Robert P. Perrillo M.D.

Zhou, K., A. S. Wahed, S. Cooper, A. M. Di Bisceglie, R. J. Fontana, M. G. Ghany, M. Khalili, A. S. Lok, R. Perrillo, W. M. Lee, D. T. Y. Lau, R. Sterling, H. L. A. Janssen and N. A. Terrault (2019). “Phase Transition Is Infrequent Among North American Adults With e-Antigen-Negative Chronic Hepatitis B and Low-Level Viremia.” Am J Gastroenterol Oct 24. [Epub ahead of print].

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INTRODUCTION: Patients with hepatitis B early antigen (HBeAg)-negative chronic hepatitis B (CHB) and low-level viremia are a heterogeneous group. Identifying those at risk of developing active CHB requiring antiviral therapy is important. In this study, we prospectively characterize incidence rates and predictors of transitioning from inactive to active CHB in a North American adult cohort. METHODS: Participants in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Hepatitis B Research Network cohort who were HBeAg negative with baseline hepatitis B virus (HBV) DNA 10,000 IU/mL and alanine aminotransferase (ALT) > 2x upper limit of normal or initiated treatment during follow-up. RESULTS: Of 970 participants meeting inclusion criteria, 15% experienced phase transition or initiated treatment over a median follow-up of 4 years: 9% of those with baseline HBV DNA 1,000 IU/mL, and hyperlipidemia. Only higher ALT, higher HBV DNA, and lower platelets were associated with phase transition when patients starting treatment were censored. DISCUSSION: Most adults in this North American cohort with HBeAg-negative CHB and low-level viremia remained inactive and off treatment over 4 years. Transition from inactive to active CHB is infrequent and predominantly associated with viral rather than host factors.

Brahmania, M., M. Lombardero, B. E. Hansen, N. A. Terrault, A. S. Lok, R. P. Perrillo, S. H. Belle, A. M. Di Bisceglie, J. J. Feld, W. M. Lee, M. W. Fried and H. L. A. Janssen (2019). “Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection.” Clin Gastroenterol Hepatol 17(12): 2541-2551.

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BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. METHODS: We collected data from the Hepatitis B Research Network-an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th-75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. CONCLUSION: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

Feld, J. J., N. A. Terrault, H. S. Lin, S. H. Belle, R. T. Chung, N. Tsai, M. Khalili, R. Perrillo, S. L. Cooper, M. G. Ghany, H. L. A. Janssen and A. S. Lok (2019). “Entecavir and Peginterferon Alfa-2a in Adults With Hepatitis B e Antigen-Positive Immune-Tolerant Chronic Hepatitis B Virus Infection.” Hepatology 69(6): 2338-2348.

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Monotherapy with interferon or nucleoside analog is generally not recommended during the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection. Recognition that high HBV DNA levels are associated with hepatocellular carcinoma has increased interest in treating HBV in the IT phase. Small pediatric studies reported efficacy with combination nucleoside analog and interferon therapy. The aim of this study was to evaluate the safety and efficacy of the combination of entecavir and peginterferon in adults in the IT phase of chronic HBV infection. Hepatitis B e antigen (HBeAg)-positive adults with HBV DNA > 10(7) IU/mL and alanine aminotransferase (ALT) 5 times the ULN occurred in eight (29%) participants, and none were associated with icterus. Forty-eight weeks posttreatment, HBV DNA rebounded to baseline levels in all participants, including the participant who lost HBeAg, and ALT values returned to near baseline levels in all but four participants. Conclusion: A lead-in strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir therapy for 40 weeks had limited efficacy in adults in the IT phase of chronic HBV infection and cannot be recommended.

Brahmania, M., M. Lombardero, B. E. Hansen, N. A. Terrault, A. S. Lok, R. P. Perrillo, S. H. Belle, A. M. Di Bisceglie, J. J. Feld, W. M. Lee, M. W. Fried and H. L. A. Janssen (2019). “Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection.” Clin Gastroenterol Hepatol Feb 8. [Epub ahead of print].

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BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous groups of patients in North America. METHODS: We collected data from the Hepatitis B Research Network-an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th-75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. CONCLUSION: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

Brouwer, W. P., Q. Zhao, B. E. Hansen, D. Lau, M. Khalili, N. A. Terrault, A. M. Di Bisceglie, R. P. Perrillo, M. W. Fried, D. Wong, J. J. Feld, S. H. Belle and H. L. A. Janssen (2019). “Improved Definition of HBV Phenotypes based on Genotype-specific Levels of Hepatitis B s Antigen.” Clin Gastroenterol Hepatol Jan 7. [Epub ahead of print].

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Quantitative HBsAg levels are increasingly important in the management and treatment of CHB. In clinical practice, it is essential to differentiate HBV phenotypes, and previous studies point to quantitative HBsAg as a potential additional serologic marker to this end. However, HBV genotype may influence HBsAg levels as well. Indeed, in the current study we found that HBsAg levels differed across both HBV phenotype and genotype, with highest levels observed in HBV genotype A and lowest in genotype B. The considerable variation in HBsAg levels among different HBV genotypes has important clinical implications, particularly for IC patients, since HBsAg levels >1000 IU/mL are associated with a higher risk of active hepatitis and HCC development. The reason for the observed variation in HBsAg levels between HBV genotypes may be sought in difference in ethnic background, the patient’s age at infection, duration of infection, and different frequencies of HBV precore, basal core and preS mutational patterns. Given the current findings, it is important to assess, also for the future guidelines, whether HBV genotype influences longitudinal HBsAg levels and the probability of HBV phenotype change over time. Moreover, since all IT participants were infected with HBV genotype B or C, further study is needed to elaborate on HBsAg levels of HBV genotype A and D in the IT phase. These patients may however be very rare and this could in fact be one of the reasons of why we found a more even distribution of different HBV genotypes in the IC phase. Overall, it would have been preferable to have a larger subset of non-Asian participants, however our cohort is a non-biased reflection of present clinical practice in North America. Concluding, when using HBsAg levels to assist in determination of HBV phenotype in clinical practice, HBV genotype specific HBsAg level cut-offs will be required. (Excerpt from text of this article in press, p.7.)