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Long-acting Injectable Cabotegravir + Rilpivirine Maintains HIV Suppression for 32 Weeks

A combination of 2 long-acting injectable antiretrovirals -- ViiV Healthcare's experimental integrase inhibitor cabotegravir and Janssen's NNRTI rilpivirine -- given once every 4 or 8 weeks maintained viral suppression as well as a standard oral regimen and appears safe and well-tolerated, the companies announced this week. These findings from the Phase 2b LATTE 2 trial follow earlier reports from the original LATTE study showing that oral cabotegravir plus rilpivirine suppressed HIV as well as an efavirenz-based regimen, but with fewer side effects.

Long-acting drugs could offer an attractive option for people with HIV facing lifelong antiretroviral therapy (ART). Such agents have the advantages of being more convenient and potentially improving adherence, but the drawback is that a long-lived drug cannot be easily removed from the body once administered, so it is especially important to establish safety in advance.

The Phase 2b LATTE (Long-Acting Antiretroviral Treatment Enabling) trial evaluated cabotegravir plus rilpivirine as a simple 2-drug maintenance regimen for people who had already achieved undetectable viral load using standard 3-drug combination ART. Evidence that the 2 drugs are effective when taken as once-daily pills laid the groundwork for testing their long-acting injectable formulations.

Cabotegravir (formerly GSK1265744) is an integrase inhibitor related to the currently available dolutegravir (Tivicay), while rilpivirine (Edurant) is an approved non-nucleoside reverse transcriptase inhibitor.

David Margolis from ViiV/GlaxoSmithKline presented 48-week findings from the oral maintenance therapy evaluation at the 2014 Conference on Retroviruses and Opportunistic Infections and 96-week results at this year's CROI; these results were recently published in the October 2015 edition of Lancet Infectious Diseases.

LATTE (study LAI116482) started with a 24-week induction period comparing 3 oral doses of cabotegravir (10, 30, or 60 mg once-daily) or 600 mg once-daily efavirenz (Sustiva) plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). After 24 weeks, cabotegravir recipients with stable viral suppression (<50 copies/mL) discontinued their NRTIs and substituted 25 mg once-daily rilpivirine through week 96.

This analysis included 243 previously untreated people with HIV in the U.S. and Canada. Almost all (96%) were men, about 60% were white, about 30% were black, the median age was 33 years, and 4% were coinfected with hepatitis C. At baseline the median CD4 T-cell count was 416 cells/mm³ and 14% had high viral load (>100,000 copies/mL).About 60% initially used tenofovir/emtricitabine (Truvada) while about 40% used abacavir/lamivudine (Epzicom).

At the end of the 24-week induction period, 86% of participants in the combined cabotegravir arms (with little difference between doses) and 74% in the efavirenz arm had undetectable viral load. At 48 weeks, 82% of participants who continued on cabotegravir plus rilpivirine and 71% assigned to efavirenz maintained viral suppression. These differences were not statistically significant.

At 96 weeks, 76% of cabotegravir recipients and 63% of efavirenz recipients maintained undetectable viral load. Looking only at participants who entered the maintenance period, 86% and 83%, respectively, had continued viral suppression. Week 96 response rates did appear to improve with higher cabotegravir doses (68%, 75%, and 84% using 10, 30, and 60 mg, respectively).

Differences in response were more pronounced at high viral loads. Among people with HIV RNA <100,000 copies/mL at baseline, response rates were 71%, 75%, and 88% in the 10, 30, and 60 mg cabotegravir dose arms and 59% in the efavirenz arm. Among those with >100,000 copies/mL, rates were 50%, 71%, 67%, and 88%, respectively. However, the researchers stressed that when stratified by viral load, the numbers in each subgroup were small.

The lower treatment failure rate in the cabotegravir arms compared to the efavirenz arm was driven by both fewer virological non-responders (10% vs 16%) and fewer withdrawals due to adverse events (3% vs 13%), the researchers noted.

Cabotegravir was generally safe and well-tolerated. At 96 weeks, 51% of cabotegravir recipients -- again with little difference between doses -- and 68% of efavirenz recipients reported treatment-related adverse events of any severity. In particular, central nervous system side effects such as dizziness (6% vs 23%) and insomnia (4% vs 15%) were more common with efavirenz.

"Results from LATTE indicating that the 2-drug regimen of cabotegravir plus rilpivirine provides viral suppression that is at least similar to the 3-drug regimen of efavirenz plus dual NRTIs for 72 weeks of maintenance therapy in an antiretroviral-naive adult population are informative for further assessment and development of long-acting injectable formulations of cabotegravir and rilpivirine," the study authors concluded.

Long-acting Injectables

Once these results confirmed that cabotegravir plus rilpivirine is an effective oral maintenance regimen for people who have achieved viral suppression on a standard regimen, the researchers evaluated the long-acting injectable formulations of these drugs in the LATTE 2 trial (NCT02120352).

This analysis included 309 previously untreated participants who first started on an oral 3-drug regimen consisting of 30 mg once-daily cabotegravir plus 2 NRTIs. After achieving viral suppression they were randomly assigned either to stay on the oral regimen or to receive cabotegravir and rilpivirine injections every 4 weeks (Q4W) or 8 weeks (Q8W). Prior research showed that injectable cabotegravir remains at therapeutic levels with either monthly or quarterly dosing.

After 32 weeks (the primary endpoint), 94% and 95% of participants receiving injections every 4 or 8 weeks, respectively, maintained viral suppression, as did 91% of those on the oral regimen, according to press releases issued by ViiV and Janssen. The 2 people who met the protocol-defined criteria for virological failure (1 in the Q8W injection arm and 1 in the oral arm) did not show evidence of drug resistance.

People who switched to the Q4W injections reported more adverse events leading to withdrawal than those receiving Q8W shots or the oral regimen (5%, 2%, and 2%, respectively). The most common side effect was injection site pain (93% of injection recipients). Two patients in the Q8W arm -- but none in the Q4W arm -- withdrew due to injection intolerance.

The 32-week results will be presented at a forthcoming scientific conference, according to the press releases. Follow-up will continue through week 96.The companies are now planning to further evaluate the long-acting injectable regimen in a larger Phase 3 trial.

The long-acting 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 rectal exposureor vaginal exposure.

Results from LATTE "challenge the notion that dual therapy is not a realistic option compared with triple therapy," Mark Alastair Boyd and David Cooper from the Kirby Institute at the University of New South Wales wrote in a accompanying commentary to the Lancet report. "The LATTE study might therefore herald not only the beginning of a new era of long-acting intramuscular injection as an option for long-term HIV management, but also the dawn of an effective and well tolerated 2-drug [NRTI]-sparing and protease-inhibitor-sparing single tablet regimen for long-term oral ART."

11/3/15

References

DA Margolis, CC Brinson, GHR Smith, WR Spreen, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infectious Diseases 15(10):1145-1155. October 2015.

MA Boyd and DA Cooper. The LATTE study: a provocative brew (Commentary). Lancet Infectious Diseases 15(10):1116-1117. October 2015.

Other Sources

ViiV Healthcare. ViiV Healthcare announces positive headline results from a study of two drug injectable regimen for HIV maintenance therapy. Press release. November 3, 2015.

Janssen Sciences Ireland UC. First Investigational All Injectable Long Acting HIV Combination Regimen Study Results at 32 Weeks Announced. Press release. November 3, 2015.