An analysis of immune markers measured in a sub-study of ViroStatics' proof-of-concept Phase 2a trial showed that VS411 was able to reduce immune activation while producing a median 1.5 log10 reduction in viral load. VS411 is a first-generation AV-HALT (antiviral-hyperactivation limiting therapeutic) designed to reduce both viral load and the state of chronic activation that exists in HIV-infected individuals. The analysis was presented today at the 18th Conference on Retroviruses and Opportunistic Infections.
Results were obtained from 32 HIV-infected individuals enrolled in a Phase 2a study who were randomized to receive one of several escalating once-daily doses of oral VS411 for 28 days. In addition to antiviral activity and safety, several immune markers were assessed, including the surface activation markers, CD38 and HLA-DR; Ki-67, a cell surface protein indicative of cell replication; and PD-1, a marker of cell exhaustion after chronic activation. Rapid and statistically significant reductions were measured in each of the above immune markers.
"These reductions in activation are similar to the effect of several years of suppressive antiretroviral therapy and were accomplished in only one month. This indicates the potency of the anti-hyperactivation component of our strategy," Franco Lori, MD, chief executive officer of ViroStatics, commented. "Notably, this effect was generated without completely suppressing HIV, suggesting that VS411 was able to specifically target the immune system hyperactivation."
The median decrease in HIV viral loads at day 28 was 1.5 log10, with HIV levels falling below the level of detection (<50 copies/mL) in only two subjects. The median CD4+ cell increase was 108 cells/mm. At day 28, the percentage of CD4+ and CD8+ T cells expressing the activation markers CD38 and HLA-DR had decreased 28.9% and 34.4%, respectively. Elevations of these markers are indicative of HIV infection and its progression to AIDS.
At day 28, significant declines were also detected in Ki-67, a protein expressed on T cells that is up-regulated during cell proliferation. Declining Ki-67 expression suggests a decrease in T-cell proliferation and, therefore, a reduction in immune system hyperactivation. Likewise, declines were observed for PD-1, a receptor that is up-regulated on the surface of exhausted T cells. "T-cell exhaustion," which results when the immune system has become unable to replenish the pool of CD4+ T cells that are lost during active HIV infection, is a main contributor to the progression of HIV infection to AIDS. Reduction of PD-1 expression suggests a restoration of normal T-cell function. No significant adverse changes in blood chemistry were observed in the course of the trial, nor were there any signs of drug resistance.
"Current HIV/AIDS treatments have been successful in reducing viral loads, in many cases to undetectable levels," said Elly T. Katabira, MB ChB, FRCP, lead investigator and professor of medicine at Makerere University in Uganda. "However, we will never be able to address the entire disease state without reducing the chronic immune hyperactivation that exists in HIV-infected individuals and the resulting destruction of CD4+ T cells."