Results from an ongoing clinical trial of Isentress (raltegravir), Merck's experimental integrase inhibitor, suggest that it has comparable efficacy to Sustiva (efavirenz) after 48 weeks of treatment. The new data, involving patients beginning HIV treatment for the first time, were reported today at the fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007) in Sydney by Martin Markowitz, MD, of the Aaron Diamond AIDS Research Center in New York.
Encouraging 24-week data from studies involving treatment-experienced patients using Isentress in combination with an optimized background regimen were reported at the 14th Conference on Retroviruses and Opportunistic Infections (CROI) in February.
Integrase inhibitors block a middle step in HIV's lifecycle. After HIV has entered a CD4 cell and its RNA has been reverse transcribed to viral DNA, it must then be integrated into the CD4 cell's DNA. The HIV DNA then hijacks the CD4 cell, turning it into a viral factory. Isentress blocks the viral DNA integration, hence its classification as an integrase inhibitor.
The new data comes from a two-part clinical trial of Isentress. The first part of the study, reported in November 2005, evaluated different doses of MK-0518 given as monotherapy (without other HIV drugs): 100 mg, 200 mg, 400 mg or 600 mg, all taken twice a day.
Dr. Markowitz's presentation focused on the research conducted in the second part of the study. It enrolled 198 HIV-positive people starting treatment for the first time—including 30 participants enrolled in part one of the study—to receive either Isentress at one of the six doses explored in part one of the study or Sustiva. All patients in the study also received Viread (tenofovir) and Epivir (lamivudine).
Upon entering the study, average viral loads in the various treatment groups ranged from approximately 43,000 to 68,000. After 48 weeks of therapy, 83 percent to 88 percent of patients in the four Isentress dosing groups saw their viral loads reduced to less than 50 copies. In the Sustiva group, approximately 87 percent of patients experienced viral load reductions to less than 50. The differences between the various Isentress dosing groups and the Sustiva group were not statistically significant, meaning that the variations could have been due to chance.
CD4 counts, ranging from 271 to 338 cells at the start of the study, increased in all patients after 48 weeks or treatment. Among patients in the Isentress groups, CD4 counts increased by 144 to 221 cells. In the Sustiva group, CD4 counts increased by 170 cells. As with the viral load results, these differences were not statistically significant.
Five patients (3%) in the Isentress groups and one patient (3%) in the Sustiva group experience virologic failure while in the study, defined as either a viral load that failed to go undetectable by week 24 or a viral load rebound after an initial undetectable result. Mutations believed to be associated with resistance to integrase inhibitors—N155H, V151I, D232D/N and G163R/G in HIV’s integrase gene—were documented in two of the five Isentress-treated patients.
Dr. Markowitz reported that, thus far, treatment with Isentress or Sustiva seems to be well tolerated. Nausea, dizziness and headache appear to be the most frequently reported side effects. Neuropsychiatric adverse events—such as abnormal dreams, depression and suicidal thoughts—were less common in patients in the Isentress groups compared to those in the Sustiva group, occurring respectively in 13 percent and 29 percent of patients through week 48.
As for lipid levels, total cholesterol decreased my 2.3 mg/dL in the Isentress groups, compared to a 20.7 mg/dL increase in the Sustiva group. LDL “bad” cholesterol decreased by 7.5 mg/dL in the Isentress group, compared to an increase of 3.0 mg/dL in the Sustiva group. Differences between the Isentress and Sustiva groups with response to triglyceride and HDL cholesterol changes were not statistically significant.
Based on these encouraging results, along with preliminary data from the clinical trials involving treatment-experienced patients, Merck has submitted a new drug application (NDA) to the U.S. Food and Drug Administration seeking approval for the drug. A decision from the agency is expected sometime this fall.
Source:
Markowitz M, Nguyen B-Y, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment HIV-1 infected patients: 48-week data [Abstract TUAB104]. Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, 2007.
