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. 2014 May 1;30(5):446–456. doi: 10.1089/aid.2013.0208

Sex Differences in HIV Outcomes in the Highly Active Antiretroviral Therapy Era: A Systematic Review

Jessica L Castilho 1,✉, Vlada V Melekhin 1,,2, Timothy R Sterling 1
PMCID: PMC4010172  PMID: 24401107

Abstract

To assess sex disparities in AIDS clinical and laboratory outcomes in the highly active antiretroviral therapy (HAART) era we conducted a systematic review of the published literature on mortality, disease progression, and laboratory outcomes among persons living with HIV and starting HAART. We performed systematic PubMed and targeted bibliographic searches of observational studies published between January, 1998, and November, 2013, that included persons starting HAART and reported analyses of mortality, progression to AIDS, or virologic or immunologic treatment outcomes by sex. Risk ratios (relative risks, odd ratios, and hazard ratios) and 95% confidence intervals were obtained. Sixty-five articles were included in this review. Thirty-nine studies were from North America and Europe and 26 were from Latin America, Asia, and Africa. Forty-four studies (68%) showed no statistically significant difference in risk of mortality, progression to AIDS, or virologic or immunologic treatment outcomes by sex. Decreased risk of death among females compared to males was observed in 24 of the 25 articles that included mortality analyses [pooled risk ratio 0.72 (95% confidence interval=0.69–0.75)], and decreased risk of death or AIDS was observed in 9 of the 13 articles that examined the composite outcome [pooled risk ratio=0.91 (0.84–0.98)]. There was no significant effect of sex on the risk of progression to AIDS [pooled risk ratio=1.15 (0.99–1.31)]. In this systematic review, females starting HAART appeared to have improved survival compared to males. However, this benefit was not associated with decreased progression to either AIDS or to differences in virologic or immunologic treatment outcomes.

Introduction

Since early in the HIV-1 epidemic, sex disparities in HIV-1 transmission, infection, and disease outcome have been examined and have often shown contradictory results. HIV-infected females tend to be younger, have lower HIV-1 RNA, and have higher CD4+ lymphocyte counts at the time of HIV-1 infection or entry into care than males.1–6 However, despite these favorable baseline characteristics, females do not consistently have lower rates of HIV-1 disease progression or death. Studies from the era before highly active antiretroviral therapy (HAART) showed mixed results: while some studies found increased rates of death among females compared with males, others found no difference in death or disease progression by sex.7–11

In the HAART era, HIV-1 disease progression and treatment outcomes by sex have also been inconsistent. A review article by Nicastri et al. in 2007 examined sex differences in HIV-1 outcomes among individuals receiving HAART.12 They reviewed 41 cohort studies from 2002 to 2005 that included data on the effect of sex on timing of HAART initiation, adverse events following treatment initiation, and clinical and laboratory outcomes. That review highlighted the heterogeneous, but largely nonsignificant, differences by sex. Of note, that review included only six studies form outside North America or Europe. In developing countries, females represent a larger proportion of persons living with HIV/AIDS and have had increased access to HAART in recent years. Additionally, the epidemic in North America and Europe has shifted over time with females representing a larger proportion of persons living with HIV/AIDS.13

This systemic review was performed to assess sex disparities in AIDS clinical and laboratory outcomes among persons starting HAART in both developed and developing countries.

Materials and Methods

Studies included in this systematic review were observational cohort studies of HIV-infected adults starting HAART that analyzed outcomes of death, progression to AIDS, virologic outcomes (viral response), or immunologic outcomes (CD4+ lymphocyte count response). A PubMed search of all articles published from January, 1998, though November, 2013, included MeSH terms of “HIV-1” or “Acquired Immunodeficiency Syndrome,” “prognosis” or “mortality” or “disease progression, ” and “gender” or “sex” or “male” or “female. ” Articles were limited to human studies written in English. Following the PubMed search, titles were reviewed and selected for abstract review, and from abstract review, selected for manuscript review-based meeting inclusion criteria and the absence of exclusion criteria. A targeted bibliographic review was also performed on selected articles to search for additional studies meeting inclusion criteria. All studies with risk ratio assessments (hazard ratios, odds ratios, relative risk ratios) for sex and clinical or laboratory outcomes that noted a statistical analysis by way of 95% confidence interval were included. Studies were excluded if they included only one sex group (since conclusions regarding disparities could not be obtained), if they did not include or report specific outcome data of sex analyses (i.e., risk ratios and corresponding confidence intervals), or if they included cohort participants who were not started on HAART. Randomized trials were excluded since clinical trial participants may not accurately reflect general epidemiologic patterns of all individuals infected with HIV-1.

Studies meeting inclusion criteria were reviewed. Particular attention was made to the studies' cohort location (North America and Europe or Latin America, Africa, and Asia), size of the cohort, and percentage of females in the cohort. Given the increased risk of mortality among HIV-infected individuals with anemia and the increased rates of anemia among females, inclusion of hemoglobin in multivariable analyses was also noted.14–16 For consistency, “males” and “females” were used in the reporting of results to indicate the biological definition of sex rather than the psychosocial, gender terminology of “men” and “women.”

Statistical analysis

To compare percentages of females included in studies by cohort geographic region and over time (year of publication), we used the Wilcoxon rank-sum test and univariable regression models, respectively. We compared risk assessments (hazard ratios, relative risk ratios, odds ratios) graphically with forest plot displays. Weighted-pooled risk ratios were calculated using meta-analysis statistics. For consistency, results from studies were assessed as the risk ratio of females compared to males, including confidence intervals. All statistical analyses and graphic displays were performed by Stata 12.1 (Stata Corporation, College Station, TX).

Results

There were 2,851 articles identified in the PubMed search (Fig. 1). After reviewing titles for inclusion criteria, 435 were selected for abstract review. From those abstracts, 173 were selected for manuscript review. An additional 34 articles were identified from bibliographic review, yielding a total of 207 manuscripts reviewed. From those 207 articles, 141 met at least one exclusion criterion and were therefore excluded. One study was unavailable through interlibrary loan services and could not be retrieved.

FIG. 1.

FIG. 1.

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Search results. PubMed Search Query: (HIV[mh] OR Acquired Immunodeficiency Syndrome[mh]) AND (Prognosis[mh] OR Mortality[mh] OR Disease Progression[mh]) AND (gender[tw] OR sex[mh] OR sex[tw] OR (male[mh] AND female[mh])) AND English[la] AND adult[mh] AND human[mh] AND 1998:2013[dp].

Of the 65 articles included in the review, 13 included sex as their primary variable of interest in the analyses. Studies generally included similar baseline variables of sex, age, HIV-1 transmission risk factor, and often CD4+ lymphocyte count and HIV-1 RNA in multivariable analyses. Eleven studies adjusted for hemoglobin in multivariable analyses. Fifty-one unique epidemiologic cohorts were included, 32 of which were multisite cohorts. Forty studies were from cohorts in North America (Canada and the United States) or Europe. There were 17 studies from African cohorts, five from Asian cohorts, one Latin American cohort, one from the ART-LINC cohort (a multicenter cohort from Africa, Asia, and Latin America), and one from the HIV Netherlands, Australia, and Thailand Collaboration cohort. Cohorts from North America and Europe had smaller percentages of females compared to those from Latin America, Africa, and Asia (median percentage of females 22.6 vs. 54.3%, p<0.001). The percentage of females included in study cohorts did not statistically change over time among studies from North America and Europe (0.97% per year of publication, p=0.07). Forty-one studies examined the clinical outcomes of progression to AIDS and/or death; 28 examined virologic and/or immunologic outcomes. None of the studies included transgender or transsexual individuals.

Clinical outcomes: mortality and disease progression

Figure 2a–c includes studies that examined the outcomes of death and/or AIDS by sex.5,17–56 Figure 2a displays the studies that examined risk of death (stratified by global region), Fig. 2b includes those that examined risk of AIDS, and Fig. 2c includes those that examined risk of the composite outcome of AIDS or death.

FIG. 2.

FIG. 2.

FIG. 2.

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(a) Risk of death. (a) “Early” mortality following HAART initiation, as defined by the study. (b) “Late” mortality following HAART initiation, as defined by the study. (c) Mortality among patients with CD4+ lymphocyte count 351–500 cells/μl at HAART initiation. (d) Mortality among patients with CD4+ lymphocyte count >500 cells/μl at HAART initiation. n, number of individuals in the study cohort; Hgb, hemoglobin (as a marker for anemia), indicated as whether or not included in multivariable analyses; uHR, univariable hazard ratio; aHR, adjusted hazard ratio from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Females, a risk ratio less than one indicates a decreased risk of death for females compared to males; Favors Males, a risk ratio greater than one indicates an increased risk of death for females compared to males. (b) Risk of AIDS. n, number of individuals in the study cohort; Hgb, hemoglobin (as a marker for anemia), indicated as whether or not included in multivariable analyses; aIRR, adjusted incidence rate ratio from multivariable analyses; aHR, adjusted hazard ratio from multivariable analyses; aOR, adjusted odds ratio from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Females, a risk ratio less than one indicates a decreased risk of AIDS for females compared to males; Favors Males, a risk ratio greater than one indicates an increased risk of AIDS for females compared to males. (c) Risk of AIDS or death. n, number of individuals in the study cohort; Hgb, hemoglobin (as a marker for anemia), indicated as whether or not included in multivariable analyses; TLC, total lymphocyte count; uHR, univariable hazard ratio; aHR, adjusted hazard ratio from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Females, a risk ratio less than one indicates a decreased risk of AIDS or death for females compared to males; Favors Males, a risk ratio greater than one indicates an increased risk of AIDS or death for females compared to males.

Figure 2a reports risk of death estimates from studies stratified by region. The overall pooled risk ratio for risk of death from the 25 studies demonstrated a statistically significant decreased risk of death for females compared to males [pooled risk ratio=0.72 (95% confidence interval=0.69–0.75)]. This association was particularly driven by studies from developing countries [pooled risk ratio=0.70 (0.69–0.75)], which included results of “early” and “late” mortality following HAART initiation. Of the studies from North America and Europe, only two point estimates for adjusted hazards ratios (aHR) indicated increased risk of death for females. A large study of patients from the NA-ACCORD cohort examined outcomes of early (CD4+ lymphocyte count 351–500 cells/μl or CD4+ lymphocyte count >500 cells/μl) versus deferred (waiting for CD4+ lymphocyte count to fall below either threshold) initiation of HAART.26 Among individuals who started HAART with CD4+ lymphocyte count 351–500 cells/μl, females had a 47% increased risk of death [aHR=1.47 (1.02–2.12)], though sex was no longer statistically significant when hepatitis C virus infection and injection drug use history were included in multivariable models (numeric data not provided). Among those with CD4+ lymphocyte count >500 cells/μl at HAART initiation, females again had an increased risk of death, though not statistically significant [aHR=1.35 (0.85–1.32)]. Thus, the only study that found a statistically significant increased risk of mortality for females found these results to no longer be significant when analyses accounted for additional baseline variables.

Figure 2b lists the studies that examined progression to AIDS. All six studies included cohorts from developed regions. The pooled risk ratio for risk of AIDS demonstrated a slightly increased risk of AIDS for females but was not statistically significant [pooled risk ratio=1.15 (0.99–1.31)]. Two studies specifically looked at sex as the primary variable, both of which yielded an aHR of less than one (indicating a decreased risk of AIDS progression for females), though neither was statistically significant.5,28 Of the studies whose point estimates were greater than one, one study from the Johns Hopkins Hospital clinic cohort that examined HIV-1 outcomes and substance abuse found a statistically significantly increased risk of AIDS among females compared to males.30

Lastly, Fig. 2c lists the results from those studies that used a composite outcome of AIDS or death. Assessed together, risk of AIDS or death was slightly decreased for females compared to males [pooled risk ratio=0.91 (0.84–0.98)]. Of these 13 studies, only one was from a developing region.55 Nine of the studies had risk ratios less than one (indicating decreased risk of AIDS or death for females). Only two had risk ratios indicating increased risk for females. One multicenter study from Spain demonstrated a 45% decreased risk of AIDS or death for females [aHR=0.55 (0.34–0.88)].31 In this study, females tended to be older at baseline and had a higher CD4+ lymphocyte count and lower HIV-1 RNA. One study from British Columbia, Canada, demonstrated an increased risk of AIDS or death for females compared to males starting HAART; however, this risk was not statistically significant and was assessed only in univariable analysis [univariable HR=1.33 (0.72–2.44)].

Laboratory outcomes: virologic and immunologic response to HAART

Figure 3a and b display study results of virologic outcomes.5,24,33,57–77 Fifteen studies examined likelihood of virologic suppression, of which three were from developing regions. Together, there was a slightly decreased likelihood of viral suppression for females compared to males [pooled risk ratio=0.94 (0.89–0.99)]. Of the seven studies with point estimates less than one (suggesting decreased rates of viral suppression for females) one multicenter study from Canada reported a small but statistically significant effect of sex [aHR for females=0.86 (0.78–0.94)].70 Five of the studies specified sex as the primary variable of interest and all had point estimates greater than one, reflecting increased likelihood of suppression for females, though none met statistical significance.5,33,61,62,66 Of the eight studies that demonstrated point estimates greater than one, only a small study of patients starting HAART in Mexico demonstrated a borderline significant effect in which females had a 3-fold increased likelihood of achieving viral suppression in univariable analyses [univariable HR 3.30 (1.00–7.14)].63

FIG. 3.

FIG. 3.

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(a) Risk of virologic suppression. n, number of individuals in the study cohort; uHR, univariable odds ratio; uOR, univariable odds ratio; aHR, adjusted hazard ratio from multivariable analyses; aOR, adjusted odds ratio from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Males, a risk ratio less than one indicates a decreased likelihood of virologic suppression for females compared to males; Favors Females, a risk ratio greater than one indicates an increased likelihood of virologic suppression for females compared to males; (b) Risk of virologic failure. n, number of individuals in the study cohort; uHR, univariable odds ratio; uOR, univariable odds ratio; aHR, adjusted hazard ratio from multivariable analyses; aOR, adjusted odds ratio from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Females, a risk ratio less than one indicates a decreased risk of virologic failure for females compared to males; Favors Males, a risk ratio greater than one indicates an increased risk of virologic failure for females compared to males.

Figure 3b examines those studies that looked at risk of virologic failure (either viral rebound following suppression or failure to suppress) and sex. Overall, there was no statistically significant difference in risk of virologic failure for males and females [pooled risk ratio=0.93 (0.85–1.01)]. Of the nine studies, five studies were from developing countries.57,59,74–76 Two studies from Europe by Moore et al. included sex as the primary variable of interest, both of which showed decreased rates of virologic failure for females compared to males in multivariable models; however, neither result was statistically significant.5,61

Lastly, Fig. 4a and b examine immunologic results and sex.5,24,42,57–60,78–81 Figure 4a reports studies that looked at likelihood of immunologic success (appropriate or robust CD4+ lymphocyte count recovery after starting HAART) and sex, and together, showed no significant difference [pooled risk ratio=1.05 (0.97–1.12)]. Seven studies were included, one of which was from developing regions.57 Only one study included sex as the primary variable of interest and showed no difference in immunologic responses by sex [aHR=0.98 (0.88–1.14)].5 Two studies of a national cohort from the Netherlands demonstrated a statistically significant increased rate of immunologic success for females compared to males.78,80 Additionally, a single-center study from the United States found that among patients with a CD4+ lymphocyte count of <200 cells/μl at HAART initiation, females were over 3-fold more likely than males to have a count >350 cells/μl after 12 months in multivariable analyses.81

FIG. 4.

FIG. 4.

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(a) Risk of immunologic response. (a) Odds of achieving CD4+ lymphocyte count >200 cells/μl after 12 months for patients with CD4+ lymphocyte count <200 cells/μl at HAART initiation. (b) Odds of achieving CD4+ lymphocyte count >350 cells/μl after 12 months for patients with CD4+ lymphocyte count <200 cells/μl at HAART initiation. n, number of individuals in the study cohort; aHR, adjusted hazard ratio from multivariable analyses; aOR, adjusted odds ratio from multivariable analyses; aRR, adjusted relative risk from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Males, a risk ratio less than one indicates a decreased likelihood of immunologic response for females compared to males; Favors Females, a risk ratio greater than one indicates an increased likelihood of immunologic response for females compared to males. (b) Risk of immunologic failure. (a) Odds of CD4+ lymphocyte count <200 cells/μl after 12 months of HAART. (b) Odds of CD4+ lymphocyte count <200 cells/μl after 24 months of HAART. n, number of individuals in the study cohort; uHR, univariable hazard ratio; aHR, adjusted hazard ratio from multivariable analyses; aOR, adjusted odds ratio from multivariable analyses; ES, effect size of risk ratio, reported as comparing females to males; 95% CI, 95% confidence interval; Favors Females, a risk ratio less than one indicates a decreased risk of immunologic failure for females compared to males; Favors Males, a risk ratio greater than one indicates an increased risk of immunologic failure for females compared to males.

Figure 4b includes four studies that examined rates of immunologic failure (inappropriate or lack of CD4+ lymphocyte count recovery following HAART initiation) and sex. Together, these studies suggest a decreased risk of immunologic failure for females compared to males [pooled risk ratio=0.83 (0.70–0.96)]. Two of the studies were from developing countries and both suggested decreased rates of immunologic failure among females compared to males, though neither was statistically significant individually. A Thai study found that 12 weeks after starting HAART, females were 24% less likely to have a CD4+ lymphocyte count of less than 200 cells/μl compared to males [aHR=0.76 (0.56–1.02)].59 Similarly, a large study using the ART-LINC data found that among patients starting HAART, females were 15% less likely [aHR=0.85 (0.70–1.03)] to have a discordant outcome of viral suppression but a CD4+ lymphocyte count increase of 50 cells/μl or less after 6 months of therapy.57

Discussion

This systematic review assessed published studies to answer the question of whether sex differences in HIV-1 clinical and laboratory outcomes exist among persons starting antiretroviral therapy in the HAART era. A broad, systematic search of the literature identified studies that focused on sex as well as studies that included sex in multivariable analyses. The studies came from both developed and developing countries. Together, these studies suggest that around the globe, females with HIV-1 infection have slightly improved survival outcomes compared to males. However, studies showed no clear sex disparity in HIV-1 disease progression or in treatment effects of viral suppression and immunologic recovery.

While most studies individually yielded statistically nonsignificant results, collectively, there was suggestion of improved survival of females with HIV-1 compared to males. Improved female survival was observed from studies from both resource-rich and resource-limited countries with all but one study reporting risk ratios favoring females. Additionally, studies that adjusted for anemia all had point estimates of mortality less than one, demonstrating decreased risk of death in females compared to males when controlling for anemia.5,17,44–46,48–52 The difference in mortality was seen without parallel evidence in the outcomes related to HIV-1 disease outcomes—namely progression to AIDS or virologic or immunologic outcomes—a pattern that has been seen in a meta-analysis of sex and HIV outcomes among participants in clinical trials.2 Interpretation of these results is limited without knowledge of cause of death (AIDS-related or non-AIDS-related). In developed countries, death from non-AIDS-defining events (NADEs) has increasingly replaced AIDS-related causes of mortality.82 Studies from HIV-1 cohorts from developing countries, as well, have suggested the importance of non-AIDS mortality. A recent study from a large South African cohort found a decreased risk of death for females starting HAART that was parallel to sex disparities seen in the background population, not just among the HIV-1 infected.45 Attention to possible differences in rates of non-AIDS mortality is needed to better understand the observed mortality difference in this review.

The results for disease progression to AIDS and immunologic and virologic treatment effects did not show a clear sex disparity, though the results were limited by the small number of studies included. There was a significant, small, decreased risk of immunologic failure for females compared to males, but this was drawn from only four studies.

This study has a number of limitations. While the search was designed to capture a broad catchment of studies, it was limited by only including those studies that identified “sex” or “gender” or “male” or “female” words as MeSH terms. This was done to not miss studies that included sex as the primary predictor variable, but in turn, meant that many studies that examined HIV-1 outcomes and included sex in their analyses but did not identify sex by MeSH terms were not included in this study. Additionally, this study only queried PubMed as a search engine. The literature on HIV-1 outcomes is vast and it is likely that some studies were not included. However, the retrieval of nearly 3,000 articles (the majority of which did not focus on sex primarily) speaks to the large sample drawn. Similarly, many studies were excluded for not reporting risk ratios point estimates for sex or for simply stating that sex was not predictive of the outcome of interest. Without a point estimate, we were unable to assess if the nonsignificant result they reported was in favor of females or males and thus these studies were excluded. It is impossible to know if the majority of those studies yielded unreported point estimates contradictory to the studies reported in this review. However, that the majority of the studies in this review, too, had statistically nonsignificant results argues that the sample included may be representative of others' results. Lastly, this study is limited by its lack of formal meta-analysis. Given that studies from developed countries, in particular, are limited by small percentages of females included in cohorts and decreased power, a meta-analysis would allow for more definitive statements regarding HIV-1 outcomes and sex. However, a meta-analysis could not be pursued given the heterogeneity of studies and their primary statistical aims, as well as the risk of oversampling from cohorts used repeatedly in multiple studies.

With the above limitations acknowledged, this systematic review addressed several questions regarding sex disparities in HIV-1 outcomes among persons starting antiretroviral therapy. Females starting HAART in developed and developing countries had improved survival compared to males; however, this benefit was not seen in risk of progression to AIDS or in virologic or immunologic outcomes of HIV-1 therapy. Questions regarding cause of death and sex require further investigation, with particular attention to noninfectious morbidity and mortality.

Acknowledgments

Supported by the National Institutes of Health: T32 AI007474 (J.L.C.), NIAID K23AI080227 (V.V.M.), and K24 AI65298 (T.R.S.). Vanderbilt University has received research grants from Pfizer, Bristol Myers Squibb, and Virco to perform HIV observational studies.

Author Disclosure Statement

No competing financial interests exist.

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