The topic ‘Milestones and Perspectives in Viral Hepatitis B’ is a wide and rapidly evolving chapter of Modern Hepatology. This paper is my personal and hopefully objective view of certain aspects to this question based on my experience from the mid 1960s to the present. This 50-year period represents a revolution in hepatology. This revolution began for hepatitis B in the early 1960s with the discovery of the so-called Australia (Au) antigen and has since extended to all aspects of the infection, from diagnosis, epidemiology, clinical spectrum and natural course of the disease to molecular virology, immunology, pathogenesis and treatment. There are too many milestones to cover all of them in this paper; therefore, I will first summarize some of the major developments in the field of hepatitis B, which I consider fundamental and then focus mainly on the milestones and treatment perspectives. After all, the topic of the fourth Paris International Conference is ‘The management of patients with Viral Hepatitis B’.
There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in indentifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.
Fifty years of landmark studies in hepatitis B
In 1967, Saul Krugman and his colleagues described two clinically, epidemiologically and immunologically distinctive types of infectious hepatitis caused by two different viruses, the MS-1 and MS-2, which corresponded to hepatitis A (formerly epidemic hepatitis) and to hepatitis B (formerly serum hepatitis) (1). A few years earlier, Blumberg et al. (2), while studying the heterogeneity of lipoproteins, had discovered a new antigen in the serum of an Australian aborigine, the so-called Au antigen. In 1967, Au antigen was reported to be linked to viral hepatitis (3) and in 1969 to be specifically associated with serum hepatitis and with the MS-2 Willowbroook strain of hepatitis B (4, 5). A number of pioneer studies followed this, in which the particles of hepatitis B virus (HBV) were detected, the Au antigen was shown to represent the surface protein of the virus, and other clinically relevant proteins of HBV such as the core and e antigens were discovered (6–10). Au antigen was then renamed first as the hepatitis-associated antigen and finally as the HBsAg.
These discoveries were followed by an explosion of clinical, epidemiological, fundamental and experimental research throughout the world, which had significant impact on the prevention and treatment of hepatitis B over the years (11–15).
Within this context, I am including a list of references of a few of the early clinical and epidemiological studies and reviews from Europe and Asia documenting that chronic HBV infection is a major health problem in terms of morbidity and mortality worldwide (16–31), as well as a few selected reports on non-liver disorders caused by HBV (32, 33) and the expression of HBV and its proteins in serum, liver and other tissues (34–41). These studies have helped to identify the difference between active, inactive and past HBV infection and reveal the pathogenesis and natural course of this disease. Finally, I have also listed reference studies on certain aspects of the molecular virology of HBV and its heterogeneity including the selection of HBV variants and mutants (40, 42–50).
Landmarks in the treatment of hepatitis B
The first milestones in the treatment of hepatitis B were linked to the advances in interferon-alpha (IFN-α) production by recombinant DNA technology and the discovery that this substance could be effective in patients with HBV replication and liver disease activity on the basis of its biological antiviral and immunomodulatory properties (51). However, for several years the indication for IFN-α therapy was restricted to HBeAg-positive patients with increased alanine aminotranferase (ALT) levels only, with a short-term end point of HBeAg seroconversion and returning ALT to normal levels (52–55). It was only several years after the discovery of HBeAg-negative chronic hepatitis B (CHB) and the confirmation that this was part of the natural course of chronic infection that treatment indications were significantly extended and the ultimate goals of treatment were properly defined (14).
Within this context, a brief account on HBeAg-negative CHB is necessary.
HBeAg-negative chronic hepatitis B
In my opinion, the recognition, pathogenesis and treatment of HBeAg-negative CHB were major milestones in the understanding and treatment of HBV. In particular, the studies from Greece and Italy in the 1980s on HBeAg-negative/anti-HBe-positive CHB (56–59), followed by the discovery of precore HBV mutants preventing the formation of HBeAg in 1989 (60–62), were major milestones for both treatment and overall discoveries in the field of viral hepatitis including the application of the molecular biology of HBV to clinical medicine.
Until the 1980s, all HBsAg+/anti-HBe+patients were considered to harbour an inactive HBV infection without liver necro-inflammation, with integrated HBV sequences coding for HBsAg production. Episomal HBV replication was considered to be completely eliminated in these individuals [reviewed in (13, 28, 63)]. It took nearly 20 years to realize that this was an oversimplification of the natural course of chronic HBV infection and that CHB can also develop after HBeAg loss and seroconversion to anti-HBe. Thus, two types of CHB were recognized not only in the Mediterranean area but worldwide (14). In the early 2000s, the first multicentre randomized controlled trials (RCTs) of IFN-α in HBeAg-negative CHB using pegylated compounds were begun, based on the results of the earlier studies with standard IFN-α (63, 64).
From a historical point of view, it is interesting to note that HBeAg-negative CHB with replicating HBV was identified quite early in the late 1970s by immunofluorescent detection of HBcAg expression in the liver (35). However, the clinical, immunological, virological and laboratory aspects of this entity, its role in the natural course of chronic HBV infection as well as indications for treatment and the efficacy of standard IFN treatment were described several years later (63–68).
At present, HBeAg-negative CHB is the main type of CHB worldwide as well as the most difficult to treat in terms of achieving sustained virological response.
The current state of treatment in chronic hepatitis B
Although HBeAg-negative CHB has been added to the indications for treatment, for the moment very few individuals with chronic HBV infection are actually treated, estimated as <15% of those known to be infected with HBV in the developed countries.
Although the cure of chronic HBV infection is the desired goal of therapy, for the moment the goal of treatment is to prevent or delay the progression of CHB to cirrhosis and its life-threatening complications including hepatocellular carcinoma (HCC) (66, 67). Thus, the practicing clinician should always remember that serological events such as ALT normalization, HBeAg seroconversion, non-detectability of HBV DNA in serum and even HBsAg loss and seroconversion to anti-HBs are only intermediate end points to this ultimate goal.
Landmarks in the development of current anti-hepatitis B virus therapies
There have been numerous milestones and landmark events in the management of hepatitis B, mostly linked to the development of existing therapies.
There are three consecutive periods in drug development, beginning with the approval of standard IFN-α2b in 1992, followed by the introduction of lamivudine into clinical practice in 1998, the newer oral antivirals (from 2002 to present) and then as standard IFNs use declined and was limited to a few HBeAg-positive patients, with the approval of PEG-IFN-α, IFNs were again indicated both in HBeAg-positive and HBeAg-negative CHB.
The era of standard interferon-α
In the 1980s, with the production of recombinant IFN-α2a, -2b and lymphoblastoid IFN, these drugs were indicated for the treatment of CHB. Based on several RCTs and the approval of these agents in the treatment of CHB, 3–6-month finite courses of treatment were only shown to be effective in a limited percentage of patients with HBeAg-positive CHB, inducing HBeAg seroconversion, returning ALT to normal levels and even HBsAg clearance (69). On the other hand, the results of small trials in Mediterranean patients with HBeAg-negative CHB were rather disappointing because of high relapse rates after stopping short courses of IFN, while increased sustained response rates resulting in HBsAg loss were reported with longer IFN treatment and retreatment (68).
A meta-analysis has shown that IFN is effective in terminating viral replication and in eradicating the carrier state in patients with chronic HBV infection who are HBeAg positive when these patients are treated for 3–6 months and followed for 6–12 months after cessation of therapy (69).
There were few new treatment options until the mid 1990s when the nucleoside analogue, lamivudine, a reverse trascriptase inhibitor that had been used in HIV, was attempted in the treatment of CHB because HBV replication involves a reverse transcription phase. Lamivudine revolutionized the treatment of HBV, and was administered to HBeAg-positive (70) and HBeAg-negative (71) CHB patients as well as to patients with end-stage liver disease. However, it also resulted in genotypic HBV resistance to antivirals and motivated new research for the development of highly potent compounds with high barriers to HBV resistance (50). However, none of these drugs have been found to be effective in the immune tolerance phases of chronic HBV infection and very little progress has been made in the goal of curing HBV.
The topic of treatment of CHB patients with oral antivirals, its pros, cons and perspectives will be described by Dr Papatheodoridis and others in separate presentations in this conference.
Back to interferon treatment with pegylated compounds
The efficacy and safety of treatment with PEG-IFNs were first evaluated in CHB in the 2000s and in 2005, when tenofovir became commercially available for hepatitis B and PEG-IFN-α2a was also approved both for HBeAg-positive and HBeAg—negative CHB.
One-year finite treatment courses of PEG-IFNs were compared with lamivudine alone and in combination. These studies included long-term post-treatment follow-up and retrospective evaluation of several baseline and on-treatment variables as predictors and determinants of sustained response and HBsAg loss, the outcome of treatment, which is the closest to a cure for the moment (72).
The recent large multicentre randomized controlled trials (RCTs) with 1 year of PEG-IFN treatment and a long post-treatment follow-up in HBeAg-positive and HBeAg-negative CHB patients are based on the earlier studies with standard IFNs (73–75). The re-evaluation of the results of these studies based on recent variables, especially serum HBsAg concentrations (76, 77), shows an increased interest in HBeAg-negative CHB and the involvement and contribution of investigators from Europe, in particular France, the Netherlands, Germany and northern Italy (78–84).
These newer studies emphasize HBsAg clearance induced by the immunostimulatory properties of IFN. At the same time, an unexpected high prevalence of HBsAg clearance has recently been reported in the long-term follow-up of HBeAg-negative CHB patients after 4 or 5 years of adefovir treatment (85).
Perspectives in the treatment of hepatitis B
Based on the results of available drugs, we cannot be particularly optimistic for the near future. In addition to the problems of cost, availability and side effects, a realistic summary of the current state of the art in HBV treatment includes a couple of IFNs and several nucleoside analogues (NUCs) – whose aim is to cheat the reverse transcriptase of HBV without affecting the enzymes of the host – which can only result in partial efficacy without cure in a small fraction of patients with chronic HBV-induced liver disease.
However, the perspectives of treatment in hepatitis B are promising if we focus upon optimizing the application of existing therapies and those under clinical development rather than expecting new milestones. Wide availability of existing drugs, treatment with indicated first line therapies, appropriate monitoring and application of reliable predictors of response and no response are potentially achievable goals in individualized therapy. Achievement of high SVR rates and next to cure responses in patients eligible for treatment and for all phases of the infection are not foreseeable. However, limiting HBV resistance to antivirals by appropriate monitoring and early identification of patients based on proper management is a realistic perspective for current therapies.
Extensive and earlier administration of existing therapies is another achievable perspective, which is possible by nationwide HBsAg screening programmes. This approach would significantly increase access to treatment in populations in need of treatment, as well as, hopefully, treatment efficacy.
Obviously, new milestones are needed to make effective and safe therapy available to everyone infected with HBV. Thus, future anti-HBV treatment options must include new agents acting on all possible sites of the viral replication cycle, from its entry into the hepatocytes to the assembly of new virions and their release into the circulation. Specific immunological drugs and tools are also needed to modify host immune responses that are not effective enough to clear HBV during the natural course of infection but are involved in the pathogenesis of ongoing HBV-induced liver damage by maintaining hepatic necro-inflammation and promoting the development of fibrosis, cirrhosis and even of HCC.
For the moment, these reflections are wishful thinking rather than perspectives for the foreseeable future. However, if these advances are achieved, the portrait of the hepatologist, first drawn by the late Jacques Caroli, will have to be transformed to include having the expertise necessary for appropriate monitoring and personalized handling of all individuals with known HBV infection.
Finally, everyone in clinical practice must remember that despite the benefits of treatment, the disease cannot be eradicated by even the most effective therapies and that the best visible perspective is prophylaxis from HBV infection by universal vaccination that also originated from the first landmark studies in the 1960s (2).
Despite the many landmark studies and the many years since the discovery of the HBV, treatment efficacy is still far from satisfactory. Eradication of the infection is not an achievable goal with current therapies, while HBsAg loss, the closest to the outcome of a cure, is only possible in a minority of patients. Nevertheless, the ultimate goal of current therapies to prevent or delay the progression of HBV-induced liver disease to cirrhosis and HCC is still primordial. Therefore, efforts to provide unrestricted availability of existing therapies and national programmes for optimal administration are necessary to reduce the morbidity and mortality of hepatitis B until the future when it can be successfully eradicated by vaccination.
Conflicts of interest
The author has declared no potential conflicts.