Data From Landmark Study Evaluating Gender Differences in Response to an HIV Therapy Published in Annals of Internal Medicine

TITUSVILLE, N.J., Sept. 20 /PRNewswire/ -- Data from the GRACE (Gender, Race And Clinical Experience) study will be published in the September 21st issue of the Annals of Internal Medicine. GRACE is the largest-ever study of treatment-experienced adult women with HIV-1 to examine gender differences in response to HIV therapy. Sponsored by Tibotec Therapeutics Clinical Affairs, a division of Centocor Ortho Biotech Services, LLC, the GRACE study enrolled 67 percent women, demonstrating that it is possible to recruit large numbers of women into U.S.-based HIV treatment studies. The company has launched www.TheGraceStudy.com to share learnings from the GRACE study and other information for women living with HIV.

Among patients who completed the study, there were no significant differences in treatment responses between men and women who were given PREZISTA® (darunavir) 600 mg coadministered with 100 mg ritonavir twice daily, as part of combination therapy. The GRACE study was designed in partnership with the HIV community and used unique strategies to encourage women living with HIV to participate in the trial. However, even with its novel enrollment strategies, the study showed a higher discontinuation rate among female study participants — making the overall response rate lower among women than among men, and shedding light on the need for additional efforts to retain diverse populations in clinical studies.

"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 Judith Currier, MD, Professor of Medicine, Associate Division Chief, Division of Infectious Diseases, University of California, Los Angeles, Director of the Clinical Trials Unit, UCLA Center for Clinical AIDS Research and Education (CARE), and primary investigator in the GRACE study.  "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."

In the United States, women account for an increasing proportion of people living with HIV/AIDS, including more than one quarter of new diagnoses. Yet despite their growing numbers, women have been under-represented in HIV treatment studies. This may be due to recruitment and retention challenges including family commitments, time constraints with jobs, and other socioeconomic factors. These observations have been noted in clinical trials of other therapeutic areas, including heart disease and cancer, suggesting that difficulties in recruiting women are not specific to HIV clinical trials. As a result of having a low number of women in these studies, gender-based conclusions are limited, and there remains a gap in clinical data.

"Unlike most studies of HIV medicines, GRACE was specifically designed and powered to assess gender differences in response to treatment," said Dr. Currier. "We took steps that have never before been used to make sure our study population was reflective of the demographics of women with HIV in the United States."

GRACE Study Design and Results

GRACE was a multi-center (65 sites), open-label Phase 3b trial that compared the efficacy, safety, and tolerability of the protease inhibitor PREZISTA (600 mg) boosted with a low dose of ritonavir (100 mg) twice a day, in combination with an investigator-selected optimized background regimen for 48 weeks in men (n=142) and women (n=287).  

The study was designed to enroll a high proportion of North American, treatment-experienced women that was reflective of the distribution and demographics of women with HIV in the United States.  Trial sites were selected to correspond with the geographic distribution of women with HIV, with the majority of sites located in the Northeastern (16 sites) and Southeastern (29 sites) United States.  Study sites were initially required to enroll three women before enrolling a man, and thereafter, each site was required to maintain at least 70 percent female enrollment. Men could only be enrolled if their addition did not compromise the 70 percent female quota.

GRACE participants also received support to cover costs associated with study participation, including assistance for travel, childcare and food vouchers, and study sites could access grants for patient support activities such as lunch-and-learn sessions and patient support groups for ongoing education and camaraderie.

At the end of the study period, there were no statistically significant differences in virologic response (defined as a viral load of <50 copies/mL) rates between women and men. Results from an intent-to-treat time-to-loss of virological response analysis (ITT-TLOVR) showed that 50.9 percent of women reached an undetectable viral load (<50 copies/mL) at week 48 compared with 58.5 percent of men (p=not significant). These figures included men and women who had discontinued the study. When treatment discontinuations for reasons other than virologic failure were discounted, 73 percent of women and 73.5 percent of men reached an undetectable viral load (p=not significant).

Discontinuation rates driven by reasons other than virologic failure were 32.8 percent for women versus 23.2 percent for men.  Loss to follow-up was the most common reason for discontinuation. There were no clinically relevant differences in safety or tolerability between women and men. In adult patients receiving a PREZISTA/r-containing regimen, the most common treatment-related adverse events (≥ 2 percent) reported of at least moderate to severe intensity (≥ Grade 2) were nausea (5.2 percent for women and 2.8 percent for men), diarrhea (4.5 percent for women and 4.9 percent for men) and rash (2.1 percent for women and 2.8 percent for men).

Additional analyses were conducted as part of the GRACE study, including a sub-study examining efficacy and safety differences in response to race, as well as an immunology sub-study.

PREZISTA Indication: Adults

PREZISTA, co-administered with ritonavir (PREZISTA/r), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

This indication is based on analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and treatment-experienced patients, and two controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

In treatment-experienced adult patients, the following points should be considered when initiating therapy with PREZISTA/r:

• Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/r.
• The use of other active agents with PREZISTA/r is associated with a greater likelihood of treatment response.

Important Safety Information

PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

Drug Interactions

• Coadministration of PREZISTA/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, alfuzosin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, oral midazolam, triazolam, lovastatin, simvastatin, or sildenafil for the treatment of pulmonary arterial hypertension)
• Coadministration of PREZISTA/r is also contraindicated with rifampin and products containing St. John's wort (Hypericum perforatum) because this may cause significant decrease in plasma concentration of darunavir, resulting in loss of therapeutic effect and development of resistance
• Coadministration is not recommended with indinavir, lopinavir/ritonavir, saquinavir, pravastatin, salmeterol, and colchicine in patients with hepatic or renal impairment
• Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving PREZISTA/r. This list of potential drug interactions is not complete

Warnings & Precautions

• PREZISTA must be coadministered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir. Please refer to ritonavir prescribing information for additional information on precautionary measures
• Drug-induced hepatitis (eg, acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/r. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/r. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse events

Postmarketing cases of liver injury, including some fatalities, have been reported. A causal relationship with PREZISTA/r therapy has not been established

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/r and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA/r treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/r should prompt consideration of interruption or discontinuation of treatment

• Severe Skin Reactions: Severe skin reactions (0.4%), accompanied by fever and/or elevations of transaminases in some cases, Stevens-Johnson syndrome (<0.1%), and toxic epidermal necrolysis (postmarketing experience) have been reported in patients receiving PREZISTA/r. Discontinue PREZISTA/r immediately if signs or symptoms of severe skin reactions develop (including, but not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia)

In clinical trials (N=3063), rash (all grades, generally mild to moderate, regardless of causality) occurred in 10.3% of patients receiving PREZISTA/r. Discontinuation due to rash was 0.5%

• Sulfa Allergy: PREZISTA should be used with caution in patients with known sulfonamide allergy
• Diabetes Mellitus/Hyperglycemia and Hemophilia: New-onset or exacerbations of preexisting diabetes mellitus, hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. A causal relationship between protease inhibitors and these events has not been established
• Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established
• Immune reconstitution syndrome has been reported in patients treated with ARV therapy
• Resistance/Cross-Resistance: The potential for HIV cross-resistance among protease inhibitors has not been fully explored in PREZISTA/r-treated patients

Use in Specific Populations

• Hepatic impairment: PREZISTA/r is not recommended for use in patients with severe hepatic impairment. There are no pharmacokinetic or safety data available in patients with severe hepatic impairment
• Pregnancy: PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. No adequate and well-controlled studies have been conducted in pregnant women

Adverse Reactions

• In treatment-naive adult patients, the most common adverse drug reactions (greater than or equal to 5%) reported of at least moderate intensity (greater than or equal to Grade 2) in the PREZISTA/r arm through 96 weeks were diarrhea (8%), headache (6%), abdominal pain (5%), and rash (5%)
• In treatment-experienced adult patients, the most common adverse drug reactions (greater than or equal to 5%) reported of at least moderate intensity (greater than or equal to Grade 2) in the PREZISTA/r arm through 96 weeks were diarrhea (14%), nausea (7%), rash (7%), abdominal pain (6%), and vomiting (5%)

This is not a complete list of all adverse drug reactions reported with the use of PREZISTA/r.

Please see accompanying full Prescribing Information for more details. Full prescribing information is also available at www.PREZISTA.com.

You are encouraged to report negative side effects of prescription drugs to the FDA.  Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

About Tibotec Therapeutics

Tibotec Therapeutics, a division of Centocor Ortho Biotech Products, L.P., headquartered in Titusville, NJ, is dedicated to delivering innovative virology therapeutics that help healthcare professionals address serious unmet needs in people living with HIV.

SOURCE Tibotec Therapeutics

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