Sunlenca

In the CAPELLA study, 65% of study participants experienced injection site reactions (ISRs) at Week 52 attributed to LEN. Most (44%) were mild (Grade 1) and resolved within 15 days. There was one discontinuation due to ISR. Nodules (bumps) and indurations (skin thickening) may be persistent. For Grade 3 and 4 laboratory abnormalities, 5% experienced hyperglycemia (high blood sugar), 6% experienced glycosuria (excess sugar in urine) and 13% experienced low creatinine clearance (eGFR) or high creatinine. The hyperglycemia, glycosuria, and creatinine changes observed were related to the individual’s diabetes or were either transient or unconfirmed. Nausea occurred in 4% of participants given LEN.

Do not take with Evotaz or Reyataz (but can be taken with Prezcobix); the antimycobacterials carbamazepine, oxcarbazepine, phenobarbital or phenytoin; rifampin (taking with rifabutin or rifapentine is not recommended); or St. John’s wort. Start the following medications at the lowest dose, titrate carefully and monitor for safety: dexamethasone, hydrocortisone or cortisone; and lovastatin or simvastatin. Not recommended with ergot derivatives (dihydroergotamine, ergotamine and methylergonovine) or tadalafil (for pulmonary arterial hypertension, or PAH). See package insert for dose recommendations with erectile dysfunction drugs sildenafil and vardenafil. Dose adjustment may be needed for buprenorphine or methadone; initiate these medications by titrating to desired effect but use lowest feasible doses for initiation or maintenance and monitor effects. Carefully monitor the effects of fentanyl and oxycodone; tramadol dose may need to be decreased. Avoid naloxegol (for opioid-induced constipation); if unavoidable, decrease its dose and monitor for adverse reactions. Use caution with triazolam and oral midazolam (Versed). Okay to take with the antacid famotidine (Pepcid), the cholesterol drug rosuvastatin (Crestor), tenofovir alafenamide (TAF, found in Descovy and other medications), tenofovir DF (TDF, found in Truvada and other medications), HCV medications and the antifungal voriconazole. Other acid-reducing medications can also be used, such as H2 blockers (including Axid, Tagamet and Zantac) and proton pump inhibitors (including Nexium, Prevacid and Prilosec). Tell your provider or pharmacist about all medications, herbals, and supplements you are taking or thinking of taking, prescribed or not, as there may be other drug interactions which are not listed here.

Sunlenca long-acting subcutaneous injection—administered just once every six months—is the first in its drug class. It must be used with other HIV medications as the background therapy. The approval is for heavily treatment-experienced (HTE) individuals with resistance to multiple HIV drug classes in combination with other antiretrovirals. Lenacapavir is highly potent at low doses. Drug efficacy was similar across demographic groups (race, sex at birth, age, and geographic region), CD4 cell count and viral load at study entry, and which background HIV medications were used. Sunlenca is a capsid assembly inhibitor, and inhibits HIV replication by interfering with multiple essential steps of the viral lifecycle. Ultimately, it prevents viral RNA from entering the nucleus of human CD4 T cells, halting virus assembly and protein formation, and inhibiting assembly of new viral particles. As always with HIV therapy, remember that adherence remains important for good results. Adherence may be an issue for some people whose HIV therapy has led to drug resistance—information and support is available. Future drug development plans include lenacapavir-containing complete regimens, including a once-weekly pill, and use as a single drug for HIV prevention (PrEP). At this time, there aren’t sufficient data to support the initiation of Sunlenca during pregnancy. People who become pregnant while on Sunlenca do not necessarily have to switch to another regimen, but may undergo closer monitoring of viral load. Pregnant individuals can voluntarily enroll in the Antiretroviral Pregnancy Registry through their provider; go to apregistry.com.

Dr. Melanie Thompson:

Lenacapavir (LEN) is a first-in-class capsid inhibitor administered by subcutaneous injection every 6 months. It is now FDA-approved (in combination with other HIV therapy) for treatment of multidrug-resistant HIV in individuals whose virus is not responding to their current regimen. Approval was based largely on the 36 patients in cohort 1 of the CAPELLA study in people with multidrug-resistant virus. 

Thirty-six people with “stable viremia” and at least 400 copies/mL during the 30 days after study enrollment were randomized to LEN (24 people) or placebo (12 people) on top of their current failing therapy. At 15 days, 88% of those on LEN achieved at least a 0.5 log decrease in viral load, compared to only 17% of those on placebo. After day 15, the background regimen was optimized for all patients and those on oral LEN began injectable LEN while those on placebo began an oral LEN lead in followed by injectable LEN. At 26 weeks, 81% of the entire group had viral load below 50 copies/mL and an average gain of 75 CD4 cells/µL. Although the group was small, this was a good response for people with limited treatment options. A second nonrandomized cohort of 36 persons were started on LEN and optimized background regimen on Day 1. At 26 weeks, 83% of this group had viral load below 50 copies/mL and an average gain of 104 CD4 cells/µL. There were no serious adverse events in either group, and the most common side effects were gastrointestinal symptoms and injection site reactions that were generally mild/moderate but tolerable. 

Of concern, however, is that LEN resistance arose in 8 patients. This stresses the importance of having a strong backbone of active drugs to support LEN, which appears to have some genetic fragility. Excellent adherence with oral regimens and LEN will also be essential. It was hoped that islatravir, a long-acting investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), would be a partner for LEN, but plans for implantable or injectable islatravir are now on hold due to safety issues. Studies with once weekly oral LEN and a lower dose of islatravir for initial therapy are moving forward. In addition, a phase 2 trial recently reported promising initial results for injectable LEN or daily oral LEN (both with other drugs) compared with Biktarvy for people without prior HIV treatment experience, but phase 3 studies will be required for approval in this population. LEN is being studied in the PURPOSE 1 and 2 trials as a single-drug PrEP agent. 

The FDA specifies two ways of dosing with LEN. The first requires oral LEN on the day of injectable dosing and the day after, or on days 1, 2, and 8 before injectable dosing starts on day 15. This allows levels of the drug to build quickly to decrease the possibility of resistance.  

LEN also is subject to a fair number of drug-drug interactions that can be present up to 9 months after the last dose. Drugs that decrease LEN levels should not be co-administered because they invite resistance to LEN. These include the HIV medications efavirenz, etravirine, nevirapine, atazanavir/cobicistat, and tipranavir + ritonavir (rarely used today), some medications for tuberculosis and seizures, and St. John’s wort. LEN can increase the levels of some drugs, causing side effects that may be dangerous: sildenafil (Viagra), tadalafil, vardenafil, ergot drugs, some steroids, and the statins lovastatin and simvastatin. There are other drugs that may have interactions, so be sure your clinician knows all of the drugs and supplements you take, even those that are OTC.  There are no interactions with gender affirming hormones or oral contraceptives.

And now, the price. Gilead says the 2 injections plus 2 or 3 lead-in pills of LEN will cost $42,250 for the first year of treatment, dropping to $39,000 for 2 injections annually (at $19,500 each.) That’s an average of $3,250 a month for maintenance therapy in year two and beyond. But you won’t be buying a month of drug at a time, so that nearly $20k expenditure could rack up a whopping co-insurance cost for a single dose. And what will happen for those on Medicare for whom company co-pay assistance programs do not work? Will endless rounds of “prior authorization” delay dosing and promote resistant virus? At the time of publication, it’s too soon to tell. Let’s just hope that Gilead does the right thing and makes this valuable drug available to people who need it without undue cost sharing. 

Activist Joey Wynn:

Lenacapavir is the first in class of ARV drugs called capsid inhibitors. This treatment is specifically aimed at heavily treatment-experienced populations and long-term survivors. Since it was only FDA approved in December 2022, the jury is still out. This is another injectable in the long march towards a world of injectables, sub-dermals and other long-acting agents on the horizon. The future is definitely brighter with this new choice available.