Importance: Whether people infected with human immunodeficiency virus (HIV) are at an increased risk of acute myocardial infarction (AMI) compared with uninfected people is not clear. Without demographically and behaviorally similar uninfected comparators and without uniformly measured clinical data on risk factors and fatal and nonfatal AMI events, any potential association between HIV status and AMI may be confounded.Objective: To investigate whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care.

These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions.

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Background: HIV infection leads to chronic inflammation and alterations in levels of inflammatory cytokines. The association between cytokine levels and mortality in HIV-infection is not fully understood. Methods: We analyzed data from a cohort of HIV-infected adults with alcohol problems who were recruited in 2001-2003, and were prospectively followed until 2010 for mortality using the National Death Index. The main independent variables were inflammatory biomarkers [IL-6, IL-10, TNF-alpha, C-reactive protein (CRP), Serum Amyloid A, Monocyte Chemotactic Protein-1 and Cystatin-C], measured at baseline in peripheral blood and categorized as high (defined as being in the highest quartile) vs. low. A secondary analysis was conducted using inflammatory burden score, defined as the number of biomarkers in the highest quartile (0,1,2 or ≥3). Cox models were used to assess the association between both biomarker levels and inflammatory burden with mortality adjusting for potential confounders. Results: Four hundred HIV-infected patients were included (74.8% male, mean age 42 years, 50% HCV-infected). As of 31st December 2009, 85 patients had died. In individual multivariable analyses for each biomarker, high levels of IL-6 and CRP were significantly associated with mortality [HR=2.49 (1.69-5.12), p<0.01] and [HR=1.87 (1.11-3.15), p=0.02], respectively. There was also a significant association between inflammatory burden score and mortality [HR=2.18 (1.29; 3.66) for ≥3 vs. 0, p=0.04]. In the fully adjusted multivariable analysis high levels of IL-6 remained independently associated with mortality [HR=2.57 (1.58-4.82), p<0.01]. Conclusions: High IL-6 levels and inflammatory burden score were associated with mortality in a cohort of HIV-infected adults with alcohol problems.

BackgroundAssessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C-reactive protein) to represent inflammation may not be appropriate in HIV/HCV co-infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers.MethodsWe compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use.ResultsDetectable HIV and HCV RNA (OR = 2.49; 95% CI = 1.05–5.89) and detectable HCV RNA alone (2.95; 1.08–8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90–31.97) and TNF-α (7.70; 1.42–41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84).ConclusionsDetectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities.

Both HIV and hepatitis C virus (HCV) cause chronic inflammation and alterations in serum inflammatory cytokines. The impact of inflammatory cytokines on liver fibrosis is not well understood. We studied the association between interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α and liver fibrosis in HIV-infected patients with current or past alcohol problems (CAGE ≥2 or physician investigator diagnosis). Liver fibrosis was estimated with FIB-4 (FIB-4 <1.45 defined the absence of liver fibrosis and FIB-4 >3.25 defined advanced fibrosis). Logistic regression was used to assess the association between cytokines and fibrosis, adjusting for age, sex, CD4, HIV RNA, current antiretroviral therapy, body mass index, and HCV. Secondary analyses explored whether the association between HCV and liver fibrosis was mediated by these cytokines. Participants (n=308) were all HIV-infected; 73% were male with a mean age of 42 years; half had detectable HCV-RNA, 60.7% had an absence of liver fibrosis, and 10.1% had advanced fibrosis. In models that adjusted for each cytokine separately, higher levels of IL-6 were significantly associated with an absence of fibrosis [adjusted OR (95% CI): 0.43 (0.19, 0.98), p=0.05] and were borderline significant for advanced fibrosis [adjusted OR (95% CI): 8.16 (0.96, 69.54), p=0.055]. In the final model, only higher levels of IL-6 remained significantly associated with advanced liver fibrosis [adjusted OR (95% CI): 11.78 (1.17, 118.19), p=0.036]. Adjustment for inflammatory cytokines attenuated the adjusted OR for the association between HCV and fibrosis in the case of IL-6 [for the absence of fibrosis from 0.32 (0.17, 0.57) p<0.01 to 0.47 (0.23, 0.96) p=0.04; and for advanced fibrosis from 7.22 (2.01, 25.96) p<0.01 to 6.62 (1.20, 36.62) p=0.03], suggesting IL-6 may be a partial mediator of the association between HCV and liver fibrosis. IL-6 was strongly and significantly associated with liver fibrosis in a cohort of HIV-infected patients with alcohol problems. IL-6 may be a useful predictive marker for liver fibrosis for HIV-infected patients.

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Depression is associated with an increased risk of heart failure (HF) among HIV infected (HIV+) and uninfected (HIV-) veterans. Antidepressants are commonly prescribed to mitigate psychosocial symptoms related to major depressive disorder (MDD). The purpose of this study was to determine whether antidepressant use was associated with lower HF risk among a large cohort of HIV+ and HIV- veterans with MDD. We analyzed data on 13,849 veterans (36.5% HIV+) from the Veterans Aging Cohort Study (VACS), a prospective study of HIV+ and matched HIV- veterans who had a diagnosis of MDD (ICD-9 codes 296.2x & 296.3x) and were free of cardiovascular disease (CVD) at baseline. Antidepressant use was defined as documentation of selective serotonin reuptake inhibitor (SSRIs), tricyclic antidepressant (TCAs), and non-SSRI, non-TCA antidepressant use from the VA pharmacy records during the baseline period (1998 - 2003). Incident HF was identified using ICD-9 codes and defined as first HF event on or after 4/1/2003 until 12/31/2009. We used Cox proportional hazards regression to assess the association between HIV infection, antidepressant use and incident HF, adjusting for covariates (Table). Most participants were on antidepressant therapy [90.2% (12,498 of 13,849)]. In the total sample, baseline antidepressant use was associated with a lower risk of HF, adjusting for all covariates including HIV (adjusted HR = 0.76, 95% CI = 0.58 - 0.99). The rates of incident HF were highest among HIV+ participants who did not use antidepressants (Table). Among the HIV+ participants, the association between antidepressant use and lower HF risk neared significance (p = 0.053). Antidepressant use was common among this cohort of veterans with MDD and was associated with a lower risk of incident HF. Our study lends support to further investigations to determine the importance of antidepressants as additional therapy for CVD prevention among MDD patients with and without HIV.