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Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures
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D. Lavanchy
World Health Organization (WHO), Communicable Disease Surveillance and Response
Journal of Viral Hepatitis
Volume 11 Issue 2 Page 97 - March 2004
TOPICS
Transmission of HBV infection
HBV-related morbidity and mortality
The economic burden of HBV infection
HBV association with hepatocellular carcinoma
Role of vaccination in controlling HBV infection
Treatment of HBV infection
--Conventional IFN-a in the treatment of chronic hepatitis B
--Nucleoside and nucleotide analogues in the treatment of chronic hepatitis B
Treatment of HBeAg-positive chronic hepatitis B
--Response to treatment with conventional IFN
--Response to treatment with lamivudine
Treatment of HBeAg-negative chronic hepatitis B
--Response to treatment with conventional IFNa
--Response to treatment with lamivudine
Influence of conventional IFNa on the natural history of chronic hepatitis B
Emergence of viral resistance to lamivudine
Summary of currently available treatments for chronic hepatitis B
Emerging treatments for chronic hepatitis B
--Adefovir dipivoxil
--Entecavir
--Pegylated IFNa
Potential of combination therapy
Summary. Hepatitis B virus (HBV) infection is a serious global health problem, with 2 billion people infected worldwide, and 350 million suffering from chronic HBV infection. The 10th leading cause of death worldwide, HBV infections result in 500 000 to 1.2 million deaths per year caused by chronic hepatitis, cirrhosis, and hepatocellular carcinoma; the last accounts for 320 000 deaths per year. In Western countries, the disease is relatively rare and acquired primarily in adulthood, whereas in Asia and most of Africa, chronic HBV infection is common and usually acquired perinatally or in childhood. More efficacious treatments, mass immunization programs, and safe injection techniques are essential for eliminating HBV infection and reducing global HBV-related morbidity and mortality. Safe and effective vaccines against HBV infection have been available since 1982. The implementation of mass immunization programs, which have been recommended by the World Health Organization since 1991, have dramatically decreased the incidence of HBV infection among infants, children, and adolescents in many countries. However, not all countries have adopted these recommendations and there remains a large number of persons that were infected with HBV prior to the implementation of immunization programs. Antiviral treatment is the only way to reduce morbidity and mortality from chronic HBV infection. Conventional interferon alfa and lamivudine have been the primary treatments to date. Conventional interferon alfa produces a durable response in a moderate proportion of patients but has undesirable side-effects and must be administered subcutaneously three times per week. Lamivudine also produces a response in a modest proportion of patients and causes few side-effects. However, prolonged treatment is often necessary to prevent relapse on cessation of therapy, and continuous treatment can lead to the development of lamivudine resistance. Promising emerging new treatments include adefovir, entecavir and peginterferon alfa-2a (40 kDa).
Introduction
Hepatitis B virus (HBV) infection is a major global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 350 million are chronic carriers of HBV]. Approximately 15-40% of infected patients will develop cirrhosis, liver failure, or hepatocellular carcinoma (HCC). HBV infection accounts for 500 000 to 1.2 million deaths each year and is the 10th leading cause of death worldwide. Hepatocellular carcinoma incidence has increased worldwide, and the disease is now the 5th most frequent cancer, killing 300 000-500 000 people each year.
The prevalence of HBV infection varies markedly in different geographic areas of the world, as well as in different population subgroups. Overall, approximately 45% of the global population live in areas of high chronic HBV prevalence. In sub-Saharan Africa, the Pacific, and particularly Asia, HBV infection is highly endemic, with the majority of individuals becoming infected during childhood. Outside of the endemic areas, regions with high rates of chronic HBV infection include the southern parts of Eastern and Central Europe, the Amazon basin, the Middle East, and the Indian subcontinent. In western and northern European countries and North America, HBV infection is relatively rare and acquired primarily in adulthood.
Regions with a high prevalence of HBV infection also have high rates of HCC. HBV causes 60-80% of the world's primary liver cancer, one of the three major causes of death in Asia, the Pacific Rim and Africa.
Transmission of HBV infection
Hepatitis B virus is present in the blood, saliva, semen, vaginal secretions, menstrual blood, and to a lesser extent, perspiration, breast milk, tears, and urine of infected individuals. A highly resilient virus, HBV is resistant to breakdown, can survive outside the body, and is easily transmitted through contact with infected body fluids.
In areas of high endemicity, the most common route of transmission is perinatal or the infection is acquired during the preschool years. In areas of intermediate endemicity, transmission is either perinatal or horizontal. The route of transmission has important clinical implications, because there is a very high probability of developing chronic hepatitis B (CHB) if the infection is acquired perinatally or in the preschool years. The use of unsafe injections poses a particular public health problem in developing countries. Contaminated needles cause 8-16 million HBV infections each year, compared with 2.3-4.7 million hepatitis C virus infections, and 80 000-160 000 human immunodeficiency virus infections.
In areas of low endemicity, most HBV infections are acquired by horizontal transmission in early adult life, i.e. through intravenous drug use or unprotected sexual activities. Blood transfusions were once a common route of transmission, but improved diagnostic tests and progressively broader screening for HBV infection in recent years, such as occurred in Latin American countries from 1994 to 1997, has dramatically reduced the risk of acquiring HBV infection through transfusion.
Other sources of infection include contaminated surgical instruments and donor organs. Health care workers, dentists, and others who have frequent contact with infected blood or blood products are at highest risk.
HBV-related morbidity and mortality
The natural course of CHB-- The early phase of CHB is characterized by the presence of hepatitis B e antigen (HBeAg) and high serum levels of HBV DNA (referred to as HBeAg-positive CHB). Following infection, the immune system attempts to clear the HBV by destroying infected hepatocytes. This leads to increasing circulatory blood levels of alanine aminotransferase (ALT). However, the majority of patients will clear HBeAg (and produce anti-HBe antibodies) and achieve a state of nonreplicative infection, characterized by low or undetectable serum levels of HBV DNA and normal ALT levels. High HBV DNA and ALT levels may persist in some anti-HBe-positive patients (referred to as HBeAg-negative CHB) because of the presence of an HBV variant that is unable to produce HBeAg (HBeAg-negative variant, also called HBV precore stop codon mutant). Over time, 25% of persons who acquire HBV as children will develop primary liver cancer or cirrhosis as adults. Cirrhosis may develop as a consequence of repeated immune system attacks. Once established, cirrhosis cannot be cured; however, its progress may be stopped if the cause (in this case, HBV infection) is removed. Without treatment, the typical progression is from compensated cirrhosis to decompensated cirrhosis. The latter is characterized by cessation of enzymatic processes in the liver and subsequent severe clinical complications such as fluid retention in the abdomen (ascites), jaundice, internal bleeding, and hepatic encephalopathy. Patients with decompensated cirrhosis are candidates for liver transplantation, without which death results from end-stage liver disease.
HBV association with hepatocellular carcinoma
Hepatitis B viral infection is strongly associated with the development of HCC. In North America, among Alaska natives in whom HBV infection is hyperendemic, HCC is the most common complication, with a reported incidence of 1.9 per 1000 (2.3 in men, 1.2 in women). The risk for HCC also increases with age among Yupik Eskimos and among carriers reverting to HBeAg from anti-HBe. Despite a declining incidence of HBV infection in the United States, the incidence of HCC has almost doubled in the last 15 years, and mortality from HCC has increased by 41%, because of the large pool of individuals infected prior to the implementation of HBV immunization programs.
In the highly endemic Asia-Pacific region, HBV infection accounts for only 17% of HCC cases in Japan, but it is associated with up to 80-90% of HCC cases in Korea, China, Singapore, India and Vietnam. In other regions with high rates of HBV infection such as Turkey, HBV infection is also the predominant cause of HCC. In a retrospective study conducted from 1994 to 1997 in 207 Turkish patients with HCC, 56% were found to have HBV infection. The incidence of HCC associated with HBV ranges from 16% in Italy to 60% in Greece. In comparison, the results of a European-concerted action found that about 20% of European patients with HCC showed HBV infection. Cirrhosis, liver failure, or HCC will develop in approximately 15-40% of individuals with HBV.
The economic burden of HBV infection
The economic burden of HBV infection is substantial because of the high morbidity and mortality associated with end-stage liver disease, cirrhosis, and HCC. In the United States, where most cost-analysis data are available, 1.25 million people - many of them immigrants from areas of high endemicity - are currently chronic HBV carriers. Approximately a third will develop clinical complications of CHB. In one study, health care costs during the first 7 months after diagnosis were 3.3 times higher for CHB patients than for control patients. Costs escalate with increasing severity of illness. One US-based study estimated that the average cost per hospitalization was $8464 (in 1999, US$ dollars) for a patient with 'liver inflammation' (presumably chronic active hepatitis) compared with $14 063 for a patient with cirrhosis. Overall, a US-based study of New England health care databases found that patients with CHB accounted for an average of $40 512 in costs over 2 years for health care services and medication. In a 1995 US study that stratified costs by stage of liver disease, annual costs were estimated at $4175 for a patient with compensated cirrhosis, $22 072 for a patient with decompensated cirrhosis, and $19 589 for a patient with HCC. The cost of liver transplantation is higher still, estimated at $89 076.
Because such serious liver problems develop over a number of years, direct medical costs as well as indirect costs attributable to lost work days and lost productivity are substantial. This cost is likely to be even more pronounced in countries with higher endemicity for HBV infection, although good data are mostly lacking. In a South Korean study conducted in 1997, the total annual societal cost was estimated to be $959.7 million (US$); 13.2% of this sum was attributable to prevention costs (vaccine), 20.9% to indirect costs of HBV-related diseases, and the remaining $632.3 million to direct disease-related medical costs. Of the direct and indirect disease-related costs, 45.3% were related to cirrhosis. The direct costs (prevention- and disease-related) of HBV disease, amounting to $696.2 million, were equivalent to 3.2% of the South Korean national health care expenditure for 1997.
Role of vaccination in controlling HBV infection
Hepatitis B viral infection is a preventable disease. A safe and effective vaccine, which has been available for more than 20 years, is 95% effective in preventing the development of chronic infection. In 1991, the World Health Organization (WHO) recommended adding HBV vaccination to all national immunization programs. By May 2002, 154 countries had routine infant immunization with hepatitis B vaccine (WHO, unpublished data).
The world's first nationwide universal vaccination program for HBV infection was launched in 1984 in Asia (Taiwan). During the first 2 years of the program, coverage was provided mainly for infants whose mothers were carriers of HBsAg. Vaccination was subsequently extended, first to all newborns and then to unvaccinated preschool-age and elementary school-age children. Since 1991, catch-up vaccinations have been given to children in the first grade. This program reduced the overall HBsAg prevalence rate from 9.8% in 1984 to 1.3% in 1994 among children <15 years of age. The HBV carrier population was further reduced through improved maternal screening. In 1999, vaccination rates were 80-86% for young children and higher than 90% for older children; the prevalence of HBsAg was reduced to 0.7% for children younger than 15 years of age. Among children aged 6-9 years, HCC decreased from 5.2 cases per million population before the neonatal vaccination program began in 1984 to 1.3 cases per million population in the first vaccinated cohort.
Vaccination against HBV infection has been strongly recommended and offered free of charge in Italy since 1984. In 1991, vaccination became compulsory for infants 3 months of age and children 12 years of age. Between 1987 and 1994, the incidence of HBV infection decreased from 10.4 to 3.4 per 100 000 population; it has remained stable since that time. These declining incidence rates are attributable in part to improved socio-economic and sanitary conditions, but immunization against HBV infection has been the greatest contributor, especially among those 15-24 years of age. Although HBV infection is now uncommon among native Italian children, immigration flow and international adoptions have resulted in a peak in the incidence of the disease between immigrant and adopted foreign-born children in Italy. Cost savings due to the decline in acute viral hepatitis cases equalled two thirds of the cost of mass vaccination against HBV infection. Additional savings can be expected to accrue as the incidence of new HBV infections continues to decline, along with the incidence of cirrhosis and HCC.
A global review of economic evaluations of HBV immunization spanning from 1994 to 2000 found universal HBV vaccination strategies to be cost-saving in countries of intermediate to high endemicity. The results were less consistent in countries of very low endemicity. However, vaccination efforts may also be important in countries of low endemicity with communities with a high prevalence of HBV infection, such as immigrant Asian communities in the United States. Indeed an analysis of an HBV immunization project (1994-1996) directed at Asian American children in Philadelphia showed that a 12% increase in vaccination coverage resulted in a discounted cost saving of $11 525 per discounted year of life saved and in a total of 106 years of life saved. This study demonstrated that even a modest increase in vaccination coverage is cost-effective and cost-beneficial.
Vaccination is the most effective tool in preventing the transmission of HBV infection. Strategies targeting just high-risk groups cannot control HBV infection throughout the population. Broader vaccination programs are required including infants, children, health care workers and pregnant women.
The use of safe and effective vaccines against HBV infection is expanding through the support of the 74 poorest countries of the world by the Global Alliance for Vaccines and Immunization (GAVI).
Available data show the positive impact of the HBV vaccine on reducing the disease burden. There are still many challenges to be overcome before achieving the goal of universal childhood immunization against HBV infection. Therefore, to continue to promote access to HBV vaccines worldwide, the following recommendations are offered: --Universal infant immunization is the most effective way to reduce the global burden of disease due to HBV infection
--The global community must support poorer countries to strengthen their health care delivery systems and, in particular, national immunization programs, so that vaccines are delivered safely and high coverage is attained and sustained.
Treatment of HBV infection
Although chronic HBV infection is highly preventable through vaccination, once it has been established, the sole option for thwarting long-term liver disease is treatment. Currently, two therapies are widely approved globally (Europe, North America and Asia) for treatment of CHB: conventional interferon alfa (IFN-a) and lamivudine (3TC, a nucleoside analogue). Adefovir dipivoxil is approved in the USA and in Europe.
Conventional IFN-a in the treatment of chronic hepatitis B
In contrast to nucleoside and nucleotide analogues, conventional IFN-a has a dual mode of action involving immunomodulatory actions as well as antiviral activity. The immunomodulatory properties of conventional IFN that can alter the course of chronic HBV infection include activation or induction of macrophages, natural killer cells, and cytotoxic T cells, and modulation of antibody production. Antiviral activity includes the induction of the enzyme 2,5-oligo adenyl synthetase and induction of protein kinase.
Nucleoside and nucleotide analogues in the treatment of chronic hepatitis B
Nucleoside/nucleotide analogues suppress HBV replication through inhibition of HBV DNA polymerase.
Treatment of HBeAg-positive chronic hepatitis B
Response to treatment with conventional IFN
Four to 6 months of therapy with conventional IFN a-2a (2.5, 5.0 and 10 MIU thrice weekly) has produced encouraging results, with rates of HBeAg loss of 20-50%. Response to treatment with conventional IFN-a is sustained, as approximately 90% of end-of-treatment responders maintain a positive response. A study conducted at the National Institute of Health confirmed that a sustained response was maintained following treatment with conventional IFN-a (patients were followed for a mean of 4.3 years). HBeAg loss was followed by loss of HBsAg in 87% of patients after conventional IFN-a therapy. Conventional IFN has been shown to have beneficial long-term effects on disease outcome, incidence of HCC development and complication-free survival.
Response to treatment with lamivudine
After 12 months of therapy with lamivudine 100 mg daily, end-of-treatment seroconversion rates (disappearance of HBeAg and appearance of anti-HBe) range from 17 to 21%. However, reversion to HBeAg-positive status after cessation of lamivudine therapy has been observed, and a positive response (sustained response 2 years after cessation of therapy) is maintained in 50% of end-of-treatment responders to lamivudine therapy.
Treatment of HBeAg-negative chronic hepatitis B
Hepatitis B e antigen-negative CHB is less susceptible to therapy than HBeAg-positive 'wild-type' virus and is associated with a poorer prognosis. Therefore, treatment needs to be given early during the natural course of HBV infection before mutation to the HBeAg-negative variant occurs, thereby preventing the HBeAg-negative variant from becoming the prevalent form of the virus. Severe disease progresses quickly with HBeAg-negative HBV; 60% of patients with this form of disease develop cirrhosis within 6 years.
Response to treatment with conventional IFNa
After up to 12 months of therapy, approximately 50-70% of patients treated with conventional IFN showed a positive response (normalization of ALT values and disappearance of HBV DNA). However, data from various studies indicate that sustained response rates are highly variable, with 6-24% of patients maintaining a sustained response (12-18 months after cessation of therapy). A longer duration of therapy has been shown to improve response rates. Indeed, in one study, an end-of-follow-up sustained response was achieved in 33% of patients who received 24 months of conventional IFN therapy.
Long-term follow-up analyzes suggest that sustained response is maintained in a modest percentage of patients. In a Greek study of 209 patients, 27.3% of them maintained a sustained clinical response after a mean follow-up period of 6 years. Results of a large retrospective analysis showed that 54% of the 216 patients who had received conventional IFN for the first time had normal ALT levels and undetectable HBV DNA at the end of treatment. Although 56% of initial responders relapsed after discontinuing conventional IFN , 33% of initial responders were still in remission at the end of the follow-up period (median follow-up 7 years). HBeAg-negative CHB patients with a sustained response to therapy had a significantly improved disease outcome and complication-free survival compared with non-sustained responders.
Response to treatment with lamivudine
Lamivudine shows moderate 1-year response rates in patients with HBeAg-negative CHB disease. Lamivudine demonstrates a positive response (ALT normalization and HBV DNA suppression) in 65-87% of patients after 12 months of therapy, and in 40% of patients at the end of 30 months of continuous treatment. However, in the majority of patients, a positive response is not maintained when treatment is stopped; only 13-17% of patients show a sustained response 6 months after cessation of therapy.
Lamivudine therapy produced favorable effects on histological features of HBV infection. In a 52-week, randomized, placebo-controlled US efficacy study of 143 patients, 52% of patients in the lamivudine group had a reduction of at least two points in the Histologic Activity Index (HAI) compared with 23% of those in the placebo group (P < 0.001). However, the clinical relevance of a two-point drop in the HAI score has not yet been defined.
Influence of conventional IFNa on the natural history of chronic hepatitis B
Treatment with conventional IFN not only results in loss of viremia and normalization of liver enzymes, but also improves long-term outcomes and survival, and alters the natural history of the disease. In addition, treatment with conventional IFN was also associated with improved outcome of HBeAg-negative CHB (P < 0.001), reducing by 2.5-fold the risk of disease progression as assessed by cirrhosis or end-stage complications of cirrhosis. Patients with HBeAg-positive CHB followed for up to 20 years, who achieved sustained virological and biochemical remission with IFN therapy, also had a decreased incidence of liver-related complications and improved 5-year survival, even when liver-compensated cirrhosis was present. Furthermore, in patients with HBeAg-negative CHB, sustained biochemical remission resulting from IFN treatment was associated with significantly improved overall and complication-free survival (P = 0.027 and P = 0.019).
Emergence of viral resistance to lamivudine
After 6-9 months of lamivudine therapy, drug-resistant HBV species with mutations in the polymerase gene develop (by disruption of the YMDD motif containing the tyrosine-methionine-aspartate-aspartate amino acid motif of HBV DNA polymerase. The mutation consists usually of either a methionine to valine (M552V) or a methionine to isoleucine (M552I) substitution). The incidence of YMDD mutations increases with duration of lamivudine therapy. Within 18 months of treatment with lamivudine, lamivudine-resistant YMDD mutants make up 30% of the HBV population within the treated patient. Within 30 months, up to 70% of the HBV population may be composed of YMDD mutants.
The emergence of YMDD mutations is associated with the reappearance of HBV DNA and frequently with ALT elevation (virologic and biochemical relapse). The benefit of long-term lamivudine therapy must therefore be balanced against concerns about YMDD mutations. Its oral mode of administration and good side-effect profile make lamivudine an attractive therapeutic option for the treatment of CHB. Nonetheless, its use is limited by the propensity to cause viral resistance and the emergence of YMDD mutants.
Summary of currently available treatments for chronic hepatitis B
Conventional IFNa, with its dual immunomodulatory and antiviral effects, is an option for the treatment of CHB. Patients who are sustained responders to conventional IFNa have an improved disease outcome and complication-free survival. However, conventional IFN has a modest efficacy rate, is associated with undesirable side-effects, and three-times-weekly dosing by injection is an inconvenient regimen for patients. These disadvantages may be partially overcome with pegylated interferon.
Lamivudine offers the advantages of minimal side-effects and ease of administration. Its major disadvantages are its modest efficacy rate, the need for long-term therapy to maintain response, and its association with a high rate of viral resistance, particularly with prolonged use.
Emerging treatments for chronic hepatitis B
Adefovir dipivoxil
The adenine nucleotide analogue adefovir dipivoxil is an oral antiviral drug with activity against both wild-type and lamivudine-resistant HBV. A 48-week course of treatment with adefovir (10 mg daily for chronic therapy) in patients with HBeAg-positive CHB resulted in significant reductions in HBV DNA levels. However, the HBeAg seroconversion rate was only 12% at 48 weeks, increasing to 21% when treatment was continued to 100 weeks. At this time, HBV DNA was undetectable and ALT levels had normalized in 70% of patients. In a separate multicentre study, adefovir treatment was associated with significant histological improvement, but again, the HBeAg seroconversion rate was only 12% at 48 weeks. Adefovir was found to have similar antiviral efficacy against all types of HBV, including lamivudine-resistant YMDD mutant HBV strains, but a recent study has demonstrated low level resistance to adefovir treatment after 96 weeks of therapy. Similar to lamivudine, patients experience a viral rebound on cessation of therapy. There is no evidence that sustained responses and HBsAg clearance can be achieved with adefovir monotherapy. Although a promising drug, further studies will have to determine the long-term efficacy of adefovir and its potential to be combined with other drugs.
Entecavir
The guanosine nucleoside analogue entecavir is an oral antiviral drug with activity against both wild-type and lamivudine-resistant HBV. In a 28-day, randomized, placebo-controlled, dose-escalating, phase 1/2 study, a pronounced decrease of HBV DNA was observed and there were no significant side-effects. The drug is currently being evaluated in phase 3 clinical trials.
Pegylated IFNa
Pegylated IFN was developed through the process of pegylation, in which a polyethylene glycol (PEG) polymer molecule is attached to the base IFN molecule to produce a drug with a prolonged half-life. In the last few years, there have been extensive trials carried out with two larger polymers, namely, the 12 kDa PEG, with linkage of IFN a-2b to a linear PEG molecule, and the 40 kDa branched PEG linked to IFN a-2a. The binding sites of the two molecules differ, and thus the stability of these molecules also differ both in vitro and in vivo. Furthermore, the different size of the two molecules leads to different volumes of distribution, the organs in which the drug is distributed, and its sites of catabolism. In short, the peginterferon alfa-2a (40 kDa) (PEG IFN -2a) has a longer half-life (>100 h), and its breakdown products are biologically active. It is largely restricted to the liver where it is metabolized. Peginterferon alfa-2b (12 kDa) (PEG IFN -2b) has a shorter half-life and is somewhat more of a prodrug acting as a depot of IFN with the release of free IFN. Peginterferon alfa-2b (12 kDa) is widely distributed. The two pegylated IFNs have been used in a variety of trials in patients with chronic hepatitis C, and results show considerable improvement in efficacy over conventional IFNa raising the question as to whether pegylated IFNs would be of use in patients with CHB. Data for PEG IFN -2a (40 kDa) are now available on patients with CHB. Preliminary results indicate that more than twice as many HBeAg- positive patients receiving PEG IFN -2a (40 kDa) 180 g weekly for 6 months achieved the combined response (HBeAg loss, HBV DNA <500 000 copies/mL, ALT normalization) compared with patients receiving conventional IFN -2a, (28 and 12%, respectively). Patients treated with PEG IFN -2a (40 kDa) for 6 months had substantially higher rates of HBeAg clearance and seroconversion than did patients treated with conventional IFN -2a (33%vs 25%). Of particular interest is the finding of improved responses to PEG IFN -2a (40 kDa) in those patients traditionally considered to have difficult-to-treat HBV infection, such as those with low pretreatment ALT levels and high pretreatment HBV DNA levels. Within this group of patients response rates were also substantially higher in those patients treated with PEG IFN -2a (40 kDa) than in those treated with conventional IFN a-2a.
Validation of these promising results is eagerly awaited from ongoing, large-scale, multicentre trials in both HBeAg-positive and HBeAg-negative patients. In addition, these studies will hopefully clarify whether the combination of lamivudine and PEG IFN a-2a (40 kDa) is better than monotherapy with PEG IFN -2a (40 kDa) in the treatment of CHB.
Potential of combination therapy
Lamivudine in combination with conventional IFN appears to be more effective than either agent alone in increasing the rate of HBeAg seroconversion. In a comparison of the three treatments in patients with HBeAg-positive chronic HBV infection, the HBeAg seroconversion rates after 52 weeks of therapy were 29% for combination therapy, 18% for lamivudine monotherapy, and 19% for conventional IFN -2a monotherapy. Clinical trials of combination therapy with PEG IFN -2a (40 kDa) are currently under way and the results are eagerly awaited.
Conclusion
The large reservoir of patients worldwide who are chronically infected with HBV creates an enormous burden of illness related to chronic infection, cirrhosis, liver failure, and HCC. Only through a dual approach of integrating HBV vaccine into all national immunization programs and providing safe, effective treatment of HBV infection, can the burden of the disease be eliminated and HBV-related morbidity and mortality contained.
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