July 20, 2009

GRACE Shows Similar Treatment Response Rates in Women and Men on Prezista Treatment

Long-awaited 48-week data from the Gender, Race and Clinical Experience (GRACE) study indicate that Norvir (ritonavir)–boosted Prezista (darunavir) can be used in women and men with similar safety and efficacy outcomes. Reported by Kathleen Squires, MD, of Jefferson Medical College in Philadelphia and her colleagues on Monday, July 20, at the Fifth International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, GRACE also documented higher rates of study discontinuation among women, underscoring the need for further investigation into ways to better retain women in clinical trials.

Women account for an increasing proportion of people living with HIV/AIDS in the United States, yet data on the efficacy and safety of antiretroviral (ARV) therapy in women remain limited. According to Squires, several challenges, including socioeconomic factors, have led to difficulties in recruiting—and keeping (retaining)—women in HIV treatment studies.

Prezista, combined with low-dose Norvir, has been approved in the U.S. as a protease inhibitor option for treatment-experienced patients, as well as first-time treatment takers and HIV-positive children between the ages 6 and 17.

GRACE was designed to enroll a high proportion of treatment-experienced women in order to assess gender-based differences in efficacy and safety of Norvir-boosted Prezista treatment. The 48-week follow-up data were reported by Squires on the first full day of the IAS gathering in Cape Town.

The study enrolled 429 treatment-experienced HIV-positive individuals—287 women (66.9 percent) and 142 men (33.1 percent)—to receive Prezista/Norvir plus an optimized background regimen for 48 weeks. At the start of the study, women were younger and tended to have less advanced disease, less resistance and less treatment experience than the men enrolled.

About 66 percent of the women enrolled were black, compared with 51.4 percent of the men. Hispanics/Latinos accounted for 20.9 percent and 25.4 percent, respectively. The average length of infection upon entering the study was about 11 years; in addition, 58.5 percent of the women and 64.8 percent of the men had used at least two protease inhibitors before enrolling in GRACE. Average CD4 counts at study entry were 210 cells in the women, compared with 175 cells in the men.

The rate of treatment discontinuation was higher in women (32.8 percent) compared with men (23.2 percent). This difference was statistically significant, meaning it was too great to have occurred by chance. The primary reasons for study discontinuation were loss to follow-up and side effects; however, there were no trends toward a specific type of side effect driving discontinuations in either group.

In the strict “intention-to-treat (ITT)” analysis, in which all participants in the study are compared regardless of whether or not they completed the study, the virologic response rate—defined as a viral load below 50 copies/mL after 48 weeks—was not surprisingly better among men compared with women: 58.5 percent versus 50.9 percent, respectively. However, when those who discontinued the study for any reason other than documented virologic failure were removed from the analysis, treatment success rates were similar: 73.5 percent of the men enrolled compared with 73.0 percent of the women.

Similarly, men experienced a slightly better CD4 cell recovery compared with women after 48 weeks in the ITT analysis: gains of 89 versus 68 cells, respectively. But in the less stringent analysis, women faired better with a 131 CD4 cell gain, compared with a 104 cell gain among men.

Resistance data were available for 27 women with confirmed virologic failure and for whom drug-resistance test results (genotypes) were available at the start of the study, as well as 17 men with confirmed virologic failure and for whom genotypes were available at baseline. Among these individuals, twenty-six developed new HIV resistance mutations while participating in GRACE. Two (7.4 percent) women, compared with two (11.2 percent) men, were found to have a new major protease inhibitor-resistance mutation after experiencing virologic failure.

Overall, 90.2 percent of the women and 83.1 percent of the men experienced at least one adverse event, the majority of which were mild-to-moderate in severity. In total, 46.7 percent of women and 43.0 percent of men experienced at least one adverse event considered by Squires’s group to be at least possibly related to the use of Prezista/Norvir.

The most common side effects were nausea (24.4 percent of the women versus 14.1 percent of the men), diarrhea (16.4 versus 22.5 percent, respectively), upper respiratory tract infections (11.1 versus 7.7 percent, respectively) and vomiting (11.5 percent versus 6.3 percent). Interestingly, serious adverse events were less common among women compared with men: 16.4 percent versus 22.5 percent, respectively.

In conclusion, Squires pointed out that the GRACE study successfully enrolled a high proportion of women and is, to date, the largest North American study to assess sex-based differences in the efficacy and safety of an ARV regimen. Overall, she said, the data reported suggest that Prezista/Norvir can be used in women and men with similar safety and efficacy outcomes.

As for the higher rate of discontinuations, Squires pointed to the need to explore ways to retain women in treatment studies and argued that GRACE provides insight for the development and design of future clinical trials.

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