Highlights
The INSIGHT study confirms that twice-daily bictegravir-emtricitabine-tenofovir alafenamide (B/F/TAF) achieves 94 percent viral suppression at week 24 in patients with HIV receiving rifampicin-based tuberculosis treatment. No treatment failures or emergent resistance were observed in the bictegravir group, highlighting its robust genetic barrier even in the presence of potent enzyme inducers. Furthermore, the safety profile was manageable, with grade 3 or higher adverse events comparable between the bictegravir and dolutegravir-based control arms, suggesting that BID dosing is a viable clinical strategy for this complex patient population.
Background: The Challenge of HIV-Tuberculosis Co-management
Tuberculosis (TB) remains the leading cause of morbidity and mortality among people living with HIV (PLWH), particularly in resource-limited settings like sub-Saharan Africa. The co-management of these two infectious diseases is notoriously difficult due to overlapping toxicities, pill burden, and, most significantly, profound drug-drug interactions. Rifampicin, a cornerstone of first-line TB therapy, is a potent inducer of the cytochrome P450 (CYP) 3A4 enzyme and the UDP-glucuronosyltransferase (UGT) 1A1 pathway. These metabolic pathways are responsible for the clearance of most integrase strand transfer inhibitors (INSTIs), which are currently the preferred first-line antiretroviral therapy (ART) worldwide.
The Pharmacokinetic Barrier
Bictegravir is a potent, second-generation INSTI with a high genetic barrier to resistance, typically administered once daily as part of a fixed-dose combination with emtricitabine and tenofovir alafenamide (B/F/TAF). However, previous pharmacokinetic studies indicated that rifampicin reduces bictegravir plasma concentrations by approximately 75 to 80 percent, which would likely lead to subtherapeutic levels and a high risk of virologic failure if dosed standardly. Until the INSIGHT trial, the only INSTI with robust data supporting its use with rifampicin was dolutegravir, when adjusted to twice-daily dosing. The lack of data for bictegravir meant that patients on B/F/TAF who developed TB often had to switch their entire ART regimen, complicating clinical care and increasing the risk of errors.
Study Design and Methodology
The INSIGHT study was a phase 2b, open-label, randomized, non-comparative controlled trial conducted in Durban, South Africa. The trial aimed to evaluate the efficacy, safety, and pharmacokinetics of twice-daily B/F/TAF in adults with HIV who were beginning or already receiving rifampicin-based TB treatment.
Participant Selection and Randomization
The study enrolled 122 adults (aged 18 years and older) who were treatment-naive for HIV (or had minimal prior exposure) and had a CD4 count of at least 50 cells per microliter. Participants were recruited from South African Department of Health and Municipal clinics. They were randomized in a 2:1 ratio to one of two arms:
Intervention Arms
1. The Bictegravir Group (n=80): Participants received the fixed-dose combination of bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) twice daily during the period they were taking rifampicin. After completing TB treatment, they transitioned to the standard once-daily B/F/TAF regimen.2. The Dolutegravir Group (n=42): Participants received 50 mg of dolutegravir twice daily, combined with a once-daily fixed-dose combination of tenofovir disoproxil fumarate and lamivudine (300/300 mg). This served as the standard-of-care control arm.The primary endpoint was the proportion of participants in the bictegravir group with an HIV-1 RNA level of less than 50 copies per mL at week 24, assessed using the US Food and Drug Administration (FDA) snapshot algorithm in a modified intention-to-treat population.
Key Findings: High Efficacy and Viral Suppression
The trial results provide compelling evidence that doubling the frequency of B/F/TAF administration successfully overcomes the inductive effect of rifampicin.
Virologic Success Rates
At the primary endpoint of week 24, 75 of 80 participants in the bictegravir group (94 percent; 95 percent CI 86–98) achieved viral suppression of less than 50 copies per mL. In the dolutegravir group, 40 of 42 participants (95 percent; 95 percent CI 84–99) reached this threshold. This high level of efficacy was maintained through week 48, with 95 percent of the bictegravir group and 93 percent of the dolutegravir group remaining suppressed. Notably, the viral suppression was achieved regardless of the baseline viral load, which had a median of over 75,000 copies per mL in both groups.
Resistance and Treatment Failure
One of the most significant findings was the absence of emergent resistance in the bictegravir arm. In contrast, one participant in the dolutegravir arm experienced the emergence of the M184VI mutation, which confers resistance to lamivudine and emtricitabine. There were no treatment failures or discontinuations due to lack of efficacy in the bictegravir group, reinforcing the drug’s robust profile even under pharmacologic stress.
Safety and Tolerability Profile
The safety of the twice-daily B/F/TAF regimen was a primary concern, as doubling the dose of tenofovir alafenamide and emtricitabine could theoretically increase the risk of side effects. However, the trial found the regimen to be well-tolerated.
Adverse Events
Grade 3 or higher adverse events occurred in 45 percent of participants in the bictegravir group and 55 percent in the dolutegravir group. Serious adverse events (SAEs) were observed in 11 participants (14 percent) in the bictegravir arm and 3 participants (7 percent) in the dolutegravir arm. Importantly, none of these serious events were deemed by the investigators to be related to the study drugs. Most adverse events were consistent with the known side effects of TB therapy or the initial phase of starting ART. There were no deaths related to the study treatment, and no participants discontinued the study due to drug-related toxicity.
Expert Commentary: Bridging the Gap in HIV-TB Co-management
The INSIGHT trial represents a significant step forward in simplifying the treatment of HIV and TB. For clinicians, the ability to maintain a patient on a single-tablet-based regimen (even if taken twice daily) during TB treatment reduces the complexity of care and potentially improves adherence.
Pharmacokinetic Significance
The success of this strategy is a testament to the predictable pharmacokinetics of bictegravir. By using a twice-daily dosing schedule, the study ensured that the trough concentrations of bictegravir remained above the protein-adjusted 95 percent inhibitory concentration (paIC95) throughout the dosing interval, despite the presence of rifampicin. This pharmacologic ‘brute force’ approach effectively neutralizes the drug interaction.
Clinical Implications
While dolutegravir remains a vital tool, the inclusion of B/F/TAF as a validated option provides clinicians with a necessary alternative, especially for patients who may have intolerance or contraindications to other INSTIs. Furthermore, the use of tenofovir alafenamide (TAF) instead of tenofovir disoproxil fumarate (TDF) may offer long-term benefits regarding bone and renal health, although this study was not long enough to assess those specific outcomes.
Study Limitations
As a phase 2b, open-label, non-comparative trial, the study was not designed to prove non-inferiority between the two arms. However, the high absolute rates of suppression in the bictegravir arm are clinically sufficient to support its use. The trial was also conducted in a single geographic region, though the biological mechanisms of the drug-drug interactions studied are expected to be consistent across different populations.
Conclusion and Future Directions
The INSIGHT trial provides the first clinical evidence supporting the use of twice-daily bictegravir-emtricitabine-tenofovir alafenamide in people with HIV taking rifampicin-based tuberculosis treatment. With viral suppression rates exceeding 90 percent and a favorable safety profile, this regimen offers a potent and reliable option for one of the most challenging patient populations in infectious disease medicine. Future research should focus on whether these findings can be replicated in children and pregnant women, as well as evaluating the long-term metabolic impacts of twice-daily TAF/FTC dosing.
Funding and ClinicalTrials.gov
The INSIGHT study was supported by the National Institutes of Health (NIH) and the South African Medical Research Council. The trial is registered with ClinicalTrials.gov under the identifier NCT04734652.
References
1. Naidoo A, Naidoo K, Letsoalo MP, et al. Fixed-dose combination bictegravir-emtricitabine-tenofovir alafenamide twice-daily for treatment of HIV during rifampicin-based tuberculosis treatment (INSIGHT Study): a phase 2b, open-label, randomised non-comparative trial. Lancet HIV. 2026 Jan;13(1):e9-e20. doi: 10.1016/S2352-3018(25)00200-0. 2. Dooley KE, Kaplan R, Mwelase N, et al. Dolutegravir-based antiretroviral therapy for patients with HIV-associated tuberculosis: 48-week results of the INSPIRING study. J Acquir Immune Defic Syndr. 2019;81(5):589-596. 3. World Health Organization. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: WHO; 2021. 4. Custodio JM, West SK, Collins S, et al. Pharmacokinetics of bictegravir administered twice daily with rifampin. Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2018; Boston, MA.
