Lenacapavir is an HIV capsid inhibitor. The HIV capsid is a cone-shaped structure that provides a container for viral proteins and enzymes. When the virus enters a target cell, the capsid opens up in a pre-programmed sequence to allow HIV proteins to integrate into the host cell’s DNA. Capsid inhibitors interrupt the disassembly of the capsid, preventing HIV infection of a cell, as well as the assembly of new capsids.
Lenacapavir is the first HIV capsid inhibitor. Developed by Gilead Sciences, it was previously known as GS-6207. Lenacapavir has been licensed in the United States, European Union and United Kingdom for the treatment of multi-drug resistant HIV and is marketed as Sunlenca.
Lenacapavir is also being evaluated as a first-line treatment and as pre-exposure prophylaxis (PrEP).
Lenacapavir remains in the body for an exceptionally long time, so it only needs to be dosed by subcutaneous injection twice a year.
The CAPELLA study tested lenacapavir in people with HIV that is resistant to at least two drugs from three of the four commonly used drug classes who had no more than two active drugs available from those four classes. (Segal-Maurer) The study enrolled 72 people. Those who experienced a viral load increase of >0.5 log in the 2-week period between initial screening visit and treatment initiation received lenacapavir and an optimised background regimen selected by resistance testing. Those who did not experience a viral load increase between screening and initiation were randomised to receive lenacapavir or placebo in addition to their failing regimen for two weeks, followed by lenacapavir and an optimised background regimen selected by resistance testing. The study recruited 36 participants to each cohort.
Eighty-eight per cent of those who received lenacapavir in the randomised arm had a viral load reduction of at least -0.5log by day 15 of treatment, compared to 17% who received the placebo. At week 26, 81% in the randomised arm and 83% in the non-randomised arm had a viral load below 50 copies/ml. Fifty-two week follow-up of participants in the randomised arm showed that 83% had a viral load below 200 copies, but response rates differed according to the number of active agents in the background regimen. (Ogbuagu)
The phase II CALIBRATE study tested lenacapavir in previously untreated people. (Gupta) The study randomised 182 people with HIV to receive lenacapavir with tenofovir alafenamide (TAF)/emtricitabine for 6 months followed by lenacapavir with either TAF or bictegravir for six months, or to continue with TAF/emtricitabine. A control group received TAF/emtricitabine plus bictegravir. At week 54, viral suppression was similar across the four study arms, ranging from 85% in the two-drug treatment arms to 92% in the control arm. Two participants with unsuppressed viral load developed lenacapavir resistance mutations.
Lenacapavir is being tested as PrEP in the PURPOSE-2 study.
Lenacapavir treatment starts with oral dosing to establish stable blood levels. You will take two 300mg tablets on days 1 and 2, then one 300mg tablet on day 8.
On day 15, you will receive two subcutaneous injections of lenacapavir in different places in your abdomen. These injections should be repeated every six months (26 weeks) and no more than 28 weeks after the last lenacapavir injection. If the next dose is delayed by more than 28 weeks after the previous injections, dosing should begin again with oral lead-in before injections are resumed.
Nausea is the most common side effect reported in clinical trials of lenacapavir. Temporary injection site reactions have been reported in clinical trials.
Lenacapavir should not be used with the following medicines:
- Tadalafil for pulmonary artery hypertension
- Rifampicin, rifabutin for tuberculosis or mycobacterial infections
- Carbamazepine, phenytoin, oxcarbazepine, phenobarbital (anticonvulsants)
- St John’s wort.
Lenacapavir should not be used with the antiretrovirals atazanavir/cobicistat or efavirenz. Use with nevirapine or etravirine may lower blood levels of lenacapavir but the extent of the drug interaction is unknown.
The following medicines should be used with caution as lenacapavir may increase their levels in the blood: dihydroergotamine or ergotamine (ergot derivatives); dexamethasone, hydrocortisone/cortisone (corticosteroids); lovastatin, simvastatin (statins); digoxin (antiarrhythmics); midazolam or triazolam (sedatives); rivaroxaban, dabigatran, edoxaban (anticoagulants).
Levels of drugs used to treat erectile dysfunction (sildenafil, tadalafil, vardenafil) should be reduced when taking lenacapavir. See the lenacapavir package insert for information on safe dosing for each drug.
Lenacapavir will remain in the blood for up to nine months after the last dose and so will continue to influence the levels of the drugs listed in this section for some time after discontinuation.
Lenacapavir is active against HIV that is resistant to other classes of antiretrovirals.
In the CAPELLA study, 11% of participants who were not virally suppressed between weeks 4 and 52 developed high-level resistance to lenacapavir.
Lenacapavir has not been studied in pregnant women. The use of lenacapavir should be avoided during pregnancy unless it is needed to assemble an effective treatment regimen.
Lenacapavir has not been studied in children and is not recommended for use in people aged under 18 years.
Segal-Maurer S et al. Capsid inhibition with lenacapavir in multi-drug resistant HIV infection. New England Journal of Medicine, 386: 1793-1803, 2022
Ogbuagu O et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: week 52 results. Conference on Retroviruses and Opportunistic Infections, abstract 491, 2022.
Read our news report on this study.
Gupta S et al. Lenacapavir as part of a combination regimen in treatment naïve PWH: week 54 results. Conference on Retroviruses and Opportunistic Infections, abstract 138, 2022.