Lenacapavir- Dosage, Indications, and Side Effects

Overview

Lenacapavir is a drug used in combination with other antiretroviral medicines for treating human immunodeficiency virus type-1 (HIV-1) (a type of viral infection that affects the immune system) in adult patients who are experiencing failure in their current treatment due to intolerance, drug resistance, or other safety considerations. It is a long-acting drug taken orally and administered subcutaneously once every six months. Lenacapavir was approved by the United States Food and Drug Administration (US FDA) on December 22, 2022, and by the European Medicines Agency (EMA) on August 22, 2022. Though the drug does not cure the condition, it lowers the chance of developing acquired immunodeficiency syndrome (AIDS) (a severe stage of HIV infection) and other HIV-related illnesses like infections and cancer.

How Does the Drug Work?

Lenacapavir belongs to a group of drugs known as HIV capsid inhibitors and works by reducing the number of HIV organisms in the blood. Lenacapvir acts by binding to the HIV capsid (structural component) in multiple stages of the virus's lifecycle, thus inhibiting viral replication. Taking this drug along with certain lifestyle changes and practicing safer sex can decrease the risk of transmission of HIV to other individuals.

Indications of Lenacapavir

Lenacapavir is used along with other antiretroviral medications for treating HIV-1 in adult patients who are heavily treatment-experienced and have failed in their current drug regimen due to intolerance, resistance, or safety aspects.

Contraindications of Lenacapavir

Lenacapavir is not recommended for children, pregnant women, or lactating women.

It is also not indicated for patients with severe liver disorders.

Available Doses and Dose Forms

Lenacapavir is available as oral tablets and single-dose vials for injection. Oral tablets can be taken with or without food. Therapy is initiated using any one of the recommended dose regimens.

Option 1:

• Day 1 - 927 mg (milligrams) of subcutaneous Lenacapvir injection (two doses of 1.5 milliliters each) and 600 mg oral tablets (two Lenacapavir oral tablets, 300 mg each).

• Day 2 - 600 mg oral tablets (two Lenacapavir oral tablets, 300 mg each).

Option 2:

• Day 1 and Day 2 - 600 mg oral tablets (two Lenacapavir oral tablets, 300 mg each).

• Day 8 - One 300 mg oral tablet

• Day 15 - 927 mg of subcutaneous Lenacapvir injection (two doses of 1.5 ml each)

Maintenance Dose: Both option 1 and option 2 are followed by a maintenance dose of 927 mg of subcutaneous Lenacapavir injection (two doses of 1.5 ml each) once every six months or 26 weeks.

Warnings and Precautions

• Combination antiretroviral therapy can cause some patients' immune reconstitution syndrome (hyperinflammatory response). This can lead to inflammation, lung infections, such as pneumonia, tuberculosis, other residual opportunistic infections (infections occurring when the immune system is impaired), and autoimmune disorders (diseases caused by the immune system attacks healthy cells), thus requiring further evaluation and treatment.

• After the last subcutaneous dose, residual concentrations of Lenacapavir can be present in the systemic circulation for around 12 months or longer (prolonged period). Therefore, maintenance therapy is required every six months, and missing doses or non-adherence to treatment can cause resistance to or ineffectiveness of the drug.

• If Lenacapavir is discontinued, an alternative, fully suppressive antiretroviral therapy must be initiated not later than 28 weeks after the final dose of Lenacapavir.

• Following the administration of Lenacapavir, injection site reactions such as pain, swelling, pruritus (itching), induration (thickening of the skin), erythema (redness), nodule (lump), extravasation (leakage of body fluids), or mass formation can occur. Hence, appropriate evaluation and treatment must be considered for such patients.

Adverse Effects of Lenacapavir

Some of the adverse effects of Lenacapavir include:

• Nausea and vomiting.

• Injection site reactions.

• Fever.

• Joint pain.

• Skin rash.

• Abdominal pain.

• Yellowish discoloration of the skin and eyes.

• Numbness or weakness of the arms and legs.

• Unusual tiredness.

• Dark urine.

• Light-colored stools.

For Patients

What Is HIV-1 Infection?

The human immunodeficiency virus is a type of retrovirus that attacks the body’s immune system and makes individuals vulnerable to infections and diseases. If left untreated, it can lead to acquired immunodeficiency syndrome (AIDS). Of the two subtypes of HIV, HIV-1 is more prevalent worldwide than HIV-2. It is sexually transmitted and spreads through blood contact, semen, vaginal fluids, or the sharing of needles or syringes. There is no permanent cure available for HIV infection or AIDS, but it can be controlled through medications and prevent the progression of the disease. When patients develop resistance to two or more drugs from at least three or four main classes of antiretroviral therapies, it is known as HIV multi-drug resistance.

Some of the common symptoms of HIV infection include:

• Fever.

• Headache.

• Diarrhea.

• Sore throat.

• Skin rash.

• Swollen lymph nodes.

• Weight loss.

• Cough.

• Night sweats.

• Muscle and joint pain.

What Is Lenacapavir?

Lenacapavir is a prescription medicine used along with other medications for treating adult patients with human immunodeficiency virus type-1 (HIV-1) infection. It is used in patients who have received HIV-1 medications in the past, have resistance to other HIV-1 medicines, or whose current treatment methods are ineffective due to intolerance or safety. Lenacapavir belongs to a group of medicines called HIV capsid inhibitors and works by reducing HIV organisms in the blood. This drug does not completely cure the disease but lowers the chance of developing acquired immunodeficiency syndrome (AIDS) and other associated illnesses such as infections and cancer. Practicing safer sex and following a healthy lifestyle along with these medications are also necessary to prevent transmission of the virus to other people.

How Effective Is Lenacapavir?

Lenacapavir is a recently approved drug for the treatment of multidrug-resistant HIV in adult patients. It is currently the longest-acting and potent multistage inhibitor of the HIV-1 capsid. Lenacapavir is highly effective, and the subcutaneous dose must be taken only twice a year. Studies have shown that the drug is safe and possesses high antiviral effectiveness for HIV-1 without affecting the quality of life of patients. When taken exactly as prescribed, daily oral pre-exposure prophylaxis (PrEP) is also highly effective for preventing the transmission of HIV-1.

How Should Lenacapavir Be Taken?

Lenacapavir treatment consists of tablets and injections. Lenacapavir solution is administered subcutaneously (under the skin) into the abdomen by a healthcare provider. The treatment has two options:

• Option 1: Two doses of Lenacapvir injections are administered with two oral Lenacapavir tablets, followed by two tablets on day 2.

• Option 2: Two tablets of Lenacapavir are given on day 1 and day 2 each, one tablet on day 8, and two injections on day 15. After completing treatment with option 1 or 2, the patients will receive Lenacapavir injections every six months from the last dose. This treatment must be continued even if the patient feels better and must not be discontinued without the doctor’s consent.

What Are the Side Effects of Lenacapavir?

Some of the side effects of Lenacapavir include:

• Nausea.

• Fever.

• Skin rash.

• Fatigue.

• Body ache.

• Stomach pain.

• Muscle weakness.

• Joint pain.

• Swelling.

• Injection site reactions such as pain, redness, itching, and lump formation.

What Must the Patient Inform the Doctor Before Taking Lenacapavir?

• Patients must tell the doctor if they are allergic to Lenacapavir, its components, or any other medications before starting the treatment.

• Some medicines may interact with Lenacapavir, hence, patients must discuss with the doctor about changing or stopping current medications before starting the treatment.

• Patients must inform the doctor if they are taking any vitamins, herbal supplements, including St.John’s wort, over-the-counter drugs, or any other medications before beginning treatment with Lenacapavir.

• Female patients must tell the doctor if they are pregnant, planning pregnancy, or breastfeeding before taking Lenacapavir.

What Are the Precautionary Measures to Be Followed While Taking Lenacapavir?

• The doctor must be informed if any signs and symptoms of infection or inflammation are observed, as they may occur as soon as anti-HIV treatment is started.

• Patients must continue the medication and follow scheduled appointments to maintain suppression of the virus and reduce the risk of drug resistance.

• Lenacapavir can interact with or affect other medicines if taken for up to nine months after the last dose; hence, it is better to inform the doctor when the last dose of Lenacapavir was administered before starting any new medications.

• Women must not breastfeed while taking Lenacapavir or if infected with HIV, as the infection can spread to the breastfeeding infant.

• During treatment with Lenacapavir, injection site reactions such as pain, swelling, redness, itching, or nodules may occur.

Dietary Considerations

Consuming grapefruit or its juice must be avoided while taking Lenacapavir. No other dietary considerations are required unless advised by the prescribing doctor.

Missed Dose

To get Lenacapavir administered, it is necessary to follow scheduled appointments. The medication may be ineffective if there is a long gap between the doses. If it has been more than 28 weeks since the last dose, the doctor may have to start again with the initial dose regimen of oral Lenacapavir.

Overdose

No information is available regarding the overdose of Lenacapavir in patients. However, in the case of an overdose, the patient must be monitored immediately, and general supportive measures such as checking vital signs and the clinical status of the patient must be undertaken.

Storage

Leanacapavir tablets and vials must be stored in their original packaging at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), away from excess light and moisture.

For Doctors

Pharmacological Aspects of Lenacapavir

Mechanism of Action

Lenacapavir is an HIV-1 anti-retroviral agent that acts by targeting and directly binding to the subunits of the HIV capsid and interferes with viral life cycle processes. It is a long-acting, potent inhibitor of the HIV-capsid protein that has in vitro activity against viral strains resistant to other antiretroviral drugs. The drug inhibits viral replication at the early and late stages of the HIV cycle and has an extended pharmacokinetic profile.

Pharmacodynamics

Lenacapavir demonstrated antiviral activity against all major subtypes of HIV-1. It selectively inhibits the function of the HIV-1 capsid and HIV-1 replication by directly binding to the capsid protein subunit interface. This occurs at multiple stages of the virus's lifecycle, including nuclear import, virion assembly, and capsid core assembly. In vitro, studies have suggested that Lenacapavir combined with drugs such as Rilpivirine, Cabotrgtavir, and Islatravir has an additive antiviral effect, specifically at higher doses.

Pharmacokinetics

• Absorption: Lenacapavir is completely absorbed via subcutaneous administration, but the drug is slowly released. The absorption profile is complex, and the peak plasma concentration occurs 84 days postdose. After an oral administration, the peak plasma concentration (Cmax) occurs approximately four hours after the administration, and the absolute bioavailability is around 6 to 10 percent.

• Distribution: About 99.8 percent of Lenacapavir is bound to plasma proteins, and the steady-state volume of distribution in heavily treatment-experienced patients was around 976 liters.

• Biotransformation: Lenacapavir is metabolized primarily by the CYP3A4 and UGT1A1 enzymes. After a single intravenous dose of radiolabeled Lenacapavir was administered to healthy subjects, approximately 76 percent of the total radioactivity was recovered in the feces, and less than one percent was present in urine.

• Elimination: The median half-life of Lenacapavir after oral and subcutaneous administration was 10 to 12 days and 8 to 12 weeks, respectively. The clearance of the drug in heavily treatment-experienced patients with HIV-1 infection was based on population pharmacokinetic analysis and was approximately 3.62 L/h (liters per hour).

Drug Interactions

Some of the drugs that interact with Lenacapavir include:

• Carbamazepine.

• Phenytoin.

• Rifampin.

• St.John’s wort.

• Apalutamide.

• Enzalutamide.

• Apixaban.

• Budesonide.

• Codeine.

• Cyclosporine.

• Dexamethasone.

• Ergotamine.

• Itraconazole.

• Ketoconazole.

• Sildenafil.

• Tramadol.

• Tadalafil.

• Vardenafil.

• Venetoclax.

Clinical Studies

The safety and efficacy of Lenacapavir in the treatment of HIV-1 infected individuals who were heavily treatment-experienced and associated with multidrug resistance were assessed in a randomized, double-blind, placebo-controlled multicentre trial (CAPELLA) for over 52 weeks. This trial was conducted in 72 subjects satisfying criteria for the use of Lenacapavir with a viral load of at least 400 copies/ml (copies per milliliter), resistance documented for at least two antiretroviral drugs belonging to at least three of the four antiretroviral medicine groups (protease inhibitors, integrase strand transfer inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors). The subjects were placed in Cohort-1 if they demonstrated less than 0.5 log10 decline in HIV-1 RNA load compared to screening or placed in Cohort-2. In Cohort-1, post-introduction treatment with Lenacapavir along with a failing antiretroviral regimen demonstrated a mean change in CD4 cell count of 81 cells/cumm (cells per cubic millimeter) at the end of 26 weeks and 82 cells/cumm at the end of 52 weeks. In comparison, those started on treatment in cohort 2 demonstrated a mean change in CD4 cell count by 97 cells/cumm at the end of 26 weeks and 113 cells/cumm at the end of 52 weeks.

Nonclinical Toxicology

• Carcinogenesis: Lenacapavir was found to be non-carcinogenic in male and female mice at doses of up to 300 mg/kg/dose (milligrams per kilogram per dose) administered every 13 weeks for six months.

• Mutagenesis: In vitro and in vivo assays demonstrated that Lenacapavir was not mutagenic, including chromosome aberration, microbial mutagenesis, and micronucleus assays.

• Impairment of Fertility: No significant effects on fertility were observed in rats when Lenacapavir was administered at doses up to five times the human dose exposure.

Specific Considerations

• Pregnancy: Sufficient data is not available to determine any Lenacapavir-associated birth defects, miscarriage, or any other adverse effects in the fetus or pregnant women.

• Lactation: It is unclear whether Lenacapavir is present in breast milk, its effects on the breastfed infant, or milk production.

• Pediatric Use: Lenacapavir is not recommended for children, as the safety and effectiveness of the drug are not determined in this population.

• Geriatric Use: The clinical studies of Lenacapavir did not include a sufficient number of individuals above 65 years of age to determine the difference in response compared to younger adults.

• Hepatic and Renal Impairment: Dose modification is not required in patients with mild, moderate, or severe renal disorders and mild or moderate liver impairment. However, Lenacapavir is not recommended in patients with severe hepatic impairment.