HIV therapy has dramatically improved over the past few decades due to advances in new drug discoveries and reformulations allowing for simple oral regimens. These advancements have helped to combat resistance and reduce pill burden for patients. Once-daily antiretroviral regimens are quickly becoming new standards for new patients; however, adherence is still a concern. But what if patients no longer had to take a pill every day? This could be possible with the new, long-acting injectable antiretrovirals cabotegravir and Edurant.
The components of the injectable regimen consist of a non-nucleoside reverse transcriptase inhibitor (NNRTI), Edurant (rilpivirine, Janssen Therapeutics), and a new integrase strand transfer inhibitor (INSTI), cabotegravir (ViiV Healthcare). Rilpivirine is a second-generation NNRTI approved in 2011 for the indication of treatment-naive patients with HIV-1 RNA less than 100,000 copies/mL. Its increased potency, longer half-life (oral: 50 hours; intramuscular: 20-40 days) and reduced adverse effect profile in comparison with a first-generation NNRTI such as Sustiva (efavirenz, Bristol-Myers Squibb) made it ideal to combine with the new INSTI.
The discovery of integrase inhibitors in the late 2000s was pivotal for drug regimens as these agents were associated with few adverse reactions and were very effective for treatment-naive patients. Despite being new agents, Isentress (raltegravir, Merck) and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Gilead Sciences), already have documented resistance in treatment-naive and previously treated patients, thus prompting the development of the second-generation Tivicay (dolutegravir, ViiV Healthcare), an INSTI that is more sustained against resistance and has an improved administration profile. Cabotegravir, a potent analog of dolutegravir, possesses a long half-life (oral: 40 hours; intramuscular: 30-90 days), allowing for once-daily dosing with no need for a booster.
Impact of an injectable regimen
Current results appear promising for this new injectable therapy option. It is unique to have a two-drug regimen for maintenance therapy of HIV, but thus far development of resistance does not appear significant. The utility of an injection could pose several challenges for the patient. Adherence may continue to be an issue given that the initial induction phase is similar to many other current once-daily oral regimens. Patients still need to prove adherence to the oral regimen before starting an injectable maintenance therapy. Additionally, adherence to an injectable may pose its own setbacks. While satisfaction was reported to be high, it may be unfavorable to request that patients visit the clinic every 1 to 2 months when it could be reduced to once- or twice-yearly visits. If patients are able to administer the injections at home, this regimen could be a game-changer for those who are nonadherent. However, a gluteal injection may be too complicated for self-administration. The company expressed the possibility of investigating administration of the thigh, which sounds very reasonable as a new standard regimen. Lastly, the cost of these injectables will be another debate as current oral regimens are well-covered by insurance companies. The price of these new formulations is not currently available, but to incentivize use, they will likely need to be comparable to oral regimens.
More results from the phase 2b study and a future phase 3 study will determine if this is a feasible therapy regimen from an efficacy and safety standpoint. The once-daily, triple-therapy oral regimens show good tolerability and low resistance rates, making this regimen fit within the current standards. The major appeal to an injectable regimen would be the potential for improved adherence. This could dramatically change a patient’s quality of life as they are able to return to a pill-less (or at the least, a lower pill burden) life.
Source: LATTE Trial
by
Dr.Akshaya S Bhagavathula, Pharm.D
