Objective(s):HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment.Design:Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls).Methods:Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R.Results:Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF.Conclusions:Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HAND that may be augmented with aging.

Elevated cholesterol and APOE ε4 genotype were independent risk factors for cognitive decline in antiretroviral therapy–adherent human immunodeficiency virus (HIV)-infected men aged 50–65 years, whereas higher high-density lipoprotein attenuated cognitive decline. Treatment of dyslipidemia may reduce midlife cognitive decline among HIV-infected individuals.

SummaryLong-term, heavy marijuana use was associated with increased cardiovascular events in human immunodeficiency virus (HIV)–infected men aged 40–60 independent of tobacco smoking, viral load, and other risk factors, while there was no significant association with HIV disease markers, progression to AIDS, or mortality.

Cocaine use is prevalent among HIV-infected individuals. While cross-sectional studies suggest that cocaine users may be at increased risk for depression, long-term effects of cocaine on depressive symptoms remain unclear. This is a longitudinal study of 341 HIV-infected and uninfected men (135 cocaine users and 206 controls) ages 30 to 60 enrolled in the Multicenter AIDS Cohort Study during 1996–2009. The median baseline age was 41; 73% were African-American. In mixed-effects models over a median of 4.8 years of observation, cocaine use was associated with higher depressive symptoms independent of age, education level, and smoking (n=288; p= 0.02); HIV infection modified this association (p= 0.03). Latent class mixed models were used to empirically identify distinct depressive trajectories (n=160). In adjusted models, cocaine use was associated with 3-fold increased odds of membership in the class with persistent high depressive symptoms (95% confidence interval (CI) 1.38–6.69) and 8-fold increased odds (95% CI (2.73–25.83) when tested among HIV-infected subjects only. Cocaine use is a risk factor for chronic depressive symptoms, particularly among HIV-infected men, highlighting the importance of integrating mental health and substance use treatments to address barriers to well-being and successful HIV-care.

Objectives:Nitrite inhalants (poppers) are commonly used recreational drugs among MSM and were previously associated with elevated rates of high-risk sexual behavior, HIV and human herpesvirus type 8 (HHV-8) seroconversion, and transient immunosuppressive effects in experimental models. Whether long-term popper use is associated with cancer risk among MSM in the HAART era is unclear.Design:Prospective cohort study of cancer risk in 3223 HIV-infected and uninfected MSM in the Multicenter AIDS Cohort Study from 1996–2010.Methods:Poisson regression models were used to examine the association between heavy popper use (defined as daily or weekly use for at least 1 year) and risk of individual cancers or composite category of virus-associated cancers.Results:Among all participants, heavy popper use was not associated with increased risk of any individual cancers. Among HIV-uninfected men aged 50–70, heavy popper use was associated with increased risk of virus-associated cancer with causes linked to human papillomavirus, HHV-8, and Epstein–Barr virus in models adjusted for demographics, number of sexual partners, immunological parameters (CD4+ cell counts or CD4+/CD8+ ratios), and hepatitis B and C viruses [incidence rate ratio (IRR), 95% confidence interval (CI) 3.24, 1.05–9.96], or sexually transmitted infections (IRR 3.03, 95% CI, 1.01–9.09), as was cumulative use over a 5-year period (IRR 1.012, 95% CI 1.003–1.021; P = 0.007). There was no significant association between heavy popper use and virus-associated cancer in HIV-infected men.Conclusions:Long-term heavy popper use is associated with elevated risk of some virus-associated cancers with causes related to human papillomavirus, HHV-8, and Epstein–Barr virus infections in older HIV-uninfected MSM independent of sexual behavior and immunological parameters.

Immunological parameters that influence susceptibility to virus-associated cancers in HIV-seronegative individuals are unclear. We conducted a case–control cohort study of immunological parameters associated with development of incident virus-associated cancers among 532 HIV-seronegative men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study (MACS) with median (IQR) 21 (8–26) years of follow-up. Thirty-two incident virus-associated cancers (anal cancer, non-Hodgkin lymphoma, liver cancer, other cancers with etiologies linked to human papillomavirus, Epstein–Barr virus, hepatitis B virus, or human herpesvirus-8) were identified among 3,408 HIV-seronegative men in the MACS during 1984–2010. Cases were matched for demographics, smoking, and follow-up to 500 controls without cancer. Mixed-effects and Cox regression models were used to examine associations between nadir or recent CD4, CD8, and white blood cell (WBC) counts or CD4:CD8 ratios and subsequent diagnosis of virus-associated cancers. Men with incident virus-associated cancers had lower CD4 and WBC counts over a 6-year window prior to diagnosis compared to men without cancer (p = 0.001 and 0.03, respectively). Low CD4 cell count and nadir, CD4 count-nadir differential, and CD4:CD8 ratio nadir were associated with increased 2-year risk of incident virus-associated cancers in models adjusted for demographics and smoking (hazard ratios 1.2–1.3 per 100 or 0.1 unit decrease, respectively; p < 0.01). Other associated factors included heavy smoking and past or current hepatitis B virus infection. These findings show that low CD4 cell counts, CD4 nadir, and CD4:CD8 cell ratios are independent predictors for subsequent risk of virus-associated cancers in HIV-seronegative MSM.Electronic supplementary materialThe online version of this article (10.1007/s10552-018-1090-4) contains supplementary material, which is available to authorized users.

Purpose African American men have the highest incidence of prostate cancer among ethnic groups, and racial disparity is highest in younger men. Prostate cancer prevalence is rising in HIV-infected men due to improved survival on antiretroviral therapies, yet little is known about racial differences in prostate cancer risk by HIV-infection status and age. Methods Prospective cohort study of prostate cancer risk in 2800 HIV-infected and -uninfected men who have sex with men (MSM) ages 40–70 (22% African American) in the Multicenter AIDS Cohort Study from 1996–2010. Poisson regression models were used to examine associations between race or HIV-infection status and prostate cancer risk among men ages 40–70, 40–55, and 56–70. Results Among men ages 40–70, incidence rates (IR) per 100,000 person years were 169 among all men and 276 among African American HIV-infected men. Prostate cancer risk was similar by HIV-infection status (IRR 1.0, 95% CI 0.55–1.82), but nearly 3-fold higher in African Americans compared to non-African Americans in adjusted models (IRRs 2.66 and 3.22, 95% CIs 1.36–5.18 and 1.27–8.16 for all or HIV-infected men, respectively). Racial disparity in prostate cancer risk was greatest in African American men ages 40–55 (adjusted IRR 3.31, 95% CI 1.19–9.22). Prostate cancer risk showed associations with family history of prostate cancer (p =0.001), but not heavy smoking, androgen supplement use, or HIV-related factors. Conclusions Among MSM, African American HIV-positive and HIV-negative men ages 40–55 have nearly a 3-fold increased risk of young-onset prostate cancer compared to non-African American men, highlighting the need to make informed decisions about screening in this population.