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Differences in Cognitive Function Between Women and Men With HIV
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JAIDS Sept 1 2018 - Pauline M. Maki, PhD,* Leah H. Rubin, PhD,* Gayle Springer, MLA, Eric C. Seaberg, PhD, Ned Sacktor, MD, Eric N. Miller, PhD, Victor Valcour, MD, PhD, Mary A. Young, MD,# James T. Becker, PhD,** and Eileen M. Martin, PhD, for the Neuropsychology Working Groups of the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study
Abstract
Background:
Women may be more vulnerable to HIV-related cognitive dysfunction compared with men because of sociodemographic, lifestyle, mental health, and biological factors. However, studies to date have yielded inconsistent findings on the existence, magnitude, and pattern of sex differences. We examined these issues using longitudinal data from 2 large, prospective, multisite, observational studies of US women and men with and without HIV.
Setting:
The Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS).
Methods:
HIV-infected (HIV+) and uninfected (HIV-) participants in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study completed tests of psychomotor speed, executive function, and fine motor skills. Groups were matched on HIV status, sex, age, education, and black race. Generalized linear mixed models were used to examine group differences on continuous and categorical demographically corrected T-scores. Results were adjusted for other confounding factors.
Results:
The sample (n = 1420) included 710 women (429 HIV+) and 710 men (429 HIV+) (67% non-Hispanic black; 53% high school or less). For continuous T-scores, sex by HIV serostatus interactions were observed on the Trail Making Test parts A & B, Grooved Pegboard, and Symbol Digit Modalities Test. For these tests, HIV+ women scored lower than HIV+ men, with no sex differences in HIV- individuals. In analyses of categorical scores, particularly the Trail Making Test part A and Grooved Pegboard nondominant, HIV+ women also had a higher odds of impairment compared with HIV+ men. Sex differences were constant over time.
Conclusions:
Although sex differences are generally understudied, HIV+ women vs men show cognitive disadvantages. Elucidating the mechanisms underlying these differences is critical for tailoring cognitive interventions.
Approximately 50% of HIV-infected (HIV+) individuals develop cognitive impairment.1,2 Cognitive function in HIV+ men has been well characterized because most HIV+ individuals living in the United States and participating in cohort studies are men.1-3 Women comprise approximately 25% of HIV cases4 in the United States and half of global cases.5 HIV+ women in the Women's Interagency HIV Study (WIHS)6 show small but significant deficits in cognitive function, particularly in verbal learning and memory, and processing speed.6,7 Few studies have directly compared cognitive function of HIV+ women and men, even though cognitive profiles of HIV+ women cannot be assumed to be the same as HIV+ men.8 Including HIV-uninfected (HIV-) controls in such comparisons is important to determine the expected pattern of sex differences.
Women may be more vulnerable to HIV-associated cognitive impairment compared with men because of biological differences (eg, hormonal and pharmacokinetic) as well as poverty, low literacy, low education, substance abuse, poor mental health, early life stressors, trauma, and barriers to health care. Some studies suggest greater cognitive vulnerabilities in HIV+ women compared with HIV+ men,3,9,10 whereas others suggest no difference11 or show differences only in the pattern of impairment.12
We compared cognitive test performance in a matched subset of HIV+ and HIV- women from the WIHS and HIV+ and HIV- men from the Multicenter AIDS Cohort Study (MACS) who were comparable in age, education, and black race. Given previous findings,13-15 we predicted that HIV+ women would perform worse than HIV+ men.
DISCUSSION
Cognitive function was examined in a large sample women from the WIHS (n = 710) and men (n = 710) from the MACS-the 2 longest-running longitudinal studies of HIV disease progression in the United States. We found evidence to support the hypothesis that HIV+ women compared with HIV+ men show cognitivevulnerabilities in aspects of psychomotor speed, attention, processing speed, and motor skills. To determine whether those differences were clinically significant, we also examined sex differences in the odds of scoring in the impaired range. We found that compared with HIV+ men, HIV+ women had a higher odds of scoring in the impaired range in psychomotor speed and attention (TMTA) and motor skills (GP).
For comparison with previous studies of sex differences in HIV+ individuals alone (ie, no controls), we note that HIV+ women in the current study performed worse than HIV+ men on 4 of 5 tests, including the TMTA, TMTB, SDMT, and GP, but not the Stroop. Overall, those findings are in agreement with those from a study of 149 HAART-naive HIV+ adults and 58 HIV- controls from Nigeria.9 Compared with HIV+ men, HIV+ women were more impaired in speed of processing, as well as verbal fluency, learning and memory, and global impairment. In that study, sex differences were influenced by women's higher plasma levels of HIV and higher circulating levels of monocyte-driven inflammatory markers (sCD14 and sCD163). In the current study, most HIV participants were treated, and the sex differences remained after controlling for HIV RNA and CD4 counts, which did not differ by sex. Current findings are also in general agreement with findings from 436 HIV+ individuals (80% men) enrolled in CHARTER (CNS HIV Antiretroviral Therapy Effects Research cohort).
Compared with HIV+ men, HIV+ women showed a 76% increased risk of decline in a global estimate of cognitive function over a 35-month follow-up.3 We found that the lower performance of HIV+ women compared with HIV+ men did not worsen over a 30-month follow-up.
Previous studies demonstrate some of the factors that may contribute to these findings of a female disadvantage across cognitive measures. We controlled for depression in this study, but other mental health factors that are not available in the MACS have been shown to negatively influence cognitive function in HIV+ women, including stress and post-traumatic stress disorder.21,22,25 Previous studies show that these psychological factors affected cognitive function in HIV+ women more than HIV- women.21,22 Although we controlled for recent substance use in this study, a more thorough examination of substance use is warranted. In the WIHS, cocaine and heroin use had a greater influence on cognition in HIV+ women compared with HIV- women, an effect that was associated with alterations in prefrontal function. Recent work shows an interactive effect of sex and HIV on cognition among substance-dependent individuals, with HIV+ women showing poorer cognitive function compared with other groups.26-28 Finally, these effects may also reflect the influence of menopause20 and sexual dimorphism in immune function,29 pathogenesis,30 and/or antiretroviral pharmacokinetics.31 These possibilities will be addressed in the ongoing studies of WIHS and MACS. Overall, our results show that cognitive findings from HIV+ men cannot be uncritically generalized to HIV+ women, and that instead sex should be considered in studies of the pathogenesis, clinical presentation, and treatment of cognitive dysfunction in HIV.
Limitations of this study include no comparison of sex differences in verbal learning and memory because different measures were used (the Rey Auditory Verbal Learning Test in the MACS and the Hopkins Verbal Learning Test in the WIHS), and the magnitude of sex differences may differ between these tests given differences in test construction (eg, ability to semantically cluster on the Hopkins Verbal Learning Test but not the Rey Auditory Verbal Learning Test). Non-Hispanic blacks comprised 67% of the total sample here compared with 40% of individuals living with HIV in the United States,4 so results may not generalize to the broader population of HIV+ individuals. Given differences in definitions of certain covariates between the WIHS and MACS (ie, income, education, and substance use), we determined covariates that could be applied across studies. For strengths, our study has the largest sample size to date of HIV+ men and women and controls. We had a longitudinal design with a follow-up time of 2.45 years with an average of 2.6 assessments per participant. Continued follow-up of this cohort is needed to examine these sex differences with advancing age.
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