December 7, 2015
Combined with the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (Edurant), the integrase inhibitor cabotegravir maintained viral control just as well as efavirenz (Sustiva, Stocrin) plus two nucleoside reverse transcriptase inhibitors (NRTIs) in a multicenter randomized dose-ranging trial. In the 24-week induction phase, cabotegravir plus two NRTIs yielded better virologic response rates than efavirenz plus two NRTIs.
Cabotegravir, a structural analogue of the licensed integrase inhibitor dolutegravir (Tivicay, DTG), has no pharmacokinetic interactions with rilpivirine (Edurant) when both are dosed orally. Parenteral long-acting formulations of the two antiretrovirals are in development as a treatment regimen with a multiweek dosing interval.
At centers in the United States and Canada, the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial randomized antiretroviral-naive adults 1:1:1:1 to 10, 30 or 60 mg of oral cabotegravir once daily plus two NRTIs; or to standard-dose efavirenz plus two NRTIs. At week 24, participants with a viral load below 50 copies/mL continued their efavirenz regimen or switched from cabotegravir plus NRTIs to cabotegravir plus 25 mg of oral rilpivirine once daily for another 72 weeks. Participants and physicians were blinded to cabotegravir dose but not to cabotegravir-versus-efavirenz assignment.
At the end of the 24-week induction phase, a U.S. Food and Drug Administration (FDA) snapshot analysis determined that proportions with a viral load below 50 copies/mL were 87% with 10 mg of cabotegravir, 85% with 30 mg, 87% with 60 mg and 74% with efavirenz. Four patients in the efavirenz arm and one each in the cabotegravir arms had protocol-defined virologic failure by week 24. None of these participants had treatment-emergent resistance mutations. At that point 12% randomized to cabotegravir and 24% randomized to efavirenz had discontinued treatment.
At week 96 (72 weeks after the switch to cabotegravir/rilpivirine), proportions with a viral load below 50 copies/mL by FDA snapshot analysis were 68% with 10 mg of cabotegravir, 75% with 30 mg, 84% with 60 mg and 63% with efavirenz. Respective proportions of virologic nonresponders were 15%, 10%, 5% and 16%. And respective proportions of patients who discontinued because of adverse events were 2%, 2%, 7% and 13%. These differing nonresponder and discontinuation rates explained the difference in overall 96-week response between the cabotegravir groups and the efavirenz group.
During the maintenance phase, two patients in the 10-mg cabotegravir arm, one in the 30-mg arm and two in the efavirenz arm had protocol-defined virologic failure. The two patients taking 10 mg of cabotegravir had treatment-emergent integrase inhibitor- and/or nonnucleoside-related resistance mutations. No mutations emerged in the two efavirenz patients with virologic failure.
Among people with a pretreatment viral load above 100,000 copies/mL, 96-week response rates were 50% with 10 mg of cabotegravir, 71% with 30 mg, 67% with 60 mg and 88% with efavirenz. At the 96-week point median, gain in CD4+ counts measured 259.5 cells/mm3 in the combined cabotegravir groups and 289 cells/mm3 in the efavirenz group.
Through 96 weeks, grade 3 or 4 treatment-emergent laboratory abnormalities developed in 26% of participants randomized to cabotegravir and 37% randomized to efavirenz.
On the basis of these efficacy and safety findings, the investigators selected the 30-mg once-daily dose for ongoing study of oral cabotegravir.
Mark Mascolini writes about HIV infection.
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