Pietro Filippini

SERUM LEVELS OF HEPATITIS B SURFACE AND CORE ANTIGENS DURING IMMUNOSUPPRESSIVE TREATMENT OF HBsAg-POSITIVE CHRONIC ACTIVE HEPATITIS

One of the following treatments was randomly assigned to 101 consecutive patients with biopsy-proven chronic active hepatitis: prednisone 20 mg daily, azathioprine 100 mg daily, prednisone 20 mg and azathioprine 50 mg daily, or B vitamins 2 tablets daily (control group). Patients were observed at the beginning of the study, then at 2, 6, and 12 months after treatment. At each visit levels of HBsAg and Dane-particle-associated core-antigen (HBcAg) and their corresponding antibodies were determined. 42 patients were HBcAg positive at the beginning of the study. Of these 42 patients, the 34 who were under treatment remained HBcAg positive and showed a rise in HBcAg titre, while the 8 who were not treated had a fall in HBcAg titre (6 patients) or became HBcAg negative (2 patients) in 6 months. Among 59 patients who were HBcAg negative at the beginning of the study, this antigen became persistently detectable in 40% of the 42 patients who were treated, and was transiently present in 2 (12%) out of the 17 untreated patients (p < 0.05). Our data indicate that long-term prednisone and/or azathioprine treatments favour the replication of hepatitis-B virus in patients with HBsAg-positive chronic active hepatitis.

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.

Does HIV infection favor the sexual transmission of hepatitis C

Background There are widely discrepant findings on the sexual transmission of hepatitis C virus (HCV), commonly transmitted by the parenteral route. Coinfection with HCV is common in subjects infected with HIV. Goal This case–control study evaluated the prevalence of anti–HCV in subjects with hetero- or homosexual contact and no history of intravenous drug abuse or blood transfusion, according to the presence or absence of HIV infection. Study Design In this case–control study, the cases considered were 106 consecutive patients who showed positive anti-HIV test results. For each case, two control subjects were selected who had been screened for HIV infection at the authors’ center and found to have anti–HIV-negative test results, and who matched the case in terms age (± 5 years), gender, and risk factor for parenterally transmitted infections. Results The prevalence of subjects with positive test results for hepatitis B surface antigen (HBsAg) was similar between cases and control subjects (4.7% versus 2.4%). Positivity for anti-hepatitis B core antigen in connection with negative test results for HBsAg was observed more frequently in the 106 cases than in the 212 control subjects (33.9% versus 15.6%;P = 0.0003). Anti–HCV positivity was more frequent in the cases than in the control subjects (15.1% versus 5.2%;P = 0.005). In particular, among subjects who had hetero- or homosexual intercourse with a steady partner who had positive anti-HIV test results, anti-HCV positivity was observed in 18.7% of the 32 cases and 1.6% of the 64 control subjects (P = 0.008). Conclusion This study demonstrated that in subjects who had only a sexual risk factor for parenterally transmitted infections, HIV may enhance the sexual transmission of HCV.

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.)

Treatment of chronic hepatitis B in children with prednisone followed by alfa-interferon: a controlled randomized study.

The efficacy and safety of sequential treatment with prednisone and interferon was evaluated in a randomized, controlled study on 43 children with biopsy proven HBsAg/HBeAg/hepatitis B virus-DNA positive, anti-delta negative, chronic hepatitis (34 chronic persistent hepatitis, 9 chronic active hepatitis). Patients received either a 1-month course of prednisone (0.6 to 0.3 mg/kg per day) followed by interferon alfa-2a (3 MU/m2, thrice weekly, for 12 months; 22 patients) or no treatment (21 patients). At the end of the study (20 months), clearance of hepatitis B virus-DNA and HBeAg seroconversion were observed in nine (41%) of the patients treated with prednisone and interferon and in two (9.5%) of the untreated controls (p = 0.020). Two of the treated patients who lost HBeAg, also cleared HBsAg. In the treated group, 13 (59%) patients had stable normal levels of alanine aminotransferase on their last examination. The baseline serum level of hepatitis B virus-DNA was an important predictor of response. In fact, HBeAg clearance was observed in 75% of patients with a baseline hepatitis B virus-DNA level lower than 100 pg/ml and in none with a level above 100 pg/ml. We suggest that combined treatment with prednisone followed by alfa-interferon may be safe and effective in inducing a stable clearance of HBeAg and, in some cases, of HBsAg in children with chronic hepatitis B and with a low level of viral replication. For children with high levels of viral replication, this regimen seems to be ineffective.

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 and Virological Improvement of Hepatitis B Virus-Related or Hepatitis C Virus-Related Chronic Hepatitis with Concomitant Hepatitis A Virus Infection

BACKGROUND We evaluated the clinical and virological characteristics of hepatitis A virus infection in persons concomitantly infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). METHODS We enrolled 21 patients with acute hepatitis A and chronic hepatitis with no sign of liver cirrhosis, 13 patients who were positive for hepatitis B surface antigen (case B group), 8 patients who were anti-HCV positive (case C group), and 21 patients with acute hepatitis A without a preexisting liver disease (control A group). Two control groups of patients with chronic hepatitis B (control B group) or C (control C group) were also chosen. All control groups were pair-matched by age and sex with the corresponding case group. RESULTS Fulminant hepatitis A was never observed, and hepatitis A had a severe course in 1 patient in the case B group and in 1 patient in the control A group. Both patients recovered. On admission, HBV DNA was detected in 1 patient in the case B group (7.7%) and in 13 patients (50%) in the control B group; HCV RNA was found in no patient in the case C group and in 16 patients (81.2%) in the control C group. Of 9 patients in the case B group who were followed up for 6 months, 3 became negative for hepatitis B surface antigen and positive for hepatitis B surface antibody, 2 remained positive for hepatitis B surface antigen and negative for HBV DNA, and 4 became positive for HBV DNA with a low viral load [corrected] Of 6 patients in the case C group who were followed up for 6 months, 3 remained negative for HCV RNA, and 3 had persistently low viral loads. CONCLUSION Concomitant hepatitis A was always self-limited, associated with a marked inhibition of HBV and HCV genomes, and possibly had a good prognosis for the underlying chronic hepatitis.

Acute Hepatitis B and C Virus Coinfection: A Virological and Clinical Study of 3 Cases

We report the virological interaction in, clinical presentation of, and course of disease observed in 3 male injection drug users with acute hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection. In all 3 cases, HBV infection presented first and quickly resolved. Diagnosis of acute HBV/HCV coinfection requires a long follow-up period with careful observation.

Hepatitis C virus infection among drug addicts in Italy

There is a lack of updated nationwide records regarding hepatitis C virus (HCV) infection among drug addicts in Italy. The prevalence and characteristics of HCV infection in a national sample of drug addicts in Italy were determined. Five hundred forty‐three drug addicts (mean age 35.3 years, 85.1% males), selected from 25 Italian Centers for Substance Dependence were enrolled to be evaluated for anti‐HCV, HCV‐RNA, HCV genotype, HBV markers, anti‐HDV, and anti‐HIV during the period of April–November 2009. Anti‐HCV prevalence was 63.9%. HCV‐RNA was detected in 68.3% of patients positive for anti‐HCV. Genotypes 1 and 3 prevailed (49.3% and 39.7%, respectively). However, 9.3% of the subjects had genotype 4, a rate over threefold higher than the one observed in 1996 among drug addicts in central Italy. Needle sharing was the strongest independent predictor of the likelihood to contract an HCV infection (OR 8.9; 95% CI: 5.0–16.0). Only 19.3% of subjects received antiviral treatment for HCV. The prevalence of HBsAg and HIV positivity was 2.8% and 3.1%, respectively. The pattern of HBV markers showed that nearly one‐third of subjects had been vaccinated, while 42.3% were negative for any marker of HCV. The prevalence of HCV infection is high among drug addicts in Italy. The incidence of Genotype 4 is increasing and this may lead to the spreading of the disease to the general population in the near future. Efforts should be made to improve the rate of antiviral treatment for drug addicts with HCV infection and vaccination against hepatitis B. J. Med. Virol. 84:1608–1612, 2012.

Occult HBV infection in HCC and cirrhotic tissue of HBsAg-negative patients: a virological and clinical study

Aim To evaluate the virological and clinical characteristics of occult HBV infection (OBI) in 68 consecutive HBsAg-negative patients with biopsy-proven cirrhosis and HCC. Methods HBV DNA was sought and sequenced in plasma, HCC tissue and non-HCC liver tissue by PCRs using primers for HBV core, surface and x regions. OBI was identified by the presence of HBV DNA in at least two different PCRs. Results OBI was detected in HCC tissue of 13 (20%) patients and in non-HCC liver tissue of 3 of these 13. OBI was detected in HCC tissue of 54.5% of 11 anti-HBs- negative/anti-HBc-positive patients, in 29.4% of 17 anti-HBs/anti-HBc-positive and in 5% of 40 anti-HBs/anti-HBc-negative (p < 0.0005). The 13 patients with OBI in HCC tissue more frequently than the 55 without showed Child-B or -C cirrhosis (53.9% vs. 5.5%, p < 0.0001) and BCLC-B or -C stages (46.1% vs. 1.8%, p < 0.0001). The pre-S1, pre-S2 and S region sequences in HCC tissue showed amino acid (AA) substitutions (F19L, P24L, S59F, T131I, Q129H) and deletions (in positions 4,8, 17 and 86) in the S region, AA substitutions (T40S, P124K, L54P, G76A, N222T and I273L) in pre-S1 region and AA substitutions in pre-S2 region (P41H and P66L). In the 3 patients showing OBI also in non-HCC liver tissue the S, pre-S1 and pre-S2 sequencing displayed patterns of mutations different. Conclusions The study showed a significant correlation between OBI and the severity of liver damage, several patterns of mutations in the S, pre-S1 and pre-S2 regions in HCC tissue, some at their first description.