ADVANCEMENTS IN HIV TREATMENT AND PREVENTION: FOCUSING ON CABOTEGRAVIR AND LENACAPAVIR

Vecchiet J, Turroni S. Advancement in HIV treatment and prevention: focusing on cabotegravir and lenacapavir. International Journal of Infection. 2023;7(3):64-67.

J. Vecchiet^1* and S. Turroni²

¹ Department of Medicine and Ageing Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy;
² Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

*Correspondence to:
Jacopo Vecchiet,
Department of Medicine and Ageing Sciences,
“G. d’Annunzio” University of Chieti-Pescara,
66100 Chieti, Italy.
e-mail: jacopo.vecchiet@unich.it

ABSTRACT

Two new drugs for treating human immunodeficiency virus-1 (HIV-1), cabotegravir (CAB) and lenacapavir (LEN), are currently being targeted. These drugs are still under clinical investigation, but as to date, they have been shown to be effective in the prevention and treatment of HIV-1. CAB and LEN have a different mechanism of action; the former is an integrase inhibitor, while the latter is a capsid inhibitor. These new drugs hold promise in the fight against HIV-1, the powerful virus that causes acquired immunodeficiency syndrome (AIDS).

KEYWORDS: Human immunodeficiency virus, HIV, cabotegravir, lenacapavir, antiretroviral treatment

INTRODUCTION

Human immunodeficiency virus-1 (HIV-1) is usually transmitted through blood and sexual transmission. The first phase of the infection, after the virus has crossed the mucous membranes, affects the lymphatic tracts where the virus attacks the immune system and, in particular, the CD4 T lymphocytes, until reaching the advanced stage of infection- acquired immunodeficiency syndrome (AIDS) (1).

CD4 cells play an important role in the immune system and HIV-1 therapies aim to restore immune defences by attempting to raise the number of CD4 lymphocytes. After infection, CD4 cell counts slowly decline to below 200 cells/mm³, a state that defines the onset of AIDS (2).

For HIV-1 infection, highly active anti-retroviral therapy (HAART) is a highly effective anti-retroviral therapy based on the combination of multiple drugs with different antiviral mechanisms of action (3). This combined therapy has made it possible to reduce mortality and the progression of HIV-1 infection, resulting in a near normal life expectancy of infected individuals when compared to that of healthy individuals of the same age.

This article will mainly discuss cabotegravir (CAB), an integrase inhibitor, and lenacapavir (LEN), a capsid inhibitor, which are two antiretroviral drugs for treating HIV that have different modes of administration and frequency.

DISCUSSION

Drugs used to treat HIV-1 work with various mechanisms to block the virus outside the cell wall, inhibiting the initial step necessary for the virus to enter the target cell (4). Anti-HIV-1 drugs include integrase inhibitors, HIV-1 reverse transcriptase inhibitors, protease inhibitors, and inhibitors of virus binding, fusion, and entry (5).

Cabotegravir (CAB) Therapy

CAB is an integrase strand transfer inhibitor (INSTI) utilized for both the treatment and prevention of HIV-1 infection (6). This antiretroviral drug is given as an intramuscular injection every month or every other month and has a long duration of action (7). CAB, which has shown satisfactory results when used in combination with LEN, works by blocking the HIV-1 integrase enzyme, which is important for viral DNA to integrate into the host cell’s genome. By inhibiting this enzyme, CAB prevents the virus from replicating within host cells.

CAB is indicated in combination with rilpivirine, for the treatment of HIV-1 infection in virologically suppressed adults (RNA <50 copies/mL) on a stable antiretroviral regimen, without current or past evidence of viral resistance (8). CAB and rilpivirine should be taken for approximately one month, to evaluate tolerability (9). One 30 mg CAB tablet should be taken with one 25 mg rilpivirine tablet once daily.

Various drugs have been compared to understand their different preventive and therapeutic efficacy for treating HIV-1. CAB is a powerful drug that has been shown to reduce HIV-1 incidence in diverse, at-risk populations (10). CAB is highly effective in suppressing viral load and preventing HIV-1 infection. However, like other drugs of its kind, it causes side effects such as headache, nausea, fatigue, pain, redness, swelling at the injection site, and occasionally, fever (7).

Lenacapavir (LEN) Therapy

Some drugs, such as LEN (or GS-6207), an investigational antiretroviral drug that targets HIV-1, can inhibit the maturation of virions by blocking the formation of HIV-1-capsid pentamerases, leading to a reduced risk of HIV-1 infection (11,12). The HIV-1 capsid contains approximately 1,500 capsid proteins that are divided into approximately 250 hexameres and 12 pentameres. Capsid proteins contribute in various ways to the replication of the virus cycle. LEN is part of a new class of HIV-1 drugs known as capsid inhibitors and is under scientific scrutiny for its potential to both treat and prevent HIV-1 infection (13). Various studies are ongoing to further evaluate LEN’s efficacy and safety.

Functional monotherapy with LEN has resulted in a decline in plasma HIV-RNA viremia which appears slightly higher than that found after functional monotherapy with ibalizumab and fostemsavir (14). LEN is the first-class inhibitor of HIV-1 capsid that functions in clinical trials. By targeting the capsid, LEN interferes with the virus’s ability to replicate and infect new cells (15). This mechanism is different from other classes of antiretroviral drugs, making it a promising option in HIV-1 therapy. By utilization of electron microscopy, LEN has been seen to act on the assembly of capsomeres (16). LEN-resistant mutation inhibits the viral replication with a mechanism that is still unclear.

HIV-1 therapy should be primarily focused on preventing viral replication. LEN is potentially capable of inhibiting capsid formation. Indeed, during assembly of capsid particles in vitro, LEN specifically blocks the formation of only capsid pentamers. When LEN is incubated with monomers and processed to form pentamers, there is specific inhibition, with no effects on exomers (17). Virological assays have revealed an opposite effect with inositol hexaphosphate (IP6) and LEN during viral maturation (18). Capsid monomers assemble into pentamers and exomers, which are important for proper maturation of infectious virions.

Thus, LEN interferes with virion maturation and appears to act in the assembly of pentamers, but not exomers. LEN may even promote the formation of exomers. This information is certainly useful and innovative for developing a new drug that inhibits the capsid, a crucial structural component of the virus that protects its RNA and proteins and increases the resistance barrier.

Regarding the administration of LEN, the subcutaneous formula is preferable to the oral one, because it allows the possibility of a long-acting dosage. LEN is a new drug that is demonstrating its effectiveness against different strains of HIV and is still under clinical observation to evaluate its safety and effectiveness in different ethnic groups.

However, the administration of LEN for HIV-1 therapy does cause some side effects such as fatigue, headache, nausea, diarrhea, and, in subcutaneous administration, reactions have occurred at the injection site (19).

CONCLUSIONS

CAB represents a new possibility for HIV-1 prevention and treatment. LEN is another new, experimental drug for the treatment and prevention of HIV-1 which is capable of inhibiting the capsid and could represent a new weapon against the virus responsible for AIDS.

Studies with CAB and LEN in clinical trials will continue to reveal the potential for these drugs. However, there are still important challenges to address in the global AIDS pandemic.

Conflict of interest

The authors declare that they have no conflict of interest.

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