Hepatitis and cholestasis in a middle-aged woman.
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Adult↗
Biomedical subjects
R P Perrillo
Publications and source records attributed to R P Perrillo.
Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis Interventional Therapy Group.
To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.
Adolescent↗
The A to Z of new hepatotropic agents: human hepatitis viruses and monkey business.
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Acute Disease↗
Prolonged survival in fibrosing cholestatic hepatitis with long-term ganciclovir therapy.
A 45-yr-old man underwent liver transplantation for cirrhosis due to hepatitis B and developed recurrent infection. Serial liver biopsies revealed fibrosing cholestatic hepatitis, an entity that is associated with rapid graft failure, and this was treated with long-term intravenous ganciclovir therapy. The patient is alive and well 2 yr after transplantation, despite the presence of well-established cirrhosis and a marked accumulation of intrahepatic hepatitis B surface and core antigens. It is postulated that partial reduction of viral replication resulted in an incomplete syndrome in which rapid graft failure did not occur, but progressive fibrosis developed. Our case suggests that newer nucleoside analogues that provide a greater degree of inhibition to hepatitis B virus replication may greatly improve the outcome of patients with recurrent infection after liver transplantation.
Antiviral Agents↗
A preliminary trial of lamivudine for chronic hepatitis B infection.
BACKGROUND: Better treatments for chronic hepatitis B are needed. Lamivudine, the (-)enantiomer of 3'-thiacytidine, is a potent inhibitor of hepatitis B virus (HBV). METHODS: In a double-blind trial, we randomly assigned 32 patients with chronic hepatitis B (including 17 who had no response to earlier treatment with interferon) to receive 25, 100, or 300 mg of oral lamivudine daily for 12 weeks. The patients were then followed for 24 additional weeks. All the patients had hepatitis B antigen in serum. RESULTS: Levels of HBV DNA became undetectable (< or = 1.5 pg per milliliter) in 70 percent of the patients who received the 25-mg dose of lamivudine and 100 percent of those treated with the 100-mg or 300-mg dose. In most patients, HBV DNA reappeared after therapy was completed; however, six patients (19 percent), including five who had not responded to interferon, had sustained suppression of HBV DNA accompanied by normalization of alanine aminotransferase levels. Hepatitis B e antigen disappeared in four of these six patients (12 percent), three of whom had had no response to interferon. Levels of HBV DNA fell in all patients, including those who had had high levels at base line or normal alanine aminotransferase levels at base line, but sustained responses were more likely in patients with initially low HBV DNA levels and high alanine aminotransferase levels. During and after therapy, alanine aminotransferase levels at least doubled in five patients (50 percent) given the 25-mg dose and eight patients (36 percent) given the 100-mg or 300-mg dose. Minor adverse events occurred that were not related to the dose, as did transient, asymptomatic elevations of amylase, lipase, and creatine kinase levels. CONCLUSIONS: In a preliminary trial, 12 weeks of lamivudine therapy was well tolerated, and daily doses of 100 mg and 300 mg reduced HBV DNA to undetectable levels.
Adolescent↗
Genomic variations in the hepatitis B core gene: a possible factor influencing response to interferon alfa treatment.
BACKGROUND/AIMS: Interferon treatment causes a sustained loss of virus replication only in a proportion of patients with chronic hepatitis B. This study investigated whether genomic variations in the precore/core gene of hepatitis B virus affect the response to interferon alfa. METHODS: The precore/core region was sequenced in 46 serum samples obtained before, during, and after interferon treatment of 12 patients. RESULTS: In 23 samples from 7 responders (group A), there were 24 missense mutations, whereas in 23 samples from 5 patients who did not respond or relapsed after treatment (group B), there were 141 missense mutations (P < 0.001). All group B patients had cirrhosis, but only 2 of 7 patients in group A had cirrhosis (P = 0.026). Substitutions in amino acids 21-27 of the core protein, known to diminish HLA-A2-restricted cytotoxic T-cell function, were found in all nonresponders but in none of the responders. No significant changes occurred in the precore/core region in responders after seroconversion to antibody to hepatitis B e antigen, but multiple variations persisted in group B during treatment and new mutations appeared with the relapse of hepatitis. CONCLUSIONS: Specific mutations in the core protein that can interfere with T-cell function occur frequently in patients with advanced chronic hepatitis B and may affect the response to interferon.
Adult↗
Quantitation of HBV DNA in human serum using a branched DNA (bDNA) signal amplification assay.
The aim of this study was to establish the performance characteristics of a nonradioisotopic branched DNA (bDNA) signal amplification assay for quantitation of hepatitis B virus (HBV) DNA in human serum. Quantitation was determined from a standard curve and expressed as HBV DNA equivalents/mL (Eq/mL; 285,000 Eq = 1 pg of double stranded HBV DNA). The bDNA assay exhibited a nearly four log dynamic range of quantitation and an analytical detection limit of approximately 100,000 Eq/mL. To ensure a specificity of 99.7%, the quantitation limit was set at 700,000 Eq/mL. The interassay percent coefficient of variance for quantification values ranged from 10% to 15% when performed by novice users with different sets of reagents. Using the bDNA assay, HBV DNA was detected in 94% to 100% of hepatitis B e antigen-positive specimens and 27% to 31% of hepatitis B e antigen-negative specimens from chronic HBV-infected patients. The bDNA assay may be useful as a prognostic and therapy monitoring tool for the management of HBV-infected patients undergoing antiviral treatment.
DNA Probes↗
Application of six hepatitis C virus genotyping systems to sera from chronic hepatitis C patients in the United States.
Serum samples from 139 US patients with chronic hepatitis C virus (HCV) infection were studied using six different genotyping systems, including both molecular and serologic methods, to determine the applicability of these approaches and the prevalence of various HCV subtypes. The concordance of genotyping results based on the various systems (except for core polymerase chain reaction genotyping) was good (93.5%). Subtypes 1a and 1b were prevalent (37.4%). Subtypes 2a (2.2%), 2b (8.6%), and 3a (5.8%) were less common. HCV genotypes could not be determined in 3.4%-16.5% of samples depending on the method used. HCV type 2 was associated with greater histologic activity but lower serum HCV RNA levels (P < .05), whereas type 3 was associated with lower serum alanine aminotransferase levels (P < .05). These data demonstrate a high concordance between HCV genotyping systems and provide a foundation for comparison of genotyping data between studies using different systems. HCV types 1a and 1b are both prevalent in the United States.
Adult↗
Chronic hepatitis B: problem patients (including patients with decompensated disease).
Most patients with chronic hepatitis B do not respond to a 4-month course of interferon alpha (IFN-alpha) and require alternative therapy. This paper focuses on alternative treatments for patients who are resistant to conventional IFN regimens (primary nonresponders) and those in whom therapy presents a special challenge. Problem patients include healthy hepatitis B surface antigen (HBsAg) carriers and those with minimal serum aminotransferase elevations, immunosuppressed patients, and patients with end-stage liver disease. Special emphasis is given to patients with decompensated liver disease. While dramatic responses to IFN-alpha can occasionally occur in these patients, serious side-effects are common.
Chronic Disease↗
The management of chronic hepatitis B.
The immediate goals of hepatitis B virus (HBV) therapy are to suppress the histologic progression of the disease and diminish infectivity. Although many drugs have been used in the treatment of this condition, only interferon has proven to be consistently effective. The ideal candidate for interferon therapy is a patient who has a high baseline aminotransferase level and a low HBV DNA level. Responders to interferon therapy usually demonstrate an alanine aminotransferase (ALT) flare to at least twofold the baseline value during the second or third month of therapy, indicating that the patient has become immunologically activated. Low baseline ALT levels before treatment (i.e., < 100 U/liter) are associated with a low response rate. An improvement in response rates occurs when patients with low ALT levels are primed with a short course of prednisone. Piecemeal necrosis markedly improves within a short time after a response is achieved, although residual portal tract inflammation often is demonstrated on biopsy. The loss of HBV DNA and hepatitis B e antigen is generally maintained after interferon therapy, but relapse occurs in approximately 10% of the patients. Further studies with interferon are indicated in multiple patient groups.
Chronic Disease↗
Clinical predictors of response to recombinant interferon-alpha treatment in patients with chronic non-A, non-B hepatitis (hepatitis C). The Hepatitis Interventional Therapy Group.
Chronic non-A, non-B hepatitis (NANBH) is a common and often progressive liver disease. Based on current serological tests, hepatitis C virus (HCV) infection is responsible for most cases. Interferon-alpha (IFN) treatment at a dose of 3 x 10(6) units given three times per week for 24 weeks has been shown to be effective in normalizing serum alanine aminotransferase (ALT) levels and reducing hepatic inflammation in approximately 40% of these patients. The purpose of this study was to identify pretreatment characteristics in patients with chronic hepatitis C(CH-C) which would best predict a favourable response to IFN treatment (normalization of serum ALT). One hundred and sixty-three adult patients who had participated in a large multicentre treatment trial were included in the study group; 84 had been treated with 3 x 10(6) units of recombinant IFN-alpha-2b (rIFN) subcutaneously three times per week for 24 weeks and 79 patients had been treated with 1 x 10(6) units rIFN in the same dosage schedule. Forty-one pretreatment historical, clinical, laboratory and histological variables were evaluated. In addition, early biochemical improvement during treatment was evaluated as a predictor of ultimate response. Univariate analysis identified six variables (dose, dose m-2, weight, body surface area, ongoing ethanol use, white blood cell count and the presence of symptoms) as potential predictors of response (two-tailed, P < 0.15). By multivariate analysis, however, only the 3 x 10(6) dose of rIFN was independently predictive of response (P < 0.01). When the analysis of response was confined to those patients who received treatment with 3 x 10(6) units of rIFN, seven variables [body weight, surface area, dose m-2, current ethanol use, serum albumin and the presence of chronic persistent hepatitis (CPH) on entry liver biopsy] were more frequent in patients who responded to therapy. In a multivariate model, only CPH and body weight predicted an increased likelihood of response (P < 0.01). However, the model was not a sensitive predictor of response as only 18% of the study group had CPH on liver biopsy. A decrease in serum ALT levels within the first 12-16 weeks of rIFN treatment was found to be the strongest indicator of an ultimate response to treatment. Thus, assessment of early response to IFN treatment is the only practical means of predicting complete response and avoiding prolonged and unnecessary therapy in those with little chance of response.
Adult↗
Therapy for hepatitis B virus infection.
Major advances have been made in the therapy of chronic viral hepatitis B during the past several years. This period has witnessed the publication of large, multicenter trials of recombinant interferon alfa for chronic hepatitis B in the United States and the completion of several similarly designed studies in North America, Europe and Asia. These studies have defined an initial response rate of approximately 40% to 50%. In contrast to the experience with chronic hepatitis C, loss of viral replication is generally sustained. Repeat courses of therapy are likely to result in the same type of response as that observed initially. Quantitative assessment of viral replication (HBV DNA, HBeAg) is important in predicting the likelihood of response and in monitoring patients during therapy. Perhaps the most compelling reason to treat chronic hepatitis B with interferon is the disappearance of circulating HBsAg in one third of responders with a further increase in frequency of this phenomenon as follow-up continues. Another important advantage to treatment is the striking degree of histologic improvement that is frequently observed years after a response has been achieved. Although a substantial number of patients do not respond to interferon, several promising agents that should allow for a greater degree of success, when used either alone or in combination with interferon, are under study. A short course of corticosteroids prior to interferon appears to improve response rates in patients who have low ALT levels at baseline and has been the preferred approach for these patients at our medical center. Progress is being made in the development of safer interferon regimens for patients with mild-to-moderate hepatic decompensation. Nonetheless, even patients with marginal synthetic function, as reflected by albumin levels within the low-normal range, appear to be at greater risk for complications during therapy and should preferably be referred for inclusion in research programs. Appropriate patient selection remains a critical step for maximizing the safety as well as efficacy of interferon treatment.
Adrenal Cortex Hormones↗
Quantitative detection of hepatitis C virus RNA with a solid-phase signal amplification method: definition of optimal conditions for specimen collection and clinical application in interferon-treated patients.
To determine the optimal conditions for preparation of serum specimens for quantitative hepatitis C virus RNA determination, patient samples were processed such that differences in time from clot formation to centrifugation, centrifugation to separation of serum and collection of serum until freezing could be independently assessed. The effects of multiple cycles of freezing and thawing were also determined. There was progressive and significant loss of hepatitis C virus RNA activity when the time from the formation of the clot until centrifugation was longer than 2 hr. This reduction reached 32% after 6 hr and 49% after 24 hr. If centrifugation was performed immediately after formation of the clot, loss of hepatitis C virus RNA activity was reduced to less than 10% even though the serum remained unseparated from the clot for up to 6 hr. Centrifugation of blood through a paraffin plug (serum separator tube) prevented loss of hepatitis C virus RNA activity for up to 24 hr. There was no loss of hepatitis C virus RNA activity with up to three freeze-thaw cycles. When patient specimens were prepared under these optimal conditions, the sensitivity of the quantitative branched DNA signal amplification assay in patients with hepatitis C virus infection was 83% and the specificity in patients with liver disease was 100%. Fluctuations in hepatitis C virus RNA levels were shown to correlate with biochemical changes observed in patients treated with recombinant interferon-alpha 2b. These data demonstrate that improper or inconsistent methods of serum preparation may result in falsely low and unreliable levels of hepatitis C virus RNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Alanine Transaminase↗
Hepatitis B and liver transplantation. Problems and promises.
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Contraindications↗
Interferon in the management of chronic hepatitis B.
Many drugs have been used in the treatment of chronic hepatitis B, but with the exception of interferon, none have proved to be effective. Several studies have found that a sustained loss of viral replication occurs in approximately 40% of patients who started with a 16-week course of recombinant interferon alfa-2b given in a dose of 5 million units daily or 10 million units three times weekly. Moreover, disappearance of hepatitis B surface antigen in serum has been observed in 10-15% of treated patients. Based on these results, the Food and Drug Administration approved the use of this form of interferon in chronic hepatitis B in July 1992. This article reviews the importance of chronic hepatitis B as a health problem as well as the mechanisms of action, benefits, and adverse effects associated with interferon. Particular emphasis is given to the safety and efficacy data for recombinant interferon alfa-2b.
Chronic Disease↗
Increased hepatocyte expression of hepatitis B virus transcription in patients with features of fibrosing cholestatic hepatitis.
BACKGROUND: Recurrent hepatitis B after liver transplantation may be complicated by fibrosing cholestatic hepatitis. This syndrome is associated with rapid graft failure and is characterized by ballooning degeneration of hepatocytes and abundant viral antigen expression. METHODS: To study this disorder further, in situ hybridization studies were performed on 36 liver biopsy specimens from 14 transplanted patients with recurrent hepatitis B and 18 nontransplanted controls with chronic hepatitis B. Biopsy specimens were scored for histological features and intensity of riboprobe hybridization signal to hepatitis B virus (HBV) DNA and RNA. RESULTS: HBV DNA hybridization signals of 2+ to 3+ intensity were observed in 53% of the posttransplant biopsies but none of the nontransplanted samples (P < 0.001). HBV RNA signals of this intensity were found in 42% of the transplant biopsy specimens compared with 17% of the nontransplant specimens (P < 0.07). Features of fibrosing cholestatic hepatitis were noted in 12 biopsies; 11 of these displayed RNA signals of 2+ to 3+ intensity (92%) compared with 4 of 24 (17%) biopsy specimens without this diagnosis (P < 0.001). The level of hepatocyte RNA correlated with the extent of hepatocellular ballooning (P < 0.007). CONCLUSIONS: These data suggest that fibrosing cholestatic hepatitis is associated with enhanced hepatitis B virus transcription and support a cytopathic role for the virus in the development of this syndrome.
Adult↗
Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group.
BACKGROUND: Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain. METHODS: In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens. RESULTS: Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1). CONCLUSIONS: These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.
Biopsy↗
Antiviral therapy of chronic hepatitis B: past, present, and future.
A wide variety of agents has been used to treat chronic hepatitis B, but none has proved effective with the exception of interferon. Toxicity has been a major problem with some drugs whereas in others a lack of antiviral potency has been demonstrated. Alpha-interferon represents a good compromise because it has both immunomodulatory and antiviral properties; moreover, it is generally well tolerated. Loss of HBeAg and hepatitis B virus DNA may be anticipated in 40-50% of patients who are treated with doses of 5 million units daily or 10 million units thrice weekly for 16 weeks. While drug-related adverse effects occur commonly, the majority of clinically stable patients are able to tolerate this regimen, and withdrawal from drug is necessary in approximately 5% of patients. Unlike the situation with chronic hepatitis C, loss of viral replication tends to be sustained years later. Disappearance of HBsAg only occurs in 10-15% of treated patients within the first year after therapy, but an increasing number of responders demonstrate HBsAg seroconversion upon prolonged follow-up. Hepatitis B virus DNA usually disappears from serum by polymerase chain reaction at the time of HBsAg loss. Low copy numbers of residual viral DNA are still detectable in liver tissue at this time, but this has uncertain significance. Marked improvement in histological features has been observed years after loss of HBsAg. Pre-therapy levels of circulating viral DNA and aminotransferase activity, degree of histologic activity, and HIV status appear to influence the response to therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Antiviral Agents↗