Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in 'real world' patients with chronic hepatitis C.

BACKGROUND: Interferon-alpha plus ribavirin therapy for chronic hepatitis C is associated with adverse effects that lead to therapy discontinuation in up to 27% of patients in randomized controlled trials. AIM: To examine the causes and predictive factors for therapy discontinuation in patients treated in current clinical practice. METHODS: We retrospectively enrolled 441 consecutive patients, scheduled to receive interferon-alpha + ribavirin for chronic hepatitis C, in five centres. Patients had been treated with 3 or 6 MU interferon-alpha three times a week plus ribavirin, 800-1200 mg daily, for 6 or 12 months. RESULTS: One hundred and eight [24.5%; confidence interval (CI), 20.5-28.8%] patients failed to finish combination therapy because of adverse events. The discontinuation rate was higher during the first 6 months of treatment; anaemia was an important cause (36.1% of discontinuations); unexplained lipothymia resulted in discontinuation in 11 patients. Female gender [hazard ratio (HR) = 1.85; CI, 1.17-2.92], an interferon-alpha dose > 15 MU/week (HR = 1.79; CI, 1.12-2.86) and no previous interferon-alpha treatment (HR = 1.63; CI, 1.04-2.57) were independent factors associated with discontinuation. The simultaneous presence of these factors identified patients at high risk for discontinuation [odds ratio (OR) = 10; CI, 3.98-25.13]. CONCLUSIONS: The study identified some predictive factors for adverse event-related discontinuation, which may improve the safety profile and effectiveness of interferon-alpha + ribavirin combination therapy in chronic hepatitis C.

Non responders to interferon therapy among chronic hepatitis patients infected with hepatitis C virus.

We studied a series of 268 chronic hepatitis C patients (31 chronic persistent hepatitis CPH, 69 mild chronic active hepatitis CAH, 125 severe CAH, and 43 active cirrhosis) enrolled from 1988 to 1991 in different therapeutic protocols using lymphoblastoid or recombinant interferon (IFN) at a dosage of 3 mega units (M.U.), three times a week for 12 months. Of these patients 54.8% showed a complete response (normalization of aminotransferases), 14.2% a partial response (decrease in aminotransferases of over 50%), 27.6% no response, and 3.4% a substantial progressive increase in the liver enzymes during IFN (becoming worse). The prevalence of non responders was lower in CPH (9.7%) than in CAH patients (31.9% in the mild form and 20.8% in the severe), and significantly higher in patients with cirrhosis (53.5%). No correlation was observed between non response and the baseline aminotransferase level or the patient's sex. Patients under 35 had a better response to IFN when compared with patients 36-50 years. This is probably due to the higher prevalence of CPH patients with a good response to IFN in the youngest group. No effect was gained in non responders by increasing the dose or shifting from recombinant to lymphoblastoid IFN; three patients were then treated with steroids, but only one benefitted. For 5 of the 9 patients who became worse, steroids were started after discontinuation of IFN therapy, and they induced a favorable response only for the 3 who had developed autoantibodies during IFN treatment.

Effect of prednisone priming followed by alfa-interferon in treatment of children with chronic hepatitis B: an interim analysis of a controlled trial.

A six-month analysis of a controlled trial on the treatment of chronic hepatitis B in children shows that prednisone priming followed by alpha-interferon 2A was effective in 6 of 9 treated patients in reducing HBV replication and disease activity.

HBsAg carriers among blood donors in Italy; a retrospective survey of data from 189 blood banks.

Data of occasional or periodic blood donors from 189 banks scattered throughout Italy were retrospectively surveyed for the period between 1974 and 1977. The prevalence of HBsAg positive subjects (PHA or RIA) among occasional donors during 1975-1977 was about 3% with no appreciable annual variation. The rate of HBsAg positivity in southern Italy (i.e. Campania, 4.32%) was higher than in northern Italy (i.e. Trentino, 0.30%). Only 0.27% of the occasional donors showed both HBsAg positivity and elevated serum transaminases levels. Among periodic donors the rate of infection, as indicated by the appearance of HBsAg in serum subsequent to the last donation, was approximately 0.5% per year. Only one-tenth of the periodic donors who acquired HBsAg also had hypertransaminasemia.

The etiology of chronic hepatitis in Italy: a multicenter study.

In a multicenter retrospective study, we reviewed the etiology of chronic hepatitis (CH) in Italy during the period 1980-1989, before the laboratory diagnosis of HCV hepatitis had become possible. Among the 5,461 patients investigated, 31.3% had HBV-CH, 5.5% HDV-CH, 3.0% serological markers of autoimmune hepatitis and 3.7% post-transfusion NANB CH. Alcohol abuse was considered responsible in 10.9% of the cases and a diagnosis of crytogenic CH was made in 42.5%. Considering that most cryptogenic cases were actually due to chronic HCV infection, we may assume that as many as two-thirds of our cases were due to a hepatitis virus infection. Some differences were observed between patients with chronic hepatitis of different etiologies. Drug abuse was frequently recorded only in HDV-CH; patients with HBV-CH and HCV-CH were younger than those in other etiological groups; a histological picture of chronic active hepatitis was more frequently recorded in HDV-CH and autoimmune CH. The only identifiable geographical differences observed were a higher prevalence of HDV-CH in the south and of alcoholic chronic liver diseases in the north. During the period under observation, we noted a clear reduction in the percentages of HBV chronic hepatitis cases after 1984 and, accordingly, the mean age of HBV-CH progressively increased from 1980 to 1989 by almost a year each year. This observation is in agreement with recent data suggesting a reduction in HBV endemicity in Italy in recent years.

Immunosuppressive therapy in chronic active hepatitis (CAH). A multicentric retrospective study on 867 patients. A report from a study group for CAH of the Italian Association for the study of the liver.

We retrospectively reviewed the clinical, biochemical and histological features of 867 patients with biopsy-proven CAH observed in 12 Italian Liver Units for at least one year. Either HBsAg positive or HBsAg negative patients (473 and 394 patients, respectively) were left untreated, or were treated with one of the following regimens: a) prednisolone or prednisone 10 to 30 mg daily, referred to as Steroids; b) azathioprine 50 to 100 mg daily; c) prednisolone or prednisone 10 to 20 mg daily associated with azathioprine 50 to 100 mg daily, referred to as Combination. The outcome was evaluated on the basis of clinical, biochemical and histological parameters. Among the 473 patients with HBsAg positive CAH those treated with combination, as compared to those untreated, more frequently, improved (P less than 0.001), and less frequently deteriorated (P less than 0.001). Under Steroids or Azathioprine improvement was more frequent than in untreated patients, but deterioration was not prevented. The results were similar among the 394 HBsAg negative patients. The data indicate that combination is effective in treating either HBsAg positive CAH or HBsAg negative CAH.

Treatment of chronic active hepatitis (CAH): a retrospective review of 130 patients.

The authors review the course of disease in 130 patients (87 HBsAg-positive and 43 HBsAg-negative) with chronic active hepatitis (CAH) observed in the last six years. Patients were treated with prednisone (36 HBsAg-positive an 8 HBsAg-negative), azathioprine (7 HBsAg-positive and 12 HBsAg-negative) or a combination of prednisone and azathioprine (23 HBsAg-positive and 14 HBsAg-negative), or remained untreated (21 HBsAg-positive and 9 HBsAg-negative). Among HBsAg-positive patients improvement was observed in 54% of the 66 patients treated, and in none of the 21 untreated patients (P less than 0.001). Treatment did not modify the course of the disease in HBsAg-negative patients with CAH; this is probably related either to the small number of patients in each treatment group, or to geographical differences. Furthermore treatment was not effective in patients older than 40 years, whether HBsAg-positive or HBsAg-negative. Three out of 87 HBsAg-positive patients, and two out of the 43 HBsAg-negative patients had died by the end of the observation period irrespective of treatment. Full remission with clearance of HBsAg was observed only in one patient after 4 years of treatment with steroids.

Hepatitis B virus DNA in chronic HBsAg carriers: correlation with HBeAg/anti-HBe status, anti-HD and liver histology.

Hepatitis B virus DNA was determined in the sera of 198 chronic hepatitis B surface antigen (HBsAg) carriers by the spot hybridization technique. The results were correlated with hepatitis Be antigen (HBeAg) and antibody (anti-HBe), delta antibody (anti-HD) and liver histology. All subjects had a liver biopsy. The prevalence of HBV DNA was 63% in HBeAg-positive subjects and 8.8% in anti-HBe positives. HBV DNA was not found more frequently in chronic HBsAg carriers who had histological evidence of liver disease than in carriers without such evidence. Anti-HD was detected in 48.5% of subjects, with an increasing trend (p less than 0.001) according to the severity of liver disease. Among patients with more severe liver disease (CAH and cirrhosis), HBV DNA and HBeAg were detected less frequently in anti-HD-positive than in anti-HD-negative subjects (7% vs. 42.3%, p less than 0.001 and 7% vs. 34.4%, p less than 0.005, respectively). These findings indicate that HDV infection jointly affects both HBeAg status and HBV DNA.

[Maternal-fetal transmission of hepatitis B virus. Follow-up study of 21 infants born to HBSAG-positive mothers, and 6 born to HBSAG-negative mothers with anti-HBV antibodies]. / La trasmissione materno-fetale del virus della epatite B (HBV). Osservazione nel tempo di 21 nati da madri HBsAg positive e di 6 nati da madri HBsAg negative con anticorpi anti-HBV.

Vertical transmission of hepatitis B virus (HBV) was studied in 21 mother-infant pairs. A transient HBs-antigenemia was observed in 60% of the 10 children born to HBsAg healthy carrier mothers and 91% of the 11 babies born to mothers with HBsAg-positive CAH. Among the 16 children showing HBs-antigenemia, 3 developed acute viral hepatitis two of whom showed progression to chronicity.

[Epidemiological evaluations of human immunodeficiency virus, herpes simplex virus type 1 and 2 and cytomegalovirus infections in drug addicts]. / Valutazioni epidemiologiche sulle infezioni da human immunodeficiency virus, herpes simplex virus tipo 1 e 2 e cytomegalovirus in tossicodipendenti.

Eighty-eight drug addicts from the "BAN Center" in Torre Annunziata (Naples) and 88 normal subjects pair-matched for age and sex were tested for IgG to human immunodeficiency virus (HIV), herpes simplex virus (HSV) type 1 and 2 and cytomegalovirus (CMV). A high prevalence of subjects with antibodies to HSV-1 and CMV (80.7% and 65.9%) were recorded in the control group testifying to the high level of these infections in Campania. Prevalences were higher in drug addicts, and drug abuse was identified as a risk factor for the acquisition of CMV infection (odds ratio = 2.3). Moreover, drug addiction is also a risk factor for HSV-2 and HIV infection as demonstrated by the observation that drug abusers were anti-HSV-2 (9.1 vs. 1.1%, odds ratio = 6.16) or anti-HIV (11.4 vs. 0%, odds ratio = 23.6) positive more frequently than normal controls. Thus, drug addiction is a risk factor for the acquisition of HIV, HSV-2 and CMV infections. This is probably due to similar habits, frequent among drug addicts from our geographic area and uncommon in the normal population, such as tattooing, needle-sharing needlestick and unsafe sex. Some of these habits, such as unsafe sex and tattooing, seem to be, per se, risk factors for the acquisition of both HIV and CMV infections. The data also suggest that HIV infection was probably introduced in Campania more recently than in northern and central Italy where the prevalence of anti-HIV positive cases among drug addicts is definitely higher.

[Serum anti-HIV IgA in seropositive patients and in subjects at risk of HIV infection]. / IgA sieriche anti-HIV in pazienti sieropositivi ed in soggetti a rischio di infezione da HIV.

To detect the presence of anti-HIV IgA in HIV infected subjects and in seronegative subjects at risk of infection, we assessed a Western Blot using nitrocellulose strips with HIV separated proteins. We tested at least 2 different serum samples from 9 anti-HIV positive subjects (Group A), 9 anti-HIV negative subjects at risk of infection (Group B) and 9 controls (Group C). One subject in Group B became anti-HIV positive during the observation. Anti-HIV IgA were detected in all patients of Group A, in 66.6% of patients of Group B and in no patient of Group C. The subject who seroconverted during the observation showed positivity for IgA anti-HIV in both serum samples, while anti-HIV IgG became detectable only on the second serum sample. A newborn from a seropositive mother showed maternal anti-HIV IgG on the first 2 out of 3 serum samples while showed anti-HIV IgA positivity on the third sample only. This child is still anti-HIV negative.

[Polymerase chain reaction (PCR) for the detection of HIV proviral DNA (pDNA) in subjects at risk of infection]. / Polymerase chain reaction (PCR) per la determinazione di DNA provirale (pDNA) di HIV in soggetti a rischio di infezione.

To detect HlV proviral DNA in lymphocytes from subjects at risk of acquiring HIV infection, we assessed a Polymerase Chain Reaction Assay using the SK38 and SK39 primers for the amplification and the SK19 probe for the hybridization. The detection of amplified HIV-DNA was obtained by a new colorimetric method, the DNA enzyme immunoassay (DEIA). The PCR we performed allowed to detect HIV-pDNA in lymphocytes of 13 out of 64 subjects at risk of acquiring HIV infection. Seven of these 13 became anti-HIV positive during a follow up of 8 months.

[HIV Antigens as complement fixing circulating immune complexes]. / Antigeni di HIV in immunocomplessi circolanti fissanti il complemento.

To detect HIV antigens in circulating complement fixing immune complexes (ICs) we assessed an ELISA using wells of microtitre plates coated with F(ab)2 anti-C3b and monoclonal antibodies anti-HIV gp120 and anti-HIV p24. We tested 24 anti-HIV positive subjects (Group A), 10 anti-HIV negative subjects at risk of acquiring HIV infection (Group B), 20 normal controls (Group C) and 2 seroconversion panels. We found HIV antigens in ICs in all sera from seroconversion panels, in 25.5% of sera from subjects in Group A, in 28.6% of sera from subjects in Group B and in no serum from subjects in Group C. A subject in Group B acquired HIV infection during the observation. HIV antigens in ICs by our assay were detected 8 months before Anti-HIV and Ag by commercial ELISA.

[Anti-HAV screening patients with chronic hepatitis]. / Screening per anti-HAV in pazienti con epatite cronica.

Following the decrease in HAV endemic levels in the last decades, nowadays in Italy most people aged less than 30 years are susceptible to the infection. We have tested for serum anti HAV IgG 194 chronic hepatitis patients from Naples to evaluate the level of protection against HAV in a category of patients in whom an acute necrosis due to HAV might induce liver failure. The study shows that 90.7% of Neapolitan chronic hepatitis patients has serologic evidence of prior HAV infection. Specifically, 98.1% of the patients over 40 years of age, but only 54.6% of those under 40 tested positive for anti HAV IgG. 102 patients had cirrhosis and only one tested negative. The data suggest that HAV vaccination in susceptible chronic hepatitis patients should be judged by the physicians in care on the basis of the severity of disease, patient's age, real risk of exposure to the infection, and level of education.

The spread of viral hepatitis in Italian dialysis units.

In order to evaluate the spread of viral hepatitis to dialysis patients and staff, 83 out of the 134 dialysis units operating in Italy at present were surveyed. The results were statistically evaluated. Of the 81 Italian centres surveyed, 66 were affected by viral hepatitis. There were 450 cases of infection among patients on regular dialysis treatment (9.7% of all dialysed patients). Of these 450, 163 had icteric viral hepatitis (116 HBsAg positive), 145 has non icteric hepatitis (100 HBsAg positive) and 142 were HBsAg carriers. The mortality rate among the dialysis patients with hepatitis was 9.1% with death occurring most frequently in icteric cases. Of the 133 cases of viral hepatitis observed among medical and nursing staff, 103 of these were HBsAg positive. Moreover, there was a higher risk of hepatitis infection observed in patients on regular dialysis treatment by multi-patient central system plate dialysers, in carriers of exteriorized arteriovenus shunt in patients who were submitted to frequent dialysis sessions and haemotransfusions.