment completion and safety for 1HP and 3HP in 500 virally suppressed PLHIV on dolutegravir in India and South Africa. Both 1HP and 3HP were self-administered with adherence measured by self-report, pill counting, and an electronic monitoring device measuring when pill bottles were opened. Regimens were considered completed when over 90% of doses were taken. This study found that the daily 1HP regimen had lower completion rates (75%) as compared to the once weekly 3HP regimen (88%) when measured by electronic monitoring with both regimens measuring completion rates over 90% when measured by self-report and pill count. Participants in the 1HP arm had higher rates of discontinuation (3.2%) as compared to 3HP (0%). Results from the study suggest that both 1HP and 3HP are safe but 3HP may carry adherence advantages.

The key takeaway from CROI 2026 for TB preventive treatment is that 3HP with dose-unadjusted dolutegravir is a safe and effective treatment option for adults, pregnant persons, and children living with HIV. 1HP is emerging as a good option for PLHIV and further studies of 1HP in additional groups including children and pregnant women would bring greater flexibility and choice to communities and TB programs.

Salazar-Austin N, Perez Solans B, Hernandez Morfin N, et al. DOLPHIN-KIDS: Phase I/II Trial of Dolutegravir With 3HP for TB Prevention in Children With HIV [OA-150]. Oral Abstract Presented at CROI 2026. 24 Feb 2026; Denver, Colorado. Available from: Link

Mathad JS, Lacourse S, Perez Solans B, et al. DOLPHIN-Moms: Pharmacokinetics and HIV Suppression With Once-Daily Dolutegravir and 3HP in Pregnancy [OA-147]. Oral abstract presented at CROI 2026. 24 Feb 2026; Denver, Colorado. Available from: Link

Avihingsanon A, Jirajariyavej S, Palakawong Na Ayuthaya T, et al. One-Month Versus 3-Month Rifapentine-Based Tuberculosis Preventive Therapy in People With HIV [OA-145]. Oral Abstract Presented at CROI 2026.  24 Feb 2026; Denver, Colorado. Available from: Link

Moodley J, Maraba N, Beattie T, et al. Safety and Treatment Completion of 1HP Versus 3HP in People With HIV: The One-to-Three Trial [OA-148]. Oral Abstract Presented at CROI 2026. 24 Feb 2026; Denver, Colorado. Available from: Link

Understanding Novel Treatment Regimens

CROI 2026 featured studies that addressed outstanding questions in existing TB treatment regimens including targeted linezolid dosing strategies and clofazimine-associated skin discoloration.

The AIDS Clinical Trials Group (ACTG) study A5356 team presented interim findings on their exploration of linezolid dosing strategies for drug-resistant TB treatment. A5356 (NCT05007821) hypothesized that a higher dose would optimize linezolid concentration and decrease the risk of adverse events or treatment discontinuation. The study compared two dosing strategies of linezolid in six-month bedaquiline, delamanid, clofazimine, and linezolid-containing regimens. The experimental arm featured high-dose linezolid (1200 mg daily for 4 weeks then 3-times weekly until week 26) while the control arm dosed linezolid at the current standard of 600 mg daily throughout treatment. The experimental, high-dose linezolid arm demonstrated higher concentrations of linezolid as anticipated, but treatment outcomes were worse. In fact, the experimental regimen converted TB cultures more slowly than the standard regimen (primary endpoint). In the high-dose linezolid arm, treatment discontinuation, dose reductions, treatment interruptions, the absence of cure, and death were more common. Despite this, there was no significant differences between overall or treatment-related adverse events between the two arms and both arms showed similar culture conversion (94% in experimental arm; 97% in control arm) at week 26. Findings from the interim analysis suggests that 600 mg dose of linezolid is emerging as the target dose for treatment of drug-resistant TB, but further analysis will investigate outcomes at the end of treatment and the follow-up period (week 72).

Earlier reporting on the ACTG CLO-Fast (NCT04311502) trial demonstrated that a three-month clofazimine and high-dose rifapentine regimen for the treatment of pulmonary drug-sensitive TB was safe but ineffective as compared to the standard of care. The three-month regimen was associated with noticeable clofazimine-driven skin color change throughout treatment. Data presented at CROI 2026 examined skin color change to better understand the impact on patient acceptability and reversibility of pigmentation. Investigators measured skin color change by participant self-report and digital colorimetry and found significant and noticeable skin color change, peaking at week 13 of the regimen. Skin color changes were consistent with melanin-based hyperpigmentation rather than color deposits from clofazimine itself. While no one discontinued treatment due to skin color changes, by the end of treatment, 33% of participants reported increased distress in the clofazimine arm as compared to 8% in the standard of care arm. The study followed participants through week 65 and found substantial reversal in skin color changes following the end of treatment, with most participants returning to normal. Despite the return to normal, the treatment associated distress due to the color changes raised concerns about the acceptability of clofazimine containing treatments such as those for drug-resistant TB.

During the development of CLO-Fast, several community advisory boards (CABs), including the Global TB CAB and the Community Research Advisors Group (CRAG), reviewed the protocol and provided feedback. CABs were split in their endorsement of CLO-Fast with CRAG declining to endorse due to concerns about clofazimine-associated skin coloration being too severe a side effect to be acceptable. The results presented suggest that the CRAG’s initial concerns about treatment-associated distress from hyperpigmentation were reasonable — even if no participants stopped treatment because of distress. On initial review of the protocol, it was unclear if skin color changes from clofazimine would be due to color deposits or hyperpigmentation which would affect populations differently. Division among the CABs who reviewed this protocol and the participant outcomes in the study highlights the reality that a single treatment regimen won’t be acceptable for everyone; TB treatment is not and should not be “one-size fits all.” Although the CLO-Fast regimen will not be implemented in program settings, these data can inform how clofazimine is used in other regimens and help individuals weigh clofazimine-containing regimens in the future.

Benson C, Kendall M, Dawson R, et al. Novel Linezolid Dosing With Bedaquiline, Delamanid, and Clofazimine for Drug-Resistant TB Treatment [OA-149]. Oral Abstract Presented at CROI 2026. 24 Feb 2026; Denver, Colorado. Available from: Link

Scarsi K, Kendall M, Benson C, et al. Delamanid and Linezolid PK in the Treatment
of Drug-Resistant Pulmonary TB: Results From ACTG 5356 [P-788]. Poster Presented at CROI 2026. 25 Feb 2026; Denver, Colorado. Available from: Link

Metcalfe J, Hughes M, Wei M, et al. Skin Color Changes With a 3-Month Clofazimine- Containing TB Regimen: Results From the Clo-Fast Trial [P-763]. Poster Presented at CROI 2026. 23 Feb 2026; Denver, Colorado. Available from: Link

Long-Acting Technologies for TB

TB Alliance presented early preclinical data on the efficacy of long-acting formulations of pretomanid and the novel compound TBAJ-876 (a.k.a. sorfequiline) for tuberculosis treatment. The trial investigated the efficacy of injectable, implant-forming, long-acting formulations of pretomanid and TBAJ-876 for the continuation phase of DS-TB treatment in mice. The experimental arm of the study had an intensive treatment phase with oral medication for two months followed by a continuation treatment phase with long-acting TBAJ-876 and pretomanid. The long-acting injectables were optimized for a high initial drug release load followed by continuous drug release in the 2 months following implant. Both long-acting pretomanid and long-acting TBAJ-876 showed sustained drug levels in vivo exceeding the 8-week continuation phase, with TBAJ-876 providing sustained release over three months. This study demonstrates successful proof of concept of the potential of long-acting injectables for the continuation phase of treatment when adherence is lower. Viewed with data from long-acting technologies for HIV presented at CROI, this study reinforces the potential of integrating long-acting technologies with existing regimens to improve adherence and outcomes. While long-acting pretomanid and TBAJ-876 are still in preclinical development, TB Alliance has expressed clear intent to move to early clinical trials soon.

Begum N, Doyon G, Murphy JN, et al. Long-Acting Formulations of Pretomanid and Diarylquinoline TBAJ-876 for Tuberculosis Treatment [P-782]. Poster Presented at CROI 202625 Feb 2026; Denver, Colorado. Available from: Link

One Sentence Summaries of Other TB Data Presented at CROI 2026:

Treatment Innovation:

• OA-123, Intensification of Tuberculosis Treatment in Severely Immunocompromised Individuals With HIV, In individuals with advanced HIV disease (AHD), intensifying TB treatment did not decrease risk of TB-associated mortality and offered no measurable alternative benefit to those living with AHD. Link.
• OA-124, Adjunctive Prednisone for Inpatients with Disseminated HIV-Associated TB, Inclusion of a two-week course of prednisone during intensified TB treatment in adults living with AHD did not reduce risk of death from intensified treatment. Link.
• OA-146, Twice-Daily Dolutegravir With a 4-Month Rifapentine-Based Regimen for HIV-Associated Tuberculosis, Twice-daily dolutegravir is safe and effective at maintaining target concentrations and viral suppression during 4-month regimen for treatment of DS-TB with minimal safety concerns. Link.
• P-783, Decreased Serum Drug Levels of Second-Line Antimycobacterial Agents in People With HIV, PLHIV demonstrated lower levels of all DR-TB drugs in serum as compared to those living without HIV. Link
• P-785, Effect of Metformin on the PopPK of Rifamycin, Isoniazid, and Pyrazinamide in Adults with TB/HIV, Metformin taken alongside TB treatment can result in lower levels of rifampicin and isoniazid and extra attention is needed to ensure safe and effective treatment. Link
• P-786, Impact of Rifabutin on Bictegravir Ctrough and Viral Control in PWH with Mycobacterial Infection, Bictegravir concentration drops significantly when taken with anti-TB rifamycins but remains above target levels and maintains viral suppression. Link.
• P-787, Timing of Isoniazid Initiation in Pregnancy Among Women Living with HIV and Perinatal Outcomes, Initiation of isoniazid-containing regimens in PLHIV on dolutegravir during the first trimester of pregnancy is associated with higher risk of preterm and still birth as compared to second-trimester initiation. Link
• P-850 PK and Safety of Twice-Daily Dolutegravir in 3 kg to 20 kg Children with HIV and TB on Rifampicin, Twice-daily dolutegravir is safe and effective during treatment with rifampicin for children (3-20kg). Link.

Diagnostics:

• P-773, Efficiency of Portable Chest X-Ray Compared to Symptom-Based TB Screening in Southwest Nigeria, Portable chest X-ray screening of household contacts was 8-times more efficient at diagnosing TB when assisted by artificial intelligence as compared to standard screening methods while using less time and resources. Link.
• P-774, High Prevalence of Asymptomatic Tuberculosis in an African Cohort of People with HIV (CoVPN 3008-TB), Symptom-based screening alone misses most asymptomatic TB cases, new diagnostic guidelines are necessary to identify asymptomatic TB and begin treatment. Link.
• P-775, The Case for Routine Testing and Empiric Treatment of TB Meningitis in High HIV-Prevalence Settings, High HIV burden settings in Africa have high TB meningitis burden that can only be successfully identified with nucleic-acid based testing (e.g., Xpert MTB/RIF). Link.
• P-776, Very Promising New Urinary LAM Assay for Tuberculosis Diagnosis in Children, Urine PathFast LAM holds potential as a near point of care diagnostic tool for children living with HIV, with 83% sensitivity for pediatric TB diagnosis in CHLIV. Link.

Pediatrics:

• P-849, Dolutegravir Pharmacokinetics During Standard- and High-Dose Rifampicin Among Children with TB/HIV, The recommended rifampicin dose in TB treatment regimens for CLHIV fails to meet the target level in the body and an experimental high-dose regimen achieved target levels without increasing the risk of adverse events. Link.

 

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