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  EACS - 12th European AIDS Conference
November 11-14, 2009
Cologne, Germany
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Gender-Based Differences in Antiretroviral-Naïve Patients Treated With Ritonavir-Boosted Protease Inhibitors: Results From the CASTLE Study Through 96 Weeks
  Reported by Jules Levin
EACS Nov 13 2009 Cologne Germany
M. Johnson1, K. Squires2, T. Hosey3, J. Uy3, M. DeGrosky4, R. Yang4, A. Farajallah3, L. Sheppard5, D. McGrath4 for the CASTLE Study Group 1Royal Free and University College London, London, UK; 2Thomas Jefferson University, Philadelphia, PA, USA; 3Bristol-Myers Squibb, Plainsboro, NJ, USA; 4Bristol-Myers Squibb, Wallingford, CT, USA; 5Bristol-Myers Squibb, Braine-l'Alleud, Belgium
The findings were similar to the overall results for the CASTLE study.10,11
In the ITT analysis, women and men receiving ATV/RTV had higher virological response rates than those receiving LPV/RTV, and women in either treatment arm had lower virological response rates than men.
These differences were not observed in the on-treatment analysis.
Through 96 weeks, GI AEs and lipid profiles were lower in women and men receiving ATV/RTV than those receiving LPV/RTV.
Consistent with other ARV clinical trials,7 gender differences in treatment efficacy were primarily due to higher discontinuation rates among women.
Once-daily ATV/RTV is an effective and well-tolerated therapeutic option for treatment-naïve female and male patients.
To assess the virological, immunological, and safety profiles of an ATV/RTV-based regimen and an LPV/RTV-based regimen by gender using 96-week data from the CASTLE study.
Of the 35 million people worldwide infected with HIV, approximately 17 million (48%) are women.1,2
Gender-based differences in efficacy and safety reported among HIV-infected individuals receiving combination antiretroviral therapy (cART) may relate to gender-based differences in pharmacokinetic and pharmacodynamic drug handling.2-5
Women may respond differently to antiretroviral (ARV) drugs for both socioeconomic and physiological (eg, toxicity profile) reasons both in clinical trials and during routine clinical care.5,6 Long-term data are limited, and it is challenging to recruit and retain women in ARV clinical trials.7 However, it is important to consider gender differences that may affect response to or tolerability of an ARV when selecting a treatment regimen.
Atazanavir (ATV) is a potent, once-daily HIV-1 protease inhibitor (PI) with proven efficacy in both treatment-naïve and treatment-experienced men and women.8,9
The CASTLE study demonstrated that in combination with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), ATV/ritonavir (RTV) is noninferior to lopinavir (LPV)/RTV in antiviral efficacy in treatment-naïve patients at both 48 and 96 weeks, with a better lipid profile and better gastrointestinal (GI) tolerability.10,11
Results of gender differences in the CASTLE study at 48 weeks have previously been presented.12
CASTLE is an international, randomised, open-label, prospective study of once-daily ATV/RTV versus twice-daily LPV/RTV, both with fixed-dose TDF/FTC in 883 treatment-naïve HIV-infected patients (Figure 1).
Figure 1. The CASTLE Study Design


Patients randomised to LPV/RTV were able to switch from the soft-gel capsule to the tablet formulation after 48 weeks; however, only 39 patients switched to the tablet formulation.
The primary end point was the proportion of patients with HIV RNA < 50 copies/mL at Week 48. This end point was also assessed at Week 96.
The 96-week principal analysis was based on the confirmed virological response (CVR) noncompleter=failure (NC = F; intent-to-treat [ITT]) and supportive analyses included were: time to loss of virological response (TLOVR: an ITT analysis that defined response as 2 consecutive on-treatment HIV RNA < 50 copies/mL achieved and maintained through week 96 without intervening discontinuation and virological rebound), and virological response-observed cases (VR-OC) - an on-treatment analysis.
Secondary assessments included: CD4 cell count change and safety parameters (adverse events [AEs] and laboratory tests [eg, serum chemistry and haematology, fasting lipid profile]) at 48 and 96 weeks.
Efficacy and safety analyses for each treatment by gender were pre-specified.
Of the 883 randomised patients within CASTLE, 277 patients (31%) overall were female. Baseline characteristics were comparable by gender for both arms (Table 1).
21% of women in the ATV/RTV group and 29% of women in the LPV/RTV group discontinued prior to Week 96 (Table 2).
Discontinuation rates were lower for male patients: 14% and 18% in the ATV/RTV and LPV/RTV groups, respectively.



aInsufficient viral load response determined by investigators; b2 cases of rash, 1 tuberculosis (TB), 1 thrombocytopenia, 1 GI problem, 1 GI
problem plus dizziness, jaundice, hepatomegaly, hyperbilirubinaemia; c2 cases of jaundice, 2 GI problems, 1 abdominal pain, 1
mycobacterium infection, 1 Fanconi syndrome; d2 cases of TB, 1 hypersensitivity, 1 hypertrophic cardiomyopathy, 1 rash, 1 proteinuria; e7
cases of diarrhoea, 1 furnicle, 1 major depression, 1 rash, 1 rhabdomycosis, 1 lipoma, 2 hyperlipidaemia, 1 lipodystrophy, 1 Kaposi sarcoma; fprotocol-defined for discontinuation.
Virological and Immunological Responses
Once-daily treatment with ATV/RTV was noninferior to twice-daily LPV/RTV: 74% of patients on ATV/RTV and 68% on LPV/RTV achieved HIV RNA < 50 copies/mL at Week 96 (difference estimate 6.1% [95% confidence interval [CI], 0.3%-12.0% ; P < 0.05]) using an ITT analysis, CVR, NC = F (Figure 2).


Consistent with the overall 96-week efficacy analysis by treatment arm, CVR rates were higher in both male and female patients receiving ATV/RTV than those receiving LPV/RTV. CVR rates were generally lower in female patients than in male patients in both treatment arms (Figure 3).
The TLOVR analysis showed that more patients in the ATV/RTV- than the LPV/RTV-treatment group had HIV RNA < 50 copies/mL at 96 weeks (ATV/RTV 64% female and 73% male patients; LPV/RTV 57% female and 66% male patients).
The VR-OC on-treatment analysis showed that all observed virological response rates were comparable between treatment groups and between genders (Figure 3).
Figure 3. Patients With HIV RNA < 50 copies/mL at 96 Weeks by Gender


Mean CD4 cell count changes from baseline at Week 96 were similar: 265 cells/mm3 in female patients and 269 cells/mm3 in male patients on ATV/RTV; 298 cells/mm3 in female patients and 286 cells/mm3 in male patients on LPV/RTV (Table 3).


Adverse Events
The rates of select GI grade 2 to 4 treatment-related AEs, by gender and treatment arm, are shown in Figure 4.


Most GI AEs occurred at higher frequencies in patients on the LPV/RTV regimen compared with the ATV/RTV regimen.
Women and men receiving LPV/RTV had a tendency to experience more nausea and more diarrhoea, respectively (Figure 4).
Other grade 2 to 4 treatment-related GI AEs were reported by ≤ 1% of men or women in either treatment arm through 96 weeks.
Jaundice or scleral icterus occurred in 4% of women and 5% of men receiving ATV/RTV.
Rash occurred in 3% and < 1% of women and 2% and 1% of men receiving ATV/RTV and LPV/RTV, respectively.
Rates of other grade 2 to 4 treatment-related AEs differed less than 5% between genders for both regimens.
Lipid Parameters
Differences have been reported between ATV/RTV and LPV/RTV at 96 weeks in the overall CASTLE population in terms of changes in lipid profile from baseline.11
- Mean percent changes from baseline in fasting total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TGs) were significantly higher with LPV/RTV than ATV/RTV (all P < 0.0001).
- More patients taking LPV/RTV (9%) than ATV/RTV (2%) initiated lipid-lowering therapy after start of study therapy.
Lipid analyses by gender at 96-weeks show that the median fasting TC, non-HDL-C, and TG levels were lower on ATV/RTV than LPV/RTV, regardless of gender (Figure 5).
At Week 96, men receiving LPV/RTV had median TG levels higher than the National Cholesterol Education Program (NCEP) cut-offs. Women and men in both treatment groups had median HDL-C levels above the NCEP cut-offs (Figure 5).
In the ATV/RTV arm mean changes from baseline in fasting lipids were lower in women than in men. In the LPV/RTV arm, mean changes from baseline were lower in women than in men for non-HDL-C and TG; higher in women than in men for HDL-C; and similar in men and women for TC and LDL-C.
Figure 5. Fasting Lipid Parameters at Week 96 By Treatment Group and Gender



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