A. Pellicelli

Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial

BACKGROUND/AIMS To evaluate the therapeutic efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. METHODS One hundred and fifty-one patients were randomly assigned to receive either recombinant interferon alpha-2b (nine million units three times per week) and lamivudine (100 mg/daily per os) for 24 weeks or lamivudine alone (100 mg/daily per os) for 52 weeks. Patients were followed up for a further 48 weeks. RESULTS Sustained HBeAg seroconversion with undetectable serum levels of HBV DNA was observed in 25 of 76 patients (33%) treated with the combination therapy and in 11 of 75 patients (15%) treated with monotherapy (P=0.014). Histological improvement defined as a reduction of at least two points in the inflammation score as compared with pretreatment score was observed in 35 of 76 patients (46%) treated with combination therapy and in 20 of 75 patients (27%) treated with monotherapy (P=0.021). Both therapeutic regimens were well tolerated. CONCLUSIONS Six-month treatment with interferon alpha-2b and lamivudine in combination appeared to increase the rate of sustained HBeAg seroconversion compared to 1-year lamivudine monotherapy. However, the potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Primary Pulmonary Hypertension in HIV Patients: A Systematic Review

The relationship between grade of pulmonary hypertension and factors associated with human immunodeficiency virus among patients with HIV infection is poorly documented. This report documents the most extensive attempt made thus far to determine whether a relationship exists between degree of pulmonary hypertension and the following conditions: HIV risk factor, degree of immunosuppression, presence or absence of AIDS, and presence or absence of liver cirrhosis. A retrospective study involving a search of the published literature on primary pulmonary hypertension among HIV cases from 1987 to 1998, using the Medline and Aidsline databases was conducted. Patients for whom secondary causes of pulmonary hypertension could be excluded were selected, and the following information for each was recorded: age, gender, risk factors for HIV infection, HIV disease stage according to the Centers for Disease Control, previous oppor tunistic and neoplastic diseases, CD4+ cell count (cells/L), presence or absence of liver cirrhosis, pulmonary systolic artery pressure level, and lung pathology specimens. Information about the patients survival time was also recorded. Seventy-six patients were judged to have primary pulmonary hypertension and were included in the study. While no correlation was found between pulmonary systolic artery pressure level and CD4+ cell counts, a statistically significant difference was found between HIV-positive patients with and without AIDS as determined by the Centers for Disease Control criteria with regard to the degree of pulmonary hypertension, expressed as pulmonary systolic artery pressure level (85.4 ± 17 mm Hg vs 71.8 ± 15 mm Hg, p < 0.013). Although a higher PAPS was present in HIV cirrhotic patients, a statistically significant difference was not found between degree of pulmonary hyper tension and evidence of hepatic cirrhosis (85 ±21 mm Hg vs 73.1 ± 15 mm Hg, p < 0.062). Patients with AIDS and primary pulmonary hypertension present a higher degree of pulmonary hypertension than non-AIDS patients. Pulmonary hypertension associated with HIV seems to be related to a cytokine-related stimulation and proliferation of endothelium. High levels of cytokines present in AIDS patients can favor pulmonary hypertension, but the role of a host response to HIV—determined by one or more HLA subtypes—is suspected to enhance high cytokine production levels.

Intensity of Myocardial Expression of Inducible Nitric Oxide Synthase Influences the Clinical Course of Human Immunodeficiency Virus-Associated Cardiomyopathy

BACKGROUND Increased levels of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) have been reported in patients with dilated cardiomyopathy. We investigated the myocardial expression of TNF-alpha and iNOS in patients with HIV-associated cardiomyopathy (HIV-DCM) compared with patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS Endomyocardial biopsy specimens from 82 HIV-DCM and 80 IDCM patients were processed for determination of the immunostaining intensity of TNF-alpha and iNOS and for virological examination. Negative controls were derived from autopsy myocardium specimens from 32 HIV-negative patients without known heart disease. The mortality rate for congestive heart failure between groups according to the intensity of iNOS staining was also evaluated. The mean intensity of both TNF-alpha and iNOS staining was greater in patients with HIV-DCM (0.81 and 1.007, respectively) than in patients with IDCM (0.44 and 0.49, respectively) and controls (0.025 and 0.027, respectively). The staining intensity of both TNF-alpha and iNOS was inversely correlated with CD4 count. The staining intensity of iNOS was greater in HIV-DCM patients with HIV/coxsackievirus B3 (CVB3) or with HIV/cytomegalovirus coinfection than in IDCM patients showing infection with CVB3 and adenovirus alone. The staining intensity of iNOS correlated to mortality rate, because it was higher in HIV-DCM patients and, in particular, in those with an optical density unit >1. CONCLUSIONS Cytokine activation seems to play a significant pathogenetic role in both HIV-DCM and IDCM. In HIV-DCM patients, the state of immunodeficiency may favor the selection of viral variants of increased pathogenicity, influencing the clinical course of cardiomyopathy by enhancement of the inflammatory process.

Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: Potent antiviral activity but no clinical benefit if treatment is given late

BACKGROUND We evaluated efficacy and safety of sofosbuvir and daclatasvir±ribavirin in liver transplant recipients with severe recurrent hepatitis C. METHODS Patients included in an international compassionate use programme for treatment with sofosbuvir and daclatasvir±ribavirin for 24 weeks were prospectively studied. Serum hepatitis C virus RNA was measured at treatment weeks 4, 12, and 24 and during follow-up at weeks 4, 8, and 12. RESULTS Twelve patients (3 with fibrosing cholestatic hepatitis and 9 with cirrhosis; median model for end-stage liver disease score 20) received sofosbuvir 400mg/day+daclatasvir 60mg/day, and 6 patients (50%) also received ribavirin 200-800mg/day. Nine patients completed 24 weeks of treatment (75%), and all had undetectable hepatitis C virus RNA at week 24; 3 patients died (25%, liver failure, gastrointestinal bleeding and sepsis); 4 patients experienced severe liver disease-related adverse events. Post-treatment hepatitis C virus RNA was available for 5 patients (week 8, n=2; week 4, n=3) and was undetectable in all cases. Mean Child-Pugh score and albumin level improved significantly at week 24. No changes in immunosuppressant doses were needed. CONCLUSION All-oral sofosbuvir plus daclatasvir combination shows high virological efficacy in liver transplant recipients and does not interact with immunosuppressants. All adverse events were unrelated to study drugs. These data strongly suggest that this combination must be initiated before decompensation.

HIV-Associated Coronary Arteritis in a Patient with Fatal Myocardial Infarction

To the Editor: Coronary disease has been reported previously in patients infected with the human immunodeficiency virus (HIV) who are receiving protease inhibitors1 or who are also infected with cy...

Role of Human Immunodeficiency Virus in Primary Pulmonary Hypertension Case Reports

Previous cases of pulmonary hypertension (PH) in human immunodeficiency virus (HIV) infection have been reported in the literature. The role of HIV in PH is still debatable. The purpose of this report was to analyze whether HIV plays a direct or indirect role in PH pathogenesis. Between February and November 1997, 56 HIV-infected patients with cardiac symptoms and signs were studied by serial color Doppler echocardiography. In four patients (7.1%), PH not related to other well-known associated conditions, was disclosed. In spite of a low serum HIV RNA viral load and a high-efficacy antiretroviral therapy, including a protease inhibitor in two patients, PH developed and worsened. It could be hypothesized that in some patients with an individual immunogenetic predis position, a high secretion of cytokines and endothelin-1 stimulated by an unidentified pathogen different from HIV could lead to PH. Antiretroviral therapy seems not to prevent or reduce right ventricle pressure gradient in PH.

Pathogenesis of HIV‐Related Pulmonary Hypertension

Abstract: Human immunodeficiency virus (HIV)‐related pulmonary hypertension (HRPR) is a cardiovascular complication of HIV infection that has been recognized in the last years with increasing frequency. The etiology of HRPH is unknown. All the attempts to isolate HIV on pulmonary vessels in HRPH patients failed, and an indirect role for HIV in this disease has been hypothesized. Current theories on the pathogenesis focus on abnormalities of endothelial and smooth muscle cells of pulmonary vasculature. Endothelial and smooth muscle cell injury could be due to a high production or to a reduced clearance of cytokines in these patients. In fact, in several studies high levels of ET‐1, IL‐1α, IL‐6 and PDGF in primary pulmonary hypertension (PPH) and in HRPH have been found. HIV gp 120 could induce the production of these cytokines by a stimulation of monocytes/macrophages. A high α1‐adrenoreceptors stimulation of pulmonary vessels could be also implicated in the pathogenesis of HRPH. Chronic hypoxia is observed with increased frequency in HIV patients, and this could induce a chronic stimulation of α1‐receptors of pulmonary vasculature with typical pathological changes. However, only a small percentage of HIV− patients develop HRPH. This observation suggests the existence of an idiosyncratic susceptibility to the development of vascular disease. This susceptibility could have a genetic basis, and might be determined by particular major histocompatibility complex alleles.

Highly active antiretroviral therapy compared with HAART and bosentan in combination in patients with HIV-associated pulmonary hypertension

Pulmonary arterial hypertension (PAH) is an increasingly recognised complication of HIV disease. The effects of highly active antiretroviral therapy (HAART) on the clinical course of HIV-associated PAH are still debated.1 Bosentan, a dual endothelin 1 receptor antagonist, may be an effective approach to treatment of PAH in both HIV-uninfected and HIV-infected patients.2–4 We report the results of an open-label, six-month prospective,observational, preliminary study of previously untreated HIV-infected patients with PAH. They were followed up to assess the effect of HAART compared with HAART and bosentan in combination on their exercise capacity and cardiopulmonary haemodynamic parameters. Previously untreated HIV-infected patients with PAH were elegible for the study. The patients were screened by clinical examination and tranthoracic echocardiography. Patients with an echocardiographic right ventricular systolic pressure > 35 mm Hg underwent right heart catheterisation. PAH was defined on the basis of mean pulmonary artery pressure (mPAP) at rest > 25 mm Hg, pulmonary capillary wedge pressure 240 dyn·s·cm−5 by right heart catheterisation.4 Exclusion criteria were age < 18 years; history of drug addiction and use of drugs known to have a definite cardiotoxic action (for example, cocaine and amphetamines); recent HIV-associated opportunistic infections; previous treatment with antiretroviral or immunomodulating drugs, or both; history of chronic obstructive pulmonary disease (assessed by analysis of clinical records and by pulmonary function tests); previous congenital or acquired heart disease (assessed by analysis of clinical records …

Epicardial Adipose Tissue is Related to Carotid Intima-Media Thickness and Visceral Adiposity in HIV-Infected Patients with Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome

BACKGROUND High cardiovascular risk and accelerated atherosclerosis are associated with human immunodeficiency virus (HIV). Recently, the use of highly active antiretroviral therapy (HAART) for the treatment of HIV infection is correlated with the development of HAART-associated metabolic syndrome and lipodystrophy (LDS). Detection of epicardial fat thickness, new index of visceral adiposity in non HIV-infected patients, might be important as diagnostic tool in HIV-infected patients on HAART. OBJECTIVE Primary objective of this study was to evaluate whether echocardiographic epicardial adipose tissue is related to visceral adipose tissue (VAT) and Carotid Intima-Media Thickness (IMT), index of atherosclerosis in HIV-infected patients on HAART with LDS. DESIGN We studied 60 consecutive HIV-infected subjects with HAART-associated metabolic syndrome and LDS and 45 HIV-infected subjects on HAART without LDS. MAIN OUTCOMES MEASURES Epicardial fat thickness and IMT were measured by ultrasonography in both study and control groups. Magnetic resonance imaging (MRI) was used to calculate VAT in HIV-infected subjects on HAART with LDS. RESULTS Epicardial adipose tissue thickness showed an excellent correlation with MRI-VAT (r=0.85; P<0.001) and IMT (r=0.78;P<0.001) in HIV-infected patients on HAART-with LDS. Multiple regression analysis showed that epicardial fat thickness was best predicted by MRI-VAT and IMT (R2=0.57, p<0.001 and p<0.01, respectively). HIV-infected patients with HAART-associated metabolic syndrome and LDS showed higher epicardial fat thickness and IMT (8 vs 6.5 mm; 0.71 vs 0.66 mm, respectively, p<0.01 for both) than HIV-infected subjects on HAART without LDS. CONCLUSION Echocardiographic assessment of epicardial fat may have the potential to be a simple and reliable marker of visceral adiposity and increased cardiovascular risk in HIV-infected patients with HAART-associated metabolic syndrome and LDS.

Relation of Epicardial Fat and Alanine Aminotransferase in Subjects With Increased Visceral Fat

Background: Increased visceral adipose tissue (VAT) is a risk factor for an unfavorable cardio‐metabolic profile and fatty liver. Individuals with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) can be associated with metabolic syndrome (MS) and higher visceral fat. However, the potential link between cardiac adiposity, emerging index of visceral adiposity, and fatty liver is still unexplored.