JAC Advance Access originally published online on August 21, 2007
Journal of Antimicrobial Chemotherapy 2007 60(4):724-732; doi:10.1093/jac/dkm302
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Systematic review |
Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review
1 National Institute for Infectious Diseases, IRCCS ‘Lazzaro Spallanzani’, Rome, Italy 2 Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy 3 Department of Public Health, University of Rome Tor Vergata, Rome, Italy
* Corresponding author. Tel: +39-0655170420; Fax: +39-0655170400/7; E-mail: nicastri{at}inmi.it
Received 19 December 2006; returned 11 July 2007; accepted 15 July 2007
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Abstract |
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Background: Since the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality rates have sharply decreased among HIV-infected patients. Studies of possible differences between men and women in the course of HIV infection give conflicting results. The objective of this study was to assess sex differences during HAART.
Methods: A literature search by using the MEDLINE database between March 2002 and February 2007 was performed to identify all published studies on the sex-specific differences on the impact of HAART. All articles with measures of effect (preferably adjusted odds ratio, relative risk or hazard ratio with 95% CI) of sex on viroimmunological and clinical parameters during HAART were included. Five different topics of interest in our research were selected: time of initiation of HAART, adherence, viroimmunological response, clinical response and adverse reactions during HAART.
Results: US data report an initiation of HAART at an earlier disease stage in men compared with women. After initiation of HAART, most authors do not report any viroimmunological difference, although a few clinical studies showed a significantly better virological response in women compared with men. Nevertheless, women were more likely to be less adherent to antiretrovirals and to have non-structured treatment interruptions than men. This is likely to be related to the higher number of adverse reactions they experience during HAART. Finally, discordant opinions with regard to clinical benefits during HAART exist, but recent clinical and observational trials suggest a better clinical outcome for women.
Conclusions: We found little evidence of sex differences during antiretroviral treatment. Nevertheless, most of these studies were underpowered to detect sex differences and had limited follow-up at 6 or 12 months. Design of new gender-sensitive clinical trials with both prolonged follow-up and sample size representative of the current HIV prevalence among women are strongly needed to detect the likely sex differences of antiretroviral agents during HIV infection.
Keywords: gender , HAART , long-term clinical progression
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Introduction |
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Different rates of HIV disease progression and of virological and immunological response to antiretroviral therapy were found among HIV-infected women compared with men. In early studies, the more rapid clinical progression observed in women was attributed to the delay in starting highly active antiretroviral therapy (HAART), to the high gynaecological morbidity and to other sex-related stressful conditions such as discrimination, violence and stigma.1,2 Nowadays, in the HAART era, studies of a possible difference between men and women in viroimmunological and clinical response during HAART still give conflicting results. Guidelines for initiating and changing antiretroviral therapy are applied uniformly to women and men. This review will briefly touch upon clinical relevance of sex differences in the time of initiation of HAART, virological and immunological outcomes, adherence, long-term clinical response and adverse reactions during HAART.
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Methods |
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A literature search to identify all original articles assessing the impact of specific sex differences of HAART on viroimmunological and clinical parameters during HAART was performed. A full-text search of the MEDLINE database in the last 5 years (March 2002–February 2007) using the following MeSH terms ‘sex’ and ‘HIV’, ‘sex’ and ‘HAART’, ‘gender’ and ‘HIV’, ‘gender’ and ‘HAART’, revealed 392 references. A review of the bibliographies of relevant articles was also conducted. Abstracts of all identified articles were reviewed, and any relevant study, as determined on the basis of the abstract, was reviewed in full. We identified 41 articles for review on the basis of the criteria stated below (Table 1). Any studies that did not clearly meet these criteria were reviewed by two investigators (E. N. and S. L.) who reached a consensus regarding inclusion or exclusion of the article. The investigators established inclusion and exclusion criteria before reviewing abstracts and articles. Studies were included if they were written in English, involved human subjects, involved adults and reported data on sex differences in the viroimmunological and clinical parameters during HAART. The studies that evaluated gender disparities only on sociodemographic and psychosocial aspects of people living with HIV were excluded. Studies were excluded if odds ratio (OR), relative risk (RR), relative hazard (RH) or hazard ratio (HR) with 95% CI were not provided. Meta-analyses, reviews of literature and case reports were excluded.
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Results |
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Time of initiation of HAART
Lower plasma HIV-RNA levels in HIV seroconverter women compared with men and no difference in progression to AIDS were reported by Sterling et al.3 in 2001: women have lower plasma HIV-RNA levels than men at a similar anticipated risk of progression to AIDS. It is a matter of discussion if this difference influences the time of initiation of HAART between genders (Figure 1). Recently, in a large French cohort of 5735 patients, no gender differences were found in the interval between enrolment and HAART initiation during chronic infection, but this interval was shorter in homosexual patients than in other transmission groups.4 In the Italian ICoNA study, Murri et al.5 observed that the median time to start HAART was longer in women than men (28 weeks versus 17 weeks, respectively; P < 0.01 by log-rank), nevertheless the difference did not reach statistical significance at adjusted analysis. In a prospective cohort study of 2864 US adults receiving HIV care, Sayles et al.6 showed that women had twice the odds of reporting difficulty taking medications openly compared with homo/bisexual men, although this gender difference was not significant in the adjusted model. Data from 10 US HIV primary care sites reported that male gender was significantly associated with an increased likelihood of HAART initiation during chronic infection.7 Similarly, Giordano et al.8 reviewing the medical and pharmacy records of 354 US HIV-infected patients observed that female sex was an independent predictor of not receiving HAART (P = 0.001). In a large cohort of 9530 US HIV-infected patients, McNaghten et al.9 showed that female gender was associated with decreased likelihood of HAART prescription.
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Immunological and virological response to HAART
Discordant data have been published on the immunovirogical response in patients during HAART, but most authors, after adjustment for potential confounders including CD4 cell count and adherence, do not report any difference in terms of virological and immunological outcome (Figures 2 and 3). Fardet et al.4 observed that the probability of a CD4 count increment of at least 100 cells/mm3 and the percentage of patients who achieved a viral load below 500 copies/mL were similar in women and men. Conversely, an observational trial conducted in the US reported different conclusions. Hunt et al.10 showed that lower pre-therapy CD4 cell count, younger age, female sex and infrequent low-level viraemia (versus sustained undetectable viraemia) were all factors associated with increased CD4 cell count gains from month 3 to year 4. In contrast, in an Italian multicentre cohort study of 2460 HIV-infected persons during HAART, no sex differences were reported in terms of proportion of patients (66.2%) achieving viral suppression, exhibiting rebound after viral suppression or recovering CD4 cell counts from baseline.11 The EuroSIDA cohort showed that virological and immunological response was not associated with sex, but an increased hazard of virological rebound in females was reported but not confirmed as an independent factor at adjusted analysis (crude HR 1.40, 95% CI 1.18–1.67).12 Consistent with such data, two population-based cohort studies reported an increasing number of virological rebound among females and a lower number of female patients with undetectable HIV-RNA viral load at 1 year (46.7% versus 64.8%, P = 0.001).13,14 Nevertheless, these findings were not confirmed at adjusted analysis. In a simplification-based study in patients enrolled in the French Hospital Database on HIV (FHDH), Abgrall et al.15 observed that after month 12, male sex was associated with a lower risk of virological rebound, with no gender difference in the immunological outcome during the switching therapy. Furthermore, few data from structured interruption trials have been presented. In a multicentre prospective French trial, Hoen et al.16 showed that female gender was an independent predictor of viral response (P = 0.02). However, it is noteworthy that two of the five women included in this trial were infected with a non-B viral subtype. In a longitudinal cohort study performed in Alabama, USA, on 71 patients, Bedimo et al.17 showed that the female gender was independently associated with the non-virological rebound status (P = 0.04). Finally, a recent study performed in Uganda and Zimbabwe on the viroimmunological outcome of 
300 HIV-infected adults treated with triple nucleoside reverse transcriptase inhibitors (NRTIs), showed a 2.3-fold significantly higher virological response in women compared with men (P =0.001).18
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Adherence to HAART and treatment discontinuation
Multiple factors have been related to adherence: among them, Wang et al.19 reported sex, racial/ethnic distribution, age, personality traits, education and alcohol use. A systematic primary search of the literature for the years 1998–2002 by Ammassari et al.20 failed to find any difference in adherence to HAART between the sexes. More recent data are presented in Figure 4. In a retrospective cohort study, Turner et al.21 showed that women were less adherent than men (18% versus 25%, respectively; P < 0.001) and more likely to be diagnosed with depression (34% versus 29%). In separate models by gender, psychiatric care plus antidepressants had a slightly stronger association with adherence in women than men. In intravenous drug users without depression, antidepressants alone were associated with greater adherence (OR, 1.23; 95% CI, 1.02–1.49) with no difference by gender. In an analysis on adherence of prisoners, Palepu et al.22 showed that older age (AOR: 0.81; 95% CI: 0.72–0.91), male sex (AOR: 0.50; 95% CI: 0.38–0.65) and higher physician HIV-related experience (AOR: 0.97; 95% CI: 0.96–0.98) were all factors negatively associated with non-adherence. Murri et al.5 showed that the proportion of men who discontinued at least one drug of initial HAART because of toxicity was lower compared with that of women (20.0% versus 26.7%, respectively; P = 0.002). In a multivariate Cox regression model, the adjusted hazard was 1.41 times higher in women than in men. In the European CASCADE study on persons with HIV seroconversion, Touloumi et al.23 observed that women were more likely to have an interruption than men in the same exposure group (35.8% versus 24.2% among drug users, 22.1% versus 13.3% among heterosexuals). As previously mentioned, Sayles et al.6 observed that women had twice the odds of reporting difficulty taking medications openly compared with homo/bisexual men, although this gender difference was no longer significant in the adjusted model. For women, having difficulty taking medications openly at home was associated with a substantial decrease in the probability of being on HAART in the adjusted model. Finally, in a population-based cohort of British Columbia, Kuyper et al.13 reported a female-specific reduced adherence to HAART.
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Clinical response to HAART
A sex difference in terms of clinical response to HAART has been described but this is not consistently reported among different authors (Figure 5). Recent data reported by Hulgan et al.24 showed that sex was not a significant predictor of a new AIDS-defining illness (ADI) and death P = 0.22. In a cohort study involving 62 French hospitals, Fardet et al.4 observed no significant difference in the clinical progression rate according to gender. In the Italian ICoNA study, there was no significant difference in the risk of developing clinical events between genders (P = 0.40).5 In EuroSIDA adjusted analysis, Moore et al.12 reported no difference in new ADI and death between females and males (P = 0.59 and P = 0.57, respectively). Egger et al.25 analysed data on 12 574 adult patients starting HAART and found no difference in prognosis between men and women. Moore et al.26 observed in univariate analysis that women experienced a slower but not significantly different rate of progression compared with men and that progression rates were similar among white and non-white women. Hall et al.27 using data from the CDC national HIV/AIDS Reporting System from 1996 to 2001 observed substantial survival differences between sexes. Women with HIV infection had slightly higher 3 year survival and lower progression rate to ADI compared with men (91.5% versus 89.5% and 52.4% versus 59.6%, respectively), whereas women already diagnosed with AIDS had slightly lower survival at 3 years compared with men (78.4% versus 79.6%). In the Italian IATG study, an incidence ratio of 3.9 AIDS-events per 100 person-years was found and a significant sex difference in terms of proportion of patients experiencing a new ADI or death during the follow-up period was found (Kaplan–Meier curve, P = 0.008). Particularly female patients experienced a reduced rate of clinical progression whether or not they achieved virological suppression within the first 12 months of HAART (P = 0.12 and P = 0.01, respectively). However, at multivariate analysis the difference was not significant, but considering the interactions between risk factor and gender, a lower proportion of intravenous drug user (IVDU) female patients experienced clinical progression compared with IVDU male patients.11 In a survey on 1300 patients on a simplified antiretroviral regimen in Malawi, Ferradini et al.28 showed that male sex was an independent determinant of death in the first 6 months. Recent data from a large cohort of 6861 patients enrolled in the generic fixed dose antiretroviral treatment programme promoted by Médecins Sans Frontieres, mainly in Africa, reported an independent association of male gender with death (adjusted HR 1.75, 95% CI, 1.34–2.27, P < 0.001).29 Otherwise, the GEMES group (the Spanish Multicenter Study Group of Seroconverters) found that the progression to AIDS and death was slower in women.30 The analysis of the adjusted HR for death in a longitudinal cohort of 929 Spanish IVDUs showed a significantly worse outcome of men than women.31 Similarly, in the CASCADE study, Porter et al.32 noted a greater risk decrease in clinical progression among female drug users than in their male counterparts. On the other hand, the analysis of the Italian NeuroAIDS Investigative Registry showed that female sex significantly increased the risk of toxoplasmic encephalitis (P = 0.02).33 Similarly, Betz et al.34 studied the admissions for AIDS-related illnesses and, at adjusted analysis, observed that women had higher hospitalization rates than men for ADI (P < 0.001) and gastrointestinal diseases (P = 0.003). Conversely, in a prospective cohort study of IVDUs, Floris-Moore et al.35 observed that female gender in the HAART era (P = 0.03) and in the pre-HAART era (ARR = 1.36, P = 0.05) independently predicted an increased hospitalization risk while the hospitalization rate for ADI did not differ by gender. Consistent with such data, Palepu et al.36 showed that the occurrence of new ADI during HIV infection between genders was not significantly associated with the early hospital re-admission for Pneumocystis carinii pneumonia. Finally, in a prospective cohort study of 346 patients receiving HAART between 1996 and 2005 in South Africa, Lawn et al.37 observed that the risk of tuberculosis was not independently associated with sex (P = 0.19).
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Adverse reactions during HAART
Specific literature on the gender differences in terms of cardiovascular events and metabolic complication during HAART is rapidly increasing (Figure 6). In a retrospective cohort from southeast Michigan, Richter et al.38 showed that male sex was significantly associated with an increased risk for dyslipidaemia (P < 0.001), whereas female sex was significantly associated with a diagnosis of disorders of glucose metabolism (P < 0.05). Galli et al.39 showed that female gender, other than hepatitis C virus infection and age, was independently linked to an increased risk of developing morphological alterations. Similarly, in multivariate analysis, Bonfanti et al.40 showed that the risk of lipodystrophy was correlated with female sex. Consistently, Heath et al.41 found that female gender was independently associated with lipoatrophy and lipohypertrophy. In an interview-based survey on 457 patients in Brazil, Santos et al.42 observed that the self-perceived central fat gain was more frequent among women living with HIV/AIDS than men. In an observational study on 891 HIV-positive patients in South Africa, Geddes et al.43 observed that all 14 cases of lactic acidosis were female with a case mortality rate of 29% and Boulassel et al.44 confirmed such data reporting that in a large population-based cohort of HIV-1-infected Canadian patients, women had a significantly higher risk of developing lactic acidosis than men (P < 0.001). Finally, the female gender appears to be associated with the occurrence of rash and/or hypersensitivity reactions during HAART. In a large randomized clinical trial to evaluate the use of ritonavir and indinavir in 1251 nucleoside-experienced patients with advanced HIV infection (CD4 count < 50 cells/mm3), Floridia et al.45 observed that the risk of rash was significantly associated with females at multivariate analysis (P = 0.048). Boulassel et al.44 in the above mentioned article confirmed that hypersensitivity reactions were more frequent in women than men. In a post hoc analysis, within the randomized controlled 2NN trial, van Leth et al.46 showed that the incidence of rash in the nevirapine group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the efavirenz group were not associated with CD4 cell count. The authors observed that women with a CD4 cell count >200 cells/mm3 had a significantly increased risk of developing a rash compared with men within the same stratum.
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Discussion |
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Longitudinal studies have consistently showed that women have higher CD4 cell count and lower HIV-RNA levels at seroconversion and during the first course of HIV infection. In a few original articles, all from US cohorts, female patients have a significant delay in the initiation of a new antiretroviral treatment.6–9 This difference could be due to the above mentioned lower zenith viral load and to the greater fear of drug effects on the fat body distribution compared with males. In European countries, this difference in the access to HAART has been reported but it never reached a statistical significance at adjusted analysis.4,5 This geographical divergence may be due to the different national health policies between the USA and Europe. HIV-infected patients from Western European countries are usually cared for by a completely free-of-charge health public system without any user fees in terms of cost sharing for drugs, diagnostic and therapeutic procedures and hospitalization.
In the recent literature, few authors report a reduced adherence of women to HAART over the course of HIV infection.5,6,13,21–23 This could be related to the higher number of adverse reactions they experience, i.e. morphological alterations such as lipoatrophy and lipohypertrophy, dyslipidaemia, lactic acidosis and hypersensitivity reactions, among others. This higher toxicity profile may be related to the higher antiretroviral concentrations in females compared with males recently shown in pharmacokinetic studies in plasma and cellular reservoirs.47,48 Although publication bias cannot be ruled out, administering the same drug dosage to women and men, without considering physical differences, might predispose women to develop dose-related adverse reactions to certain drugs. With the growing number of antiretrovirals and their narrow therapeutic index, it becomes especially important to assess potential sex differences in drug pharmacodynamics.
Despite such toxicity, after initiation of HAART, a similar long-lasting immune and virological response during HAART has been reported between genders. However, three original trials conducted in France, USA and Uganda and Zimbabwe with a limited number of enrolled patients reported a better virological outcome.16–18 In the two trials conducted in the northern countries, the female patients had a better virological outcome after a structured treatment interruption, whereas in the African trial, 48 weeks after the initiation of a triple NRTI regimen, the proportion of female patients with undetectable viral load was higher than that of men.16–18 Finally, discordant opinions with regard to different clinical benefits between genders during HAART exist. In the Italian IATG study, female patients experienced a reduced clinical progression, but at adjusted analysis only female drug users had a favourable clinical outcome.11 Similar observations have been recently published in two longitudinal Spanish cohorts.31,49 In particular, Collazos et al.49 reported a better clinical outcome in a large cohort of 2620 HIV-infected patients among females, 12 months after initiating a nelfinavir-based HAART. Recent data from a large US multicentre cohort showed that HIV-infected females have a lower clinical progression rate to ADI and death, whereas females already diagnosed with AIDS had a lower survival rate than males.27 Consistently, two cohorts of patients enrolled by MSF reported an independent association of male gender with death.28,29 Conversely, other authors did not observe any difference in clinical progression to ADI or death between genders. This apparent contradiction can be explained by the following points. First, few virological and clinical benefits in females were observed in clinical trials conducted in low-resource countries.19 Epidemiological characteristics and antiretroviral regimens prescribed in such trials are substantially different from those reported in high-resource countries. Nevertheless, recently few authors affirm that virological response and adherence to HAART in low-resource countries is not inferior, but somewhat better than those reported among patients enrolled in studies conducted in high-resource countries.50,51 Second, most clinical studies are underpowered to detect sex differences in terms of clinical or surrogate parameters of HIV progression, and most of them are not adjusted for age, race/ethnicity and socio-economic factors.52 However, the number of sex-specific studies in HIV infection is still very low and our systematic review may be affected by bias in the MeSH terms used for the search literature on MEDLINE. Third, prolonged follow-up periods in randomized clinical trials are needed to assess minimal differences. In this review, we showed that only observational cohorts have such duration whereas the few clinical trials assessing the sex-specific impact of antiretroviral drugs usually have a shorter follow-up. The design of new gender-sensitive clinical trials with long follow-up and sample size representative of the current HIV prevalence among women is strongly needed to detect the likely sex differences of antiretroviral agents during HIV infection.
Our review of sex differences and HIV infection may be subject to publication bias, meaning that some studies may have evaluated sex difference but failed to report these results if they were insignificant or inconclusive. Nevertheless, the preliminary observation that HIV-infected women live somewhat longer than men needs to be evaluated in light of the fact that this is also the case in the general population. The age-specific female:male mortality ratio needs to be carefully compared in the HIV- and non-HIV-infected populations; otherwise the gender-specific clinical benefit could be equivocally related to the antiretroviral regimen rather than to the intrinsic sex-related differences of human beings.
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None to declare.
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Acknowledgements |
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We are grateful to Adriana Ammassari (National Institute for Infectious Diseases, Rome) for his technical advice and support in revising the manuscript and to Carla Nisii (National Institute for Infectious Diseases, Rome) for her English language revision.
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References |
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31
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