aUniversity Health Network, University of Toronto, Toronto, Canada
bJefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
cUniversité Paris Descartes, Faculté de Médecine; AP-HP, Hôpital Européen Georges Pompidou, Paris, France
dKing's College Hospital, London, UK
eClinica di Malattie Infective, Lecco, Italy
fBoehringer Ingelheim, Ingelheim, Germany.
Received 8 October, 2008
Accepted 27 October, 2008
Correspondence to Sharon Walmsley, Professor of Medicine, University Health Network, Eaton North Wing, 13th floor Rm. 218, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail: firstname.lastname@example.org
Of the adults living with HIV, the percentage of infected women has risen from 35% to 48% since 1985 and now an estimated 18 million women live with HIV worldwide [1,2]. Although trends are similar in all parts of the world, women of African and Latin American descent are disproportionately affected. Increasingly, data suggest that antiretroviral (ARV) tolerability is different in women compared to men. Possible reasons for this include body size and body fat distribution and percentage; concentration of enzymes responsible for drug metabolism; and hormonal differences, which may be endogenous or caused by oral contraceptive use or hormone replacement therapy , and the potential impact on drug distribution and pharmacokinetics. Women are under-represented in most clinical HIV studies  and further data to investigate the impact of gender on the efficacy and safety of ARV drugs are therefore required. The present subanalysis evaluated the efficacy and safety of tipranavir/ritonavir (TPV/r) in treatment-experienced women who participated in Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients with Tipranavir (RESIST)-1 and RESIST-2 . Pharmacokinetic data were also analyzed to determine any relationship between TPV plasma levels and its safety and tolerability profile.
Unless otherwise stated, efficacy analyses used week 48 data and intent-to-treat, noncompleter = failure methodology. Safety analyses were based on all available data up to week 96. Samples for pharmacokinetic analysis were taken at steady state and 10–14 h after dosing.
Of the 1483 patients who participated in the RESIST trials, 203 (13.7%) were women and 1280 (86.3%) were men. Of the 203 women, 117 were randomized to TPV/r 500/200 mg b.i.d. and 86 to ritonavir-boosted comparator protease inhibitor (CPI/r). Of the 1280 men, 629 were randomized to TPV/r and 651 to CPI/r. At baseline, mean age, BMI, viral load, and CD4 cell count; proportion of patients who were classed as CDC class C; and a number of prior ARVs were similar in men and women. Most male and female patients were white; however, the percentage of women who were black was more than twice the percentage of men who were black: 23.1 vs. 10.7%, respectively, in the TPV/r group and 25.6 vs. 11.7%, respectively, in the CPI/r group. Hepatitis B and/or C coinfection rates were marginally higher in men than women in the TPV/r group (11.1 vs. 9.4%). In the CPI/r group, the converse was true, with marginally higher hepatitis coinfection rates in women than men (17.4 vs. 15.5%). The majority of women in both the CPI/r and TPV/r groups were enrolled from Europe (42.7% and 51.2%, respectively) and the majority of men were from North America (44.2% and 44.1%, respectively).
Overall, in the RESIST studies, TPV/r use resulted in durable long-term virological responses with 22.7%, 22.8% and 20.4% of TPV/r patients achieving viral load less than 50 copies/ml at 24, 48 and 96 weeks, respectively. Of the 169 patients with viral load less than 50 copies/ml at 24 weeks, 78% and 67% maintained undetectable viral load at 48 and 96 weeks, respectively. At week 48, 25.6% (30/117) of women and 22.1% (139/629) of men randomized to TPV/r had viral load less than 50 copies/ml. In comparison, 11.6% (10/86) of women and 10.0% (65/651) of men randomized to CPI/r achieved viral load less than 50 copies/ml.
Mean viral load change from baseline at week 48 (adjusted for protease inhibitor stratum, any enfuvirtide use and background reverse transcriptase inhibitor sensitivity) was −1.46 [95% confidence interval (CI) −1.74, −1.18] log10 copies/ml in women and −1.30 (95% CI −1.49, −1.10) log10 copies/ml in men taking TPV/r (P = 0.19). In comparison, in CPI/r recipients, mean viral load change from baseline at week 48 was −0.75 (95% CI −1.01, −0.49) log10 copies/ml in women and −0.66 (95% CI −0.82, −0.50) log10 copies/ml in men (P = 0.4508). A logistic regression analysis for TPV/r virological responses (week 48 viral load <50 copies/ml) in women vs. men gave an odds ratio of 1.15 (95% CI 0.71–1.84; P = 0.57). These data show that there were no significant gender-related differences in virological responses to TPV/r.
Immunological responses to TPV/r were significantly greater in women than in men: mean CD4 cell count change from baseline at last observation up to week 48 (adjusted for protease inhibitor stratum, any enfuvirtide use, background reverse transcriptase inhibitor sensitivity and baseline CD4 cell counts) was +81.2 (95% CI 58.5–103.9) cells/μl in women and +48.6 (95% CI 32.9–64.3) cells/μl in men (P = 0.0012). The difference in immunological response remained statistically significant (P = 0.0049) after additional adjustments were made for baseline resistance and previous protease inhibitor exposure, both of which were significantly higher in men vs. women (P = 0.0491 for comparing virtual phenotypic sensitivity scores of men and women, P = 0.0443 for comparing number of previous protease inhibitors).
The adjusted geometric mean steady-state plasma TPV trough concentration (Cminss) was 17% higher in women [45.3 μmol/l, geometric coefficient of variability (gCV) 137.6%] than in men (38.8 μmol/l, gCV 91.0%). The rate of overall adverse events per 100 patient exposure years (PEY) was 556.3 in women and 459.9 in men receiving TPV/r. However, despite the greater Cminss in women, PEY-adjusted rates of adverse events leading to discontinuation were similar in TPV/r-treated women (10.6) and men (10.3). Furthermore, among TPV/r-treated patients, PEY-adjusted rates of severe adverse events (women = 24.2; men = 29.6), serious adverse events (women = 19.9; men = 22.9), and moderate adverse events (women = 117.5; men = 119.8) were higher for men, whereas the PEY-adjusted rate of mild adverse events was correspondingly higher in women (343.4) than in men (225.6). Most adverse events in both women and men were mild to moderate and resolved without clinical sequelae. Rates of key adverse events were not significantly different between women and men (Table 1). PEY-adjusted rates of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations were also similar in women (ALT = 1.6; AST = 1.6) and men (ALT = 2.0; AST = 1.2) receiving TPV/r.
This subanalysis did not find any significant gender-related differences in virological efficacy (at 48 weeks) or in safety and tolerability (at 96 weeks) in RESIST patients randomized to TPV/r. Women had higher Cminss and significantly greater increases in CD4 cell count than men at week 48. Pooled efficacy data from RESIST-1 and RESIST-2 at week 96  and week 156  demonstrate that virological suppression with TPV/r treatment is durable. Among women in RESIST, week 48 data show that 25.6% of TPV/r patients achieved a viral load less than 50 copies/ml. Further trials will help characterize gender-related and racial differences in treatment responses to ARVs in HIV-infected patients.
We are grateful to the RESIST-1 and RESIST-2 study participants, the study coordinators and personnel and the coinvestigators for their involvement in the trial.
Sharon Walmsley, Kathleen Squires, Philippa Easterbrook and Anna Orani were involved in the recruitment of participants and execution of the study. All of the authors were involved in the preparation and review of this manuscript before submission. Euro RSCG Life UK provided editorial assistance in preparing the manuscript.
Conflict of interest statements: Sharon Walmsley is a consultant on advisory boards, speaker bureaus, and has participated in the conduct of clinical trials with Boehringer Ingelheim, Roche, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Tibotec, Merck and Pfizer. She is the recipient of a career scientist award from the Ontario HIV Treatment Network.
Kathleen Squires is a consultant on advisory boards and/or has participated in the conduct of clinical trials with Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Koronis, Merck, Pfizer, Schering-Plough, Tibotec and Tobira.
Laurence Weiss is a consultant on advisory boards, speaker bureaus, and has participated in the conduct of clinical trials with Boehringer Ingelheim, Roche, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Gilead and Tibotec.
Philippa Easterbrook has participated in the conduct of clinical trials with Boehringer Ingelheim, Roche, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Tibotec and Pfizer.
Anna Orani received no fees from biomedical industries or other commercial sources in 2007.
Michael Kraft and Joseph Scherer are employees of Boehringer Ingelheim.
RESIST-1 and RESIST-2 studies were funded by Boehringer Ingelheim.
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