New interim 24-week data from an ongoing phase II dose-ranging study with MK-0518 twice daily (n=198), an investigational oral HIV integrase inhibitor under development by Merck & Co., Inc., Whitehouse Station, NJ, USA, in combination with tenofovir (Viread) and lamivudine (Epivir) showed comparable viral load reduction to below 50 copies/mL of HIV RNA (85 to 95 per cent of patients) to efavirenz (Sustiva) once daily combined with the same agents (92 per cent). This effect was observed at all four doses of MK-0518 studied (100 mg, 200 mg, 400 mg and 600 mg administered orally twice daily), in treatment naïve (previously untreated), HIV-infected patients with documented genotypic susceptibility to tenofovir, lamivudine and efavirenz.
Moreover, patients on the MK-0518-based regimen achieved HIV RNA reductions to levels less than 50 copies/mL earlier than patients on the efavirenz-based regimen. These data will be presented here at the 16th International AIDS Conference.
"This early study showed a rapid and significant reduction in viral load up to 24 weeks with MK-0518 in treatment-naïve patients. In this study MK-0518 was generally well tolerated," said lead study investigator Martin Markowitz, M.D., clinical director and staff investigator at the Aaron Diamond AIDS Research Center, New York City, and the Aaron Diamond Professor at the Rockefeller University. "This study should lend further insight into the potential of HIV integrase inhibitors as a new and exciting class of antiretroviral agents."
MK-0518 belongs to a new class of investigational antiretroviral therapy (ART) agents called integrase inhibitors that inhibit the insertion of the HIV viral DNA into human DNA. Inhibiting integrase from performing this essential function blocks the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit the other two enzymes - protease and reverse transcriptase - but there are no approved drugs that inhibit integrase.
These new results are from week 24 of an ongoing, two-part 48 week multi-center, double-blind, randomized trial of previously untreated patients. The first part of the study demonstrated antiviral activity of MK-0518 given orally as monotherapy at doses of 100 mg, 200 mg, 400 mg, or 600 mg twice daily for 10 days and was presented at the European AIDS Clinical Society meeting held in Dublin, Ireland in November 2005.
The second part of the study being presented at the International AIDS Conference meeting in Toronto compared MK-0518 to efavirenz both in combination with tenofovir and lamivudine in terms of reductions in HIV viral RNA, improvements in CD4 cell counts from baseline, and evaluation of safety and tolerability. In the study, 198 treatment-naïve, HIV-infected patients received either MK-0518 (100 mg, 200 mg, 400 mg or 600 mg, each administered orally twice daily) in combination with tenofovir and lamivudine or 600 mg efavirenz dosed orally once daily in combination with tenofovir and lamivudine. Thirty (30) of the 198 patients had participated in Part 1 (10 day monotherapy) before entering Part 2 of the study.
At enrolment, patients had less than seven days of prior exposure to antiretroviral therapy, HIV RNA of at least 5000 copies/mL and CD4 counts of at least 100 cells/uL. The majority of patients were male (73 to 90 per cent across all arms of the study), non-white (65 to 82 per cent across all arms of the study) and were between 34 to 37 years old. Patients undergoing immunosuppressive therapy or with diagnosed acute hepatitis, chronic liver disease or renal disease were excluded from the study.
After 24 weeks of therapy, 85 to 95 per cent of patients achieved reductions in HIV viral RNA to less than 50 copies/mL on the MK-0518-based regimen across all doses studied. At baseline, HIV RNA for patients in the MK-0518 arm of the study were 58206 copies/mL (100 mg; n=39), 64715 copies/mL (200 mg; n=40), 43083 copies/mL (400 mg; n=41) and 57919 copies/mL (600 mg; n=40), respectively. Results were similar for patients taking the efavirenz combination, with 92 per cent of patients achieving reductions in HIV RNA reductions to less than 50 copies/mL. Baseline HIV RNA for patients in the efavirenz arm of the study was 67554 copies/mL (600 mg; n=38). Reductions in HIV RNA viral load to less than 50 copies/mL occurred earlier for patients taking the MK-0518 combination than for patients taking the efavirenz combination.
Mean baseline CD4 cell counts ranged from 271 to 314 cells/uL. After 24 weeks of treatment, mean increase from baseline in CD4 cell counts ranged from 139 cells/uL to 175 cells/uL in the MK-0518 groups compared with 112 cells/uL in the efavirenz group.
Both treatment regimens were generally well tolerated. Clinical adverse experiences were mild to moderate, with nausea, dizziness and headache reported most frequently. There were eight serious non-drug-related adverse experiences between the two treatment groups (7/160 or 4 per cent in the MK-0518 arm and 1/38 or 3 per cent in the efavirenz arm). One patient in the MK-0518 600 mg group discontinued due to elevated AST/ALT.
"The HIV virus continues to be very challenging to suppress. Longer-term studies should provide more information as to what these results may potentially mean for infected patients," said Dr. Markowitz.