Final data from the Tibotec Therapeutics–funded 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. GRACE, however, also documented higher rates of study discontinuation among women, underscoring the need for further investigation into ways to better retain women in clinical trials.
The results of GRACE are published in the September 21 issue of the Annals of Internal Medicine. Preliminary 48-week data from the clinical trial—the largest-ever study of treatment-experienced HIV-positive women examining gender differences in response to antiretroviral (ARV) therapy—were reported at the Fifth International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town.
Women account for an increasing proportion of people living with HIV/AIDS in the United States, yet data on the efficacy and safety of ARV therapy in women remain limited. There are several reasons for this, including socioeconomic factors that 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 United States as a protease inhibitor option for treatment-experienced patients, as well as first-time treatment takers.
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 data from the study, conducted at 65 sites in the United States, Puerto Rico and Canada, were authored by Judith Currier, MD, of the University of California, Los Angeles and her colleagues.
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 10.9 years among the women and 12.2 years among the men; 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.
As for CD4 recovery, there was a documented increase of 152 cells among the women, compared with 122 cells among the 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, 26 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, serious adverse events were documented in 47 (16.4 percent) women and 33 (23.2 percent) men. A total of two women and two men died during the study. However, all four deaths were not considered to be related to Norvir-boosted Prezista therapy. Roughly 90 percent of the women and 83 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 Currier'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 23.2 percent, respectively.
“Better representation of women in clinical trials is essential for generating accurate information on the efficacy and safety of medicines and, ultimately, guiding treatment decisions,” said Currier in a Tibotec press release announcing the Annals of Internal Medicine publication of the GRACE results. “The GRACE study has the potential to shape how future studies are conducted because it addressed the social and economic barriers that historically have prevented women from participating in clinical research. It also showed that we have a long way to go before we can fully overcome these barriers.”