Interferon retreatment in chronic hepatitis C: which patients to choose, and what schedule to use.

UNLABELLED: OBJECTIVE; To evaluate the results of a large cohort of non-responder or relapsing responder patients with chronic hepatitis C retreated with various schedules of interferon (IFN). METHODS: Our study included 276 patients (158 non-responders and 118 relapsing responders) who underwent IFN retreatments. Among the non-responder group, 158 patients underwent further courses of IFN. In particular, 108 patients underwent one course of IFN retreatment, 40 patients underwent two courses, eight patients underwent three courses, and two patients underwent four courses. Regarding the relapsing responder group, the 118 patients were retreated with the same dosage for varying periods. In particular, 50 patients were treated for 6 months, 43 patients for 12 months, and 25 for 24 months. Patients in the subgroups of IFN retreatment were homogeneous as far as age and gender distribution, as well as virological and histological characteristics, are concerned. Qualitative and quantitative HCV-RNA was evaluated at baseline, at the end of treatment and at the last check-up of follow-up. HCV genotype was determined on baseline serum samples. Alanine transaminase (ALT) levels were tested monthly. RESULTS: Long-term biochemical (normal ALT levels) and virological (HCV-RNA negative) response was obtained in 2.6% of non-responder retreated patients, and in 33.9% of relapsing responder retreated patients. Evaluation of response on the basis of the duration of treatment showed that 48%, 19% and 16% of relapsing responder patients retreated for 24, 12 and 6 months, respectively, obtained long-term biochemical and virological response. CONCLUSION: Non-responder patient retreatment is inefficient especially in cirrhotic and/or genotype 1 b patients. IFN retreatment is warranted in relapsing responder patients. In particular, 24-month therapy induces significant long-term biochemical and virological response.

[Bacterial infections in HIV patients]. / Infezioni batteriche in pazienti con malattia da HIV.

AIM OF THE STUDY AND METHODS: Retrospective analysis of bacterial infections occurring in 400 admissions of HIV-positive patients in the Infectious Diseases Unit of the Azienda Ospedale Santa Corona, Pietra Ligure (SV), from January 1994 to September 1996. RESULTS: 56 episodes were documented (14% of admissions): 24 (43%) hospital acquired (11 sepsis, 5 pneumonias, 6 urinary-tract infections, 1 infection of a prosthetic device) and 32 (57%) community-acquired (9 sepsis, 13 pneumonias [6 with bacteremia] 9 urinary-tract infections, 1 endocarditis). At time of diagnosis mean absolute CD4-lymphocyte count was 106/cmm (95% Cl 62-150) and mean neutrophil count was 4.690/cmm (95% Cl 3.466-5.914); 11 patients had a central venous catheter, 9 a vesical catheter and 7 severe skin lesions. Methicillin-resistant S. aureus (11/24, 46%) and Pseudomonas (8/24, 33%) were the most frequently isolated pathogens in hospital infections, while the majority of community acquired episodes were due to S. pneumoniae (10/32, 31%). In six episodes (11%) the patient died because of the bacterial infection. CONCLUSIONS: Bacterial infections are quite frequent in this cohort of HIV-infected patients. Methicillin-resistant S. aureus and Pseudomonas represented the major cause of hospital acquired infections, while S. pneumoniae represented the major cause of community acquired episodes.

Dorfman-Chanarin syndrome: a case with prevalent hepatic involvement.

BACKGROUND/AIMS: Dorfman-Chanarin syndrome is a very rare condition determined by an autosomal recessive inherited disorder of neutral lipid metabolism. The syndrome is defined by the association of ichthyosiform nonbullous erythroderma, vacuoles in the leukocytes and variable involvement of liver, muscle and central nervous system. Only 19 cases have been described worldwide. METHODS: We studied a 16-year-old patient with congenital ichthyosis, liver and spleen enlargement and abnormal gamma-glutamyltransferase. Liver biopsy, skin biopsy and blood smear showed abnormal intracellular neutral lipid storage. RESULTS/CONCLUSION: On the basis of clinical and histological findings, the patient was diagnosed as having Dorfman-Chanarin syndrome. This is the fourth reported Italian case, with a prominent skin and hepatic involvement. Liver biopsy, performed in the first instance, was of great importance in reaching a diagnosis.

Behavior of soluble HLA class I antigens in patients with chronic hepatitis C during interferon therapy: an early predictor marker of response?

Soluble HLA class I antigens (sHLA-I), beta 2-microglobulin (beta 2-mu) and alanine aminotransferase (ALT) serum levels have been evaluated in 16 patients affected by chronic hepatitis C treated for six months with recombinant interferon-alpha (rIFN-alpha, 3 MU three times a week). The predictor role of sHLA-I and ALT modifications with respect to the response to rIFN-alpha therapy was also evaluated. Six patients responded (group 1), five patients relapsed followed in initial responses (group 2), and five did not respond to rIFN-alpha treatment (group 3). The baseline serum levels of sHLA-I and beta 2-mu were significantly higher in all three groups of HCV-positive patients with respect to HCV-negative controls (P < 0.05). A significant increase of sHLA-I serum level with respect to baseline value (P < 0.001) was observed in group 1 patients after two weeks of rIFN-alpha treatment. sHLA-I serum level then decreased, although remaining steadily and significantly increased with respect to baseline (P values ranging from 0.05 to 0.01) in the following five months and then returned to baseline one month after the end of rIFN-alpha administration. No significant variations of beta 2-mu serum levels were detected throughout the observation period. In group 1 patients ALT serum levels significantly decreased after two weeks of rIFN-alpha treatment (P < 0.001) and then remained in the normal range throughout the observation period. In the other two groups of patients no relevant variations of sHLA-I and beta 2-mu serum levels were found during and after rIFN-alpha therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphoblastoid interferon therapy in chronic hepatitis C: biochemical, virological and histological evaluation of two different doses.

Sixty patients of both sexes with biopsy-proven chronic hepatitis C were randomized to receive lymphoblastoid interferon 3 MU or 6 MU three times weekly for 6 months. A follow-up period of 3 months at the end of the therapy was scheduled. Thirty-two patients (53.3%) normalized alanine aminotransferase at the end of the therapy. Of these, 17 received 3 MU (56.7%) and 15 (50%) received 6 MU. Eighteen of the 32 patients (56.2%) relapsed in the follow-up period after treatment. No significant difference in relapse rate was observed between the two groups. The overall percentage of the non-responder patients was 36.6%. The treatment was discontinued because of non-compliance and/or side effects in six patients (10%): three in the 3-MU group and three in the 6-MU group. An improvement in liver histology was observed in about a quarter of chronic active hepatitis patients whose overall diagnosis changed to chronic persistent hepatitis. Knodell's score system showed a significant improvement (p < 0.05) with regard to peripheral necrosis, fibrosis and total score. HCV-RNA was positive at the beginning in all patients and it became undetectable in almost all responder patients. In some cases there was no correlation between viraemia and biochemical signs of liver disease. Our study shows that 6 MU does not increase the response rate compared to 3 MU. Moreover, the lower dose is able to improve the liver histology and to abolish the HCV viraemia in responder patients.

Biochemical scores could reflect histological activity in chronic hepatitis C.

Eighty-one patients with HCV positive chronic active hepatitis (CAH) were studied to correlate, in multivariate regression analysis, liver tests with the histological activity index (HAI). The median HAI value (9.4) divided the patients into two groups; 44 under the 9.4 value (moderate CAH) and 37 above (severe CAH). Multiple regression improved the significance of nine biochemical parameters related to HAI in univariate analysis, and backward stepwise analysis identified the combination of alanine-aminotransferase (ALT), gammaglobulins (gamma GL), gammaglutamyl transpeptidase (gamma GT) and prolyl-hydroxylase (PH) as the best relationship with HAI (R = 0.520, p < 0.0001). A biochemical activity index (BAI) calculated as: 2.304 + ALT x 0.013 + gamma GL x 1.76 + gamma GT x 0.008 + PH x 0.012 showed the higher significant difference between moderate (7.7 +/- 1.3) and severe (12.2 +/- 2) CAH (p < 0.0001). These results suggest that this BAI could be a pointer for checking activity of chronic liver diseases.

Sex hormones and sex hormone-binding globulin in males with chronic viral hepatitis during recombinant interferon-alpha 2b therapy.

The effect of long-term treatment with recombinant interferon-alpha 2b (IFN-alpha 2b) on luteinizing hormone (LH), testosterone, free testosterone, and sex hormone-binding globulin (SHBG) was evaluated in 7 male patients suffering from chronic viral hepatitis. The drug was given three times a week for 6 months in a single standard dose of 3 x 10(6) units. Hormone evaluations were performed in basal conditions and every 2 months for 12 months. Serum testosterone values decreased after IFN treatment, reaching the lowest levels at the 6th month. However, testosterone values did not fall below the normal range. Serum SHBG concentrations, which were above the normal range in basal conditions, also decreased after IFN. Serum-free testosterone and LH concentrations did not change during IFN therapy. IFN-alpha 2b at the dose and schedule employed was not responsible for any measurable imbalance in male sex hormones.

Long term therapy with recombinant interferon alpha 2 b in patients with chronic hepatitis C: effects on thyroid function and autoantibodies.

Twelve anti HCV-positive patients (8 males and 4 females; 37-62 yrs) suffering from chronic active viral hepatitis have been evaluated in order to determine serum thyroid hormones and autoantibody pattern during recombinant interferon alpha 2b (IFN-alpha 2b) therapy. The interferon was given subcutaneously three times per week for six months in a single standard dose of 3 MU. For a further six months 5 patients (Group A) received the same interferon at 1MU dose three times per week and 7 (Group B) had no treatment. Serum T3, T4, FT4, TBG, TSH, TGAb and TMAb were determined on serum collected before the start of the treatment and every month for 12 months thereafter. Except for one case, in which a transient reduction in thyroid hormone values and an increase in TSH levels was recorded, none of the patients studied showed a significant variation of serum hormonal parameters or appearance of pathological TGAb and/or TMAb levels. The data indicate that the administration of recombinant IFN-alpha 2b to HCV positive chronic active hepatitis patients at the dose and schedule employed in the present study may result in a reduction in the incidence of thyroid dysfunction related to the IFN therapy.

Interferon therapy in chronic hepatitis C. Evaluation of a low dose maintenance schedule in responder patients.

Evidence has accumulated that interferon therapy can be effective in reducing transaminase levels and improving liver histology in patients with chronic hepatitis C. Unfortunately, the relapse rate after discontinuing treatment remains a problem. In this study the efficacy of a low dose of interferon was investigated for preventing relapses in patients who completely responded to a 6-month course of 3 MU 3 times a week. Eighteen out of 30 patients (60%) had normal ALT at the end of the 6th month of therapy. These patients were randomly allocated to receive either 1 MU interferon 3 times a week for 6 months or no treatment. Three patients (33.3%) without maintenance schedule and 4 (44.4%) treated with 1 MU relapsed. HCV-RNA was positive in 23 tested patients at entry and became undetectable in patients with sustained response. Relapse was associated with RNA reappearance. A post-therapy liver biopsy, performed in 8 patients, showed Knodell's score improvement. In conclusion, our study confirms the efficacy of interferon at the dose of 3 MU 3 times a week for 6 months. A low maintenance dose of interferon seems to be ineffective in preventing relapse in patients with chronic HCV infection who have responded to a prior treatment course.

Anti-hepatitis C virus antibodies and hepatitis C virus viraemia in haemodialysis patients.

Sera from 82 haemodialysis patients were tested for anti-HCV, HCV-RNA, and HBsAg. Alanine aminotransferase (ALT) activity was monitored weekly for 2 months. Anti-HCV was positive in 31 patients (37.8%), showing different single-peptide patterns. HCV-RNA was detected in 26 anti-HCV-positive patients (84%) and also in two of 21 anti-HCV-negative patients. Twenty-seven (87%) of the 31 anti-HCV-positive patients had persistently normal ALT values; 22 of these patients were HCV-RNA positive. The four patients with elevated ALT values had HCV viraemia. HBsAg was positive in nine anti-HCV-negative patients. The close correlation between HCV viraemia and HCV status, independently of ALT values, requires that anti-HCV dialysis patients must be considered potentially infective and dialysed with reserved machines and/or in separate shifts.

Increased steady-state levels of alpha-fetoprotein mRNA in hepatocellular carcinoma: an analysis by in situ hybridization.

The molecular basis for the augmented production of alpha-fetoprotein is unknown. We have used in situ hybridization of alpha-fetoprotein cDNA to malignant hepatocytes to establish if increased serum alpha-fetoprotein concentrations are related to detectable steady-state levels of alpha-fetoprotein mRNA in hepatocytes. Tumor tissue from four patients with histologically confirmed hepatocellular carcinoma were examined, and the results compared to fetal liver. Northern blot hybridization for alpha-fetoprotein mRNA in tumor tissue was also analyzed. As expected a high number of grains was observed in fetal liver tissue, indicative of high levels of alpha-fetoprotein mRNA physiologically present during pre-natal development. Sections from all patients with high serum concentrations of alpha fetoprotein showed appreciable hybrid formation, which correlated semi-quantitatively with the serum concentrations. However, hybrids were not detected in a patient with a normal serum alpha-fetoprotein. The high alpha-fetoprotein mRNA levels in fetal and neoplastic liver suggest that gene transcription is the mechanism of alpha-fetoprotein production in malignancy, although the control of this mechanism remains speculative.

A percutaneous liver biopsy technique in ducks (Anas platyrhynchos) experimentally infected with duck hepatitis B virus.

Aylesbury ducks (Anas platyrhynchos) chronically infected with the duck hepatitis B virus provide a useful model for studying hepadna-virus infection, replication and the effects of antiviral therapy. In these studies, it is necessary to have an effective method for obtaining repeat liver specimens for histological and molecular analyses. We have therefore developed a percutaneous liver biopsy technique which has a low rate of complications, can be performed at repeated intervals, and provides sufficient quantities of liver tissue for histological and nucleic acid hybridization analysis.

Antimycobacterial chemotherapy in inflammatory bowel disease.

We report on a case, ulcerative colitis and another of Crohn's disease. During a relapse which was unresponsive to conventional therapy, acid-fast bacilli were found in colonic biopsies. Conventional therapy was substituted with antimycobacterial chemotherapy (rifampicin, isoniazid and ethambutol) which was responsible for a marked improvement. However, a relapse occurred during chemotherapy and no acid-fast bacilli were found. The patients became responsive to sulphasalazine and corticosteroid therapy once again. It appears that Mycobacteria play a collateral role in inflammatory bowel disease and that once they have been eliminated the original disease re-emerges.