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Original article

Outcomes in the first year after initiation of first-line HAART among heterosexual men and women in the UK CHIC Study

Tristan J Barber1,*, Anna Maria Geretti2, Jane Anderson3, Achim Schwenk4, Andrew N Phillips5, Loveleen Bansi5, Richard Gilson6, Teresa Hill5, John Walsh7, Martin Fisher8, Margaret Johnson5, Frank Post9, Philippa Easterbrook9, Brian Gazzard10, Adrian Palfreeman11, Chloe Orkin12, Clifford Leen13, Mark Gompels14, David Dunn15, Valerie Delpech16, Deenan Pillay17, Caroline A Sabin5, UK CHIC Study Steering Committee

1St Stephen’s AIDS Trust Clinical Trials Unit, Chelsea and Westminster NHS Foundation Trust, London, UK
2Department of Virology, Royal Free Hampstead NHS Trust and UCL Medical School, Royal Free Campus, London, UK
3Homerton University Hospital NHS Trust, London, UK
4North Middlesex University Hospital NHS Trust, London, UK
5Royal Free NHS Trust and Department of Infection & Population Health, UCL Medical School, London, UK
6UCL Medical School and The Mortimer Market Centre, London, UK
7Imperial College Healthcare NHS Trust, London, UK
8Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
9King’s College Hospital, London, UK
10Chelsea and Westminster NHS Trust, London, UK
11University Hospitals of Leicester, Leicester, UK
12Barts and The London NHS Trust, London, UK
13The Lothian University Hospitals NHS Trust, Edinburgh, UK
14North Bristol NHS Trust, Bristol, UK
15Medical Research Council Clinical Trials Unit, London, UK
16Health Protection Agency Centre for Infections, London, UK
17MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, UK

*Corresponding author e-mail: t.barber@nhs.net

A complete list of the UK CHIC Steering Committee is found in Additional file 1

Citation: Antiviral Therapy 2011; 16:805-814
doi: 10.3851/IMP1818

Date accepted: 03 January 2011
Date published online: 10 June 2011

Copyright (c) 2011 International Medical Press, all rights reserved.

Abstract

Background: We analysed the influence of gender on use and outcomes of first-line HAART in a UK cohort.

Methods: Analyses included heterosexuals starting HAART from 1998–2007 with pre-treatment CD4+ T-cell count <350 cells/mm3 and viral load (VL)>500 copies/ml. Virological suppression (<50 copies/ml), virological rebound (>500 copies/ml), CD4+ T-cell counts at 6 and 12 months, clinical events and treatment discontinuation/switch in the first year of HAART were compared using linear, logistic and Cox regression.

Results: Compared with women (n=2,179), men (n=1,487) were older and had lower CD4+ T-cell count and higher VL at start of HAART. Median follow-up was 3.8 years (IQR 2.0–6.2). At 6 and 12 months, 72.7% and 75.3% had VL≤50 copies/ml, with no large differences between genders at either time after adjustment for confounders (6 months, OR 0.92 [95% CI 0.76–1.13]; 12 months, OR 1.06 [95% CI 0.85–1.31]). Overall, 79.4% patients achieved virological suppression and 19.2% experienced virological rebound, without gender differences, although men had an increased risk of rebound after excluding pregnant women (adjusted relative hazard [RH] 1.33 [95% CI 1.04–1.71]). Mean CD4+ T-cell count increases at 6 and 12 months were, respectively, 112 and 156 cells/mm3 overall, with mean differences between men and women of -14.6 cells/mm3 (95% CI -24.6–-4.5) and -12.1 cells/mm3 (95% CI -24.4–0.2) at 6 and 12 months, respectively. Clinical progression was similar in men and women, but men were less likely to experience treatment discontinuation/switch (adjusted RH 0.72 [95% CI 0.63–0.83]).

Conclusions: Despite higher discontinuation rates among women, men had an increased risk of virological rebound and slightly poorer CD4+ T-cell count responses. Identifying the reasons underlying treatment discontinuation/switch may help optimize treatment strategies for both genders.

Introduction

Increasing numbers of heterosexual men and women are receiving care for HIV in the UK. Most are from ethnic minority and migrant communities, in particular from sub-Saharan Africa. Gender differences exist within this population, with almost twice as many women as men seeking care [1].

Clinical trial data on HIV therapies have traditionally been generated from studies of predominantly male subjects; despite the lack of female participants, it is presumed that findings can be extrapolated across genders. Whether there are sex-specific differences in response to antiretroviral drugs is unclear; a recent review concluded that most studies were underpowered to detect differences between men and women [2]. Psychosocial and cultural determinants of womens’ lives may affect access and adherence to antiretroviral drugs and may affect treatment outcomes [3], as may biological sex differences relating to drug handling, metabolism and toxicity [4]. Several authors have found that women start antiretroviral therapy at a later disease stage than men [57], although this may be explained by a higher CD4+ T-cell count in women [7] and a greater propensity to initiate treatment in homosexual men than other risk groups [8]. Furthermore, when starting antiretroviral therapy, women may be more likely to initiate suboptimal therapy (that is, mono- or dual-therapy) than men [7]. Despite this, a study amongst an ethnically diverse population in east London showed that once into clinical care, gender did not influence treatment uptake [9]. Survival rates for individuals with a known date of seroconversion may be longer for women than men; this difference has become more prominent in the HAART era [10].

A recent review of 48-week data from FDA registration trials showed no clinically or statistically significant gender differences in outcomes of HAART, although the numbers of women within these studies were relatively small [11]. A recent UK study indicated that, although achieving similar rates of plasma viral load (VL) suppression <50 copies/ml on first-line HAART, women showed a two-fold increased risk of subsequent virological rebound relative to men [12]. Although the study was not designed to compare virological responses between genders, its findings suggest potential problems with maintaining long-term adherence among women [3].

The aim of this study was to analyse the effect of -gender on outcomes in the first year of HAART amongst heterosexual men and women in the UK -Collaborative HIV Cohort (CHIC) Study.

Methods

Study population

Patients were selected from the UK CHIC Study, a collaboration of some of the largest HIV clinics in the UK [13]. Participating centres provide routinely collected data on all patients aged ≥16 years attending for care since 1996, including demographic information, AIDS events, deaths, antiretroviral use, CD4+ T-cell count and VL; the dataset used for the present analysis comprises 29,055 patients seen at 11 clinical centres to the end of 2007. Eligible patients were heterosexual men and women who started first-line HAART from 1 January 1998 to 31 December 2006. The latter cutoff was chosen to allow for the potential for ≥12 months of follow-up for each individual after starting HAART, although patients were only required to have ≥1 day of actual follow-up. Eligible patients were also required to have pre-treatment CD4+ T-cell count <350 cells/mm3 (reflecting current guidelines for initiation of HAART [4]) and VL>500 copies/ml (to reduce the risk of erroneously including previously treated patients for whom treatment information had not been captured in the database).

HAART was defined as any regimen including one of a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI) or abacavir, with no restriction on the number of drugs in the combination. Regimens were classified as ritonavir-boosted PIs (PI/r), unboosted PIs, efavirenz, nevirapine or other regimens, including patients on nucleoside reverse transcriptase inhibitor (NRTI) regimens, as well as those receiving combinations including both PIs and NNRTIs. Patients on non-HAART regimens (that is, NRTI regimens without abacavir) were excluded.

Outcomes measured and statistical analysis

The following outcomes were analysed: HIV RNA levels at 6 and 12 months after starting HAART; time to virological suppression <50 copies/ml (initial virological response); time to virological rebound (the first of two consecutive VL>500 copies/ml); CD4+ T-cell count changes from pre-treatment to 6 and 12 months of starting HAART; discontinuation/switch of any drug in the initial regimen in the first year for reasons other than virological failure; the proportion of time spent on treatment (regardless of changes to the regimen) in the first year; and the development of a new AIDS event/death during the first year.

For the analyses of time to virological suppression, patient follow-up was right-censored on the date of the last clinic visit, or at the end of the first year, if the patient had not experienced virological suppression by this time. Time to virological rebound was considered only in those patients who had experienced virological suppression within 6 months of starting HAART; follow-up of those who did not experience virological rebound was censored in a similar way. The association between gender and both outcomes was investigated using proportional hazards regression, before and after adjustment for age at start of HAART, ethnicity (White, Black African, other or unknown), pre-treatment CD4+ T-cell count and VL, AIDS status at start of HAART, the type of initial HAART regimen (categorized above), and calendar year of starting HAART. In both analyses, changes to treatment (discontinuation or treatment switches) were ignored – thus, virological rebounds may have occurred either on treatment (virological failure) or after treatment discontinuation. Sensitivity analyses were also performed in which follow-up was censored at the time of treatment failure. Analyses of clinical outcomes in the first year after starting HAART were performed using univariate and multivariate logistic regression, with adjustment for the same covariates.

The nearest HIV RNA levels to 6 and 12 months after starting HAART were identified as long as these had been measured within 3 months of the time of interest (that is, from 3–9 months and 9–15 months, respectively); the proportions of men and women with HIV RNA levels ≤50 copies/ml at each time point were compared using logistic regression. The nearest CD4+ T-cell counts to these times were identified in a similar manner; changes in these measurements from pre-treatment levels were analysed using multiple linear regression.

We considered the time to discontinuation/switch of any drug in the initial HAART regimen in the first year after starting HAART, as long as each specific drug was discontinued for >14 days. We used a previously developed algorithm [15] to classify treatment discontinuations due to reasons other than virological failure. Such discontinuations were those that occurred in the first 3 months, regardless of the VL; occurred in months 3–6 among individuals with a VL <1,000 copies/ml; occurred in months 6-12 among individuals with a VL <50 copies/ml; or occurred at any time in the first year among individuals without a pre-discontinuation VL. Of note, treatment intensifications that did not involve the discontinuation or switch of a drug would not be captured in this end point; further analyses were performed to assess whether these had an effect on virological rebound rates. Proportional hazards regression models were used to describe the association between gender and treatment discontinuation, with follow-up again right-censored at the end of the first year after starting HAART. The proportion of time spent on any antiretroviral therapy in the first year after starting HAART was categorized as <25%, 25–50%, 50–75%, 75–99% or 100%, and the proportions spending <100% of time on treatment (compared with 100% of time) were compared between men and women using logistic regression. As sensitivity analyses, we repeated the treatment discontinuation/switch analyses after excluding patients receiving drugs known to be associated with toxicities that occur at a different frequency in men and women, or drugs not recommended among women wishing to become pregnant, including patients receiving efavirenz, patients receiving zidovudine, and women receiving nevirapine with a pre-CD4+ T-cell count >250 cells/mm3 .

As all eligible individuals were required to have a pre-treatment nadir CD4+ T-cell count <350 cells/mm3 , we assumed that any pregnant women starting HAART would require treatment for their own health. However, as discontinuation rates may differ during or after pregnancy, sensitivity analyses were performed in which women who initiated HAART for the first time whilst known to be pregnant or who became pregnant in the first year after starting HAART were excluded. Dates of pregnancy were obtained through linkage with the UK National Study of HIV in Pregnancy and Childhood (NSHPC) [16].

Results

Study population and use of HAART

Of 10,353 heterosexual patients identified, 4,698 were excluded as they had either not started HAART by 31 December 2006 or had started treatment prior to entering the cohort. A further 1,320 patients were excluded as they had either received non-HAART regimens, or had started HAART before 1998. Further exclusions comprised 62 patients who were not seen after initiating HAART, 334 patients who started HAART with a pre-treatment nadir CD4+ T-cell count >350 cells/mm3 and 273 patients who had a pre-treatment VL≤500 copies/ml. This left 3,666 eligible patients, of whom 1,487 (40.6%) were men and 2,179 (59.4%) were women. There were no major differences in the proportions of men and women excluded at each stage, although as expected because of the use of HAART to prevent mother-to-child transmission, a greater proportion of women were excluded due to a pre-HAART CD4+ T-cell count >350 cells/mm3 .

A greater proportion of men were of white ethnicity and a greater proportion of women of Black African ethnicity (Table 1). Compared with men, women were younger and less likely to have had a previous AIDS diagnosis. Women also had a higher pre-treatment CD4+ T-cell count and a lower pre-treatment VL. The majority of patients (94.4%) were receiving standard HAART combinations comprising two NRTIs with either one PI/r, one unboosted PI, or one NNRTI or three NRTIs including abacavir, without large differences between men and women. Zidovudine plus lamivudine was the most commonly prescribed NRTI backbone followed by tenofovir plus emtricitabine or lamivudine. Efavirenz was prescribed more frequently in men than in women, whereas nevirapine was more commonly prescribed in women than in men. Among unboosted PI regimens, nelfinavir was more commonly used in women than in men, whereas indinavir tended to be used more frequently in men than in women. Among the patients receiving PI/r regimens, most were receiving lopinavir/ritonavir, although women were more likely to receive ritonavir-boosted saquinavir than men. Patients were followed for a median of 3.8 years (IQR 2.0–6.2), with follow-up time being similar in men and women (medians of 3.8 and 3.9 years, respectively).

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Table 1.  Characteristics of heterosexual patients starting first-line HAART
Table 1. Characteristics of heterosexual patients starting first-line HAART

a Pre-treatment CD4+ T-cell counts were measured a median of 18 days (IQR 5–36) prior to start of HAART in women and 20 days (IQR 6–38) prior to start of HAART in men; pre-treatment viral loads were measured a median of 20 days (IQR 5–40) and 21 days (IQR 7–41) prior to start of HAART in the two groups respectively. ABC, abacavir; ddI, didanosine; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; NRTI: nucleoside/nucleotide reverse transcriptase inhibitors; NVP, nevirapine; PI/r, ritonavir-boosted protease inhibitor; TDF, tenofovir; ZDV, zidovudine; 3TC, lamivudine.

Virological responses to first-line HAART

Men and women had similar numbers of HIV RNA assessments in the first year after starting HAART (median 4, IQR 3–6; Table 2). Of the 3,071 patients with an VL measurement in the 6-month window, 2,231 (72.7%) had a VL≤50 copies/ml, with no evidence of a large difference between men and women, either before (OR 1.05 [95% CI 0.89–1.24]) or after (adjusted OR 0.92 [95% CI 0.76–1.13]) adjustment for potential confounders (Table 2). By 12 months, 2,172/2,883 patients with available measurements (75.3%) had a VL≤50 copies/ml; the proportion attaining this level was slightly higher in men (77.7%) than women (73.8%), although this was largely explained by differences in age between the genders (adjusted OR 1.06 [95% CI 0.85–1.31]; Table 2).

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Table 2.  HIV RNA and CD4+ T-cell count responses among men and women starting HAART
Table 2. HIV RNA and CD4+ T-cell count responses among men and women starting HAART

a n=3,071. b n=2,883. c n=3,153. d n=2,829. e n=2,966. f n=2,664.

Overall, 3,308 (90.2%) patients achieved virological suppression (<50 copies/ml) at some stage after starting HAART. By 3, 6, 9 and 12 months after starting HAART, 40.3%, 68.2%, 76.3% and 79.9% of women, respectively, and 32.2%, 63.6%, 75.2% and 78.8% of men, respectively, had achieved (but not necessarily maintained) virological suppression (P=0.006, log-rank test; Figure 1). The median times to virological suppression were 3.7 and 4.3 months in women and men, respectively. The slower time to virological suppression in men in univariate analyses (relative hazard [RH] for men versus women 0.89 [95% CI 0.82–0.96]), was attenuated after adjustment for demographic and pre-HAART clinical characteristics, most notably the pre-HAART VL (adjusted RH 0.94 [95% CI 0.86–1.03]; Table 3).

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Figure 1.
Figure 1. Kaplan–Meier plots showing progression to various outcomes, stratified by gender

(A) Initial virological suppression, (B) virological rebound (among those with achieving virological suppression in the first 6 months after starting HAART) and (C) first discontinuation/switch of any drug in the regimen for reasons other than virological failure, stratified by gender.

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Table 3.  Summary of estimates from multivariable regression models for each end point including all eligible patients and excluding pregnant women
Table 3. Summary of estimates from multivariable regression models for each end point including all eligible patients and excluding pregnant women

a The analysis excluded women who were either pregnant at the time of starting HAART or who became pregnant in the first year after starting HAART. b Estimates are relative hazards (proportional hazards regression) for time to initial virological suppression (<50 copies/ml), time to virological rebound (first of two consecutive viral load measurements >500 copies/ml) among those who achieved virological suppression with 6 months of starting HAART and time to treatment discontinuation/switch for reasons other than virological failure in the first year after starting HAART; odds ratio (logistic regression) for a new AIDS event or death in the first year after starting HAART and for analyses of HIV RNA ≤50 copies/ml at 6 and 12 months; and mean value (linear regression) for CD4+ T-cell count changes at 6 and 12 months. All viral load rebounds were included in the analyses, regardless of an individual’s treatment status at the time.

Of the 2,398 patients achieving virological suppression within the first 6 months of starting HAART, 461 (19.2%) experienced virological rebound. Kaplan–Meier estimates of rates of virological rebound at 6 and 12 months after virological suppression were 6.5% and 10.9%, overall, 4.5% and 7.7% in men and 7.8% and 13.0% in women (P=0.008, log-rank test), respectively. Whilst men were less likely to experience virological rebound than women in univariate analyses (RH 0.77 [95% CI 0.63–0.93]), there was no evidence of a large difference between genders after adjustment for demographic (particularly age) and pre-HAART characteristics (adjusted RH 1.17 [95% CI 0.93–1.47]; Table 3). Of note, 63 men and 101 women added at least one new drug to their HAART regimen after achieving virological suppression and prior to any virological rebound (intensification or switches were included so patients may also have dropped drugs in their regimen at the same time); adjustment for this as a time-dependent covariate did not modify the results (adjusted RH 1.20 [95% CI 0.95–1.51]). Furthermore, sensitivity analyses in which we censored the follow-up of patients who discontinued treatment also suggested no evidence of a difference in virological rebound rates between men and women (adjusted RH 0.92 [95% CI 0.59–1.46]).

Time to treatment discontinuation/switch and proportion of time spent on treatment

There were 1,426 patients who discontinued/switched their first drug in the first year, with 1,170 (31.9%) classified as having discontinued/switched at least one drug in their regimen due to reasons other than virological failure; of these, 637 (54.4%) discontinued the drug in the first 3 months, 248 (21.2%) discontinued in months 3–6, 222 (19.0%) in months 6–12 and the remaining 63 (5.4%) did not have a pre-discontinuation VL. In multivariable analyses, men were less likely than women to discontinue/switch at least one drug in their regimen for reasons other than virological failure (adjusted RH 0.72 [95% CI 0.63–0.83]; Table 3).

Overall, 88.6% of men but only 80.7% of women spent 100% of the first year after starting HAART on treatment (Figure 2). Women were less likely than men to spend 100% of the first year on treatment, either before (OR 0.54 [95% CI 0.44–0.65]) or after (adjusted OR 0.73 [95% CI 0.58–0.92]) adjustment for demographic and pre-HAART clinical characteristics.

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Figure 2.
Figure 2. Proportion of time spent on treatment in first year after HAART initiation

*Women who started HAART whilst known to be pregnant or who became pregnant in the first year.

CD4+ T-cell count responses

As with VL measures, men and women had similar numbers of CD4+ T-cell count measurements in the first year (median 4 [IQR 3–6]). Median CD4+ T-cell counts at 6 and 12 months, as well as changes from baseline are shown in Table 2. Mean CD4+ T-cell count increases at 6 and 12 months were 112 and 156 cells/mm3 overall, with evidence of smaller increases in men than women at both time points. In multivariable models (adjusted for demographic and pre-HAART clinical characteristics including the pre-treatment CD4+ T-cell count), the increase in CD4+ T-cell count remained lower in men than in women with a mean difference of -14.6 cells/mm3 (95% CI -24.6– -4.5) at 6 months, and -12.1 cells/mm3 (95% CI -24.4–0.2) at 12 months.

Clinical outcomes

In total, 282 patients (7.7%) experienced a new AIDS event (n=228) or death (n=66) in the first year, with rates being higher in men (140 events, 9.4%) than women (142 events, 6.5%). In unadjusted analyses, men were 49% more likely to experience a new clinical event than women (OR 1.49 [95% CI 1.17–1.90]); this difference was attenuated markedly towards 1 (OR 1.08 [95% CI 0.80–1.46]) after adjusting for demographic and pre-HAART clinical characteristics, particularly the pre-HAART CD4+ T-cell count and VL (Table 3). There were no major differences between men and women in terms of the first new AIDS event that occurred, with the most commonly occurring events being Mycobacterium tuberculosis/M. avium infections, cytomegalovirus, herpes simplex virus, toxoplasmosis and lymphoma.

Sensitivity analyses

Of the 2,179 women in the analyses, 273 (12.5%) started HAART whilst known to be pregnant. An additional 40 (1.8%) women became pregnant in the first year after starting HAART. Exclusion of these women from the analyses did not change the overall findings (Table 3). However some gender differences became more pronounced: men were more likely to have virological rebound (RH 1.33 [95% CI 1.04–1.71]), but remained less likely to discontinue treatment for reasons other than virological failure (RH 0.76 [95% CI 0.65–0.88]). Mean CD4+ T-cell count gains remained lower in men at both 6 (-11.1 cells/mm3 ) and 12 (-10.9 cells/mm3 ) months.

After excluding patients receiving efavirenz, the adjusted HR for treatment discontinuation/switch was attenuated towards 1 (0.80 [95% CI 0.65–0.98], n=685 men and n=1,412 women). Similar results were obtained after excluding patients receiving zidovudine (adjusted HR 0.79 [95% CI 0.63–0.99], n=784 men and n=1,327 women). Exclusion of the 146 women receiving nevirapine with a pre-HAART CD4+ T-cell count of >250 cells/mm3 had only a minimal effect on estimates (adjusted HR 0.73 [95% CI 0.63–0.85]).

Discussion

Overall, we found no major differences in VL, virological suppression or virological rebound rates in the first year after starting HAART between heterosexual men and women after adjustment for other potential confounders. Whilst CD4+ T-cell count increases were slightly lower in men compared with women, there were no large differences in rates of clinical progression. Interestingly, when we excluded women known to be pregnant from the analyses, men were more likely to experience virological rebound than women, suggesting that some of the rebounds in women may have been a consequence of treatment discontinuations or poorer adherence (possibly resulting from morning sickness) in those who became pregnant or who gave birth shortly after starting HAART.

Findings from the literature surrounding virological response rates in men and women are inconsistent. In the EuroSIDA study, no differences were reported between men and women in either initial suppression or virological rebound [17], with a similar lack of association noted by others [18]. By contrast, several studies have reported poorer virological responses in women than men [12,19]. Kuyper et al. [19] studied individuals who had achieved virological suppression, reporting higher virological rebound rates in women than men. The differences seen could largely be explained by poorer adherence in women, although other confounders, including a history of drug use, also contributed. Collazos et al. [20] noted that women tended to have more favourable virological responses than men; this association could not be explained by differences in adherence, although the effect was small.

Information regarding CD4+ T-cell responses in men and women is equally inconsistent. In a study of patients achieving virological suppression in the first year of HAART, better CD4+ T-cell count responses were seen in women than men [5]. Among participants in the Swiss HIV Cohort Study achieving virological suppression in the first year of HAART, CD4+ T-cell count increases were greater in women than men over the first 5 years [21]. Similar findings regarding better CD4+ T-cell count responses in women than men have been reported by others [20,22,23]. By contrast, several studies [2,8,17] have reported no difference in CD4+ T-cell count increase between men and women. Of note, our large study suggests that if a beneficial immunological outcome is present in women, it is likely to be relatively small and of limited clinical relevance. Whilst several studies have reported a higher risk of clinical progression in men than women [20,24,25], these differences may reflect other differences in lifestyle factors between men and women. Interestingly, using data from a large European multicohort collaboration, Lewden et al. [26] showed that whilst mortality rates of successfully treated men (that is, those with a CD4+ T-cell count >500 cells/mm3 ) reached similar levels to those seen in the general population after 3 years, this was not the case among women, in whom mortality rates remained higher than those in the general population even after 5 years of successful treatment.

Women in UK CHIC were more likely than men to discontinue treatment for reasons other than virological failure. Two main explanations were considered for this. Firstly, although our analysis included only patients with a CD4+ T-cell count <350 cells/mm3 , who would be expected to be receiving HAART for their own benefit, some pregnant women who had started HAART during pregnancy may discontinue treatment early after the baby’s birth. After exclusion of women who either started HAART when pregnant, or who become pregnant within the first year, discontinuation rates remained higher among women than men. Secondly, we explored whether the higher discontinuation rates in women could reflect an increased tendency for women to experience toxicities by excluding patients receiving drugs known to be associated with toxicities that occur at a different frequency in men and women. Despite these exclusions, discontinuation rates remained higher in women. Whilst overall rates of treatment discontinuation are generally similar between men and women, Kempf et al. [27] reported that the reasons for discontinuation were different, with women being more likely to discontinue treatment in the first year of a new regimen due to poor adherence, dermatological symptoms, depression, weight loss, and fatigue and other concomitant medical conditions (including pregnancy). By contrast, men were more likely to discontinue treatment due to virological resistance, presumed to be transmitted. Gender differences in the incidence of several toxicities have been reported [20], in particular body changes to the lower limbs and buttocks and lipohypertrophy [28], anaemia [29], lactic acidosis [30] and hypersensitivity reactions [3032]. The reasons for these higher rates are unclear, although this may reflect greater drug exposure due to differences in drug transportation/metabolism [4,33,34]. In the CASTLE study [35], discontinuation rates were higher in women than men, in patients receiving atazanavir/r (21% versus 14%) and in patients receiving lopinavir/r (29% versus 18%). More generally, women have been reported to be more likely to take treatment interruptions than men and are less likely to restart therapy once interrupted [36].

Many of the conflicting results in the literature may be explained by differences in study design. For example, many studies have included patients infected with HIV through various routes. However, homosexual men, in particular, tend to have better outcomes on HAART [8], whereas injection drug users generally tend to have poorer outcomes [19,37], largely due to adherence, lifestyle factors and the presence of other comorbidities. Adjustment for risk group may be insufficient to remove all residual confounding due to these factors. Whilst our analysis was restricted to those infected with HIV through heterosexual sex, gender differences may still be confounded by other variables. For example, while there is equal healthcare access in the UK, a higher proportion of women are of Black ethnicity. Ethnic and cultural influences can affect health-seeking behaviour and attitudes toward initiating/continuing HAART [38]. These women may also be in poorer socioeconomic circumstances, which may affect their HAART adherence and outcomes.

Several other limitations remain with our database. Whilst we made the assumption that all eligible individuals would require treatment for their own health, guidelines recommending treatment for those with a CD4+ T-cell count ≤350 cells/mm3 were more conservative in the early years of the study period [14,39]. It is possible that some pregnancies may have been missed through incomplete linkage. To avoid the complexities introduced by treatment switches, our analyses were restricted to the first year after HAART initiation. However, it is possible that greater differences in outcome may be apparent over the longer term. Our study did not capture direct information on patient adherence and other lifestyle factors that may have affected the outcomes of HAART. Although patients were identified as being infected with HIV through heterosexual sex, it is possible that some of the individuals included in the study had a history of injecting drug use. Finally, consistent with other studies, our analyses of virological rebound were conditional on the fact that patients had experienced an initial virological response within the first 6 months after starting HAART; patients who did not achieve this were excluded.

In summary, despite a higher rate of treatment discontinuations among women, men and women had similar virological outcomes on HAART, with women having somewhat better CD4+ T-cell count responses. Further investigation into the reasons for discontinuation may shed light on the different CD4+ T-cell count responses and improve antiretroviral therapy sequencing options for men and women.

Disclosure statement

All authors have completed the unified competing interest form and declare that they have no relationships with companies that might have an interest in the submitted work in the previous 3 years; their spouses, partners or children have no financial relationships that may be relevant to the submitted work; and they have no non-financial interests that may be relevant to the submitted work.

Additional file

Additional file 1: A list of members of the UK CHIC Steering Committee, central coordination and participating centres can be found at http://www.intmedpress.com/uploads/documents/AVT-10-OA-1943_Barber_Add_file1.pdf

References

-
1. The UK Collaborative Group for HIV and STI Surveillance. Testing times – HIV and other sexually transmitted infections in the United Kingdom: 2007. London: Health Protection Agency, Centre for Infections 2007.
-
2. Nicastri E, Leone S, Angeletti C, et al. Sex issues in HIV-1-infected persons during highly active antiviral therapy: a systematic review. J Antimicrob Chemother 2007; 60: 724-732. Medline doi:10.1093/jac/dkm302
-
3. Pence BW, Ostermann J, Kumar V, Whetten K, Thielman N, Mugavero MJ. The influence of psychosocial characteristics and race/ethnicity on the use, duration, and success of antiretroviral therapy. J Acquir Immune Defic Syndr 2008; 47: 194-201. Medline doi:10.1097/QAI.0b013e31815ace7e
-
4. Floridia M, Giuliano M, Palmisano L, Vella S. Gender differences in the treatment of HIV infection. Pharmacol Res 2008; 58: 173-182. Medline doi:10.1016/j.phrs.2008.07.007
-
5. Giordano TP, White AC, Sajjia P. Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an urban clinic. J Acquir Immune Defic Syndr 2003; 32: 399-405. Medline doi:10.1097/00126334-200304010-00009
-
6. McNaghten AD, Hanson DL, Dworkin MS, et al. Differences in prescription of antiretroviral therapy in a large cohort of HIV-infected patients. J Acquir Immune Defic Syndr 2003; 32: 499-505. Medline doi:10.1097/00126334-200304150-00006
-
7. Murri R, Cozzi Lepri A, Phillips AN, et al. Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex. Evidence from the I.Co.N.A. Study. J Acquir Immune Defic Syndr 2003; 34: 184-190. Medline doi:10.1097/00126334-200310010-00008
-
8. Fardet L, Mary-Krause M, Heard I, Partisani M, Costagliola D. Influence of gender and HIV transmission group on initial highly active antiretroviral therapy prescription and treatment response. HIV Med 2006; 7: 520-529. Medline doi:10.1111/j.1468-1293.2006.00414.x
-
9. Elford J, Ibrahim F, Bukutu C, Anderson J. Uptake of antiretroviral treatment among people living with HIV in London: ethnicity, gender and sexual orientation. Sex Transm Infect 2008; 84: 176-178. Medline doi:10.1136/sti.2007.029249
-
10. Jarrin I, Geskus K, Bhaskaran K, et al. Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women. Am J Epidemiol 2008; 168: 532-540. Medline doi:10.1093/aje/kwn179
-
11. Struble K, Soon G, Min M, Chan-Tack K, Murray J, Birnkrant D. Meta-analysis of efficacy outcomes for treatment-naive and treatment-experienced HIV-infected women in randomized controlled clinical trials: 2000 to 2008. 16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, QC, Canada. Abstract 987b.
-
12. Geretti AM, Smith C, Haberl A, et al. Determinants of virological failure after successful viral load suppression in first line highly active antiretroviral therapy. Antivir Ther 2008; 13: 927-936. Medline
-
13. UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: the UK Collaborative HIV Cohort (CHIC) Study. HIV Med 2004; 5: 115-124. Medline doi:10.1111/j.1468-1293.2004.00197.x
-
14. BHIVA Treatment Guidelines Writing Group Writing Committee. Gazzard BG. British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med 2008; 9: 563-608. Medline doi:10.1111/j.1468-1293.2008.00636.x
-
15. Sabin CA, Smith CJ, Delpech V, et al. The associations between age and the development of laboratory abnormalities and treatment discontinuation for reasons other than virological failure in the first year of highly active antiretroviral therapy. HIV Med 2009; 10: 35-43. Medline doi:10.1111/j.1468-1293.2008.00654.x
-
16. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Trends in management and outcome of pregnancies in HIV-infected women in the UK and Ireland, 1990–2006. BJOG 2008; 115: 1078-1086. Medline doi:10.1111/j.1471-0528.2008.01706.x
-
17. Moore AL, Kirk O, Johnson AM, et al. Virologic, immunologic, and clinical response to highly active antiretroviral therapy: the gender issue revisited. J Acquir Immune Defic Syndr 2003; 32: 452-461. Medline doi:10.1097/00126334-200304010-00017
-
18. Patterson K, Napravnik S, Eron J, Keruly J, Moore R. Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. HIV Med 2007; 8: 406-410. Medline doi:10.1111/j.1468-1293.2007.00485.x
-
19. Kuyper LM, Wood E, Montaner JSG, Yip B, O’Connell JM, Hogg RS. Gender differences in HIV-1 RNA rebound attributed to incomplete antiretroviral adherence among HIV-infected patients in a population-based cohort. J Acquir Immune Defic Syndr 2004; 37: 1470-1476. Medline doi:10.1097/01.qai.0000138379.39317.62
-
20. Collazos J, Asensi V, Carton JA. Sex differences in the clinical, immunological and virological parameters of HIV-infected patients treated with HAART. AIDS 2007; 21: 835-843. Medline doi:10.1097/QAD.0b013e3280b0774a
-
21. Wolbers M, Battegay M, Hirschel B, et al. CD4+ T-cell count increase in HIV-1-infected patients with suppressed viral load within 1 year after start of antiretroviral therapy. Antivir Ther 2007; 12: 889-897. Medline
-
22. Zaragoza-Macias E, Cosco D, Nguyen ML, Del Rio C, Lennox J. Predictors of success with highly active antiretroviral therapy in an antiretroviral-naive urban population. AIDS Res Hum Retroviruses 2010; 26: 133-138. Medline doi:10.1089/aid.2009.0001
-
23. Önen NF, Overton ET, Presti R, Blair C, Powderly WG, Mondy K. Sub-optimal CD4 recovery on long-term suppressive highly active antiretroviral therapy is associated with favourable outcome. HIV Med 2009; 10: 439-446. Medline doi:10.1111/j.1468-1293.2009.00711.x
-
24. Lemly DC, Shepherd BE, Hulgan T, et al. Race and sex differences in antiretroviral therapy use and mortality among HIV-infected persons in care. J Infect Dis 2009; 199: 991-998. Medline doi:10.1086/597124
-
25. Moore AL, Sabin CA, Johnson MA, Phillips AN. Gender and clinical outcomes after starting highly active antiretroviral treatment: a cohort study. J Acquir Immune Defic Syndr 2002; 29: 197-202. Medline
-
26. Lewden C, the Mortality Working Group of COHERE. Time with CD4 cell count above 500 cells/mm3 allows HIV-infected men, but not women, to reach similar mortality rates to those of the general population: a 7-year analysis. 17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 527.
-
27. Kempf M-C, Pisu M, Dumcheva A, Westfall AO, Kilby JM, Saag MS. Gender differences in discontinuation of antiretroviral treatment regimens. J Acquir Immune Defic Syndr 2009; 52: 336-341. Medline doi:10.1097/QAI.0b013e3181b628be
-
28. Cabrero E, Griffa L, Burgos A. Prevalence and impact of body physical changes in HIV patients treated with highly active antiretroviral therapy: results from a study on patient and physician perceptions. AIDS Patient Care STDS 2010; 24: 5-13. Medline doi:10.1089/apc.2009.0191
-
29. Tedaldi EM, Absalon J, Thomas AJ, Shlay JC, van den Berg-Wolf M. Ethnicity, race, and gender. Differences in serious adverse events among participants in an antiretroviral initiation trial: results of CPCRA 058 (FIRST Study). J Acquir Immune Defic Syndr 2008; 47: 441-448. Medline doi:10.1097/QAI.0b013e3181609da8
-
30. Boulassel M-R, Morales R, Murphy T, Lalonde RG, Klein MB. Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons. J Med Virol 2006; 78: 1158-1163. Medline doi:10.1002/jmv.20676
-
31. Knobel H, Guelar A, Montero M, et al. Risk of side effects associated with the use of nevirapine in treatment-naive patients, with respect to gender and CD4 cell count. HIV Med 2008; 9: 14-18. Medline doi:10.1111/j.1468-1293.2008.00513.x
-
32. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr 2004; 35: 538-539. Medline doi:10.1097/00126334-200404150-00014
-
33. Clark RA, Squires KE. Gender-specific considerations in the antiretroviral management of HIV-infected women. Expert Rev Anti Infect Ther 2005; 3: 213-227. Medline doi:10.1586/14787210.3.2.213
-
34. Ofotokun I. Sex differences in the pharmacologic effects of antiretroviral drugs: potential roles of drug transporters and phase 1 and 2 metabolizing enzymes. Top HIV Med 2005; 13: 79-83. Medline
-
35. Johnson M, Squires K, Hosey T, et al. Gender based differences in antiretroviral-naive patients treated with ritonavir-boosted protease inhibitors: results from the CASTLE study through 96 weeks. 12th European AIDS Conference. 11–14 November 2009, Cologne, Germany. Abstract PE7. 3/8.
-
36. Moore DM, Zhang W, Yip B, et al. Non-medically supervised treatment interruptions among participants in a universally accessible antiretroviral therapy programme. HIV Med 2010; 11: 299-307. Medline doi:10.1111/j.1468-1293.2009.00779.x
-
37. Egger M, May M, Chêne G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360: 119-129. Medline doi:10.1016/S0140-6736(02)09411-4
-
38. Braitstein P, Boulle A, Nash D, et al. Gender and the Use of Antiretroviral Treatment in resource-constrained settings: findings from a multicenter collaboration. J Womens Health (Larchmt) 2008; 17: 47-55. Medline doi:10.1089/jwh.2007.0353
-
39. BHIVA Writing Committee. Gazzard B. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Med 2005; 6 Suppl 2: 1-61. Medline doi:10.1111/j.1468-1293.2005.0311b.x

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