Teresa L. Wright

Diagnosis, management, and treatment of hepatitis C

These recommendations provide a data-supported approach. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (Medline search); (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines1 ; (3) guideline policies, including the American Association for the Study of Liver Diseases’ (AASLD) Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association’s Policy Statement on the Use of Medical Practice Guidelines2; the guideline procedures of the Infectious Diseases Society of America3; and (4) the experience of the authors in the specified topic. These recommendations are fully endorsed by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1).

Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States

BACKGROUND AND METHODS Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

Peginterferon Alfa-2a in Patients with Chronic Hepatitis C and Cirrhosis

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with cirrhosis is difficult to treat. In patients with chronic hepatitis C but without cirrhosis, once-weekly administration of interferon modified by the attachment of a 40-kd branched-chain polyethylene glycol moiety (peginterferon alfa-2a) is more efficacious than a regimen of unmodified interferon. We examined the efficacy and safety of peginterferon alfa-2a in patients with HCV-related cirrhosis or bridging fibrosis. METHODS We randomly assigned 271 patients with cirrhosis or bridging fibrosis to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 microg of peginterferon alfa-2a once weekly (96), or 180 microg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. We assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index. RESULTS In an intention-to-treat analysis, HCV RNA was undetectable at week 72 in 8 percent, 15 percent, and 30 percent of the patients treated with interferon alfa-2a and with 90 microg and 180 microg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). At week 72, alanine aminotransferase concentrations had normalized in 15 percent, 20 percent, and 34 percent of patients, respectively (P=0.004 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). In the subgroup of 184 patients with paired liver-biopsy specimens, the rates of histologic response at week 72 were 31 percent, 44 percent, and 54 percent, respectively (P=0.02 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). All three treatments were similarly tolerated. CONCLUSIONS In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.

HCV-related fibrosis progression following liver transplantation: increase in recent years

BACKGROUND/AIMS The natural history and predictors of HCV-related disease severity post-transplantation are uncertain. The aims of this study were to define the natural history of post-transplantation HCV infection by assessing the rate of fibrosis progression, to determine if the post-transplantation natural history differs from that observed pre-transplantation, and to identify predictors of post-transplantation disease progression. METHODS Post-transplantation biopsies (mean: 3+/-1.6/patient) from 284 patients were scored according to histologic stage, using the method of Desmet et al. Change in fibrosis score (fibrosis progression/year) post-transplantation was used as the primary outcome. Predictors analyzed included viral factors (genotype and viral load at transplantation), patient demographics, year of transplantation, country of transplantation, pre-transplantation fibrosis progression, immunosuppression and laboratory data. RESULTS There was a linear association between change in fibrosis score and time from transplantation, with a median rate of fibrosis progression per year of 0.3 (0.004-2.19/year). Using parametric time-to-event analysis, the expected median duration to cirrhosis was 10 years. The rate of post-transplantation fibrosis progression was significantly higher than pre-transplantation (0.2/year (0.09-0.8) p<0.0001), and higher in Spanish than US centers (0.48 (0.01-2.19) vs 0.28 (0.004-2.08); p=0.09) despite similar progression rates prior to transplantation. Variables independently associated with post-transplantation progression included year of transplantation (p=0.0001), race (p=0.02), number of methyl-prednisolone boluses (p=0.03), and HCV RNA levels at transplantation (p=0.01). CONCLUSIONS HCV-related disease progression is accelerated in immunocompromised compared to immunocompetent patients, with a progressive increase in patients who have recently undergone liver transplantation. Changes in patient management post-transplantation over time and between transplant centers may account for the increase in fibrosis progression observed in recent years.

Recurrent and acquired hepatitis C viral infection in liver transplant recipients

To examine the postliver transplant recurrence of hepatitis C virus (HCV) infection in patients with pretransplant infection, as well as its acquisition in patients without prior infection, we used the polymerase chain reaction to amplify HCV RNA in serum and/or liver samples of 89 patients with alcoholic and cryptogenic cirrhosis undergoing liver transplantation. Results were correlated with histologic findings from posttransplant liver biopsies. Ninety-five percent of patients with pretransplant infection had posttransplant viremia. In contrast, 35% of patients without pretransplant infection acquired the virus (P less than 0.0001). Pretransplant HCV infection predisposed patients to hepatitis in the new graft. HCV RNA was present in serum of 96% of patients with posttransplant hepatitis. Fifty-six percent of patients with posttransplant HCV infection had no evidence of liver damage at least 1 year posttransplant. However, of those patients with histologic hepatitis, chronic active hepatitis was common. It is concluded that although HCV infection recurs posttransplant in almost all infected patients, acquisition of the HCV infection with transplant is common. Pretransplant HCV infection is an independent risk factor for the development of posttransplant hepatitis. HCV infection accounts for the majority of posttransplant hepatitis not due to cytomegalovirus, and although many patients with posttransplant viremia have little evidence of histologic hepatitis, significant hepatic damage may occur.

A treatment algorithm for the management of chronic hepatitis B virus infection in the United States

BACKGROUND AND AIMS Chronic hepatitis B is an important public health problem worldwide and in the United States. A treatment algorithm for chronic hepatitis B virus (HBV) infection was developed by a panel of US hepatologists based on new developments in the understanding of the virology of HBV, availability of more sensitive molecular diagnostic testing, and advantages and disadvantages of currently approved therapies. METHODS This algorithm is based on available evidence, but where data are lacking, the panel relied on clinical experience and consensus expert opinion. RESULTS Serum HBV DNA can be detected at levels as low as 100-1000 copies/mL by using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest level possible. The threshold level of HBV DNA for determination of candidacy for therapy is >/=10(5) copies/mL for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A lower serum HBV DNA threshold is appropriate for patients with HBeAg-negative chronic hepatitis B and those with decompensated cirrhosis, and the panel recommends thresholds of 10(4) copies/mL and 10(3) copies/mL, respectively. CONCLUSIONS Interferon alfa-2b, lamivudine, and adefovir dipivoxil are all approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost. Studies are under way to explore the safety and efficacy of combination therapy, which may prove to be more effective than monotherapy in suppressing viral replication and may decrease or delay the incidence of drug resistance.

Occult hepatitis B virus as source of infection in liver transplant recipients

Hepatitis B virus (HBV) infection almost always recurs after liver transplantation in patients who were surface antigen (HBsAg) positive before surgery but apparent de novo acquisition of infection in a transplant setting has not previously been reported. We have used sensitive techniques to elucidate the origin of such infections in patients in a California transplantation programme. We tested post-transplant serum from 207 patients who had been HBsAg negative and found 20 to be HBsAg positive. The origin of infection was identified in 7 patients, being occult pre-transplant infection in 5 and occult infection in the donor in 2. No pre-transplant patient nor donor with demonstrable HBV DNA had serological markers of hepatitis B. Post-transplant HBV DNA was present in serum from 19 patients. Analysis of the variable pre-S region of HBV demonstrated 100% sequence homology between recipient liver and post-transplant serum (2 patients) and between donor serum and recipient post-transplant serum (2). There was only 84% homology between the 2 different patients infected with subtype adw. 19 patients are alive, 9 without histological evidence of hepatitis (mean follow-up 33 months), and survival was significantly greater than that of a group with recurrent HBV infection. Apparent acquisition of HBV infection with liver transplantation is not rare, and may be due to occult pre-transplant infection or occult infection in the donor. The post-transplant outcome of this infection tends to be benign but our findings do underscore the clinical relevance of HBV infection in the absence of serological markers.

A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C

Clinical factors such as age, gender, alcohol use, and age‐at‐infection influence the progression to cirrhosis but cannot accurately predict the risk of developing cirrhosis in patients with chronic hepatitis C (CHC). The aim of this study was to develop a predictive signature for cirrhosis in Caucasian patients. All patients had well‐characterized liver histology and clinical factors; DNA was extracted from whole blood for genotyping. We validated all significant markers from a genome scan in the training cohort, and selected 361 markers for the signature building. Using a “machine learning” approach, a signature consisting of markers most predictive for cirrhosis risk in Caucasian patients was developed in the training set (N = 420). The Cirrhosis Risk Score (CRS) was calculated to estimate the risk of developing cirrhosis for each patient. The CRS performance was then tested in an independently enrolled validation cohort of 154 Caucasian patients. A CRS signature consisting of 7 markers was developed for Caucasian patients. The area‐under‐the‐ROC curves (AUC) of the CRS was 0.75 in the training cohort. In the validation cohort, AUC was only 0.53 for clinical factors, increased to 0.73 for CRS, and 0.76 when CRS and clinical factors were combined. A low CRS cutoff of <0.50 to identify low‐risk patients would misclassify only 10.3% of high‐risk patients, while a high cutoff of >0.70 to identify high‐risk patients would misclassify 22.3% of low‐risk patients. Conclusion: CRS is a better predictor than clinical factors in differentiating high‐risk versus low‐risk for cirrhosis in Caucasian CHC patients. Prospective studies should be conducted to further validate these findings. (HEPATOLOGY 2007.)

High-Risk Human Papillomavirus Testing in Women With ASC-US Cytology

This study evaluated the clinical performance of the cobas 4800 HPV Test (Roche Molecular Systems, Pleasanton, CA) for high-risk human papillomavirus (HR-HPV) testing with individual HPV-16/HPV-18 genotyping in women 21 years or older with atypical squamous cells of undetermined significance (ASC-US). Women (N = 47,208) were recruited in the United States during routine screening, and liquid-based cytology and HPV testing were performed. The ASC-US prevalence was 4.1% (1,923/47,208), and 1,578 women underwent colposcopy with valid results. The cobas 4800 HPV Test demonstrated performance comparable to the Hybrid Capture 2 test (QIAGEN, Gaithersburg, MD) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse and grade 3 or worse. HPV-16/HPV-18+ women had a greater absolute risk of CIN 2 or worse compared with pooled HR-HPV+ and HR-HPV- women (24.4%, 14.0%, and 0.8%, respectively). The cobas 4800 HPV Test is clinically validated for ASC-US triage. HPV-16/HPV-18 genotyping can identify women at highest risk for high-grade cervical disease, and this additional risk stratification may be used in formulating patient management decisions.

The impact of pretransplantation hepatitis C infection on the outcome of renal transplantation.

Controversy exists regarding the impact of pre-transplantation HCV infection on the outcome of renal transplantation. We compared the prevalence of post-transplantation liver disease and graft and patient survival among kidney transplant recipients with and without anti-HCV at the time of transplantation. Pre-transplantation sera from 103 randomly selected recipients of kidneys from anti-HCV-negative donors were tested for anti-HCV using a second generation ELISA. Twenty-three (22%) were positive for anti-HCV and 80 (78%) were negative. Anti-HCV-positive recipients had a longer time on dialysis (P=0.003) and had a higher number of previous transplants (P=0.01). Further, 61% of anti-HCV-positive patients had a history of liver disease compared with 13% of anti-HCV-negative patients (P<0.001). HCV RNA was detected in the pretransplantation serum in 61% of anti-HCV positive recipients compared with 5% of anti-HCV-negative recipients (P<0.001). Clinical follow-up on both anti-HCV-positive and -negative patients was obtained until December, 1993. Median posttransplantation follow-up among recipients with anti-HCV prior to transplantation (45 months) was shorter (P=0.05) than that for recipients without anti-HCV (66 months). For recipients with anti-HCV prior to transplantation, the relative risk of posttransplantation liver disease was 5.0 (95% confidence intervals of 2.4 to 10.5); the relative risk of graft loss was 1.3 (95% confidence intervals of 0.6 to 2.6); the relative risk of death was 3.3 (95% confidence intervals of 1.4 to 7.9), and the relative risk of death due to sepsis was 9.9 (95% confidence intervals of 2.6 to 38.3). The results of this study demonstrate that pretransplantation HCV infection is associated with an increased risk of liver disease and death after renal transplantation. These results raise the question of whether anti-HCV-positive patients on dialysis should be offered renal transplantation as opposed to continuing dialysis.