icon- folder.gif   Conference Reports for NATAP  
 
  XVII International AIDS Conference
Mexico City
3-8 August 2008
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Gender-Based Differences in ART-Naives in CASTLE Study: viral response, lipids, adverse events; and Other Gender-Based Studies at IAC
 
 
  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-naive (ARV) Subjects: Results from Study M05-730
 
Lopinavir/ritonavir (LPV/r) in Pregnancy: ART Pregnancy Registry
 
Nevirapine Is Best Semen Penetrator in Study of Six PIs and Nonnucleosides
 
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)
 
Pharmacokinetics of etravirine are not affected by sex, age, race, treatment duration or use of enfuvirtide in HIV-1-infected subjects
 
Abbott's Kaletra(R) Tablet Dosed Once-Daily or Twice-Daily Demonstrated Similar Clinical Results Across Race and Gender Lines
 
PrEP for Prevention Has Arrived-Researchers Look to Daily Pill to Avert H.I.V.
 
Gender-Based Differences in ARV-Naive Patients Treated With Boosted Protease Inhibitors: Results From the CASTLE Study (AI424138)
 
Reported by Jules Levin
IAC Mexico City Aug 3-8, 2008
 
AUTHOR CONCLUSIONS
In treatment-naive patients, once-daily ATV/RTV demonstrated similar antiviral efficacy to twice-daily LPV/RTV, and both regimens were associated with robust increases in CD4 cell count, regardless of gender.
 
Once-daily ATV/RTV was associated with a lower incidence of GI-related AEs and a significantly better lipid profile than LPV/RTV, regardless of gender.
 
ATV/RTV is an effective once-daily boosted PI regimen that in combination with other ARVs is well tolerated and is appropriate for use in HIV-infected treatment-naive female and male patients.
 
INTRODUCTION
 
Gender-based differences in efficacy and safety have been reported among HIV-infected individuals receiving highly active antiretroviral therapy (HAART) and may relate to sex-based differences in pharmacokinetic and pharmacodynamic drug handling.1-4
 
It has been noted that women may experience higher toxicity profiles while receiving antiretroviral (ARV)-treatment regimens; however, data from randomized clinical trials are limited.4,5
 
Women are recognized as the fastest growing population of patients with HIV/AIDS.2
 
Gender differences affecting either response to, or safety of, ARV-treatment regimens may be important to consider when selecting regimens intended for long-term control of HIV infection, particularly among women.
 
Atazanavir (ATV) is a potent, generally well-tolerated, once-daily HIV-1 protease
inhibitor (PI) extensively studied in treatment-naive and treatment-experienced patients and a common component of HAART.6,7
 
The CASTLE study demonstrated that in combination with tenofovir disoproxil fumarate/emtricitabine, ATV/ritonavir (RTV) is noninferior to lopinavir (LPV)/RTV
in antiviral efficacy in treatment-naive patients at 48 weeks, with significantly
less elevation of lipids and better gastrointestinal (GI) tolerability.8
 
CASTLE is an international randomized clinical trial in 134 sites in 29 countries.a
 
This large-scale study, which included male and female HIV-infected, ARV-naive patients, affords the opportunity to assess potential gender differences in the efficacy and safety profiles of the 2 most commonly used PIs in HIV treatment.
 
OBJECTIVE
 
To assess and compare the virologic, immunologic, and safety profiles of an ATV/RTV-based regimen with an LPV/RTV-based regimen by gender using 48-week data from the CASTLE study.
 
METHODS
 
CASTLE is a randomized, open-label, prospective study comparing once-daily ATV/RTV with twice-daily LPV/RTV, both in combination with fixed-dose tenofovir/emtricitabine (TDF/FTC) in 883 treatment-naive HIV-infected patients (Figure 1).
 

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Through the first 48 weeks of the study, the protocol required patients to receive the capsule formulation of LPV/RTV.
 
The primary end point was the proportion of patients with HIV RNA < 50 c/mL at Week 48.
 
Secondary assessments included CD4 cell count change and safety parameters (adverse events [AEs] and laboratory tests [eg, serum chemistry and hematology, fasting lipid profile]).
 
Treatment comparisons by gender were prespecified; however, comparisons of lipid parameters by gender were post hoc analyses.
 
RESULTS
 
Baseline patient characteristics by gender are presented in Table 1.
 
Of the 883 randomized patients within CASTLE, 277 patients (31%) overall were female. Baseline characteristics were comparable by gender for both arms (Table 1).
 

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Virologic and Immunologic Responses
 
Overall, once-daily ATV/RTV-based HAART demonstrated similar efficacy to twice-daily LPV/RTV-based HAART: 78% of patients on ATV/RTV and 76% on
LPV/RTV achieved HIV RNA < 50 c/mL at Week 48 (difference estimate 1.7% [95% CI, -3.8% to 7.1%]) using an intent-to-treat (ITT) analysis, confirmed virologic response (CVR) noncompleter = failure (NC = F).
 

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Virologic response rates were consistently high in both male and female patients (Table 2).
 
Overall, mean CD4 cell count changes from baseline at Week 48 were 203 cells/mm3 on ATV/RTV and 219 cells/mm3 on LPV/RTV. These results were consistent in both male and female patients (Table 2).
 

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Adverse Events
 
AEs were not treatment-limiting in most cases.
 
The rates of select GI grade 2 to 4 treatment-related AEs, by gender and treatment arm, are shown in Table 3.

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GI adverse events generally occurred at higher frequencies in patients on the LPV/RTV rather than the ATV/RTV regimen.
 
In the LPV/RTV-treatment group there appeared to be a tendency for women to experience more nausea and men to experience more diarrhea.
 
Other grade 2 to 4 treatment-related GI AEs were reported by ≦ 1% of men or women in either treatment arm through 48 weeks.
 
Grade 2 to 4 treatment-related jaundice was reported in 4% of male patients and 3% of female patients receiving ATV/RTV, and in no patients receiving LPV/RTV.
 
The rates of other grade 2 to 4 treatment-related AEs differed less than 5% between genders within system organ class for both regimens.
 
Lipid Parameters
 
Differences have been reported between ATV/RTV and LPV/RTV at 48 weeks in the overall CASTLE population in terms of changes in lipid profile from baseline.8
-- Mean percent increases in fasting total cholesterol, non–high-density lipoprotein cholesterol (non–HDL-C), and triglycerides (TGs) were higher with LPV/RTV than ATV/RTV (all P < 0.0001).
-- More patients taking LPV/RTV (8%) than ATV/RTV (2%) initiated lipid-lowering therapy.
 
Post hoc analyses of 48-week data show that the changes in fasting total cholesterol, non–HDL-C, and TGs remained lower on ATV/RTV than LPV/RTV, regardless of gender (Table 4).
 

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REFERENCES
 
1. Clark RA, Squires KE. Expert Rev Anti Infect Ther. 2005;3(2):213-27.
2. Cohn SE. AIDS Read. 2003;13(5):241-2, 244.
3. Gandhi M, et al. Annu Rev Pharmacol Toxicol. 2004;44:499-523.
4. Rodriguez-Novoa S, et al. AIDS Rev. 2005;7(2):103-12.
5. Tedaldi EM, et al. J Acquir Immune Defic Syndr. 2008;47(4):441-8.
6. Johnson M, et al. AIDS. 2006;20(5):711-8.
7. Malan DR, et al. J Acquir Immune Defic Syndr. 2008;47(2):161-7.
8. Molina JM, et al. Presented at: 15th Conference on Retrovirus and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA.
 
aCountries of research: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Costa Rica, Dominican Republic, France, Germany, Guatemala, Hong Kong, Indonesia, Mexico, The Netherlands, Panama, Peru, Portugal, Puerto Rico, Singapore, South Africa, Spain, Taiwan, Province of China, Thailand, United Kingdom, United States.