Sex differences in cognition are controversial. Poorer neurological outcomes in HIV-infected (HIV+) women compared to men have been reported in several cohorts [1,2]. HIV+ women have a higher prevalence of neuropsychological impairment compared with HIV negative (HIV−) women regardless of symptom status and AIDS diagnosis [3,4], with impairment in psychomotor tasks being particularly noted .
Many studies examining the relationships between sex, cognition, and HIV have utilized limited cohorts with numerous confounders, often comparing HIV+ men to HIV+ women, or HIV+ women with HIV− women, but rarely all four groups of interest.
We investigated the relationship between cognition according to HIV status and sex, and determinants of cognition in a highly homogenous HIV-infected young cohort. We also aimed to describe the pattern and magnitude of impairment evaluated in different cognitive domains according to HIV status, viral and immunological characteristics, and sex.
All 322 participants were evaluated at ‘Dr Victor Babes’ Hospital for Infectious and Tropical Diseases, a reference center in Bucharest, Romania. The study was approved by the institutional review boards of Dr Victor Babes’ Hospital for Infectious and Tropical Diseases and the University of California at San Diego. All participants provided written informed consent to participate. HIV+ (n = 250) participants in this study are representative of the Romanian cohort of nosocomial HIV-infected children in their first years of life in the late 1980s, with HIV clade F .
The exclusion criteria have previously been described .
Age-matched HIV− participants (n = 72) with similar socioeconomic backgrounds were recruited. These participants were siblings (n = 14) or partners (n = 10) of HIV+ patients, or peers from school or work.
All participants completed tests assessing seven ability domains (verbal fluency, speed of information processing, attention/working memory, executive function, learning and memory, and motor) and underwent medical evaluations as previously described .
Scores of the HIV− controls were used to convert raw scores to normally distributed scaled scores with a mean of 10 and a SD of 3, such that higher values represent a better performance for all measures. The conversion formulas were then applied to HIV+ participants. For each participant, scaled scores were averaged to calculate the domain summary scaled score, which were then averaged to obtain the global scaled score.
Current and past alcohol and substance use were determined using a substance use history questionnaire and the MINI-International Neuropsychiatric Interview (MINI-Plus). Depression was evaluated with Beck depression inventory II .
To evaluate the impact of neurocognitive impairment on day-to-day functioning, the patient's assessment of own functioning inventory , was administered.
The neuromedical examination included a review of medical files for medical and neurological histories, current or past antiretroviral medications, and a brief medical and neurological examination. Current CD4+ and HIV ribonucleic acid (RNA) were measured with an HIV RNA detection limit of 50 copies/ml.
For each participant, the ‘first visit’ was considered the first visit where a CD4+ cell count was determined; an ‘interim visit’ was considered any visit after the first visit and before the current study visit; the ‘last visit’ was considered the study visit. The total days lived with CD4+ less than 200 cells/μl was obtained by summing up estimates from individual visits where CD4+ was below 200 cells/μl, as follows: if first visit: the number of days from the visit to half way to the next visit, if that visit was CD4+ more than 200 cells/μl; if interim visit: the number of days from half way between the previous visit and the visit added to the number of days from the visit to half way to the next visit; if last visit: the number of days from half way as the previous visit to the visit. For any participant with CD4+ at least 200 cells/μl at all times, this estimated variable would be zero. For the analyses, days were converted to years. The approach for calculating total time lived with detectable RNA was similar.
All control participants had HIV− serology.
For all participants, standard laboratory testing was performed to assess coinfections (hepatitis B virus, hepatitis C virus, and syphilis), renal, liver insufficiency, severe anemia, and thrombocytopenia.
Demographic and clinical characteristics were compared between HIV status and sex, and their four combinations, using independent samples t-test and χ2 test (or Fisher's exact test where more appropriate) for numeric and categorical variables, respectively. P values from the tests of differences between four HIV by sex groups were adjusted for multiple comparisons using false discovery rate method .
The primary analysis used global and domain summary scaled scores as the outcomes, followed by the secondary analysis of the scaled scores for each test. In separate models for each primary and secondary measure, linear regressions assessed effect of sex and HIV on these outcomes, adjusting for demographic covariates (age and education) that may affect cognition. Interactions between HIV and sex were explored; only significant interactions were kept in the models.
For the HIV+ subset, in multivariable analyses, global and domain scaled scores were regressed on sex, controlling for age, education, and those HIV disease covariates that either differed between sexes or showed an association with a specific scaled score in a univariable analyses with a significance level of 0.15. The HIV covariates were kept in the multivariable model only if their P value was below 0.05, after adjusting for other predictors.
Of particular interest, interactions between sex and the following HIV covariates were investigated in multivariable models for global and domain scaled scores: time lived with CD4+ less than 200 cells/μl, current CD4+ (<200 cells/μl vs. ≥200 cells/μl), detectable plasma HIV viral load (HIV RNA >50 copies/ml), and AIDS. Selective interactions between these HIV covariates were also examined. All models controlled for age and education.
The effect size for the strength of associations between the outcomes and predictors in linear regressions was estimated with the standardized β (hereafter β). Negative and positive values of β, respectively, represent an association with a worse and a better cognitive outcome.
The cohort consisted of 322 participants, 250 (78%) of whom were HIV+. Participants were on average 23 years old and half were women (N = 160, 50%). The distribution of sexes was not statistically different between HIV+ and HIV− groups (% women = 52 vs. 43%, P = 0.25). HIV− participants were on average more educated (12.7 vs. 11.6 years, P = 0.002) and more likely to be employed or in school (72 vs. 48%, P = 0.001). However, controlling for these variables in the models did not significantly change the effects of HIV status on cognitive scaled scores. Table 1 lists demographic and psychological characteristics of the participants by HIV/sex groups. There were no differences between HIV+ and HIV− groups and men and women regarding drug use, hepatitis C coinfection (<2.4%), and patient's assessment of own functioning inventory complains. Overall, the HIV+ group had more depressive symptoms, but this did not change the effects of HIV status when controlled for statistically. Men had a slightly higher proportion of alcohol use than women (7.4% vs. 0.8%, P = 0.01), but no effect of lifetime cumulative alcohol abuse was found on cognition (data not shown).
In the HIV+ group, there were no statistical sex differences in proportions of patients with AIDS, nadir CD4+ levels, cumulative time lived with CD4+ less than 200 cells/μl, estimated durations of HIV infection, or exposure to antiretroviral treatments. Men had a lower current CD4+ cell count, lower CD4+/CD8− ratio, a greater proportion of patients with detectable HIV viral load, and spent a longer cumulative time with detectable HIV viral load (Table 1).
Sex differences in cognitive outcomes
Table 2 shows the results of multivariable analyses by cognitive domain. On average, regardless of HIV status, men performed significantly better than women in working memory (β = 0.21, P < 0.001) and executive functioning (β = 0.12, P = 0.01) domains. There was no statistical difference in global scaled scores between sexes (β = 0.07, P = 0.14).
When assessed separately within the HIV+ and HIV− groups, and controlling for age and education, men outperformed women in working memory in HIV+ group (β = 0.23, P < 0.001), but not in the HIV− group (β = 0.19, P = 0.10). For the executive function domain, the male sex effect was found to be significant only in the HIV− group (β = 0.22, P = 0.048), consistent with the overall model. Results of these subgroup analyses are shown in Table 3. The results of multivariable models regressing individual scaled scores for each test on HIV status and sex, controlling for age and education, are shown in Table 2.
Cognitive outcomes between HIV positive vs. HIV negative groups
Multivariable analysis of the global scaled score showed that HIV status was associated with lower neurocognitive performance (β = −0.22, P < 0.001) with a significant effect of HIV infection on summary scaled scores seen in most domains (β range = −0.17 to −0.21, P < 0.001), except verbal fluency (β = −0.08, P = 0.11), when controlling for age and education (Table 2).
Interaction effect of sex and HIV status on cognitive outcomes
For outcomes presented in Table 2, interactions between sex and HIV status were investigated for all measures. The interaction was not statistically significant for the global scaled score (P = 0.54) and most domain scaled scores (P > 0.05), suggesting that the effect of HIV on those measures does not differ statistically between women and men.
The exception was within the motor domain, for which the interaction between sex and HIV status was significant (P = 0.045, Fig. 1). Specifically, after controlling for age and education, HIV+ women had worse motor skills than HIV− women (β = −0.32, P < 0.001), but there was no difference in mean motor scaled scores between HIV+ and HIV− men (β = −0.10, P = 0.17), suggesting a specific effect of HIV on motor functioning in HIV+ women only. These results are consistent with the subset analyses presented above.
When looking at individual test scores, the interaction between sex and HIV status was significant only in the analysis of the grooved pegboard test (GPT) for nondominant hand (P = 0.03), showing that HIV seropositivity was associated with a worse outcome in women (β = −0.26, P = 0.002), but not in men (β = −0.02, P = 0.83; Table 2).
HIV-positive group analysis
When looking at the subset of HIV+ participants, the effects of most HIV characteristics listed in Table 1 on scaled scores were not significant in presence of age, education, and sex in multivariable models (models are not shown).
In the analysis of the verbal scaled score, a significant interaction was observed between low CD4+ cell count and detectable plasma HIV viral load (P = 0.03, Fig. 2a). Specifically, among participants with a detectable plasma HIV viral load, those with CD4+ less than 200 cells/μl had a significantly lower verbal scaled score compared with participants with CD4+ at least 200 cells/μl (β = −0.16, P = 0.03). This effect was not observed in the group with undetectable plasma HIV viral load (β = 0.11, P = 0.27).
For the learning and memory domains, while the mean scaled scores for all HIV+ participants were below the mean scaled scores for the HIV− participants, the multivariable regression analysis within HIV+ group showed that participants with AIDS had a higher mean memory scaled score than participants without AIDS (β = 0.12, P = 0.047).
In the analysis of the motor domain, a significant interaction of sex with time lived with CD4+ less than 200 cells/μl (P = 0.023, Fig. 2b) showed that longer duration of low CD4+ was negatively correlated with the motor scaled score in women (β = −0.22, P = 0.03), but not in men (β = 0.08, P = 0.32). In a separate model, a similar association was found between the motor scaled score and the current CD4+ less than 200 cells/μl (interaction with sex P = 0.01, Fig. 2c). For women, the association was significant (β = −0.32, P = 0.007).
Our study is unique in that it addresses sex differences on neurocognition in young adults with lifelong HIV infection acquired in early childhood. The HIV+ group has approximately 25 years of chronic HIV infection, a balanced sex distribution, about 15 years of exposure to continuous antiretroviral treatment (cART), and no significant medical, psychiatric or behavioral confounding conditions.
In this highly homogenous group, when controlling for age and education, we show a significant effect of HIV+ status on neurocognition. The effect of HIV does not differ between women and men on global cognition and most cognitive domains with the remarkable exception of the psychomotor domain, where an effect of HIV status on cognitive functioning is present only in women, suggesting a sex effect.
These findings are particularly interesting as HIV+ women have better HIV-associated overall status (higher levels of current CD4+ cell count, higher CD4+/CD8− ratio, lower proportion with detectable HIV viral load, and shorter cumulative estimated time spent with detectable HIV viral load).
As the study group is young and has no other known neurocognitive morbidity except HIV infection, we can postulate that the neurocognitive alterations seen are mainly linked to HIV itself and its impact on the developing brain.
Consistent with previous research examining sex and cognition, sex differences were found irrespective of HIV status. In our study, men performed significantly better than women in working memory and executive functioning domains, but women outperformed men in the motor domain, which is also consistent with previous reports [10–13]. Although it has been hypothesized that differences in male/female finger sizes [14,15] might account for performance differences, studies using the small pegboard for the GPT and accounting for finger size have found that women still do better than men , contradicting some previous reports . Regardless, in our study women outperformed men in the motor domain in HIV− group, but within the HIV+ group no differences were found.
Cognition and HIV serostatus
In our cohort, HIV+ status was associated with worse performance, compared with HIV− group, on all but the verbal fluency tests. Several possible factors could have contributed to lower performances, namely uncontrolled HIV infection and low nadir CD4+ cell count. Indeed, all our HIV+ participants had a history of at least 8–10 years of chronic untreated HIV infection.
Uncontrolled HIV replication in the central nervous system (CNS) has previously been linked to cognitive deficits [18,19]. Most of the HIV+ participants in the present study had a low nadir CD4+ cell count, which may allow greater virus access to the CNS  and lead to higher risk of neurocognitive impairment in both adults [21,22] and children .
Although verbal fluency performances were not significantly different between HIV+ and HIV− participants, those with advanced HIV disease (detectable plasma HIV viral load and current CD4+ <200 cells/μl) achieved a significantly lower verbal scaled score compared with participants with better HIV infection markers as previously described in HIV+ individuals in the preantiretroviral therapy period .
HIV+ participants scored below HIV− participants in learning and memory domains. However, within the HIV+ group, participants without AIDS had slightly lower mean memory scaled scores than those with AIDS (β = 0.12, P = 0.047). The factors leading to this are not clear, but were not related to other variables collected in the present study. Several other factors, such as quality of education and better retention in care might have contributed to the differences. Children with AIDS spent more time hospitalized and were more closely monitored after discharge. During these periods, according to their health state, they attended the on-site provided schooling. Indeed, schooling with a normal schedule has been available in our pediatric clinic for all hospitalized HIV-infected children and patients with AIDS attended it for prolonged periods of time. Conversely, the educational opportunities for nonhospitalized children were variable.
Unfortunately, it is impossible for us to evaluate the extent and impact of these periods of time on their neurocognitive performance, but we hypothesize that it may have favorably influenced their learning and memory abilities as compared with patients who haven’t attended the same courses. We acknowledge, however, that this is a hypothesis that we are unable to resolve.
Effects of HIV on cognition in men and women
Within the HIV+ group, women had less advanced HIV disease compared to men, but performed significantly worse in the working memory domain. Other studies, examining individuals infected in adulthood, have reported lower performances in HIV+ women compared to HIV+ men [25–30]. Two other studies using a similar testing battery, found that despite better HIV indicators, women had poorer cognitive performances compared to men [25,26]. It has been speculated that immunogenic responses, which might be influenced by hormonal patterns, impact the size of the viral reservoir , including in the CNS.
Previously, different patterns of cognitive impairment have been described in HIV+ men and women [32,25,26]. Among the HIV+ group, Zambian women had worse performances in memory and learning domains compared to men , whereas Nigerian HIV+ women had worse performance compared to HIV+ men in speed of information processing, verbal fluency, learning and memory domains .
Conversely, in a prospective study on a US HIV-infected cohort, no evidence of differential declines regarding neuropsychological functioning between HIV+ men and HIV+ women was found .
Notably, many of the studies above were not able to examine differences in male and female performance within both HIV+ and HIV− participants.
Differences between the effects of HIV positive status on sexes
In our study, the effect of HIV differed between women and men in the psychomotor domain. However HIV+ status has an equally detrimental effect on cognitive performances of both sexes, in all other cognitive domains.
A recent study of 1521 women from the Women's Interagency HIV Study showed that the largest cognitive deficit associated with HIV infection was in the domain of verbal memory, particularly delayed verbal memory when compared with uninfected women. Secondarily, deficits were also found in speed of information processing and attention .
In the present study, the psychomotor domain was the only cognitive domain where a significant interaction between female sex and HIV status was found, such that HIV+ women had worse psychomotor skills than HIV− women. This was characterized by HIV− women performing better than seronegative men, but that difference disappearing within the HIV+ groups.
It has already been described that HIV+ women, especially those with AIDS diagnosis, had slower psychomotor speed when compared with HIV− women  and that HIV+ status was a predictor for motor slowing in women , but no specific interactions were described between sex and HIV status.
In our study though, a preferential, negative effect of HIV+ status on cognition was observed, only in women, despite them having better HIV overall status (higher current CD4+ cell count and CD4+/CD8− ratio, greater proportion of patients with current undetectable HIV viral load, and longer cumulative time spent with undetectable HIV viral load) compared to men.
Moreover, current low CD4+ cell count and longer time with CD4+ less than 200 cells/μl was associated with worse motor performance in HIV-infected women. The findings were driven by the GPT on the nondominant hand.
The GPT has been one of the most sensitive psychomotor measures over the years [37–39]. Not merely a ‘motor’ measure, the GPT involves fine motor control and dexterity, visual processing, speed, attention, and continuous coordination and monitoring of accuracy .
It is possible that there were hormonal influences on this finding. Estradiol acts as a protector in striatal dopamine neurons  where high concentrations of estrogen receptors exist  and in a study of men and women, better performance on the GPT was related to higher striatal specific uptake values in women, but not in men . However, the linkage between the role of estrogen and motor performance differences seen in the present report remains speculative.
As our cohort experienced untreated HIV in the first decade of life, it is likely that damage occurred in several brain regions. We propose that the myelination process was impaired, leading to altered motor performances and connectivity between motor areas, as it has been described in the pre-cART period . Although preliminary, it might be posited that HIV-related disruption of developmental, and perhaps, hormonal influences in women resulted in the preferential deficits seen in psychomotor performance.
There are several limitations to our study. On average, participants without HIV were more educated and more likely to be employed or in school, but this did not change the effect of HIV status when controlled for statistically. Also, the control group was small, but very homogenous given that the majority of the participants were friends, siblings, or colleagues of HIV+ and thus had similar socioeconomic status. The design of the study was cross-sectional. Future studies involving a longitudinal evaluation are necessary to determine if the cognitive pattern that we found is influenced by the further development of these young adults. Hormonal influences would also be interesting to follow in women vs. men in this maturing cohort.
Given the unique characteristics of early childhood infection and their young age, as well as their long-term infection, these patients are a valuable model for evaluating HIV-related neurocognitive impairment. The impact of other factors known to contribute to alterations in cognition in older patients (cardiovascular disease, metabolic disorders, and so on) is low in this cohort, thus allowing a more accurate evaluation of the effects of HIV. We have shown that, although HIV has an equally detrimental effect on cognitive performances of both sexes in most cognitive domains of a developing brain, the effect of HIV on psychomotor performances in women and its long-term consequences warrants further study.
R.B. contributed to the study design and conception and interpretation of the data and drafted the manuscript. L.E., T.D.M., C.L.A., S.M.R. contributed to the study design and conception, to the interpretation of the data, and edited the manuscript. A.U. performed the statistical analysis, contributed to drafting, and edited the manuscript. R.B., L.E., A.L., R.R. contributed to patient recruitment and testing and assisted with the collection of data. S.G. helped with data interpretation and edited the manuscript. All authors read and approved the final manuscript.
The authors thank all the participants in the study, Terence Hendrix from the HIV Neurobehavioral Research Center in San Diego for neuropsychological training and study coordination as well as Adina Bulacu-Talnariu and Adrian Luca (psychologists) for their help with neuropsychological testing.
The work was supported by 1R01MH094159 and P30 MH62512 from National Institute of Mental Health (NIMH). R.B. and A.U. report grants from National Institute of Mental Health (NIMH), during the conduct of the study. L.E. reports grants from National Institute of Mental Health (NIMH), during the conduct of the study; personal fees and nonfinancial support from Abbvie, personal fees from Johnson & Johnson. S.M.R. reports grants from National Institute of Mental Health (NIMH), during the conduct of the study. R.R. reports grants from National Institute of Mental Health (NIMH), during the conduct of the study; personal fees from Abbvie, personal fees from Bristol Meyers Squibb, personal fees from Johnson & Johnson, personal fees from Merck Sharp Dohme, outside the submitted work. A.L. reports grants from National Institute of Mental Health, during the conduct of the study; grants from University College Dublin, School of Medicine, Ireland, outside the submitted work.
Conflicts of interest
There are no conflicts of interest.
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