Hepatitis B and C in 2009

From Liver International

Hepatitis B and Hepatitis C in 2009
Posted 03/17/2009
Patrick MarcellinAuthor Information
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are among the most frequent viral infections in humans, and represent a major global public health problem. HBV- and HCV-related chronic hepatitis are the main causes of cirrhosis and hepatocellular carcinoma (HCC) that are responsible for a high rate of morbidity and mortality. End-stage HBV- and HCV-related liver disease and HCC are the main causes of liver transplantation. In the last few years, knowledge of the epidemiology and the natural history of HBV and HCV infection has markedly improved. Furthermore, considerable progress has been made in the efficacy of therapy. New drugs and new therapeutic strategies that are currently under evaluation could further improve the efficacy of therapy in the near future.
Hepatitis B
Epidemiology
Approximately one-third of the world population has serological evidence of past or present infection by HBV and 350 million people are chronically infected.[1,2] The prevalence of HBV infection is especially high in South-East Asia and Sub-Saharan Africa, where more than 8% of the population are HBsAg chronic carriers.[3] While perinatal transmission or transmission during early childhood is responsible for the high rate of chronic infection in Asia and Africa, sexual or parenteral exposure accounts for most cases in industrialized countries.[4] In most developed parts of the world, the prevalence of chronic HBV infection is <1%, and the overall infection rate is 5-7%. Within these areas, most infections occur among high-risk adult populations that include injection drug users, persons with multiple heterosexual partners, men who have sex with men and health-care workers. The risk of perinatal HBV transmission has been well described. This risk is greatest for infants born to women who are HBeAg-positive, and ranges from 70 to 90% at 6 months of age; about 90% of these children remain chronically infected.[5] The risk of perinatal infection among infants born to HBeAg-negative mothers ranges from 10 to 40%, with 40-70% of these infected infants remaining chronically infected. Children born to HBsAg-positive mothers who do not become infected during the perinatal period remain at a high risk of infection during early childhood. HBV-related end-stage liver disease or HCC are responsible for over 1 million deaths per year and currently represent 5-10% of cases of liver transplantation.[1,3,4] HCC is one of the most common cancers worldwide and HBV is responsible for at least 75% of this cancer.[6] The availability of safe and effective vaccines allowed wide immunization programmes which led to a reduction of the burden of diseases caused by HBV, with clear benefits in terms of prevention of cirrhosis and HCC.[7]
Natural History
The natural course of HBV chronic infection is variable, ranging from an inactive HBsAg carrier state to a more or less progressive chronic hepatitis, potentially evolving to cirrhosis and HCC.[8-10] Chronic hepatitis may present as typical HBeAg-positive chronic hepatitis B (CHB) or HBeAg-negative CHB. Apart from the molecular biology of HBV and host factors, co-infection with other hepatitis viruses, e.g. HCV, hepatitis delta virus, as well as with other non-primary hepatotropic viruses, e.g. the human immunodeficiency virus (HIV), can affect the natural course of HBV infection as well as the efficacy of antiviral strategies.[11] HBeAg-positive chronic hepatitis is owing to wild-type HBV; it represents the early phase of chronic HBV infection. HBeAg-negative chronic hepatitis is due to a naturally occurring HBV variant with mutations in the precore or/and the basic core promoter regions of the genome; it represents a late phase of chronic HBV infection.[12] The latter form of the disease has been recognized as increasing in many countries within the last decade and it represents the majority of cases in many countries. HBeAg-negative CHB is generally associated with a more severe liver disease with a very low rate of spontaneous disease remission and a low sustained response rate to antiviral therapy.[12-14] Longitudinal studies of patients with CHB indicate that, after diagnosis, the 5-year cumulative incidence of developing cirrhosis ranges from 8 to 20%. Morbidity and mortality in CHB are linked to evolution to cirrhosis or HCC. The 5-year cumulative incidence of hepatic decompensation is approximately 20%,[15] the 5-year probability of survival being approximately 80-86% in patients with compensated cirrhosis. Patients with decompensated cirrhosis have a poor prognosis (14-35% probability of survival at 5 years). HBV-related end-stage liver disease or HCC is responsible for about one million deaths per year. A recent study performed in France showed that HBV-related mortality, due to decompensated cirrhosis or HCC, was at least 1500 cases per year.[16] HCC is one of the most common cancers worldwide, about 75% of which are related to chronic HBV infection. The incidence of HCC has increased worldwide and nowadays it constitutes the fifth most frequent cancer, representing around 5% of all cancers worldwide. The incidence of HCC appears to vary geographically and correlates with the underlying stage of liver disease. The annual incidence in HBV carriers ranges between 0.2 and 0.6%, but it reaches 2% when hepatic cirrhosis is established.[17] The oncogenic mechanism leading to liver cancer involves different pathways that are not fully elucidated. Prevention through universal vaccination has effectively decreased the incidence of liver cancer and new therapeutic agents may delay or avoid the establishment of cirrhosis. The only chance for long-term survival after an HCC diagnosis is to achieve early detection through regular surveillance by ultrasound and α-foetoprotein determination.[18] This allows effective therapy such as surgical resection, liver transplantation or percutaneous ablation.
Therapy
Seven drugs are currently available for the treatment of CHB: conventional interferon-α (IFN α), lamivudine, adefovir dipivoxil, pegylated interferon α-2a (PEG-IFN α-2a), entecavir, telbivudine and tenofovir.[8,9,19]
Interferon α. Interferon has antiviral, antiproliferative and immunomodulatory effects and was used in the treatment of CHB for many years. A meta-analysis including 15 randomized-controlled trials has demonstrated the superiority of IFN compared with placebo regarding the undetectability of HBV DNA (37 vs. 17%) and HBeAg loss (33 vs. 12%).[20] Conventional IFN α is associated with a poor tolerability that limits the duration of therapy. However, long-term follow-up studies have shown the long-term benefit of this treatment in responders. After IFN α therapy, a progressive increasing rate of HBsAg seroconversion has been observed that is associated with an improved outcome with a decreased risk of decompensation and HCC and improved survival.[21,22]
Lamivudine. Lamivudine was the first oral drug approved for the treatment of CHB, and it remains in widespread use around the world. However, lamivudine has a poor resistance profile, with 23% of patients developing resistance in the YMDD domain of the DNA polymerase (codon rtM204V/I/S) at Year 1 of therapy, increasing to 46% at Year 2, 55% at Year 3 and then 65-71% at Years 4 and 5.[23,24]
Adefovir. Adefovir, a nucleotide analogue, was the second oral agent introduced for the treatment of CHB. Despite its improved resistance profile over lamivudine, this agent did not confer a greater degree of viral suppression than lamivudine at the dose of 10 mg daily introduced to avoid the nephrotoxicity at higher doses of adefovir. In the pivotal trials, HBV DNA undetectability at 1 year was attained in 21 and 51% of HBeAg-positive and HBeAg-negative patients.[25,26] HBeAg seroconversion occurred in 12% of patients after 1 year, but the rate progressively increased to 48% after 5 years.[27] Adefovir has a far better resistance profile than lamivudine, with cumulative genotypic resistance rates of 0 and 3% at 1 and 2 years, respectively, although the rate of genotypic resistance increased to 29% in the 5-year pivotal extension trial conducted in HBeAg-negative patients.[28] However, in patients with HBV DNA <1000 copies/ml at 1 year, the 4-year resistance rate was only 4%.[29]
Entecavir. Entecavir is a potent anti-HBV agent. In 1-year pivotal studies, entecavir 0.5 mg daily induced high rates of undetectable HBV DNA: 67% of HBeAg-positive and 90% of HBeAg-negative patients compared with 36 and 72%, respectively, with lamivudine.[30,31] Despite this potent antiviral efficacy, the HBe seroconversion rate was relatively low and comparable with that observed with other oral antiviral agents (21 and 18% with entecavir and lamivudine respectively). Long-term observations in a subgroup of the HBeAg-positive patients from this programme demonstrated a cumulative rate of HBV DNA clearance of more than 90% after 4 years. Interestingly, a very low rate of entecavir resistance was observed in naïve patients after 4 years of therapy, with a cumulative genotypic resistance rate of 1.2% at 4 years in lamivudine-naïve patients.[32] In lamivudine-resistant patients, by contrast, approximately 35% of patients developed resistance to entecavir 1.0 mg daily within 3 years of being switched to entecavir.[33] This difference is because of the high genetic barrier to resistance of entecavir that occurs through a two-hit mechanism with initial selection of rtM204 I/V mutations (which are also resistant to lamivudine), followed by an additional 'signature' entecavir-associated mutation at the rtI169, rtM250 or rtT184, rtS202 locus. Once the secondary substitutions occur, high-level resistance to entecavir occurs. Therefore, entecavir monotherapy must now be regarded as a suboptimal choice for lamivudine-resistant patients.
Telbivudine. Telbivudine is a new potent agent administered at the dose of 600 mg daily in pivotal trials. After 1 year of treatment, HBV DNA was undetectable in 60% of HBeAg-positive and 88% of HBeAg-negative patients.[34] HBeAg seroconversion occurred in 23% of telbivudine recipients at 1 year compared with 21% of lamivudine recipients. The resistance profile of telbivudine is superior to that of lamivudine, but there is still a risk of resistance of 5 and 2% after 1 year in HBeAg-positive and HBeAg-negative patients respectively. Most notably, the rate of resistance at Week 92 was 4% in HBeAg-positive patients and 2% in HBeAg-negative patients who had undetectable HBV DNA at Week 24. By contrast, 30-60% of both HBeAg-positive and HBeAg-negative patients developed telbivudine resistance after 92 weeks if they had HBV DNA above 4 log10 copies/ml at Week 24, with intermediate rates of resistance for patients with lesser degrees of residual viraemia at Week 24.[35]
Tenofovir. Tenofovir is a nucleotide analogue differing from adefovir in the presence of one methyl group. It was approved for the treatment of HIV in 2002 and HBV in 2008. Recent data from pivotal large randomized comparative trials have shown that tenofovir 300 mg daily is associated with impressive rates of viral suppression at 48 weeks of therapy in HBV-monoinfected patients. In these studies, 76% of HBeAg-positive patients and 93% of HBeAg-negative patients had undetectable HBV DNA after 48 weeks of tenofovir therapy compared with only 13 and 63% of HBeAg-positive and HBeAg-negative patients on adefovir respectively.[36] No genotypic resistance or viral breakthroughs related to resistance were seen in either group of patients receiving tenofovir. Recent 96-week data demonstrated HBV DNA undetectability in 79 and 91% of HBeAg-positive and HBeAg-negative patients, respectively, without resistance.[37,38]
Pegylated Interferon. Pegylated IFN α-2a has replaced the use of IFN in hepatitis B because of its more convenient once-weekly administration and more potency. In this respect, PEG-IFN α-2a resulted in a steeper decline in HBV DNA levels and a higher rate of HBeAg seroconversion (33 vs. 25%) when compared with IFN.[39] The efficacy of PEG-IFN α-2a in HBeAg-positive and -negative patients has been established in two large pivotal trials including 814 and 552 patients respectively.[40,41] In both studies, PEG-IFN α-2a monotherapy, the combination of PEG-IFN plus lamivudine and lamivudine monotherapy were compared in a 48-week treatment course. At the end of 24 weeks post-treatment follow-up, HBeAg seroconversion rates were 32, 27 and 19%, respectively, in the HBeAg-positive study and serum HBV DNA was <400 copies/ml in 19, 20 and 7%, respectively, in the HBeAg-negative study. Recently, 4-year follow-up data were reported for a subgroup of patients of the HBeAg-negative trial who agreed to enrolment in a long-term follow-up study.[42] Interestingly, sustained off-treatment response (HBV DNA <400 copies/ml) was maintained in 18% of patients treated with PEG-IFN α-2a. Importantly, HBsAg loss occurred with a high steady rate (more than 10% per year) in these patients. These findings confirm those observed in the long-term conventional IFN studies,[10] and are in accordance with the dual antiviral and immunomodulatory effects of PEG-IFN α-2a, which result in the suppression of viral replication, but also the clearance of infected hepatocytes. Interestingly, recent data have demonstrated a better tolerability of PEG-IFN α-2a in CHB compared with hepatitis C patients, with a lower incidence of common IFN-related adverse events and a significantly lower incidence of depression.[43] Interestingly, a recent pilot study including a small number of HBeAg-negative patients has shown a significant decrease in the serum HBsAg level during the early phase of treatment in patients with a virological response to PEG-IFN α-2a in comparison with non-responders, suggesting that quantitative serum HBsAg may be used as an early predictor for a sustained virological response (SVR) and subsequent HBsAg loss after PEG IFN therapy.[44]
Perspectives
The ultimate objective of treatment in CHB is to induce HBs seroconversion that is associated with complete and sustained remission of the liver disease and an improved outcome. Although currently available analogues are potent and induce high rates of virological response, in the large majority of patients, they rarely induce HBs seroconversion. In contrast, PEG-IFN induces an SVR, after a limited duration of treatment, only in a minority of patients; however, in these responders, in the long term, the rate of HBs seroconversion is high. It is less probable that new analogues (such as clevudine) can achieve this objective.[45-47] Combinations of analogues may decrease the long-term risk of resistance but did not show increased antiviral efficacy and increased seroconversion rates.[48,49] In addition, the long-term safety of such combinations is unknown. The only combination that showed an increased antiviral efficacy was the combination of PEG-IFN with lamivudine with a synergistic antiviral effect and a decreased rate of resistance to lamivudine. Clinical trials on the combination of PEG-IFN with the most potent available analogues (entecavir and tenofovir) are needed with the objective to increase HBs seroconversion rates.
Hepatitis C
Epidemiology
Approximately 3% of the world population, 170 million people, are chronically infected by HCV. The prevalence of chronic hepatitis C ranges from 0.1 to 5% in different countries.[50-52] It is estimated that there are 4 million HCV chronic carriers in the US and 5 million HCV chronic carriers in Western Europe. The prevalence seems to be higher in Eastern Europe than in Western Europe.[52] In industrialized countries, HCV accounts for 20% of cases of acute hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of HCC and 30% of liver transplants.[53,54] The incidence of new symptomatic infection has been estimated to be 1-3 cases/1 000 000 persons annually. The actual incidence of new infections is obviously much higher (the majority of cases being asymptomatic). The incidence is declining for two reasons: (a) transmission by blood products has been reduced to near zero and (b) universal precautions have markedly reduced transmission in medical settings. Intravenous drug use remains the main mode of transmission, but, even here, the rate of transmission is diminishing due to a heightened awareness of the risk of needle sharing and, in some countries, the availability of needle-exchange programmes. In the US, in 1999, there were 3759 deaths attributed to HCV, although this is likely an underestimate.[55] In France, it is estimated that around 3500 deaths per year are related to HCV.[16] In the US, there was a five-fold increase in the annual number of patients with HCV who underwent liver transplantation between 1990 and 2000.[55] The total direct health-care cost associated with HCV is estimated to have exceeded $1 billion in 1998. Future projections predict a four-fold increase between 1990 and 2015 in persons at risk of chronic liver disease, suggesting a continued increase in the burden of HCV in the US in the foreseeable future.
In France, the prevalence of anti-HCV-positive adults is estimated to be between 1.1 and 1.2%, out of whom 80% are viraemic. Therefore, it is estimated that 400 000-500 000 subjects have chronic HCV infection. The prevalence varies widely in different populations: 60% in intravenous drug users, 25% in incarcerated subjects and 25% among HIV-positive patients (25 000-30 000 subjects have HCV/HIV co-infection).[54]
Natural History
In the last few years, the natural history of chronic HCV infection has been better understood. The progression of fibrosis determines the ultimate prognosis and thus the need and urgency of therapy. Fibrogenesis is a complex dynamic process that is mediated by necro-inflammation and activation of stellate cells.[56] The liver biopsy remains the gold standard to assess fibrosis. Scoring systems allow a semiquantitative assessment and are useful for cross-sectional and cohort studies and in treatment trials. The rate at which fibrosis progresses varies markedly between patients. The major factors known to be associated with fibrosis progression are older age at infection, male gender and excessive alcohol consumption.[56-58] Viral load and genotype do not seem to influence the progression rate significantly. Progression of fibrosis is more rapid in immunocompromised patients.[59] Recently, the importance of hepatic steatosis, obesity and diabetes has been recognized and studies are in progress to understand the relationship between metabolic disorders, insulin resistance, HCV replication and liver steatosis and progression of fibrosis.[60] There are no tests that reliably predict the rate of progression of fibrosis in an individual patient. High serum alanine aminotransferase (ALT) levels are associated with a higher risk of fibrosis progression. On the contrary, worsening of fibrosis is uncommon in patients with persistently normal serum ALT levels.[61] Only a small proportion of these patients may present an increase of ALT levels and may develop a more progressive liver disease. Serum markers for fibrosis are not fully reliable and need to be improved and validated. Liver biopsy provides the most accurate information on the stage of fibrosis and grade of necro-inflammation, both of which have prognostic significance. Repeating the liver biopsy 3-5 years after an initial biopsy is the most accurate means of assessing the progression of fibrosis.[56,57]
Therapy
Combination of Pegylated Interferon With Ribavirin. The most impressive progress has been achieved in the efficacy of therapy. With the combination of PEG-IFN and ribavirin that is nowadays known as reference therapy,[62,63] an SVR is observed in roughly 50% of patients.[64-66] The absence of detectable serum HCV RNA 6 months after therapy, which defines the SVR, may nowadays be considered as a cure of HCV infection because long-term follow-up studies have shown that 97-100% of patients retain undetectable serum HCV RNA.[67] Furthermore, some studies have shown that HCV RNA is no longer detectable in the liver and peripheral blood mononuclear cells of sustained responders up to many years after therapy, confirming the eradication of HCV.[67,68] In addition, recent studies have shown that SVR is associated with an improved outcome in patients with extensive fibrosis or cirrhosis with a decreased risk of complications, development of HCC and improved survival.[69]
The SVR rate is as high as 90% in patients with genotype 2 or 3 and a low viral load. The SVR rate is lower, <50%, in the most difficult-to-treat patients with genotype 1 and a high viral load. The presence of bridging fibrosis or cirrhosis is associated with a decreased but not negligible chance of response.[64-66] The compliance with continuation of therapy with adequate dosing increases the response rates, and studies on adjuvant treatments are needed to improve clinical and haematological tolerability in order to increase compliance and the chance of response.
Optimization of Therapy
Recent studies have shown that treatment duration could be tailored according to the genotype and rapid virological response (RVR) defined by undetectable HCV RNA at 4 weeks. In 'easy-to-treat patients' with genotype 2 or 3 with RVR, SVR rates were not different with 12 or 16 weeks of therapy as compared with those who received 24 weeks of therapy.[70,71] In patients with genotype 1, a low baseline viral load and RVR, 24 weeks of treatment may be sufficient.[72] In contrast, in 'difficult-to-treat patients' with genotype 1 and a slow virological response, a longer duration of therapy (72 weeks) might be considered.[73] In patients with genotype 4, 36 or 48 weeks of therapy seem to be generally needed to obtain relatively high SVR rates (66-69%).[74]
Perspectives
Still, about half of the patients do not respond or relapse after therapy and current treatment has significant side-effects and is poorly tolerated. Therefore, new, more effective and better tolerated anti-HCV drugs are needed. Many drugs with different mechanisms of action are under investigation. The use of enzyme inhibitors appears to be the most promising strategy.
Many enzyme inhibitors, protease and polymerase inhibitors, are currently at different stages of development. Two protease inhibitors, telaprevir and boceprevir, currently in phase 3, could achieve, in combination with PEG-IFN and ribavirin, SVR rates of 60-70% in patients with genotype 1.[75-79] In addition, triple therapy could achieve high rates of SVR with a shorter duration of treatment (24 weeks instead of 48 weeks) in genotype 1 patients. These triple therapies could be registered in about 2 years. Other promising drugs (polymerase inhibitors and second generation protease inhibitors) are currently being evaluated in phase 1 or phase 2 studies.[79-82] The management of hepatitis C must include better knowledge of mechanisms of non response.[83] In the next decade, it is likely that IFN-based therapy plus RBV will remain the backbone of the treatment of chronic hepatitis C. IFN and RBV are needed in order to increase antiviral potency and prevent HCV resistance to specifically targeted antiviral therapy for HCV (STAT-C) drugs, and subsequently increase SVR. Thus, genotypic and phenotypic resistance tests will also enter the therapeutic arena. Once several STAT-C agents become available, treatment strategies will include the combination of several drugs with different mechanisms of action (protease inhibitors plus polymerase inhibitors) that could hopefully result in IFN- and/or ribavirin-sparing regimens.
Conclusion
Hepatitis B virus- and HCV-related liver diseases represent a major public health problem. In the last few years, considerable progress has been made in the knowledge of epidemiology, natural history, factors influencing the course of the liver disease and mainly efficacy of therapy. Still important efforts are needed for screening campaigns for early diagnosis in order to improve the management of patients with chronic hepatic B or C. The understanding of the mechanisms of resistance to therapy and the development of new more potent drugs and new therapeutic strategies are a challenge to decrease the global burden related to chronic viral hepatitis in the future.