Nicola Squillace

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.

Severity of Lipodystrophy Is Associated with Decreased Health-Related Quality of Life

The impact of lipodystrophy (LD) on quality of life is high, but it has not been demonstrated in literature. The objective of the study was to assess the impact of LD on the health-related quality of life (HRQOL) in HIV-infected people on highly active antiretroviral therapy (HAART). Patients with LD phenotype defined by the Multicenter AIDS Cohort Study (MACS) were included. Three different methods were used to define LD severity: both patient and physician evaluation using the HIV Outpatient Study (HOPS) severity scales and the Lipodystrophy Case Definition (LDCD). The HRQOL was evaluated by MOS-HIV Health Survey. Four hundred one patients on HAART for a mean of 108 +/- 52 months were evaluated for LD at the Metabolic Clinic of Modena and Reggio Emilia University were enrolled from January 2003 to July 2006. According to self-perceived or physician-based HOPS, 106 (26.5%) and 122 (30.4%) patients had severe LD. Females had significantly more severe LD. Few HRQOL scores correlated to LD severity using the physician-based score (both HOPSph and LDCD), while all the HRQOL scores correlated with LD severity when a patient-based score was used (HOPSpt). In multiple linear regression analysis, Mental Health HRQOL score, gender, body mass index, age, body image satisfaction were independent predictors of patient-based (HOPSpt) LD, while none of the HRQOL scores, but female gender, age, waist-to-hip ratio, limb fat, and body image satisfaction were correlated with physician-estimated HOPSph LD severity. HRQOL was strongly correlated with LD severity when a patient-based score was used. For an overall assessment of the impact of LD on HIV-infected people, both patient-based and physician-based measures are required.

Multidisciplinary Approach to the Treatment of Metabolic and Morphologic Alterations of HIV-Related Lipodystrophy

Abstract Background: Treatment for metabolic and morphologic alterations in HIV-related lipodystrophy include medical therapy, physical exercise, and surgical interventions. Method: We assessed the efficacy and safety of a comprehensive multidisciplinary approach for treating morphological and metabolic alterations of the lipodystrophy syndrome in consecutive patients attending the Metabolic Clinic (MC) of the University of Modena and Reggio Emilia who had at least 2 evaluations over a 48-week period. 245 patients were evaluated: 143 (62.4%) were men, 74 (36.1%) presented with lipoatrophy, 10 (4.9%) with fat accumulation, 93 (45%) with mixed forms, 24 (11.3%) had hypercholesterolemia (LDL >160 mg/dL), 87 (38%) had hypertriglyceridemia (TG >150 mg/dL), 13 (5.7%) had diabetes (glucose >126 mg/dL), and 78 (44%) had insulin resistance (HOMA-IR >4). Results: At follow-up, a significant improvement was observed in both objective and subjective variables. Anthropometric improvement was observed in waist to hip ratio, waist circumference, and right and left cheek dermal thickness measurements. A nonsignificant improvement was observed in fat and lean regional mass by DEXA; CT showed improvement in visceral and subcutaneous adipose tissue. Glucose, HOMA-IR, total cholesterol, and APO B improved. Subjective variables improved in aesthetic satisfaction. Conclusion: We conclude that the medical and surgical interventions proposed in this multidisciplinary therapeutic approach are efficacious and safe in the management of lipodystrophy.

Detectable HIV viral load is associated with metabolic syndrome.

Background:The aim of our study was to assess the association between HIV viral load (HIV-VL) and metabolic syndrome (MS) in a cohort of HIV-infected patients. Methods:This is a cross-sectional study including 1324 consecutive HIV-infected patients on stable antiretroviral therapy regimens. Results:Variables significantly associated with MS in univariate analysis were: age [mean ± SD: 47.04 ± 7.41 vs 44.07 ± 6.82, (P < 0.0001)]; male sex [224 (69.35%) vs 614 (61.34%) (P = 0.009)]; Apo B (mg/dL) [111.51 ± 29.64 vs 100.57 ± 31.22, (P < 0.0001)]; homeostasis model assessment equation [median (interquartile range), 5.14 (3.00-8.15) vs 2.95 (1.93-4.57), (P < 0.0001)]; body mass index [25.17 ± 4.40 vs 22.80 ± 3.38, (P < 0.0001)]; protease inhibitor current use (%) [199 (61.61) vs 529 (52.85), (P = 0.006)]; and log10 HIV-VL [2.17 ± 0.94 vs 2.02 ± 0.79, (P = 0.0048)]. MS associated variables in multivariable analysis were: log10 HIV-VL [odds ratio (OR): 1.25; P = 0.003], age (per 10-year increment) [OR: 1.60; P < 0.0001], homeostasis model assessment equation ≥3.8 [OR: 2.77; P < 0.0001]. Conclusions:Persistent viremia is a significant predictor for the development of MS. Viral control through effective antiretroviral therapy is paramount not only for the control of HIV disease progression but also for the prevention of MS and associated cardiovascular disease.

Prevalence of and risk factors for pubic lipoma development in HIV-infected persons.

Background:The natural history of HIV-associated body habitus changes is unclear. In this report, we describe a novel manifestation of HIV-associated lipoaccumulation. Methods:We noted the presence of suprapubic fat pads (pubic lipomas [PLs]) in several patients with preexisting HIV-associated body habitus abnormalities. Subsequently, we evaluated the prevalence of and associated risk factors for development of PLs by undertaking an observational cross-sectional study among patients with known lipodystrophy who attended a metabolic clinic in northern Italy. Inclusion criteria were a physician-confirmed diagnosis of lipodystrophy according to the Multicenter AIDS Cohort Study definition and, for those affected with PL, a readily noticeable PL on physical examination. Results:We evaluated 582 patients with lipodystrophy: 214 female (36.7%) and 368 male (63.3%). The overall PL prevalence was 9.4% (95% confidence interval [CI]: 7.2% to 12.1%; P < 0.0001). PLs were more common among obese than nonobese individuals (34.5%, 95% CI: 17.9% to 5l.3% vs. 8%, 95% CI: 5.9% to 10.6%, respectively; P < 0.0001) and those with preexisting dorsocervical fat pads, commonly called “buffalo humps” (BHs) (18.5%, 95% CI: 12.7% to 25.4% vs. 6.1%, 95% CI: 4.03% to 8.83%, respectively, P < 0.0001; relative risk = 3.02, 95% CI: 1.84% to 4.96%, P < 0.0001). The PL prevalence in the nonobese HIV-infected population (body mass index [BMI] <30, n = 550) was 8.0% (95% CI: 5.9% to 10.6%; P < 0.0001). Logistic regression analyses identified the following factors as associated with a greater likelihood for PL: BMI >30 (β = 0.18, SE = 0.04; P < 0.001), female gender (β = 1.06, SE = 0.31; P < 0.001), and shorter duration of HIV infection (β = −0.005, SE = 0.003; P = 0.04). We used a chain graph model to evaluate risk factors for BH and PL simultaneously. A nonnull interaction between these entities was evident, and this association seemed to be independent of factors positively associated with both (BMI and gender). Conclusions:PL is a newly recognized manifestation of HIV-associated lipoaccumulation that is more likely to occur among those with coexisting dorsocervical fat pads, suggesting the possibility of a common pathogenesis between the 2 entities. Likewise, PLs are more common among women, obese individuals, and those with a shorter duration of HIV infection. We suggest that PL should be considered part of the HIV-associated lipodystrophy syndrome.

Glomerular filtration rates in HIV-infected patients treated with and without tenofovir: a prospective, observational study.

OBJECTIVES The aim of our study was to assess the impact of plasma HIV-1 RNA level [viral load (VL)] variation and tenofovir exposure on kidney functions by analysing changes in calculated glomerular filtration rates (GFRs) over a 48 week period in patients with mild renal impairment. PATIENTS AND METHODS A prospective observational study that included data from all consecutive HIV-infected patients who attended a metabolic clinic was conducted. Included were adult, antiretroviral (ARV)-experienced, tenofovir-naive patients, whose kidney functions were evaluated by calculated GFR using the simplified Modification of Diet in Renal Disease study equation (MDRD). Tenofovir-exposed patients were patients who initiated tenofovir therapy at baseline and tenofovir-unexposed patients were patients whose ARV therapy did not include tenofovir. Participants were stratified into three sub-groups according to the plasma HIV-1 RNA (VL) changes observed: sub-groups 1, 2 and 3 were patients with stable VL < or =50 copies/mL, >0.5 log(10) VL increases and >0.5 VL log(10) decreases, respectively. RESULTS Ninety-nine patients were enrolled and included in the analysis. Within the tenofovir-unexposed group, GFRs remained stable (ANOVA, P = 0.94) over the follow-up period. Within the tenofovir-exposed group, mean GFR changes varied significantly by sub-group (ANOVA, P < 0.01). In particular, GFR changes in sub-group 3 (+8.4 +/- 12.4 mL/min) were different from those seen in sub-group 1 (-1.0 +/- 8.8 mL/min) (P < 0.05) and sub-group 2 (-4.6 +/- 8.8 mL/min) (P < 0.01). CONCLUSIONS Observed improvements in GFR that occurred as a consequence of highly active ARV therapy-induced viral suppression may have more than offset any potential negative effects of tenofovir on renal function.

Hyperhomocysteinaemia in HIV-infected patients: determinants of variability and correlations with predictors of cardiovascular disease.

We evaluated hyperhomocysteinaemia (HHcy) in a cohort of HIV‐infected patients in order to assess its relation to cardiovascular risk (CVR) and identify determinants of HHcy variability.

Metabolic disorders induced by highly active antiretroviral therapy and their relationship with vascular remodeling of the brachial artery in a population of HIV-infected patients

Antiretroviral therapy has positively modified the natural history of HIV infection; but this treatment can induce metabolic abnormalities, including dyslipidemia, fat redistribution, high blood pressure, and insulin resistance. The metabolic syndrome, a clustering of the metabolic disorders, is frequently detected among HIV patients, especially those on antiretroviral treatment. All the arteries can modify their diameter in response to a chronic injury. This process, defined vascular remodeling, was demonstrated for the brachial artery. It is well known that the diameter of the brachial artery was correlated with the number of the elements of the metabolic syndrome and was associated with the severity of coronary artery disease. On this basis, we postulate that brachial arterial enlargement may be a process potentially correlated with the metabolic disorders induced by antiretroviral therapy. We tested this hypothesis in a large population of HIV-infected patients in which we measured brachial artery diameter, as an indicator of artery remodeling, by noninvasive, ultrasonographic technique. Our population consisted of 570 patients, with a mean age of 46.3 +/- 7.1 years. All the patients were chronically treated with highly active antiretroviral therapy. Brachial artery diameter was correlated with insulin resistance, evaluated by the homeostasis model assessment of insulin resistance index (r = 0.18, P < .0001). There was a significant linear increase in brachial artery diameter as the number of components of the metabolic syndrome increased: brachial artery diameter for those with 0, 1, 2, 3, or + characteristics was 39.3 +/- 7.2, 41.0 +/- 6.8, 42.0 +/- 7.3, and 43.8 +/- 7.9 mm, respectively (P < .001 for trend). In multivariable logistic regression analysis, brachial artery diameter was independently correlated with the presence of metabolic syndrome. Our results are in line with the hypothesis that, among HIV-infected patients chronically treated with antiretroviral therapy, those with a larger brachial artery diameter are at high risk for metabolic disorders, including a more severe insulin resistance and the presence of metabolic syndrome.

Brachial and central blood pressure in HIV-infected subjects

HIV infected subjects present an unfavorable cardiovascular (CV) risk profile that is determined by the infection itself, highly active anti-retroviral therapy (HAART) and other factors, such as chronic kidney disease (CKD). Information is scant and contradictory on whether these factors are associated with arterial stiffness and blood pressure (BP) alteration. Our study aimed to evaluate those parameters in HIV-positive subjects both with and without HAART and with and without CKD, which was defined as the presence of microalbuminuria with a normal glomerular filtration rate. We enrolled 94 HIV-infected subjects without known CV risk factors and compared them with 37 control subjects. We recorded brachial and central BP (pulse wave analysis) and pulse wave velocity ( SphygmoCor). HIV-positive subjects of similar ages and with similar BP values showed central pulse pressure values that were significantly greater than those of controls; this was also the case for the Aix value. Central systolic and pulse pressure values and Aix were significantly greater in HIV-positive subjects with HAART and CKD than in the other HIV-positive subgroups and control subjects. PWV was also superimposable between groups when the data were analyzed relative to the presence of HAART and CKD. Our study shows that the unfavorable CV risk profile associated with HIV infection includes an increase in both central BP and Aix. The central BP increase seems to be favored by renal damage, which apparently has a role in the early stages of the disease.

A Case of Cerebrospinal Fluid Viral Escape on a Dual Antiretroviral Regimen: Worth the Risk?

TO THE EDITOR—Among human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), incomplete viral suppression in cerebrospinal fluid (CSF) may occur even with undetectable plasma viremia [1–4]. Treatment simplification with “less-drug regimens” may favor adherence and reduce toxicity, but raises concerns on lower central nervous system (CNS) drug penetration and subsequent CNS viral escape [5, 6], as in the case we report herein. A 47-year-old HIV-infected woman, receiving different ART regimens since 2002, in 2007 withdrew emtricitabine due to lower-limb neuropathy, and maintained plasma viral control with darunavir/ritonavir 600/100 mg twice daily and tenofovir (in February 2013: HIV RNA <40 copies/mL; CD4 lymphocyte count, 508 cells/μL). InMarch 2013, shewas hospitalized after complaining of lower-limb weakness and pain, headache, dizziness, and dysarthria. Brain magnetic resonance imaging (MRI) showed extensive signal abnormalities (Figure 1A); lumbar puncture revealed CSF total protein of 76 mg/dL with oligoclonal immunoglobulin G bands, normal glycorrhachia, and cell count. CSF cultures and examinations for opportunistic infections (Cryptococcus neoformans, Epstein-Barr virus, cytomegalovirus, human herpesvirus 8, JC virus) were negative, and the CSF HIV RNA load was 2715 copies/mL. Genotypic testing showed the presence of multiple protease inhibitor (PI)–associated mutations (V32I, I54V, V82A, I84V, L10I, L33F, K20R, M36I) conferring intermediate resistance to darunavir, and nucleoside/nucleotide reverse transcriptase inhibitor–associated mutations (M41L, T215Y, V90I), conferring intermediate resistance to tenofovir. Thus, antiretroviral treatment was changed with darunavir/ritonavir 600/ 100 mg twice daily plus raltegravir 400 mg twice daily plus etravirine 200 mg twice daily. Two months later, the patient reported significant symptom improvements: the CD4 count was 759 cells/μL; both plasma and CSF HIV RNAwere undetectable. One year later, brain MRI showed clear improvements in radiological signs (Figure 1B). To our knowledge for the first time, here we describe a case of CSF viral escape in an HIV-infected patient on suppressive ART with a dual regimen. Previous cases of CSF viral escape (with or without neurological symptoms) were reported in patients with incomplete plasma HIV RNA suppression, or treated with suboptimal ART [1, 2]. Compared to others, this case clearly illustrates the improvements of neurological symptoms and radiological signs (Figure 1A and 1B) after switching ART, guided by genotypic resistance testing on CSF. Recently, a higher CNS penetration effectiveness ranking score of ART has been associated with lower levels of CSFHIVRNA, as well as improvements in neurological and cognitive functions [7, 8]. Meanwhile, new therapeutic schemes have been proposed for patients on suppressive therapy to reduce toxicity and costs, such as switching to dual regimens or to boosted PI monotherapy [5,9].These approaches may, however, be limited by lower CNS drug penetration, potentially leading to CSF viral escape (already described with boosted PI monotherapy) [5, 6]. In this report, the results of HIV genotyping in CSF suggest a CNS virus compartmentalization, with subsequent selection of