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Gene Stollerman Professor of Medicine
Chief, Division of Infectious Diseases
Northwestern University Feinberg School of Medicine
Babafemi Taiwo, MBBS: consultant/advisor/speaker: Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, ViiV Healthcare.
Lenacapavir (LEN) is a first-in-class, highly potent HIV capsid inhibitor that was granted Breakthrough Therapy Designation by the FDA in 2019, triggering an accelerated clinical development program that includes a once-daily oral formulation, a long-acting once-weekly oral formulation, and a long-acting SC formulation dosed every 6 months.
The long-acting SC formulation of LEN dosed every 6 months following oral loading is the furthest along in clinical development. This formulation has received regulatory approval in Europe for use in combination with other antiretrovirals in viremic, highly treatment–experienced (HTE) people with HIV (PWH) and is under review by the FDA for the same indication with a Prescription Drug User Fee Act action date of December 27, 2022. This situation is significant because effective, convenient, and well-tolerated therapies for HTE people with multidrug-resistant HIV remain a partially met need in HIV therapeutics. In the CAPELLA study, ≥75% (75% to 79%) of viremic HTE individuals with multidrug-resistant HIV receiving SC LEN plus an optimized background regimen (OBR) achieved viral suppression at 52 weeks, regardless of the number of fully active agents in the OBR (none, 1, or ≥2). LEN was generally well tolerated, and the most common adverse events were injection-site reactions such as pain, swelling, and nodule formation, which were generally of low grade and rarely led to treatment discontinuation. Based on these findings, SC LEN represents a novel option for building salvage antiretroviral therapy regimens for patients with multidrug-resistant HIV.
A key advantage of LEN is its novel mechanism of action, which explains its activity in individuals with HIV resistant to drugs from the 4 most commonly prescribed classes of antiretroviral drugs. Furthermore, the 6-month dosing of LEN makes it uniquely suitable for directly observed therapy tied to routine clinic visits. However, resistance emerged in some individuals in the CAPELLA study, although all cases of resistance emergence occurred in the context of suboptimal adherence to the OBR and/or a lack of any fully active agent in the OBR. Nevertheless, the emergence of LEN resistance mutations in the CAPELLA study—as well as in the CALIBRATE study evaluating maintenance therapy with SC LEN every 6 months plus daily oral bictegravir or tenofovir alafenamide after induction therapy in treatment-naive persons—indicates that healthcare professionals need to be vigilant about the emergence of LEN resistance in routine practice.
In virologically suppressed individuals, an oral once-weekly LEN formulation is under investigation in combination with once-weekly islatravir, the first-in-class nucleoside reverse-transcriptase translocation inhibitor. This study was placed on clinical hold after lower lymphocyte counts were observed in early clinical trials of islatravir but recently was reopened under an amended protocol with a lower dose of islatravir. If successful, this would be the first once-weekly HIV regimen. Previous surveys of PWH have shown a preference for once-weekly oral therapy among some who are receiving daily oral therapy.
Finally, in the HIV prevention space, long-acting SC LEN is being investigated for pre-exposure prophylaxis (PrEP) in 2 large phase III clinical trials (PURPOSE 1 and PURPOSE 2) that span subgroups at higher risk for HIV infection. PrEP with SC LEN may be amenable to self-administration every 6 months, which could have a transformative impact on PrEP options.
In summary, SC LEN is an emerging antiretroviral drug option for HTE PWH who have multidrug-resistant HIV. Other long-acting parenteral agents that can be combined with SC LEN are needed to meet the needs of HTE patients who are unable to adhere to an oral OBR. Meanwhile, researchers are eagerly awaiting the results of ongoing studies to determine additional roles for long-acting oral and SC LEN across the HIV prevention and treatment continuum.
How do you anticipate using long-acting SC LEN for patients with limited HIV treatment options in your clinical practice? Join the discussion and share your experiences by posting a comment.