Mugilan Poongkunran*, Asad Javaid
Department of Medicine, Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Received: 03 August, 2015; Accepted: 29 August, 2015; Published: 28 August, 2015
Mugilan Poongkunran, Department of Medicine, Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, LMOB Suite 4A, Liver Research Center, Boston 02215, Massachusetts, USA, Tel: +1-347-896-3626; Fax: +1-617-632-1125; Email:
Poongkunran M, Javaid A (2015) A Review on Therapeutic Management of Chronic Hepatitis B Infection. Arch Clin Gastroenterol 1 (2): 020-034. DOI: 10.17352/2455-2283.000006
© 2015 Poongkunran M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Chronic hepatitis B; Interferon; Entecavir; Tenofovir; Hepatocellular carcinoma
The current therapeutic goal in the management of chronic hepatitis B (CHB) infection is to persistently suppress hepatitis B virus (HBV) replication and prevent its progression to liver failure and the development of hepatocellular carcinoma (HCC). At present, the therapeutic strategies for CHB includes either a short course of pegylated-interferon-alfa (PEG-IFNa) and/or a long term course of nucleos(t)ide analogues (NA's). NA's are more preferable to PEG-IFNa, majorly for its easier route of administration and excellent tolerance and safety profiles. Entecavir (ETV) and tenofovir (TDF) are the current first line options for its potency to maintain sustained virological response (SVR) in almost 100% of the adherent individuals along with minimal to no long-term resistance. These sustained inhibitions of HBV replication have been shown to be associated with histological improvement, modifying the long-term outcomes. However, HBsAg seroconversion, the best surrogate marker for viral clearance is still unachievable with the current first line agents and hence the risk for hepatocellular carcinoma (HCC) still exists among them. This makes us to still consider, a finite duration of PEG-IFNa that has shown considerable results with regards to HBsAg loss, as an attractive add-on or monotherapy option despite its adverse events profile. Existing evidences do not recommends its usage. However, numerous studies are ongoing and also further studies to evaluate the reliable baseline predictors of response to PEG-IFNa and early on-treatment stopping rules based on age, alanine aminotransferase levels (ALT), HBV DNA levels and HBsAg kinetics would be ideal.
CHB: Chronic Hepatitis B; PEG-IFNα: Pegylated Interferon-alfa; NA's: Nucleos(t)ide Analogues; ETV: Entecavir; TDF: Tenofovir; HCC: Hepatocellular Carcinoma; SVR: Sustained Virological Response; ALT: Alanine Aminotransferase;
Chronic hepatitis B (CHB) infection is defined at large by the presence of hepatitis B surface antigen (HBsAg) for more than 6 months; though some patients may test positive only for anti-HBc without HBsAg or anti-HBs . An estimated 240 million people are chronically infected with hepatitis B and a 15% to 40% lifetime risk of death exist in these affected population due to serious sequelae such as cirrhosis, hepatic decompensating, and hepatocellular carcinoma (HCC) [1,2]. The increasing prevalence, morbidity and mortality of CHB can be linked to its diverse and variable natural course; which in general, is serologically illustrated either by the presence or absence of hepatitis B virus (HBV) e antigen (HBeAg) indicating earlier and late phases of the disease, respectively [3,4]. The ultimate goal of CHB therapy is to arrest the progression of liver injury and to prevent the development of liver failure, HCC and hence liver transplantation. Despite the advent of potent anti-HBV agents such as interferon-alpha (INFα) and nucleos(t)ide analogues (NA's), the current management is majorly ineffective in eradicating the virus, providing only apparent virological suppression [3,5]. Hence an absolute cure or functional cure, where the risk of death from liver disease is same as a person who was never infected or same as a person with naturally resolved infection, remains impracticable yet . Also, though the existing practice guidelines such as that of American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) assist physicians in the diagnosis and optimal management of CHB; they are still expected to individualize the management considering various factors like cost-effectiveness, compliance, efficacy and duration of anti-viral agents, existence of co-infections etc. [1,3,4]. This article reviews the basis for those guideline recommendations, the natural history of the disease, treatment options and what we do in our practice to illustrate factors that may influence the management of CHB.
Natural history of chronic hepatitis B infection
Continuous advances have been made in understanding the natural history of the disease, which is majorly determined by the interplay between host-immune responses and viral replication. Such knowledge and identification of which natural history phase of the disease the patients are in would be the ideal first step in the management of CHB infection, as the criteria and endpoints of treatment differ accordingly. The dynamic natural course of CHB infection can be categorized into at least five phases; however, these need not be in sequence and exist in all patients with the disease .
• The initial phase is characterized by high levels of HBV replication with no evidence of active liver disease and hence termed as “high replicative, low inflammatory phase”. This phase is more common in patients with prenatally acquired CHB infection and is widely known as the “immune tolerant phase”, for the inability of immature immune system to identify the virus aided by the HBeAg protein [1,3]. However, researchers state a hypothesis of trained immunity, evidenced by enhanced innate immune cell maturation and Th1 development resulting in a similar T cell response to that seen in the immune clearance phase of CHB [7,8]. These immune trained HBeAg positive patients are characterized by very high levels of serum HBV DNA that is commonly above 20,000 IU/mL or 1 million IU/mL, normal to low levels of serum aminotransferases, and no to minimal liver necroinflammation and fibrosis [1,3]. During this phase, the reverse transcriptase properties of HBV may support its integration randomly into the host hepatocyte DNA resulting in persistently elevated HBV DNA levels over many years; thereby increasing the risk of cirrhosis and HCC.
• In the "immune clearance phase”, the host's immune system initiate it's response to HBV resulting in hepatocyte injury. It is more common and rapidly reached in patients infected during adulthood resulting in spontaneous HBeAg clearance, paralleling the maturity of innate and adaptive immune responses. Patients early in this phase are mostly HBeAg positive, with high levels of serum HBV DNA, elevated levels of serum aminotransferases, and moderate to severe liver necro-inflammation with more progression to fibrosis [1,3]. Over the time, in many cases spontaneous HBeAg clearance occurs, accompanied with exacerbations in serum alanine aminotransferases (ALT) and HBV DNA levels . This phase ends with the appearance of anti-Hbe and such clearance either spontaneously or by antivirals during early stages of the disease has been shown to significantly reduce the risk of complications .
• Patients in the "HBeAg-negative CHB phase” have HBV virions in the precore and/or the basal core promoter regions with nucleotide substitutions. These patients are generally characterized by HBeAg negativity, with periodic reactivation due to ineffective immune clearance, resulting in moderate to high levels of viral load (usually >2000 IU/ml) and aminotransferases levels [1,3]. The serum HBV DNA and ALT levels are much lower compared to HBeAg positive individuals in the immune clearance phase. They have continued necro-inflammation in the liver and are at risk of complications due to low rates of prolonged remissions.
• Predominantly patients in the “non-replicative phase”; widely known as “inactive HBV carrier” phase, are characterized by seroconversion of HBeAg to anti-Hbe, very low or undetectable serum HBV DNA levels (usually < 2000 IU/ml) and normal serum aminotransferases (approximately 40 IU/m) conferring a favorable long-term outcome due to immunological control of the infection [3,6]. However, care should be taken in categorizing these patients as inactive carriers with minimum three consecutive serological readings over a 12-month period of observation.
• Patients in the “occult HBV phase” are defined by the loss of the hepatitis B surface antigen, hence also termed as “HBsAg-negative phase”. However, a low level of HBV replication persist in the liver, characterized by intrahepatic presence of cccDNA chromatinized episomes. Most patients in this phase have very low to undetectable HBV DNA levels, with anti-HBc and with or without anti-HBs. Generally they have a better prognosis, if HBsAg loss occurs before the onset of cirrhosis [3,6].
Factors related to chronic hepatitis B progression
The clinical scenario following hepatitis B infection is determined by the interplay of other associated factors such as sex, age, genotypes, co-infections, alcohol consumption etc. Hence its consideration should always be taken prior to the initiation of therapy for CHB.
Genotype: To date, 10 genotypes (A through J) have been reported across different geographic regions and numerous studies have revealed their clinical importance on the chronicity of the disease, response to therapy and progression to complications. Genotype C, which is common in Asian population, have been shown to be associated with the longest average age of HBeAg seroconversion; thereby carrying the highest risk for HCC than any other genotypes . Genotype B is regularly divided into Bj (B1 and B6, found in japan) and Ba (B2-5, found in rest of Asia) sub-types. The genome of Ba group has a portion of genotype C genome; thereby making these people prone for complications and basal core promoter (BCP) mutations than those with Bj . Persons infected with genotype D, which is common in Eastern Europe, Southern Europe and Middle East; have been shown to go frequently into either “HBeAg-negative CHB phase”, harboring precores variants with high risk for HCC or into “inactive HBV carrier” with low risk for complications [12,13]. Genotype A, which is classified into A1 and A2, is widespread in Western Africa, sub-Saharan Africa and Northern Europe. Genotype A1 is associated with HCC in HBeAg negative young patients with low HBV DNA levels and cirrhosis rate . Though, genotype A2 is associated with HCC in older persons, its risk is comparatively lower to genotype D with higher clearance of HBsAg . Across different genotypes, though treatment response to nucleos(t)ide analogues have been reported to be similar, genotypes A and B have shown better response rates to interferon substitutes than genotypes C, D [15,16]. The recently included genotypes are genotype I and J, reported in Vietnam, Laos and in Ryukyu islands of Japan, respectively [17,18]. However, its clinical importance is not yet clearly studied.
Age: Persons who are infected via perinatal transmission from HBeAg-positive mothers tends to be in the “high replicative, low inflammatory phase” phase of the disease for a longer duration. These young infected individuals are associated with lower rate of clearance of HBeAg and poor prognosis, compared to the older individuals .
Co-infections: Patients with chronic hepatitis B may be co-infected with more than one genotype or with other viruses. Though studies have demonstrated co-infections with different HBV genotypes, it's clinical consequences still remains unclear . Coexistent hepatitis C virus (HCV) infection is mostly either acute co-infection of HCV and HBV, or acute HCV on preexisting chronic HBV; where HCV becomes the dominant virus and suppresses HBV DNA levels. However, both these presentations have been reported to increase the risk of severe hepatitis, fulminant hepatic failure, cirrhosis and HCC development compared to patients infected by either virus alone . Hepatitis delta virus (HDV) is an incomplete RNA virus that obliges the presence of HBV within the hepatocytes to complete its assembly and replication. Such interactions either presents as a co-infection with HBV or as super-infection occurring in chronic HBV carriers. However, on contrary to HCV co-infection with HBV, HDV co-infection is usually transient and self-limited, with rates of chronicity and complications similar to HBV mono-infected patients . Super-infection with HDV, in most cases presents as self-limiting severe acute hepatitis with establishment of HDV chronicity and exacerbation of the pre-existing HBV chronicity . Co-infection of HBV with HIV is a rising global health problem with lower rates of spontaneous HBeAg seroconversion, and hence the serious sequelae. Also, these patients may have occult HBV infections characterized by the presence of anti-HBc, high HBV DNA levels, without HBsAg .
NASH/NAFLD: Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) is an important cause of chronic liver disease, with increasing prevalence paralleling to the global rise of obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). Studies analyzing NAFLD or NASH in chronic hepatitis B patients have shown its added impact on the development of fibrosis .
Cirrhosis: Several studies have shown the strong associations between HBeAg and high levels of HBV DNA to the development of cirrhosis. Also, though cirrhosis is an independent risk factor for HCC, its absence doesn't rule out the development of the HCC in CHB patients .
Mutations: Several prospective studies have established that, BCP mutation [adenine (A) to thymine (T) transversion at nucleotide 1762 together with a guanine (G) to adenine (A) transition at nucleotide 1764] and precore mutation [nucleotide 1896 mutation from guanine (G) to adenine (A)] are independent risk factors for HCC in CHB patients even after adjusting for their genotypes. On the other hand, the presence of the PC mutation was associated with a lower risk of developing HCC .
Available treatment options
The U.S. Food and Drug Administration (FDA) have approved seven agents for the treatment of CHB . The first licensed agent for the treatment of chronic HBV infection was the conventional form of interferon alfa (in 1991); which have antiviral, antiproliferative, and immunomodulatory effects. Pegylated interferon (PEG-IFNα), an agent that is almost identical to that of standard IFNα, was licensed in 2005. Other agents that are currently in use are nucleoside and nucleotide analogues; which are pure anti-virals that act via suppression of HBV replication through inhibition of the reverse transcriptase and DNA polymerase activities. Lamivudine, a nucleoside analogue, was the first among them to be licensed in 1998. During the past decade, two other nucleoside analogues; entecavir (in 2005) & telbivudine (in 2006), and two nucleotide analogues; adefovir (in 2002) and tenofovir disoproxil fumarate (in 2008) were licensed.
The ultimate goal of CHB treatment is to prevent or decrease the development of cirrhosis, hepatic failure and HCC. These endpoints are reached by the suppression of viral replication, which are monitored through parameters such as reduction in HBV DNA to undetectable levels; reduction of serum ALT to normal levels; loss of HBeAg with or without detection of anti-HBe; and improvement in the histological findings. But, viral eradication is nearly unachievable because of the tendency HBV to integrate into the host genome or remain latent as cccDNA . Considering the extensive cost, the risk of adverse events and the drug resistance with long-term treatment, the most important question that arises is, which CHB patients need to be treated now and which patients can be monitored and have treatment deferred. And, as the efficacy and the optimal timing to initiate antiviral strategies are greatly influenced by the dynamic course of the disease and the above-mentioned host, viral, and environmental factors associated with progression of CHB; we have tried to focus on the current therapeutic strategies on two separate grounds based on the HBeAg status.
Optimal management for HBeAg positive chronic hepatitis B patients
Approach to HBeAg positive patients for anti-viral therapy (Figure 1):