Miriam Cesari

Does fluvastatin favour HCV replication in vivo? A pilot study on HIV-HCV coinfected patients.

Summary.  Fluvastatin showed anti‐hepatitis C virus (HCV) activity in vitro, through the inhibition of geranylgeranylation of cellular proteins, and a synergistic effect with interferon (IFN)‐α. Nevertheless statins up‐regulate low‐density lipoprotein (LDL) receptor, required for HCV cell entry, and the closely related scavenger receptors SRBI and CD36; moreover they reduce class II major histocompatibility complex expression on antigen presenting cell, modulating T‐cell activation. In vivo LDL levels have been identified as prognostic indicator of sustained viral response to IFN in patients with HCV infection, suggesting that lipid‐lowering agents might conversely favour HCV entry into the hepatocytes and translate into higher viral replication. We evaluated the effect of fluvastatin on HCV‐RNA levels, CD36 expression and T‐cell homeostasis in HCV‐RNA positive patients. HCV‐RNA was measured at baseline and after 4 weeks in 42 HCV/HIV‐1 co‐infected patients, randomized to receive either fluvastatin 80 mg qd or no treatment. CD36 expression and markers of T‐cell activation were evaluated by means of flow cytometry. Plasma interleukin (IL)‐10, IFN‐γ and IL‐7 were measured by ELISA. Serum cholesterol and LDL decreased significantly in the treatment group (P = 0.0001 and 0.01, respectively). Surprisingly a significant increase of HCV‐RNA levels was seen after 4 weeks of fluvastatin (P = 0.03). The percentages of naive/activated/apoptotic cells and CD36 expression remained unchanged. Fluvastatin did not inhibit HCV‐RNA replication in vivo; conversely we observed a significant increase of HCV‐RNA levels. CD36 expression on monocytes were not up‐regulated by statins as previously reported in vitro. The correlation between HCV infectivity, oxidized‐LDL receptor and statins in HCV infection need further evaluation.

MYCOBACTERIUM LENTIFLAVUM INFECTION IN IMMUNOCOMPETENT PATIENT

Mycobacterium lentiflavum is a recently described nontuberculous mycobacterium that has mainly clinical importance in young children with cervical lymphadenitis and in immunocompromised patients. We describe a case of chronic pulmonary infection in an immunocompetent patient. Our observation confirms clinical, diagnostic, and treatment difficulties in the management of M. lentiflavum infection.

Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C virus genotype 1 co-infected patients: an open-label randomized controlled study

OBJECTIVES Recent reports demonstrated in vitro the efficacy of fluvastatin in inhibiting hepatitis C virus (HCV) replication and a synergistic effect in association with interferon-alpha (IFN-alpha). In vivo the inhibition of HCV replication by statins has not been demonstrated. We evaluated in this open-label, randomized controlled study the efficacy of fluvastatin as adjuvant to pegylated-(PEG)-IFN and ribavirin in HIV/HCV genotype 1 co-infected patients. PATIENTS AND METHODS Forty-four HIV/HCV co-infected patients were randomized to receive, in addition to PEG-IFN-alpha 2b and ribavirin, 80 mg of fluvastatin once daily or no medication. Primary and secondary endpoints were the achievement of sustained virological response (SVR) and rapid virological response (RVR), respectively. RESULTS By intent-to-treat analysis, 25% of the patients achieved an SVR. An SVR was observed in 8/21 patients in the fluvastatin arm and in 3/23 patients in the standard therapy arm (P = 0.08). A significantly higher RVR rate was obtained in the fluvastatin arm compared with the standard therapy [7/21 (33%) and 1/23 (4%), respectively; P = 0.02]. Baseline alanine aminotransferase (ALT) values and fluvastatin treatment arm were the only predictors of RVR at the univariate analysis; however, no predictors were independently associated with RVR or SVR at the multivariate analysis. CONCLUSIONS Fluvastatin addition to standard therapy did not significantly increase the SVR rate in HIV/HCV genotype 1 co-infected patients; however, it did significantly improve the RVR. Further studies are needed to confirm these promising results and to investigate the mechanisms of action of statins in HCV infection.

Interferon-γ and Granulocyte-Macrophage Colony Stimulating Factor Therapy in Three Patients with Pulmonary Aspergillosis

An immune response mediated by type 2 cytokines is thought to contribute to the development and unfavorable outcome of aspergillosis. Adjuvant therapy with interferon-γ (IFN-γ) and granulocyte-macrophage colony stimulating factor (GM-CSF) was added to antifungal treatment in three nonneutropenic patients (one HIV-positive and two HIV-negative patients) with culture proven aspergillosis refractory to classical antifungal therapy. Clinical improvement was observed concomitantly with an increase in peripheral blood leukocyte proliferation and type 1 cytokines production. Our findings suggest an association between the improvement in type 1 cytokine production observed during IFN-γ and GM-CSF administration and a better control of Aspergillus infection in patients with progressive disease despite adequate antifungal therapy.

FDG-PET imaging in HIV-infected subjects: relation with therapy and immunovirological variables

PurposeTo characterise tissue sites of immune activation and HIV replication we performed FDG-PET in ART-treated and ART-naive HIV-infected individuals. Specific aims were to establish whether HIV-infected patients can be differentiated on the basis of the detection of specific locations of viral replication, even in the presence of an apparently optimal immunovirological response to ART, and whether these FDG-PET findings can be related to immunovirological variables and AIDS history status.Patients and methodsPatients were divided into five groups as follows: subgroup A1 (full responders, n = 8): current ART treatment, CD4+ T lymphocytes >500/mL, viral load <50 copies/mL; subgroup A2 (full responders, n = 5): same criteria as A-1, but with a previous history of AIDS; subgroup A3 (immunological non responders, n = 5): current ART treatment, viral load <50 copies/mL, low CD4+ T lymphocytes (<200/mL); group B (virological non responders, n = 2): current ART treatment, CD4+ T lymphocytes around 500/mL, viral load >50,000 copies/mL; group C (ART-naïve, n = 5): no current or previous ART treatment, increased viral load.ResultsPET images revealed different patterns of FDG uptake. All ART-treated patients with either suppressed (<50 copies/mL; Group A) or high viremia (group B) showed a normal pattern of FDG uptake. On the contrary, the ART-naïve subjects with high viraemia (group C) displayed multiple foci of increased glucose metabolism in the lymph nodes. In the ART-naïve subjects, FDG uptake, apparently related to viraemia level, was observed in the upper torso mainly in the axillary nodes bilaterally in patients with viraemia below 100,000 copies/mL; in those with viraemia higher than 100,000 copies/mL, FDG uptake was also observed in the inguinal lymph nodes.ConclusionsThe emergence, in our study, of a correlation between the percentage of CD8+/CD38+/RO+ T cells (well established markers of progression to AIDS independently of CD4+ T lymphocytes) and positive FDG-PET in ART-naive patients is a novel finding that seems to confer prognostic value on FDG uptake. FDG uptake is strongly associated with response to ART independently of a previous AIDS diagnosis. Notably, no differences were observed between ART-treated subjects classed as immunological responders and those classed as non responders. Data herewith indicate that FDG uptake and immunological variables are unrelated when ART is being administered. This is evidence of the complementarity of immunological and FDG measures. FDG uptake is a sensitive marker of disease state and its relation with CD8+/CD38+/CD45RO+ T cells indicates that it can be considered a marker of disease status. The lack of a correlation between FDG uptake and immunological variables in patients under ART warrants further investigation.

Effect of Antioxidants on Mitochondrial Function in HIV-1-Related Lipoatrophy: A Pilot Study

We investigated the effect of antioxidant supplementation on mitochondrial function, fat distribution, and lipid and glucose metabolism in HIV-1-infected patients with antiretroviral therapy (ART)-related lipoatrophy. 61 ART-treated HIV-1-infected patients with lipoatrophy were randomized to receive either n-acetyl-L-carnitine (n = 21), lipoic acid + n-acetylcisteine (LA/NAC) (n = 20), or no supplementation (n = 20) for 48 weeks. At baseline and at the end of treatment, mitochondrial function was studied by (13)C-methionine breath test and by mitochondrial (mt)-DNA quantification on circulating T-cells and subcutaneous adipose tissue. Body composition was assessed by dual-energy X-ray absorpiometry (DEXA). (13)CO(2)-exhalation increased between baseline and week 48 in both supplementation arms as evidenced by a higher delta over baseline excretion at 45 min (from mean ± SEM of 7.8 ± 1.08 to 9.9 ± 0.6, p = 0.04 in the n-acetyl-carnitine arm, and from 7.4 ± 0.8 to 11.5 ± 1.6, p = 0.01 in LA/NAC arm). Cumulative (13)CO2 excretion increased from median (interquartile range; IQR) of 3.25 (2.55-4.2) to 4.51 (4.12-5.2) in the carnitine arm; from 3.79 (2.67-4.37) to 4.83 (4.25-5.56) in the LA/NAC arm; p = 0.004, 0.02, respectively. mtDNA content increased in CD4+ T-cells from patients who received n-acetyl-carnitine (+30 copies/cell; p = 0.03), without significant difference by the overall comparison of the study groups. Fat body mass and lipid profile did not change significantly in any of the arms. Our study showed that antioxidant supplementation may have a protective role on mitochondrial function, with limited effects on the reversal of clinical lipodystrophic abnormalities in HIV-1-infected patients.

Noncirrhotic Portal Hypertension in HIV-Infected Patients: A Case Control Evaluation and Review of the Literature

Idiopathic noncirrhotic portal hypertension (NCPH) is an infrequent but possibly underestimated cryptogenetic liver disease recently described in small series of HIV-infected patients. The exposure to antiretroviral drugs, a direct role of HIV itself, microbial translocation from the gut, or a thrombophilic propensity have been suggested as possible pathogenic mechanisms. In this case control study, we describe 11 HIV-infected patients with idiopathic NCPH and compare the activity of protein C and S, and soluble CD14 levels (a surrogate marker of the translocation of intestinal bacterial products) with 10 age- and gender-matched HIV-infected controls with no liver disease. The clinical presentation of the 11 patients with NCPH was characterised by acute variceal bleeding (2/11), ascites (2/11), portal thrombosis (2/11), and ultrasonographic and endoscopic signs of portal hypertension (11/11), with slightly high alanine transaminase (ALT) and γglutamyl transpeptidase (γ-GT) levels. The FibroScan median liver stiffness was 8.1 kPa, which is inconsistent with significant fibrosis, and nodular regenerative hyperplasia was diagnosed in the 5 patients who underwent liver biopsy. The NCPH patients showed no impairment of hepatic synthesis, but had lower serum albumin levels and a higher international normalized ratio (INR) than the controls (p = 0.01), and lower protein C and S activity, although within the normal range (p = 0.02 and 0.3, respectively). No significant difference in soluble CD14 was seen between the two groups. In conclusion, the etiology of NCHP is not still established, but in order to prevent the dramatic complications of portal hypertension, all HIV-infected patients with unexplained liver enzyme abnormalities or thrombocytopenia should be considered for further investigations by means of thrombophilic screening, Doppler ultrasound evaluation, and in the presence of portal hypertension, endoscopy and liver biopsy.

HIV-infected long-term nonprogressors display a unique correlative pattern between the interleukin-7/interleukin-7 receptor circuit and T-cell homeostasis.

We hypothesized that there may be a correlation between the interleukin‐7 (IL‐7)/IL‐7 receptor (IL‐7R) regulatory system and parameters of T‐cell homeostasis in HIV‐infected long‐term nonprogressors (LTNPs) as compared with patients with disease progression.

Impact of hyperglycaemia and cholesterol levels on the outcome of hepatitis C virus (HCV) treatment in HIV/HCV‐coinfected patients

High serum total cholesterol and low‐density lipoprotein (LDL) levels have been demonstrated to increase the probability of a sustained viral response (SVR) in chronic hepatitis C. Conversely, insulin resistance reduces SVR rates. We investigated the influence of baseline glucose and lipid values on the outcome of hepatitis C virus (HCV) treatment in HIV‐1 infected subjects.

Low interleukin-10 production is associated with diabetes in HIV-infected patients undergoing antiviral therapy.

Reduced interleukin-10 (IL-10) production is associated with type 2 diabetes in elderly individuals. Antiviral therapy (ARV)-induced immune modulation results in diminished IL-10 production, and diabetes can be observed in ARV-treated human immunodeficiency virus (HIV)-infected individuals. We analyzed, in a cross-sectional pilot study, HIV-antigen-stimulated IL-10 and tumor necrosis factor alpha (TNFα) production, and intracellular concentration (ICC), as well as B7-H1 expression, a marker preferentially presented by IL-10-producing cells, in 20 ARV-treated individuals in whom diabetes did (n=10; diabetes mellitus, DM) or did not (n=10; controls) develop. Pre-ARV glucose, cholesterol, and triglycerides levels, duration of HIV infection and of therapy, exposure to protease inhibitors (PI), HIV plasma viremia, CD4 counts, and nadir were similar in DM and control patients. Results showed that: (1) IL-10 production was lower; (2) IL-10 ICC was reduced; (3) B7-H1-expressing CD19+ cells were diminished; and (4) TNFα production and ICC by CD4+ T cells was augmented in DM patients. Development of diabetes in HIV infected, ARV-treated individuals could be a response to therapy. Similar to what is observed in elderly individuals, low IL-10 production is associated with diabetes in antiviral-treated HIV infection. Further studies will be necessary to clarify whether low IL-10 is a risk factor for, or a consequence of, diabetes.