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1.  Improvements in Immune Function and Activation with 48-Week Darunavir/Ritonavir-Based Therapy: GRACE Substudy 
ISRN AIDS  2013;2013:358294.
Objective. During the course of HIV infection, progressive immune deficiency occurs. The aim of this prospective substudy was to evaluate the recovery of functional immunity in a subset of patients from the GRACE (Gender, Race, And Clinical Experience) study treated with a DRV/r-based regimen. Methods. The recovery of functional immunity with a darunavir/ritonavir-based regimen was assessed in a subset of treatment-experienced, HIV-1 infected patients from the GRACE study. Results. 19/32 patients (59%) enrolled in the substudy were virologically suppressed (<50 copies/mL). In these patients, median (range) CD4+ cell count increased from 222 (2, 398) cells/mm3 at baseline to 398 (119, 812) cells/mm3 at Week 48. CD8+% decreased significantly from baseline to Week 48 (P = .03). Proliferation of CD4+ lymphocytes in response to CD3+/CD28+, phytohemagglutinin, and pokeweed was significantly increased (P < .01) by Week 12. Proliferation in response to Candida and tetanus was significantly increased by Week 48 (P < .01 and P = .014, resp.). Staphylococcal enterotoxin B-stimulated tumor necrosis factor-alpha and interleukin-2 in CD4+ cells was significantly increased by Week 12 (P = .046) and Week 48 (P < .01), respectively. Conclusions. Darunavir/ritonavir-based therapy demonstrated improvements in CD4+ cell recovery and association with progressive functional immune recovery over 48 weeks. This trial is registered with NCT00381303.
PMCID: PMC3874356  PMID: 24396625
2.  Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks 
AIDS Research and Human Retroviruses  2012;28(10):1184-1195.
We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.
PMCID: PMC3448095  PMID: 22352336
3.  Darunavir, Ritonavir, and Etravirine Pharmacokinetics in the Cervicovaginal Fluid and Blood Plasma of HIV-Infected Women▿  
We report darunavir, ritonavir, and etravirine pharmacokinetics in cervicovaginal fluid and blood plasma for women from the Gender, Race and Clinical Experience (GRACE) study. Eight women received darunavir-ritonavir (600/100 mg) twice daily (b.i.d.); two also received etravirine (200 mg) b.i.d. Week 4 paired blood plasma and cervicovaginal fluid samples were collected over 12 h. Darunavir and etravirine cervicovaginal fluid exposures were higher than blood plasma exposures; ritonavir cervicovaginal fluid exposure was lower than blood plasma exposure. The high exposures of darunavir and etravirine in cervicovaginal fluid warrant further evaluation of these drugs for use in HIV-1 prevention.
PMCID: PMC3067092  PMID: 21173188
4.  Recruitment and Retention of Diverse Populations in Antiretroviral Clinical Trials: Practical Applications from the Gender, Race And Clinical Experience Study 
Journal of Women's Health  2011;20(7):1043-1050.
Women, particularly women of color, remain underrepresented in antiretroviral (ARV) clinical trials. To evaluate sex-based differences in darunavir/ritonavir-based therapy, the Gender, Race And Clinical Experience (GRACE) study was designed to enroll and retain a high proportion of women representative of the racial/ethnic demographics of women with HIV/AIDS in the United States. The recruitment and retention strategies used in GRACE are described in this article.
Recruitment and retention strategies targeting women included selecting study sites that focused on women, involving community consultants, site-specific enrollment plans, access to other ARV drugs, study branding, site and patient toolkits, targeted public relations, site grants for patient support, and subsidized child care and transportation.
The recruitment strategies were successful; 287 (67%) women were enrolled, primarily women of color (black, n=191 [67%], Hispanic, n=60 [21%]). Despite the focus on retention, a greater proportion of women (32.8%) discontinued compared with men (23.2%).
The successes of GRACE in enrolling a representative population of women were rooted in pretrial preparation, engagement of community advisors, enrollment quotas, choice of study sites and site support. Lessons learned from GRACE may be applied to future study design. Further focus on factors that influence discontinuation is warranted.
PMCID: PMC3130514  PMID: 21663416
5.  Sex-Based Outcomes of Darunavir–Ritonavir Therapy: The GRACE (Gender, Race, and Clinical Experience) Study 
Annals of internal medicine  2010;153(6):349-357.
Women account for an increasing proportion of patients with HIV-1 but remain underrepresented in antiretroviral clinical trials.
To evaluate sex-based differences in efficacy and adverse events in treatment-experienced HIV-positive women and men receiving darunavir–ritonavir-based therapy over 48 weeks.
Multicenter, open-label, phase IIIb study designed to enroll a high proportion of women, with sample size determined on the basis of a noninferiority design with a maximum allowable difference of 15% in virologic response favoring men. ( registration number: NCT00381303)
65 sites in the United States, Puerto Rico, and Canada.
287 women and 142 men.
Patients received darunavir–ritonavir, 600/100 mg twice daily, plus an investigator-selected optimized background regimen.
Virologic response (HIV-1 RNA <50 copies/mL using a time-to-loss of virologic response [TLOVR] algorithm) and adverse events were assessed over 48 weeks.
67% of patients were women; 84% of patients were black or Hispanic. A higher proportion of women discontinued treatment than men (32.8% vs. 23.2%; P = 0.042); more women than men discontinued for reasons other than virologic failure. Response rates in women and men at week 48 were 50.9% and 58.5%, respectively (intention-to-treat TLOVR), and 73.0% and 73.5%, respectively (TLOVR-censored for patients who withdrew for reasons other than virologic failure . The absolute difference in response, based on logistic regression and adjusted for baseline log10 viral load and CD4+ cell count, was −9.6 percentage points (95% CI, −19.9% to 0.7 percentage points;; P = 0.067) for intention-to-treat TLOVR and −3.9 percentage points (CI, −13.9% to 6.0 percentage points; P = 0.438) for TLOVR-population that censored patients who withdrew for reasons other than virologic failure. Adverse events were similar between the sexes. The most common grade 2 to 4 adverse events that were considered at least possibly treatment-related in women and men were nausea (5.2% and 2.8%, respectively), diarrhea (4.5% and 4.9%, respectively), and rash (2.1% and 2.8%, respectively).
Baseline characteristics differed between women and men.
Nonsignificant, sex-based differences in response were found during the 48 weeks of the GRACE study; however, these differences were probably due to higher discontinuation rates in women, suggesting that additional efforts are needed to retain women in clinical trials.
Primary Funding Source
Tibotec Therapeutics.
PMCID: PMC3056066  PMID: 20855799

Results 1-5 (5)