Dolutegravir in combination with 2 non-nucleot(s)ide reverse transcriptase inhibitors (NRTIs) is well tolerated and may produce rapid virologic and immunologic responses in patients with tuberculosis (TB) and HIV who have not previously received treatment , according to a study published in Clinical Infectious Diseases.
As result of drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS), concurrent treatment of TB and HIV is very challenging. However, TB is the leading cause of death in people living with HIV. The current cornerstones of TB therapy are rifamycins (eg, rifampicin) because of their unique sterilizing activity against Mycobacterium tuberculosis. However, rifampicin is a potent inducer of cytochrome P450 (CYP450) isoenzyme expression, which significantly reduces the effectiveness and plasma concentrations of antiretroviral therapy (ART), such as NNRTIs and protease inhibitors, as they are also substrates of CYP450.
The World Health Organization recommends dolutegravir-based ART as the preferred first-line regimen for people with HIV who are initiating ART, therefore evidence on the safety and efficacy of dolutegravir for the treatment of HIV-associated TB is important. Dolutegravir is metabolized primarily by UDP-glucuronosyltransferases (UGT), specifically UDP-UGT 1A1, and thus may be a better candidate for ART in those co-infected with TB and HIV. Therefore, the INSPRING study assessed the efficacy and safety of dolutegravir in adults with HIV and drug‑susceptible TB treated with rifampicin(ClinicalTrials.gov identifier: NCT02178592).
INSPRING is a noncomparative, randomized, open-label study of people with HIV who never received ART and had drug-sensitive TB. Included in the study were 37 sites spanning 7 countries: Argentina, Brazil, Mexico, Peru, Russia, South Africa, and Thailand. Patients were included if they were aged ³18 years, had an HIV viral load of ³1000 copies/mL, a CD4+ count ³50 cells/mm3, and culture-proven, rifampicin‑susceptible pulmonary, pleural, or lymph node TB. Patients received rifampicin-based TB treatment for 8 weeks or less prior to baseline. Patients were randomly assigned at a 3:2 ratio to receive either dolutegravir (50 mg twice daily for the duration of TB treatment, and 2 weeks post-TB therapy, then 50 mg once daily, n=69) or efavirenz (600 mg daily, n=44) with 2 NRTIs for 52 weeks, respectively. The primary end point was the proportion of participants with plasma HIV RNA <50 copies/mL at week 48 (responders) in the dolutegravir group.
In the dolutegravir group, 52 (75%) patients were considered responders at week 48; in the efavirenz arm, 36 (82%) patients were considered responders at week 48. Nonresponders (n=17) in the dolutegravir group which were a result nontreatment-related reasons, such as loss‑to‑follow‑up. Further, in the dolutegravir group, TB treatment success was achieved in 88% of patients with no treatment failures. In the efavirenz group, TB treatment success was achieved in 91% of patients. Of note, 1 patient in the efavirenz group experienced treatment failure, which resolved in 9 months. In total, 75% of patients in the dolutegravir group and 91% of patients in the efavirenz group experienced adverse events; however, grade 3 or 4 adverse events and serious adverse events were rare.
Overall, the study authors concluded that, “[O]ur trial provides efficacy, safety, and pharmacokinetic evidence that dolutegravir is effective and well tolerated in HIV treatment-naive patients who have drug-susceptible TB and are taking rifampicin-containing TB treatment, provided the dolutegravir dose is increased to 50 mg twice daily during (and for 2 weeks after) TB treatment.”
By Zahra Masoud
Reference
Dooley KE, Kaplan R, Mwelase N, et al. Dolutegravir-based antiretroviral therapy for patients co-infected with tuberculosis and HIV: a multicenter, noncomparative, open-label, randomized trial [published online March 28, 2019]. Clin Infect Dis. doi:10.1093/cid/ciz256
Source: Infectious Disease Advisor