Lenakapavir proves to be an effective antiretroviral option in salvage therapy

Lenakapavir proves to be an effective antiretroviral option in salvage therapy

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There are several antiretroviral treatment options for people living with HIV. However, in the presence of multiple drug-resistant mutations, treatment options become limited and complex. For this reason, new options are desirable.

Lenacapavir is a novel antiretroviral drug from the class of capsid inhibitors capable of interfering with viral replication at different stages of the viral cycle.study in vitro showed that the drug retains antiviral activity even in the presence of mutations in the main class of antiretroviral drugs.

also read: CROI 2022: HIV and Long-Term Antiretroviral Therapy – lenacapavir and Other New Drugs

Another feature of lenacapavir that makes it a drug of interest is that it can be used as a long-acting drug that can be administered subcutaneously every six months or orally every week.

The results of the Phase 3 study – CAPELLA – were published in New England Journal of Medicineto evaluate the efficacy and safety of lenacapavir in patients with multidrug-resistant HIV-1 infection.

lenacapavir pill, the new HIV antiretroviral drug

Materials and methods

This is an international multicenter study conducted at 42 sites in 11 countries between November 2019 and January 2021. Subjects were eligible if they were 12 years of age or older, had been on stable antiretroviral therapy for at least 8 weeks, and had virological evidence. Evidence of failure and resistance to at least two of at least three of the four major antiretroviral drugs.

Participants were divided into two groups. The first design included copies/mm³ between screening and follow-up study visits with a viral load of at least 400 copies/mm³. Participants in this cohort were randomized 2:1 to receive functional monotherapy, either oral lenacapavivir or a placebo related to the regimen they were using. On D15, participants in both groups began receiving subcutaneous lenacapavivir every six months along with optimized antiretroviral therapy.

The second group was designed to include volunteers with at least a 0.5 log decrease in copy number/mm³ between visits and/or a viral load below 400 copies/mm³. All participants in this cohort received oral lenacapavivir and optimized antiretroviral therapy on day 1 of the study, followed by subcutaneous injections of lenacapavivir every six months starting on day 15.

Primary and secondary efficacy endpoints were assessed in Cohort 1. The primary endpoint was defined as the percentage of participants with at least a 0.5 log reduction in copies/mm³ at day 15. Secondary endpoints were the percentage of participants with a viral load below 50 copies/mm³ and a viral load below 200 copies/mm³, and changes in viral load and counts at week 26 after starting SC lenacapavir. T-CD4 lymphocytes. All participants who received at least one dose of lenacapavir were evaluated for safety outcomes.

result

Of the 144 volunteers initially screened, 72 were included, 36 in cohort 1 (24 in the lenacapavir group and 12 in the placebo group) and 36 in cohort 2. The demographics of the cohort 1 group were considered to be homogeneous, but the mean viral load in the placebo group was higher than in the group receiving lenacapavir. Median T-CD4 lymphocytes were also higher in the lenacapavir group.

In Cohort 1, participants had a median of 9 drugs prior to treatment. 47% of these patients were resistant to all four major antiretroviral drugs. Of the 36 volunteers, 17% did not have a fully effective drug in their optimized regimen. All included participants—in both cohorts—completed a functional monotherapy period of oral lenacapavir and all received their first subcutaneous dose of lenacapavir.

During functional monotherapy in Cohort 1, a reduction in viral load of 0.5 log copies was observed in 21 of 24 (88%) participants in the lenacapavir group and 2 of 12 (17%) in the placebo group /mm³ for the efficacy endpoint, which represented an absolute difference of 71%. During the maintenance period at week 26, 29 of 36 participants (81%) had a viral load below 50 copies/mm³ and 32 (89%) had a viral load below 200 copies/mm³. In cohort 2, 30 of 36 patients (83%) reported a viral load <50 copies/mm³ and 31 participants (86%) had a viral load <200 copies/mm³.

The proportion of volunteers with a viral load < 50 copies/mm³ at week 26 was higher among women, individuals under the age of 50, and volunteers with a viral load < 100,000 copies/mm³ at baseline. lenacapavir is similar in efficacy to backboneChanges in CD4 T lymphocyte counts were also observed: at the end of the 26-week maintenance period, the proportion of participants with CD4 < 50 cells/mm³ enrolled in both cohorts decreased from 24% (17 of 72 participants) to 0% (0 of 67 participants).

During the study period, 19 participants were assessed for development of resistance. Eight mutations associated with capsid replacement were detected during the maintenance phase, four in cohort 1 (1 in the lenacapavir group and 3 in the placebo group) and 4 in cohort 2. Nonetheless, 4 of these patients had suppressed viral load on maintenance therapy with lenacapavir.

Regarding safety data, 38% of participants in the lenacapavir group and 25% in the placebo group reported at least one adverse event during functional monotherapy. However, no serious adverse events were reported, and neither group discontinued the study product. In an analysis combining cohorts 1 and 2, 7 of 72 patients experienced serious adverse events, none of which were considered to be related to the investigational product. Besides subcutaneous injection site reactions, the most common adverse events were nausea, constipation, and diarrhea. The most common local reactions are pain, swelling, erythema, and nodule formation.

Practical information

– Lenacapavir has shown salvage efficacy in HIV-1 patients with multidrug resistance and limited treatment options, with a favorable safety profile.

– This was a small study but had favorable results in using lenacapavir as rescue therapy. The possibility as a long-term drug and an alternative route of administration make this drug an attractive option for people with compliance problems.

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