The experimental oral integrase inhibitor raltegravir (Isentress) achieves HIV RNA reductions in antiretroviral treatment-naïve patients comparable to the NNRTI efavirenz (EFV; Sustiva) and demonstrates a more favorable lipid and tolerability profile, according to 48 week results of a study presented this week at the 4th IAS conference in Sydney (July 22-25, 2007). Both drugs were used in combination with the nucleoside analogs tenofovir (TFV; Viread) and lamivudine (3TC; Epivir).

Raltegravir is an integrase inhibitor that is currently being investigated for use in treatment-experienced patients.  If approved by US and European drug regulatory agencies, as expected, raltegravir will be the first in a new class of oral HIV/AIDS drugs.

In the present Phase 2 study, raltegravir produced reductions in HIV viral load to undetectable levels <50 copies/ mL in 83-88 percent of patients compared to efavirenz in 87 percent of patients. Study investigators observed these results in all four doses of raltegravir studied (100mg, 200mg, 400mg, and 600mg twice daily). Compared with efavirenz, raltegravir showed minimal impact on total and low-density lipoprotein (LDL) serum cholesterol, serum triglycerides and the ratio of total cholesterol to HDL cholesterol. 

In addition, at week 48, the mean increase in CD4 cell counts from baseline among patients treated with raltegravir ranged from 144 to 221cells/microliter.

“These findings are consistent with the efficacy and tolerability profiles that were seen with Isentress [at] 24 weeks [presented at the 2006 International AIDS Conference in Toronto]," said Martin Markowitz, MD, lead study investigator and clinical director of the Aaron Diamond AIDS Research Center in New York.

The results also parallel the conclusions of the BENCHMRK-1 and BENCHMRK -2 Phase 3 studies, conducted in treatment-experienced HIV patients, namely that raltegravir "demonstrated potent and superior antiretroviral activity" compared with placebo in combination with optimized background therapy in patients with triple-class resistant HIV. In all arms of those studies, the rate of serious drug-related adverse events was 2.5% or less.

Trial Design and Objectives

The current study was a multicenter, double-blind, randomized, Phase 2 study of raltegravir (100, 200, 400, or 600 mg bid) vs efavirenz (600mg qd) both in combination with TFV/3TC. 198 treatment-naïve patients were treated (mean age 36 years, 80% male, 69% non-white, 34% with AIDS), had HIV-1 RNA >/=5000 copies/mL and CD4+ count  >/=100 cells/microliter.

Mean baseline viral load of study participants ranged from 4.6 to 4.8 log₁₀ copies/mL; mean CD4 counts were 271 and 338 cells/microliter for raltegravir and efavirenz, respectively. Patients were monitored for safety, tolerability, and efficacy (HIV-1 RNA and CD4+ T cell count) over 48 weeks.

48-week Results

·         83 to 88 percent of patients in the raltegravir arm (at all doses studied) maintained reductions in HIV RNA viral load <50 copies/mL. 

·         87 percent of patients receiving efavirenz maintained reductions in HIV RNA viral load <50 copies/mL.

·         Patients in all raltegravir groups experienced HIV RNA <50 copies/mL earlier than patients in the efavirenz group; however, by week 24, both groups had similar responses that were sustained to week 48.

·         Mean increase from baseline in CD4 cell counts of the raltegravir groups was 144 to 221 cells/microliter;

·         Mean increase from baseline in CD4 cell counts of the efavirenz group was 170 cells/microliter.

·         Raltegravir showed minimal effect on total and LDL serum cholesterol, serum triglycerides and the ratio of total cholesterol to HDL cholesterol;

·         Mean changes from baseline for raltegravir (all doses combined) and efavirenz, respectively, were -2.3 mg/dL and +20.7 mg/dL (p <.001) for total cholesterol; -7.5 mg/dL and +3.0 mg/dL (p=.0016) for LDL cholesterol; -1.0 mg/dL and +49.5 mg/dL (p=.068) for triglycerides, and     -0.59 mg/dL and -0.47 mg/dL (p=0.52) for the ratio of total cholesterol to HDL cholesterol.

·         Clinical adverse experiences were generally mild to moderate: nausea, dizziness and headache were the most frequently reported events.

·         Neuropsychiatric adverse events (abnormal dreams, depression, nightmare and suicidal thoughts) were less frequently reported in patients receiving raltegravir (13%) compared to those receiving efavirenz (29%).

·         Five of 160 patients receiving raltegravir (3 percent) and one of 38 (3 percent) receiving efavirenz experienced virological failure.

·         Proportions of patients achieving HIV RNA <400 or <50 copies/mL at Weeks 24 and 48 are shown in Table 1:

Table 1: Proportions of patients achieving HIV RNA <400 or <50 copies/mL at Weeks 24 and 48

In conclusion the study authors wrote, “Raltegravir with TFV/3TC at all doses studied had potent and durable antiretroviral activity similar to EFV/3TC/TFV and was generally well-tolerated in ART-naive patients.”

Aaron Diamond AIDS Research Center, New York, NY, United States, Merck Research Laboratories, West Point, PA, United States, Hospital Nacionale Cayetano Heredia, Lima, Peru, Hospital Nacionale Edgardo Rebagliati, Lima, Peru, Siriraj Hospital, Bangkok, Thailand, Canadian Immunodeficiency Research Collaborative, Toronto, Canada.

[Editor’s Note: Raltegravir Expanded Access Program (EAP)]

Expanded access programs (EAPs) are FDA-sanctioned procedures that provide access to promising experimental therapies free of charge to patients with serious illnesses who have limited or no treatment options. Currently, more than 4,000 patients worldwide are participating in the EAP for Merck’s raltegravir. For more information on the program, visit www.benchmrk.com

07/24/07

Reference
M Markowitz, B-Y Nguyen, E Gotuzzo, and others (for the Protocol 004 Part II Study Team). Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week data. 4^th IAS. July 22-25, 2007. Sydney, AU. Abstract (oral) TuAb104.                                                                                       

4th IAS
Main Conference Page