Sex-Based Outcomes of Darunavir–Ritonavir Therapy: The GRACE (Gender, Race, and Clinical Experience) Study

In 2006, an estimated 1 106 400 adults and adolescents in the United States were living with HIV or AIDS (1). Of the new cases of HIV reported in 2006, 27% were women, and 45% were black (2). Since the beginning of the epidemic, women have accounted for an increasing proportion of persons with the disease (3). Furthermore, women of color are disproportionately affected: 64% and 15% of women living with HIV/AIDS in the United States in 2005 were black and Hispanic, respectively, yet these groups collectively represent only approximately 25% of the U.S. female population (3, 4). Women, and particularly women of color, have been underrepresented in antiretroviral clinical trials for treatment-experienced patients (5). This may reflect challenges in both recruiting and retaining women in clinical trials as a whole and highlights barriers to continuous medical care for this population, such as family commitments, job-related time constraints, or other socioeconomic factors. These observations have been noted in clinical trials of several other therapeutic areas (6–9), including cardiovascular, lung, and cancer research, suggesting that the challenges of recruiting women and persons or color are not specific to trials of antiretroviral therapy. An analysis (6) of the enrollment of women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute showed that studies of congestive heart failure enrolled only 26% women, although women account for 43% of patients with congestive heart failure. Likewise, examination of high-impact cancer studies published in 2006 (10) showed that women were underrepresented in studies of non–sex-specific types of cancer, averaging only 38.8% of enrolled participants. This has resulted in a paucity of clinical data for diverse populations. Although sex-based analyses are required for registration trials (11), studies with less than 25% female enrollment generally have limited statistical power to assess sex differences, thereby limiting sex-based conclusions in most trials (12). The recruitment and retention of women in clinical trials are essential to provide accurate information on the efficacy and safety of therapeutic agents in all patients and, ultimately, to guide treatment decisions for women (13, 14). Darunavir, a protease inhibitor, combined with a low dose of ritonavir, was initially introduced as a therapeutic option (600/100 mg twice daily) for treatment-experienced patients with HIV (15). Subsequently, darunavir–ritonavir was approved for use in treatment-naive adults (800/100 mg once daily) and treatment-experienced children (aged 6 to 17 years; weight-dependent twice-daily dosing) (15). In the POWER (Performance Of TMC114/r When evaluated in treatment-Experienced patients with PI [protease inhibitor] Resistance) and TITAN (TMC114/r In Treatment-experienced pAtients Naive to Lopinavir) trials, which assessed the efficacy and safety of darunavir–ritonavir, the number of women enrolled was approximately 10% to 21% of the overall population (16, 17). In the ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects) trial, treatment-naive women accounted for 30% of patients in the darunavir–ritonavir group, with results showing similar safety and efficacy between the sexes at week 96 and no differences in discontinuation rates due to adverse events (18). To expand the clinical data available for darunavir–ritonavir in treatment-experienced women, the GRACE (Gender, Race, And Clinical Experience) trial, conducted from 6 October 2006 to 19 December 2008, was specifically designed and powered to assess sex-based differences in efficacy and to evaluate the incidence of adverse events (5). The study was also designed to enroll a high proportion of treatment-experienced North American women to reflect the distribution and demographic characteristics of women with HIV in the United States. We report the efficacy outcomes and incidence of adverse events in women and men who received darunavir–ritonavir-based therapy over 48 weeks during the GRACE study; data on outcomes by race and ethnicity will be presented elsewhere.