Cabotegravir + Rilpivirine in Long-Lasting Injectable Formulation Maintains Viral Suppression for 32 Weeks

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The combination of two long-acting injectable antiretrovirals — ViiV Healthcare's experimental integrase inhibitor cabotegravir and Janssen's NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitor) rilpivirine — given once every 4 to 8 weeks has 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 2 b LATTE Study follow previous reports from the original LATTE study showing that oral Cabotegravir+rilpivirine keeps HIV suppressed, as well as a three-drug therapy regimen with efavirenz, but with fewer side effects.

Long-acting drugs may offer an attractive option for people living with HIV seeking lifelong antiretroviral therapy (ART). These agents have the advantage of being more convenient and have the potential to improve adherence, but the disadvantage is that a long-lived drug cannot be easily removed from the body once administered, therefore it is especially important to establish safety in advance. .

The phase 2 b of the LATTE study evaluated Cabotegravir plus rilpivirine as a simple treatment regimen, a two-drug regimen for people who had already achieved an undetectable viral load using standard treatment that uses a combination of at least three drugs in ART, proving, above all, that both drugs are effective when taken as daily tablets, providing the necessary basis to test their time in action injectable formulations.

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

David Margolis of ViiV/GlaxoSmithKline: Presenting the findings from the 48th week.

The Evaluation of Oral Maintenance Therapy at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI) and the results of the 96th week this year (link opens in another tab, another website, in English); These results were recently published in the issue of October 2015 Lancet on Infectious Diseases. (link opens in another tab, another website, in English)

LATTE (study LAI116482) began with a dose available in the 24th 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 (NRTI). After 24 weeks, those receiving Cabotegravir with stable viral suppression (<50 copies/mL) had NRTIs discontinued and replaced with rilpivirine 25 mg once daily throughout treatment until the 96th week.

This analysis included 243 people with HIV with no prior treatment history in the US and Canada. Almost all (96%) were male, around 60% were white, around 30% were black, the average age was 33 years old and 4% were co-infected with the hepatitis C virus. median T-CD4 cell count was 416 cells/mm 3 , and 14% had a high viral load (>100.000 copies/mL). Around 60% had initially used tenofovir/emtricitabine (Truvada) while around 40% had used abacavir/lamivudine (Epzicom).

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

At 96 weeks, 76% of cabotegravir recipients and 63% of efavirenz recipients had undetectable viral loads. Looking only at participants who entered the maintenance period, 86% and 83%, respectively, continued viral suppression. At week 96, response rates did not appear to improve with higher doses of cabotegravir (68%, 75%, and 84%, using 10, 30, and 60 mg, respectively).

Differences in responses were more pronounced in patients with high viral loads. Among people with HIV RNA <100.000 copies/ml at baseline, response rates were 71%, 75%, and 88% at 10, 30, and 60 mg doses in the cabotegravir arm and 59% in the efavirenz arm. Among those with viral load > 100.000 copies/ml, the rates were 50%, 71%, 67% and 88%, respectively. However, the researchers stressed that, when stratified by viral load, the difference in numbers in each subgroup was small.

The lower rate of treatment failure in the cabotegravir arm relative to the efavirenz arm was driven by lower virologic response rates (10% vs 16%) and fewer withdrawals due to the occurrence of adverse events (3% vs 13%), which researchers.

Cabotegravir was generally safe and well tolerated. At 96 weeks, 51% of cabotegravir beneficiaries — again with little difference between doses — and 68% of efavirenz beneficiaries 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.

“The LATTE results indicating that the two-drug regimen using Cabotegravir plus Rilpivirine provides viral suppression that is at least similar to the three-drug regimens with efavirenz and two NRTIs during 72 weeks of maintenance therapy on ART in adult population with no previous experience of Antiretroviral Therapy are instructive to carry out a more in-depth evaluation and the development of long-acting injectable formulations with cabotegravir and rilpivirine,” concluded the study authors.

Injectables with long-lasting action

 

Since these results confirm that cabotegravir plus rilpivirine form an effective oral maintenance regimen for people who have achieved viral suppression on a standard regimen, researchers evaluated the time of action of injectable formulations of these drugs in the LATTE Study (NCT02120352).

This analysis included 309 previously untreated participants initiating treatment for the first time with oral presentation of a three-drug regimen consisting of 30 mg once daily cabotegravir plus two NRTIs. After achieving viral suppression, they were randomly assigned to remain on the oral regimen or to receive injections of rilpivirine plus cabotegravir every 4 weeks (Q4W) or 8 weeks (Q8W). Previous research has shown that injectable cabotegravir Remains at therapeutic levels  (link opens in another tab, another website, in English) with monthly or quarterly dosages.

After 32 weeks (the primary endpoint), 94% and 95% of participants who received the injections every 4 or 8 weeks, respectively, maintained viral suppression, as did 91% of those who received oral treatment, according to press releases. press issued by ViiV and Janssen. The 2 people who met the virological failure criteria definition protocol (1 in the Q8W injection arm and 1 in the oral arm) show no evidence of drug resistance.

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

Study results at 32 weeks will be presented at the next scientific conference, according to press releases. Study follow-up will continue for 96 weeks.

The companies are now planning to further evaluate the long-acting injectable solution in a larger, phase III study.

The long duration of action of cabotegravir and rilpivirine formulations is also being studied for pre-exposure prophylaxis, or PrEP. In animal studies protected by monthly cabotegravir injections in monkeys against infection with a virus such as HIV delivered via exposure by rectal examination or vaginal exposure *link opens in another tab, another website, another language.

The results of the LATTE Study “challenge the notion that dual therapy is a realistic option over triple therapy,” Mark Alastair Boyd and David Cooper of the Kirby Institute at the University of New South Wales wrote in some comments to LANCET . “The LATTE Study may therefore not only be the beginning of a new era of long-acting intramuscular treatments, a long-term management option against HIV, but also the dawn of an effective and well-tolerated dual-drug therapy [NRTI] sparing patients from protease inhibitors as well as long-term single-tablet oral ART regimens.”

3/11/15

Translated by Claudio Souza from the Original in Long-acting Injectable Cabotegravir + Rilpivirine Maintains HIV Suppression for 32 Weeks

Reviewed by Mara Macedo on November 18, 2015

Written by Liz Highleymande medicines put your personal safety at risk

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 randomized, phase 2b, dose-ranging trial. Lancet Infectious Diseases15 (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 injectable drug regimens 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.