Liz Higheyman
Long-acting cabotegravir ( Vocabria ) and rilpivirine ( Rekambys ) injections maintain viral suppression for two years, according to follow-up study results presented this week at the Conference on Retroviruses and Opportunistic Infections (CROI).
The European Medicines Agency (EMA) approved the injectable combination, the first complete HIV regimen that doesn't require daily pills, in December 2020. The regimen involves two separate injections in the buttocks administered by a healthcare provider. The EMA approved a once-monthly regimen and a once-every-two-month regimen. However, regulators in the United States and Canada (where the injections are marketed together as Cabenuva ) only approved the monthly regimen. The treatment that can be taken just six times a year would be more convenient and could improve adherence.
At CROI 2019, researchers reported results from the phase 3 ATLAS trial, which enrolled people with undetectable viral loads who switched from a standard oral antiretroviral regimen, and the FLAIR trial, which enrolled people starting HIV treatment for the first time. These studies showed that once-monthly cabotegravir and rilpivirine maintained viral suppression in treatment-experienced individuals and brought viral loads below detectable levels in treatment-starters.
The ATLAS study found that drug levels remained in the body for more than a month, setting the stage to test a regimen every two months in the ATLAS-2M study.
ATLAS-2M included 654 participants with undetectable viral loads who switched from a daily oral regimen and 391 people who switched from the monthly cabotegravir/rilpivirine arm of the original ATLAS trial. In the total study population, over 70% were male, the median age was 42 years, and the median CD4 count exceeded 600.
Participants were randomly assigned to receive injections of either 400 mg of cabotegravir and 600 mg of rilpivirine every four weeks or 600 mg of cabotegravir and 900 mg of rilpivirine every eight weeks after an initial two-week period of cabotegravir and rilpivirine in pill form.
At last year's CROI, researchers reported that after 48 weeks of treatment, 94% of participants taking the once-a-month or once-every-two-month regimen still had an undetectable viral load (below 50), demonstrating that the less frequent regimen was non-inferior to monthly administration.
This year, Dr. Hans Jaeger of the MVZ Karlsplatz HIV Research and Clinical Care Center in Munich presented the longer-term results of ATLAS-2M, extending the follow-up to 96 weeks.
After two years, 90.2% of participants in the once-a-month group and 91.0% in the every-two-month group maintained viral suppression, demonstrating that the programs remained equally effective; 1.1% and 2.1%, respectively, had a detectable viral load (data were missing for the remainder).
Two participants in the once-a-month group (0.4%) and nine in the every-two-month group (1.7%) experienced confirmed virological failure, defined as two consecutive viral load measurements above 200; only one person in the latter arm met the criteria during the second year of follow-up.
One of the two participants with virologic failure in the once-monthly group was found to have viral mutations associated with rilpivirine resistance, and both had integrase inhibitor resistance mutations. Seven of the nine people in the every-two-month group had rilpivirine resistance, and five had integrase inhibitor resistance.
All but one of these 11 participants regained viral suppression when they switched to a different regimen (the remaining individual had evidence of poor adherence to the new regimen), and all had a virus that remained susceptible to dolutegravir, another integrase inhibitor.
Two other analyses presented at CROI suggest that receiving injections on time is particularly important for those using the every-two-month regimen. The once-monthly schedule is likely to be more forgiving. Dr. Kelong Han of GlaxoSmithKline and colleagues conducted a pharmacokinetic modeling study of cabotegravir, while Dr. Stefaan Rossenu of Janssen and colleagues performed a similar analysis of rilpivirine.
Han's team concluded that adherence to the bimonthly dosing schedule is "strongly recommended." While delays in cabotegravir injections of up to one week were predicted to have minimal effect, longer delays would have a greater impact. Similarly, Rossenu's team found that receiving rilpivirine injections one week early or late should have minimal impact on drug levels, but recommended adhering to the bimonthly schedule. Cabotegravir and rilpivirine pills can be used as a "bridging" strategy if someone plans to miss an injection appointment.
"Receiving the injections on time is particularly important for those using the every-two-month regimen."
Cabotegravir and rilpivirine injections were safe and generally well tolerated. Approximately 12% in both groups experienced serious side effects, falling to 2% when injection-site reactions were excluded. The most common side effect was injection-site pain, reported by 14% in the once-monthly group and 21% in the every-two-monthly group. Injection-site reactions were mostly mild or moderate and lasted a median of three days. Adverse events leading to study discontinuation were uncommon (4% in the once-monthly group and 3% in the every-two-monthly group).
In previous studies, most participants said they preferred injections to daily pills despite injection-related side effects. Reasons included greater convenience, not having to think about HIV and its treatment every day, and not having pill bottles that could reveal their serological status. The drawback is the need to see a provider more frequently than most people to monitor viral load while on stable oral therapy.
Injectable cabotegravir is also being studied for pre-exposure prophylaxis (PrEP) alone. Cabotegravir injections administered every other month were found to be more effective for HIV prevention than daily tenofovir disoproxil fumarate/emtricitabine ( Truvada ) in both cisgender men and transgender women who have sex with men in the HPTN 083 trial and in cisgender women in the HPTN 084 study. References
Jaeger H et al. Week 96: Efficacy and safety of cabotegravir + rilpivirine every 2 months: ATLAS-2M . Conference on Retroviruses and Opportunistic Infections, 2021, abstract 401.
Han K et al. Simulation of C abotegravir PPK to inform Q2M strategies after dosing interruptions . Conference on Retroviruses and Opportunistic Infections, 2021, abstract 373.
Rossenu S et al. POPPK modeling of Q2M IM RPV LA to manage dosing interruptions in HIV-1 patients . Conference on Retroviruses and Opportunistic Infections, 2021, abstract 403.