The past decade has seen major advances in the treatment of both hepatitis C (HCV) and hepatitis B (HBV) virus infections. Indeed sustained virological responses (SVR) for HCV infection, perhaps tantamount to cure, have increased from under 10% over 50% for the genotype 1 infections and to 70–80% for genotype 2 and 3 infections. Although sustained virological clearance is less common for HBV infections, for those who can be treated with interferon, this frequency is about 30% and for others, it is now possible to achieve prolonged suppression of viral replication using a variety of nucleoside and nucleotide inhibitors. Although these antiviral effects are encouraging and although many additional treatments are in the pipeline, the array of therapies has vastly increased the complexity of patient management and this paper will attempt to place such treatments into perspective and to draw upon consensus algorithms developed by leaders in the field and adopted by the American Association for the Study of Liver Diseases.
This paper is not intended to be a comprehensive review of the subject, but rather to serve as a synthesis of opinion and as a practical guideline for those managing patients with chronic hepatitis that is often compounded by the coexistence of HIV infection. Because treatment of chronic HBV infection is more complex and less understood and because space is limited, this chapter will deal primarily with the management of chronic hepatitis B. While the decision of when and whom to treat and the selection of the appropriate antiviral agent is a shifting and evolving process, there is uniformity in the belief that for both HBV and HCV, suppression or eradication of viral replication is the sine qua non of therapy and, if successful, is associated with diminished inflammation and fibrosis progression and a marked reduction in the most severe hepatitis outcomes, namely cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC).
Management of hepatitis B virus infection
Burden of disease
Hepatitis B virus infection is one of the most prevalent diseases in the world with an estimated 350 million chronic carriers . Most of these infections are concentrated in areas of high population density, such as Asia and sub-Saharan Africa, where vertical transmission from mother to infant is the predominant route of transmission. More than 70% of all people with chronic HBV infection are Asian. The United States is a low prevalence area with a projected prevalence of 1.25 million carriers . This prevalence is, however, likely to be an underestimate because it does not sample many high risk populations and does not uniformly sample the large number of immigrants coming from areas of high (5–20%) HBV prevalence. Despite a declining incidence of new infections as the result of vaccination and needle exchange programs, the Centers for Disease Control and Prevention estimates that 70 000 new infections occur each year in the United States  and that 5000 people in the United States die each year of complications of chronic HBV infection .
Stages of HBV infection
Hepatitis B virus infection runs diverse clinical, virological and serological courses depending on the age of acquisition, the mode of acquisition and the viral genotype, all of which correlate with HBV prevalence and geographic localization (Table 1). In areas of high HBV prevalence such as Asia and Africa, the predominant mode of transmission is from mother to infant. In these settings, an HBV carrier mother who is hepatitis B e antigen positive (HBeAg+), connoting a high level of viral replication, has a 90% probability of transmitting infection to the newborn and there is then a 90–95% chance the neonate will become a chronic carrier. This materno-foetal cycle is repeated from generation to generation, perpetuating HBV endemicity in areas with high birth rates and high HBV prevalence. The infected neonate generally does not mount an adequate cell-mediated immune response and behaves as if tolerized to HBV, developing neither clinical hepatitis nor alanine amino transferase (ALT) elevations. This pattern is designated the ‘immune tolerant’ stage of HBV infection, a stage that can persist for many decades. Subsequently, however, immune tolerance wanes and these patients develop evidence of hepatocellular inflammation that can progress over time and result in fibrosis/cirrhosis and HCC. It is this vertical route of infection that is being so effectively interdicted by global HBV vaccination programmes, but millions of such HBV carriers already exist and create the enormous global burden of this infection.
Table 1. Stages of chronic hepatitis B virus infection.
|Immune tolerant*||Pos||+ or −||Low||Normal|
|Chronic: HBeAg−||Pos||−||Low||Normal or ↑|
|Inactive HBsAg carrier||Pos||−||Low||Normal|
|Resolution||Neg (anti-HBs +)||−||−||Normal|
Chronic hepatitis acquired in adulthood is categorized as HBeAg-positive or HBeAg-negative (Table 1). HBeAg, a soluble, circulating portion of the HBV core protein, is an indirect marker of viral replication and thus correlates with the level of HBV DNA. During the HBeAg+ phase, HBV DNA levels generally exceed 20 000 IU L−1 (approximately 100 000 copies mL−1), ALT levels are elevated and liver biopsy shows varying degrees of inflammatory activity that can be severe and progressive. The HBeAg+ phase can last for years to decades, but ultimately there can be a spontaneous shift to a low replicative state with a fall in HBV DNA to <20 000 IU L−1, seroconversion from HBeAg+ to HBeAg-negative and the appearance of anti-HBe. During this stage, there is ongoing, but low-level viral replication and hepatic inflammation; the patient remains infectious to others, but to a much lesser degree than those HBeAg-positive. In those who seroconvert to anti-HBe+, the infection can become inactive with very low level to undetectable HBV DNA, normal ALT and minimal necroinflammatory activity on liver biopsy. This phase is termed the ‘inactive HBsAg carrier state’ and it persists for long periods in about two thirds of HBeAg seroconverters, but in others can reactivate (flare) to HBeAg+ with a return of high-level HBV DNA, elevated ALT and worsening liver histology. Recurrent flares can result in fibrosis progression and severe liver disease. A small proportion of inactive carriers undergo spontaneous resolution of HBV infection with loss of HBsAg and HBV DNA and seroconversion to anti-HBs. This may represent spontaneous cure of chronic infection, but in the vast majority, chronic hepatitis B is controllable, but not curable. Still another scenario has become apparent since molecular characterization of HBV has become readily available. Some persons who have undergone HBeAg seroconversion remain HBeAg-negative, but develop disease flares characterized by high level HBV DNA, elevated ALT and worsening hepatic necroinflammation. Such persons have been found to have mutations in the precore or core promoter regions of the HBV genome that serve as a stop codon and block the production of HBeAg, but allow for active viral replication of the mutant virus and progressive liver disease. The long-term prognosis for HBeAg-negative chronic hepatitis is worse than HBeAg-positive chronic hepatitis .
Eight HBV genotypes have been identified and designated A to H. Genotype A is found primarily in North America, northern Europe, India and Africa; genotypes B and C in Asia; genotype D in southern Europe, the Middle East and Africa; genotype E in West and South Africa; F in South and Central America; G in the US and Europe and H in Central America. These genotypes have some clinical correlations in that development of HBeAg-negative precore mutants is most common in genotypes B, C and D explaining the concentration of these mutants to Asia and southern Europe, particularly the Mediterranean basin. In Asia, genotype C has been associated with more severe liver disease and a higher prevalence of HCC than genotype B. Genotypes do not seem to affect the outcomes of nucleoside/nucleotide therapy, but genotypes A and B have higher response rates to interferon than genotypes D and C, such that genotype now enters into decisions of whether to use interferon as first line therapy. Thus, HBV genotyping should now be part of the pretreatment evaluation of chronically infected patients.
Treatment: general principles
These distinctions in the stages of HBV infection are important in promulgating therapeutic decisions. A large proportion of HBV-infected individuals do not require therapy while others will have an inexorable disease progression unless treated and these probabilities are best determined by proper staging of the disease according to the parameters outlined in Table 1. In general, persons in the immune tolerant or inactive HBsAg carrier state do not require treatment, unless there is contravening evidence for disease activity by low-level ALT elevations or liver biopsy; recent studies have shown that 12–43% of patients with persistently normal ALT had stage 2 fibrosis or greater on liver biopsy [5–7]. Thus, HBV carriers with normal ALT need to be closely monitored for changes in their HBeAg and HBV DNA status and sometimes to be considered for biopsy. It is also to be noted that the limits of normality for ALT have been redefined and the upper limit of normal is now considered to be 30 IU L−1 for men and 19 IU L−1 for women .
Persons with chronic hepatitis B, whether HBeAg-positive or negative, who have evidence for active disease as evidenced by ALT elevations or inflammation/fibrosis on liver biopsy, are candidates for therapy as outlined below. The underlying rationale for treatment is the need to prevent the well documented progression of chronic hepatitis B to bridging fibrosis, cirrhosis, end-stage liver disease and HCC. It is now well documented that HBV-related HCC can occur in the absence of pre-existing cirrhosis and that the risk increases with increasing levels of HBV DNA . One large study has shown a clear dose–response relationship between HBV DNA level and the incidence of HCC . Thus, suppression/eradication of HBV DNA is the key element in preventing both fibrosis progression and cancer evolution.
Treatment of HBsAg positive chronic hepatitis B
The treatment recommendations that follow are adapted from treatment algorithms developed by a panel of US hepatologists that were published in 2006 . These algorithms incorporated and updated prior guidelines from the American Association for the Study of Liver Diseases , the Asian-Pacific consensus statement , and the European Association for the Study of Liver Disease International Consensus Conference on Hepatitis B . While some differences exist in these various guidelines, the algorithms published in 2006  are inclusive, updated and the general consensus of the hepatology community. There are five approved drugs for first line therapy of patients with chronic hepatitis B: adefovir dipivoxil, entecavir, interferon (IFN) alfa-2b, lamivudine and peginterferon alfa-2a. However, clinical experience has narrowed these options such that lamivudine (3TC), the first approved nucleoside, is now rarely used as first line therapy because of the frequent development of lamivudine resistance and because adefovir and entecavir have proved to be superior options. Also, IFN alfa -2b has been supplanted by pegylated IFN because the latter maintains more stable drug levels and allows once-a-week administration. In treating subjects with any of these agents, the first goal of therapy is to reduce and maintain HBV DNA at the lowest possible level (durable HBV DNA suppression) which, in turn, will lead to ALT normalization and histological improvement. The second goal is the loss of HBeAg with seroconversion to anti-HBe. If anti-HBe seroconversion is achieved, there is reasonable likelihood that the treatment benefit will be maintained after therapy is stopped. While it is highly desirable that therapy also achieve the loss of HBsAg, this is uncommon and not a primary goal of therapy.
A difficult initial therapeutic decision is whether to initiate therapy with a nucleoside/nucleotide inhibitor or to use the more global antiviral agent, pegylated IFN. The advantage of peg-IFN is that approximately 30% of subjects will have a SVR such that after the prescribed course of therapy, generally 1 year, treatment can be stopped and the likelihood of virological or disease recurrence is very low. In addition, resistance to IFN does not develop. The problem with IFN therapy are its multiple, often debilitating, side effects, the 70% failure rate and the fact that many subjects are not candidates for therapy. IFN works best when the serum ALT is high and the HBV DNA level is low indicating that the host has mounted a good, albeit not adequate, immune response. Thus, the large number of Asian patients who tend to have normal ALT levels and high HBV DNA levels respond poorly to IFN. Nucleoside and nucleotide inhibitors, on the other hand, can be given orally, are very well tolerated and can result in log reductions of HBV DNA equal to or superior to IFN. The problem with these agents is that they most often require continuous therapy to maintain suppression of HBV DNA and that resistance can occur, particularly with lamivudine where resistant mutants occur in about 70% within 5 years of treatment onset.
Excellent HBV DNA suppression has been achieved with both adefovir and entecavir and resistance profiles are far superior to lamivudine. After 1 year of therapy with adefovir, 21% had HBV DNA loss in serum, with a mean HBV DNA reduction of 3.52 logs and after 144 weeks of therapy 48% had HBV DNA undetectability, 80% had ALT normalization, 53% had HBeAg loss and 46% anti-HBeAg seroconversion . In contrast to lamivudine, no adefovir resistance was found after 1 year, and the rate increased only slowly to 3%, 11%, 18% and 29% at years 2–5 respectively. Adefovir resistant strains were found susceptible to lamivudine and entecavir. Entecavir is the most potent of licensed treatments achieving a 67% HBV DNA loss and a 6.9 log reduction in mean HBV DNA level after 48 weeks of treatment. After 2 years of treatment, HBV DNA loss was 80% and HBeAg seroconversion was seen in 31% . Importantly, no polymerase mutations (YMDD) were noted after 2 years of therapy. Thus, entecavir has excellent potency and negligible resistance in early studies. Clinical trials have not demonstrated improved efficacy when nucleoside/tide inhibitors are combined with IFN. However, a small trial combining adefovir and entecavir showed significantly greater HBV suppression than adefovir alone . The greatest benefit of combined therapy may be in preventing the emergence of resistant strains, but this has not been well documented and the low resistance profile of entecavir may make combination therapy unnecessary.
The consensus recommendations for treatment of HBeAg+ patients are summarized in Table 2. Lamivudine is not included in the table because it is no longer first-line therapy. However, for patients currently on lamivudine who become resistant, it is recommended that adefovir be added.
Table 2. Recommendations for treatment: HBeAg-positive patients*.
|Positive||<20 000||Normal||No treatment; monitor ALT every 3 months for 1 year and then every 6–12 months|
|Positive||≥20 000||Normal||Low rate of HBeAg seroconversion for all treatments. Consider liver biopsy if older than 35; if significant disease found treat with adefovir, entecavir or peg-IFN§. Monitor ALT closely in untreated subjects|
|Positive||≥20 000||Elevated||Treat with adefovir, entecavir or peg-IFN; if high HBV DNA adefovir or entecavir preferred over peg-IFN|
The durability of treatment response is a key component of therapeutic decisions. HBeAg loss after a standard course of IFN has been found durable in 80–90% of patients in follow-up extending to 8 years . Durability of HBeAg seroconversion after adefovir was 91% 1 year after cessation of therapy  and 82% for entecavir after 6 months of follow-up .
Treatment of HBeAg-negative chronic hepatitis B
Most patients with HBeAg-negative hepatitis have normal or only minimally elevated ALT elevations and relatively low-level HBV DNA, but nonetheless are still at risk for the most serious consequences of HBV infection. This is a reflection of the age at acquisition in that the vast majority of patients with HBeAg-negative chronic hepatitis are Asians who acquired infection at birth and their long-term outcome after HBeAg loss is different from, and more severe than, persons who acquire HBV infection later in life.
Although medications to treat HBeAg-positive and HBeAg-negative chronic hepatitis are the same, the parameters for initiating therapy are different and are summarized in Table 3. The most profound difference is that the treatment trigger for HBeAg-positive cases is an HBV DNA level of >20 000 IU L−1, whereas the trigger for HBeAg-negative cases is ≥2000 IU L−1. In HBeAg-negative hepatitis, HBV DNA suppression and ALT normalization are the only practical measures of treatment response and long-term therapy is generally required to maintain these responses. Aside from the lower trigger level for initiating therapy, treatment recommendations are similar for HBeAg-positive and negative patients. Adefovir and entecavir are the optimal choices for first line therapy and decreases in HBV DNA level to undetectable can be achieved in 80–90% of patients after one or more years of treatment with commensurate histological improvement. Patients who become resistant to adefovir can be switched to entecavir. Peg-IFN can also be used as first-line therapy, but is less effective in those with normal ALT. Long-term therapy is required for the oral agents and patients should be monitored every 6 months. In patients with elevated ALT, peg-IFN should be given for 6–12 months. Many new oral agents for the treatment of both HBeAg-positive and HBeAg-negative hepatitis are in clinical trials at this writing; these include emtricitabine, telbivudine and tenofovir.
Table 3. Recommendations for treatment: HBeAg-negative patients*.
|Negative||<2000||Normal||No treatment; majority inactive HBsAg carriers; monitor every 3 months for 1 year and then every 6–12 months; consider therapy if significant histological disease on biopsy |
|Negative||≥2000||Normal||Consider liver biopsy; treat if disease present; in the absence of biopsy, observe as above for ALT elevations. If treated use adefovir, entecavir or peg-IFN|
|Negative||≥2000||Elevated||Treat with adefovir, entecavir or peg-IFN; long-term treatment required for oral agents|
Treatment of chronic hepatitis B patients coinfected with HIV
In the United States and Europe, approximately 10% of all HIV patients are coinfected with HBV  and this proportion is higher in the haemophilia population and others heavily transfused prior to HIV blood screening. Coinfection of HBV and HIV confers increased mortality compared with either virus alone and the relative increased risk has been estimated to be 14-fold . Medications now used in HAART therapy, including lamivudine, tenofovir and emtricitabine, also have activity against HBV. Adefovir in a dose of 10 mg day−1 has been shown to be effective in HIV/HBV coinfected patients resistant to lamivudine showing a >5 log reduction in HBV DNA and ALT normalization in 64% of patients with sustained therapy . Because adefovir is not effective against HIV, it is unlikely to select mutants resistant to HIV therapy. Entecovir is also effective in HBV/HIV coinfected patients as is tenofovir, but there is some concern for renal toxicity from tenofovir. Because some drugs used for HIV therapy also have activity against HBV (tenofovir, entecavir, lamivudine, emtricitibine) and because some of the most potent HBV drugs (adefovir, entecavir) do not have activity against HIV and because of toxicity issues and complex interactions among drugs, the treatment of the coinfected patient is complicated and must be individualized.
Treatment of chronic hepatitis B patients coinfected with HCV
Injection drug users and multiply transfused patients are often coinfected with HBV and HCV. The outcome of this combined hepatitis infection is more severe than disease from either agent alone. Interestingly, in most coinfected patients, one infection tends to predominate and the other is suppressed. More often, HCV infection is dominant such that patients have HCV RNA with low levels of HBV DNA and are HBeAg-negative. In HCV dominant infection, HCV should be treated first with the combination of peg-IFN and ribavirin (see below) in an attempt to clear the HCV infection and then reassess residual HBV infection. However, if HBV DNA levels are initially high or rise during 3 months of HCV therapy, entecavir or adefovir can be added to the treatment regimen. Fortunately, HCV/HBV coinfected patients respond as well to HCV therapy as do patients with HCV infection alone and it is rare to have activation of HBV during HCV-directed therapy [23,24].
Management of hepatitis C virus infection
Space does not allow a comprehensive discussion of HCV management issues and the reader is referred to several critical reviews [25–28]. The key elements of HCV management can be summarized as follows:
- 1As opposed to HBV infection, most HCV infections are acquired in adulthood, generally from shared needle-exposure or blood transfusion prior to 1990. Perinatal transmission is rare.
- 2The course of chronic hepatitis C is variable, but most patients have an indolent course that spans multiple decades. Based on retrospective-prospective analyses, it appears that <30% of HCV-infected patients progress to the severe outcomes of cirrhosis and HCC. There are no good predictive markers to assess which patients will have progressive fibrosis. However, it is clear that progression is not linear and that most patients have only minimal or no fibrosis.
- 3The treatment of chronic hepatitis C is well standardized and the outcomes are genotype dependent. The current recommended therapy is a combination of pegylated interferon, 180 mg given SQ once per week, plus oral ribavirin in a weight adjusted dose of 800–1200 mg day−1. With this regimen, 45–50% of patients with genotype 1 infection will have a SVR after 1 year of therapy. SVR is defined as HCV RNA negativity 6 months after cessation of treatment. Once SVR is achieved, the virus does not appear to reactivate, suggesting true cure. In patients with the less common genotype 2 or 3 infections, 70–80% will have an SVR after only 6 months of therapy. If HCV RNA does not become undetectable 12 weeks after initiation of treatment, the patient will be a therapeutic failure and medication can be stopped.
- 4Because interferon has multiple side effects and the treatment is arduous, because the natural history is benign in most individuals and because treatment failures are common for genotype 1 infections, the decision to treat must be weighed carefully. Patients with normal ALT should not be treated. Patients with minimal ALT elevations should ideally have treatment decisions based on biopsy evidence of significant inflammation or fibrosis. In persons with bleeding disorders or other contraindications to liver biopsy, the decision to treat is more difficult and must be individualized. Predictive algorithms, based on biochemical and haematological markers, have been developed and are successful in distinguishing patients with no fibrosis from those with severe fibrosis, but they do not discriminate between intermediate stages of fibrosis. Less stringent criteria can be used for initiating therapy in patients with genotype 2 or 3 infection because the success rate is so high.
- 5Patients with chronic HCV infection generally do not have significant symptoms or signs until they develop bridging fibrosis, and particularly, cirrhosis. Almost all untoward events, including HCC, follow in the wake of evolution to cirrhosis. After cirrhosis develops, follow-up should include 3–6 monthly screening for HCC with ultrasound and measurement of alpha-fetoprotein. Early HCC is surgically or chemically curable.
- 6Many new drugs for HCV are in development and they are characteristically directed to HCV-specific enzymes such as protease, helicase and polymerase. These HCV-specific viral inhibitors are very potent, but rapidly induce resistant strains and have run into some toxicity issues such that none is currently licensed. It is probable that these virus-specific treatments will be added to, rather than replace, interferon.
- 7Although the individual patient with chronic HCV infection can be reasonably optimistic on the basis of indolent natural history of the disease and the at least 50% probability of a sustained treatment response, the global impact of this infection is enormous based on the sheer magnitude of the number infected (estimated 100 million) and the probability that 20–30% of these infected individuals will have a severe outcome.