What is the current data on Lenacapavir (investigational antiretroviral drug) for HIV infection?

Lenacapavir: Current Data and Clinical Applications for HIV Treatment and Prevention

Lenacapavir is a first-in-class HIV-1 capsid inhibitor that demonstrates potent antiviral activity as a long-acting injectable administered every 6 months, with proven efficacy for treating multidrug-resistant HIV and promising results for HIV prevention. 1

Mechanism of Action and Potency

• Lenacapavir is a novel first-in-class HIV-1 capsid inhibitor that disrupts multiple stages of the viral life cycle, including nuclear entry, viral assembly, and capsid formation 2, 1
• The drug demonstrates picomolar potency in vitro with no cross-resistance to existing antiretroviral classes 2
• Lenacapavir's unique mechanism of action differs from all prior antiretrovirals as it interferes with multiple stages rather than a single enzyme, resulting in impressive intrinsic antiretroviral potency 3

Formulations and Administration

• Lenacapavir is available as both oral tablets and injectable solution 1
• The subcutaneous injection is administered every 26 weeks (6 months) after initial oral loading doses 4, 1
• For the injectable formulation, the first subcutaneous injection should be overlapped with 2 daily oral doses of lenacapavir (600 mg) 5
• The favorable pharmacokinetic profile supports the extended dosing interval, which may improve adherence by reducing daily pill burden 6

Clinical Applications

Treatment of Multidrug-Resistant HIV

• Lenacapavir is FDA-approved for treatment in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection in combination with optimized background therapy 4, 1
• In clinical trials, lenacapavir in combination with other antiretroviral agents led to high rates of virologic suppression in heavily treatment-experienced persons with multidrug-resistant HIV-1 2
• The CAPELLA trial demonstrated efficacy in viral load reduction from baseline compared to placebo in patients receiving optimized background therapy 4, 7

Emerging Role in HIV Prevention

• The PURPOSE-1 study found no detected HIV infections among cisgender women in Southern and Eastern Africa using lenacapavir as PrEP, in a population with background HIV incidence of approximately 2.41 per 100 person-years 5
• The PURPOSE-2 trial in cisgender men, transgender people, and nonbinary individuals had only 2 incident HIV infections (HIV incidence 0.10/100 person-years) in a population with an estimated HIV incidence of 2.37 per 100 person-years (96% reduction) 5
• After regulatory approval, lenacapavir is recommended for prevention of HIV infection for all routes of sexual exposure 5
• Lenacapavir is currently under review at the FDA for HIV prevention and was named the biggest science breakthrough for HIV prevention in 2024 1

Safety Profile

• Lenacapavir is generally well-tolerated with the most common adverse effects including injection site reactions, gastrointestinal symptoms, and headache 6
• In clinical trials, injection site reactions occurred in 63% of participants but were typically mild to moderate 7
• Both injectable cabotegravir and injectable lenacapavir have been associated with injection site reactions, which often diminish in severity over time 5

Resistance Considerations

• There was no preexisting resistance to lenacapavir in persons with HIV-1 regardless of treatment history 2
• The antiretroviral activity of lenacapavir is unaffected by any mutation conferring resistance to older antiretrovirals 3
• Among participants with virologic failure who developed lenacapavir resistance-associated substitutions in capsid, several had emergent resistance when lenacapavir was combined with a background regimen with no fully active antiretrovirals 4
• Given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to lenacapavir in the treatment regimen 4

Future Directions

• Lenacapavir is being studied in combination with other long-acting agents, including a once-weekly combination with islatravir 5
• Several exploratory studies of long-acting broadly neutralizing antibodies (bNAbs) to maintain HIV RNA suppression in people with HIV switching off oral therapy have been presented, including combinations with lenacapavir 5
• A single daily pill of lenacapavir/bictegravir (LEN/BIC) is being studied in a phase 3 trial for persons with multidrug-resistant virus without known integrase resistance 5
• Ongoing studies are evaluating lenacapavir for HIV prevention in cisgender women and people who inject drugs (PWID) in the US 5

Clinical Implications and Recommendations

• For heavily treatment-experienced patients with multidrug-resistant HIV, lenacapavir in combination with optimized background therapy provides a valuable treatment option 4, 7
• Adherence to other antiretroviral drugs in the regimen should be optimized while the patient is receiving lenacapavir to prevent resistance development 4
• After approval by regulatory authorities, lenacapavir is recommended for prevention of HIV infection for all routes of sexual exposure 5
• The combination of 2 bNAbs with lenacapavir as an every-6-months regimen is now being tested in a phase 2b trial in which people with suppressed virus using oral ART are randomly assigned to switch to the every-6-months regimen or remain using their oral regimen 5