Lenacapavir in MDR HIV: phase 3 results of CAPELLA study published
Full results from the phase 3 CAPELLA study of lenacapavir in people with multidrug resistant HIV are now published in the NEJM, together with editorial comment. [1, 2]
Lenacpavir is a first-generation capsid inhibitor that retains efficacy against mutations that confer resistance to other ARV classes. Approvals for an MDR indication were sought from the FDA and EMA June and August 2021, respectively. 
The results were also presented at CROI 2022 and EACS 2021 and in earlier issues of HTB. [4, 5]
Notably, lenacapavir is given by subcutaneous injection every six months, but is used in combination with other ARVs. This is likely to include oral dosing, until other long-acting options become available.
Without combination therapy, resistance to lenacapavir can develop easily if viral load remains unsuppressed or adherence to other ARVs in the combination is low. Viral failure was reported in 8/72 participants in CAPELLA, generally early, and with 4/8 linked to low adherence.
The CAPELLA study included a highly treatment-experienced population, with half having MDR to at least four classes and including resistance to fostemsavir and ibalizumab in roughly one-third of participants (to each drug).
Lenacapavir has so far been associated with few side effects, other than injection site reactions which are generally mild; only two participants reported grade 3 events, both of which resolved. None of the serious events reported in seven participants were judged to be lenacapavir-related.
The accompanying editorial positively notes that although numbers were small in CAPELLA, it included adolescents (older than 12), 25% woman, low CD4 count (median 150 cells/mm3, range: 3 to 1296). Viral load was also low however (<15,000 copies/mL), making it easier to achieve the secondary endpoints of suppression to undetectable (<50 copies/mL). Although the editorial refers to a relatively high baseline BMI, this doesn’t seem to be included in online results.
The editorial also raises importance of safety issues in PrEP studies that are currently ongoing and on the challenge of generating safety data during pregnancy and access for people living in the global South.
- Segal-Maurer S et al for CAPELLA Study Investigators. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N Engl J Med 2022; 386:1793-1803. DOI: 10.1056/NEJMoa2115542. (12 May 2022).
- Marrazzo J. Lenacapavir for HIV-1 — Potential Promise of a Long-Acting Antiretroviral Drug. N Engl J Med. Editorial comment. 2022; 386:1848-1849. DOI: 10.1056/NEJMe2204376. (12 May 2022).
- Lenacapavir submitted to EMA for MDR HIV, HTB (21 September 2019).
- CROI 2022: Lenacapavir in treatment-experienced participants, and as PrEP in macaques. HTB (1 March 2022).
- EACS 2021: Lenacapavir: drug resistance after viral rebound in treatment experienced participants. HTB (30 November 2022).
This report was first published on 12 May 2022.