Long-Acting HIV Drug Promising for Treatment-Naive Patients

Lenacapavir (Sunlenca) given every 26 weeks along with daily antiretroviral therapy (ART) suppressed HIV on par with conventional regimens in the first-line setting in the phase II CALIBRATE trial.

Viral suppression to fewer than 50 copies/mL at week 54 was 85-90% across all three groups given the drug whether orally or subcutaneously every 26 weeks (in combination with two daily oral ART drugs for the first 28 weeks, then one after that), which was not significantly different than the 94% rate with oral daily bictegravir, emtricitabine, and tenofovir alafenamide (Biktarvy).

"These data suggest that lenacapavir combined with a second potent agent can be effective in maintaining virological suppression, which is consistent with previous studies of two-drug regimens," Samir K. Gupta, MD, of Indiana University School of Medicine in Indianapolis, and colleagues reported in The Lancet HIV.

Lenacapavir is a first-in-class capsid inhibitor that is active at multiple points in the viral life cycle. It was recently FDA-approved for heavily pretreated HIV-1 patients with drug-resistant infections, and for those who cannot tolerate other available options, in combination with ART, based on data from the CAPELLA trial.

However, despite findings of efficacy in studies when given every day, every week, or as an injectable up to every 6 months, lenacapavir is dependent on antiretroviral drugs that need to be given daily.

"These are undoubtedly promising results; however, lenacapavir needs a long-acting partner if it is to deliver on the promise of being part of a complete long-acting regimen," noted Chloe Orkin, MBBCH, of Queen Mary University in London, writing in a commentary accompanying the study. "With the development of islatravir slowed by unexpected immunological findings, the identity of this partner is far from clear."

Islatravir clinical trials were put on hold after the drug caused decreases in total lymphocyte and CD4+ T-cell counts in some participants.

While no other long-acting antiretrovirals are currently available, Gupta and co-authors noted "ongoing efforts to develop a long-acting partner agent that can be combined with lenacapavir as a complete synchronous regimen, offering the best potential for sustained adherence."

The trial with lenacapavir included 182 adult patients randomly assigned to treatment in four groups. Group 1 (n=52) and group 2 (n=53) were assigned to 927 mg lenacapavir subcutaneously every 26 weeks (after 2 weeks of oral loading) along with oral daily emtricitabine and tenofovir alafenamide (Descovy) for 28 weeks. Then following a second dose of subcutaneous lenacapavir, group 1 continued on 25 mg oral daily tenofovir alafenamide alone while group 2 switched to bictegravir at a dose of 75 mg.

The 52 people in group 3 got oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) plus emtricitabine and tenofovir alafenamide. Group 4 (n=25) acted as a control group, and these patients received oral daily bictegravir, emtricitabine, and tenofovir alafenamide.

Of the 182 participants who received treatment, 22 did not complete the study -- 17 of whom were in the lenacapavir group.

All participants were treatment-naive with plasma HIV-1 RNA of at least 200 copies/mL and CD4 cell counts of at least 200 cells/μL without hepatitis B or C infection. The trial was largely male (93%), and most patients were Black (52%) or white (43%), with 45% identifying as Latinx.

The most common adverse events with lenacapavir were injection-site reactions, including erythema (27%), swelling (23%), and pain (19%). Other adverse events included headache and nausea (13% each).

Limitations of the study included the small sample size, very few women participants (12 in total), and limited duration. While several participants discontinued (three due to grade 1 injection-site reactions), the researchers said that discontinuation was not due to safety or efficacy.

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