A New Era in HIV Prevention: The Long-Acting Power of Lenacapavir

Dr. B. Kumar*, Chennuru Charanya, K.V. Rajasri, Shaik Abidha Begum, Mungara Rakesh Kumar, Uttukuru Poojitha.

Department of Pharmacy Practice. Swathi College of Pharmacy. Nellore District, Andhra Pradesh.

*Correspondence: kvrajasri15@gmail.com 

DOI: https://doi.org/10.71431/IJRPAS.2025.4908      

INTRODUCTION

Human immunodeficiency virus (HIV) continues to be a major global health concern, affecting over 39.9 million people worldwide.[1] Despite the availability of effective antiretroviral therapy (ART), approximately 1.3 million new infections and nearly 630,000 HIV-related deaths were reported in 2023, highlighting the persistent global burden of the disease. One of the key challenges in HIV management is the emergence of multidrug-resistant (MDR) HIV-1 strains, which significantly reduce the effectiveness of conventional ART regimens [2]. Current treatment approaches also face limitations due to the requirement for strict daily dosing, pill fatigue, and poor adherence, which often lead to treatment failure and resistance development. These challenges have driven the need for novel, long-acting therapeutic agents with unique mechanisms of action to improve clinical outcomes and enhance patient quality of life [3].

Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and helps restore CD4+ cell counts. With proper treatment, individuals on cART can achieve a life expectancy comparable to those without HIV-1 and, when viral loads are undetectable, cannot transmit the virus to sexual partners [4,5]. Additionally, pre-exposure prophylaxis (PrEP) has proven highly effective in preventing new infections among high-risk individuals. However, both oral cART and PrEP require strict daily adherence to prevent drug resistance (in the case of cART) and ensure protection (for PrEP).  Poor adherence remains a significant challenge, often leading to incomplete viral suppression. Barriers to adherence include inconvenience, side effects, stigma, and discrimination [6]. Over time, some people with HIV-1 (PWH) may experience treatment failure, resulting in limited options for those with extensive drug resistance. As a result, developing safe and effective therapies for heavily treatment-experienced (HTE) individuals with multidrug-resistant HIV-1 is crucial. 

  Lenacapavir (LEN), developed by Gilead Sciences, represents a significant breakthrough in HIV therapy. As the first-in-class HIV-1 capsid inhibitor, LEN targets the viral capsid, a mechanism distinct from other antiretroviral drugs, thereby retaining activity against MDR HIV-1 strains [1]. Lenacapavir, a groundbreaking first-in-class HIV capsid inhibitor, has shown strong antiviral activity in clinical trials. A single subcutaneous dose can maintain therapeutic levels for up to six months.  Clinical trials from phases 1, 2, and 2/3 studies support using it alongside other antiretroviral drugs for both heavily treatment-experienced and treatment-naive people with HIV.

 Approved in multiple countries, LEN is administered as a twice-yearly subcutaneous injection, offering a convenient and long-acting alternative to traditional daily ART.LEN is effective for both treatment and pre-exposure prophylaxis (PrEP), addressing unmet needs in HIV prevention [7]. Its ability to combine with existing antiretroviral agents, favourable pharmacokinetic profile, and minimal drug resistance make it a promising option for the future of HIV management.

EPIDEMIOLOGY:

In the PURPOSE 1 study, there were 16 new HIV infections in the TDF/FTC group (1.69 per 100 person years; 95% CI: 0.96–2.74), while no infections were reported in the LEN group (0 per 100 person-years; 95% CI: 0.00–0.19). In PURPOSE 2: nine incident HIV infections were identified in the TDF/FTC group (0.93 per 100 person-years; 95% CI: 0.43–1.77) compared with two in the LEN group (0.10 per 100 person-years; 95% CI: 0.01–0.37). Both participants

who acquired HIV in the LEN group of PURPOSE 2 had LEN levels consistent with the expected pharmacokinetic range. These infections occurred after the first injection but before the second, at weeks 13 and 26. Investigators noted that there was no evidence of delayed HIV detection in either of these cases.

Adherence levels have differed between the LEN and TDF/FTC groups across both studies. LEN adherence was measured as on-time injections, defined as within 28 days of the scheduled dose, while TDF/FTC adherence was assessed through tenofovir diphosphate levels in dried blood spots from a randomly selected subset of participants. At week 52, 92.8% of participants receiving LEN in both trials had received injections on time. In PURPOSE 1 adherence to TDF/FTC was low for most participants and declined over time, with many taking fewer than two pills per week. In PURPOSE 2, 82% of participants had high adherence to oral TDF/FTC (four or more pills per week) at week 8, but this declined to 62% at week 52.

 LEN significantly reduced HIV acquisition in both the PURPOSE 1 and PURPOSE 2 studies, with strong supporting evidence. In PURPOSE 1 participants assigned to LEN group acquired no HIV infection, whereas in PURPOSE 2, two HIV cases were detected in the LEN group. When compared with background HIV incidence, LEN showed 100% efficacy in PURPOSE 1 (RR: 0.00; CI 95%: 0.00-0.04) and 96% efficacy in PURPOSE 2 (RR: 0.04; CI 95%: 0.01-0.18). LEN demonstrated complete (100%) effectiveness in PURPOSE 1 (RR: 0.00; CI 95%: 0.00-0.10) and 89% effectiveness in PURPOSE 2 (RR: 0.11; 95% CI: 0.02-0.51) [8,9].

A single subcutaneous injection of lenacapavir provided sufficient pharmacokinetic exposure for up to six months, and it received approval for HIV prevention in the European Union in 2022 [10].

Figure 1. The winding road of the red ribbon in HIV prevention and control. From initial behavioural interventions to advancements in HIV vaccines, PEP, and PrEP, the journey of HIV prevention has Citation: Wen, Z.; Shi, M.; Sun, C. Treatment as the Best Prevention: Twice-Yearly Lenacapavir, a Game Changer in Ending the AIDS Epidemic. Viruses 2024, 16, x. https://doi.org/10.3390/xxxxx Academic Editor: Eric O. Freed Received: 2 August 2024 Revised: 26 August 2024 Accepted: 27 August 2024 Published: 28 August 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).

LENACAPAVIR: CHEMISTRY AND STRUCTURE:

    Lenacapavir (LEN) is a novel long-acting capsid inhibitor approved for the treatment of multi drug resistant HIV-1 infection. It targets the HIV-1 capsid protein (p24) interfering with multiple stages of the viral life cycle. Lenacapavir is sold under the brand name of Sun Lenca which is an antiretroviral.

IUPAC NAME:  N-[(1S)-1-{3-[4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-[3-(methanesulfonyl)-3-methylbut-1-yn-1-yl]pyridin-2-yl}-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamide.

STRUCTURE:

MECHANISM OF ACTION:

Lenacapavir acts by binding directly to the interface between the HIV-1 viral capsid protein (p24) subunits in the capsid hexamers, interfering directly with essential steps of viral replication, including the capsid-mediated nuclear uptake of HIV-1 proviral DNA, virus assembly and release, production of capsid protein subunits, and capsid core formation [11,12]. The US Food and Drug Administration (USFDA) considers it as first-class medication [13,14].

LENACAPAVIR INDICATIONS:

Lenacapavir is the first of a new FDA-approved class of drugs called as capsid inhibitors to treat HIV-1 infection [15].  This drug is indicated for the patients who have been heavily treated with ARVs and have developed resistance to many HIV-1 medications, and are failing their current ARV (antiretroviral) regimen because of medication resistance, intolerance, or the safety considerations.

PHARMACOLOGY/PHARMACOKINETICS:

·         Lenacapavir’s oral bioavailability is 6% -10%

·          The SC (subcutaneous) bioavailability is 100%.

·         The T_max (time it takes to reach the maximum plasma concentration) is 4 hours when taken orally and 77- 84 days when it is injected through SC route.

·         The apparent volume of distribution is 19,240 L in oral route and SC route apparent volume of distribution is 9,500-11,700 L.

·         Lenacapavir’s half-life is 10-12 days when administered orally and its SC half-life is 8 -12 weeks. 

DOSAGE AND ADMINISTRATION:

Ø  Lenacapavir is commercially available as 300-mg tablets form and 463.5-mg/1.5-mL single-dose vial for subcutaneous injection [15].  

Ø  Lenacapavir is administered as a combination of oral tablets and SC injection for its initiation dose and is followed by SC maintenance dose for every 6 months.

Ø   FDA-approved dosing options for the drug lenacapavir is noted in TABLE 1 [15].

Ø  Lenacapavir subcutaneous injection is used directly by administrating it into the abdominal region by a healthcare provider using aseptic conditions.

Ø  The injection is a yellow-coloured solution and it should not be used if the solution is discoloured or contains particulate matter.

Ø  After the withdrawal of the drug from the vial, the subcutaneous injection of lenacapavir shall be administered into the patient’s abdominal region. The injection kit components must be used once only.

Ø  Two sets of 1.5mL of Lenacapavir’s subcutaneous injections are required for a complete dose administration to the patient. No dosage form adjustments are required for renal or hepatic insufficiency patients.

Ø  Analytical data on the use of lenacapavir drug in pregnant women are lacking. Healthcare providers are encouraged to register the patients with the ARV (anti- retro viral) pregnancy register, which can be used to monitor pregnancy outcomes in individuals exposed to drug lenacapavir during their gestation period.

RESISTANCE:

 The Drug-resistant mutations are documented for all antiretroviral class of drugs and can be significantly used to decrease the effectiveness of Antiretroviral therapy [16]. The key mutations of M66I and Q67H genes are specific to the capsid inhibitors of HIV-1. The Mutations which are seen with the first-line therapy i.e., NRTIs when combined with an NNRTI, PI, or INSTI which are different from those that develop with the drug class of capsid inhibitors [17].  Lenacapavir works against resistant variants with NRTI (Nucleotide reverse transcriptase inhibitors), NNRTI (Non- nucleotide reverse transcriptase inhibitors), PI (Protease inhibits), and INSTI (Integrase strand transfer inhibitors) gene mutations, making it a most suitable option for the patients who are heavily pretreated with multidrug-resistant HIV-1 infection. For the patients who are nonadherent to lenacapavir drug, an alternative drug which totally suppresses the ARV regimen activity shall be initiated for not less than 28 weeks followed by the last injection of lenacapavir in order to reduce the chances of viral resistance development occurrence [15].

ADVERSE DRUG REACTIONS:

·         Injection site reactions (ISRs) -65% and nausea -4% are Lenacapavir’s most common side effects.

·         ISRs may involve swelling, pain, discomfort, redness, hardened skin, lumps, and itching of skin at injection site [15].

·         Certain Nodules and hardened areas of skin at injection site may persist longer than other ISRs.

·         Clinical data shows that 30% of nodules and 13% of indurations-affecting 10% and 1% of patients, respectively were associated with the initial dose of lenacapavir injection has not completely healed even after a median follow-up of 553 days. Most of the nodules and indurations at the site of injection were felt but are not visible, and their maximum sizes ranges from 1-4 cm [15].

·         Most of the patients had mild (Grade-1 or 44%) or moderate (Grade-2 or 17%) ISRs.

·         4% of patients have experienced a severe (Grade -3) ISR like-erythema, pain, and swelling which has been resolved within 15 days of drug administration.

·         The ISRs are reported in more than 1% of subjects includes-swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%), and masses (3%). ISRs reported within that 1% of subjects included discomfort, hematoma, oedema, and ulcer [15].

DRUG-DRUG INTERACTIONS:

Ø  Lenacapavir is a moderate inhibitor of the enzyme cytochrome P450 3A (CYP3A) and also acts as a substrate for P-glycoprotein (P-gp) and UGT1A1 [15,18].

Ø  Lenacapavir’s plasma concentrations can be decreased by using medications which are strong or moderate CYP3A inducers (ketoconazole, itraconazole, erythromycin, diltiazem, rifampicin). Co-administration of these medications is not advised.

Ø  Strong CYP3A inhibitors when paired with P-gp, and UGT1A1 inhibitors, it should not be taken with lenacapavir because they significantly increase the drug’s plasma concentration in the body.

Ø  Lenacapavir may increase the levels of drugs mainly metabolized by CYP3A enzyme if they are started within 9 months after the last subcutaneous dose due to its long half-life.

Ø  LEN shows additive or synergistic effects when combined with other antiretroviral agents like-Rilpivirine, Cabotegravir, Islatravir, Bictegravir and Tenofovir.

DRUG-FOOD INTERACTIONS:

·         Take with or without food. Oral lenacapavir should be taken orally with or without food, as food has negligible effects on drug absorption.

·         Oral lenacapavir has shown mild interaction with grapefruit juice as it is a CYP3A inhibitor.

·         No specific restrictions on the type of food but taking it on an empty stomach is not advised.

DRUG-DISEASE INTERACTION:

    Lenacapavir shows interactions with-

ü  Liver diseases- severe hepatic impairment (caution is advised)

ü  Kidney diseases- use in severe renal impairment or end stage renal disease (caution is advised)

ü  Active Tuberculosis disease- shouldn’t be used alone especially rifampicin-based therapy due to serious drug-drug interactions and risk of treatment failure.

HOW LENACAPAVIR PREVENTS HIV (PRE-EXPOSURE PROPHYLAXIS):

LEN is given as a subcutaneous injection, only twice a year (every 6 months)

Shields against the HIV in the body

If a person is exposed to HIV, LEN prevents the virus from entering and multiplying in immune cells

This stops HIV from establishing infection offering long-term protection.

CONCLUSION:

Lenacapavir is a ground breaking in the new category of HIV capsid inhibitors. It is both highly effective and long lasting, with a unique resistance profile, that makes it a promising treatment option for patients with prior resistance to ARV’s. Initially administered as a combination of oral tablets and subcutaneous injection, with a convenient SC dosing schedule of once every 6 months. The most frequent side effects include ISRs (INJECTION SITE INJECTIONS) and nausea. Lenacapavir may interact with other drugs through the CYP3A, P-gp, and UGT1A1 pathway. It is the first medication in its class of drugs to target three separate stages of HIV life cycle, offering new hope for individuals living with HIV.

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