Dolutegravir Effective and Well-Tolerated in HIV/TB Co-Infected Adults

Although the presence of tuberculosis (TB) / HIV coinfection is common, with data from the World Health Organization (WHO) indicating that the risk that an HIV-infected individual will develop TB is about 16 to 27 times greater than an uninfected individual, treatment in this population of patients remains a challenge because of interactions between TB and HIV medications, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). Specifically, because rifampicin (an essential drug for TB) is a potent inducer of metabolizing enzymes, many HIV drugs cannot be given together with first-line TB treatment because of the risk for low HIV drug concentrations.

We sat down with Kelly Dooley, MD, PhD, MPH, associate professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland, who elaborated on these challenges (see video).

Treatment options that take relevant drug interactions into account and are well-tolerated and do not increase the risk of toxicity or IRIS are sorely needed. To this end, investigators from multiple institutions, led by Dr. Dooley, sought to determine the efficacy and safety of dolutegravir (DTG) in antiretroviral treatment- (ART) naïve adults with HIV-1 (CD4+ ≥50 cells/µL) and drug-sensitive TB coinfection. Interim week 24 results from this phase 3b, non-comparative, active control, randomized, open-label study (INSPIRING (NCT02178592)) were presented at the 25th Conference for Retroviruses and Opportunistic Infections (CROI) held in Boston, Massachusetts.

For the phase 3b trial, “participants on rifampin-based TB treatment for up to 8 weeks were randomized (3:2) to receive DTG (50 mg twice daily during and for 2 weeks post-TB therapy, followed by 50 mg once daily [OD]) or efavirenz (EFV) (600 mg OD), with 2 investigator-selected nucleoside reverse-transcriptase inhibitors (NRTIs) for 52 weeks,” according to the study authors.

A total of 69 out of the 113 participants enrolled in the study were randomized to DTG and the remaining 44 were randomized to EFV. The study authors reported that “median baseline HIV-1 RNA and CD4+ cell counts were 5.10 log10 c/mL and 208 cells/µ in the DTG arm and 5.24 log10 c/mL and 202 cells/µ in the EFV arm.” Eighty-one percent (56 / 69) of participants in the DTG arm had HIV-1-RNA <50 c/mL at Week 24 (95% CI: 72%, 90%), compared with 89% (39 / 44) of those in the EFV arm (95% CI: 79%, 98%). There were no deaths or ART switches in either arm, and there were no drug discontinuations for toxicity in the dolutegravir arm. Dolutegravir drug concentrations were well above the minimal trough concentrations required for dolutegravir to be effective. Dr. Dooley spoke about these results in her interview with Contagion^® (see video).

Study authors reported that “median CD4+ cell increases at week 24 were 146 cells/µL (interquartile range (IQR): 71, 214) for DTG and 93 cells/µL(IQR: 47, 178) for EFV.” In addition, “TB-Associated IRIS rates (adjudicated and investigator reported) were low (DTG, n=4 [6%]; EFV, n=4 [9%]).” None of the subjects discontinued the study because of IRIS or liver events.

The clinical significance of these results is exciting. Dr. Dooley shared with us potential next steps for continuing this research in other populations (see video).