Long-acting injectables may be better than daily pills for people with adherence challenges

Antiretroviral treatment using monthly cabotegravir and rilpivirine injections is more effective than daily pills for people who have had difficulty achieving good adherence and  maintaining viral suppression, according to an announcement this week from ViiV Healthcare.

The company said that after reviewing interim findings, the data safety and monitoring board for the LATITUDE trial recommended that randomisation should be stopped and study participants taking daily pills should be offered the long-acting injectables.

“The interim data indicating the superiority of long-acting therapy compared to daily oral therapy in individuals who have difficulty taking pills for HIV every day is a remarkable outcome,” Dr Kimberly Smith, head of R&D at ViiV, said in a press release. The announcement did not include detailed data, which will presented at an upcoming conference, according to the company.

All modern antiretroviral therapy (ART) is highly effective and generally well tolerated, so treatment success often comes down to consistent use. Some people have difficulty maintaining good adherence because they forget to take their pills or don’t want to think about HIV every day, are concerned about having pill bottles that could reveal their HIV status, or are in living situations where their pills could be lost or stolen. According to the US Centers for Disease Control and Prevention, about a third of people with diagnosed HIV in the United States do not have viral suppression, which means they are at risk for disease progression and could transmit the virus to their sex partners. For some of these individuals, long-acting treatment may be a preferrable option.

Injectable formulations of the next-generation integrase inhibitor cabotegravir (Vocabria) and the NNRTI rilpivirine (Rekambys) comprise the first complete antiretroviral regimen that does not require daily pills. (In the United States and Canada, the two drugs are marketed together as Cabenuva.) The treatment involves two intramuscular injections in the buttocks administered by a healthcare provider once monthly or every two months.

As previously reported at the 2019 Conference on Retroviruses and Opportunistic Infections, two phase III clinical trials showed that the long-acting injectable regimen works as well as daily pills.

The ATLAS study evaluated injectable cabotegravir and rilpivirine as maintenance therapy for treatment-experienced people with a stable undetectable viral load on a standard oral regimen. They were randomly assigned to either stay on their current daily oral regimen or switch to monthly injections after a month-long lead-in of cabotegravir and rilpivirine pills. Virological response rates were 96% and 93%, respectively, showing that the injectables were non-inferior to continued oral therapy. The FLAIR study enrolled previously untreated people who briefly used a standard oral regimen to achieve viral suppression before being randomised to either stay on the pills or switch to the injections. Response rates were again comparable, at 93% and 94%, respectively.

Since that time, other research has looked at refinements to the injectable treatment. The ATLAS-2M and SOLAR trials showed that administering the injections every other month works as well as once-monthly dosing. Another study showed that the cabotegravir and rilpivirine oral lead-in is not necessary.

The European Medicines Agency and the US Food and Drug Administration have approved both dosing schedules for people with viral suppression who have no history of treatment failure and no known or suspected resistance to either drug. Some clinicians in the UK have said that the criteria for prescribing cabotegravir and rilpivirine are too strict and that the people who most need a new option can’t access them.

The LATITUDE (Long-Acting Therapy to Improve Treatment Success in Daily Life) trial (NCT03635788), sponsored by the US National Institutes of Health (NIH) and implemented through the ACTG clinical trials network, focuses on people who face challenges taking daily oral treatment and have evidence of detectable virus. Launched in 2019, the study is ongoing at 31 sites in the United States.

Participants were screened to ensure that their HIV was not resistant to the study drugs and that they met other health and safety criteria. They started on a three-drug oral regimen (including dolutegravir- and bictegravir-based combinations) for 24 weeks while receiving comprehensive adherence support and economic incentives to achieve viral suppression. Eligible participants were then randomly assigned to either continue taking the same oral regimen or switch to injectable cabotegravir and rilpivirine (with or without the optional oral lead-in) administered once monthly for a year. The every-other-month dosing schedule was not used in this study.

Based on a planned interim review on February 12, the injectable regimen “demonstrated superior efficacy in maintaining viral load suppression compared to daily oral therapy in individuals with a history of ART adherence challenges,” according to the ViiV announcement.

“Study participants are being notified of these findings, and those currently taking daily oral ART will decide with their providers which ART method suits their needs best,” according to a NIH statement. All study participants will be monitored for another year. 

“There are many reasons why people may find it challenging to stay on daily oral treatment and the LATITUDE study shows cabotegravir and rilpivirine injectable treatment can help them keep their virus suppressed, which benefits their overall health,” Smith said. “Optimising therapy for all people living with HIV, including those with adherence challenges, is critical to the effort to end the HIV epidemic.”

As noted, the injectable regimen is only approved for people with an undetectable viral load. LATITUDE participants received support to achieve viral suppression on an oral regimen before switching to the injections, so the study results do not apply to people who are unwilling or unable to take pills consistently for several months in order to get their HIV under control. Pilot studies, however, have shown that the long-acting regimen is also a feasible option for people without viral suppression if given with adequate support.