AV-HALTs in the treatment of HIV/AIDS

What are "AV-HALT" drugs?
Highly active antiretroviral therapy (HAART) constitutes the current standard of care for treating the Human Immunodeficiency Virus (HIV). Although HAART is quite effective in reducing viral load and raising CD4+ counts, latent virus reservoirs persist and as many as 60 years therapy may be required to eradicate the virus. People receiving HAART are also likely to experience drug-related toxicity and may have to change therapy due to the emergence of drug-resistant strains. For these reasons, the search for new therapeutic approaches continues.

There is a growing recognition that successful long-term therapy for the treatment of HIV infection should not only reduce viral replication, but also limit the hyper-activation of the immune system now proposed as the cause of the eventual progression to the Acquired Immunodeficiency Syndrome (AIDS). It is believed that immune system hyperactivation is primarily driven by the "leaking" of microbes and pieces of microbes (ie, microbial translocation) across the gut. Once passing the gut, these antigens create an elevated immune response that persists throughout HIV infection and drives the loss of CD4+ T helper cells that eventually leads to AIDS, opportunistic infections and death.

ViroStatics is developing new Anti-Viral Hyper-Activation Limiting Therapeutics (AV-HALT) drugs and drug combinations to slow this progressive loss of immune system function.

Proof-of-Concept AV-HALT: VS411 - A two-drug combination
The combination of dideoxyinosine, an antiviral, and hydroxycarbamide, a cytostatic agent, has been suggested as a potential therapeutic approach to accomplish the dual goals of decreasing viral replication and down-regulating immune hyper-activation. ViroStatics is developing VS411, a fixed drug combination of didanosine and hydroxyurea, as a Proof-of-Concept AV-HALT.
In a multinational Phase IIa study of VS411 presented at the International AIDS Society's "AIDS 2010" conference in Vienna, VS411 safely lowered HIV replication by 1.5 logs (96.8%) without inducing drug resistance, significantly increased CD4+ T cells by up to 135 cells/mm3 in the dideoxyinosine 200 mg/hydroxycarbamide 900 mg cohort (doses lower than traditionally investigated) in only 28 days. VS411 also rapidly and significantly reduced four key markers of excessive immune activation, becoming the first HIV/AIDS therapy to achieve both goals of an AV-HALT after only four weeks of therapy.


Second Generation AV-HALT: Dual activity in a single molecule
ViroStatics Research and Development has developed a proprietary screening methodology that facilitates the selection of single molecules that incorporate the two dual activities of AV-HALTs – direct antiviral activity combined with antiproliferative properties. Utilizing this technology, ViroStatics has identified two-second generation AV-HALTS. Now known as VS1-002 and VS1-004, these two molecules are moving into preclinical development as potential treatments for HIV/AIDS and possibly other chronic diseases.

AV-HALTs Pathogenic rationale in HIV/AIDS
Original model of HIV disease (ie, progression to AIDS). Current model reflecting chronic immune hyperactivation		AV-HALTs reduce viral replication and limit immune hyperactivation to reduce disease progression
New learnings suggest the majority of immune activation is caused by "bystander" cell activation due to microbial translocation leading to cell death		While HAART can reduce HIV replication, AV-HALTs that are both antiviral and antiproliferative limit hyperactivation and preserve the immune system (CD4+ cells)