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Gender-based differences in patients receiving antiretroviral therapy

Polly Clayden, HIV i-Base

Several studies looked at the impact of gender on different aspects of antiretroviral treatment.

UK CHIC Study

The UK Collaborative HIV Cohort (CHIC) Study analysed the impact of starting HAART among heterosexuals initiating treatment between 1 January 1998 and 1 January 2007 at <350 CD4cells/mm3 and viral load (VL) >500copies/mL. [1]

The analyses used logistic and Cox regression models adjusted for age, ethnicity, calendar year, initial ART, previous AIDS and pre-ART CD4/VL. Sensitivity analyses were performed in which women who initiated HAART for the first time during pregnancy or became pregnant in their first year of HAART were excluded.

Of 3666 eligible patients for this study, 1487 (40.6%) were male and 2179 (59.4%) female. The investigators reported that men who started therapy in this group were significantly older than women, median 38 vs 33 years; had lower CD4 counts, 122 vs 160 cells/mm3 and higher viral load, 5.0 vs 4.7 log copies/mL, both p=0.0001.

Men were less likely than women to start with a nevirapine-based regimen (18.4 vs 34.7%).

They found no significant differences in initial viral load response, adjOR men vs women 0.95 (95% CI 0.87-1.03), p=0.19; or time to rebound, adjRH, 1.17 (0.93-1.47), p=0.19. However, men were less likely to stop a drug in their regimen, for reasons other than viral failure. (In this analysis, 79.4% of the group experienced initial viral load response (defined as <50 copies/mL) and 19.2% experienced viral rebound (two consecutive viral load >500 copies/mL).

CD4 counts increased across the cohort by a mean of 112 and 156 cells/mm3 at 6 and 12 months respectively. Men had significantly lower increases than women at both time points by 14.6 (p=0.005) and 12.1 (p=0.05) cells/mm3 respectively.

The overall findings remained unchanged when the investigators excluded pregnant women from the analysis. Of 2179 women included, 273 (12.5%) started HAART in pregnancy and 40 (1.8%) became pregnant within a year of starting.

The investigators noted that some gender differences became more pronounced and statistically significant in this sensitivity analysis.

Men were more likely to have viral rebound than women, RH 1.33 (1.04-1.71), p=0.02, but they continued to be less likely to discontinue treatment for reasons other than virological failure, RH 0.76 (0.65-0.88), p=0.0002. CD4 increases remained lower in men by 11.1 cells/mm3, p=0.03; and 10.9 cells/mm3, p=0.07, at 6 and 12 months respectively.

The investigators concluded that virological outcome was similar between men and women in this cohort. They suggested that the higher CD4 increase on treatment may be explained by their higher nadir and baseline CD4 count.

They also suggested that the finding that women were more likely to discontinue their treatment for reasons other than viral failure may be associated with a higher incidence of adverse events such as CNS toxicities associated with efavirenz. They wrote: “Further investigation into the reasons for discontinuation may shed light on the different CD4 responses and improve ART sequencing options for men and women.”

STAR and STELLA cohorts

STAR and STELLA are two German prospective, multicentre cohort studies for antiretroviral naïve patients starting a lopinavir/r-based regimens.

A 48-week analysis comparing treatment outcomes, adverse events and self reported symptom distress, between men and women, was performed. [2]

Of a study population including 1136 patients, 984 were men and 172 were women. Men were older (median 41 vs 38 years, p=0.001), had higher median viral load (5.1 vs 4.9 log copies/mL, p<0.001), a lower CD4 percentage (12% vs 14%) and similar absolute CD4 counts (194 vs 214 cells/mm3).

At 48 weeks in ITT analysis, 308/467 (66%) men and 50/74 (68%) women had viral load <50 copies/mL. Median increases in CD4 count were 218 vs 198 cells/mm3 in men and women respectively.

Using the ASDM self-reported questionnaire to look at symptom distress revealed similar scores in men and women, 11.0 vs 12.5 respectively at baseline. Scores in both groups decreased significantly at week 48, by 3 and 2 in men and women respectively, both p<0.01.

Baseline symptoms of adverse events of any grade were documented in 16% men and 10% women, p=0.05. At 48 weeks 26% men and 15% women reported adverse events, p=0.04.

A similar proportion of men (7%) and women (5%) discontinued lopinavir/r for toxicities and 1% and 2% due to virological failure.

In Kaplan Meier analysis the investigators found the probability of remaining on treatment was similar, (76% vs 78%) in men vs women.

They reported no differences in virological and immunological outcomes and similar rates of discontinuation due to adverse events between men and women initiating lopinavir/r based regimens.

CASTLE study

The CASTLE study was a multinational noninferiority study comparing atazanavir/r- to lopinavir/r- based regimens both with background tenofovir and emtritabine in 883 patients.

An analysis was performed at 96 weeks to look at virological, immunological and safety profiles by gender. [3]

Overall 277/883 (31%) patients in this study were women. Baseline characteristics were similar in men and women in this study.

As previously reported, once-daily treatment with atazanavir/r was noninferior to twice-daily lopinavir/r, 74% of patients receiving atazanavir/r and 68% of patients receiving lopininavir/r achieved VL <50 copies/mL at week 96; difference estimate 6.1% (95% CI, 0.3-12%, p<0.05).

Discontinuation rates were higher for women than men in both treatment groups: 21% vs 14% and 29% vs 18%, women vs men, in patients receiving atazanavir/r and lopinavir/r, respectively.

In ITT analysis, more men than women had VL <50 copies/mL at 96 weeks: 77% vs 67% and 71% vs 63%, men vs women, in patients receiving atazanavir/r and lopinavir/r respectively. These differences were not observed in on treatment analysis.

Mean CD4 cell increases from baseline, rates of adverse events and lipid profiles were similar between genders. GI adverse events and lipid profiles were lower in both men and women receiving atazanavir/r than lopinavir/r.

The investigators wrote: “Consistent with other ARV clinical trials, gender differences in treatment efficacy were primarily due to higher discontinuation rates in women.”

GRACE

GRACE (Gender, Race and Clinical Experience) was a multicentre open label phase 2b study to access the safety and efficacy of duranavir/r plus optimised background regimen.

A post hoc analysis was conducted to investigate factors correlated with adherence in GRACE. [4]

In this study the mean age of patients was 42.9 years, 66.9% patients were women, and 61.5% and 22.4% of the total population were black and Hispanic respectively. At baseline women were younger on average and tended to have less advance disease and be less treatment experienced than men.

The virologic response (VL<50 copies/mL) at week 48 was 53.4% in ITT analysis. See Table 1 for response rates by sex and race.

Table 1: Virologic response <50 c/mL at week 48 by sex and race, n (%)

Black Hispanic Caucasian
Women 89/191 (46.6) 35/60 (58.3) 21/34 (61.8)
Men 39/73 (53.4) 24/36 (66.7) 18/31 (58.1)

The response rate in patients with >95% adherence was 63.1% compared to only 34.7% in those with <95% adherence.

In multivariate analysis the investigators found no significant differences between sexes or across race in GRACE. More IAS/USA major protease resistance associated mutations, participation at a non-academic site, fewer NRTIs in the OBR, being a non-smoker and having a CV medical history were predictive of >95% adherence.

References:

All references are abstracts from the 12th European AIDS Conference (EACS), 11-14 November 2009, Cologne.

  1. Barber T et al. Outcomes of first line highly active antiretroviral therapy (HAART) among men and women in the UK CHIC study. Abstract
  2. Koegl C et al. No subjective or objective gender differences in ART-naïve patients initiating a lopinavir/ritonavir-based regimen. 48 week data from the German STAR and STELLA cohorts. Abstract PE 7.9/19.
  3. Johnson M et al. Gender based differences in antiretroviral-naïve patients treated with ritonavir-boosted protease inhibitors: results from the CASTLE study through 96 weeks. Abstract PE7.3/8
  4. Squires K et al. Rates and predictors of adherence in treatment experienced women and men in GRACE (Gender, Race And Clinical Experience). Abstract PE10.1/2.

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