Background:  The HIV-1 integrase enzyme represents a new target for antiretroviral therapy (ART). L-000810810 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV (IC95 of 100 nM in human serum), and good bioavailability in uninfected subjects. Resistant mutants are difficult to select and were observed only after many months in cell culture. We wanted to provide proof-of-concept for the efficacy of integrase strand transfer inhibitor (ISTI).

Methods:  Multicenter, double-blind, randomized, placebo-controlled study of L-000870810 or placebo (4:1) as monotherapy for 10 days in 2 groups of HIV-1-infected patients (total = 30) on no ART at entry. Doses of L-000870810 were 400 mg or 200 mg twice daily. Patients were monitored for safety and efficacy. Subsequent to initiation of this study, the clinical development program was put on hold due to toxicity observed in dogs during long-term dosing.

Results:  Including 10 ART-experienced, 17 patients with geometric mean baseline HIV RNA of 42,663 copies/mL (7906 to 264,327) received the 400-mg dose. Including 5 ART-experienced, 7 patients with geometric mean baseline HIV RNA of 49,293 copies/mL (12,548 to 277,493) received the 200-mg dose. On day 10, at 400 mg twice daily, the observed mean decrease in HIV RNA from baseline was 1.77 log₁₀ copies/mL (range 0.95 to 2.49 log₁₀ copies/mL) (n = 16). At 200 mg twice daily, the observed mean decrease in HIV-RNA was 1.73 log₁₀ copies/mL (range 1.08 to 2.27 log₁₀ copies/mL) (n = 5). L-000870810 at both doses was generally well-tolerated with no discontinuation due to drug-related adverse events and no serious adverse events.

Conclusions:  The potent antiretroviral effect observed after a short period of monotherapy in both ART-experienced and ART-naïve patients provided proof-of-concept for the antiviral activity of ISTI as a new chemotherapeutic class. L-000870810 was generally well-tolerated in patients.

Keywords: HIV integrase inhibitors; antiviral therapy; new antiretroviral class