|Year : 2004 | Volume
| Issue : 1 | Page : 113-139
|Management of chronic hepatitis due to hepatitis B virus infection
Subrat Kumar Acharya, Yogesh Batra
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110 029, India
Click here for correspondence address and email
|How to cite this article:|
Acharya SK, Batra Y. Management of chronic hepatitis due to hepatitis B virus infection. Hep B Annual 2004;1:113-39
Hepatitis 'B' virus (HBV) is the most important cause of chronic hepatitis, cirrhosis of the liver and liver cancer. HBV is considered to be the etiology in 40 to 60% of patients with chronic hepatitis and cirrhosis in India.,, About 80 to 90% of primary liver cancers in India have been reported to be associated with HBV infection.,, While, medical management for HBV induced cirrhosis and liver cancer remains unsatisfactory, therapy in chronic hepatitis 'B' (CH-B) is progressively improving with the availability of newer and effective antiviral chemotherapy. The ultimate goal of such therapy in chronic hepatitis is to heal hepatic inflammation and necrosis, there by halting progression to cirrhosis and hepatocellular cancer. However, before elucidating the effectiveness of various therapeutic strategies against chronic HBV infection it may be important to briefly discuss the natural course and life cycle of HBV infection in humans, because HBV induced disease in humans occurs due to the result of interaction between the virus and the host immune system.
Life Cycle and Natural course of HBV infection [Table - 1]
Under most circumstances, HBV is not cytopathic. An intact immune system is a necessity for viral clearance and hepatocyte injury. The severity of liver injury reflects the vigour of the immune response; the most complete immune response is associated with the greatest likelihood of viral clearance and the most severe liver injury. Ninety five percent of infected neonates with immature immune systems become asymptomatic chronic HBV carriers, as compared to 30 percent children infected after neonatal period but before six years of age. Only 2 to 3 percent of adults following an acute HBV infection continue to remain chronically infected, and the remaining patients, due to a competent immune system, clear HBV infection. In Asian countries, evidence suggest that most of the chronic HBV infections are acquired in the childhood. While in the South East Asian countries, chronic HBV infection in the population occurs due to neonatal infection (vertical transmission from HBV infected mother to baby during confinement), in India it is due to HBV infections in the post neonatal period through horizontal spread (child to child) before the age of 6 years. About 86 percent of chronic HBV infections are considered to be due to horizontal infection in the paediatric age group, and the remaining 14 percent presumably get infected during neonatal period (vertical transmission). These HBV infected children when they grow up with acquision of a more robust and complete immune system, the effort of the immune system to clear the HBV from the infected hepatocyte gets obtunded by the various viral strategies to evade the host immune attack, As a result, the obtunded immune system causes mild but ongoing injury in 15 to 25% of such cases resulting in chronic hepatitis. Therefore, enhancing the immune system further, or decreasing the viral load (so that its tolerising effect on immune system is reduced) causing immune restitution, has become the rationale for present therapeutic strategy. In the following paragraphs, the life cycle of HBV in human being will illustrate the above facts more lucidly and this constitutes the basis of all therapeutic design to remove HBV from the human liver. The life cycle of HBV can be categorized into four stages, present in some form in all infected individuals [Table - 1].
The first stage, following HBV entry into human hepatocyte is considered as the phase of immune tolerance, during which the HBV replicates in the liver and starts getting released into the circulation. In the healthy adult, this incubation period lasts for about two to six weeks. In contrast, in neonatal infection, this period usually lasts for decades (asymptomatic HBV carrier state), during which in most infected individual HBV replication continues without any liver injury (normal transaminases and no symptoms).
In the second stage, an immunologic response develops (as in adult infection) or improves (in childhood infection as the child grows, his immune system matures) following sensitization of the immune system to immunogenic peptides of HBV (HBsAg and HBeAg). Resultant cytokine release and T-cell (CD8) mediated cell lysis causes HBV clearance from infected hepatocytes leading to hepatic inflammatory process. In the wild type of HBV infection, HBeAg secretion continues in this stage but HBV DNA level drops and the number of infected hepatocytes declines. In adult patients with acute HBV infection, it is the phase of symptomatic hepatitis and this typically lasts 4 to 6 weeks. However, those who cannot clear the virus completely due to inadequate immune attack (as in the grown up child) the second stage may persist for 10 or more years resulting in cirrhosis. In such patients HBcAg expressed on hepatocytes during HBV replication constitutes the dominant antigenic target for cell mediated immune system which gets sensitized by HBeAg (having similar peptide structure to HBcAg). Therefore, as a part of survival strategy, HBV in an effort to evade such immune attack undergoes nucleotide mutation (mutation at nucleotide 1896 of Pre 'C' region or at esnucleotide 1762 or 1764 of promoter region of Pre 'C' region) resulting in a form of HBV which continues to replicate without synthesizing HBeAg. Such immune selection of HBeAg negative chronic HBV infection may also continue to be associated with ongoing indolent liver damage over years causing cirrhosis. Repeated reactivation of both wild type and precore mutant infection occurs in 40-50% of such patients causing progressive liver damage and cirrhosis.
Stage 3 ensues only in those who are able to mount an adequate immune response with resultant clearance of most infected hepatocytes; as a result, cessation of active viral replication occurs causing HBeAg seroconversion (HBeAg -ve and anti HBe +ve) associated with marked decrease in HBV DNA and normalization of ALT level. However, patients with childhood infection continue to remain HBsAg +ve due to integration of HBV with hepatocyte genome, where as among adults, over a few months time HBsAg seroconversion to anti HBs usually occurs. With disappearance of HBsAg the 4th stage begins, during which HBV DNA become undetectable. Patients reaching 4th stage are unlikely to get reinfected or to have reactivated infection.
The goal of therapy in patients with chronic hepatitis 'B' is to convert stage '2' disease to stage '3' or stage '4' disease. The major determinants for such process includes, age at infection, sex, viral characteristics such as high viral load or development of HBeAg -ve strain, and immuno suppression state. Therefore before treating patients with CH-B, evaluation of the above mentioned factors assists the treating clinician to provide the best possible treatment schedule.
Chronic hepatitis B is a heterogeneous disease
As described earlier, HBV may modify its structure under immune pressure and selection of such mutant virus associated with progressive liver damage may not respond to therapy well. Therefore, based on viral characteristic, CH-B can be grouped into HBeAg +ve and HBeAg -ve variants. Recently, from our centre we have described HBsAg -ve CH-B, which may constitute a third variety of CH-B. The host characteristics may also influence the natural course of the patients with CH-B. For example CH-B infection among HIV infected individuals, chronic alcoholics, patients with chronic renal failure or renal transplant, patients with haematological malignancy, patients undergoing chemotherapy for other form of malignancies usually do not behave like CH-B patients without any such associated comorbid illnesses. While treating a patient with CH-B, these factors may influence the outcome of therapeutic interventions. In such patients therapy should be individualized as per patient and viral characteristics.
Therapeutic end points in the management of CH-B
During the last two decades experience on the management of CH-B has been substantial. Published studies on the therapeutic results in CH-B, clearly indicate that, eradication of HBV or suppression of HBV replication is associated with decrease in hepatic inflammatory process. While, HBsAg loss subsequent to successful treatment has been frequent among Caucasians, such outcome among the Asians is rare., Such differences in therapeutic outcome have been presumed to be due to the age at which HBV infection occurs in these communities. Usually chronic HBV infection among the former population occurs in adults, where as among Asians, persistent HBV infection is a child hood event., Presumably due to the long duration of infection, the HBV genome integrated into the host hepatocyte genome continues to secrete HBsAg despite arrest of HBV replication in the latter patients.
Therefore the primary aim of therapy in patients with CH-B is to eradicate or permanently suppress HBV replication and to prevent reactivation of HBV replication in long term. The terms used to express such successful results are sustained viral response (SVR) and sustained biochemical response (SBR). Sustained viral response conventionally indicates persistent and continued arrest of HBV replication (HBeAg sero conversion and HBV-DNA loss) even after 6 months of stopping treatment. Similarly, SBR denotes normal ALT beyond 6 months of cessation of therapy. Histological improvement invariably accompanies SVR and SBR. The severity of liver damage among patients with CH-B can be objectively assessed during histological evaluation by grading the severity of inflammation and liver cell necrosis and by assessing stage of the disease in which degree of fibrosis is scored on an arbitrary scale. Certain viral and host factors have been found to be associated with SVR. A low viral load (HBV-DNA level <200pg/ml), more active immune system (ALT > 100IU/dl), lesser degree of hepatic fibrosis and higher histological activity index (HAI > 10) have been associated with excellent SVR. On the other hand, co infection with another virus like HIV, advanced hepatic fibrosis, low ALT, male sex, high BMI and associated alcohol consumption are factors associated with suboptimal therapeutic response. Further, it has been documented that HBeAg -ve CH-B are extremely difficult to treat because of a high relapse rate documented in these patients after cessation of therapy, and the relapse rate increases in these patients with passage of time. The role of HBV genotypes and their association with response to therapy is yet to elucidated.
Therapy in CH-B
By now many immunomodulators and antivirals have been developed to treat patients with CH-B [Table - 2]. However the results of treatment with Interferon, Lamivudine and Adefovir have been well evaluated and the present discussion would be limited to these three drugs predominantly.
Interferon a was first reported to have beneficial effects in chronic hepatitis B in small uncontrolled studies in 1970s. Interferon was the first drug to be approved for the treatment of chronic hepatitis B. A meta analysis published in 1993 reviewed 15 randomised controlled trials involving 837 adults with HBeAg +ve CH-B who received 5-10 million units (MU) Interferon daily or thrice weekly for 4 to 6 months. HBV-DNA loss was documented in 37% of treated patients compared to 17% of controls, loss of HBeAg occurred in 33% of treated patients compared to 12% in the controls, and the loss of HBsAg was observed in 7.8% of the treated patients while it was 1.8% in the controls [Figure - 1]. Another metaanalysis which included 1200 patients and 22 trials, documented that interferon increased the rates of serum HBV-DNA clearance and aminotransferase normalization by a factor of 3 at one year. The accepted conventional dose of interferon is 5 million units daily or 10 million units three times a week. The duration of such a regimen for HBeAg positive disease has been recommended for 4-6 months. However, the optimal duration of interferon therapy for hepatitis B is not well established. A multicentric trial from Europe demonstrated added benefit of continuing therapy for 32 weeks among patients in whom HBeAg is not cleared by 16 weeks but who had low levels of HBV-DNA (<10pgm/ml). Therapeutic response to interferon a has been reported to be different among various races and ethnic population. However, such differences are difficult to be assessed, because trials in Asia have included only Asians, while Western trials included mostly white subjects. Published and unpublished trials of Interferon a among the Indian HBeAg +ve CH-B patients revealed a HBeAg seroconversion rate of about 30% in comparison to a 9% HBeAg loss among untreated controls. Irrespective of ethnicity or race, patients with normal or minimally elevated ALT, universally have been reported to respond poorly (<3%) to Interferon. Several methods to increase the response in such patients have been suggested. One of the most popular approach described was 'priming with a short course of steroid'. However, convincing and reproducible data on its efficacy particularly on long term follow up is lacking. The durability of responses and continued benefit of therapy were recently assessed in several long term follow up studies. Studies from the West suggest that 95-100% of the responders remained HBeAg -ve during 5-10 years follow up and 30 to 80% of them ultimately lose HBsAg.,, In contrast, studies from South East Asian countries revealed lower rates of durable responses, only rare loss of HBsAg and ultimately a loss of HBeAg in similar proportions of controls and treated patients.,, Data on long term durability of response among South Asians (India, Pakistan and Nepal) is not known. Interferon therapy is associated with side effects like fever, myalgia and influenza like symptoms in most (60-90%) of the patients; these tend to ameliorate with continuing use of the drugs. Other problematic side effects include leuopenia, thrombocytopenia, hypothyroidism and behavioural abnormalities. Discontinuation of therapy due to such side effects have been reported in 5-10% of cases.,
Data on the results of interferon therapy among HBeAg -ve CH-B patients are limited and complicated by heterogeneity of the virus, the diseases, and the study designs. Heterogeneity of the disease is reflected through markedly different patterns of serum ALT elevation viz: continuous (25%), fluctuating (50%), and relapsing (25%). The virus may also be heterogenous; HBeAg negativity in such cases may be due to classical G1896A precore mutation or due to core promotor mutation (A1762T, G1764A). The heterogeneity in study design is reflected by various types and regimens of interferon, different end points and various types of control populations. All the trials have documented an end of therapy response rate of 40 to 60%, but with cessation of treatment half the patients relapsed within 6 months. Unlike the durable response rate among HBeAg +ve patients, relapse among HBeAg -ve CH-B continues to occur with passage of time and a durable response to a 12 month course of interferon in such patients has been reported to vary from 15% to 25%. Further, unlike HBeAg +ve patients, the predictors of response to treatment in HBeAg -ve patients are not clear. However, longer duration of treatment in such patients and early normalization of ALT values have been reported to be associated with better sustained response.
In both, HBeAg +ve and HBeAg -ve patients, a sustained viral response has been reported to be associated with lower rates of death and HCC.,
Interferon a therapy has been shown to be effective and is recommended for use in children above 2 years of age with HBeAg +ve CH-B. Two hundred forty children included in 15 studies were treated with a dose of 3-10 MU/m 2 given thrice weekly for 12-48 weeks. A SVR of 23% among treated patients and 11% among untreated controls was reported. Predictors of response among children were similar to those in adults. However, an Italian study reported that at long term, HBeAg loss among treated and controls were similar. Data on therapeutic results of interferon treatment of Indian children are not available.
Interferon has a short half life of about 4 hours only. To increase its half life and prolong its duration of action, it has been tagged with polyethylene glycol molecule to form pegylated interferon. Pegylated interferon has a longer trough level, weekly dosing and a higher efficacy. This fact has been documented in many trials involving patients with chronic hepatitis C and the initial studies with the drug in HBV have also shown promising results; however its long term efficacy is yet to be evaluated. Studies using a combination of Pegylated interferon and Lamivudine have also shown excellent initial results, however, the long term results of such therapy needs evaluation.
Lamivudine (3-Thia-cytidine) is a dideoxynucleoside (a pyrimidine nucleoside analogue) which acts by inhibiting viral DNA synthesis by terminating the nascent proviral DNA chains. It is well absorbed orally and has been found to possess marked antiviral activity against HBV and HIV. Long term treatment using Lamivudine monotherapy for 52 weeks has been evaluated in 4 large multicentric, randomized controlled trials [Figure - 2] in patients with HBeAg +ve CH-B. In these trials, HBeAg loss and HBeAg seroconversion was documented in 17-32% and 16-18% respectively, in contrast to 11% and 5% respectively in controls.,,, One out of these 4 trials was conducted among Chinese patients where as the remaining three were conducted among Western patients with CH-B.,, The factors identified as predictors for response (HBeAg loss/seroconversion) in the above mentioned studies were similar to those documented among responders to interferon. Patients with CH-B having ALT levels 5 times normal had HBeAg loss/seroconversion in 65% of the patients. However, an unresolved issue of lamivudine therapy in CH-B is the durability of the response. Even though HBeAg seroconversion has been reported to be associated with durable response in 70-80% of cases in the above studies, a single centre study reported a relapse rate of 50%. The high rate of relapse after cessation of lamivudine treatment, its ease of administeration, lack of side effects, and potent antiviral effects make long term therapy an attractive approach for patients who donot clear HBeAg during the initial 52 weeks treatment. As a part of the extended follow up of the Asian multicentric trial, 58 of 357 patients continued long term lamivudine treatment; cumulative HBeAg seroconversion with loss of HBV-DNA (hybridization assay) was documented in 22% at 1 yr, 29% at 2 yr, 40% at 3yr and 47% at 4yr of therapy.
Although the initial results with lamivudine were promising, drug resistance has emerged as a problem, occuring in 16-32% patients at the end of one year of therapy and increasing with the duration of therapy to 67% at the end of 4 years of therapy. Resistance to lamivudine occurs as a result of selection of the mutant strains of virus, the mutation occuring at the tyrosine- methionine-aspartate-aspartate (YMDD) motif of the DNA polymerase region of the virus. The substitutions were most commonly due to replacement of the methionine at codon 552 with isoleucine or valine. Lamivudine resistance is associated with a rise in ALT/AST value with increase in HBV-DNA level.
Eighty patients with chronic hepatitis B at our centre were treated with Lamivudine of whom 40 are continuing therapy till date. While on therapy, virological response (HBeAg loss/seroconversion) was documented in 62.5% of the patients, and sustained response among those who discontinued therapy after HBeAg loss or seroconversion was observed in 19/40 (51.3%) of the patients. ALT flare during treatment with lamivudine (presumably YMDD mutants) were documented in 13 (16.3%) of patients.
Most studies on the therapy in CH-B have focussed on HBeAg +ve CH-B. However in India, approximately 15-30% of patients with CH-B are associated with HBeAg-ve CH-B. About 6 studies have evaluated the efficiency of lamivudine for 12 months among patients with HBeAg-ve CH-B.,,,,, HBV-DNA loss by hybridization assay with normalisation in ALT values at the end of 12 months of therapy have been documented in 63 to 96 % of the cases. However, with cessation of therapy, relapse frequency was very high with a sustained response of only about 10-12% during 1 year post therapy follow up.
Therefore long term or even life long Lamivudine therapy has been contemplated as an alternative, but long term treatment with lamivudine for more than 12 months has been associated with progressively increasing virological and biochemical breakthrough indicating lamivudine resistance. Despite the increased frequency of breakthroughs about one third of such patients on long term lamivudine treatment have been reported to be associated with HBV-DNA negativity, normal ALT and improved liver histology.
Thus, lamivudine therapy leads to improvments in biochemical, virological and histiological features of the disease in more than three fourths of the HBeAg-ve CH-B patients, but relapse is frequent when therapy is stopped and long term treatment is associated with a high rate of viral resistance.
It is believed that clearance of HBV or prevention of viral replication can reduce further liver damage and progression of disease in patients with HBV associated decompensated cirrhosis and may result in development of the 'stable cirrhotic state'. Interferon is contraindicated in this subgroup of patients. Lamivudine treatment has been reported to be associated with a rapid suppression of viral DNA to undetectable levels and a rapid improvement in the biochemical and the clinical profile among such patients with cirrhosis., In a prospective North American study, 80% of those treated with lamivudine had undetectable HBV-DNA levels within 8 weeks at the begining of therapy. In addition, 35% of patients lost previously detectable HBeAg and 20% acquired anti-HBe. Yao et al from China reported that patients with HBV induced cirrhosis listed for liver transplant and receiving Lamivudine were less likely to undergo transplantation.
Improvement in hepatic inflammation subsequent to Lamivudine therapy may be associated with reduction in the development of HCC as has been demonstrated in Woodchuck hepatitis virus induced cirrhotics among woodchucks.
Several studies have now demonstrated the efficacy of lamivudine in preventing post transplant recurrences of HBV infection deterioration of graft as well as patient survival. Because of the appearance of lamivudine resistant HBV with long term use, most liver transplant centres now treat transplanted patients having high risk of HBV reinfections with combination of Lamivudine and hepatitis B immunoglobulin (HBIG).
Minimal toxic effects have been reported in most studies on Lamivudine. Analysis of Lamivudine effect on mitochondrial morphology and functions has not shown any mitochondrial toxicity either after 6 months or 3 years of therapy. Other reported side effects are anorexia, nausea, vomiting, leukopenia and peripheral neuropathy.
Adefovir is the most recent drug in the armamentarium against HBV. It has an excellent oral absorbtion, an intracellular half life which permits once daily dosing and in vitro studies have documented its antiviral activity against both wild type and lamivudine resistant HBV. However in large doses (60 to 120mg daily) it causes reversible nephrotoxicity such renal tubular acidosis, renal insufficiency and phosphate wasting. In two recently published reports, adefovir was found to be effective in both HBeAg positive and HBeAg negative chronic hepatitis. In the study by Marcellin et al which included HBeAg positive patients and was conducted in 32 centres across the globe, 512 patients were randomised to receive adefovir 30mg or placebo and the following results were documented after 48 weeks of therapy. Histological improvement was found in 53% of those receiving 10mg adefovir daily, 59% in those receving 30 mg of the drug daily and 25% in those receiving the placebo. The reduction of serum HBV-DNA levels was by 3.52 logs, 4.76 logs and 0.55 logs respectively. Undetectable levels of serum HBV-DNA by branched chain assay was documented in 21%, 39% and 0% respectively and HBeAg seroconversion took place in 12%, 14% and 6% respectively. Adefovir resistance was not reported in any of the patients who were treated. Both 10mg and 30 mg doses of adefovir had a similar efficacy; however nephotoxicity was more common among the patients who recevied 30 mg of the drug. Therefore the authors recommended the use of 10mg as the preferable dose in the treatment of CH-B.
Another study published at the same time by Hadziyannis et al, included 185 HBeAg negative CH-B patients and randomised them to receive either 10 mg of adefovir daily or placebo over a period of 48 weeks. 64% had improvement in the liver histology in the treatment group as compared to 33% of placebo group. Undetectable HBV-DNA was found in 51% of the treated patients and none in the placebo group; the median decline in the HBV DNA levels was 3.91 logs in the treatment group while it was 1.35 logs among the patients receiving placebo. There was no evidence of emergence of viral resistant mutants despite 12 months therapy in these patients.
So far more than 100 patients with lamivudine resistance and decompensated cirrhosis have been treated with adefovir,., the majority of the patients had a 3 to 4 log reduction in the serum HBV-DNA levels and a stablisation of their liver disease. Although adefovir in 10 mg doses has not been shown to result in nehrotoxicity, 28% of decompensated cirrhotic patients had an increase in the serum creatinine by levels greater than 0.5mg%. It seems that adefovir may be an excellent agent to treat CH-B over long duration without the apprehension of occurrence of resistant HBV strains.
Other Nucleoside Analogues
Famciclovir is a nucleoside analogue which has been used among patients with CH-B and the initial results were promising. Its use in combination with lamivudine was considered to be the next step in the therapy for CH-B. However, development of drug resistant mutants and availability of more potent as well as safe antiviral agents like adefovir, clevudine and emtricitabine has made famciclovir a less preferred agent against HBV. Phase II trials of Entecavir have recently been reported with promising results. Clevudine and Emcritabine are currently undergoing trials and they are likely to be available for therapy within the next 2 years. These drugs in woodchuck models have shown excellent antiviral properties against woodchuck hepatitis virus and these in vitro studies have shown that inhibition of viral replication with these agents may be sustained after discontinuation of the drugs.,
Since HBV biology is similar to HIV and most of the nucleoside analogues have been developed as a byproduct of HIV research, therapy against HBV may include 2 or more nucleoside analogues, similar to the highly active antiretroviral therapy (HAART) used for patients with HIV. The first combination to be used was that of lamivudine and famciclovir in a small study in which 9 patients were treated with lamivudine monotherapy and 12 were treated with a combination of lamivudine and famciclovir. A 2 log DNA reduction was present in both the groups at the end of 12 weeks treatment; however a relapse was documented in 4 patients in the lamivudine monotherapy treated patient whereas none relapsed in the combination group after cessation of therapy. A recent study using a combination of lamivudine and adefovir has documented that the reduction of HBV DNA was similar among patients treated with adefovir monotherapy and combination of adefovir and lamivudine. Till date, combination therapy using nucleoside analogues among homogeneous patients with CH-B is lacking and such trials are needed to improve therapeutic results among patients with CH-B.
Since interferon therapy was associated with durable long term responses and lamivudine is associated with greater response rates, both the drugs have been used in combination in an attempt to improve the results. These studies in the past could not document any therapeutic benefit over monotherapy. However, a recent study by Barabaro et al has revealed better sustained response with combination therapy.
The future of HBV therapy would be dominated by wide and extensive use of adefovir which is likely to replace both interferon and lamivudine as the monotherapy of choice for patients with CH-B. With the advent of newer nucleoside analogues, combination therapy is also likely to be extensively evaluated. Combination of pegylated interferon and nucleoside analogues also holds promise for an improved sustained response rate. Although initial studies presented at various international conferences have claimed that the combination treatment was better than available conventional therapy, its ability to achieve long term sustained response among HBeAg+ve and HBeAg-ve CH-B patients remains to be evaluated.
There are other exciting developments in the field of management of CH-B which include nucleocapsid inhibitors, cytokine and genetherapy However, the role of these therapeutic approaches is being evaluated and although they do hold promise, their efficacy against HBV is yet unclear.
Current Treatment Recommendations
After a number of consensus meetings of the Asian (APASL), European (EASL) and American (AASLD) liver societies, various consensus recommendations have been made for the treatment and monitoring of patients with chronic hepatitis. Recommendations by the APASL for the treatment of CH-B are provided below.
2. Doses and duration of therapy
The recommended dose for interferon is 5 MU daily or 10 MU thrice weekly for 4-6 months for HBeAg positive chronic hepatitis and for 12 months for HBeAg negative chronic hepatitis.
The recommended dose for Lamivudine is 100 mg daily for at least one year; longer therapy may be considered for non responders. The treatment duration for HBeAg negative chronic hepatitis is not certain.
The recommended dose for Adefovir is 10 mg daily for one year in HBeAg positive patients; the duration of therapy for HBeAg negative patients is not clear.
3. Lamivudine Breakthrough
Patients on lamivudine therapy, may develop YMDD mutants which is usually manifested by sudden rise in ALT levels and increase in HBV DNA quantity. In these patients lamivudine may be continued provided the raised ALT & HBV DNA levels are less than pre treatment levels. Alternatively, lamivudine may be replaced with adefovir.
4. HIV Coinfection
Lamivudine 150 mg should be a part of HAART.
5. Immmunosuppressed patients
Adefovir is being considered as the drug of choice.
6. Monitoring of patients of chronic hepatitis B
Patients with mild chronic hepatitis B should have their ALT levels measured at least once in 6 months. Treatment should be instituted when there is a sustained rise in the level of transaminases.
Those with newly diagnosed chronic hepatitis B should be monitored with 1-3 monthly ALT levels for 6 months before starting therapy. This period is not needed for those with HBeAg negative diseases.
Those with moderate to severe chronic hepatitis should be monitored irrespective of the fact whether they are being treated or not.
Liver Biopsy should be done in all patients prior to therapy.
Those with cirrhosis should be monitored to minimize the risk of variceal bleeding and HCC. HCC screening should be done 6 monthly with AFP and ultrasound examination.
In those receiving therapy, aminotransferases should be monitored every 1-3 months during the first 6 months and every 6 months thereafter.
For those treated with interferon, HBeAg, anti-HBe and HBV-DNA should be done at the end of therapy, and 6 months thereafter, to assess the virological response. Patients treated with Lamivudine and Adefovir should be tested every 3 months after the transaminases are normal.
For patients with HBeAg negative disease, HBV DNA is the only way of assessing the response to therapy.
Durability of virological response should be established by testing 1-3 monthly for 12 months after stopping therapy and every 6-12 months thereafter.
It is not clear whether liver biopsy should be repeated in those showing a sustained biochemical and virological response.
Chronic HBV infection is a heterogeneous disease and is difficult to treat. At present although many effective antiviral strategies against HBV have been developed, beneficial therapeutic response with these agents are documented in only 30 to 50% of patients. Continuous effort to improve the results further, has resulted in recruitment of newer therapeutic molecules against HBV and these are currently under evaluation. Hopefully, the future of HBV treatment will be more rewarding and satisfying.
| References|| |
|1.||Tandon B.N, Acharya S.K, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut 1996;38:S56-9. |
|2.||Tandon BN, Acharya SK, Tandon A. Seroepidemiology of HBV and HCV in India. Strategy for Control of maternal transmission of HBV and its effect. Screening methods of blood donors for control of post transfusion hepatitis and their effects. Info Hepatol Communic 1996;5:14-8. |
|3.||Irshad M, Acharya SK. Status of hepatic viral markers in patients with acute and chronic liver diseases in northern India. Intervirology 1994;37:369-72. [PUBMED] |
|4.||Lok ASF. Chronic hepatitis B. N Engl J Med 2002; 346:1682-3. |
|5.||Lee WM. Hepatitis-B Virus infection. N Engl J Med 1997;337:1733-45. [PUBMED] [FULLTEXT]|
|6.||Nayak NC, Panda SK, Zuckerman A, et al. Dynamics and impact of perinatal transmission of hepatitis B virus in north India. J Med Virol 1987;21:137-45. |
|7.||Aggarwal R, Naik SR. Prevention of hepatitis B infection: the appropriate strategy for India. Natl Med J India 1994;216-20. |
|8.||Perllo RP, Mason AL. Therapy for Chronic hepatitis B virus infection. Gastroenterol Clin N America 1994;23:581-8. |
|9.||Chaudhuri V, Hazari S, Acharya SK, et al. Magnitude of HBsAg negative chronic HBV induced liver disease and complete genome analysis of HBV isolates from nine such patients. J Gastroenterol Hepatol 2002;17 (Suppl 1):A89. |
|10.||Torresi J, Locarnini S. Antiviral Chemotherapy for the treatment of hepatitis B virus infection. Gastroenterology 2000;118:S83-5. [PUBMED] |
|11.||Lin SM, Sheen IS, Chien RN, et al. Long term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29:971-5. [PUBMED] [FULLTEXT]|
|12.||Lok ASF, Healthcote JE, Hoofnagle JH. Management of hepatitis B: 2000 - Summary of a work shop. Gastroenterology 2001;120:1828-53. |
|13.||Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of Chronic Hepatitis : Diagnosis, grading and staging. Hepatology 1994;95:1513-20. |
|14.||Malik AH, Lee WM. Chronic hepatitis B virus infection: Treatment strategies for the next millennium. Ann Int Med 2000;132:723-31. [PUBMED] [FULLTEXT]|
|15.||Maillaird ME, Gallan JL. Suppressing hepatitis B without resistance - So far so good. N Engl J Med 2003;348:848-50. |
|16.||Greenbreg HB, Pollard RB, Lutwick LI, et al. Effect of human leokocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Engl J Med 1976;295:517-22. |
|17.||Wong D, Cheung A, O'rourke K, et al. Effect of alfa interferon in patients with hepatitis Be antigen positive chronic hepatitis B. Ann Intern Med 1993;119:312-3. |
|18.||Tine F, Liberati A, Craxi A, et al. Interferon treatment in patients with chronic hepatitis B: A meta-analysis of published literature. J Hepatology 1993:18:154-62. [PUBMED] |
|19.||Lau DY, Everhart J, Kleiver DE, et al. Long term follow up of patients with chronic hepatitis B treated with interferon a Gastroenterology 1997;26:1338-42. |
|20.||Janssen HL, Gerken G, Carreno V, et al. Interferon a for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European concerted action on viral hepatitis (EUROHEP). Hepatology 1999;30:238-43. [PUBMED] [FULLTEXT]|
|21.||Panda SK, Acharya SK. A review of therapeutic outcome in Indian patients with chronic hepatitis due to hepatitis B virus and hepatitis C virus. Hepatitis - B in the Asian Pacific region (Vol 3). (ed) A. Zuckerman. Royal college of Physicians, Sarum prints Ltds., Salisbury, Wiltshire, UK 1999, pp55-74. |
|22.||Niederauc C, Heintges T, Lange S, et al. Long term follow up of HBeAg positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334:1422-7. |
|23.||Lau DY, Everhart J, Kleiner DE, et al. Long term follow up of patients with chronic hepatitis B treated with interferon a. Gastroenterology 1997:113:1660-7. |
|24.||De Marc V, Lo lacono O, Camma C, et al. The long term course of chronic hepatitis B. Hepatology 1999:30:257-64. |
|25.||Lok ASF, Chung HT, Liu VWS, et al. Long term follow up of chronic hepatitis B patients treated with interferon alfa. Gastroenterology 1993;105:1833-8. |
|26.||Lin SM, Sheen IS, Chien RN, et al. Long term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29:971-5. [PUBMED] [FULLTEXT]|
|27.||Ikeda K, Saitoh S, Suzuki Y, et al. Interferon decreases hepatocellular carcinogenisis in patients with cirrhosis caused by the hepatitis B virus. Cancer 1998:82:827-35. |
|28.||Manesis E, Savas S, Petraki F, et al. Interferon treatment and retreatment of HBeAg negative Chronic Hepatitis B: twelve years follow up of 209 patients (abstract). Hepatology 1999;30:349A. |
|29.||Papatheodoridis GV, Manesis E, Hadziyannis SJ. Long term follow up after initial response to interferon therapy in patients with HBeAg negative chronic hepatitis B (abstract). Hepatology 1999;30:343A. |
|30.||Torre D, Tambini R. Interferon-Alfa therapy for chronic hepatitis B in children: a meta analysis. Clin Infect Dis 1996:23:131-7. |
|31.||Bortolotti F, Jara P, Barbera C, et al. Longterm effect of alfa interferon in children with chronic hepatitis B. Gut 2000;46:715-8. [PUBMED] [FULLTEXT]|
|32.||Delgado C, Francis GE, Fischer D. The uses and properties of PEG linked problems. Crit Rev Ther Drug Carrier Syst 1992;9:249-304. |
|33.||Manns MP, Mc Hutchison JG, Gordon SC, et al. Pegintron alfa 2b plus ribavirin compared with interferon plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65. |
|34.||Oliveri F, Santantonio T, Bellati G, et al. Long term response to therapy of anti-HBe positive chronic Hepatitis patient is poor, independent of type and schedule of interferon. Am J Gastroenterol 1999;94:1366-72. [PUBMED] |
|35.||Sung JJY, Chan HLY, Hui HY, et al. Combination of pegylated interferon and Lamivudine is superior to Lamivudine monotherapy in the treatment of chronic hepatitis B - A randomised trial. Abstract of paper presented at EASL 2003, Geneva Switzerland. |
|36.||Sokal EM, Bortolotti F. Update on prevention and treatment of viral hepatitis in children. Curr Opin Pediatr 1999;11:384-9. [PUBMED] [FULLTEXT]|
|37.||Lai CL, Chien RN, Leung NWY, et al. Asia Hepatitis Lamivudine Study Group. A one year trial of lamivudine for Chronic hepatitis B. N Engl J Med 1998:339:61-8. |
|38.||Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999:341:1256-63. |
|39.||Schalm SW, Heathcote J, Cianciara J, et al. International Lamivudine Study Group Lamivudine and alfa interferon combination treatment of patients with chronic hepatitis B infection : a randomised trial. Gut 2000:46:562-8. |
|40.||Schiff ER, Karayalcin S, Grimm I, et al. A placebo controlled study of lamivudine and interferon alfa 2b in patients with chronic hepatitis B who previously failed interferon therapy (abstract). Hepatology 1998:28:388A. |
|41.||Song BC, Suh DJ, Lee HC, et al. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32:803-6. [PUBMED] [FULLTEXT]|
|42.||Liaw YF, Leung NWY, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000; 119:172-80. |
|43.||Ling R, Mutimer D, Ahmed M, et al. Selection of mutations in the hepatitis B virus polymerase during the therapy of transplant recipients with Lamivudine. Hepatology 1996;3:711-3. |
|44.||Liaw YF. Impact of YMDD mutations during Lamivudine therapy on patients with Chronic hepatitis B. Antiviral Chem Chemother 2000;12:67-71. |
|45.||Tassopoulous C, Volpes R, Pasore G, et al. Efficacy of lamivudine in patients with hepatitis Be Antigen negative Hepatitis B virus DNA - positive (pre core mutant) chronic hepatitis B. Hepatology 1999;29:889-96. |
|46.||Santantonoi T, Mazzola M, lacovazzi T, et al.. Long term follow up of patients with anti-HBe/HBV DNA positive chronic hepatitis B treated for 12 months with lamivudine. J Hepatol 2000;32:300-6. |
|47.||Rizzetto M, Voces R, Smedile A. Response of pre core mutant chronic hepatitis B infection to lamivudine. J Med Virol 2000;61:398-400. |
|48.||Cho SW, Hahm KB, Kim JH. Reversion from precore/ core promoter mutants wild type hepatitis B virus during the course of lamivudine therapy. Hepatology 2000;32:1163-9. [PUBMED] [FULLTEXT]|
|49.||Hadziyannis S, Papatheodoridis G, Dimou E, et al. Efficacy of long term lamivudine monotherapy in patients with hepatitis Be antigen negative chronic hepatitis B (abstr ). Hepatology 2000;32:456A. |
|50.||Fontana RJ, Hann HL, Perillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.Gastroenterology 2002;123:719-27. |
|51.||Yao FY, Bass NM. Lamivudine treatment in patients with severly decompensated cirrhosis due to replicating hepatitis B virus infection. J Hepatol 2000;33:301-7. [PUBMED] [FULLTEXT]|
|52.||Peek S, Toshkov I, Erb H, et al. 3, thiacytadine (3TC) delays development of hepatocellular carcinoma in woodchucks with experimenttally induced woodchuck hepatitis virus (WHV) infection. Preliminary results of a lifetime study (abstract). Hepatology 1997;26:A957. |
|53.||Grellier L. Mutimer D, Ahmed M, et al. Lamivudine prophylaxis against re-infection in liver transplantation for hepatitis B cirrhosis. Lancet 1996;348:1212-5. |
|54.||Markowitz JS, Martin P, Conard AJ, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination Lamivudine and Hepatitis B immune globulin. Hepatology 1998;28:585-9. |
|55.||Honkoop P, De Man RE, Scholte HR, et al. Effect of lamivudine on morphology and function of mitochondria in patients with chronic hepatitis B. Hepatology 1997;26:211-5. |
|56.||Liaw Y F, Chien R-N, Yeh C-T, et al. Acute exacerbation and hepatitis B virus clearence after emergence of YMDD motiff mutation during lamivudine therapy. Hepatology 1999;30:567-72. |
|57.||Mutimer D, Naoumov N, Honkoop Marinos G, et al. Combination alfa interferon and lamivudine therapy for alfa interferon-resistant chronic hepatitis B infection :results of a pilot study. J Hepatol 1998;28:923-9. |
|58.||Marcellin P, Chang TT, Lim SG, et al. Adefovir Dipivoxil for the treatment of Hepatitis Be antigen -positive Chronic Hepatitis B. N Engl J Med 348;9:808-16. |
|59.||Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir Dipivoxil for the treatment of hepatitis Be antigen negative chronic hepatitis B. N Engl J Med 348;9:800-7. |
|60.||Westland C, Gibbs C, Miller M, et al. Loss of lamivudine resistance mutations after patients shifted to adefovir dipivoxil therapy (abstract). J Hepatol; 336(Suppl 1):7. |
|61.||Perillo R, Schiff E, Yoshida E, et al. Adefovir dipivoxil for the treatment of lamivudine resistant hepatitis B mutants. Hepatology 2000;32:129-34. |
|62.||Schiff E Lai CL Neuhaus P, et al. Adefovir Dipivoxil for the treatment of chronic hepatitis B in patients pre and post liver transplantation with Lamivudine resistant hepatitis B virus patients (Abstract). Hepatology 2002;36:371A. |
|63.||De Man RA, Marcellin P, Habal F, et al. A randomised placebo controlled study to evaluate the efficacy of 12 month famciclovir treatment in patients with chronic hepatitis B e antigen positive hepatitis B. Hepatology 2000;32:413-7. [PUBMED] [FULLTEXT]|
|64.||Lau GK, Tsaing M, Hou J, et al. Combination therapy with lamivudine and famciclovir for chronic hepatitis B infected Chinese patients: a viral dynamics study. Hepatology 2000;32:394-9. |
|65.||Lai CL, Rosmwati M, Loa J, et al. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 2002;123:1831-8. |
|66.||Peek SF, Cote P, Jacob JR, et al. Antiviral activity of clevudine [ L-FMAU,(1-(2-flouro -5 methyl - beta ,-L- arabinofuranosyl) uracil) against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks(Marmota monax). Hepatology 2001;33:254-66. |
|67.||Gish RG, Leung NW, Wright T, et al. Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emcritabine in adults with hepatitis B virus infection. Antimicrob Agents Chemother 2002;46:1734-40. |
|68.||Peters M, Hann HW, Martin P, et al. Adefovir dipivoxil (ADV) alone and in combination with Lamivudine (LAM) suppresses Lamivudine resistant Hepatitis B virus replication :16 weeks interim analysis (Abstract). J Hepatol 2002;36 (suppl 1):7. |
|69.||Barbaro G, Zechemi F, Pellicelli AM, et al. Long term efficacy of interferon alpha 2b and Lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicentre, randomized trial. J. Hepatol. 2001;35:406-11. |
|70.||Deres K, Schroder CH, Passens A, et al. Inhibition of hepatitis B virus replication by drug induced depletion of the nucleocapsids. Science 2003;299:893-6. |
|71.||Zeuzem S, Carreno V. Interleukin-12 in the treatment of chronic hepatitis B and C. Antiviral Res 2001;52:181-8. [PUBMED] [FULLTEXT]|
|72.||Wang L, Kaneko S, Honda M, et al. Approach to establishing a liver targeting gene therapeutic vector using naturally occurring defective hepatitis B viruses devoid of immunogenic T cell epitope. Virus RES.2002;85:187-97. |
|73.||Core working party for Asia Pacific consensus on Hepatitis B and C. Consensus statement on the management of Hepatitis B and C in the Asia Pacific region. J Gastroenterol Hepatol 2000;115:825-41. |
|74.||Proceedings of the EASL international consensus conference on Hepatitis B. Hepatol 2003;38:533-40. |
Subrat Kumar Acharya
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110 029
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2]
| Article Access Statistics|
| Viewed||7280 |
| Printed||490 |
| Emailed||1 |
| PDF Downloaded||601 |
| Comments ||[Add] |