Several studies during the HAART era have shown that overall, women and men benefit equally from antiretroviral therapy. This finding has been confirmed in several clinical trials and sub-analyses looking specifically at outcomes in women, as presented at the XVII International AIDS Conference this month in Mexico City.

GRACE: Darunavir in Treatment-experienced Patients

The GRACE (Gender, Race, And Clinical Experience) trial is a multicenter, open-label Phase IIIb trial designed to assess sex and race differences in the efficacy, safety, and tolerability of ritonavir-boosted darunavir (Prezista) over 48 weeks in treatment-experienced patients.

Unlike most earlier antiretroviral drug trials, which typically included a majority of men, GRACE was designed to enroll a racially diverse, predominantly female population, and the 65 study sites in North America were selected to meet this objective.

Judith Currier and colleagues reported the first data from the trial, derived from a pre-planned interim analysis of the first 203 participants (out of a total of 429 enrolled) who completed 24 weeks of therapy or discontinued before this point.

Of the 203 adult participants analyzed, 180 were women. The mean age was 42 years. A majority (65%) were African-American, 22% were Hispanic/Latino, 12% were white, and 1% were other race/ethnicity. All participants had baseline HIV viral load > 1000 copies/mL (mean of about 4.7 log10 copies/mL); the median CD4 cell count was about 200 cells/mm3, but the range was wide (1-868 cells/mm3).

All patients received 600/100 mg twice-daily darunavir/ritonavir plus an optimized background regimen (OBR). All commercially available nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and NNRTIs were permitted, including the recently approved etravirine (Intelence; formerly TMC125).

At baseline, about 60% had used 2 or more prior protease inhibitors (PIs); most (about 70%), however, had no primary PI resistance mutations, and only about 11% had 3 or more such mutations. More than half had at least 2 active drugs besides darunavir and etravirine in their OBR; 40% used etravirine.

This planned interim analysis was conducted primarily to assess safety and tolerability. The investigators presented preliminary efficacy results using an intention-to-treat (ITT) time to loss of virological response (TLOVR) analysis, as well as a TLOVR-non-virological failure analysis that excluded patients who discontinued for reasons other than virological failure.

Results

• At 24 weeks, 51% of patients -- overall and among women -- had viral load < 50 copies/mL in an ITT-TLOVR analysis.

• In a TLOVR-non-virological failure analysis, the rates were 65% overall and 66% among women.

• The median CD4 cell gain was 83 cells/mm3 overall and 86 cells/mm3 for women.

• 23% of participants overall, and 24% of women, discontinued study treatment.

• The most common reasons for discontinuation were adverse events (about 8%), loss to follow-up (about 6%), and non-adherence (about 3%).

• Only 1% discontinued due to virological failure.

• Side effects were similar in type and frequency between women and men.

• The most common moderate-to-severe (grade 2-4) adverse events at least possibly related to study drug and occurring in at least 2% of participants were nausea (6%), diarrhea (5%), rash (3%), weight gain (3%), dizziness (2%), and dyspepsia (2%).

• 4%-6% experience elevated liver enzymes (ALT and/or AST), 12%-13% experience elevated total cholesterol, and 6%-7% experienced elevated LDL ("bad") cholesterol.

• Serious adverse events were reported in 18% of patients, the most common of which was pneumonia (4%).

Based on these findings, the researchers concluded that:

• Response rates were within the expected range based on previous clinical trials of darunavir/ritonavir in treatment-experienced patients.

• Adverse events among women were generally similar to those see in other studies of darunavir/ritonavir in treatment-experienced individuals.

• Approximately one-quarter of women discontinued the study prior to week 24, for reasons "generally unrelated" to adverse events or virological failure.

The GRACE study is now fully enrolled, with 287 women and 142 men, the investigators said, "demonstrating that HIV-infected women from North America, including women of color, can be successfully recruited to participate in clinical trials of antiretrovirals."

University of California Los Angeles School of Medicine, Los Angeles, CA; Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA; Well Project, Inc., Atlanta, GA; Tibotec, Inc., Yardley, PA; Tibotec Therapeutics, Bridgewater, NJ.

M05-730: Lopinavir/ritonavir

Researchers with Abbott Laboratories presented data from sub-analyses of study M05-730 looking at outcomes by race/ethnicity (previously reported and by gender.

This ongoing international Phase III open-label study enrolled 664 antiretroviral-naive patients with HIV RNA > 1000 copies/mL and any CD4 cell count. Participants were randomly assigned to receive lopinavir/ritonavir (Kaletra) soft-gel capsules or tablets dosed once-daily or twice-daily for 48 weeks, along with once-daily tenofovir (Viread) plus emtricitabine (Emtriva). At week 8, all patients receiving the soft-gel capsule switched to the tablet formulation, keeping their previous dosing schedule.

The study enrolled 520 men and 144 women. Mean baseline CD4 cell counts were comparable in the 2 groups. Mean viral load was 4.85 log10 copies/mL for women and 5.03 log10 copies/mL for men.

Results

• In the main analysis, once-daily dosing was found to be non-inferior to twice-daily dosing.

• At 48 weeks, in an ITT non-completer = failure analysis, 72% of women and 78% of men achieved HIV RNA < 50 copies/mL at week 48 (a non-significant difference).

• Overall CD4 cell gains were similar in women and men (204 vs 189 cells/mm3, respectively; P = 0.298).

• Among patients with a baseline CD4 count below 50 cells/mm3, however, women experienced a significantly larger gain (237 vs 167 cells/mm3; P = 0.007).

• A similar percentage of patients discontinued therapy in the once-daily and twice-daily arms.

• The most common moderate-to-severe adverse events occurring in > 5% of participants were diarrhea, nausea, and vomiting.

• These events occurred with similar frequency in women and men.

• Grade 3 or higher triglyceride elevation was reported in 1% of women vs 6% of men (P = 0.011); men, however, had higher baseline values than women.

Despite higher baseline HIV-1 viral loads in males, the investigators concluded, "lopinavir/ritonavir tablets had similar efficacy in antiretroviral-naive males and females. CD4+ T-cell increases were similar between males and females, except females with baseline CD4+ T-cell counts < 50 cells/mm3 had higher mean increases."

Abbott Laboratories, Abbott Park, IL.

CASTLE: Lopinavir/ritonavir vs Boosted Atazanavir

In the CASTLE study, researchers compared twice-daily lopinavir/ritonavir vs once-daily ritonavir-boosted atazanavir in previously untreated HIV positive adults.

A total of 883 treatment-naive patients were randomly assigned to receive either 300/100 mg once-daily atazanavir/ritonavir or 400/100 mg twice-daily lopinavir/ritonavir, both in combination with fixed-dose tenofovir/emtricitabine (Truvada). About one-third (n = 277) were women, the median age was 35 years, the median CD4 count was about 200 cells/mm3, and the median viral load was about 5 log10 copies/mL.

Results

• Overall, as previously reported, 78% of patients in the atazanavir/ritonavir arm and 76% in the lopinavir/ritonavir arm achieved viral load < 50 copies/mL at 48 weeks.

• Looking at the women in the study, the corresponding virological response rates were 76% in the atazanavir/ritonavir arm and 73% in the lopinavir/ritonavir arm.

• Among men, the response rates were 79% vs 78%, respectively.

• For women, CD4 count increases were 199 cells/mm3 in the atazanavir/ritonavir arm and 221 cells/mm3 in the lopinavir/ritonavir arm

• Among men, CD4 gains were 205 and 219 cells/mm3, respectively.

• Participants in the atazanavir/ritonavir arm (both women and men) were less likely to develop elevated total cholesterol, non-HDL ("bad") cholesterol, and triglyceride levels than those taking lopinavir/ritonavir.

• In both arms, women were more likely to experience mild-to-moderate nausea than men:

• 7% of women vs 3% of men in the atazanavir/ritonavir arm;

• 14% vs 5%, respectively, in the in the lopinavir/ritonavir arm.

• Rates of other adverse events were similar in women and men.

In treatment-naive patients, atazanavir/ritonavir "demonstrated similar efficacy, a lower incidence of GI-related adverse events, and a significantly better lipid profile" compared to lopinavir/ritonavir, regardless of gender, the investigators concluded. "Other safety findings were consistent overall between genders."

Bristol-Myers Squibb Company, Research & Development, Wallingford, CT; Bristol-Myers Squibb Company, Lawrenceville, NJ.

ARTEMIS: Darunavir vs Lopinavir/ritonavir

Finally, researchers looked at outcomes by gender in the ARTEMIS study, which compared boosted darunavir vs lopinavir/ritonavir in treatment-naive patients. (Currently, darunavir is only approved for treatment-experienced individuals.)

In this Phase III, open-label trial, 689 participants with HIV RNA levels of at least 5000 copies/mL stratified by viral load and CD4 cell count were randomly assigned to receive 800/100 mg once-daily darunavir/ritonavir or 800/200 mg once- or twice-daily lopinavir/ritonavir plus fixed-dose tenofovir/emtricitabine.

The present analysis looked at the 343 participants -- 104 women and 239 men -- in the darunavir/ritonavir arm.

Results

• Overall, as previously reported, 84% of patients in the darunavir/ritonavir arm and 78% in the lopinavir/ritonavir arm achieved HIV RNA < 50 copies/mL.

• Broken down by gender, the response rate was the same for men and women -- both 84% -- in the darunavir/ritonavir arm.

• Overall, side effects were similar among men and women taking darunavir/ritonavir.

• Women, however, were more likely to experience diarrhea and nausea.

The investigators concluded that "No clinically meaningful differences" were observed in the tolerability of darunavir/ritonavir in treatment-naive patients at week 48, "irrespective of gender, age or race." They added that darunavir/ritonavir 800/100mg once-daily "is an effective, well-tolerated once-daily treatment option for treatment-naive patients regardless of gender, age or race."

Hospital Civil de Guadalajara, Guadalajara, Mexico; Infectious Diseases Department, CIMA Hospital, San Jose, Costa Rica; Family Health International, Arlington, VA; Tibotec BVBA, Mechelen, Belgium; Janssen-Cilag BV, Tilburg, Netherlands.

8/19/08

References

J Currier, K Squires, D Averitt Bridge, and others. Safety, tolerability and efficacy of darunavir/ritonavir in treatment-experienced women with HIV infection: 24-week interim analysis of GRACE (Gender, Race, And Clinical Experience). XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008.

A da Silva, D Cohen, S Gibbs, and others. Impact of Gender on Response to Lopinavir/ritonavir (LPV/r) Tablets Dosed QD or BID Administered with Tenofovir Disoproxil Fumarate (TDF) and Emtricitabine (FTC) in Antiretroviral-naïve (ARV) Subjects: Results from Study M05-730


J Absalon, J Uy, Y Rong, and others. Gender-Based Differences in ARV-Naïve Patients Treated with Boosted Protease Inhibitors: Results From the CASTLE Study (AI424138). August 3-8, 2008.


J Andrade-Villanueva, G Herrera, P Chiliade, and others. ARTEMIS: week 48 safety and efficacy of darunavir/r by gender, age and race. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract TUPE0064.


Other source
Abbott Laboratories. Abbott's Kaletra tablet dosed once-daily or twice-daily demonstrated similar clinical results across race and gender lines. Press Release. August 5, 2008.