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Lenacapavir in first-line therapy
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Download the PDF here
Chloe Orkin
January, 2023
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.18, 19
Lenacapavir is flexible in its route of administration and dosing intervals, with oral (daily to weekly) and injectable (up to every 6 months) dosing. When combined with other antiretroviral agents with synchronous dosing schedules, a range of dosing options could be possible for people with HIV. There are currently no phase 3 trials planned for any of the specific regimens evaluated in this study, all of which include antiretrovirals requiring daily administration. Oral lenacapavir is being investigated in an all-oral, once-weekly dual combination regimen (NCT05052996). For subcutaneous injectable lenacapavir, there are 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.
Update on Gilead's HIV Prevention Trials - (12/12/22)
New PrEP Studies - Lenacapavir; Adolescent Girls, Young Women - (12/12/22)
Study to Compare Bictegravir/Lenacapavir Versus Current Therapy in People With HIV-1 Who Are Successfully Treated With a Complicated Regimen
Where are we now with long-acting therapy? Based on an extensive registrational trial programme, long-acting injectable cabotegravir and rilpivirine is the first complete regimen to be recommended for the treatment of HIV-1 infection.1, 2, 3 The regimen is indicated for the treatment of virally suppressed individuals without hepatitis B co-infection who meet other virological suitability criteria.2 It is not yet universally available.
Lenacapavir is the second long-acting injectable treatment for HIV-1 infection to receive a license.4
It is a potent, first-in-class capsid inhibitor that is active at multiple points in the viral lifecycle, with a flexible pharmacokinetic profile that facilitates subcutaneous injection every 6 months with potential for weekly oral therapy.5 The licensed indication for lenacapavir is different from long-acting injectable cabotegravir and rilpivirine. Lenacapavir has been licensed by the European Agency for the Evaluation of Medicinal Products for the treatment of individuals with HIV-1 with extensive treatment experience and for whom it is otherwise impossible to construct a viable regimen.4 The CAPELLA study5 in heavily treatment-experienced individuals showed that when lenacapavir is combined with an optimised backbone, impressive levels of viral suppression over 52 weeks are possible, as is significant immune restoration. Injection site reactions were frequent but mild and there were very few resulting discontinuations. Capsid inhibitor resistance occurred in eight participants, almost all of whom were either non-adherent to the optimised backbone or had no other active agents.
In The Lancet HIV, Gupta and colleagues present the primary endpoint of the CALIBRATE study-the first study to evaluate long-acting ART for first-line therapy.6 This is an ongoing phase 2, open label study including 183 adult participants through 52 weeks of therapy. Participants were randomised (2:2:2:1) to one of four groups further stratified by viral load (≤100 000 or >100 000 copies per mL). After oral loading dosing, groups 1 and 2 received lenacapavir (927 mg) subcutaneously every 26 weeks. For the first 28 weeks lenacapavir was provided within a three-drug regimen (together with oral daily emtricitabine plus tenofovir alafenamide), after which it was prescribed as a two-drug regimen with either oral daily tenofovir alafenamide (group 1) or bictegravir (group 2). Group 3 received oral daily lenacapavir with emtricitabine and tenofovir alafenamide. Group 4 received oral bictegravir, emtricitabine, and tenofovir alafenamide.
Of the 182 participants who received treatment, 22 did not complete the study, 21 of whom were in the lenacapavir groups, 17 in the subcutaneous groups. Efficacy was on a par with modern oral first-line therapy studies: by week 28, 94% (147 of 157) in the lenacapavir groups (groups 1, 2, and 3) were virally suppressed (HIV-1 RNA <50 copies per mL). At week 54, 90% were virally suppressed (47 of 52 patients) in group 1, 85% (45 of 53) in group 2, and 85% (44 of 52) in group 3, compared with 92% (23 of 25) in group 4. Six participants met the protocol-defined virological failure criteria and were tested for resistance. Capsid inhibitor resistance occurred in two participants dosed (one subcutaneously, one orally) with lenacapavir.
Headache and nausea were the most frequent non-injection site reaction adverse events. No serious adverse events related to study treatment occurred. The most common lenacapavir-related injection site reactions were mild or moderate and were characterised as erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105). Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions.
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. With the development of islatravir slowed by unexpected immunological findings,7 the identity of this partner is far from clear.
These new Phase 3 studies will evaluate a once-daily oral combination of doravirine 100 mg and a lower dose of islatravir (DOR/ISL).
Merck to Initiate New Phase 3 Clinical Program with Lower Dose of Daily Oral Islatravir in Combination with Doravirine for Treatment of People with HIV-1 Infection

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