Stefano Zona

Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population

BACKGROUND Human immunodeficiency virus (HIV)-infected patients may have a greater risk of noninfectious comorbidities (NICMs) compared with the general population. We assessed the prevalence and risk factors for NICMs in a large cohort of HIV-infected adults and compared these findings with data from matched control subjects. METHODS We performed a case-control study involving antiretroviral therapy (ART)-experienced HIV-infected patients treated at Modena University, Italy, from 2002 through 2009. These patients were compared with age-, sex-, and race-matched adults (control subjects) from the general population included in the CINECA ARNO database. NICMs included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. Polypathology (Pp) was defined as the concurrent presence of ≥2 NICMs. Logistic regression models were constructed to evaluate associated predictors of NICMs and Pp. RESULTS There were 2854 patients and 8562 control subjects. The mean age was 46 years, and 37% were women. Individual NICM and Pp prevalences in each age stratum were higher among patients than among controls (all P <.001). Pp prevalence among patients aged 41-50 years was similar to that among controls aged 51-60 years (P value was not statistically significant); diabetes mellitus, cardiovascular disease, bone fractures, and renal failure were statistically independent after adjustment for sex, age, and hypertension. Logistic regression models showed that independent predictors of Pp in the overall cohort were (all P < .001) age (odds ratio [OR], 1.11), male sex (OR, 1.77), nadir CD4 cell count <200 cells/μL (OR, 4.46), and ART exposure (OR, 1.01). CONCLUSIONS Specific age-related NICMs and Pp were more common among HIV-infected patients than in the general population. The prevalence of Pp in HIV-infected persons anticipated Pp prevalence observed in the general population among persons who were 10 years older, and HIV-specific cofactors (lower nadir CD4 cell count and more prolonged ART exposure) were identified as risk factors. These data support the need for earlier screening for NICMs in HIV-infected patients.

Nonalcoholic Fatty Liver Disease in HIV-Infected Patients Referred to a Metabolic Clinic: Prevalence, Characteristics, and Predictors

BACKGROUND The prevalence and predictors of nonalcoholic fatty liver disease (NAFLD) in human immunodeficiency virus (HIV)-infected highly active antiretroviral therapy-experienced patients and the association of NAFLD with risk of cardiovascular disease and subclinical atherosclerosis are unknown. METHODS We performed a cross-sectional observational study. NAFLD was defined by liver-spleen attenuation values of <1.1 on computed tomography in persons who had neither evidence of chronic viral hepatitis nor a significant history of alcohol consumption. RESULTS We enrolled 225 patients; 163 (72.4%) were men. Mean (+/-SD) HIV infection duration was 145 +/- 60 months, and mean (+/-SD) body mass index (calculated as weight in kilograms divided by the square of height in meters) was 23.75 +/- 3.59. NAFLD was diagnosed in 83 patients (36.9% of the total cohort). The following variables were significantly associated with NAFLD in univariate analyses: sex, waist circumference, body mass index, cumulative exposure to nucleoside reverse-transcriptase inhibitors, visceral adipose tissue, homeostasis model assessment of insulin resistance index, serum alanine and aspartate aminotransferase levels, and ratios of total serum cholesterol to high-density lipoprotein cholesterol. Coronary artery calcium scores and a diagnosis of diabetes were not associated with NAFLD. In multivariable logistic regression analyses, factors associated (P<0.001) with NAFLD were higher serum alanine to aspartate ratio (odds ratio, 4.59; 95% confidence interval, 2.09-10.08), male sex (odds ratio, 2.49; 95% confidence interval, 1.07-5.81), greater waist circumference (odds ratio, 1.07; 95% confidence interval, 1.03-1.11), and longer nucleoside reverse-transcriptase inhibitor exposure (odds ratio, 1.12 per year of exposure; 95% confidence interval, 1.03-1.22). CONCLUSIONS NAFLD is common among HIV-infected persons who have the traditional risk factors for NAFLD (elevations in serum alanine level, male sex, and increased waist circumference) apparent. Exposure to nucleoside reverse-transcriptase inhibitors was an independent risk factor for NAFLD, with an 11% increase in the odds ratio for each year of use.

Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis.

The magnitude of the risk of incident type 2 diabetes (T2D) and metabolic syndrome (MetS) among patients with nonalcoholic fatty liver disease (NAFLD) is poorly known. We gauged the risk of developing T2D and MetS in patients with NAFLD diagnosed by either serum liver enzymes (aminotransferases or gamma‐glutamyltransferase [GGT]) or ultrasonography.

Coronary Aging in HIV-Infected Patients

BACKGROUND Human immunodeficiency virus (HIV)-infected patients often demonstrate accelerated aging processes. We investigated whether the vascular age of a cohort of stable HIV-infected patients receiving antiretroviral therapy (ART) was increased and sought out predictors of increased vascular age. METHODS In this cross-sectional study, 400 HIV-infected patients (mean age, 48 years) attending a cardiometabolic clinic underwent cardiac computed tomography imaging to identify coronary artery calcium (CAC). Vascular age was estimated on the basis of the extent of CAC by means of previously published equations. RESULTS Increased vascular age was observed in 162 patients (40.5%), with an average increase of 15 years (range, 1-43 years) over the chronological age. In univariable analyses, chronological age, male sex, systolic blood pressure, duration of ART, fasting glucose level, fasting serum triglyceride level, total cholesterol level, low-density and high-density lipoprotein cholesterol levels, hypertension, and the presence of the metabolic syndrome were associated with increased vascular age. In multivariable linear regression analyses, current CD4+ cell count was the only predictor of increased vascular age (beta = 0.51; P = .005). CONCLUSIONS Increased vascular age is frequent among HIV-infected patients and appears to be associated with CD4+ cell count. If these findings were to be confirmed in prospective trials, a positive response to ART with an increase in CD4+ cell count may become a marker of increased risk of atherosclerosis development.

Lipodystrophy and anti-retroviral therapy as predictors of sub-clinical atherosclerosis in human immunodeficiency virus infected subjects

BACKGROUND AND OBJECTIVE Although anti-retroviral therapy (ART) prolonged survival in HIV-infected persons, an increase in cardiovascular disease has also been observed. A frequent complication of ART is the development of lipodystrophy (LD) with its multiple phenotypes that may be associated with cardiovascular disease. We assessed the contribution of chronic HIV infection, ART use and LD to the presence of sub-clinical atherosclerosis as evaluated by coronary artery calcium (CAC) imaging. METHODS Observational cross-sectional study of 372 HIV-infected patients receiving ART who attended a cardiometabolic clinic (48.2+/-8-year old; 74% men). All patients underwent CAC surveillance with computed tomography and the Agatston score was used to quantitate CAC. Presence of CAC was defined as a score >10. Multivariable logistic regression was used to evaluate associations between HIV clinical factors, ART and LD with the presence of CAC. FINDINGS CAC was found in 134 patients (36%) with a median CAC score of 50 (range 10; 1243). Lipoatrophy alone (OR 3.82, 95% CI: 1.11; 13.1), fat accumulation alone (OR 7.65, 95% CI: 1.71; 37.17) and mixed lipodystrophy phenotypes (OR 4.36, 95% CI: 1.26; 15.01) were strongly associated with presence of CAC after adjusting for age, sex, hypertension and cumulative exposure to ART. CONCLUSION CAC is common among long-term ART users. The association between CAC and LD underscores the potential atherosclerosis risk inherent with ART and the need to undertake routine cardiovascular surveillance in patients treated with these drugs.

A frailty index predicts survival and incident multimorbidity independent of markers of HIV disease severity

Objectives:Aging with HIV is associated with multisystem vulnerability that might be well characterized by frailty. We sought to construct a frailty index based on health deficit accumulation in a large HIV clinical cohort and evaluate its validity including the ability to predict mortality and incident multimorbidity. Design and methods:This is an analysis of data from the prospective Modena HIV Metabolic Clinic cohort, 2004–2014. Routine health variables were screened for potential inclusion in a frailty index. Content, construct, and criterion validity of the frailty index were assessed. Multivariable regression models were built to investigate the ability of the frailty index to predict survival and incident multimorbidity (at least two chronic disease diagnoses) after adjusting for known HIV-related and behavioral factors. Results:Two thousand, seven hundred and twenty participants (mean age 46 ± 8; 32% women) provided 9784 study visits; 37 non-HIV-related variables were included in a frailty index. The frailty index exhibited expected characteristics and met validation criteria. Predictors of survival were frailty index (0.1 increment, adjusted hazard ratio 1.63, 95% confidence interval 1.05–2.52), current CD4+ cell count (0.48, 0.32–0.72), and injection drug use (2.51, 1.16–5.44). Predictors of incident multimorbidity were frailty index (adjusted incident rate ratio 1.98, 1.65–2.36), age (1.07, 1.05–1.09), female sex (0.61, 0.40–0.91), and current CD4+ cell count (0.71, 0.59–0.85). Conclusion:Among people aging with HIV in northern Italy, a frailty index based on deficit accumulation predicted survival and incident multimorbidity independently of HIV-related and behavioral risk factors. The frailty index holds potential value in quantifying vulnerability among people aging with HIV.

Aging with HIV vs. HIV seroconversion at older age: a diverse population with distinct comorbidity profiles.

Objective People aging with HIV might have different health conditions compared with people who seroconverted at older ages. The study objective was to assess the prevalence of, and risk factors for, individual co-morbidities and multimorbidity (MM) between HIV-positive patients with a longer duration of HIV infection, and patients who seroconverted at an older age. We compared estimates across both groups to a matched community-based cohort sampled from the general population. Methods We performed a case-control study including antiretroviral therapy (ART)–experienced patients who were HIV seropositive for ≥ 20.6 years (“HIV-Aging”), or who were seropositive for < 11.3 years (“HIV-Aged”) having access in 2013 at the Modena HIV Metabolic Clinic. Patients were matched in a 1:3 ratio with controls from the CINECA ARNO database. MM was defined as the concurrent presence of >2 NICM. Logistic regression models were constructed to evaluate associated predictors of NICM and MM. Results We analysed 404 HIV-Aging and 404 HIV-Aged participants in comparison to 2424 controls. The mean age was 46.7±6.2 years, 28.9% were women. Prevalence of HIV co-morbidities and MM were significantly higher in the HIV-positive groups compared to the general population (p<0.001) and a trend towards higher rates of MM was found in aging vs aged group. This difference turned to be significant in patients above the age of 45 years old (p<0.001). Conclusions People aging with HIV display heterogeneous health conditions. Host factors and duration of HIV infection are associated with increased risk of MM compared to the general population.

Surgical correction of HIV-associated facial lipoatrophy.

Lipodystrophy was first described in HIV-1-infected patients in 1998 [1–5]. The main clinical feature is subcutaneous fat loss or lipoatrophy of the face, limbs, and buttocks [6,7]. Patients can also experience fat accumulation within the abdomen, neck or breasts [8,9]. The pathogenesis of lipoatrophy appears to be multifactorial. Contributing factors are CD4þ lymphocyte cell count, HIV clinical stage, race, sex, exercise level, age at start of antiretroviral therapy [8], and the rapidity of its onset may depend on the individual total fat mass. The driving force behind lipoatrophy is undoubtedly the cumulative exposure to thymidine analogue drugs. These drugs, in particular stavudine and to a lesser extent zidovudine, block mitochondrial DNA polymerase function producing apoptosis of fat cells [9,10]. Earlier detection and treatment of HIV infection [11], as well as the use of antiretroviral drugs with less deleterious effects on body fat, make it reasonable to hypothesize a decrease in prevalence of lipodystrophy in the coming years.

Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV

Fatty liver, which frequently coexists with necro-inflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies.

HIV-Associated Lipodystrophy: Impact of Antiretroviral Therapy

In the late 1990s, reports of unusual changes in body fat distribution named ‘lipodystrophy’ (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.