Cabotegravir and rilpivirine effective for HIV maintenance therapy at 96 weeks

An combination of two once-daily oral antiretrovirals – the next-generation integrase inhibitor cabotegravir (GSK1265744) and the approved NNRTI rilpivirine (Edurant, also in Eviplera or Complera) – was as effective as an efavirenz (Sustiva)-based regimen when used as maintenance therapy to keep viral load suppressed, according to a poster presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle.

David Margolis from GlaxoSmithKline and colleagues presented findings from the phase 2b LATTE (Long-Acting Antiretroviral Treatment Enabling) trial, which was designed to select the best oral dose of cabotegravir and to evaluate cabotegravir plus rilpivirine as a simple two-drug maintenance regimen for people who had already achieved undetectable viral load using a standard combination antiretroviral regimen. Showing that the two drugs are effective when taken as once-daily pills was intended to lay the groundwork for studies of long-acting injectable formulations of both drugs.

LATTE started with a 24-week induction phase comparing three oral doses of cabotegravir plus two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). After 24 weeks, participants with stable viral suppression discontinued the NRTIs and substituted rilpivirine. The three-drug lead-in for initial viral suppression was done because rilpivirine has been shown not to work as well for people with high baseline viral loads (>100,000 copes/ml) in some prior studies.

This multicentre trial included 243 participants starting their first antiretroviral regimen. Almost all were men, about 60% were white and the median age was about 33 years. (The low number of women was in part due to a restriction on use of hormonal contraception, since interactions with cabotegravir were not yet known.) The median baseline CD4 cell count was about 410 cells/mm³ and 14% had an initial viral load >100,000 copies/ml. About 5% had hepatitis C co-infection.

Participants in this partially blinded trial were randomly assigned to start on one of three doses of cabotegravir (10, 30, or 60mg) or 600mg efavirenz, all once daily, taken with two NRTIs selected by their provider; about 60% used tenofovir/emtricitabine (Truvada) while the rest used abacavir/lamivudine (Kivexa or Epzicom). Cabotegravir recipients with HIV RNA <50 copies/ml at 24 weeks stopped their NRTIs and substituted 25mg rilpivirine, while those in the efavirenz group stayed on their same regimen. At 96 weeks, cabotegravir recipients could continue on the same treatment in an open-label phase while efavirenz recipients finished the study.

The primary endpoint was viral suppression at 48 weeks, which Margolis reported at last year's CROI. At 24 weeks, 87% of participants in the cabotegravir arm (with little difference between doses) and 74% in the efavirenz arm had undetectable viral load. At that point, 160 people taking cabotegravir and 47 taking efavirenz entered the maintenance phase.

At 48 weeks, 82% of all participants who started on cabotegravir and 71% of participants taking efavirenz (including those who discontinued at week 24) had continued viral suppression – not a statistically significant difference. The higher rate of treatment failure with efavirenz was driven by more discontinuations due to adverse events, in particular neuropsychiatric side-effects.

This year the researchers presented 96-week findings. At 96 weeks, 76% of all participants who started on cabotegravir (all doses combined) had HIV RNA <50 copies/ml in an intent-to-treat 'snapshot' analysis, as did 63% of those who stayed on efavirenz plus NRTIs. There were six cases (3%) of protocol-defined virological failure in the combined cabotegravir arms and six cases (10%) in the efavirenz arm.

Looking only at participants who entered the maintenance phase, 86% in the combined cabotegravir arms and 83% in the efavirenz arms maintained undetectable viral load. Within this group, there were three cases (2%) of protocol-defined virological failure in the cabotegravir arms and two cases (4%) in the efavirenz arm. Two cabotegravir recipients showed evidence of treatment-emergent drug resistance.

Median CD4 cell gains were similar, 260 cells/mm³ in the combined cabotegravir arms and 289 cells/mm³ in the efavirenz arm.

Both regimens, and all cabotegravir doses, were generally safe and well-tolerated; 14% of cabotegravir recipients and 19% of efavirenz recipients reported grade 2 (moderate) or worse adverse events; in both arms, 4% of these arose during the maintenance phase. 10% of participants in the cabotegravir arm and 6% in the efavirenz arm experienced serious adverse events. 4% of cabotegravir recipients withdrew early due to adverse events compared to 15% in the efavirenz arm; most of these discontinuations occurred prior to the maintenance phase.

Headache was the only side-effect that was more common in the cabotegravir arms (3% vs 0%), while neuropsychiatric symptoms such as dizziness and insomnia were more common in the efavirenz arm.

The 30mg cabotegravir dose was selected for further development as part of oral HIV treatment.

These results confirm that cabotegravir plus rilpivirine is an effective maintenance regimen for people who have achieved undetectable viral load on a standard regimen, supporting evaluation of long-acting injectable formulations of these drugs. Other recent research has shown that long-acting injectable cabotegravir remains at therapeutic levels in the blood with either monthly or quarterly dosing.

The long-acting injectable formulations of cabotegravir and rilpivirine are also being studied for pre-exposure prophylaxis, or PrEP. In animal studies, monthly cabotegravir injections protected macaque monkeys against infection with an HIV-like virus delivered via either rectal or vaginal exposure. Other recent research showed that injectable cabotegravir may reach adequate levels in rectal and vaginal tissue to work as PrEP. However, drug level studies suggest that injectable rilpivirine does not last as long and may be more effective at preventing rectal infection than vaginal infection.