|Year : 2004 | Volume
| Issue : 1 | Page : 153-198
|Management of HBV infection in decompensated liver disease
Sudeep Khanna, Arun Kumar
Department of Gastroenterology, Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases, New Delhi, India
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|How to cite this article:|
Khanna S, Kumar A. Management of HBV infection in decompensated liver disease. Hep B Annual 2004;1:153-98
Chronic hepatitis B virus (HBV) infection is a major global public health problem with an estimated 1 million deaths per year worldwide from HBV-related hepatocellular carcinoma (HCC) and liver failure., Liver transplantation is the ultimate cure for end-stage liver disease and HCC, but the majority of patients with advanced hepatitis B worldwide do not have access to or are ineligible for liver transplantation., Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae during their lifetime. The average HBsAg carrier rate in India is around 4%, placing India in the intermediate range for hepatitis B endemicity. Out of 400 million hepatitis B virus (HBV) carriers worldwide, roughly 36 millions are in India alone. Hepatitis B e antigen (HBeAg) positivity, which denotes viral replication and high infectivity, has been reported in 7.8% to 47% of adult HBV carriers in different regions of India with wide variations in social, economic and health factors. In India, HBV infection was responsible for chronic hepatitis either alone or in association with hepatitis D virus (HDV) in nearly 70% of the cases. As high as 80% of cases of cirrhosis of the liver are due to chronic HBV infection. On the other hand, about 61.3% of patients with hepatocellular carcinoma seen at Madras, were positive for markers of HBV infection. The aim of this article is to briefly review the epidemiology of HBV infection, provide an update on the use of terms and classification of HBV infection, briefly discuss management of chronic hepatitis B and review at length the management of patients with decompensated HBV cirrhosis with an emphasis on the use of antiviral agents.
Epidemiology of Hepatitis B
HBV infection is prevalent world wide. HBV is especially endemic in Asia, the South Pacific Region, sub-Saharan Africa, in certain indigenous population groups residing in the Arctic (Alaska, Greenland, and Northern Canada), Australia, New Zealand, and populations in South America and the Mid East.,, In developed countries HBV infection is seen in immigrants from endemic areas, homosexuals, intravenous drug abusers, and promiscuous population. In China and sub-Saharan Africa, HCC associated with HBV is one of the leading causes of cancer in men., The risk of developing chronic HBV infection after acute exposure ranges from 90% in newborns of HBeAg-positive mothers to 25% to 30% in infants and children under 5 and less than 10% in adults.,, Immunosuppressed patients are more likely to develop chronic HBV infection after acute infection. Group of people who should be tested for HBV infection include persons born in hyperendemic areas, homosexuals, intravenous drug users, dialysis patients, HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons. In these patients, testing for HBsAg and antibody to HBsAg (anti-HBs) should be performed. Seronegative persons should be vaccinated while HBsAg positive persons should be evaluated for need of antiviral therapy.
Three different serologic patterns of chronic HBV infection have been identified. Pattern 1 is seen in Asia, including India and the South Pacific Islands, where almost 50% of chronic HBV infection is a result of perinatal transmission. In this group, HBeAg persists for a longer time and seroconversion does not occur in most persons until later in adulthood., A large majority of these individuals are HBeAg-positive and have high serum HBV DNA but normal ALT levels., These patients are considered to be in the "immune tolerant" phase. A large number of these patients develop pattern 2 of chronic HBV infection in later life., Pattern 2 is seen in sub-Saharan Africa, Alaska, and Mediterranean countries where transmission of HBV usually occurs from person to person in childhood., In these populations, most children who are HBeAg positive have elevated ALT levels and seroconversion to anti-HBe is common near or shortly after the onset of puberty. Pattern 3 is observed in individuals who acquired HBV infection during adulthood. This pattern is similar to pattern 2 and is most common in developed countries where sexual transmission is the predominant mode of spread.
Patients with pattern 3 generally have liver disease if HBV DNA level is high. Among adults in Asia with elevated ALT levels and carriers of all ages with childhood or adult-acquired HBV infection HBeAg clearance averages between 8% and 12% per year., The rate of clearance of HBeAg is much lower in Asian children (most of whom have normal ALT levels). It is also very low in immunocompromised subjects. Older age and elevated ALT are predictive of HBeAg clearance., HBeAg clearance may follow an exacerbation of hepatitis, manifested by an elevation of ALT levels., After spontaneous HBeAg seroconversion, 67% to 80% of carriers remain HBeAg negative and anti-HBe positive with normal ALT levels and minimal or no necroinflammation on liver biopsy. This has been referred to as the "inactive carrier state."
The course and outcome of the inactive HBsAg carrier state is usually benign but there are exceptions. Fluctuations in ALT and HBV DNA levels are common during the course of chronic HBV infection. Periodic tests should be performed before patients are labeled as inactive carriers and they should be followed up regularly. Up to 20% of carriers in the inactive state can have exacerbations of hepatitis, as evidenced by elevations of ALT levels to 5 to 10 times the upper limit of normal, with or without seroreversion to HBeAg., Repeated exacerbations or reactivations can lead to progressive fibrosis. HBeAg-negative chronic hepatitis B, characterized by HBV DNA levels detectable by nonamplified assays and continued necroinflammation in the liver, has been reported in all parts of the world but is more common in Mediterranean countries and Asia.,, Most patients with HBeAg-negative chronic hepatitis B harbor HBV variants in the precore or core promoter region.
There are also clinical differences between HBeAg-positive and HBeAg-negative chronic hepatitis B. Patients with HBeAg-negative chronic hepatitis B tend to have lower serum HBV DNA levels (mean 10 5 versus 10 8 copies/mL) and are more likely to run a fluctuating course characterized by persistently elevated or fluctuating ALT levels., Approximately 0.5% of HBsAg carriers will clear HbsAg yearly; most will develop anti-HBs. However, low levels of HBV DNA detectable only by polymerase chain reaction (PCR) assays can be found in up to half of these persons after disappearance of HBsAg. The pathogenic significance of very low levels of HBV DNA is unknown. One population-based study of HBsAg carriers found the incidence of decompensated cirrhosis to be 0.5 per 1,000 years. Prognostic factors for the development of cirrhosis include HBeAg positivity, older age, and elevated ALT levels..
For patients with compensated cirrhosis, the survival is 84% at 5 years and 68% at 10 years. In carriers with decompensated cirrhosis, 5-year survival is only 14%. In patients with compensated cirrhosis, risk factors for decompensation include presence of HBeAg and failure to respond to interferon., Patients with compensated cirrhosis who were HBeAg-negative had significantly better 5-year survival (97%) than those who were HBeAg-positive (72%).
Chances of hepatic decompensation are reduced and survival is prolonged after clearance of HBeAg, whether spontaneous or after antiviral therapy., Risk factors for HCC in patients with chronic HBV infection include male gender, family history of HCC, older age, presence of HBeAg in an adult, history of reversions from anti-HBe to HBeAg, presence of cirrhosis, and coinfection with hepatitis C virus (HCV). Clearance of HBsAg decreases the risk of hepatic decompensation and probably HCC but HCC can occur in long-term carriers who have cleared HBsAg.
Definitions and diagnostic criteria used in HBV infection
[Table - 1][Table - 2] highlight the various definitions and diagnostic criteria for various stages of chronic hepatitis B infection. The evaluation of patients with HBV infection is given in [Table - 3]. HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3 to 6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment. Patients who meet the criteria for chronic hepatitis B (serum HBV DNA >10 5 copies/mL and persistent or intermittent elevation in ALT levels) should be evaluated further with a liver biopsy. Patients in the inactive HBsAg carrier state should be monitored with periodic liver chemistries every 6 to 12 months, as the silent liver disease may become active after many years.
Counselling and Prevention of Hepatitis B
Patients with chronic HBV infection should be counselled regarding lifestyle modifications and prevention of transmission. There are no specific dietary restrictions that have been shown to have any effect on the progression of chronic hepatitis B. Heavy use of alcohol (>40 g/d) has been associated with higher ALT levels, development of cirrhosis and early HCC. Carriers of HBV should be counselled regarding the risks of transmission to others. Counselling should include precautions to prevent sexual transmission, perinatal transmission, and risk of inadvertent transmission via environmental contamination from spillage of blood. Household members are at increased risk of HBV infection and therefore should be vaccinated if they test negative for HBV serologic markers (HBsAg and antiHBs). Patients on dialysis should be immunized against HBV. Vaccination of sexual partners is effective in preventing sexual transmission of HBV. Barrier protection methods should be used if the sexual partner is not completely vaccinated. HBsAg-positive women who are pregnant should be counselled to make sure they inform their health care providers so that hepatitis B immune globulin (HBIG) and hepatitis B vaccine can be administered to their newborn immediately after delivery. Postvaccination testing should be performed 3-9 months after the last dose in infants of carrier mothers and 1-2 months after the last dose in other persons. Follow-up testing of vaccine responders is recommended annually for chronic hemodialysis patients.
As HBV can survive on environmental surfaces for at least 1 week, carriers should be advised to cover open cuts and scratches and clean up blood spills with bleach. The Centers for Disease Control and Prevention recommends that those HBV carriers who are health care workers and are HBeAg-positive should not perform invasive procedures without prior counselling and advice from an expert review panel. These circumstances would include notifying prospective patients of their HBV status prior to procedures.
Patients with HBV cirrhosis should undergo HCC surveillance using a combination of serum alpha-fetoprotein (AFP) and ultrasound imaging every 6 months., This strategy may detect HCC at an early stage, but both AFP and ultrasound surveillance have low sensitivity and specificity and ultrasound is operator dependent. In addition, this approach has not been prospectively proved to improve survival, and the cost-effectiveness of HCC surveillance remains controversial., Some investigators argue against HCC surveillance in patients with decompensated cirrhosis, as treatment options are limited unless the patient is a candidate for liver transplantation. HCC surveillance is important in liver transplant candidates as the presence of early HCC may change the priority for transplantation. Development of other tumor markers such as des-gamma-carboxyprothrombin that may improve the early detection of HCC is critical in improving survival of patients with HCC.
HBV carriers at high risk for HCC such as men over 45 years, persons with cirrhosis, and persons with a family history of HCC, should be screened periodically with both AFP and US. While there are insufficient data to recommend routine screening in low-risk patients with chronic HBV infection, periodic screening for HCC with AFP in carriers from endemic areas should be considered.
General Medical Management of Patients with Decompensated HBV-Cirrhosis
Assessment of Disease Severity and Prognosis
The severity of HBV cirrhosis can be determined by periodic clinical examination and measurement of serum albumin, bilirubin, and prothrombin time. The Child-Turcotte-Pugh (CTP) score and Model for End Stage Liver Disease (MELD) score are two commonly used indices of liver disease severity in patients with cirrhosis [Table - 4]. The CTP score was developed as a means of stratifying preoperative risk of patients with cirrhosis for portal-systemic shunt surgery. It consists of three laboratory parameters: albumin, bilirubin, and prothrombin time, and two subjective clinical parameters, ascites and hepatic encephalopathy. The CTP score is simple, intuitive to most clinicians, and easy to calculate at the patient's bedside. However, the CTP score has been shown to be a poorer predictor of short-term survival in patients with cirrhosis than the MELD score. In addition, the CTP score provides a limited range of categorical scores (5 to 15) and does not differentiate patients with moderate liver failure from those with advanced liver failure. For example, patients with serum bilirubin levels of 4 and 40 mg/dL are assigned the same CTP score. Moreover, the CTP score includes two clinical parameters that require subjective assessment.
The MELD score was initially developed to predict short-term mortality following transjugular intrahepatic portosystemic shunt (TIPS) placement and was subsequently refined to predict short-term mortality in patients with cirrhosis of varying etiology. It has also been used to predict waiting list mortality among patients listed for liver transplantation. The MELD score utilizes objective and standardized laboratory parameters (i.e., serum bilirubin, prothrombin time [International Normalized Ratio, INR], and creatinine) over a broader range of possible values to provide a more dynamic assessment of liver disease severity. However, the formula for calculating the MELD score is cumbersome and cannot be used at the bedside without the help of a calculator. In addition, the accuracy of MELD scores in predicting the natural history of patients with decompensated HBV cirrhosis has not been prospectively determined.
Indications for Referral for Liver Transplant Evaluation
Liver transplantation is a well-established means of treating patients with advanced, irreversible liver failure for which there is no alternative treatment. All patients with a complication of portal hypertension such as ascites, encephalopathy, or variceal bleeding as well as patients with cirrhosis and a CTP score >/= 7 should be referred for liver transplant evaluation. In addition, selected patients with unresectable HCC that is less than 5 cm in maximal diameter should be referred for liver transplant evaluation.
Assessment of HBV Replication
Patients with decompensated HBV-cirrhosis tend to have low or undetectable HBV replication. Most patients are HBeAg negative, and serum HBV DNA is frequently undetectable with hybridization assays. However, some patients continue to have high levels of HBV replication with serum HBV DNA detectable by hybridization assays. Suppression of HBV replication with antiviral agents may decrease hepatic necroinflammation and prevent further progression of liver disease. Because of fluctuations in HBV replication over time, serum HBV DNA levels should be rechecked at least every 6 months in patients with undetectable serum HBV DNA at presentation to determine whether antiviral therapy is indicated., An arbitrary cutoff HBV DNA value of 10 5sub copies/mL was chosen as an indication for treatment of chronic hepatitis B. Whether patients with decompensated cirrhosis and lower serum HBV DNA levels or detectable HBeAg alone will benefit from antiviral therapy is unclear.
Preventing Further Liver Damage
Patients with underlying liver disease have an increased risk of developing fatal hepatic failure when they develop superimposed hepatitis A. Therefore, in developed countries, all patients with chronic HBV should receive hepatitis A vaccination., Hepatitis A vaccine is highly immunogenic and has been shown to elicit protective antibody response in more than 90% of patients with compensated liver disease, but the immune response to hepatitis A vaccine in patients with decompensated cirrhosis has not been examined. This may not be true for developing countries like India where most adult patients are already exposed to HAV and have protective antibodies. There is agreement that complete abstinence from alcohol should be recommended to patients with decompensated cirrhosis. In addition, potentially hepatotoxic drugs should be avoided., Medications that may increase the risk of gastrointestinal bleeding or renal insufficiency such as nonsteroidal anti-inflammatory agents should also be avoided.
Endoscopic screening for esophageal and gastric varices is recommended in all patients with cirrhosis every 2 years. Patients with large varices (i.e., grade 3 or 4) should be considered for primary prophylaxis of variceal bleeding with beta-blockers or endoscopic variceal banding. Patients with a history of prior variceal bleeding should receive secondary prophylaxis with endoscopic sclerotherapy or band ligation and beta-blockers. Selected patients with uncontrolled or recurrent variceal bleeding may require placement of a TIPS. Patients with a history of spontaneous bacterial peritonitis should receive antibiotic prophylaxis. However none of these interventions have shown improvement in mortality rates in patients with decompensated cirrhosis. Therefore, unless the process of liver damage can be arrested or reversed, liver transplantation may still be required.
Anti-viral treatment of Chronic Hepatitis B
The aims of anti-viral treatment in chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. Responses to antiviral therapy of chronic hepatitis B have been categorized as biochemical (BR), virologic (VR), or histologic (HR), and as on-therapy or sustained off-therapy [Table - 5].
Interferon, lamivudine and adefovir are approved for treatment of HBV infection.O
A) Interferon (IFN)
The efficacy of IFN is limited to a small percentage of highly selected patients.
1. HBeAg-positive chronic hepatitis B with the following:
a. Persistent or intermittent elevation in ALT. A meta-analysis of 15 randomized controlled trials involving more than 800 adult patients found that virologic response was significantly more in IFN treated patients versus controls. High pretreatment ALT and lower levels of serum HBV DNA are the most important predictors of a response to IFN therapy.,
b. Normal ALT. Infection acquired in the perinatal period is usually associated with normal ALT level. The virologic response to IFN therapy is observed in less than 10% of these patients.,,
c. Asian patients. The response to IFN therapy is the same as in white patients if the ALT levels are elevated. Patients with normal ALT have a poor response.
d. Children. The efficacy and adverse effects of IFN were found similar to that seen in adults in a meta-analysis involving almost 250 children with chronic hepatitis B.
2. HBeAg-negative chronic hepatitis B
Undetectable serum HBV DNA by unamplified assays and normalization of ALT level is defined as response to treatment in these patients. The trials on these patients are heterogenous as regards the disease, the virus and the study designs. Analyses of the results of trials of IFN in HBeAg-negative chronic hepatitis B are complicated by the heterogeneity of not just of the disease, but also the virus and study designs. Results of four randomized controlled trials involving a total of 86 IFN treated patients and 84 controls showed that the 12-month sustained response rates varied from 10% to 47% among the treated patients versus 0% in the controls.,,,, The only factor predicitive of reponse was a longer duration of IFN treatment (12 vs. <6 months)., Unfortunately fifty percent of the responders in this group relapse on discontinuation of therapy, and relapses can occur after up to 5 years post-therapy. Still longer duration of therapy, up to 24 months may improve the rate of sustained response. Long-term follow-up shows that 15% to 50% of sustained responders clear HBsAg.,
3. Nonresponders to IFN treatment
Most studies found that retreatment of IFN nonresponders with IFN alone was associated with a very low rate of response.
4. HBV DNA-positive clinical cirrhosis
IFN therapy is associated with a flare in ALT level in almost one third of HBeAg positive patients with CHB. This flare is believed to be due to IFN induced immune-mediated lysis of infected hepatocytes. In patients with compensated cirrhosis, the flare may precipitate hepatic decompensation in up to 1% of these patients. In compensated cirrhosis, IFN is usually safe and may be effective in these patients., In clinical trials of patients with HBeAg-positive chronic hepatitis, up to 60% of the patients who were included had histologic cirrhosis.,
IFN has been associated with life-threatening hepatitis flares and infectious complications in prospective trials of patients with decompensated HBV cirrhosis even when used in very low doses., For example, despite the use of reduced doses of IFN in over 50% of the patients (i.e., 6 to 15 MU per week), 28% of patients developed bacterial infections and 50% developed hepatitis flares. Therefore, IFN is contraindicated in patients with clinically evident HBV cirrhosis (i.e., ascites, encephalopathy, CTP score >/= 7, or significant neutropenia/thrombocytopenia).
In an Indian study by Sarin et al. patients receiving IFN three times a week for four months versus placebo were followed up for 12 months after completion of therapy. In the interferon treated group, complete response (loss of HBV-DNA and HBeAg) was significantly higher than spontaneous clearance in the control group (50% versus 4.8%; p < 0.05). Seroconversion to anti-HBe was seen in 35% of the treated and 4.8% of the control group (p < 0.05) at 4 months; it was noticeably higher in patients with chronic hepatitis than in those with cirrhosis. In the responders, alanine aminotransferase levels nearly normalized. One year after interferon therapy, HBeAg and HBV-DNA clearance was observed in 65% of patients, with HBsAg clearance in 15%. Reactivation was not seen in any patient. Side-effects were transient and minimal. Thus it was concluded that low-dose recombinant alpha interferon therapy is quite effective and safe in Asian Indians with chronic liver disease due to hepatitis B infection. Approximately 15% of Indian patients with hepatitis B virus (HBV) related chronic liver disease (CLD) have infection with precore mutant forms. In another Indian study by Guptan et al, eighteen patients with biopsy proven CLD and precore mutant HBV infection and HBV-DNA positivity were included and Interferon alpha 2b was administered in a dose of 3 MIU on alternate days for 4 months. This study concluded that IFN therapy was beneficial, albeit to a limited extent in HBV precore mutant-related chronic liver disease in Asian Indians, but it was ineffective in eliminating the mutant HBV infection.
IFN is administered subcutaneously. The recommended dose for adults is 5 MU daily or 10 MU thrice weekly and for children 6 MU/m 2 thrice weekly with a maximum of 10 MU. The recommended duration of treatment for patients with HBeAg positive chronic hepatitis B is 16 to 24 weeks. Available literature suggests that patients with HBeAg-negative chronic hepatitis B should be treated for at least 12 months and longer duration of treatment may increase the rate of sustained response.
Pegylated interferon (PEG-IFN)
Results of a phase II trial suggest that the efficacy of pegylated IFN may be greater than that of standard IFN. Clinical trials of pegylated IFN singly and in combination with lamivudine in patients with HBeAg positive and HBeAg negative chronic hepatitis B are ongoing. The role of pegylated IFN in the treatment of chronic hepatitis B and the optimal dose and duration remain to be determined.
Long-Term Outcome of IFN Treated Patients
Eighty to ninety percent of patients who clear HBeAg on IFN therapy continue to be HBeAg negative after a follow-up period of 4 to 8 years., However, HBV DNA remained detectable in the serum from most of these patients when tested by amplification assays. Studies from Europe and the United States have reported delayed clearance of HBsAg occurring in 12% to 65% of patients within 5 years of HBeAg loss. This has however not been reported in studies from China. Residual hepatic injury is often present even in patients with a sustained virologic response, though the necroinflammation decreases. Although studies have shown that the 5-year cumulative rates of HBeAg clearance are similar in treated patients and controls, IFN treated patients are more likely to have normal ALT levels and to clear HBsAg.
There is scanty data available on effect of IFN in decreasing progression to cirrhosis or HCC. An 8-year follow-up study from Taiwan found that treated patients had a lower incidence of HCC (1.5% vs. 12%; p=0.04) and a higher survival rate (98% versus 57%; p=0.02). In another study, three patients with CHB who had clinical, biochemical and histological evidence of cirrhosis, underwent treatment with IFN or lamivudine and had follow-up liver biopsy while in clinical, biochemical, and virologic remission. The mean interval between biopsies was 5.5 years. The mean ALT level decreased from 113.7 to 28.3 U/L. The mean bilirubin level decreased from 2.4 to 0.9 mg/dL, and the mean prothrombin time decreased from 16.3 to 12.3 seconds. The mean Child-Pugh score decreased from 8 to 5. The mean fibrosis score decreased from 5.8 to 0.5 ( p = 0.004), and the mean grading score decreased from 10.8 to 3.2 ( p = 0.017).
Data on long-term outcome of patients treated for HBeAg negative chronic hepatitis B showed that 20-50% of long-term responders, defined by normal ALT levels and undetectable HBV DNA by hybridization assay cleared HBsAg after 5 years of follow-up., In addition, long-term responders appear to have reduced risks of progression to cirrhosis, HCC and liver-related deaths.,
The adverse effects of IFN therapy include flu-like symptoms, fatigue, leucopenia, and depression. Tolerance develops to the flu-like symptoms after the first week in most patients. Fatigue, anorexia, hair loss, and mood swings can persist throughout the course of treatment and for a few weeks after discontinuation of therapy. IFN may also unmask or exacerbate underlying autoimmune disorders.
Lamivudine is the (-)enantiomer of 2'-3' dideoxy-3'-thiacytidine. Incorporation active triphosphate (3TC-TP) into growing DNA chains results in premature chain termination and thereby inhibits HBV DNA synthesis.
Efficacy in Various Categories of Patients
1. HBeAg-positive chronic hepatitis B
a. Persistent or intermittent elevation of ALT.
Treatment with lamivudine for 1 year in treatment naοve patients has shown HBeAg seroconversion and loss of serum HBV DNA based on non-PCR assays in 16% to 18% of patients compared with 4% to 6% of untreated controls., Histological improvement (reduction in necroinflammatory score greater than or equal to 2 points) was observed in 49% to 56% of treated patients and in 23% to 25% of controls. The multicenter Asian study showed that HBeAg seroconversion rates increased with the duration of treatment from 17% at 1 year to 50% at 5 years. Pretreatment ALT has been found to be the most important predictor of response. The higher the value of ALT, the greater is the seroconversion rate.,
b. Normal ALT levels .
HBeAg seroconversion rate after 1 year of treatment is less than 10% in patients with pretreatment ALT levels less than 2 times normal.,
c. Asian patients .
Asians respond similarly to lamivudine as white patients.
d . Children .
Lamivudine has been shown to be safe and efficacious in children with chronic hepatitis B.
2. HBeAg-negative chronic hepatitis B
Lamivudine is efficacious in patients with HBeAg negative chronic hepatitis B.,, Most of the studies have shown a virologic and biochemical response in approximately 70% of the treated patients. Unfortunately, more than 90% of the patients relapsed when treatment was stopped. Also, extending the duration of treatment results in progressively lower rate of response due to the selection of lamivudine-resistant mutants.
3. Nonresponders to IFN treatment
In a multicenter trial which included 238 patients who did not respond to IFN, patients were randomized to receive lamivudine monotherapy for 52 weeks, lamivudine for 8 weeks followed by a combination of lamivudine and IFN for next 16 weeks, or no treatment. Patients in the lamivudine only group had HBeAg seroconversion rate of 18% which was higher than the other two groups, though this difference was not significant. These data suggest that patients who failed to respond to IFN do not differ in their reponse to lamivudine as compared to therapy naοve patients and that a combination of IFN and lamivudine does not confer any additional benefit.
4. HBsAg-positive decompensated cirrhosis
a) Uncontrolled, Open-Label Studies of Lamivudine
Lamivudine has been associated with rapid suppression of HBV DNA to undetectable levels in non-PCR based assays and improvement in biochemical and clinical parameters in both controlled and uncontrolled studies of patients with decompensated HBV cirrhosis,,,,, [Table - 6]. Yao et al reported marked improvements in CTP scores in 13 patients in their study and 5 of the patients were removed from the liver transplant waiting list because of clinical improvement. In another study from India which had 18 patients, lamivudine was associated with significant improvements in CTP scores and serum ALT levels after a mean treatment duration of 18 months. The issue that is unsettled is whether some of the patients in this study had hepatic decompensation secondary to a recent hepatitis flare as clinical and biochemical improvement upon viral suppression is more likely in this setting than in patients with hepatic decompensation secondary to end-stage liver disease.
In another report of 35 Canadian patients with decompensated HBV cirrhosis treated with lamivudine, there was objective improvement in liver disease severity in the majority of treated patients. Although five patients died and seven were transplanted within the first 6 months of lamivudine treatment, the majority of the remaining 23 patients experienced a gradual but marked improvement in biochemical parameters and CTP score. Three patients developed lamivudine resistance.
In another study by Perrillo et al, seventy seven HBsAg-positive patients on liver transplant list were given lamivudine. Stabilization or improvement in liver disease severity was seen in 27 patients without transplant who were treated for a median of 28 months. The actuarial survival observed in these patients appeared to be comparable to that of noncontemporaneous controls with untreated compensated HBV cirrhosis and better than the survival in untreated historical controls with decompensated HBV cirrhosis. As the number of patients was small and the controls were non contemporaneous controls, it is difficult to conclude that lamivudine improved the survival of these patients.
A prospective study from North America of lamivudine treatment included 154 HBsAg-positive patients with decompensated HBV cirrhosis. In more than 80% of treated patients, suppression of HBV DNA to undetectable levels by the branched-chain DNA (bDNA) assay within 8 weeks of initiating antiviral treatment was noted. Also, 27 of 78 (35%) patients lost previously detectable HBeAg and 17 of 83 (20%) patients acquired anti-HBe. The actuarial 3-year survival of all patients and those who survived beyond the first 6 months of treatment was 72 and 88%, respectively.
b) Controlled, Open-Label Studies of Lamivudine
In an effort to clearly define the potential benefits of lamivudine therapy, two retrospective, controlled trials have been conducted., Yao et al reported that liver transplant candidates receiving lamivudine were less likely to undergo transplantation than untreated historical controls who were matched for age, gender, and illness severity at the time of listing (35% vs. 74%, P = 0.04). In addition, a significantly greater proportion of the lamivudine-treated patients experienced an improvement >/= 3 points in their CTP score compared with the untreated historical controls (61% vs. 0%; p=0.0001). However, other interventions that may have prolonged transplant-free survival (e.g., TIPS, use of prophylactic antibiotics) and changes in the organ allocation scheme may have contributed to the observed improvements in clinical outcomes.
Another study evaluated the role of lamivudine in 309 North American HBsAg-positive liver transplant candidates. In this retrospective study, the outcomes of 162 lamivudine-treated patients and 147 untreated patients were compared. Although the two groups were comparable in liver disease severity before treatment, the treated patients were more likely to have evidence of active HBV replication. Overall, the actuarial pretransplant and transplant-free survival was similar in the lamivudine-treated and untreated patients and lamivudine had no apparent effect on liver disease severity in patients who underwent transplantation. However, among the patients who were still awaiting transplantation, lamivudine appeared to stabilize or improve liver disease severity.
Both of these studies suggest that lamivudine can result in clinical improvement in selected patients with decompensated HBV cirrhosis, but one study used historical controls and the other used nonrandomized controls. Because of the apparent clinical benefit of lamivudine and the acuity of patients with decompensated cirrhosis, it is unlikely that an adequately powered, prospective randomized controlled trial will ever be conducted.
c) Overall Assessment of Safety, Efficacy, and Outcomes
In all of the studies just cited, lamivudine was well tolerated with no reports of mitochondrial toxicity or other unexpected adverse events. However, most studies included a small number of patients with a short duration of follow-up and none of the studies included a parallel randomized control group. Some studies included both transplant and nontransplant candidates with heterogeneous inclusion criteria and therapeutic end points., Despite all these methodological problems, it is clear that lamivudine is safe in patients with decompensated HBV cirrhosis. It is also clear that not all patients with decompensated HBV cirrhosis will benefit from lamivudine treatment. Most studies found that clinical improvement typically takes 3 to 6 months and lamivudine may not be able to slow disease progression in patients who present late.
In one study of 154 North American patients receiving lamivudine, a biphasic survival pattern was observed with most deaths occurring within 6 months of starting treatment. In this study, multivariate analysis found that pretreatment serum bilirubin, creatinine, and detectable HBV DNA by bDNA assay were independently associated with 6-month mortality. Another study found that the only significant predictor of pretransplant mortality was the laboratory components of the CTP score. These data demonstrate that the pretreatment severity of liver disease is a more important predictor of early mortality than antiviral response in patients with decompensated HBV cirrhosis. If this is validated in other populations of patients, pretreatment risk profiles may help identify patients who may survive for long periods with antiviral therapy versus those who will require urgent liver transplantation. An important role of lamivudine will be to improve or stabilize liver disease in patients who are not transplant candidates or have no access to liver transplantation. For these patients, lamivudine may represent the only hope for better quality or longer duration of survival, decreased hospitalizations, and reduced utilization of health care resources.
d) Lamivudine Resistance
Lamivudine treatment is associated with the development of drug-resistant mutants in immunocompetent patients at a rate of 17, 39, and 57% after 1, 2, and 3 years of treatment respectively. In patients with decompensated HBV cirrhosis receiving lamivudine therapy, the reported annual rate of viral resistance varied from 7 to 21% [Table - 6]. An analysis of the pooled data for 154 patients with decompensated HBV cirrhosis who received long-term lamivudine treatment demonstrated that 22 of the 81 patients (27%) with detectable HBV DNA before treatment developed evidence of virologic breakthrough after a median treatment duration of 21 months.
Lamivudine resistance is usually seen after 6 months of continuous treatment and is clinically manifested by the reappearance of HBV DNA after its initial suppression with a variable increase in serum ALT levels. The most common mutation involves the YMDD motif of the HBV polymerase gene (M204V/I, formerly M552V/I) and is frequently accompanied by another mutation in an upstream region (L180M, formerly L528M). Although in vitro studies showed that YMDD mutants are less replication fit than wild-type HBV, some patients may experience a hepatitis flare with the emergence of YMDD mutants resulting in progressive worsening of liver disease. In one study, serum albumin and bilirubin levels remained similar in the patients with and without resistance but serum aminotransferase levels were higher in the patients with lamivudine resistance. Although the overall mortality was similar in the two groups of patients, breakthrough infection contributed to two of the observed deaths in patients with resistance. Additional mutations in the HBV genome have also been identified in some patients receiving prolonged lamivudine therapy, which may restore the replication fitness of HBV.
A clinical diagnosis of lamivudine resistance is usually based on redetection of previously undetectable HBV DNA on two consecutive visits in a compliant patient. Ideally, genotypic analysis should be performed to confirm the presence of lamivudine-resistant mutants. As diagnostic assays for lamivudine-resistant mutants become commercially available, there may be a role for resistant mutant monitoring, particularly in patients with decompensated HBV-cirrhosis. Monitoring would enable timely initiation of therapy with antiviral agents that have proven efficacy against lamivudine-resistant HBV.
e) Liver Transplantation
Liver transplantation for patients with decompensated HBV cirrhosis and HCC is associated with excellent patient and graft survival rates with the use of long-term, high-dose hepatitis B immunoglobulin (HBIG) immunoprophylaxis. However, recurrent HBV infection still occurs in 20 to 40% of patients who receive HBIG alone. Multivariate analysis showed that the presence of HBeAg or serum HBV DNA before transplantation was associated with a greater likelihood of post-transplantation HBV recurrence. Suppression of HBV replication prior to transplantation may reduce the risk of HBV recurrence after transplantation, and maintenance of antiviral therapy after transplantation may further diminish the risk of HBV recurrence.
Several studies have demonstrated that lamivudine monotherapy can decrease the rate of recurrent HBV infection after transplantation, but the efficacy diminishes over time due to the selection of drug-resistant mutants. In the North American multicenter study, the overall 1- and 3-year post-transplantation recurrence rates were 32 and 41%, respectively. However, patients with active HBV replication prior to treatment had a higher recurrence rate at 3 years than nonreplicators (60 versus 0%). These data confirm the strong association between recurrent hepatitis B after transplantation and the presence of detectable HBV replication before transplantation.
HBIG Plus Lamivudine Prophylaxis
As the rate of breakthrough infection with lamivudine alone is high, most transplant centers use both high-dose HBIG and lamivudine prophylaxis. In a retrospective analysis of 59 patients treated with high-dose HBIG plus lamivudine, none of the patients experienced HBV recurrence with a mean post-transplantation follow-up of 15 months. In an attempt to reduce the costs, several investigators have also reported the use of lower doses of HBIG administered intramuscularly in combination with lamivudine. In all of these studies, recurrence rates less than 10% have been reported.
With the increasing use of lamivudine before transplantation, concerns regarding patients with lamivudine-resistant HBV undergoing transplantation have been raised. Because the HBV surface gene completely overlaps with the polymerase gene, patients with lamivudine-resistant HBV may have reduced binding affinity to HBIG. Two studies involving five patients with lamivudine resistance before transplantation demonstrated recurrent HBV soon after transplantation despite HBIG prophylaxis., The role of indefinite high-dose HBIG after transplantation and treatment with newer antiviral agents in lamivudine resistant HBV requires further study.
f) Durability of Response
Seventy seven percent of patients continued to be HBeAg seroconverted after a median follow-up of 37 months (range, 5-46 months). The ALT levels were normal in 25 (63%) patients. In addition, 8 (20%) patients had HBsAg seroconversion. In Asian patients, lower rates of durable response have been reported., Most patients who relapsed did so within the first 12 months after cessation of treatment. The duration of additional lamivudine therapy after HBeAg seroconversion and pretreatment serum HBV DNA levels were independent predictors of post-treatment relapse.
g) Dose Regimen
The recommended dose for adults with normal renal function is 100 mg orally daily. The recommended dose for children is 3 mg/kg/d with a maximum dose of 100 mg/d. Dose reduction is necessary for patients with renal insufficiency. Patients with HIV coinfection should be given 150 mg twice daily along with other anti-retroviral therapies.The end point of treatment for HBeAg-positive patients is HBeAg seroconversion. Lamivudine should be administered for 1 year. Liver function test and quantitative HBV DNA levels (amplification technique) should be monitored every 3 months while on therapy, and HBeAg and anti-HBe tested at the end of 1 year of treatment and every 3-6 months thereafter. Treatment may be discontinued in patients who have completed 1 year of treatment and have persistent HBeAg seroconversion and serum HBV DNA undetectable by non-PCR assays on more than one occasion determined 2-3 months apart. Post-treatment relapse appears to be reduced in patients if treatment is continued for an additional 3-6 months after confirmed HBeAg seroconversion. In patients who have breakthrough infection, lamivudine-resistant mutants should be looked for as approximately 30% of breakthrough infection are due to non-compliance, and resumption of lamivudine will result in viral suppression. One of the options after emergence of lamivudine resistant strains is to stop lamivudine. This is a reasonable option in immunocompetent patients without cirrhosis with close monitoring of ALT levels and HBV DNA. Discontinuation of lamivudine should not be attempted in patients with underlying cirrhosis unless they have already been placed on adefovir. Only if ALT and HBV DNA levels continue to remain significantly lower than pretreatment values should lamivudine be continued in persons who have developed resistance. In patients with lamivudine resistance and worsening liver disease, decompensated cirrhosis, recurrent hepatitis B after liver transplant and on immunosuppressive therapy, a switch to or addition of adefovir is the best option.
After stopping lamivudine all patients should be closely monitored for at least 1 year as acute exacerbations of liver disease can occur after discontinuation of lamivudine therapy. This exacerbation is also seen in HBeAg seroconverted patients. Reinstitution of lamivudine treatment is usually effective in controlling the exacerbations in these patients. The end point of treatment for HBeAg-negative chronic hepatitis B is unknown.
Adefovir is a nucleotide analogue of adenosine monophosphate. It can inhibit both the reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA causing chain termination. Adefovir dipivoxil is an orally bioavailable pro-drug of adefovir.
Efficacy in various categories of patients
- HBeAg positive chronic hepatitis B - Five hundred and fifteen patients in the Phase III trial were randomized to receive 10 or 30 mg of adefovir or placebo for 48 weeks. Histologic response (defined as =2 point decrease in Knodell necroinflammatory score with no worsening of fibrosis) was seen in 25%, 53%, and 59% patients who received placebo, adefovir 10 mg and 30 mg, respectively (p<0.001). HBeAg loss was seen in 11%, 24%, and 27% (p<0.001 for both treatment groups compared to placebo), and HBeAg seroconversion was seen in 6%, 12%, and 14% (not significant) patients in the placebo, 10 mg and 30 mg group respectively. Serum HBV DNA levels decreased and ALT normalized in a significantly more number of patients in the tretment group versus placebo group. Eight percent of patients in the adefovir 30 mg dose group had nephrotoxicity (defined as increase in serum creatinine by 0.5 mg/dL above the baseline value on two consecutive occasions).
- HBeAg negative chronic hepatitis - Forty eight weeks of therapy with Adefovir 10 mg per day has been shown to have higher rates of response than placebo as regards to histologic response, normalization of ALT and undetectable serum HBV DNA by PCR assay.
- Children - Adefovir has not been studied in children.
- Decompensated cirrhosis - Adefovir has also been studied in more than 100 patients with lamivudine resistance and decompensated HBV-cirrhosis., The majority of treated patients experienced a 3 to 4 log 10 drop in serum HBV DNA levels and a stabilization or improvement in their liver disease. Although adefovir in 10-mg doses has not been shown to result in nephrotoxicity in patients with compensated liver disease, 28% of patients with decompensated HBV cirrhosis had an increase in serum creatinine > 0.5 mg/dL after 48 weeks of treatment. In the absence of a control group, it is not possible to determine whether the adverse effect on renal function was related to adefovir or the underlying liver disease. Until this concern is clarified, adefovir should not be used as a first-line treatment in patients with decompensated HBV-cirrhosis. However, for patients with worsening liver disease secondary to lamivudine resistance, use of adefovir as a salvage therapy is clearly indicated. An ongoing study of 58 patients with lamivudine-resistant compensated hepatitis B followed up for 16 weeks demonstrated that adefovir alone has antiviral efficacy similar to that of a combination of adefovir and lamivudine. These data suggest that patients with lamivudine resistance may discontinue lamivudine when adefovir is initiated. However, additional follow-up data are needed before a recommendation can be made regarding the need to continue lamivudine after initiation of adefovir in patients with decompensated HBV-cirrhosis.
- Lamivudine-resistant hepatitis B - Adefovir is effective in suppressing lamivudine-resistant HBV mutants.
Durability of Response
Only minimal data on the durability of response is available.
No resistance has been shown during the first year of therapy. Two out of seventy nine patients were found to have resistance to adefovir during the second year of therapy in the trial on HBeAg negative patients.
The recommended dose for adults with normal renal function (creatinine clearance >50 mL/min) is 10 mg orally daily. Dosing interval should be increased in patients with renal insufficiency. It is not clear how long should adefovir be continued. Further studies are needed to determine the optimal duration of therapy and to establish the efficacy and safety of long-term adefovir treatment.
Entecavir, another potent nucleoside analogue, also has demonstrated activity against both wild-type HBV and, to a lesser extent, lamivudine-resistant HBV.,, Entecavir is currently being evaluated in phase III clinical trials, and long-term safety and efficacy data with entecavir are awaited. Although one pilot study involving a small number of liver transplant recipients with lamivudine-resistant HBV appeared promising, recommendations on the use of entecavir in patients with decompensated HBV cirrhosis cannot be made at this time.
Tenofovir is a nucleotide analogue approved for the treatment of HIV infection. It has in vitro activity against both wild-type and lamivudine-resistant HBV. A report on 5 patients with HBV and HIV coinfection demonstrated a 4 log 10 drop in HBV DNA levels during 24 weeks of treatment. Additional studies are needed to establish the long-term efficacy of tenofovir in the treatment of patients with wild-type and lamivudine-resistant hepatitis B and its safety in patients with decompensated HBV cirrhosis.
The prognosis for patients with untreated HBV cirrhosis is influenced by the presence of active viral replication and biochemical or clinical decompensation at presentation. Suppression of HBV replication may reduce liver injury and slow disease progression. Clinical studies have confirmed that lamivudine is safe and effective in suppressing HBV replication in patients with decompensated HBV cirrhosis with resultant stabilization or improvement in liver disease in some patients. However, clinical improvement takes 3 to 6 months. The slow rate of response to lamivudine would favour early initiation of therapy. However, the increased risk of resistance with prolonged therapy and the potential for worsening liver disease and increased risk of HBV recurrence after transplantation would favour delaying therapy, at least in transplant candidates. Patients with decompensated HBV cirrhosis and evidence of active HBV replication (i.e., detectable HBV DNA by non-PCR-based assay or > 10 5sub copies/mL, and HBeAg+) are more likely to derive benefit from lamivudine. However, it remains unclear whether pretreatment serum ALT is a reliable predictor of clinical response in patients with decompensated HBV cirrhosis as it appears to be in patients with compensated chronic hepatitis B.
The goals of antiviral therapy in nontransplant candidates would be to stabilize or improve liver disease severity, improve clinical symptoms and quality of life, and possibly extend survival, although data in support of the last are lacking. In transplant candidates, the optimal time to initiate lamivudine therapy is unclear and its determination should take into account the severity of liver disease, anticipated waiting time for transplantation, and availability of alternative treatments if lamivudine resistance should arise. Close monitoring for breakthrough infection and, if available, mutant analysis should be performed to detect lamivudine resistance so that salvage therapy with adefovir can be initiated. With the approval of adefovir, its role as a first-line therapy in patients with decompensated HBV cirrhosis should be evaluated. The advantage of adefovir is that no resistance has yet been reported, but its long-term safety, especially in patients who are susceptible to renal insufficiency, must be carefully examined.
The availability of safe, orally administered antiviral agents such as lamivudine and adefovir has revolutionized the management of chronic HBV and opened up new treatment options for the large number of patients worldwide with decompensated HBV cirrhosis who previously had a dismal prognosis. However, indiscriminate use of these agents in all patients with chronic hepatitis B should be discouraged. Further studies are needed to optimize the use of these agents either alone or in combination. In addition, research should focus on more effective treatment of patients with chronic HBV to prevent them from progressing to decompensated HBV cirrhosis.
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Department of Gastroenterology, Pushpawati Singhania Research Institute for Liver, Renal and Digestive Diseases, New Delhi
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]
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