Is Low Level Viremia Acceptable During Antiviral Therapy of Patients With HBV Infection and Decompensated Cirrhosis?
2018; Elsevier BV; Volume: 16; Issue: 12 Linguagem: Inglês
10.1016/j.cgh.2018.09.010
ISSN1542-7714
Autores Tópico(s)Liver Disease Diagnosis and Treatment
ResumoDespite the availability of highly effective and safe antiviral therapies, patients with chronic hepatitis B continue to present with decompensation. Oral antivirals have been associated with significant improvements in clinical outcomes in patients with decompensated cirrhosis.1Singal A.K. Fontana R.J. Meta-analysis: oral anti-viral agents in adults with decompensated hepatitis B virus cirrhosis.Aliment Pharmacol Ther. 2012; 35: 674-689Crossref PubMed Scopus (69) Google Scholar The retrospective study from Jang et al,2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar published in Clinical Gastroenterology and Hepatology, reminds clinicians of the high mortality rate in this patient group, with 17% dying or requiring liver transplantation within the first 6 months, and 40% by year 5, even though antiviral therapy was started immediately after the development of decompensation. Short-term survival was more strongly influenced by the severity of liver disease, reflected by high model for end-stage liver disease and Child–Pugh class, rather than early response to antiviral therapy. Prior studies have highlighted the lag in clinical response among patients with decompensated cirrhosis treated with antivirals.3Fontana R. Hann H. Perrillo R. et al.Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.Gastroenterology. 2002; 123: 719-727Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Thus, any patient with chronic hepatitis B presenting with decompensation should be evaluated concurrently for liver transplantation. Beyond the first year, deaths resulting from decompensation largely plateau for those without hepatocellular carcinoma (HCC), but deaths owing to HCC continue.2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In fact, among survivors of an initial decompensating event, HCC was the greatest threat to long-term survival. Thus, this study emphasized the need to prevent acute-on-chronic decompensation in patients with cirrhosis and the importance of identifying and initiating treatment in all patients with cirrhosis. This conclusion is consistent with the American Association for the Study of Liver Diseases guideline that recommends that all patients with cirrhosis be treated with entecavir or tenofovir regardless of their alanine aminotransferase (ALT) or hepatitis B virus (HBV) DNA levels.4Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1396) Google Scholar The novel aspect of the study from Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar is the correlation of virologic responses (VRs) to antiviral therapy with liver-related outcomes. Patients who achieved and maintained an HBV DNA level less than 20 IU/mL (MVR) were compared with those who either did not achieve an undetectable HBV DNA (non-VR) or had intermittently or persistently detectable HBV DNA after becoming undetectable (suboptimal VR). Intuitively, one might predict that a MVR would yield the best outcomes in patients with advanced cirrhosis. On the other hand, achievement of a low level of viremia may be sufficient to curtail ongoing liver inflammation and injury and stabilize complications of cirrhosis. Because the virologic tools for measuring HBV DNA have improved over the years, thresholds for an undetectable HBV DNA level have decreased. Thus, what was classified as an optimal VR using assays of the past would be different using current, more sensitive, assays. Indeed, it is appropriate to re-examine the natural history of chronic HBV using current sensitive assays and, in this regard, the study by Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar makes an important contribution. An early virologic response (HBV DNA <20 IU/mL by 6 mo) was achieved in 34% of patients, but was not associated with short-term survival. The low rate of achieving an early VR is not surprising because 58% were hepatitis B e antigen positive and more than 50% had an HBV DNA level of 5.5 log10 IU/mL or greater at baseline, so attainment of an HBV DNA less than 20 IU/mL will be anticipated to take a year or more for those with a high baseline viral loads.5Kim J.H. Sinn D.H. Kang W. et al.Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment.Hepatology. 2017; 66: 335-343Crossref PubMed Scopus (121) Google Scholar, 6Shim J.H. Lee H.C. Kim K.M. et al.Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis.J Hepatol. 2010; 52: 176-182Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 7Zoutendijk R. Reijnders J.G. Brown A. et al.Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naive patients with a partial virological response.Hepatology. 2011; 54: 443-451Crossref PubMed Scopus (140) Google Scholar, 8Srivastava M. Rungta S. Dixit V.K. et al.Predictors of survival in hepatitis B virus related decompensated cirrhosis on tenofovir therapy: an Indian perspective.Antiviral Res. 2013; 100: 300-305Crossref PubMed Scopus (20) Google Scholar Importantly, improvements in Child–Pugh and model for end-stage liver disease scores were similar in those with early VR vs those without. Serum aminotransferase levels were not provided, but prior studies have shown that biochemical and clinical improvements lag behind virologic responses.3Fontana R. Hann H. Perrillo R. et al.Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.Gastroenterology. 2002; 123: 719-727Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar It is likely that what matters for reducing early mortality is a sufficient HBV DNA decrease to yield biochemical and functional improvement rather an absolute requirement for HBV DNA undetectability (<20 IU/mL). For longer-term survival, however, MVR appeared to be more important. Cumulative 10-year survival rates were 71.6% in those with MVR compared with only 18.8% for those without VR and 57.2% in those with suboptimal VR. MVR, however, did not influence incident HCC rates, with rates of 41.0%, 36.9%, and 48.0% in patients with MVR, without VR, and those with suboptimal VR, respectively. The lack of effect on HCC risk suggests that, at the stage of decompensated cirrhosis, factors other than viral are the primary drivers of HCC risk. In contrast to the Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar study, another study found that in patients with compensated liver disease (51% with cirrhosis), persistent or intermittent low-level viremia (<2000 IU/mL but detectable) was associated with a significantly higher HCC risk than in those with MVR.5Kim J.H. Sinn D.H. Kang W. et al.Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment.Hepatology. 2017; 66: 335-343Crossref PubMed Scopus (121) Google Scholar Perhaps the contribution of viral suppression to HCC risk differs by cirrhosis severity and the presence of other cofactors such as diabetes.9Hsu Y.C. Ho H.J. Lee T.Y. et al.Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir.J Viral Hepat. 2018; 25: 543-551Crossref PubMed Scopus (27) Google Scholar Until very recently, there was a paucity of data regarding whether liver-related outcomes differed in patients on treatment with HBV DNA levels persistently less than 2000 IU/mL but detectable vs those with undetectable HBV DNA.10Lok A.S. McMahon B.J. Brown Jr., R.S. et al.Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis.Hepatology. 2016; 63: 284-306Crossref PubMed Scopus (349) Google Scholar Current American Association for the Study of Liver Diseases treatment guidelines do not recommend changing therapy in patients on antiviral therapy with intermittent or persistently low-level viremia, unless criteria for virologic breakthrough are met (≥1 log10 increase from nadir).4Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1396) Google Scholar Whether any patients in the Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar study met the definition for virologic breakthrough is unclear. Presuming the non-VRs and suboptimal VRs did not meet the criterion of virologic breakthrough, the big question posed by the Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar study is whether persistently undetectable HBV DNA should be the new gold standard for HBV therapy in patients with decompensated cirrhosis? I think not for several reasons. First, there are no data showing that adding or changing antivirals to achieve MVR in patients with suboptimal VRs achieves a reduction in liver-related complications. It may be that low-level viremia is a marker of underlying bad biology that will not be altered by adding another antiviral. Second, what defines the optimal VR is not established. As highlighted by the Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar study, there was no discernable difference in outcomes among patients with HBV DNA less than 10 vs 10 to 20 IU/mL. Before MVR becomes the new gold standard, we need more longitudinal data on suboptimal responders. For example, are nonresponders with HBV DNA levels of 15 IU/mL the same as those with values of 150 IU/mL? Are suboptimal VRs with HBV DNA excursions into the detectable range every 1 to 2 years really different from those with MVR? Certainly the level of concern for the risk of liver-related outcomes is likely to be different across these various categories of non-MVR, and in the absence of more granular data it is premature to change our approach to patients on antiviral therapy with intermittent or persistent low-level viremia.4Terrault N.A. Bzowej N.H. Chang K.M. et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology. 2016; 63: 261-283Crossref PubMed Scopus (1396) Google Scholar Finally, the proportion of patients for whom a change in therapy would be needed may be extremely high. In the Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar study, only 30% of patients achieved MVR over long-term follow-up evaluation, meaning the vast majority would require a change in therapy if MVR becomes the treatment end point. In fact, this proportion may be even by higher if more intensive HBV DNA monitoring were undertaken. Implications for the cost of HBV therapy are substantial, especially if combination therapy was needed. So, how should we manage the patient with cirrhosis who shows intermittently or persistently detectable HBV DNA? First and foremost, it is important to confirm adherence. Recent data have highlighted the impact of adherence to HBV therapy and liver-related events among patients with cirrhosis, and those with medication adherence less than 90% have a higher incidence of HCC.11Shin J.W. Jung S.W. Lee S.B. et al.Medication nonadherence increases hepatocellular carcinoma, cirrhotic complications, and mortality in chronic hepatitis B patients treated with entecavir.Am J Gastroenterol. 2018; 113: 998-1008Crossref PubMed Scopus (34) Google Scholar In addition, ensuring the antiviral is the correct dose (eg, entecavir dose is 1 mg/d in patients with decompensation) and taken as prescribed (with/without food) warrants attention. Second, the pattern of suboptimal response should be considered. For patients with an occasional HBV DNA blip from undetectable to greater than 10 to 20 IU/mL, there seems little reason to consider a change of antiviral therapy, whereas a patient who never achieved undetectable HBV DNA levels and has HBV DNA levels persistently 102 to 103 log IU/mL would be more troubling. In addition, HBV DNA levels accompanied by increased ALT levels raise the level of concern. In other words, any decision to modify therapy should be based on serial HBV DNA and ALT values over time and consider the clinical context. Collectively, the available literature, now bolstered by this study from Jang et al,2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar suggests that those with decompensated cirrhosis probably warrant special consideration. Special because of the significant short- and long-term mortality risks. Although short-term mortality is driven largely by cirrhosis severity, survival beyond 6 to 12 months is dependent on virologic responses.2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 6Shim J.H. Lee H.C. Kim K.M. et al.Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis.J Hepatol. 2010; 52: 176-182Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 12Kim S.S. Hwang J.C. Lim S.G. et al.Effect of virological response to entecavir on the development of hepatocellular carcinoma in hepatitis B viral cirrhotic patients: comparison between compensated and decompensated cirrhosis.Am J Gastroenterol. 2014; 109: 1223-1233Crossref PubMed Scopus (60) Google Scholar In terms of HBV DNA levels, how low is low enough to achieve optimal long-term outcomes remains an open question, but Jang et al2Jang J.W. Choi J.Y. Kim Y.S. et al.Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis.Clin Gastroenterol Hepatol. 2018; 16: 1954-1963Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar are to be congratulated for bringing this issue to the forefront for future investigations. Effects of Virologic Response to Treatment on Short- and Long-term Outcomes of Patients With Chronic Hepatitis B Virus Infection and Decompensated CirrhosisClinical Gastroenterology and HepatologyVol. 16Issue 12PreviewLittle is known about the effects of antiviral therapy on short- and long-term survival of patients with hepatitis B virus (HBV)-related decompensated cirrhosis. We aimed to determine whether a maintained virologic response (MVR, defined as persistent undetectable HBV DNA during therapy) associates with short-term (6 mo) and long-term (6–120 mo) survival of patients with decompensated cirrhosis. 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