Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases.

Hepatitis B virus reactivation (HBVr) can be a serious complication of cancer chemotherapy. However, underutilization of HBV screening and secondary underutilization of antiviral prophylaxis have been frequently reported. The authors electronically distributed a 30-point questionnaire to members of the American Association for the Study of Liver Diseases to capture experiences with HBVr during cancer chemotherapy. The questionnaire specified diagnostic criteria and collected information on HBV screening, antiviral prophylaxis and clinical outcomes. Ninety-nine respondents reported 188 patients who met the criteria for HBV reactivation. Forty-one practised outside the United States, and most were hepatologists (n = 71) or gastroenterologists (n = 12). One hundred and twenty-six patients had haematologic malignancies, of which 88 (70%) had lymphoma. Seventy-five patients (40%) had screening for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc), and an additional 24 patients (13%) had HBsAg screening alone. Prophylactic antiviral therapy was reported in only 18 patients (10%). Chemotherapy was interrupted in 52 patients (41%) with haematologic malignancies and 26 of 41 patients (63%) with solid tumours (P = 0.01). Rituximab-treated patients (n = 66) required hospitalization more frequently (P = 0.04), but their overall survival did not differ from individuals not treated with rituximab. Death due to liver failure was reported in 43 patients overall (23%). Underutilization of prophylactic antiviral therapy occured in a substantial number of patients who were found to be HBV infected prior to the initiation of cancer chemotherapy. The reasons for this need further exploration because reactivation results in serious yet preventable outcomes.

Immune globulin and hepatitis B immune globulin. Prophylactic measures for intimate contacts exposed to acute type B hepatitis.

We studied the relative prophylactic efficacies of recently derived immune globulin containing antibody to hepatitis B surface antigen (anti-HBs) and hepatitis B immune globulin in 60 intimate contacts exposed to acute type B hepatitis. Forty susceptible contacts were randomly assigned to treatment with either a single intramuscular dose of immune globulin or hepatitis B immune globulin (0.06 mL/kg of body weight), following which observation was maintained over a 12-month period. Twenty additional contacts received the equivalent of twice the dose of immune globulin given to the first group, and follow-up was maintained for six months. Neither the hepatitis B virus (HBV) attack rates (11% to 19%) nor the frequency of clinical illness (0% to 4.8%) was substantially different in the three groups. When compared with average frequencies reported in the literature, significantly lower illness rates were noted for immune globulin recipients. These data indicate that currently derived immune globulin as well as hepatitis B immune globulin may confer protection from illness (le, passive-active immunity) in the setting of intimate exposure to HBV.

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.

Prevalence of hepatitis B antibodies in personnel at a children's hospital.

Antibody to hepatitis B core antigen and antibody to hepatitis B surface antigen were measured in serum samples from 825 personnel at St Louis Children's Hospital (702 were possibly at high risk of occupational hepatitis B virus (HBV) exposure and 123 were office personnel); 5.6% had positive findings for both antibodies, 5.6% had findings for antibody to hepatitis B surface antigens alone, and 1.3% had positive findings for antibody to hepatitis B core antigens alone. The group with positive findings for antibody to hepatitis B surface antigens alone did not have traditional risk factors for HBV infection, suggesting that this serologic finding may not be a reliable indicator of past HBV infection. After accounting for the effects of age, sex, and ethnicity, it was found that no occupational group had a significantly increased prevalence of HBV antibodies compared with prevalence in other personnel. In comparison with volunteer blood donors, only physicians older than 40 years of age had an increased HBV antibody prevalence. It is concluded that St Louis Children's Hospital has not been a high-risk environment for HBV exposure in recent years. However, caution is advised in generalizing these conclusions because other children's hospitals may serve a patient population at higher risk of HBV infection. Decisions regarding HBV immunization policy should take into consideration the fact that personnel at different hospitals may face markedly different risks of HBV exposure.

Xenon-133 retention in hepatic steatosis-correlation with liver biopsy in 45 patients: concise communication.

This study presents the results of comparison of hepatic fat content with hepatic xenon retention in 45 patients. The degree of hepatic Xe-133 retention was measured during pulmonary ventilation studies. The amount of hepatic steatosis was graded 0 to 4+ on histologic liver sections obtained by needle or surgical biopsy. There was agreement between the amount of hepatic xenon retention determined scintigraphically and the degree of steatosis determined histologically. These results suggest that Xe-133 retention in the liver provides a simple means of evaluating fatty infiltration of the liver. The potential of this technique as a noninvasive means of investigating hepatic fatty infiltration is discussed.

Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial.

BACKGROUND: Insulin sensitizing agents may be useful in treatment of non-alcoholic fatty liver disease. AIM: A pilot study to evaluate the efficacy and safety of metformin in non-alcoholic fatty liver disease. METHODS: In an open labelled study, patients with histologically confirmed non-alcoholic fatty liver disease were given metformin (20 mg/kg) for 1 year. Insulin resistance (by log homeostasis assessment model analysis for insulin resistance and Quantitative Insulin Sensitivity Check Index) and post-treatment hepatic histology were compared with pre-treatment histology. RESULTS: Fifteen patients completed 1 year of treatment. During the initial 3 months, there was improvement in alanine aminotransferase and aspartate aminotransferase (P-value 0.01 and 0.02, respectively) along with improvement in insulin sensitivity. However, after 3 months, there was no further improvement in insulin sensitivity and there was gradual rise in aspartate aminotransferase and alanine aminotransferase back to pre-treatment levels. Among the 10 patients with post-treatment biopsy, three (33%), showed improvement in steatosis, two (20%) showed improvement in inflammation score and one (10%) showed improvement in fibrosis. CONCLUSION: Metformin treatment was associated with only a transient improvement in liver chemistries. A progressive, sustainable reduction in insulin sensitivity was not noted during treatment.

Comparison of quantitative HCV RNA assays in chronic hepatitis C.

We compared the relative sensitivities of first-and-second generation branched nucleotide assays (Quantiplex HCV RNA 1.0 and 2.0, respectively, Chiron, Emeryville, Calif) for the detection of hepatitis C virus (HCV) RNA to that of a commercially available quantitative reverse transcriptase polymerase chain reaction (RT-PCR) method (Monitor, Roche Molecular Systems, Nutley, NJ) in 53 patients with chronic hepatitis C. The sensitivities of the second-generation branched DNA (bDNA) and RT-PCR assays were similar (91% and 92%, respectively), and both were significantly more sensitive (P < .001) than the first-generation method. Moreover, both assays detected HCV RNA in all 11 patients with type 2a, 2b, or 3a genotypes vs 45% with the HCV RNA 1.0 bDNA assay. We examined 174 serum samples by the bDNA 2.0 and RT-PCR assays. Major quantification differences were noted on a given specimen with the RT-PCR method reporting values an average 41-fold lower (range, 0-703-fold) than those obtained with the bDNA assay. We conclude that both methods can be used to detect HCV RNA in patients who are infected with the genotypes that are most commonly encountered in the United States. The HCV RNA 2.0 bDNA assay may offer advantages when attempting to quantify high-level viremia.

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.

Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile.

In a randomized, controlled trial that demonstrated the efficacy of interferon alfa-2b 3 million units three times a week for 24 weeks in controlling chronic hepatitic C (non-A, non-B), the Sickness Impact Profile (SIP) was used to evaluate the impact of disease and treatment on health-related quality of life (HRQOL). The SIP was self-administered by 160 patients before treatment, at the end of treatment, and at the study endpoint. Before treatment, patients with chronic hepatitis C scored significantly (P < 0.05) higher (worse) than an historical control group of the general population in mean total SIP score and in all categories except eating. The highest degree of impairment was observed in the work, sleep and rest, and recreation and pastimes categories. After treatment, patients who received interferon alfa-2b had significant (P < or = 0.05) improvement in work, sleep and rest, and recreation and pastimes scores. Numerical improvement was observed in total score, physical and psychosocial dimension scores, and most individual category scores. Mean SIP scores were unchanged or slightly worsened in untreated control patients. In responders (patients with improvement in serum alanine aminotransferase levels), the largest improvement was seen in work scores. The SIP appears to be a reliable and valid instrument for describing the impact of chronic hepatitis C on HRQOL but lacks disease-specificity and the ability to reflect clinically relevant changes. Thus the SIP is not the best instrument to evaluate the HRQOL effects of treatment with interferon alfa-2b in patients with chronic hepatitis C.

Type A and type B attentional responses to aesthetic stimuli: effects on mood and performance.

Recent investigations of the Type A coronary-prone behavior pattern have found that Type A's focus their attention on a central task and actively inhibit attention to peripheral distracting stimuli. This attentional difference has resulted in greater performance for Type A's than for Type B's. However, research on aesthetic stimuli suggests that the focused attention of Type A's may not always be adaptive for solving frustrating cognitive tasks, particularly when paying attention to a peripheral stimulus could enhance performance by reducing negative emotions. Simple, predictable, aesthetic stimuli can have a soothing effect, which reduces negative emotions and enhances performance. The present study found that Type B's had improved affect and performance from attending to a soothing peripheral stimulus (simplex melodies) while working on a frustrating cognitive task. Neither the performance nor the affect of Type A's was influenced by the simplex music, because they apparently suppressed paying attention to these melodies.

Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy.

SUMMARY: Both absolute viral load and log decline in viral load from baseline were found clinically useful in predicting sustained virological response and lack of sustained virological response (non-sustained virological response, NSVR) to treatment. We assessed the clinical utility of hepatitis C virus (HCV) RNA quantitation and changes in viral load using the VERSANT HCV RNA 3.0 Assay (bDNA) in 351 HCV-infected individuals treated with interferon plus ribavirin. We show that viral load decision thresholds provided negative predictive values (NPVs) of >95% at week 4 using a 100 000 IU/mL cut-off and at weeks 8 and 12 using 10 000 IU/mL cut-offs. A 2-log decline from baseline provided NPVs >95% at weeks 8 and 12. Combinations of absolute viral loads and changes in viral load from baseline did not enhance the performance of the decision rules for predicting NSVR. The positive predictive values (PPVs) at weeks 8 and 12 were 59.1 and 67.3%. This study highlights the critical importance of viral quantitation in gauging therapeutic response in patients with chronic HCV infection on antiviral therapy. Early changes in viral load, measured as absolute viral loads or change in viral load from baseline, are highly predictive of NSVR at 8 and 12 weeks. PPVs are modest but these data may provide encouragement to patients who are in the early phases of treatment when side effects are frequent. Additionally, we demonstrated the need for cautious interpretation of stopping rules when the values are at or near the decision thresholds.

Multicenter studies of Lamivudine for the treatment and prevention of hepatitis B after liver transplantation.

Hepatitis B is a serious liver disease that may require liver transplantation. Recurrence of the initial infection in the grafted liver occurs frequently, and this is a frequent case of death after transplantation. Treatment of recurrent infection with interferon has been ineffective, and the only therapy that has been shown to prevent infection is high dose hepatitis B immune globulin (HBIg), a material that is very expensive and in short supply. In this article the author reviews the experience with lamivudine, an orally available nucleoside analogue, as a means of preventing and treating recurrent hepatitis B after liver transplantation. The results in both areas look promising, and it is possible that lamivudine maintenance therapy may obviate the need for life-long use of HBIg after liver transplantation. This will undergo study over the next several years in a multicenter trial supported by the National Institutes of Health.

Challenges and opportunities for medical education and clinical research in a changing healthcare environment.

The current economic crisis in medicine has led to a restructuring of the way in which physicians utilize their time. Considerably more time is being spent on clinical services and less on teaching and clinical research. Multiple opportunities exist, however, for mentoring and clinical research in the current system. Academic behaviors can be integrated into the daily clinical experience. Scientific methodology can be used to address important questions that pertain to a large segment of their practice and, by so doing, lead to improved means of delivering healthcare and a reduction in healthcare expenditures. The inclusion of residents into such clinical research programs is to be encouraged. Should physicians continue to pay less and less attention to the maintenance of their professional diversity, future generations of physicians will be the recipients of a more dilute system of medical education.

Antiviral therapy to prevent and treat hepatitis B virus infection in hepatic allografts.

Hepatitis B infection of a liver allograft can have serious consequences including a negative influence on the probability of survival. Therefore, there is a need for very effective antiviral therapy for transplant recipients. In this article the early experience with nucleoside analogue antiviral agents, both to prevent and to treat hepatitis B in liver allografts, is reviewed. There are several important characteristics of these agents that are already apparent. Ganciclovir and famciclovir have limited efficacy in treating infections when they are used alone. These compounds might be beneficial if used after resistance develops to other drugs or when used in combination with other agents. Lamivudine is effective for about two-thirds of patients in preventing and treating hepatitis B infection in allografts. Hepatitis B immune globulin (HBIg) is known to increase the efficacy of lamivudine in preventing infection. A large study to further characterize this combination therapy is being organized. Resistance to famciclovir and lamivudine can occur if they are used alone for a long time. In order to lower the incidence of drug resistance, it may be necessary to utilize combinations of nucleoside analogues.

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.

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)

The use of corticosteroids in conjunction with antiviral therapy in chronic hepatitis B with ongoing viral replication.

Eleven patients with hepatitis B e antigen (HBeAg)-positive chronic active hepatitis B were treated with an 8-wk course of prednisone followed by 28 days of adenine arabinoside 5'-monophosphate. Five individuals had a complete response (loss of HBeAg and DNA polymerase) whereas 3 had a partial response (sustained loss of DNA polymerase but persistence of HBeAg). At the present time 27 +/- 3 mo has elapsed since the completion of therapy, and 4 of 5 complete responders remain negative for replicative markers while the fifth person exhibited transient reactivation of infection. Elevated DNA polymerase has reappeared in two of the three partial responders, in one 22 mo after completion of therapy. These encouraging results have led to a randomized, controlled trial using short-term prednisone followed by recombinant alpha-interferon.

Hepatitis B: transmission and natural history.

This paper reviews the transmission and natural history of hepatitis B viral infection. Means of transmission are compared by geographical region, and the association with risk factors is described. Long term outcome and overall survival are documented, and the need for universal screening programmes is discussed.

Interferon for hepatitis B: US experience.

This paper reviews the results of recent studies carried out in the USA on the treatment of chronic hepatitis B with interferon alfa-2b. In the US multicentre trial, 37% of patients lost hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV)-DNA when treated with 5 million units (MU) daily for 16 weeks, compared to 42% in the US National Institutes of Health (NIH) trial treated with 10 MU thrice weekly for 16 weeks. In both studies, the loss of HBeAg and HBV-DNA was associated with virological, biochemical, histological, and clinical improvement. Long term follow up in the National Institutes of Health study showed that 65% of responders had disappearance of HBsAg over a mean of four years, suggesting that termination of the HBV carrier state may be possible.

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.