Caterina Sagnelli

Impact of occult hepatitis B virus infection in HIV patients naive for antiretroviral therapy.

Objective:To study the impact of occult hepatitis B virus (HBV) infection in 115 consecutive anti-HIV-positive, hepatitis B surface antigen-negative patients, naive for antiretroviral treatment. Methods:Of these 115, 86 patients were followed for at least 6 months (range 6–36) with serial determinations of HIV RNA and HBV DNA by polymerase chain reaction and other laboratory tests. Results:Of the 86 patients having a follow-up, plasma HBV DNA was detected in 17 (19.8%), 13 on admission and four during follow-up. HBV DNA was more frequently found in patients with isolated anti-hepatitis B core (HBc; 35.5% of 31 cases) than in those lacking anti-HBc and anti-hepatitis B surface (8.8% of 41, P < 0.005), or showing both (21.4% of 14). Twenty-eight patients (32.5%) experienced a hepatic flare during the follow-up; this event was more frequent in the 17 HBV-DNA-positive patients than in the 69 negative (64.7% versus 24.6%, P < 0.005). Of the 13 HBV-DNA-positive patients on admission, 11 receiving HAART containing lamivudine became HBV-DNA negative, but two of these again became positive and experienced a hepatic flare during treatment and two both during and after lamivudine treatment. A hepatic flare also occurred under lamivudine treatment in two of the four patients in whom HBV DNA became detectable during follow-up. The role of immune reconstitution inflammatory syndrome and HAART in inducing a hepatic flare was found to be marginal in 49 patients with no HBV or hepatitis C virus marker. Conclusion:The study suggests that HBV occult infection, relatively frequent in anti-HIV-positive patients, is associated with hepatic flares.

HBV superinfection in HCV chronic carriers: A disease that is frequently severe but associated with the eradication of HCV

The impact of hepatitis B virus (HBV) superinfection in hepatitis C virus (HCV) chronic carriers was evaluated in a long‐term follow‐up study on 29 chronic anti‐HCV carriers with acute hepatitis B (AVH‐B) (Case group BC) and 29 anti‐HCV negative patients with AVH‐B (Control group B), pair‐matched for age (±5 years), sex, and risk factors for the acquisition of HBV infection. Patients in Case group BC and those in Control group B showed similar initial HBV viral load and a similar trend of becoming negative for HBV‐DNA. AVH‐B showed a severe course more frequently in Case group BC than in Control group B (34.5% versus 6.9%, P < 0.05). Of the 28 patients in Case group BC alive at the end of the acute illness (one death from liver failure), 24 were followed up for 2‐6 years, median 5 years: 22 patients became HBsAg‐negative and two progressed to HBsAg‐positive chronic hepatitis. HCV‐RNA was undetectable in all patients during AVH‐B; in the 24 patients with a long‐term follow‐up, HCV‐RNA was detected in seven (29.2%) after 1 year, in 14 (58.3%) after 2 years, and in 18 (75%) after 3‐6 years. The six patients who eradicated chronic HCV infection, compared with 18 showing reactivation of HCV replication, had higher values of aspartate aminotransferase and alanine aminotransferase and a higher prevalence of cases with severe AVH‐B (83.3% versus 22.2%, P < 0.05). Conclusions: Although it can be life‐threatening, HBV superinfection in HCV chronic carriers may lead to clearance of chronic HCV infection, especially in patients with severe AVH‐B. (HEPATOLOGY 2009.)

Reactivation of overt and occult hepatitis B infection in various immunosuppressive settings

The aim of the study was to evaluate clinical and virological differences in HBV reactivation between patients with overt and occult HBV infection. Twenty‐three consecutive patients with symptomatic HBV reactivation occurring during or after immunosuppressive therapy were enrolled in a retrospective study: 10 with reactivation of overt HBV infection (overt group) and 13 of occult HBV infection (occult group). Twenty‐one patients were treated with nucleot(s)ide analogues after HBV reactivation. Regimens including rituximab or fludarabine were administered more frequently in the occult group (61% vs. 31%, respectively). HBV reactivation was severe frequently in the overt (40%) and occult groups (38.4%). Patients in the overt group showed higher HBV‐DNA titers (1.1 × 108 ± 1.4 × 108 vs. 5.1 × 105 ± 6.8 × 105 IU; P < 0.005). Seven patients died during HBV reactivation, two in the overt and five in the occult group. Of these seven patients, two remained untreated and five had been treated with Lamivudine; of the 16 patients showing remission of HBV reactivation, four had been treated with Lamivudine, four with Entecavir, two with Telbivudine, and six with Lamivudine plus Adefovir. It is concluded that HBV reactivation is life‐threatening in patients with diseases inhibiting the immune response and/or receiving immunosuppressive drugs. Supportive therapy without antiviral drugs or Lamivudine monotherapy may not be effective for treating patients with HBV reactivation. J. Med. Virol. 83:1909–1916, 2011.

Epidemiology of acute and chronic hepatitis B and delta over the last 5 decades in Italy

The spread of hepatitis B virus (HBV) infection has gradually decreased in Italy in the last 5 decades as shown by the steady reduction in the incidence rates of acute hepatitis B, from 10/100000 inhabitants in 1984 to 0.85/100000 in 2012, and by the reduced prevalence of hepatitis B surface antigen (HBsAg)-positive cases among chronic hepatitis patients with different etiologies, from 60% in 1975 to about 10% in 2001. The prevalence of HBsAg chronic carriers in the general population also decreased from nearly 3% in the 1980s to 1% in 2010. Linked to HBV by its characteristics of defective virus, the hepatitis delta virus (HDV) has shown a similar epidemiological impact on the Italian population over time. The incidence of acute HDV infection decreased from 3.2/100000 inhabitants in 1987 to 0.8/100000 in 2010 and the prevalence of HDV infection in HBsAg chronic carriers decreased from 24% in 1990 to 8.5% in 2006. Before the beneficial effects of HBV mass vaccination introduced in 1991, the decreased endemicity of HBV and HDV infection in Italy paralleled the improvement in screening blood donations, the higher standard of living and impressive reduction in the birth rate associated with a marked reduction in the family size. A further contribution to the decline in HBV and HDV infections most probably came from the media campaigns to prevent the spread of human immunodeficiency virus infection by focusing the attention of the general population on the same routes of transmission of viral infections such as unsafe sexual intercourse and parenteral exposures of different kinds.

Hepatitis B virus burden in developing countries.

Hepatitis B virus (HBV) infection has shown an intermediate or high endemicity level in low-income countries over the last five decades. In recent years, however, the incidence of acute hepatitis B and the prevalence of hepatitis B surface antigen chronic carriers have decreased in several countries because of the HBV universal vaccination programs started in the nineties. Some countries, however, are still unable to implement these programs, particularly in their hyperendemic rural areas. The diffusion of HBV infection is still wide in several low-income countries where the prevention, management and treatment of HBV infection are a heavy burden for the governments and healthcare authorities. Of note, the information on the HBV epidemiology is scanty in numerous eastern European and Latin-American countries. The studies on molecular epidemiology performed in some countries provide an important contribution for a more comprehensive knowledge of HBV epidemiology, and phylogenetic studies provide information on the impact of recent and older migratory flows.

Liver microRNA hsa-miR-125a-5p in HBV Chronic Infection: Correlation with HBV Replication and Disease Progression

To study in HBsAg chronic carriers the expression of liver hsa-miR-125a-5p and its correlation with liver HBV-DNA values and clinical presentation, 27 consecutive Caucasian, HBsAg/anti-HBe/HBV-DNA-positive patients who were naive to nucleos(t)ide analogues and interferon therapy and had no marker of HCV, HDV or HIV infection and no history of alcohol intake were enrolled. For each patient, liver HBV DNA and liver hsa-miR-125a-5p were quantified by real-time PCR in relation to β-globin DNA or RNU6B, respectively. Liver fibrosis and necroinflammation were graded by applying Ishaks scoring system. Liver hsa-miR-125a-5p was detected in all patients enrolled and a correlation between its concentration and liver HBV DNA was demonstrated (p<0.0001). Higher liver hsa-miR-125a-5p concentrations were observed in patients with HBV-DNA plasma level >103 IU/ml (p<0.02), in those with HAI >6 (p = 0.02) and those with fibrosis score >2 (p<0.02) than in patients with lower scores. Higher HBV-DNA liver concentrations were found in patients with abnormal AST (p = 0.005) and ALT serum levels (p = 0.05), in those with serum HBV DNA higher than 10E3 IU/mL (p = 0.001) and those with fibrosis score >2 (p = 0.02) than in patients with a lower load. By multivariate logistic regression analysis, liver hsa-miR-125a-5p was identified as an independent predictor of disease progression: O.R. = 4.21, C.I. 95%  = 1.08–16.43, p<0.05, for HAI >6; O.R. = 3.12, C.I. 95%  = 1.17–8.27, p<0.05, for fibrosis score >2. In conclusion, in HBsAg/anti-HBe-positive patients, the liver hsa-miR-125a-5p level correlated with liver and plasma HBV-DNA values and was associated to a more severe disease progression.

Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy

AIMS To evaluate changes in Hepatitis C Virus (HCV) RNA both in plasma and Peripheral Blood Mononuclear Cells (PBMC) in onco-haematological patients. PATIENTS AND METHODS 8 consecutive anti-HCV/HCV RNA-positive patients with onco-haematological diseases (5 with B-cell Non-Hodgkin Lymphoma and 3 with chronic lymphocytic leukaemia) were observed during chemotherapy and after its discontinuation. All were naïve to chemotherapy. HCV RNA was sought by Real Time Polymerase Chain Reaction in Light Cycler 1.5 in plasma and PBMC samples collected before, during and after chemotherapy. RESULTS An increase in HCV RNA of at least 1.5 log IU/mL in plasma and 1.1 log IU/ml in PBMC was observed in all 7 patients undergoing Rituximab-based chemotherapy; these patients showed a hepatic flare after discontinuation, life-threatening in one with cirrhosis. Also the 8th patient had cirrhosis, but was treated with Rituximab-sparing chemotherapy and did not show any increase in HCV RNA or a hepatic flare. CONCLUSION Rituximab-based chemotherapy favours an increase in HCV RNA in onco-haematological patients; this is followed by a hepatic flare, possibly immune-mediated and life threatening in cirrhotic patients.

Efficacy of pegylated interferon α-2a and α-2b in patients with genotype 1 chronic hepatitis C: a meta-analysis

BackgroundTwo formulations of Pegylated interferon (Peg-IFN) are on the market for treatment of chronic hepatitis C virus (HCV) infection. The purpose of this meta-analysis was to assess the efficacy of Peg-IFN α-2a versus Peg-IFN α-2b in combination with ribavirin in anti-human immunodeficiency virus (HIV)-negative patients with genotype 1 chronic HCV infection.MethodsThe following criteria were to be met for inclusion in the meta-analysis: (a) original data from randomized and non-randomized clinical trials; (b) study on the efficacy of conventional doses of Peg-IFN α-2a (180 μg/week) versus Peg-IFN α-2b (1.5 μg/kg of body weight/week), both in combination with ribavirin, in antiviral therapy-naïve HCV-genotype 1 subjects; (c) at least one of these primary outcomes: Rapid Virological Response (RVR); Early Complete Virological Response (EVR); End of Treatment Response (ETR); Sustained Virological Response (SVR); (d) odds ratio estimates of relative risk (RR) and associated 95% confidence intervals (CIs) or at least data enabling them to be computed; (e) English language; and (f) published as a full paper up to December 2011.ResultsSeven published studies met the inclusion criteria, allowing a meta-analysis on 3,026 patients. Peg-IFN α-2a and Peg-IFN α-2b showed similar rate of RVR (RR = 1.05; 95% CI = 0.87-1.27, p = 0.62) and SVR (RR = 1.08; 95% CI = 0.99-1.18, p = 0.098). Peg-IFN α-2a more frequently than Peg-IFN α-2b achieved EVR (RR = 1.11; 95% CI = 1.02-1.21, p = 0.013) and ETR (RR = 1.22; 95% CI = 1.14-1.31, p < 0.0001).ConclusionThe standard schedules of Peg-IFN α-2a and Peg-IFN α-2b, both in combination with ribavirin, can be used indifferently for patients with chronic HCV genotype 1 who are anti- to eliminate HIV-negative and antiviral treatment-naïve.

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients.

Occult hepatitis B infection (OBI), is characterized by low level hepatitis B virus (HBV) DNA in circulating blood and/or liver tissue. In clinical practice the presence of antibody to hepatitis B core antigen in hepatitis B surface antigen (HBsAg)-/anti-HBs-negative subjects is considered indicative of OBI. OBI is mostly observed in the window period of acute HBV infection in blood donors and in recipients of blood and blood products, in hepatitis C virus chronic carriers, in patients under pharmacological immunosuppression, and in those with immunodepression due to HIV infection or cancer. Reactivation of OBI mostly occurs in anti-HIV-positive subjects, in patients treated with immunosuppressive therapy in onco-hematological settings, in patients who undergo hematopoietic stem cell transplantation, in those treated with anti-CD20 or anti-CD52 monoclonal antibody, or anti-tumor necrosis factors antibody for rheumatological diseases, or chemotherapy for solid tumors. Under these conditions the mortality rate for hepatic failure or progression of the underlying disease due to discontinuation of specific treatment can reach 20%. For patients with OBI, prophylaxis with nucleot(s)ide analogues should be based on the HBV serological markers, the underlying diseases and the type of immunosuppressive treatment. Lamivudine prophylaxis is indicated in hemopoietic stem cell transplantation and in onco-hematological diseases when high dose corticosteroids and rituximab are used; monitoring may be indicated when rituximab-sparing schedules are used, but early treatment should be applied as soon as HBsAg becomes detectable. This review article presents an up-to-date evaluation of the current knowledge on OBI.

Clinical Presentation, Outcome, and Response to Therapy Among Patients With Acute Exacerbation of Chronic Hepatitis C

BACKGROUND & AIMS The slow asymptomatic progression of chronic hepatitis C (CHC) can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of CHC. METHODS We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of CHC from January 2005 through June 2010; we followed them up for a median period of 36 months. These cases were hepatitis C virus (HCV) RNA positive, hepatitis B surface antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed up for at least 2 years. Liver biopsy specimens had been taken from 23 cases and 31 controls-once before enrollment in the study and once during the follow-up period. RESULTS HCV genotype 2 was detected in 46.4% of cases, and HCV genotype 1 was detected in 43.9%. Among cases, the mean ALT level was 1063 ± 1038 IU/dL, and the mean total bilirubin level was 15.87 ± 7.15 mg/dL. A higher percentage of cases carried the interleukin-28B CC genotype than controls (40.2% vs 24.4%; P < .05). Among cases, 43.5% had a steady increase in ALT level (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsy specimens, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by more than 2 (P < .005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necroinflammation of more than 2 points (P < .005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained virologic response was achieved in 26 cases (81.2%) and 23 controls (60.5%). CONCLUSIONS Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a sustained virologic response after treatment with pegylated interferon and ribavirin.