Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.
HIV Capsid Inhibitor + Nanoparticle technology
Day 2 CROI
My colleagues have already commented on the new HIV integrase strand transfer inhibitor, Bictegravir, so onto other potential new agents/formulation:
Presented by Gilead, the HIV Capsid Inhibitor was discussed in relation to its antiviral activity and proof of concept work. The Capsid Inhibitor, GS-CA1, is a first in class. The agent acts at multiple sites in the HIV life cycle - at the assembly site of the capsid core essential for the virion and at the disassembly site of the capsid which is necessary for nuclear translocation after reverse transcriptase. The capsid inhibitor binding site is highly conserved. The capsid inhibitor associated mutations map exclusively to the inhibitor binding site.
The EC 50 = 140 picamolar. With the activity of GC-CA1 a defective virion is produced that is non-infectious. The agent is active against all HIV1 clayds (slightly less potent against HIV2). So far, PK data in rats is maintained over ten weeks, leading to a proof of concept for monthly injectable dosing and is ideal for low dose, long acting administration.
CS-CA1 is currently in a preclinical programme.
Nanoparticle antiretroviral formulation was broadly outlined in relation to two ARVs, Efavirenz and Lopinavir (the agents were chosen in 2009, so are not necessarily in line with current ARVs). In principle, nanoparticle formulation has two benefits: it allows for lower dosing of dry nanoparticle formulations and can be used for Paediatric formulations as they can be dispersed in water. The data thus far, confirms potential for a 50% dose reduction while maintaining therapeutic exposure for a future novel combination ARV.
One final comment in this session on ARVs: Jose L Balanco et al presented on the pathways of resistance in subjects failing Dolutegravir monotherapy. It was noted that selection of genotypic resistant mutations was rapid. The Chairman noted that Dolutegravir is not approved by the regulatory body for use in monotherapy and expressed some disquiet as it appears that consent was not obtained from all patients. Refer a recent article in Antiviral Therapy (?end of 2016) on ethical issues and monotherapy.