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First Human Clinical Trial Tests New Class of Anti-HIV Medications

Drug combination reduces markers of immune-system hyperactivation (Oct. 19)

A review of the first human clinical trial to test a new class of anti-human immunodeficiency virus (HIV) medications known as antiviral hyperactivation-limiting therapeutics (AV-HALT) was published online in the October 19 issue of PLoS One. In the randomized phase II study, markers of immune-system hyperactivation, which drives HIV disease progression and cellular proliferation, were rapidly reduced by AV-HALT therapy, resulting in a proportional restoration of immune-system damage.

The study included 58 antiretroviral-naïve adults with chronic HIV-1 infection. Half of the patients were male; 50% were black; 43% were Caucasian; and 7% were Hispanic. The patients were randomly assigned to receive five dosing combinations of didanosine and hydroxycarbamide (known as VS411) — the first-in-class AV-HALT. During treatment, the investigators measured four accepted markers of immune-system hyperactivation: PD-1 (exhaustion), Ki-67 (proliferation), CD38 (activation), and HLA-DR (activation).

VS411 therapy produced significant reductions in HIV-1 RNA levels, increased CD4+ T cell counts, and led to rapid reductions in immune-activation markers after 28 days of treatment despite incomplete viral suppression and without inhibiting HIV-1–specific immune responses. The combination of didanosine 200 mg and hydroxycarbamide 900 mg once daily was associated with the greatest antiviral efficacy (HIV-1 RNA: –1.47 log10 copies/mL; CD4+ T cell count: +135 cells/mm3).

A total of 83 adverse events (AEs) were experienced by 36 of the 58 patients (62%). Sixty-one of the 83 AEs were mild in severity; 20 were moderate; and two were severe. The highest AE rate (76.9%) was reported in patients receiving didanosine 400 mg and hydroxycarbamide 600 mg, while the lowest rate (40.0%) was reported in those receiving didanosine 200 mg and hydroxycarbamide 900 mg.

The authors noted that although the two-drug combination of didanosine and hydroxycarbamide was judged to be safe for short-term use in this study, the combination is not a candidate for further drug development or as a treatment for HIV-1 disease because of significant long-term toxicities associated with didanosine, including pancreatitis, lactic acidosis, severe hepatomegaly with steatosis, and noncirrhotic portal hypertension. Work is under way to develop single-molecule, second-generation AV-HALT agents as HIV-modifying therapies.

Source: PLoS One, October 19, 2012.

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