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In a class of its own, “uniquely potent” HIV capsid inhibitor thwarts HIV replication

, by Liz Highleyman

A new type of antiretroviral drug—HIV capsid inhibitors—may offer an additional potent and long-acting treatment option if they are shown to be safe and effective in future clinical trials. Results from early laboratory and animal studies look promising so far, according to a presentation at the 2017 Conference on Retroviruses and Opportunistic Infections last month in Seattle.

Modern antiretroviral therapy is effective and well tolerated by most people living with HIV. But having more available medications that work in different ways offers more options for putting together optimal regimens, especially for treatment-experienced people with highly resistant virus.

Winston Tse  (Photo: Liz Highleyman)

Winston Tse (Photo: Liz Highleyman)

Winston Tse presented results from Gilead Sciences’ ten-year capsid inhibitor development program, which led to the discovery of a promising candidate dubbed GS-CA1—the first capsid inhibitor to enter preclinical studies.

Current antiretroviral drugs target four steps of the HIV lifecycle: reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, and integrase inhibitors. No antiretrovirals with a novel mechanism of action have come on the scene since the integrase inhibitors a decade ago.

Capsid inhibitors work at a different step, interfering with assembly and disassembly of the capsid, which encloses HIV’s genetic blueprints. The HIV p24 capsid protein plays a critical role in the viral lifecycle, forming a cone-shaped structure made up of hexamers, or six-part subunits, that surrounds the viral genome. GS-CA1 binds strongly to a conserved site on capsid hexamers, which means the site looks similar on all types of HIV and the drug will work against multiple strains of the virus.

Though designed to target HIV capsid assembly, researchers found that GS-CA1 actually acts at more than one step in the viral replication cycle. In addition to interfering with the capsid assembly step needed to produce new viral particles, it also blocks functions that happen after HIV enters a host cell to release the viral genetic material from its capsid and move it into the cell’s nucleus.

capsid inhibitor mode of action

In the HIV replication cycle, GA-CA1impairs capsid core assembly and reverse transcription prior to integration. (Slide: Winston Tse)









GS-CA1 was highly potent against HIV in laboratory cells—”at least an order of magnitude more potent” than existing antiretrovirals, according to Dr. Tse. It had similar potency against multiple HIV-1 strains isolated from patients, and it maintained full activity against viral mutants with resistance to all approved antiretroviral drug classes.

Even better, pharmacokinetic tests showed that GS-CA1 is cleared slowly from the body and it appears suitable for long-acting injections. In a study of rats, a single subcutaneous injection maintained high plasma drug levels for ten weeks. Some people with HIV may find long-acting injectable drugs more convenient than daily pills, and they could help improve adherence.

Gilead aims to move into human trials using low-dose injections of GS-CA1 administered no more than once a month, Dr. Tse said. The company plans to proceed with toxicology studies to make sure the drug has no harmful effects and then start Phase 1 clinical trials in 2018.

Liz Highleyman is a freelance medical writer and editor of HIVandHepatitis.com.

Read more HIV research from CROI 2017 on BETA.


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