E. R. Schiff

Microsporidan hepatitis in the acquired immunodeficiency syndrome

Excerpt Various infections occur in the acquired immunodeficiency syndrome (AIDS); the liver can become infected by mycobacteria, fungi, and viruses (1, 2). We report a rare case of hepatitis due t...

Resolution of a contraceptive steroid-induced hepatic adenoma with subsequent evolution into hepatocellular carcinoma.

The very rare event of 3 types of liver neoplasia occurring at different times and locations in a user or oral contraceptives is reported. The woman developed benign hepatic adenoma at 36 years of age in 1977 after using pills for 14 years. She had taken a combination of norethindrone and mestranol for the last 7 years. The tumor was 13 cm in diameter and extensively involved the inferior suface of the right lobe. She discontinued pills, the tumor resolved, and she remained well. In 1984 a necrotic hemorrhagic mass with a thick fibrous capsule was then found at the same site. It was a poorly differentiated hepatocellular carcinoma. During a second laparotomy 2 months later for curative resection, another nodular mass 2 cm in diameter was found on the left lobe, apparently a focal nodular hyperplasia. 9 months later several tumor implants appeared on the serosal surface of the transverse colon, metastatic hepatocellular carcinoma. After partial colectomy the woman has been free of tumors for 2 years. The literature on the few cases of malignant transformation of adenomas associated with contraceptive steroids is discussed. Even though such adenomas usually resolve after discontinuation of the pill, patients should probably be followed with ultrasound over several years.

Activity of adefovir dipivoxil against all patterns of lamivudine‐resistant hepatitis B viruses in patients

Summary.  One hundred and thirty‐one post‐liver transplantation patients with chronic hepatitis B and failing lamivudine therapy with detectable serum hepatitis B virus (HBV) deoxyribonucleic acid by hybridization assays or ≥1 × 106 copies/mL by polymerase chain reaction, and elevated alanine transaminase levels despite continuous lamivudine, were enrolled in an open‐label study of adefovir dipivoxil. The B and C domains of HBV polymerase were sequenced for baseline samples to determine the presence of lamivudine resistance mutations. The results showed that 98% of the samples had tyrosine‐methionine‐aspartate‐aspartate (YMDD) mutations, indicating a strong correlation between the above clinical definition of lamivudine treatment failure and the presence of YMDD mutations. In addition to the rtM204V/I and the rtL180M mutations, the mutation rtV173L was identified in 19% of patients. Four major patterns of lamivudine‐resistant HBV were identified: rtL180M + rtM204V (60%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%) and rtL180M + rtM204I (9%). Treatment with adefovir dipivoxil showed similar antiviral efficacy in patients with lamivudine‐resistant virus from all four patterns.

Long‐term clearance of hepatitis C virus following interferon α‐2b or peginterferon α‐2b, alone or in combination with ribavirin

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG‐IFN) α‐2b or IFN α‐2b. We conducted two phase 3b long‐term follow‐up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α‐2b and/or PEG‐IFN α‐2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow‐up studies. In total, 636 patients with SVR following treatment with IFN α‐2b and 366 with SVR following treatment with PEG‐IFN α‐2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α‐2b and three patients treated with PEG‐IFN α‐2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1–99.7%] for IFN α‐2b and 99.4% (95% CI, 97.7–99.9%) for PEG‐IFN α‐2b. Successful treatment of hepatitis C with PEG‐IFN α‐2b or IFN α‐2b leads to clinical cure of hepatitis C in the vast majority of cases.

Thymosin α1 treatment of chronic hepatitis B: results of a phase III multicentre, randomized, double‐blind and placebo‐controlled study

Previous clinical trials have suggested that thymosin α1 (Tα1), an immunomodulatory peptide, may be effective in the treatment of chronic hepatitis B (CHB). The aim of this study was to determine the efficacy of Tα1 in a multicentre, placebo‐controlled and double‐blind study of 97 patients with serum hepatitis B virus (HBV) DNA‐ and hepatitis B e antigen (HBeAg)‐positive CHB. Patients who had been hepatitis B surface antigen (HBsAg) positive for at least 12 months entered a 3‐month screening period prior to randomization. Forty‐nine patients received Tα1 (1.6 mg) and 48 patients received placebo, twice weekly for 6 months, and were followed‐up for an additional 6 months. At inclusion, both groups were comparable for age, gender, histological grading, and aminotransferase and HBV DNA levels. A complete response to treatment, defined as a sustained serum HBV DNA‐negative status (two negative results at least 3 months apart) during the 12‐month study, with negative HBV DNA and HBeAg values at month 12, was seen in seven (14%) patients given Tα1 and in two (4%) patients treated with placebo (P = 0.084). Five (10%) patients given Tα1 and four (8%) patients given placebo exhibited a delayed response (defined as sustained serum HBV DNA negativity achieved after the 12‐month study period with negative HBV DNA and HBeAg values at the last assessment). A total of 12 (25%) patients given Tα1 and six (13%) patients given placebo showed a sustained loss of HBV DNA with a negative HBeAg value during or following the 12‐month study period (P < 0.11). These results do not confirm observations of treatment efficacy reported in other clinical studies.

Hepatitis C virus RNA quantification in right and left lobes of the liver in patients with chronic hepatitis C

Summary. Quantification of hepatitis C virus RNA in liver tissue is likely to be useful in the study of the natural history, pathogenesis, progression and treatment of hepatitis C virus‐associated liver disease. Quantitative measurements of hepatitis C virus RNA in liver biopsy samples using the branched DNA (bDNA) signal amplification assay were carried out. The aims of this study were threefold: first, to assess the level of hepatitis C virus RNA in biopsy samples from the right and left lobes of the liver; second, to evaluate the correlation between hepatitis C virus RNA levels in serum and liver; and third, to investigate the relationship between serum and liver hepatitis C virus RNA levels and the severity of hepatic histology in non‐cirrhotic patients with chronic hepatitis C. There was a strong correlation (r= 0.92, P < 0.01) between hepatitis C virus RNA levels in the right and left lobes of the liver as well as a strong correlation between hepatitis C virus RNA levels in liver and serum (r= 0.82, P < 0.01). However, there was no significant correlation between the severity of hepatic histology and levels of hepatitis C virus RNA in serum and liver among patients with chronic active hepatitis classified according to Knodells hepatic activity index (KI). Our results indicate that hepatitis C virus RNA quantification from a single liver biopsy is representative of both lobes in patients with chronic hepatitis, and suggest that serum hepatitis C virus RNA levels are a meaningful reflection of hepatitis C virus RNA levels in the liver.

Identification of hepatitis C virus by immunoelectron microscopy

Summary. Sequencing of the hepatitis C virus (HCV) has provided a better understanding of the natural history, immunology, and epidemiology of this virus. However, the morphology of HCV has not been definitively characterized. In this study, through a sequence of concentration processes, virus‐like particles were isolated from human serum and liver tissue, visualized by transmission electron microscopy and identified as hepatitis C virion by immunoelectron microscopy. Spherical flavi‐like virus particles, approximately 70 nm in diameter, were observed in the fraction with 1.04–1.12 g ml‐1 sucrose density and bound to immunogold particles with monoclonal antibodies (mAb) against hepatitis C. The nucleocapsid of the particles, which were 50 nm in diameter, appeared to be icosahedral in structure and surrounded by an envelope covered with surface projections. A ‘tadpole’ form of particles was also observed. The findings indicate that the low buoyant density in sucrose and the morphological features of the hepatitis C virion are consistent with the characteristics of flaviviruses and pestiviruses.

Persistence of hepatitis C virus in a human megakaryoblastic leukaemia cell line.

Thrombocytopenia is a frequent clinical finding in patients with hepatitis C virus (HCV) infection. Platelets from patients with HCV infection have been identified as carriers of HCV RNA in our previous studies. The present study was designed to further investigate the possibility of HCV replication in megakaryoblasts from which platelets are eventually released. A megakaryoblastic cell line (MEG‐01), established from a chronic myelogenous leukaemia patient 13years ago, was used for this study. The MEG‐01 cells were inoculated with fresh serum from a patient with HCV infection and renamed MEG‐01‐I cells. Surprisingly, both MEG‐01 and MEG‐01‐I were positive by HCV reverse transcription–polymerase chain reaction (RT–PCR) for the existence of HCV RNA and minus‐strand HCV RNA, regardless of inoculation. This was further confirmed by in situ RT–PCR. The HCV antigens, such as core, envelope, and non‐structural (NS)3 and NS4, were also present in both cell lines, as identified by Western blotting and indirect immunofluorescence staining. In addition, virus‐like particles were observed by electron microscopy in the MEG‐01 cell line as well as in the MEG‐01‐I cell line. These findings indicate that the megakaryoblasts are vulnerable to HCV infection and that replication of HCV can occur in these cells. This may help us to better understand the pathogenesis of thrombocytopenia in patients with HCV infection. The MEG‐01 cell line, which may have been continuously shedding HCV for years, should be a useful model for experimental research into HCV.

Detection of anti-hepatitis C virus antibodies in patients undergoing dialysis by utilizing a hepatitis C virus 3.0 assay: correlation with hepatitis C virus RNA.

Hepatitis C virus (HCV) infection is endemic in long-term dialysis units. We assessed the performance of a recently developed HCV 3.0 assay for the detection of HCV antibodies in patients undergoing dialysis. The study evaluated 128 patients undergoing long-term maintenance hemodialysis. Anti-HCV was detected by 2.0 and 3.0 enzyme immunoassay (EIA). Results were confirmed with recombinant immunoblot assays (RIBA 2.0 and RIBA 3.0). HCV RNA was detected by using reverse transcriptase-polymerase chain reaction (RT-PCR). Thirty-two patients (25%) were HCV EIA 2.0 positive. Of these, 1 was RIBA 2.0 negative (PCR positive), 3 were indeterminate (3 PCR positive), and 28 were positive (23 PCR positive). Thirty-five (27%) were HCV EIA 3.0 positive. One was RIBA 3.0 negative (PCR positive), 1 was indeterminate (c33c, PCR positive), and 33 were positive (27 PCR positive) by RIBA 3.0. Thus only 1 PCR-positive patient was negative with RIBA 2.0 and 3.0 assays. Two of the 3 RIBA 2.0 indeterminate samples were positive with RIBA 3.0. One remained indeterminate but was HCV RNA positive. In summary, HCV 3.0 EIA detected 4 additional viremic patients but was positive in 6 PCR-negative subjects. A high correlation of the presence of antibody to c33c with HCV RNA (28 of 34, 82%) was found, and it was found in all anti-HCV positive samples and in 1 indeterminate sample. We conclude that the HCV EIA 3.0 test with the supplemental confirmatory RIBA 3.0 test may improve the sensitivity for the detection of anti-HCV. Nevertheless, in potentially immunocompromised patients undergoing dialysis, PCR continues to be the only reliable test for detecting viremia.

Liver enzymes elevation after HAART in HIV‐HCV co‐infection

Summary.  Hepatitis C virus (HCV) co‐infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well‐understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations.