Background:
Integrase strand transfer inhibitors, bictegravir (BIC) and dolutegravir (DTG), are currently recommended for the treatment of HIV. However, the efficacy, safety, and pharmacokinetics (PK) of BIC in people with HIV (PWH) and tuberculosis (TB) taking rifampicin-based therapy has not been evaluated.
Methods:
INSIGHT (NCT04734652) is an open-label, non-comparative, phase-2b randomised controlled trial in ART-naïve or non-naïve adults with HIV (CD4+ >50 cells/µL) and TB, taking a rifampicin-based TB regimen (for ≤ 8 weeks). Participants were randomised 2:1 to the BIC arm [bictegravir/emtricitabine (FTC)/tenofovir alafenamide (TAF)] or a standard of care DTG arm [tenofovir, lamivudine, dolutegravir (TLD)], with BIC/FTC/TAF or DTG dosed twice daily, until 2 weeks post-TB treatment and once daily thereafter, until 48 weeks. Participants underwent regular clinical and safety visits, including HIV viral load measurements at baseline and weeks 4, 8, 12, 24, 40 and 48. Semi-intensive PK sampling was performed during TB treatment and post-TB treatment. Non-compartmental PK analyses for BIC were conducted in R using the PKNCA package (version 10.2). We report preliminary endpoint results for the proportion of participants with plasma HIV-1-RNA <50 copies/mL at week 24).
Results:
We enrolled 122 participants: 80 in the BIC and 42 in the DTG arm. Overall, 43 (35%) were female, with median (IQR) baseline viral load (copies/mL) and CD4+ (cells/µL) of 75649 (22784-391299) and 172 (108-352) (BIC arm) and 73735 (21242-544830) and 139 (97-237) (DTG arm). Geometric mean (CV%) trough concentrations for twice daily BIC during TB treatment (75 PK-profiles) and once daily BIC after TB treatment (22 PK-profiles) were 0.397 (73.4%) mg/L and 2.29 (45.1%) mg/L. Serious adverse events were common in this population with advanced HIV and TB, but none of the 15 were related to study treatment. Median CD4+ (cells/µL) at week 24 was 257 (197-485) (BIC arm) and 231 (170-311) (DTG arm). HIV-1-RNA at week 24 was <50 copies/mL in 71/73 (97%) and 36/37 (97%) of participants in the BIC and DTG arms, respectively, in the per-protocol analysis (Figure 1), [71/75 (95%) in BIC arm (two early withdrawals) and 36/38 (95%) in DTG arm (one death) in FDA snapshot analysis]
Conclusions:
Data from INSIGHT suggest that twice daily bictegravir/emtricitabine/tenofovir-alafenamide is effective in PWH with TB taking rifampicin-based treatment. Safety, PK, and virologic response data support the use of this regimen in PWH and TB.
