Hepatitis: Antonucci G

Antonucci G, Antinori A, Boumis E, De Longis P, Gentile M, Girardi E, Lauria FN, Narciso P, Noto P, Palmieri F, Oliva A, Petrosillo N, Rosati S, Urso R, Tocci G, Tozzi V, Visco Comandini U, Ippolito G. · Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, Istituto di Ricovero e Cura a Carattere Scientifico, Roma, Italy. · Infez Med. · Pubmed #15329524 links to  free full text

Abstract: It is crucial to ensure an optimal clinical management of HCV infection in HIV-co-infected persons. The reasons for the development of guidelines on HCV-infection treatment in HIV-infected persons arise from the need for a standardised management of HIV/HCV coinfection in our Institute. The aim of these guidelines are: to clarify principles of clinical management of HCV infection in HIV-infected patients to care-providers; to improve the awareness of HIV-infected patients cared for our Institute on current management of HCV infection; to improve the quality of care on this topic. These guidelines, based on Evidence based Medicine principles, have been developed by a panel of experts, who conducted a systematic review of the literature, mainly taking into account current international recommendations. In the present document, the most frequent clinical presentation occurring in the management of HIV/HCV co-infected patients at our Institution are discussed. The adherence to present guidelines and their effectiveness at our Institution, outcome indicators will be evaluated. The present guidelines cannot entirely substitute the judgement of an expert clinician. However, adherence to these guidelines will contribute to the improvement of the standard of care of HIV/HCV-co-infected persons.

Craxì A, Antonucci G, Cammà C. · Clinica Medica I, Cattedra di Gastroenterologia, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy. · J Hepatol. · Pubmed #16356581 No free full text.

Abstract: The available evidence on interferon-alpha (IFN) treatment for chronic hepatitis B is sufficient to conclude that in patients with HBeAg positive chronic hepatitis, standard IFN therapy significantly improves clearance of HBeAg (number needed to treat [NNT] = 4), loss of HBV-DNA (NNT = 4) and clearance of HBsAg (NNT = 18). HBeAg positive patients with normal or slightly raised ALT should be treated only if there is histological evidence of progressive disease. In patients with HBeAg negative chronic hepatitis, less than 20% of subjects who have achieved an end-of-treatment virological response after a course of standard IFN maintain a sustained virological response in the long-term. IFN treatment could help to delay or prevent disease decompensation and liver-related deaths but further large studies are needed. Lamivudine is effective at reducing, and sometimes clearing, HBV replication in heavily immunosuppressed patients and can be safely administered to patients with advanced liver disease. Lamivudine should be continued over an undefined extended period of time, with a switch from lamivudine to adefovir if there is an HBV-DNA breakthrough under therapy. Adefovir, excluding cost, is preferable to lamivudine as a first-choice because there is less chance of inducing resistance. The long-term benefit of lamivudine and adefovir and the role of combinations is under investigation.

Nardacci R, Ciccosanti F, Falasca L, Lo Iacono O, Amendola A, Antonucci G, Piacentini M. · No affiliation provided · Cell Death Differ. · Pubmed #12655350 links to  free full text

This publication has no abstract.

Antonucci G, Goletti D, Lanini S, Girardi E, Loiacono O. · Istituto Nazionale per le Malattie Infettive; IRCCS L. Spallanzani, Rome, Italy. · Cell Death Differ. · Pubmed #12655343 links to  free full text

This publication has no abstract.

Dianzani F, Rozera G, Abbate I, D'Offizi G, Abdeddaim A, Vlassi C, Antonucci G, Narciso P, Martini F, Capobianchi MR. · National Institute for Infectious Diseases L.Spallanzani, Rome, Italy. · J Interferon Cytokine Res. · Pubmed #18370866 No free full text.

Abstract: In the pre-highly active antiretroviral therapy (HAART) era, clinical trials showed that interferon (IFN) treatment was able to delay AIDS progression and prolong survival. Along with HAART, ancillary use of IFN during primary infection and before HAART therapy initiation has been effective. Also endogenous IFN may positively affect the progression of HIV infection, as suggested in GB virus type C (GBV-C) coinfected patients. In this pilot study, we tried to prevent rebound of HIV replication in patients who interrupted HAART by covering the drug-free time with administration of pegylated IFN (PEGIFN). Twenty-four HIV-hepatitis C virus (HCV) patients who started IFN treatment for liver disease, after variable time from having interrupted HAART, were enrolled. HIV RNA was determined during a 2-month period. In patients who interrupted HAART at variable times before initiating IFN and, therefore, had experienced a complete viral rebound, IFN caused a significant reduction of viral load lasting at least 4 weeks. Moreover, 3 of the 4 patients who started IFN concomitantly with the HAART discontinuation showed complete control of viral rebound, delaying the resumption of viral replication for more than 2 weeks. These preliminary findings suggest that a structured therapy interruptions (STI) strategy may be feasible provided that IFN is administered during the drug-free times, possibly delaying drug resistance, lessening toxicity, reducing costs, and prolonging survival.

Abbate I, Cappiello G, Lo Iacono O, Longo R, Ferraro D, Antonucci G, Di Marco V, Di Stefano R, Craxì A, Solmone MC, Spanò A, Ippolito G, Capobianchi MR. · S. Pertini Hospital, Rome, Italy. · J Biol Regul Homeost Agents. · Pubmed #14518716 No free full text.

Abstract: ISDR mutation pattern and HVR-1 quasispecies were analyzed in HCV genotype 1b-infected patients treated with either PEG- or STD-IFN plus ribavirin, in order to find virological correlates of therapy outcome. ISDR region analysis, performed at baseline (T0) and at 4 weeks of therapy (T1), indicated that ISDR mutation pattern was not predictive of response to treatment. Moreover, no selection of putative resistant strains in the first month of therapy was observed. Viral load was not correlated with any parameter of HVR-1 heterogeneity. Among the HVR-1 heterogeneity parameters considered, complexity was inversely correlated to viral load decline at T1. In univariate analysis, complexity, proportion of non synonymous substitutions (NS) and NS/S ratio were lower in patients showing virological response at 6 months of treatment. Complexity was the only parameter independently associated with both decline of viral load at T1 and virological response after 6 months, even after adjustment for confounding variables. At the end of treatment or later, these correlations were lost. Evolution pattern of the HVR-1 quasispecies indicated a strong selective pressure in sustained responders, with complete substitution of pre-existing quasispecies, while minor changes occured in non responders. In relapsers both patterns were present at a similar rate. In conclusion, this study shows that HVR-1 heterogeneity may be involved in the early response to combined IFN-RBV therapy. The loss of correlation between viral heterogeneity and therapy outcome at 6 months of therapy, or later, suggests that other factors may play a role in maintaining sustained response to treatment.

Cappiello G, Abbate I, Lo Iacono O, Longo R, Solmone M, Ferraro D, Antonucci G, Di Marco V, Di Stefano R, Craxi A, Ippolito G, Capobianchi MR. · National Institute for Infectious Diseases L Spallanzani, Rome, Italy. · Antivir Ther. · Pubmed #12741622 No free full text.

Abstract: The aim of the study was to characterize the interferon sensitivity determining region (ISDR) mutation pattern and its changes at 4 weeks of treatment in a population of patients infected with hepatitis C virus (HCV) genotype 1b receiving standard or PEG-IFN plus ribavirin (RBV), to find possible early correlates of therapy outcome. Forty-five patients with chronic hepatitis due to HCV 1b were treated by PEG-IFN-alpha2b (n=23) or IFN-alpha2b (n=22) plus RBV 1000-1200 mg/day. They were classified 24 weeks after stopping therapy as sustained responders (SR), relapsers (REL) or non-responders (NR). Sixteen patients were SR, 12 REL and 17 NR. ISDR mutations were evaluated by direct sequencing at baseline in all and after 4 weeks in patients with detectable viraemia (n=30). The frequency of the three ISDR types was 26.7% wild-type, 64.4% intermediate-type and 8.9% mutant-type, without significant difference in their frequency in SR, REL and NR, independent of IFN formulation. Average numbers of mutations in SR, REL and NR were 1.88 +/- 0.54, 1.33 +/- 0.33 and 0.94 +/- 0.25, respectively, P>0.05. The baseline number of ISDR mutations was not related to the extent of viral load decline in the first month of therapy. Sequence analysis of ISDR region performed 4 weeks after starting therapy revealed qualitative or quantitative changes of ISDR sequence in only seven patients, without correlation with response. Thus, in our patients the baseline pattern of ISDR was unrelated to treatment outcome. Selection towards a dominant IFN-resistant strain did not occur under standard or PEG-IFN plus RBV.

Iacomi F, Vincenti D, Vairo F, Solmone M, Mariano A, Piselli P, Puro V, Capobianchi MR, Antonucci G. · Clinical Department of Infectious Diseases, National Institute for Infectious Disease, L. Spallanzani, Rome, Italy. · J Med Virol. · Pubmed #19475624 No free full text.

Abstract: A retrospective review was performed comparing lamivudine-resistance mutation patterns between patients infected with hepatitis B virus (HBV) with or without human immunodeficiency virus (HIV) co-infection. Medical records that included a genotypic test of patients infected with HBV and treated with lamivudine as the only anti-HBV drug were reviewed. Pol gene mutations were assessed by direct sequencing of the reverse transcriptase fragment 125-213 aa. Eighty-nine patients infected with HBV (29 co-infected with HIV) with rtM204V or rtM204I mutations were included. Multiple mutations associated with the YMDD motif were observed in 33 (55%) of 60 patients infected with HBV only and in 28 (96.6%) of patients co-infected with HIV/HBV. In this latter group, the prevalence of the rtV173L + rtL180M + rtM204V triple mutation was 31% versus a prevalence of 3.4% observed among patients infected with HBV only. All patients with the triple mutational pattern showed sE164D + sI195M changes in the envelope gene. Multivariate analysis demonstrated that HIV co-infection (adjusted OR 11.2, 95% CI 2.0-61.0) and HBV genotype A (adjusted OR 7.2, 95% CI 1.5-34.8) were the only independent variables associated with the chance of harboring rtM204V. Patients with HBV genotype A or HIV co-infection were more likely to harbor the rtM204V mutation. Patients co-infected with HIV showed multiple mutations more frequently, including the triple mutation that may elicit a vaccine escape phenotype. Among patients co-infected with HIV/HBV, strict HBV DNA monitoring is essential to detect treatment failure and adapt therapy to avoid limitations of future therapeutic options or the emergence of a public health threat.

Lalle E, Calcaterra S, Horejsh D, Abbate I, D'Offizi G, Abdeddaim A, Vlassi C, Antonucci G, Capobianchi MR. · Laboratory of Virology, National Institute for Infectious Diseases (INMI) L. Spallanzani, Rome, Italy. · J Biol Regul Homeost Agents. · Pubmed #18842168 No free full text.

Abstract: The most reliable predictor of treatment efficacy in hepatitis C is HCV viremia decay at week 12 [early virological response (EVR)]. We investigated whether the ability of peripheral blood mononuclear cells (PBMC) to mount an interferon (IFN) response in vitro could be predictive of EVR. Fifteen patients treated with PEG IFNalpha + RBV, with pre-therapy frozen PBMC, were retrospectively selected. After a 3 hr PBMC exposure to IFNalpha in vitro, up-regulation of mRNA for IFN-stimulated genes (ISG) was measured by membrane super-array. ISG mRNA levels in unstimulated PBMC were low, but beta2M and CASP1 were significantly higher in EVR vs non-EVR. ISG mRNA up-regulation by IFN was more pronounced in EVR vs non-EVR. For 7 genes (IP-10, IFIT1, IFIT2, IFIT3, TRAIL, KIAA1628 and OAS2) cut-off levels were established, by ROC analysis, able to correctly classify all EVR and non-EVR. Early virological response to PEG IFNalpha +RBV is correlated with the pre-therapy ability of PBMC to activate an IFN response in vitro. If validated in a wider cohort of patients, the ability of this set of ISG to discriminate between EVR and non-EVR may be useful for pre-therapy evaluation, particularly in patients with unfavourable combinations of conventional response predictors.

Antonucci G, Vairo F, Iacomi F, Comandini UV, Solmone M, Piselli P, Boumis E, Lauria FN, Capobianchi MR, Ippolito G, Puro V. · Clinical Department of Infectious Disease, National Institute for Infectious Diseases, L. Spallanzani, Rome, Italy. · Scand J Infect Dis. · Pubmed #18651264 No free full text.

Abstract: The role of hepatitis B virus (HBV) or hepatitis D virus (HDV) coinfections as determinants of hepatitis C virus (HCV) suppression in the setting of HIV-HCV coinfection are poorly understood. Our aim was to assess whether HCV viral replication may be affected by HBV or HDV coinfection in the setting of immunodeficiency driven by HIV.Among the 138 enrolled patients 28(20.3%) tested HCV RNA negative and 110 (79.7%) tested HCV RNA negative. The HCV RNA negative patients showed an higher rate of HBsAg positivity compared with those tested HCVRNA positive [12/28 (42.9%) and 5/110 (4.6%), respectively]. Patients with HCV-HBV-HDV coinfection had the highest chance of having an undetectable HCV RNA (adjusted odds ratio (AOR): 92.0, 95% confidence interval (CI) 5.7-1483.5, p<0.0001). Furthermore, HBV coinfection per se was also found to be independently associated with negative HCV viraemia (AOR: 18.5, 95% CI 2.4-143.5, p<0.0001). HBsAg-positive patients with negative HCV viraemia maintained undetectable levels over time. Our results support a direct role of HBV and HDV coinfections in suppressing HCV viraemia in HIV infected patients. This effect is durable over time, and is not influenced by HAART including anti-HBV drugs.

Lalle E, Sacchi A, Abbate I, Vitale A, Martini F, D'Offizi G, Antonucci G, Castilletti C, Poccia F, Capobianchi MR. · Laboratory of Virology, National Institute for Infectious Diseases, INMI, L. Spallanzani, Rome, Italy. · Int J Immunopathol Pharmacol. · Pubmed #18336742 No free full text.

Abstract: GB virus C (GBV-C) coinfection has a protective role in Human Immunodeficiency Virus (HIV) infection, and increases the duration of suppression of HIV-1 viremia in patients under Highly Active Anti-Retroviral Therapy (HAART). Since innate antiviral response may be involved in the protection, we analyzed the possible role of GBV-C as activator of innate immunity. To this aim, we measured the extent of activation of the interferon (IFN) system and of circulating Dendritic Cells (DC) in vivo, and the ability of GBV-C to activate these functions in vitro. Activation of IFN system and of circulating DC was compared in GBV-positive and -negative HIV-1 co-infected patients with HAART-driven suppression of HIV-1 viremia. Endogenous levels of IFN-gamma and RNA-dependent protein kinase (PKR) mRNA were significantly higher in peripheral blood mononuclear cells (PBMC) from GBV-C-positive when compared to GBV-C-negative patients. IFN-gamma expression was correlated with all the Interferon response genes (IRGs) and with GBV-C viremia. The frequency of circulating plasmacytoid DC (pDC) expressing the CD80 activation marker was increased in GBV-C-positive patients, and was correlated with GBV-C viral load. In vitro experiments indicated that GBV-C is able to induce IFN-gamma expression in PBMC. In addition, in PBMC cultures GBV-C induced an increase of CD80 expression by pDC, that was reduced by antibody to IFN-gamma. Our data indicate that in HIV-positive patients GBV-C coinfection promotes the activation of IFN-gamma and downstream IRG expression, as well as with the activation/maturation of circulating pDC. GBV-C-driven IFN-gamma activation is, at least in part, responsible for the increased maturation of pDC. This crosstalk may suggest a role for GBV-C coinfection in boosting the innate antiviral response to HIV infection.

Raffa G, Maimone S, Cargnel A, Santantonio T, Antonucci G, Massari M, Schiavini M, Caccamo G, Pollicino T, Raimondo G. · Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Italy. · AIDS. · Pubmed #18090043 No free full text.

Abstract: OBJECTIVE: Current data on the prevalence of occult hepatitis B virus (HBV) infection in HIV-positive individuals conflict. As occult HBV infection could have an impact on the outcome of liver disease in HIV-positive patients, we investigated a large number of HIV-positive/HBV-surface-antigen (HBsAg) negative subjects with hepatitis C virus (HCV) infection by using the 'gold standard' approach for occult HBV detection--analysis of liver DNA extracts. METHODS: The presence or absence of HBV DNA was determined by PCR testing of four different viral genomic regions in DNA extracts of needle liver biopsy specimens of 101 HBsAg negative individuals with HIV/HCV co-infection. HBV genotyping was performed by sequencing analysis of the preS-S gene in occult HBV isolates from 18 cases. RESULTS: Occult HBV infection was diagnosed in 42 of the 101 cases (41%). No clinically relevant difference was found between occult HBV-positive and -negative patients. HBV genotype D and A were detected, respectively, in 11 (61%) and 7 (39%) of 18 cases analysed. CONCLUSIONS: Occult HBV infection frequently occurs in HIV/HCV co-infected patients indicating the importance of performing prospective studies able to clarify its clinical impact in these patients. HBV genotype A is highly prevalent in HIV-infected subjects with occult HBV infection in a similar way to HBsAg/HIV-positive individuals.

Antonucci G, Longo MA, Angeletti C, Vairo F, Oliva A, Comandini UV, Tocci G, Boumis E, Noto P, Solmone MC, Capobianchi MR, Girardi E. · Clinical Department of Infectious Disease, National Institute for Infectious Disease, L. Spallanzani, Rome, Italy. · Am J Gastroenterol. · Pubmed #17403072 No free full text.

Abstract: OBJECTIVES: In many industrialized countries HCV infection is characterized by an increasing prevalence during ageing; however, data on the efficacy of treatment among older patients are scarce. This study was set up to evaluate the effect of age on the treatment of chronic HCV hepatitis with peginterferon alpha plus ribavirin. METHODS: We retrospectively reviewed medical records of 153 adult patients with chronic HCV hepatitis treated with combination therapy; 30 of them (19.6%) were 65 years of age or older. RESULTS: In multivariable analysis, age groups >/=40 years had similar odds of achieving sustained virologic response (P= 0.71) and significantly lower odds of sustained response compared with younger patients (odds ratio [OR] 0.16, 95% confidence interval [CI] 0.05-0.59, P= 0.006; OR 0.13, 95% CI 0.03-0.49, P= 0.002; OR 0.21, 95% CI 0.05-0.91, P= 0.037 for patients aged 40-49 years, 50-64 years, and older than 64 years, respectively). The effect of age was present in the 74 patients infected with genotype 1 or 4 (P= 0.04), while among the 79 patients with genotype 2 or 3 sustained virologic response rates were relatively uniform, with no statistically significant differences. CONCLUSIONS: The probability of good response to combination treatment with peginterferon alpha plus ribavirin is decreased for patients aged more than 40 years infected with genotype 1 or 4, but patients aged more than 65 had a similar rate of response to those aged 40-64 years. Combination treatment may be safely extended to elderly patients with no major contraindications.

Cicconi P, Cozzi-Lepri A, Phillips A, Puoti M, Antonucci G, Manconi PE, Tositti G, Colangeli V, Lichtner M, Monforte A, Anonymous00236. · Clinic of Infectious Diseases and Tropical Medicine University of Milan, Milan, Italy. · AIDS. · Pubmed #17314522 No free full text.

Abstract: OBJECTIVES: To investigate if the risk of liver enzyme elevation (LEE) in HIV/hepatitis B or C (HBV, HCV) co-infection is altered by HAART (two or more drugs). METHODS: Analysis comprised HIV-positive patients in the ICoNA study without acute hepatitis who had >or= 1 positive HCV antibody test and > 1 positive HBV surface antigen test. LEE was defined as > 5x baseline alanine aminotransferase (ALT) or > 3.5x baseline if the baseline was > 40 IU/l. Analysis used Poisson regression with generalized estimating equation correction to examine HBV or HCV co-infection, use of HAART, baseline ALT and demographics as LEE predictors. RESULTS: Of the 5272 patients, 47.6% were co-infected with HCV/HBV; 29.9% were female and 39% were intravenous drug users. There were 275 episodes of LEE during 18 259 person-years follow up. Taking HAART did not significantly increase risk of LEE [adjusted relative risk (RR), 1.19; 95% confidence interval (CI), 0.81-1.75; P = 0.37]. Co-infection increased the risk of LEE (adjusted RR, 5.07; 95% CI, 3.47-7.48; P < 0.001), with no significant differences if taking HAART (adjusted RR, 4.99; 95% CI, 3.38-7.37) or not (adjusted RR, 6.02; 95% CI, 2.02-17.98) (P = 0.74 for interaction). Females were at lower risk of LEE than males (adjusted RR, 0.59; 95% CI, 0.42-0.83; P = 0.02). CONCLUSIONS: HIV and HBV/HCV co-infection per se is associated with increased risk of LEE that is not modified by HAART. The recommendation for caution in HAART use in co-infected patients, simply based on a high rate of LEE in people on therapy, may be questionable.

Santantonio T, Medda E, Ferrari C, Fabris P, Cariti G, Massari M, Babudieri S, Toti M, Francavilla R, Ancarani F, Antonucci G, Scotto G, Di Marco V, Pastore G, Stroffolini T. · Clinic of Infectious Diseases, University of Bari, Bari, Italy. · Clin Infect Dis. · Pubmed #17029134 No free full text.

Abstract: BACKGROUND: The epidemiology of acute hepatitis C has changed during the past decade in Western countries. Acute HCV infection has a high rate of chronicity, but it is unclear when patients with acute infection should be treated. METHODS: To evaluate current sources of hepatitis C virus (HCV) transmission in Italy and to assess the rate of and factors associated with chronic infection, we enrolled 214 consecutive patients with newly acquired hepatitis C during 1999-2004. The patients were from 12 health care centers throughout the country, and they were followed up for a mean (+/- SD) period of 14+/-15.8 months. Biochemical liver tests were performed, and HCV RNA levels were monitored. RESULTS: A total of 146 patients (68%) had symptomatic disease. The most common risk factors for acquiring hepatitis C that were reported were intravenous drug use and medical procedures. The proportion of subjects with spontaneous resolution of infection was 36%. The average timespan from disease onset to HCV RNA clearance was 71 days (range, 27-173 days). In fact, 58 (80%) of 73 patients with self-limiting hepatitis experienced HCV RNA clearance within 3 months of disease onset. Multiple logistic regression analyses showed that none of the variables considered (including asymptomatic disease) were associated with increased risk of developing chronic hepatitis C. CONCLUSIONS: These findings underscore the importance of medical procedures as risk factors in the current spread of HCV infection in Italy. Because nearly all patients with acute, self-limiting hepatitis C--both symptomatic and asymptomatic--have spontaneous viral clearance within 3 months of disease onset, it seems reasonable to start treatment after this time period ends to avoid costly and useless treatment.

Capobianchi MR, Lalle E, Martini F, Poccia F, D'Offizi G, Antonucci G, Abbate I, Dianzani F. · Laboratory of Virology. · Cell Mol Biol (Noisy-le-grand). · Pubmed #16914092 No free full text.

Abstract: BACKGROUND: GB virus C (GBV-C) co-infection is associated with a better prognosis in HIV-infected persons. Since interferon activation can be one of the possible mechanisms involved in GBV-C-driven protection against HIV, we compared the endogenous activation of the interferon system in PBMC from GBV-C-positive and -negative patients infected with HIV-1. METHODS: The expression of interferon related genes was analyzed in 20 GBV-C positive and 20 GBV-C-negative HIV-infected patients, comparable in terms of CD4 cell counts and HIV viral loads. The levels of mRNA for interferon-related genes (2-5-OAS, MxA, interferon AR-1 and PKR) in PBMC were measured by real time RT-PCR, using B-actin as internal control. RESULTS: The endogenous levels of all the Interferon-related genes in HIV/GBV-C co-infected patients were higher than in HIV mono-infected subjects. The difference was statistically significant for PKR mRNA. Direct positive correlation was found between PKR and all the other interferon-related genes, suggesting a coordinated activation of the interferon system. CONCLUSIONS: Enhanced activation of the interferon system occurs in GBV-C-positive, as compared to GBV-C-negative patients harbouring HIV-1. These data may be relevant to understand the GBV-C-driven protection against HIV, suggesting that the endogenous activation of the interferon system can contribute to the control of HIV replication.

Solmone M, Girardi E, Lalle E, Abbate I, D'Arminio Monforte A, Cozzi-Lepri A, Alessandrini A, Piscopo R, Ebo F, Cosco L, Antonucci G, Ippolito G, Capobianchi MR, Anonymous00096, Anonymous00097. · National Institute of Infectious Diseases L Spallanzani, Rome. · Antivir Ther. · Pubmed #16518964 No free full text.

Abstract: Hepatitis C virus (HCV) variability is mainly attributed to the ability of the virus to respond to host immune pressure, acting as a driving force for the evolution of quasispecies. This study was aimed at studying the changes in HVR-1 heterogeneity and the evolution of HCV quasispecies in HIV/HCV-coinfected patients according to the pattern of response to highly active antiretroviral therapy (HAART). Sixteen HIV/HCV-coinfected patients harbouring HCV genotype 1 and who had been on HAART for at least 1 year, 8 showing increasing CD4+ T-cell counts (immunological responders) and 8 showing a stable or decreasing CD4+ T-cell counts (immunological nonresponders), were selected from a prospective cohort study. After 1 year of HAART, 11 patients showed HIV viral load <2.6 log10 cp/ml (virological responders), and 5 showed HIV viral load above this value (virological non-responders). Plasma samples, collected before starting therapy and after 1 year of HAART, underwent clonal sequence analysis for HVR-1 region of HCV. Nonsynonymous/synonymous substitutions ratio (Ka/Ks), aminoacidic complexity (normalized Shannon entropy) and diversity (p-distance), were considered as parameters of quasispecies heterogeneity. After 1 year of HAART, heterogeneity of HVR-1 quasispecies significantly decreased in virological non-responders, whereas the heterogeneity tended to increase in virological responders. The differences in the evolution were less stringent, when considering immunological response. On the other hand, profound qualitative modifications of HVR-1 quasispecies were observed only in patients with both immunological and virological HAART response. On the whole, these findings suggest that, in patients undergoing HAART, the extent of HCV variability and the evolution of HVR-1 quasispecies is influenced by the pattern of response to antiretroviral therapy.

Nisii C, Tempestilli M, Agrati C, Poccia F, Tocci G, Longo MA, D'Offizi G, Tersigni R, Lo Iacono O, Antonucci G, Oliva A. · National Institute for Infectious Diseases IRCCS L. Spallanzani, Via Portuense 292, 00149 Rome, Italy. · J Hepatol. · Pubmed #16426698 No free full text.

Abstract: BACKGROUND/AIMS: Hepatitis C virus (HCV) causes a chronic infection that can lead to fibrosis and carcinoma. Immune responses mediated by cytotoxic T lymphocytes (CTLs) could be involved in viral clearance or persistence, and therefore in determining the course of the disease. METHODS: Intrahepatic and peripheral blood CD8+T cells were obtained from 32 HCV-chronically infected patients and analysed by flow-cytometry for surface markers of differentiation, IFNgamma and TNFalpha production, degranulation capacity and perforin content, after CD3 triggering. Results were compared with those obtained from 13 patients with a non-viral liver disease. RESULTS: Intrahepatic CD8+T cells of HCV-infected patients, despite their phenotype of pre-terminally and terminally differentiated effectors (CCR7-CD45RA-/+), are poorly responsive to T cell receptor (TCR)-mediated stimulation compared with those obtained from uninfected subjects. This defect correlates with the severity of fibrosis, is more pronounced in patients with ALT<1.5xN than with ALT>1.5xNU/ml, and is not evident after mitogen stimulation. CONCLUSIONS: The present study describes the accumulation of hypo-responsive CD8+T cells in the liver of patients with chronic HCV infection. Understanding the mechanisms underlying this impairment may be helpful in the design of innovative strategies for HCV treatment.

Carosi G, Puoti M, Antonucci G, De Luca A, Maserati R, Torti C, Bonfanti P, Bonora S, Bruno R, Gaeta GB, Antinori A, Monforte A, Orani A, Sagnelli E, Cargnel A, Cauda R, Mazzotta F, Pastore G, Suter F, Vullo V, Anonymous00062, Anonymous00063. · Department of Infectious Disease, University of Brescia, Brescia, Italy. · AIDS Rev. · Pubmed #16302464 No free full text.

Abstract: Hepatitis C virus common transmission routes and HCV coinfection is frequent in persons living with HIV. Liver enzyme elevation following the initiation of antiretroviral therapy is frequently seen in HIV-infected patients with chronic liver disease, particularly those with chronic hepatitis C. This complication may lead to treatment discontinuation, complicating HIV therapeutic management. Multiple factors influence the risk of liver toxicity under antiretroviral therapy, including the specific drug in use (e.g. use of full doses of ritonavir), and environmental factors (e.g. alcohol abuse). However a beneficial effect of antiretroviral therapy on liver disease has been supported by some studies. Despite increasing knowledge of HCV/HIV coinfection, there is no clear consensus on how to treat HIV in HCV-coinfected patients An Italian group of experts were invited to discuss in detail the current risks and implications of antiretroviral treatment in HIV-infected persons with chronic hepatitis C, and their main conclusions are summarized in this consensus document.

Antonucci G, Girardi E, Cozzi-Lepri A, Capobianchi MR, De Luca A, Puoti M, Petrelli E, Carnevale G, Rizzardini G, Grossi PA, Viganò P, Moioli MC, Carletti F, Solmone M, Ippolito G, Monforte AD, Anonymous00410, Anonymous00411. · National Institute of Infectious Diseases, L. Spallanzani, Rome, Italy. · Clin Infect Dis. · Pubmed #15909251 No free full text.

Abstract: BACKGROUND: The roles of hepatitis C virus (HCV) viremia and HCV genotype in the immune response to highly active antiretroviral therapy (HAART) are poorly understood. Our aim was to assess the CD4+ cell count recovery after HAART in human immunodeficiency virus (HIV)-infected patients with HCV viremia and HIV-infected patients who tested negative for HCV antibody (HCV-Ab). We also aimed to assess whether the response to HAART in these patients varied according to HCV genotype. METHODS: The analysis focused on 1219 HCV-Ab-negative patients and 284 HCV-viremic patients from a cohort of HIV-infected subjects that includes persons who were antiretroviral naive before initiating HAART after cohort enrollment. HCV RNA load and HCV genotype were determined in plasma specimens obtained and stored during the 6-month period preceding the initiation of HAART. RESULTS: The chance of achieving a CD4+ cell count increase of > or = 100 cells/microL from the pre-HAART level tended to be poorer in HCV-viremic patients than in patients who tested negative for HCV-Ab (adjusted relative hazard [RH], 0.82; 95% confidence interval [CI], 0.66-1.01; P = .06). In contrast, a comparison of patients who had a HCV RNA load >1 x 10(6) IU/mL with patients who had a HCV RNA load of 5-1 x 10(6) IU/mL revealed no significant association between HCV RNA load and achievement of an increased CD4+ cell count (adjusted RH, 0.97; 95% CI, 0.75-1.27; P = .83). There was no clear association between HCV genotype and the probability of achieving a CD4+ cell count increase. CONCLUSIONS: An association between the presence of HCV-Ab and immune reconstitution after HAART has been shown elsewhere. Results of our large, prospective study support a direct role of HCV viremia in the CD4+ cell count response to HAART. Moreover, our results underline the fact that, in individuals coinfected with HIV and HCV, the goal of treating HCV infection is to eradicate HCV, to both slow the rate of HCV progression and limit potential interference with the response to HAART.

Antonucci G, Girardi E, Cozzi-Lepri A, Capobianchi MR, Morsica G, Pizzaferri P, Ladisa N, Sighinolfi L, Chiodera A, Solmone M, Lalle E, Ippolito G, Monforte A, Anonymous00301, Anonymous00302. · National Institute of Infectious Diseases, L Spallanzani, Roma, Italy. · Antivir Ther. · Pubmed #15751768 No free full text.

Abstract: The prognostic role of GB virus type C (GBV-C) viraemia in HIV-infected subjects treated with highly active antiretroviral therapy (HAART) is still undefined. The aim of this analysis is to assess the relationship between GBV-C infection and response to antiretroviral therapy among HIV-infected subjects initiating HAART when antiretroviral-naive. A prospective, observational study of 400 HIV-infected patients with measurements of GBV-C RNA, hepatitis C virus (HCV) antibodies and HCV RNA determined from plasma stored prior to HAART initiation. Time to virological (achieving HIV RNA < or =500 copies/ml) and immunological success (a CD4+ count increase of > or =200 cells/microl), and the time to virological relapse (confirmed HIV RNA >500 copies/ml) were assessed by Kaplan-Meier methods and Cox proportional hazard regression model. Of the subjects, 117 (29.3%) were GBV-C positive and, overall, 351 (87.8%) patients achieved virological success. After controlling for a number of confounders including HCV RNA, GBV-C viraemic patients experienced a significantly lower risk of HIV rebound than those who were GBV-C negative [relative hazard (RH)=0.56, 95% CI: 0.34-0.93, P=0.03]. Conversely, the probability of achieving initial virological success or CD4+ count response after HAART did not differ between GBV-C-negative and -positive subjects. These results suggest that GBV-C coinfection may play a role in determining the rate of HIV rebound possibly by competing with HIV replication after HIV load has been successfully suppressed by HAART.

Abbate I, Lo Iacono O, Di Stefano R, Cappiello G, Girardi E, Longo R, Ferraro D, Antonucci G, Di Marco V, Solmone M, Craxì A, Ippolito G, Capobianchi MR. · Department of Virology, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy. · J Hepatol. · Pubmed #15094232 No free full text.

Abstract: BACKGROUND/AIMS: HVR-1 quasispecies composition and evolution were investigated in patients chronically infected with genotype 1b HCV, treated with PEG-IFN alpha 2b or STD-IFN alpha 2b plus RBV. METHODS: HVR-1 heterogeneity was assessed by calculating nucleotidic complexity, diversity, synonymous (S) and non-synonymous (NS) substitutions at baseline, after 4 weeks of therapy (T1) and at follow-up (T18). Evolution of viral quasispecies was analysed by constructing phylogenetic trees. RESULTS: No correlation of baseline viremia with heterogeneity was observed. Nucleotidic complexity was lower in patients showing early virological response, and tended to be inversely correlated to viral load decline at 4 weeks of treatment. In the majority of SR, profound changes of quasispecies composition occurred during 4 weeks of treatment, while in NR virtually no major changes of pre-therapy variants were observed. Relapse showed both patterns of quasispecies evolution. Virus quasispecies after follow-up was similar to that found at T1 in both Relapsers and NR patients. CONCLUSIONS: Baseline parameters of HVR-1 heterogeneity seem to be involved in the early response to treatment, and early response is associated with profound variations in the HVR-1 quasispecies. Viral quasispecies surviving early therapeutic pressure are most likely able to give rise to either virus rebound or persistence at T18.

Abbate I, Cappiello G, Rosati S, Tocci G, Antonucci G, Solmone M, Longo R, Spanò A, Capobianchi MR. · Laboratory of Virology, S. Pertini Hospital, Rome, Italy. · AIDS. · Pubmed #15090776 No free full text.

This publication has no abstract.

Nardacci R, Lo Iacono O, Ciccosanti F, Falasca L, Addesso M, Amendola A, Antonucci G, Craxì A, Fimia GM, Iadevaia V, Melino G, Ruco L, Tocci G, Ippolito G, Piacentini M. · Istituto Nazionale per le Malattie Infettive, IRCCS L. Spallanzani, Rome. · Am J Pathol. · Pubmed #12651621 links to  free full text

Abstract: The up-regulation of "tissue" transglutaminase (TG2) gene has been shown to occur in various pathologies and can lead to severe liver injury; however, its role in the onset of liver damage has not yet been clarified. To address this issue, we have used two experimental settings: carbon tetrachloride (CCl(4))-induced liver injury in wild-type and TG2 knockout mice; and liver biopsies obtained from a large cohort of hepatitis C virus (HCV)-infected patients. Mice lacking TG2 failed to clear the hepatic necrotic tissue formed in response to prolonged CCl(4) exposure (5 weeks) and 60% of them died before the end of the treatment. By contrast, wild-type mice were able to recover after the toxic insult. CCl(4)-treated TG2 null mice showed a derangement of the hepatic lobular architecture and a progressive accumulation of extracellular matrix (ECM) components and inflammatory cells which were not observed in the liver of control animals. Consistent with this protective role, we observed that TG2 levels were much higher (up to 15-fold) during the initial stages of liver fibrosis in HCV-infected individuals (METAVIR = F2) compared with uninfected controls, in which the enzyme protein localized in the hepatocytes facing the periportal infiltrate. By contrast, the enzyme levels decreased in the advanced stages (METAVIR = F3 and F4) and their localization was limited to the ECM. Our data demonstrate that TG2 plays a protective role in the liver injury by favoring tissue stability and repair.

Galli M, Cozzi-Lepri A, Ridolfo AL, Gervasoni C, Ravasio L, Corsico L, Gianelli E, Vaccarezza M, Vullo V, Cargnel A, Minoli L, Coronado O, Giacometti A, Antinori A, Antonucci G, D'Arminio Monforte A, Moroni M, Anonymous00058. · Institute of Infectious Diseases and Tropical Medicine, University of Milan, "L Sacco" Hospital, Via G. B. Grassi, 74 20157 Milan, Italy. · Arch Intern Med. · Pubmed #12456235 links to  free full text

Abstract: BACKGROUND: Adipose tissue alterations (ATAs) are a frequent untoward effect of antiretroviral therapy, the causes of which remain incompletely explained. OBJECTIVES: To assess the incidence of ATAs and to identify the associated risk factors in patients infected with human immunodeficiency virus type 1 starting their first-line antiretroviral treatment. METHODS: In a multicenter investigation designed to study issues related to the treatment of patients starting antiretroviral therapy, physicians were requested to assess the presence of ATAs at enrollment and every 6 months thereafter. The ATAs were considered altogether and grouped as fat loss (lipoatrophy), adipose tissue accumulation (lipohypertrophy), and combined forms. RESULTS: A total of 655 patients were followed up for a median of 86 weeks; 128 patients (19.6%) were diagnosed as having at least 1 morphologic alteration during the study. Female gender and positivity for hepatitis C virus were independently linked to an increased risk of developing morphologic alterations. Age was another independent correlate of risk of developing ATAs. To have been infected through drug injection was a correlate of reduced risk of ATAs. Stavudine exposure was predictive at borderline statistical significance of lipoatrophy (but not of the other forms), and indinavir exposure was associated with a significantly higher risk of developing combined forms. Patients who started therapy with 2 nucleoside reverse transcriptase inhibitors and subsequently added a protease inhibitor during the follow-up had a significantly higher risk of having ATAs compared with patients who continued taking 2 nucleoside reverse transcriptase inhibitors up to the end of follow-up. CONCLUSIONS: Different types of ATAs might derive from distinct pathways and multifactorial causes. Adipose tissue alterations are a frequent and relatively early finding during first-line antiretroviral therapy.