Elisa Garlassi

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.

Hepatocellular Carcinoma in HIV-Infected Patients: Check Early, Treat Hard

PURPOSE Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. The aims of this study were to describe HCC tumor characteristics and different therapeutic approaches, to evaluate patient survival time from HCC diagnosis, and to identify clinical prognostic predictors in patients with and without HIV infection. PATIENTS AND METHODS A multicenter observational retrospective comparison of 104 HIV-infected patients and 484 uninfected patients was performed in four Italian centers. HCC was staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria. RESULTS Tumor characteristics of patients with and without HIV were significantly different for age, Eastern Cooperative Oncology Group performance status (PS) score ≤1, and etiology of chronic liver disease. Despite the similar potentially curative option rate and better BCLC stage at diagnosis, the median survival time was significantly shorter in HIV(+) patients. HIV(+) patients were less frequently retreated at relapse. Independent predictors of survival were: BCLC stage, potentially effective HCC therapy, tumor dimension ≤3 cm, HCC diagnosis under a screening program, HCC recurrence, and portal vein thrombosis. Restricting the analysis to HIV(+) patients only, all positive prognostic factors were confirmed together with HAART exposure. CONCLUSION This study confirms a significantly shorter survival time in HIV(+) HCC patients. The less aggressive retreatment at recurrence approach does not balance the benefit of younger age and better BCLC stage and PS score of HIV(+) patients. Thus, considering the prognosis of HIV(+) HCC patients, effective screening techniques, programs, and specific management guidelines are urgently needed.

Sorafenib for the treatment of unresectable hepatocellular carcinoma in HIV-positive patients

Few data are available on the safety and efficacy of sorafenib in HIV-infected patients with unresectable hepatocellular carcinoma (HIV-u-HCC) and concomitant highly active antiretroviral therapy (HAART). Between July 2007 and October 2010, 27 consecutive HIV-u-HCC patients were treated with sorafenib and concomitant HAART within the Gruppo Italiano Cooperativo AIDS e Tumori (GICAT). Three patients achieved a partial response, 12 achieved a stable disease, and 12 showed progression. The median time to progression and overall survival was 5.1 (range 0.5–13.3) and 12.8 (range 1.1–23.5) months, respectively. Grades 3–4 toxicities included diarrhea (four patients, 14.8%), hypertension (three patients, 11%), and hand-and-foot skin reaction (four patients, 14.9%). Most drug-related side effects were low grade and manageable. This retrospective study shows favorable survival data among HIV-u-HCC patients treated with sorafenib together with a reasonable safety profile.

Oxaliplatin Based Chemotherapy and Concomitant Highly Active Antiretroviral Therapy in the Treatment of 24 Patients with Colorectal Cancer and HIV Infection

BACKGROUND Although FOLFOX4 is considered the standard chemotherapy regimen for colorectal cancer (CRC), few data are available on its results in human immunodeficiency (HIV)-related CRC. The results were analyzed to evaluate feasibility and activity of FOLFOX4 plus highly active antiretroviral therapy (HAART) in metastatic CRC (mCRC) HIV-seropositive patients. PATIENTS AND METHODS From January 2002 to March 2007, 24 patients were selected among the CRC HIV-seropositive patients treated with FOLFOX4 and concomitant HAART within the Italian Cooperative Group on AIDS and Tumors (GICAT). RESULTS Four median cycles of chemotherapy were administered; the most common severe toxicity was neutropenia (37.5%). An overall response rate of 50% was observed; 4.2% of patients achieved complete response and 45.8% partial response. No opportunistic infections occurred during or immediately after chemotherapy. The median CD4+ count was 380 (range 220-570) at diagnosis. CONCLUSIONS To our knowledge, this is the largest study describing activity and tolerability of FOLFOX4 and HAART, in this setting. FOLFOX4 plus concomitant HAART resulted feasible and active also in HIV-seropositive patients. Moreover, the concomitant use of HAART did not to seem to increase the FOLFOX4 toxicity. This study suggests the good tolerability of the FOLFOX4, making it a reasonable option for combination with HAART.

Life expectancy in the immune recovery era: the evolving scenario of the HIV epidemic in northern Italy.

Introduction:National cohort and intercohort studies have been set to describe the differences of life expectancy (LE) of HIV-infected individuals. Objective:The aim of this study was to assess the impact of immune recovery (IR) on LE of patients with HIV undergoing combination antiretroviral therapy. Methods:In this retrospective observational study, outcome measure was LE of patients with HIV compared with LE of northern Italian population. Group categorizations were as follows: patients with no immune recovery (nIR), patients with IR, patients who are immune maintained, and pre-highly active antiretroviral therapy (HAART) and post-HAART. Abridged life tables were constructed from age-specific mortality rates (per 1000 person years) to estimate LE from the age of 20–55 years. Results:A total of 9671 patients, 71% men, were included. After 2005, we assisted to a rapid increase in the overall rate of patients attaining IR in the community coupled with a progressive decrease of AIDS death, but not of non-AIDS deaths. In a 40-year-old patient, LE was 38.10 years [standard error (SE) = 2.60], 30.08 years (SE = 0.98), and 22.9 (SE = 0.69) in the IR, post-HAART group and nIR, respectively, compared with 41.38 years of the general Italian population. An approximately 5-year gap in LE was observed in IR patients. Discussion:We describe IR at a “community” level, related to calendar year and apparent 10 years after HAART introduction. HAART community IR is significantly influencing LE and is associated with the changing clinical picture of HIV disease. An increasing gradient of LE exists between nIR, post-HAART, and IR groups, with the latter, above the age of 40 years only, reaching LE of general population.

CD8 T-cell activation is associated with lipodystrophy and visceral fat accumulation in antiretroviral therapy-treated virologically suppressed HIV-infected patients.

Objective:HIV-infected patients receiving antiretroviral treatment frequently accumulate fat at the abdominal level. It is unknown whether T-cell activation and immune phenotypes are associated with fat accumulation. Thus, the aim of the study was to search for an association between the presence of clinical lipodystrophy (LD), visceral and subcutaneous abdominal adipose tissue amount (VAT and SAT), and peripheral T-cell immune phenotypes. Design:Cross-sectional study including 87 HIV-infected antiretroviral therapy–treated virologically suppressed and immune-reconstituted patients. Methods:The patients were evaluated for clinical LD, VAT, SAT, homeostasis model of insulin resistance, and coronary artery calcium score (>10). T-cell activation (CD8/CD38), differentiation (CD4/CD8/CCR7/CD45RA), and expression/activation of the interleukin-7 (IL-7)/IL-7R system (CD4/CD8/CD127, IL-7, and CD4/CD8/pStat-5) were assessed by cytometry. Results:In multivariable analyses, CD8+ T-cell activation (CD38+) was associated with lipoatrophy and central fat accumulation (respectively, &bgr; = 5.63, P = 0.005, and &bgr; = 4.19, P = 0.020). This was also the case for IL-7R expressing CD8+ T cells (CD127+) for lipoatrophy &bgr; = 12.8, P = 0.003, and for central fat accumulation &bgr; = 9.45, P = 0.016. CD8+ T-cell activation was also associated with VAT/total adipose tissue (&bgr; = 0.01, P = 0.002) and SAT/VAT ratios (&bgr; = −0.014, P = 0.015). As expected, VAT/total adipose tissue was an independent risk factor for homeostasis model of insulin resistance (r = 0.364, P = 0.028) and cardiovascular risk (coronary artery calcium, r = 0.406, P = 0.002). Conclusions:CD8+ T-cell activation was associated with LD and the relative amount of VAT in antiretroviral therapy–controlled, virologically suppressed, HIV-infected patients. We propose that CD8 activation may be involved in the accumulation of central fat frequently observed in these patients, with resulting increased cardiometabolic risk.

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.

Switching to darunavir/ritonavir monotherapy vs. triple-therapy on body fat redistribution and bone mass in HIV-infected adults: the Monarch randomized controlled trial

Changes in body fat distribution and bone mass in HIV-infected patients may be associated with long-term use of nucleoside reverse transcriptase inhibitors (NRTIs). The Monarch trial recruited 30 patients receiving non-nucleoside reverse transcriptase inhibitor or protease inhibitor−based highly active antiretroviral therapy, with HIV RNA <40 copies/mL. Patients were randomized to either darunavir/ritonavir 800/100 mg once daily monotherapy or darunavir/ritonavir 800/100 mg once daily + two NRTIs. Bone mass, peripheral lipoatrophy and central fat accumulation were assessed using dual-energy X-ray absorptiometry scanning, supplemented by computed tomography scans. Median age was 43 years, 77% were men. Visceral adipose tissue remained stable from baseline to Week 48 in the whole group (p = 0.261) with no significant difference between arms (p = 0.56). There was a significant reduction in insulin resistance (HOMA-IR, p = 0.013) over 48 weeks in the whole group, but not of body mass index (p = 0.24). In the darunavir/ritonavir monotherapy arm, there was a small but significant increase in both lumbar and femur bone mineral density at 48 weeks and was observed after correction for baseline values. The absolute change in lumbar bone mineral density at 48 weeks was more pronounced in the darunavir/ritonavir arm compared with the darunavir/ritonavir + 2NRTIs arm. In this study, discontinuing nucleoside analogues and switching to darunavir/ritonavir monotherapy was associated with a small but statistically significant increase in bone mineral density, but stable levels of limb fat and visceral adipose tissue.

Combined Use of Waist and Hip Circumference to Identify Abdominally Obese HIV-Infected Patients at Increased Health Risk

Objectives To determine whether for a given waist circumference (WC), a larger hip circumference (HC) was associated with a reduced risk of insulin resistance, type 2 diabetes (T2D), hypertension and cardiovascular disease (CVD) in HIV-infected patients. A second objective was to determine whether, for a given WC, the addition of HC improved upon estimates of abdominal adiposity, in particular visceral adipose tissue (VAT), compared to those obtained by WC alone. Methods HIV-infected men (N = 1481) and women (N = 841) were recruited between 2005 and 2009. WC and HC were obtained using standard techniques and abdominal adiposity was measured using computed tomography. Results After control for WC and covariates, HC was negatively associated with risk of insulin resistance (p<0.05) and T2D [Men: OR = 0.91 (95% CI: 0.86–0.96); Women: OR = 0.91 (95% CI: 0.84–0.98)]. For a given WC, HC was also negatively associated with a lower risk of hypertension (p<0.05) and CVD [OR = 0.94 (95% CI: 0.88–0.99)] in men, but not women. Although HC was negatively associated with VAT in men and women after control for WC (p<0.05), the addition of HC did not substantially improve upon the prediction of VAT compared to WC alone. Conclusions The identification of HIV-infected individuals at increased health risk by WC alone is substantially improved by the addition of HC. Estimates of visceral adipose tissue by WC are not substantially improved by the addition of HC and thus variation in visceral adiposity may not be the conduit by which HC identifies increased health risk.

Morphological and Metabolic Components of Lipodystrophy in Various Nevirapine-Based Highly Active Antiretroviral Therapy (HAART) Regimens

AbstractBackground: Morphological abnormalities (lipoatrophy and central fat accumulation) and metabolic changes (dyslipidaemia and glucose regulation impairment) have emerged as components of lipodystrophy and as major tolerability issues with long-term use of highly active antiretroviral therapy (HAART) in HIV-positive patients. Protease inhibitors (PIs) are recognized as having the greatest impact in terms of metabolic complications, followed by nucleoside reverse transcriptase inhibitors, while the non-nucleoside reverse transcriptase inhibitors (NNRTIs) have the least impact. In particular, regimens based on the NNRTI nevirapine have been shown to achieve significant metabolic benefits and may help to improve dyslipidaemia. Improvements in body shape changes associated with lipodystrophy have also been reported when nevirapine replaced a PI in long-term triple therapy. Objective: The objective of this cross-sectional observational (‘real-world’) study was to investigate the effect of three HAART regimens plus stable nevirapine therapy on morphological and metabolic components of lipodystrophy in HIV-infected patients. Methods: Consecutive patients (aged >18 years) with serologically documented HIV infection, who had received HAART for at least 2 years and who had been diagnosed with lipodystrophy, were followed up as outpatients at the metabolic clinic of the University of Modena and Reggio Emilia, Modena, Italy. Patients received stable nevirapine therapy plus fixed-dose combinations of tenofovir disoproxil fumarate plus emtricitabine (Truvada®; TVD), zidovudine plus lamivudine (3TC) [Combivir®; CBV], or abacavir plus lamivudine (Kivexa®; KVX). Multivariate regression analyses were performed to analyse predictors of four components of lipodystrophy: lipoatrophy using leg fat mass measured by dual-emission x-ray absorptiometry (DXA), fat accumulation using waist circumference, dyslipidaemia using apolipoprotein (Apo)B/ApoA1 ratio, and glucose intolerance using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Results: Overall, 101 patients were enrolled (TVD group = 61, CBV group = 20, KVX group = 20); 191 observations were analysed. Male sex was associated with reduced leg fat mass, while age and body mass index (BMI) were associated with increased leg fat mass (all p<0.05). Leg fat mass and male sex were associated with increased waist circumference (p < 0.001 for both). Leg fat mass predicted reduced ApoB/ApoA1 ratio, while age and BMI predicted increased ApoB/ApoA1 ratio (all p<0.05). BMI predicted HOMA-IR increase (p = 0.0017). No differences in lipoatrophy, central fat accumulation, dyslipidaemia or glucose metabolism were observed among any of the three different nevirapine plus nucleoside backbone groups (TVD, CBV or KVX). Conclusion: HAART including nevirapine has a limited impact on components of lipodystrophy in patients with HIV infection. Further studies are needed to verify if nevirapine overcomes the expected distinct lipodystrophy risk profile associated with different nucleoside backbone therapies.