Investigational agent ABX 464 seeks to reduce HIV reservoirs
by Jeannie Wraight
ABX 464 is making its way through clinical trials, showing strong potential as an HIV therapeutic and a possible HIV cure strategy component. The drug (made by a French biotech company called Abivax) is a first-in-class, oral, small anti-viral molecule and is currently in Phase II clinical trials.
ABX 464 targets an HIV viral protein called rev, an essential component in the process of HIV replication. In studies of ABX 464 in a humanized mouse model, a sustained viral load suppression was demonstrated for up to six weeks after ABX 464 treatment was stopped, showing cause for human studies to ascertain if this effect will be substantiated in people living with HIV.
Data released in May of this year from a small safety and efficacy study showed the potential of ABX 464 to reduce HIV reservoirs and is a first step in further measuring the effect of the drug.
As a Phase IIa study, the primary objective was assessing safety, as well as assessing the drug’s pharmacokinetic effects. A secondary objective was determining any reduction of HIV reservoirs through examining total HIV DNA in peripheral blood mononuclear cells (PMBC cells).
A total of thirty participants, all of whom were fully suppressed on boosted darunavir, were enrolled in the study in Spain, Belgium, and France. Participants were given either ABX 464 or placebo at a 3:1 ratio, for a total of twenty-eight days, while they continued their antiretroviral regimen. The study drug/placebo and boosted darunavir were then discontinued.
According to Dr. Jean-Marc Steens, Chief Medical Officer of Abivax, it is difficult to measure the significance of a decrease within patients who had fewer than 50 copies of HIV DNA/Mio PBMCs. As such, those with under 50 copies of HIV DNA/Mio PBMC’s were excluded from analysis.
Responders needed to meet two criteria: viral reservoir reductions of more than 25% of total HIV DNA in PBMCs and an absolute reduction of at least 50 copies. Half of the evaluable ABX 464-treated study participants were considered “responders” and experienced a mean viral reservoir reduction of 40% (27%–67%). These results showed ABX 464 to be the first intervention to show such a decrease. No pharmacokinectic interactions were seen with ABX 464 and boosted darunavir.
In total, there have been 150 patients who have been treated with ABX 464 with safety data showing the agent to be quite benign. As with many of the current antiretrovirals, the main side effects exhibited have been headache and nausea within the first few days of treatment. These effects diminished with time. In the IIa study, one participant withdrew from the study due to Grade I/II abdominal cramps, which subsided after cessation of the study drug, and a second was discontinued due to viral escape with darunavir before Day 28.
It’s important to note that clearing viral reservoirs is unknown territory and we have no definitive knowledge of how long this would take or if it is even possible. A twenty-eight-day study such as this (at the time the longest length this study could be approved for) may or may not be a significant amount of time regardless of what drug or strategy is used. So, a study such as this, in addition to testing the safety and efficacy of a drug, helps us to gain a better understanding of the process of studying reservoir clearance.
Researchers have found that the amount of HIV DNA in viral reservoirs is important and differs from person to person. The average amount is around 100–500 per million PBMC’s. In a previous, unrelated study, it was found that when a high amount of HIV DNA is present, the likelihood of disease progression is greater than with a lower amount.
However, it is still unknown how much of a decrease in reservoirs is needed to be sufficient to prevent new viral replication when all treatments are stopped.
“In terms of research, we all have focused a lot on bringing the viral load down but work towards clearing the sanctuary regions [viral reservoirs] is in its infancy. To me, an undetectable viral load is not enough,” stated Dr. Steens.
Studies such as this not only test the safety and efficacy of a drug, but help us to better understand the HIV reservoir. Further studies with longer periods of treatment are needed to ascertain the full benefit of ABX 464 and are said to be forthcoming.
Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven (www.hivhaven.com) and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.