Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study.

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus.

Community-based real-world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States.

Sofosbuvir/ledipasvir (SOF/LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.

A simple and inexpensive point-of-care test for hepatitis B surface antigen detection: serological and molecular evaluation.

Early identification of chronic hepatitis B is important for optimal disease management and prevention of transmission. Cost and lack of access to commercial hepatitis B surface antigen (HBsAg) immunoassays can compromise the effectiveness of HBV screening in resource-limited settings and among marginalized populations. High-quality point-of-care (POC) testing may improve HBV diagnosis in these situations. Currently available POC HBsAg assays are often limited in sensitivity. We evaluated the NanoSign(®) HBs POC chromatographic immunoassay for its ability to detect HBsAg of different genotypes and with substitutions in the 'a' determinant. Thirty-seven serum samples from patients with HBV infection, covering HBV genotypes A-G, were assessed for HBsAg titre with the Roche Elecsys HBsAg II quantification assay and with the POC assay. The POC assay reliably detected HBsAg at a concentration of at least 50 IU/mL for all genotypes, and at lower concentrations for some genotypes. Eight samples with substitutions in the HBV 'a' determinant were reliably detected after a 1/100 dilution. The POC strips were used to screen serum samples from 297 individuals at risk for HBV in local clinical settings (health fairs and outreach events) in parallel with commercial laboratory HBsAg testing (Quest Diagnostics EIA). POC testing was 73.7% sensitive and 97.8% specific for detection of HBsAg. Although the POC test demonstrated high sensitivity over a range of genotypes, false negatives were frequent in a clinical setting. Nevertheless, the POC assay offers advantages for testing in both developed and resource-limited countries due to its low cost (0.50$) and immediately available results.

Hepatitis B in the Greater San Francisco Bay Area: an integrated programme to respond to a diverse local epidemic.

Although chronic hepatitis B (CHB) affects approximately 2 million United States residents, there is no systematic screening of at-risk individuals, and most remain unaware of their hepatitis B virus (HBV) infection. Unmonitored and untreated, CHB results in a 25-30% risk of death from liver cancer and/or cirrhosis, inflicting an increasing healthcare burden in high-prevalence regions. Despite high prevalence in immigrant Asians and Pacific Islanders, among whom CHB is a leading cause of death, community and healthcare provider awareness remains low. Because safe and effective vaccines and effective antiviral treatments exist, there is an urgent need for integrated programmes that identify, follow and treat people with existing CHB, while vaccinating the susceptible. We describe an extant San Francisco programme that integrates culturally targeted, population-based, HBV screening, vaccination or reassurance, management and research. After screening over 3000 at-risk individuals, we here review our operational and practical experience and describe a simple, rationally designed model that could be successfully used to greatly improve the current approach to hepatitis B while ultimately reducing the related healthcare costs, especially in the high-risk populations, which are currently underserved.

Is chronic hepatitis B being undertreated in the United States?

Chronic infection with the hepatitis B virus (HBV) is a major risk factor for development of end-stage liver disease, including cirrhosis, liver failure and primary liver cancer. There are now seven antiviral agents approved by the United States Food and Drug Administration (FDA) for the management of chronic HBV infection. Despite the fact that there are between 1.4 and 2 million chronic HBV infections in the United States, fewer than 50,000 people per year receive prescriptions for HBV antiviral medications. This report discusses possible explanations for the disparity between the number of people who are chronically infected and the number of people who receive treatment. Explanations for this incongruence include the potentially large number of infected persons who are unscreened and thus remain undiagnosed, and lack of access, including insurance, education and referral to appropriate medical care, particularly for disproportionately infected populations.

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

This retrospective analysis was conducted to describe the characteristics of nucleoside-naïve hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg-positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double-blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off-treatment follow-up. Through a maximum duration of 96 weeks on-treatment and 24 weeks off-treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside-naïve HBeAg-positive patients treated with entecavir, and that HBsAg loss is associated with sustained off-treatment suppression of HBV DNA.

Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

Entecavir is a potent inhibitor of hepatitis B virus (HBV) polymerase. The efficacy and safety of entecavir in nucleoside-naïve patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B was established in a large, international, double-dummy study (ETV-022) where patients were randomized to entecavir 0.5 mg/day (n = 354) or lamivudine 100 mg/day (n = 355) once daily. ETV-022 had a 52-week blinded treatment phase, followed by an extended blinded treatment phase for up to 44 additional weeks (96 weeks total). Treatment was discontinued for patients achieving a protocol-defined response as determined by patient management criteria that intended to test the possibility of finite therapy, which has not previously been studied for entecavir or other anti-HBV agents in a large trial. Early results from this study have been previously presented/published separately. This paper compiles the results of up to 2 years of treatment for protocol-defined responders, virologic responders and nonresponders. For responders who discontinued therapy (per protocol), 24-week off-treatment evaluation is presented to provide a more 'complete picture' of what clinicians can expect when treating nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. For patients who discontinued therapy because of nonresponse (nonresponders) and subsequently entered the rollover study ETV-901, follow-up results, including resistance profile, are provided.

Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis.

BACKGROUND: Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear. AIM: To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB. METHODS: We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total). RESULTS: Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%. CONCLUSION: The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.

Chronic hepatitis B: current epidemiology in the Americas and implications for management.

Hepatitis B virus (HBV) remains a serious health threat in many parts of the world. Although its prevalence is lower in the Americas than in Asia, Africa and the Middle East, it is responsible for significant morbidity and mortality in North, Central and South America. There is a nonuniform pattern of distribution throughout this region, with HBV prevalence related to geographical, social and cultural factors that predispose certain individuals to infection. This report details the incidence, modes of viral transmission of hepatitis B in the Americas and clinical course of disease in different regions of the Americas. Additionally, the implications for management focusing on issues predominant in high-risk populations are presented.

Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection.

A multicenter, open-label study was performed to evaluate the safety, anti-hepatitis B virus (anti-HBV) activity, and pharmacokinetics of emtricitabine therapy administered once daily for 8 weeks to patients infected with HBV. Clinical and virologic evaluations were completed at the baseline; at 7, 14, 28, 42, and 56 days during treatment; and at 24, 48, and 28 days posttreatment. Forty-nine patients were enrolled in five dose cohorts (doses of 25, 50, 100, 200, and 300 mg, all of which were administered once daily [q.d.]). Peak plasma emtricitabine concentrations occurred within 1.5 h following dosing. Plasma emtricitabine concentrations (maximum concentrations of drug in plasma and areas under the concentration-time curves) increased nearly dose proportionally over the 25- to 300-mg dose range, with relatively small intersubject variabilities. The plasma half-life of emtricitabine ranged from 6 to 9 h. HBV DNA levels were measured by the Digene HBV Hybrid Capture II assay. Viral suppression (reduction in log(10) serum HBV DNA levels) occurred in all dose cohorts. All doses demonstrated potent and rapid antiviral activities, with a trend toward a greater suppression with daily doses of 100 mg or greater. At 2 months, the median change in the serum HBV DNA level from the baseline level ranged from -1.7 log(10) for the 25-mg dose administered q.d. to -3.3 log(10) for the 300 mg dose administered q.d. Emtricitabine was well tolerated over the 2-month dosing period. These results support further clinical development of emtricitabine for the treatment of chronic hepatitis B infection.

Determination of hepatitis B virus genotype G by polymerase chain reaction with hemi-nested primers.

Hepatitis B virus (HBV) has been classified into six genotypes designated A-F by sequence divergence in the entire genome exceeding 8%. Very recently, the seventh genotype was reported and named genotype G. HBV genotype G is distinct from genomes of the other six genotypes in that it possesses an insertion of 36 nucleotides in the core gene, and has been found so far in France and the United States. A method for determining HBV genotype G was developed by polymerase chain reaction (PCR) with primers deduced from the 36-nucleotide (nt) insertion in five isolates of HBV genotype G the sequences of which have been deposited in DNA databases. The validity of this method, for specifically detecting HBV genotype G, was verified on a panel consisting of 142 HBV isolates of six major genotypes and four of genotype G. A total of 540 sera containing HBV in Japan covering symptom free carriers and patients with a spectrum of chronic liver disease were tested by this method, but not a single HBV genotype G sample was found. A possible method for serological determination of hepatitis B surface antigen of genotype G is suggested, without amplification or sequencing nucleotides, which would expand epidemiological and clinical researches on HBV genotype G.

Long-term follow-up of patients diagnosed with alcohol dependence or alcohol abuse who were evaluated for liver transplantation.

The selection of patients with cirrhosis and the diagnosis of alcohol dependence or abuse who have a long-term high probability of abstinence after orthotopic liver transplantation (OLT) may enhance patient survival and outcomes. The aim of this study is to identify factors that would predict which patients would consume alcohol after OLT. Sixty-one patients with a history of alcohol dependence or abuse underwent OLT from June 1989 to June 1994 and were followed up monthly for a median of 6.9 years after OLT (range, 2.5 to 9.3 years). Survival analysis techniques (Cox proportional hazard model) were used to identify patients at high risk for recidivism. Recidivism occurred in 12 of 61 patients (20%) after OLT during follow-up. Noncompliance, with a relative hazard of 20.9 (95% confidence interval [CI], 5.6 to 78.3; P <.001), and personality disorder, with a relative hazard of 6.0 (95% CI, 1.9 to 18.7; P =.002), independently predicted recidivism among patients who underwent OLT. These data indicate that specific behaviors and psychiatric diagnoses can be used to select patients at high risk for drinking alcohol before and after OLT.

Autoimmune liver disease. Current standards, future directions.

The diagnosis and management of autoimmune hepatitis continues to evolve as new diagnostic tests and new therapies are added to the armamentarium. Also encouraging are the advances in the understanding of the human immune system and its involvement in the origin and course of auto immune diseases in general and in the variants of autoimmune liver disease. Promising changes are expected in the next few years as new medications become available to the practicing hepatologist. New immune tests may allow therapies to be customized to patients, and antiviral therapies may also eventually be used in the management of this autoimmune liver diseases.

Long-term follow-up after liver transplantation in patients with hepatic iron overload.

Patients with hepatic iron overload who undergo orthotopic liver transplantation (OLT) have a worse 1-year survival than those who undergo transplantation for other indications; the long-term outcome in this population is unknown. The purpose of this study is to report long-term follow-up after OLT in a cohort of patients with hepatic iron overload. Five liver transplant centers in the United States reported follow-up data on 37 patients receiving a first liver transplant who had severe hepatic iron overload in their native livers. Kaplan-Meier 5-year survival among these patients was compared with survival data from all age-matched liver transplantations reported to the United Network for Organ Sharing (UNOS) over the same time period (1987 to 1993). The 5-year survival rate after OLT was 40% in the hepatic iron overload group compared with an overall survival rate of 62% for all patient groups from the UNOS registry (P =.0009). Although sepsis was the cause of 53% of all deaths occurring within the first year after OLT, cardiac complications accounted for 50% of the late mortality in patients with hepatic iron overload. In conclusion, long-term survival after OLT is significantly decreased in patients with hepatic iron overload. Infectious and cardiac complications are the most common causes of death in these patients. Further studies are needed to define the relationship between hepatic iron overload and mortality and to examine the effect of iron depletion on outcome after OLT in this patient population.

Standards of treatment in chronic hepatitis C.

Standards of treatment for patients who are infected with the hepatitis C virus have been developed from national and international consensus conferences, from extensive clinical experience with various regimens, from exhaustive literature reviews, and from opinion leaders in the general medical community. From 1987 until very recently, the standard of treatment for non-A, non-B hepatitis, later defined as hepatitis C, had consisted of alpha interferon monotherapy administered for up to 18 to 24 months. Alpha interferon has been used in a variety of regimens with varying success for the initial treatment of chronic hepatitis C, for the retreatment of patients who have relapsed after responding to interferon, and for the retreatment of alpha interferon nonresponders. Treatment standards have evolved as new agents have become available for use in our treatment armamentarium. The current treatment standards, as well as recommendations for the treatment of specific HCV subgroups, are reviewed.

GB virus C (GBV-C/HGV) and E2 antibodies in children preliver and postliver transplant.

The association of GB virus type C (GBV-C) virus and clinical disease is uncertain. The role of GBV-C and (Envelope) E2 antibody in children with liver transplants has not been determined. This study's aim is to examine the prevalence of GBV-C in children with liver transplants, to assess the relationship of GBV-C to posttransplant hepatitis, and to determine the role of E2 antibodies. Sera from 34 children, preliver and postliver transplant, between 1989-1996 were tested for GBV-C (Ribonucleic acid) RNA by the automated Abbott LCx PCR assay. Anti-E2 antibodies were detected by an Abbott immunoassay. Recent posttransplant liver biopsies were examined for hepatitis. The results of the study determined that pretransplant, four children (12%) were GBV-C RNA positive. Posttransplant, 14 (42%) children were GBV-C RNA positive. The GBV-C RNA positive conversion rate was 33% (CI 17.2-55.7%). Patients received blood products from a mean of 68 +/- 34 donors, which correlated with GBV-C acquisition. There was no difference in the incidence (32%versus 36%; p = 0.726) or severity (grade 2.00 versus 0.68; p = 0.126) of posttransplant hepatitis in the liver biopsies of GBV-C RNA negative and/or positive children, respectively. Pretransplant, nine of 32 children were anti-E2 positive. Posttransplant, eight of 32 children were anti-E2 positive, including five children who were anti-E2 positive pretransplant. Of nine children who were anti-E2 positive and GBV-C RNA negative pretransplant, three became GBV-C RNA positive posttransplant. The results of this study conclude that the prevalence of GBV-C infection in children postliver transplantation is high and that blood product transfusions correlate with GBV-C acquisition. Also, no correlation was found between GBV-C RNA and the incidence or severity of posttransplant hepatitis. Finally, E2 antibody presence before transplantation failed to provide complete protection from GBV-C acquisition.

Characterization of anti-hepatitis C virus-positive sera not genotyped by restriction fragment length polymorphism or serology.

BACKGROUND: The hepatitis C virus genome is extremely heterogeneous and has been classified into six major genotypes. Genotyping of hepatitis C has been achieved through both direct molecular approach and indirect detection of host genotype-specific antibodies by serological methods. The purpose of this study was to characterize anti-hepatitis C positive sera samples that were not genotyped either by restriction fragment length polymorphism or by serology. METHODS: Two hundred and two patients from northern California with established chronic hepatitis C virus infection were studied by restriction fragment length polymorphism analysis of the 5'-untranslated region amplicon. A serological genotyping assay, based on synthetic peptides derived from non-structural region 4 of the hepatitis C virus genome, was used to determine serological genotype. RESULTS: Of the 202 patients studied, 187 (93%) were polymerase chain reaction-positive. One hundred and eighty-six patients were able to be genotyped by restriction fragment length polymorphism, compared with 144/202 (71%) of patients genotyped by serology (P < 0.0001). Only two of 202 samples showed discordant genotyping results. The distribution of hepatitis C virus genotypes in northern California was found to be type 1a, 41%; 1b, 35%; 2a, 3%; 2b, 10%; 3a, 11%; and 4, < 1%. There was no association between hepatitis C genotypes and age, gender distribution, ethnic origin, presumptive mode of transmission, serum alanine aminotransferase levels and the proportion of patients with cirrhosis. Of the 15 patients who were not genotypable by the molecular assay, four patients were genotyped by serology, with hepatitis C virus genotypes 1, 2 and 3 represented. Of the 58 samples that were not genotyped by serology, 47 were genotyped based on the molecular assay, and the distribution of hepatitis C virus genotypes was similar to that of the overall study population. CONCLUSIONS: These data showed that: (i) molecular genotyping assay based on 5'-untranslated region is more sensitive than serologic genotyping based on the non-structural-4 region but the results were highly concordant; (ii) hepatitis C virus genotypes 1-4 are present in northern California, with genotype 1 being the most prevalent; and (iii) the failure to determine hepatitis C virus genotype based on molecular or serological genotyping assay does not appear to be related to specific hepatitis C genotypes.

Future directions in the treatment of patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infects over 170 million people worldwide. While interferon is currently the most used single agent therapy, this drug may result in a sustained loss of virus from the blood in only up to 15% of patients; new options for treatment are needed. With the release of ribavirin in North America and Europe, a viral clearance rate or 'cure' may be attained in up to 40% of patients. Developing successful antiviral therapy that prevents or delays the development of cirrhosis, liver failure and liver cancer as well as decreasing the demand for liver transplantation are clearly identified goals. Unfortunately, there is no complete in vitro model of HCV replication or translation. Due to the lack of an animal or cell culture model of HCV infection, in vitro translation screening systems to identify inhibitors of HCV protein translation are being evaluated by a large number of biotechnology companies. With advancing computer technology, high throughput screening processes are now possible and can be joined to specific in vitro model testing systems. Along with examining some of the information known about HCV therapy and the HCV genome, the present review discusses potential targets for new therapies and identifies therapeutic agents that are nearing clinical application.

Treatment of chronic hepatitis B: new antiviral therapies.

Chronic hepatitis B infection is the most important cause of cirrhosis and hepatocellular carcinoma worldwide. Interferon-alpha has been shown to be effective in approximately one third of patients, and response seems to be sustained in long-term follow-up studies in Western countries. New treatments using lamivudine and other nucleoside analogues such as famciclovir, lobucavir, and adfovir showed promising results although sustained suppression of viral replication is unusual after discontinuation of therapy. The results of recent clinical studies using these nucleoside analogues are discussed in detail in this review. Other important issues such as drug resistance and the role of combination therapy are also addressed.

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis.

Long-term hepatitis B immune globulin (HBIG) has been shown to reduce hepatitis B virus (HBV) reinfection in patients transplanted for hepatitis B. The aim of this study was to determine the prevalence of HBV S gene mutations in liver transplant recipients who developed recurrent hepatitis B despite HBIG prophylaxis, and to determine if these mutations can revert after withdrawal of HBIG. The entire S gene sequences in pre- and posttransplant sera from 20 patients who developed recurrent hepatitis B despite HBIG prophylaxis were compared. Ten (50%) patients had 18 amino acid substitutions involving the 'a' determinant in the posttransplant samples. These mutations were absent in 93% of the pretransplantation clones analyzed. There was a significant correlation between the development of mutations in the 'a' determinant region and the duration of HBIG therapy. Most of the mutations result in changes in predicted antigenicity of the S protein. During follow-up, mutations in 14 (78%) of 18 affected codons in the 'a' determinant region reverted back to the pretransplantation sequences; only 1 codon had a de novo change after the withdrawal of HBIG. Two control patients who did not receive HBIG had no change in the 'a' determinant in their posttransplantation samples. These data support the hypothesis that mutations in the S gene were induced or selected by immune pressure exerted by HBIG. HBV S mutants may play a role in HBV reinfection in liver transplant recipients who received HBIG prophylaxis.