ViiV Healthcare has released data from two phase 3 trials that showed a once-daily, two-drug regimen of dolutegravir and lamivudine was non-inferior to a standard three-drug regimen in treatment-naive patients with HIV, reports Healio.
In light of the positive results, ViiV Healthcare announced plans to submit an application seeking regulatory approval of dolutegravir/lamivudine. If approved, it would be the second two-drug HIV regimen available in the US. The first one, Juluca (dolutegravir/rilpivirine; ViiV Healthcare), was approved by the US Food and Drug Administration (FDA) in November. However, its use is strictly limited to virally suppressed patients who have been on a stable regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to any components of Juluca.
The report says the safety and efficacy of dolutegravir/lamivudine was assessed during the phase 3, parallel group GEMINI 1 and GEMINI 2 trials, which were conducted in Europe, South Africa, Asia Pacific and the Americas. The studies enrolled approximately 1,400 treatment-naive patients with a baseline viral load of less than 500,000 copies/mL. The participants were randomly assigned to receive once-daily dolutegravir/lamivudine or once-daily dolutegravir plus tenofovir disoproxil fumarate/emtricitabine.
At 48 weeks, dolutegravir/lamivudine met its primary endpoint of noninferiority in both trials, which was based on a standard measure of HIV viral suppression, the release said. No treatment-emergent resistance was observed among participants with virologic failure. A ViiV Healthcare representative is quoted as saying that additional data from the studies will be presented at the International AIDS Conference, which will take place in Amsterdam from 23 to 27 July.
Dr John C Pottage Jr, chief scientific and medical officer of ViiV Healthcare, said the new results provide further evidence that HIV can be controlled with two drugs instead of three. “People with HIV are living longer and more productive lives. However, under current standard of care, many patients still take three or more medicines every day,” he said. “Importantly, the studies show that this two-drug regimen could be an option for treatment-naive patients and can support a broad range of patients living with HIV around the world.”
Last month, the report says the FDA issued a safety alert warning patients and health care providers about a possible link between dolutegravir use during early pregnancy and serious birth defects in babies. The agency recommends that physicians consider using alternative antiretroviral drugs in women with HIV of childbearing age and to test them for pregnancy before prescribing dolutegravir. There also is evidence that dolutegravir can cause “serious toxicities” when combined with certain tuberculosis treatment regimens.
Background: Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug–drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.
Methods: This was a single-center, open-label, fixed-sequence, drug–drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1–4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5–19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points.
Results: The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27–110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%–92% higher in the subjects who developed toxicities.
Conclusions: The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.
Kristina M Brooks, Jomy M George, Alice K Pau, Adam Rupert, Carolina Mehaffy, Prithwiraj De, Karen M Dobos, Anela Kellogg, Mary McLaughlin, Maryellen McManus, Raul M Alfaro, Colleen Hadigan, Joseph A Kovacs, Parag Kumar