Search Islatravir and Lenacapavir: Where Might This Investigational Combination Fit Into the Future HIV Treatment Landscape? Source: HIV Annual Update: HIV Care in 2022 and Beyond Karine Lacombe, MD, PhD Follow Discussion Released: November 30, 2021 The advent of HIV drugs with new modes of action has considerably broadened the landscape of options for heavily treated patients harboring multidrug-resistant viral variants. Several investigational drugs in the later stages of development offer the promise of further expanding options for these patients; they include lenacapavir (LEN) and islatravir (ISL), which now are being evaluated in combination as a 2-drug regimen. LEN Plus ISL as a Potential Long-Acting 2-Drug Regimen LEN is a first-in-class capsid inhibitor that binds to capsid subunits and interferes with capsid assembly during virus production and with capsid disassembly after transport of reverse transcription products into the nucleus. This unique ability plus its long half-life have led to the clinical evaluation of a weekly oral 2-drug regimen combining LEN with ISL, another investigational drug with a novel mechanism of action and long-acting dosing potential. ISL is a first-in-class nucleoside reverse transcriptase translocation inhibitor. In phase II trials that evaluated these drugs separately in different treatment contexts, each was highly potent with no major safety concerns. Until recently, ISL has been evaluated in phase II trials as a daily oral formulation in combination with doravirine for initial HIV treatment and as an oral once-monthly formulation for use as HIV pre-exposure prophylaxis (PrEP), whereas LEN has been evaluated as a SC formulation given every 6 months (following an oral lead-in) in a phase II/III trial in combination with an optimized background regimen for patients with extensive antiretroviral therapy (ART) experience and in a phase II trial in combination with daily oral tenofovir alafenamide (TAF) or daily oral bictegravir for initial HIV treatment. These studies have targeted several unmet needs in HIV treatment and prevention, including the need for long-acting PrEP options and for longer-acting treatment options in heavily treatment-experienced patients. What Additional Needs Could Be Addressed by Combining LENand ISLin a Long-Acting 2-Drug Regimen? In considering the potential for the combination of LEN and ISL to be a potent, long-acting 2-drug regimen with a high barrier to resistance and a strong safety profile, the relevant patient populations would be quite broad. First, such a regimen would be ideal for patients receiving long-term ART with a history of nonadherence or regimen shortcomings that have led to multidrug resistance. The further development of an injectable form of a regimen with these characteristics also may help patients who are reluctant to take a long-term oral treatment. Although ibalizumab and fostemsavir each were designed to provide much-needed options for heavily treatment-experienced patients and each have proven effective in combination with optimized background regimens, a 2-drug combination involving 2 novel drug classes may allow the elimination of the optimized background regimen in this setting. Similar to the role of the new long-acting 2-drug regimen of injectable cabotegravir plus rilpivirine, a long-acting 2-drug regimen of LEN plus ISL would be attractive as a switch strategy in virologically suppressed patients. If the anticipated efficacy and safety/tolerability of this regimen is demonstrated in clinical trials, it would allow patients to switch away from drugs with safety/tolerability concerns such as weight gain (newer-generation integrase strand transfer inhibitors and TAF), kidney and bone toxicity (tenofovir disoproxil fumarate), or lipid abnormalities (protease inhibitors). The favorable drug‒drug interaction profiles demonstrated or anticipated for each of these drugs also support a potential role for their combined use in patients with polypharmacy because of comorbidities. To evaluate the efficacy, safety, and convenience of an oral once-weekly regimen of ISL in combination with LEN vs continuing daily oral bictegravir/emtricitabine/TAF, a phase II randomized switch trial in virologically suppressed patients is currently recruiting. ART-naive patients make up the third group of patients who also could benefit from a long-acting 2-drug regimen of LEN plus ISL. For treatment-naive patients, the arrival of oral 2-drug regimen strategies has disrupted the treatment paradigm of highly active ART based on 3 potent drugs, which has prevailed for many years. The availability of a 2-drug combination that could be delivered either orally or parenterally with long-acting kinetics, a high barrier to resistance, and a favorable safety profile would likely be appealing to newly diagnosed patients, particularly for several key populations whose needs have not been sufficiently met by the current daily oral ART options. Who are those patients? They include men who have sex with men who may have experienced a failure of oral PrEP and/or would experience considerable benefit from having their HIV treatment adapted to their lifestyles and preferences, rather than the treatment requiring them to adapt, a condition imposed on them in many other ways through deeply rooted societal constraints. Another important group includes vulnerable individuals from often underserved populations, such as migrants or transgender women, who are at high risk of acquiring HIV and are prone to difficulties with daily oral medication adherence primarily because of socioeconomic disparities. For these patients, offering a potent, long-acting 2-drug regimen may be a substantial asset for long-term HIV control. In summary, LEN plus ISL is a 2-drug HIV treatment regimen that offers great potential, as it includes 2 new mechanisms of action for targeting HIV and is designed to be a long-acting strategy with both oral and parenteral dosing options. Target populations include treatment-experienced patients in search of potency and good tolerability who either are experiencing failure of their current regimen or are needing to switch from a virologically suppressive regimen and ART-naive patients for whom efficacy and convenience are paramount. Of course, these proposed roles for a long-acting LEN plus ISL regimen depend on the availability of clinical trial data supporting the anticipated characteristics—specifically high potency, a strong safety/tolerability profile, and a high genetic barrier to resistance. Clinical studies are planned and underway, so time will tell if the promise of this combination will live up to our high expectations. Your Thoughts? Which of the developing 2-drug ART regimens are you most excited to be able to offer your patients if they are approved? Answer the polling question and join the discussion by posting a comment. For more discussion of current and future HIV treatment, comorbidities, prevention, and COVID-19–related issues, download the slides and watch the videos from our recent HIV Annual Update symposium. Loading... Program Contents HIV Annual Update 2021 Downloadable Slidesets ClinicalThought 2-Drug ART Future HIV Treatments Video Modules Global Perspectives Provided by Clinical Care Options, LLC Contact Info Educational grant provided by Merck Sharp & Dohme Corp. 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