AIMS OF TREATMENT [21]

• The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC.
• Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology.
Treating chronic hepatitis B [21]:
Currently, six therapeutic agents have been approved for the treatment of adults with chronic hepatitis B.
For HBeAg-positive patients, viral suppression with currently approved treatments can be sustained in 50%-90% patients if treatment is stopped after HBeAg seroconversion is achieved.
For HBeAg-negative patients, relapse is frequent even when HBV DNA has been suppressed to undetectable levels by PCR assays for more than a year; thus, the endpoint for stopping treatment is unclear.
While IFNs are administered for predefined durations, NAs are usually administered until specific endpoints are achieved.
patients with minimal disease and those who are unlikely to achieve sustained response should not be treated with NA, particularly if they are young (<30 years).

Interferon
Interferons (IFNs) have antiviral, antiproliferative, and immunomodulatory effects. IFN- alfa has been shown to be effective in suppressing HBV replication and in inducing remission of liver disease. However, its efficacy is limited to a small percentage of highly selected patients.
Efficacy in Various Categories of Patients.
1. HBeAg-positive chronic hepatitis B with the following
a. Persistent or intermittent elevation in ALT.
Significantly higher percentage of IFN alfa treated patients has a virologic response compared with untreated controls. High pretreatment ALT (greater than twice the upper limit of normal) and lower levels of serum HBV DNA are the most important predictors of a response to IFN alfa therapy.
b. Normal ALT.
HBeAg seroconversion occurs in less than 10% of these patients.

c. Asian patients.
Trials in Asian patients with HBeAg positive chronic hepatitis B found that the response in patients with normal ALT was poor, but the response in patients with elevated ALT was similar to that in Caucasian patients.
d. Children.
The efficacy of IFN-alpha is similar to that in adults.

2. HBeAg-negative chronic hepatitis B

End-of-treatment response ranges from 38% to 90% in treated patients compared with only 0% to 37% of controls. However, approximately half of the responders relapse when therapy is discontinued, and relapses can occur up to 5 years post-therapy. Longer duration of treatment, 24 months verses 6-12 months, may increase the rate of sustained response

3. Nonresponders to IFN-alpha treatment
Retreatment of IFN-alpha nonresponders with IFN-alpha alone is associated with a very low rate of response. Limited data suggest that 20%-30% HBeAg-negative patients who relapsed or had no response during previous IFN- alpha treatment had a sustained response after a second course of IFN-alpha

4. Decompensated cirrhosis
Approximately 20% to 40% of patients with HBeAg positive chronic hepatitis B develop a flare in their ALT values during IFN-alpha treatment. In patients with cirrhosis, the flare may precipitate hepatic decompensation.

Durability of Response and Long-term Outcome of IFN-alpha treated Patients.
• IFN-alpha induced HBeAg clearance has been reported to be durable in 80% to 90% of patients after a follow-up period of 4 to 8 years.
• Studies in Europe and the United States reported that delayed clearance of HBsAg occurred in 12% to 65% of patients within 5 years of HBeAg loss, but delayed HBsAg clearance was not observed in studies on Chinese patients.
• Studies comparing the outcome of responders versus nonresponders found that patients who cleared HBeAg had better overall survival and survival free of hepatic decompensation; the benefit was most apparent in patients with cirrhosis.

• Contrary to HBeAg-positive patients, relapse after cessation of IFN- alpha treatment is frequent in HBeAg-negative patients, with sustained response rates of only 15%-30%.

• Among the long-term responders, approximately 20% cleared HBsAg after 5 years of follow-up, and the risks of progression to cirrhosis, HCC, and liver-related deaths were reduced

Dose Regimen.
• IFN-alpha is administered as subcutaneous injections.
• The recommended dose for adults is 5MU daily or 10 MU thrice weekly and for children 6 MU/m2 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.
• Current data suggest that patients with HBeAg-negative chronic hepatitis B should be treated for at least 12 months, and one study suggested that 24 months treatment may increase the rate of sustained response

Pegylated Interferon alfa (pegIFN-alpha)
• PegIFN-alpha has the advantages of more convenient administration and more sustained viral suppression.
• Clinical trials suggest that the efficacy of pegIFN-alpha is similar to or slightly better than standard IFN alpha

Dose Regimen.
• PegIFN-alpha 2a is the only pegylated interferon approved for the treatment of chronic hepatitis B
• The recommended dose is 180 mcg weekly for 48 weeks.
• Whether longer duration of treatment (>48 week) will result in higher rates of sustained response in HBeAg negative patients remains to be determined.
Predictors of Response to Standard and PegIFN-alpha.
• In HBeAg-positive patients, the strongest predictor of HBeAg seroconversion to standard and pegIFN-alpha is the pretreatment ALT level.
• Other factors include high histologic activity index, low HBV DNA level, and more recently some studies have suggested that persons infected with HBV genotypes A and B respond better than those with genotypes C and D.

Adverse Events.
Standard IFN-alpha and pegIFN-alpha have similar side effect profiles.
• The most common side effect is an initial influenza-like illness: fever, chills, headache, malaise and myalgia.
• Other common side effects include fatigue, anorexia, weight loss and mild increase in hair loss.
• IFN-alpha has myelosuppressive effects but significant neutropenia (<1000/mm3) or thrombocytopenia (<50,000/mm3) are uncommon except in patients who have decreased cell counts prior to treatment.
• IFN-alpha treatment is accompanied by a flare in ALT in 30%-40% of patients.
• Hepatitis flares are considered to be an indicator of a favorable response but they can lead to hepatic decompensation, especially in patients with underlying cirrhosis.
• The most troublesome side effect of IFN-alpha is emotional lability: anxiety, irritability, depression and even suicidal tendency.
• IFN-alpha has been reported to induce the development of a variety of autoantibodies.
• Both hyper- and hypo-thyroidism that require treatment have been reported.
• Rarely, retinal changes and even impaired vision have been reported.

Lamivudine
Efficacy in Various Categories of Patients.
• Lamivudine monotherapy is effective in suppressing HBV replication and in ameliorating liver disease.
• HBeAg seroconversion after a 1-year course of lamivudine treatment is similar to that of a 16-week course of standard IFN-alpha but lower than that of a 1-year course of pegIFN- alpha.
1. HBeAg-positive chronic hepatitis B with the following

a. Persistent or intermittent elevation in ALT.
• HBeAg seroconversion occurred in 16% to 18% of patients compared with 4% to 6% of untreated controls.
• HBeAg seroconversion rates increased with the duration of treatment to 50% after 5 years of continued treatment.
b. Normal ALT levels.
• In patients with pretreatment ALT levels less than 2 times normal, the HBeAg seroconversion rate is less than 10% after 1 year and 19% after 3 years of treatment.
c. Asian patients.
• Asians respond similarly to lamivudine as Caucasian patients.
d. Children.
• In children HBeAg seroconversion is observed in about 22% of the lamivudine-treated children versus 13% placebo controls (P = 0.06).
• HBeAg seroconversion is increased to 34% after 2 years of continuous treatment.
• Lamivudine resistant HBV mutation is detected in 19%, 49% and 64% of patients after 1, 2 and 3 years of treatment, respectively.
• These data indicate that lamivudine is safe and effective in children but the benefit must be carefully balanced against the risk of selecting drug resistant mutants.

2. HBeAg-negative chronic hepatitis B
• Lamivudine has been shown to benefit patients with HBeAg-negative chronic hepatitis B.
• Several studies have reported that serum HBV DNA is suppressed to undetectable levels by PCR assays in 60% to 70% patients after 1 year of treatment.
• However, the vast majority (90%) of patients relapsed when treatment was stopped.
• Extending the duration of treatment resulted in a progressively lower rate of response due to the selection of lamivudine-resistant mutants.
• In one study of 201 patients, virologic remission (undetectable HBV DNAby PCR assay) decreased from 73% at 12 months to 34% at 48 months while biochemical remission decreased from 84% to 36%.

3. Nonresponders to IFN-alpha treatment
• A multicenter trial in IFN-alpha nonresponders found that patients had a similar HBeAg seroconversion rate to lamivudine alone (18%), a combination of lamivudine and IFN-alpha (12%) or placebo (13%) indicating that response of IFN-alpha nonresponders to lamivudine is similar to treatment-naive patients, and that retreatment with combination of IFN-alpha and lamivudine did not confer any added benefit compared with retreatment with lamivudine monotherapy.
4. Bridging Fibrosis and Compensated Cirrhosis

• Antiviral therapy can improve clinical outcomes in patients with advanced fibrosis who have maintained viral suppression.

5. Decompensated cirrhosis

• Lamivudine treatment is well tolerated and can stabilize or improve liver function in patients with decompensated cirrhosis thereby obviating or delaying the need for liver transplant.
• However, these studies showed that clinical benefit takes 3-6 months, and that HCC can occur even among patients with clinical improvement.
• Thus, prompt initiation of treatment and continued HCC surveillance are warranted.

Durability of Response
• Several factors have been found to be associated with increased durability of lamivudine-induced HBeAg seroconversion including longer duration of consolidation treatment—defined as duration of treatment beyond the time after HBeAg seroconversion, younger age, lower HBV DNA level at the time treatment was stopped, and genotype B vs. C.
• Although there are no good direct comparison data, it appears that the durability of lamivudine-induced HBeAg seroconversion is less than that for IFN-alpha.

• Among HBeAg-negative patients, the durability of viral suppression after 1-year of lamivudine treatment is less than 10%.

• One small study reported that the durability of virologic response was improved to 50% in patients who had completed 2 years of treatment and had persistently undetectable HBV DNA by PCR assay during year 2

Lamivudine Resistance.
• Selection of lamivudine-resistant mutations is the main concern with lamivudine treatment.
• Genotypic resistance can be detected in 14% to 32% after 1 year of lamivudine treatment and increases with the duration of treatment to 60% to 70% after 5 years of treatment
• Factors associated with an increase rate of lamivudine resistance include long duration of treatment, high pretreatment serum HBV DNA level, and a high level of residual virus after initiation of treatment
• Lamivudine resistance is significantly higher in patients whose serum HBV DNA level exceeded 200 IU/ml (1,000 copies/ml) after 6 months of treatment compared to those with lower HBV DNA levels (63% vs. 13%).
• Virologic breakthrough is usually followed by biochemical breakthrough (increase in ALT after initial normalization), and in some patients may be associated with acute exacerbations of liver disease and rarely hepatic decompensation and death
• Hepatitis flares may also occur after withdrawal of treatment due to rapid outgrowth of wild type virus, but two studies in Asia found that the occurrence of hepatitis flares and hepatic decompensation were similar among patients with lamivudine breakthrough who stopped or continued lamivudine treatment.
Long-term Outcome of Lamivudine-treated Patients.
• Follow-up of patients receiving continued lamivudine treatment showed that the rates of maintained virologic and biochemical response decreased with time due to selection of drug-resistant mutants.
Dose Regimen.
• The recommended dose of lamivudine for adults with normal renal function (creatinine clearance >50 ml/min) and no HIV co infection 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
• The end point of treatment for HBeAg-positive patients is HBeAg seroconversion.
• Liver chemistries should be monitored every 3 months and HBV DNA levels every 3-6 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 confirmed HBeAg seroconversion (HBeAg loss and anti-HBe detection on 2 occasions 1-3 months apart) and have completed at least 6 months of consolidation therapy after the appearance of anti-HBe.
• The durability of response after cessation of treatment is expected to be 70% to 90%
• All patients should be closely monitored after treatment is discontinued (every 1-3 months for the first 6 months, and every 3-6 months thereafter)
• Reinstitution of lamivudine treatment is usually effective in patients who have not developed resistance.
• Treatment may be continued in patients who have not achieved HBeAg seroconversion and have no evidence of breakthrough infection as HBeAg seroconversion may occur with continued treatment.
• With the availability of newer therapies with lower risk of drug resistance, a switch to an alternative treatment may be considered particularly in patients who have received lamivudine for more than 2 years.
• In patients who have breakthrough infection, testing for lamivudine-resistant mutants should be performed when possible.
• Patients whose ALT and HBV DNA levels remain significantly lower than pretreatment values may be maintained on lamivudine temporarily without resorting to rescue therapy but it must be recognized that compensatory mutations will be selected during continued treatment leading to subsequent viral rebound and possibly hepatitis flares.
• The end point of treatment for HBeAg-negative chronic hepatitis B is unknown.
• Post-treatment relapse can occur even in patients with persistently undetectable serum HBV DNA by PCR assay.
• Because of the need for long durations of treatment, lamivudine is not an optimal first-line treatment for HBeAg-negative chronic hepatitis B.
Adverse Events.
In general, lamivudine is very well tolerated. Various adverse events including a mild (2- to 3-fold) increase in ALT level have been reported in patients receiving lamivudine, but these events occurred in the same frequency among the controls.

Adefovir Dipivoxil
Efficacy in Various Categories of Patients.
1. HBeAg positive chronic hepatitis B
• Adefovir for 1-year is beneficial in patients with HBeAg-positive chronic hepatitis and that the 10-mg dose has a more favorable risk benefit profile.
• Cumulative HBeAg seroconversion rates appeared to increase during the second and third years but the exact number of patients who achieved HBeAg seroconversion was unclear.
• Some studies have reported that 20%-50% of patients receiving the 10 mg dose of adefovir have primary nonresponse indicating that the approved dose of adefovir may be suboptimal.

2. HBeAg negative chronic hepatitis
Patients who are HBeAg negative histologic response is 64% versus 33%; normalization of ALT 72% versus 29% ; and undetectable serum HBV DNA by PCR assay, 51% versus 0% at 48 weeks while still increased after 3- 5 years


3. Children
Clinical trials of adefovir in children are ongoing.
4. Decompensated cirrhosis
Adefovir has not been evaluated as a primary treatment for patients with decompensated cirrhosis.
5. Lamivudine-resistant hepatitis B
a. Decompensated cirrhosis and liver transplant recipients
• Among the patients who complets 48 weeks of treatment, 81% of the pre- and 34% of the post-transplant patients have undetectable HBV DNA by PCR assay, and 76% and 49%, respectively have normalization of ALT.
• Child-Turcotte-Pugh score improves in more than 90% of the pre-transplant patients, and 1-year survival is 84% for the pre- and 93% for the post-transplant patients.
b. Compensated liver disease
Study in patients with compensated chronic hepatitis B and lamivudine resistance found no differences in HBV DNA suppression and ALT normalization in persons treated with the combination of lamivudine and adefovir compared to those receiving adefovir alone,204 patients who discontinued lamivudine were more likely to develop ALT flares during the first 12 weeks of adefovir monotherapy.
c. HIV and HBV coinfection
Adefovir when added to existing HIV treatment regimens which included lamivudine 150 mg bid has also been shown to be effective in decreasing serum HBV DNA levels in patients with HIV and HBV coinfection and lamivudine-resistant HBV.
Adefovir Resistance.
• Resistance occurs at a slower rate during adefovir treatment compared to lamivudine
• Risk factors for adefovir resistance that have been identified include suboptimal viral suppression and sequential monotherapy.
• Sequential treatment with lamivudine followed by adefovir had also been reported to select for dual-resistant HBV mutants.
Dose Regimen.
• The recommended dose of adefovir for adults with normal renal function (creatinine clearance > 50 ml/min) is 10 mg orally daily. The dosing interval should be increased in patients with renal insufficiency.
• Adefovir has not been approved for use in children. Adefovir at the 10 mg dose is ineffective in suppressing HIV replication.
• For patients with HBeAg-positive chronic hepatitis B, treatment may be discontinued for those who have confirmed HBeAg seroconversion and have completed an additional 6 months of consolidation treatment.
• Treatment may be continued in patients who have not achieved HBeAg seroconversion but in whom HBV DNA levels remain suppressed.
• For patients with HBeAg-negative chronic hepatitis B, continued treatment (beyond 1 year) is needed to maintain the response.
• For most patients with lamivudine-resistant mutants, particularly those with decompensated cirrhosis or recurrent hepatitis B post-transplant, long-term treatment will be required.
• Increasing data indicate that lamivudine should be continued indefinitely after the addition of adefovir to reduce the risk of adefovir resistance.
• Approximately 30% of patients who have no prior treatment with NAs have primary nonresponse to adefovir, defined as a <2 log drop in HBV DNA after 6months of treatment.
• Alternative treatments should be considered for these patients.
Adverse Events.
Adefovir in 10 mg doses is well tolerated and has a similar side effect profile as placebo
• Nephrotoxicity has been reported in 3% of patients with compensated liver disease after 4-5 years of continued adefovir therapy, and in 12% of transplant recipients and 28% of patients with decompensated cirrhosis during the first year of therapy.
• Monitoring of serum creatinine every 3 months is necessary for patients with medical conditions that predispose to renal insufficiency and in all patients on adefovir for more than 1 year. More frequent monitoring should be performed in patients with pre-existing renal insufficiency.

Entecavir (Baraclude)

In vitro studies showed that entecavir is more potent than lamivudine and adefovir and is effective against lamivudine-resistant HBV mutants although the activity is lower compared to wild-type HBV.

Efficacy in Various Categories of Patients.
1. HBeAg-positive patients
Serum HBV DNA is undetectable by PCR in 81% vs. 39%, and normalization of ALT occurred in 79% vs. 68% of patients who continue entecavir and lamivudine treatment, respectively for 48 weeks

2 HBeAg-negative patients
At week 48, entecavir resulted in significantly higher rates of histologic (70% vs. 61%), virologic (90% vs. 72%) and biochemical (78% vs. 71%) responses compared to lamivudine.
3. Decompensated cirrhosis / recurrent hepatitis B after
liver transplantation
Studies on the safety and efficacy of entecavir in patients with decompensated cirrhosis are ongoing.
4.Lamivudine-refractory HBV
At week 48, entecavir resulted in significantly higher rates of histologic (55% vs. 28%), virologic (21% vs. 1%) and biochemical (75% vs. 23%) responses compared to lamivudine in a phase 2 trial.
5. Adefovir-resistant HBV
In vitro studies showed that entecavir is effective in suppressing adefovir-resistant HBV mutants.
Entecavir Resistance.
• Virologic breakthrough was rare in nucleoside-naı¨ve patients, and was observed in only 3% of patients by Week 96 of entecavir treatment in the two phase III clinical trials.
• Resistant mutations to lamivudine and entecavir were detected in only two (_1%) patients while resistant mutations to lamivudine only were found in three patients.
• However, virologic breakthrough was detected in 7% of patients after 48 weeks and in 16% after 96 weeks of treatment in the phase III trial of lamivudine refractory patients.
• Lamivudine should be discontinued when patients are switched to entecavir to decrease the risk of entecavir resistance.
• In vitro studies show that entecavir-resistant mutations are susceptible to adefovir, but there are very little clinical data on the efficacy of adefovir in patients with entecavir-resistant HBV
Adverse Events.
Entecavir had a similar safety profile as lamivudine in clinical trials.
Studies in rodents exposed to doses 3-40 times that in humans found an increased incidence of lung adenomas, brain gliomas and HCCs. To date, no difference in the incidence of HCC or other neoplasm has been observed between patients who received entecavir versus lamivudine.

Other Therapies

Other therapies approved for use in chronic hepatitis B include
• L-deoxythymidine (Telbivudine/LdT, Tyzeka)
• Emtricitabine (Emtriva, FTC)
• Clevudine (LFMAU, 2_-fluoro-5-methyl-beta-Larabinofuranosyl uracil)
• Thymosin

Combination Therapies
• Combinition therapies have been proven to be more effective than monotherapy in the treatment of HIV and HCV infections.
• Various combination therapies have been evaluated; to date, none of the combination therapies has been proven to be superior to monotherapy in inducing a higher rate of sustained response.
• Although several combination therapies have been shown to reduce the rate of lamivudine resistance compared to lamivudine monotherapy, there are as yet no data to support that combination therapies will reduce the rate of resistance to antiviral compounds that have a low risk of drug resistance when used alone.
Recommendations for the Treatment of Chronic Hepatitis B:

• Treatment is indicated if the risk of liver-related morbidity and mortality in the near future (5-10 years) and the likelihood of achieving maintained viral suppression during continued treatment are high.
• Treatment is also indicated if the risk of liver-related morbidity and mortality in the foreseeable future (10-20 years) and the likelihood of achieving sustained viral suppression after a defined course of treatment are high.
• Treatment is not indicated if the risk of liver-related morbidity or mortality in the next 20 years and the likelihood of achieving sustained viral suppression after a defined course of treatment are low.
• Because of the fluctuating nature of chronic HBV infection, the risk of liver-related morbidity and mortality and the likelihood of response may vary as patient progresses through the course of chronic HBV infection. Thus, continued monitoring is essential for risk assessment.

Recommendations on Whom to Treat and with What Antiviral Agent [21]
Patients with HBeAg-positive chronic hepatitis B
a. ALT greater than 2 times normal or moderate/ severe hepatitis on biopsy, and HBV DNA >20,000 IU/ml.
These patients should be considered for treatment.
● Treatment should be delayed for 3 to 6months in persons with compensated liver disease to determine if spontaneous HBeAg seroconversion occurs.
● Patients with icteric ALT flares should be promptly treated.
● Treatment may be initiated with any of the 6 approved antiviral medications, but pegIFN-alpha, adefovir or entecavir are preferred.
b. ALT persistently normal or minimally elevated (<2 times normal).
These patients generally should not be initiated on treatment. (
● Liver biopsy may be considered in patients with fluctuating or minimally elevated ALT levels especially in those above 40 years of age.
● Treatment may be initiated if there is moderate or severe necroinflammation or significant fibrosis on liver biopsy.
c. Children with elevated ALT greater than 2 times normal.
These patients should be considered for treatment if ALT levels remain elevated at this level for longer than 6 months.
● Treatment may be initiated with IFN-alpha or lamivudine.
Patients with HBeAg-negative chronic hepatitis B (serum HBV DNA >20,000 IU/ml and elevated ALT>2 times normal)
These patients should be considered for treatment.
● Liver biopsy may be considered for HBeAg-negative patients with lower HBV DNA levels (2,000-20,000 IU/ml) and borderline normal or minimally elevated ALT levels.
● Treatment may be initiated if there is moderate/ severe inflammation or significant fibrosis on biopsy.
● Treatment may be initiated with any of the 6 approved antiviral medications but pegIFN-alpha, adefovir or entecavir are preferred in view of the need for long-term treatment
Patients who failed to respond to prior IFN-alpha (standard or pegylated) therapy
May be retreated with nucleoside analogues (NA) if they fulfill the criteria
Patients who failed to achieve primary response as evidenced by <2 log decrease in serum HBV DNA level after at least 6 months of NA therapy
Should be switched to an alternative treatment.
Patients who develop breakthrough infection while receiving NA therapy
● Compliance should be ascertained and treatment resumed in patients who have had long lapses in medications.
● A confirmatory test for antiviral-resistant mutation should be performed if possible to differentiate primary non-response from breakthrough infection and to determine if there is evidence of multi-drug resistance (in patients who have been exposed to more than one NA treatment).
● All patients with virologic breakthrough should be considered for rescue therapy.
● For patients in whom there was no clear indication for hepatitis B treatment and who continue to have compensated liver disease, withdrawal of therapy may be considered but these patients need to be closely monitored and treatment reinitiated if they experience severe hepatitis flares.
Treatment of patients with lamivudine (or telbivudine)- resistant HBV
a. If adefovir is used, lamivudine (or telbivudine) should be continued indefinitely to decrease the risk of hepatitis flares during the transition period and to reduce the risk of subsequent adefovir resistance.
b. If entecavir is used, lamivudine or telbivudine should be stopped as continued presence of lamivudine (or telbivudine)-resistant mutations will increase the risk of entecavir resistance.
Treatment of patients with adefovir-resistant HBV
a. In patients with no prior exposure to other NA, lamivudine or entacavir may be added.
b. In patients with prior lamivudine resistance in whom lamivudine had been stopped when treatment was switched to adefovir, lamivudine may be added but the durability of response is unknown and reemergence of lamivudine-resistant mutations has been reported
Treatment of patients with entecavir-resistant HBV
Adefovir can be used as it has been shown to have activity against entecavir-resistant HBV in in vitro studies, but clinical data are lacking. Patients with compensated cirrhosis
Treatment should be considered for patients with ALT >2 times normal, and for patients with normal or minimally elevated ALT if serum HBV DNA levels are high (>2,000 IU/ml).
a. Patients with compensated cirrhosis are best treated with NAs because of the risk of hepatic decompensation associated with IFN-alpha related flares of hepatitis.
In view of the need for long-term therapy, adefovir or entecavir is preferred.
Patients with decompensated cirrhosis
Treatment should be promptly initiated with a NA that can produce rapid viral suppression with low risk of drug resistance.
a. Lamivudine or adefovir may be used as initial treatment preferably in combination to reduce the risk of drug resistance and to achieve rapid virus suppression.
Telbivudine may be substituted for lamivudine but clinical data documenting its safety and efficacy in patients with decompensated cirrhosis are lacking.
b. Entecavir would be an appropriate treatment in this setting but clinical data documenting its safety and efficacy in patients with decompensated cirrhosis are lacking.
c. Treatment should be coordinated with a transplant center.
d. IFN-alpha /pegIFN alpha should not be used in patients with decompensated cirrhosis.
In patients with inactive HBsAg carrier state
Antiviral treatment is not indicated, but these patients should be monitored
Duration of nucleoside analogue treatment
a. HBeAg-positive chronic hepatitis B — Treatment should be continued until the patient has achieved HBeAg seroconversion and completed at least 6 months of additional treatment after appearance of anti-HBe.
● Close monitoring for relapse is needed after withdrawal of treatment.
b. HBeAg-negative chronic hepatitis B — Treatment should be continued until the patient has achieved HBsAg clearance
c. Compensated cirrhosis — These patients should receive long-term treatment. However, treatment may be stopped in HBeAg-positive patients if they have confirmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg-negative patients if they have confirmed HBsAg clearance.
● Close monitoring for viral relapse and hepatitis flare is mandatory if treatment is stopped.
d. Decompensated cirrhosis and recurrent hepatitis B post-liver transplantation — Life-long treatment is recommended

Special Populations [21]
Co infection with HBV and HCV
There is scanty information on the treatment of HBV/ HCV coinfection and recommendations on treatment for HBV/HCV coinfection cannot be made at this time.

Coinfection with HBV and HDV

High-dose IFN-alpha (9 MU 3 times a week) or pegIFN-_ for 1 year appears to have long-term beneficial effects in patients with chronic hepatitis D.

Co-Infection with HBV and HIV

Patients who meet criteria for chronic hepatitis B should be treated.
● Liver biopsy should be considered in patients with fluctuating or mildly elevated ALT (1-2 x normal).
Patients who are not on HAART and are not anticipated to require HAART in the near future should be treated with an antiviral therapy that does not target HIV, such as pegIFN-alpha, adefovir or entecavir.
Although telbivudine does not target HIV, it should not be used in this circumstance.
Patients in whom treatment for both HBV and HIV is planned should receive therapies that are effective against both viruses: lamivudine plus tenofovir or emtricitabine plus tenofovir are preferred.
Patients who are already on effective HAART that does not include a drug active against HBV may be treated with pegIFN alpha, adefovir or entecavir. In patients with lamivudine resistance, tenofovir or adefovir should be added.
When HAART regimens are altered, drugs that are effective against HBV should not be discontinued
Recommendations for Treatment of Hepatitis B carriers who require Immunosuppressive or Cytotoxic Therapy [21]
• HBsAg testing should be performed in patients who are at high risk of HBV infection, prior to initiation of chemotherapy or immunosuppressive therapy.
• Prophylactic antiviral therapy is recommended for HBV carriers at the onset of cancer chemotherapy or of a finite course of immunosuppressive therapy.
a. Patients with baseline HBV DNA <2,000 IU/ml level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy.
b. Patients with high baseline HBV DNA (>2,000 IU/ml) level should continue treatment until they reach treatment endpoints as in immunocompetent patients.
c. Lamivudine or telbivudine can be used if the anticipated duration of treatment is short (<12 months).
d. Adefovir or entecavir is preferred if longer duration of treatment is anticipated. Entecavir has more rapid onset of action than adefovir and may be more appropriate in this setting.
e. IFN-alpha should be avoided in view of the bone marrow suppressive effect.
Treatment of Hepatitis B in Dialysis Patients


• Treatment is indicated in HBsAg-positive patients with evidence of disease activity, as indicated by viral replication and elevated transaminase levels, preferably corroborated by examination of liver histology.
• A level of 10(5) copies/mL for HBV DNA has been recommended to justify treatment, based upon sensitivity limits of quantitative assays [37].
• With the advent of more sensitive quantitative assays, it remains to be investigated whether a lower cut-off level may be more appropriate. It is important to realize that HBeAg can be negative in patients with precore- or core promotor-mutant infection despite active disease [37].
• In view of the side effects profile, lamivudine given for at least one year appears to be a better choice than interferon-alfa in dialysis patients.
• Available results suggest that the efficacy and the incidence of drug-resistance with lamivudine therapy appear similar to patients without renal failure [37].
• However, the optimal duration of treatment and the management of lamivudine-resistant HBV variants remain to be determined.






Treatment of complications
1. Glumerulonephritis:

INF-a therapy has been successful in treating HBV-related GN. A regimen of 5 million units of IFN-a subcutaneously daily for 4 months has achieved HBsAg seroconversion with improvement of GN. It also has been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative GN but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation
2. Polyarteritis nodosa
• Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they potentially may have a deleterious effect on the course of HBV liver disease because of viral reactivation, particularly after the withdrawal of treatment.
• Adenine arabinoside, an antiviral drug, and IFN-a, an immunomodulator and antiviral protein, have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results. Because of the fact that this is a rare complication, to date no reports have been published on the use of the newer therapies for HBV that include the nucleoside analogue, lamivudine


Liver transplantation for chronic hepatitis B virus infection
• Despite advances in treatment of chronic hepatitis B (HBV), liver transplantation remains the only hope for many patients with end-stage liver disease due to HBV [38].
• The high rate of HBV reinfection after liver transplantation is probably due to enhanced virus replication resulting from immunosuppression or from direct stimulatory effects of steroid therapy on the glucocorticoid-responsive enhancer region of the HBV genome
• Factors associated with a lower rate of graft reinfection and improved survival include:
1. HBeAg negative
2. Lower levels of serum HBV-DNA negative (by hybridization or other non-PCR-based assays)
3. Fulminant hepatitis B
4. Coexistent hepatitis D virus (HDV) infection
• HBV reinfection is diagnosed by the reappearance of HBsAg in the serum. Most reinfected patients are also HBeAg positive and have high levels of circulating HBV DNA [39]
• Reinfection is almost always accompanied by recurrent liver disease which is often severe and rapidly progressive [40]. If untreated, cirrhosis occurs within one to two years of reinfection.
• Active and passive immunoprophylaxis and antiviral strategies have been tried to prevent or delay graft reinfection.
• Currently, the most effective prophylaxis involves the use of combination prophylaxis of HBIG and lamivudine or adefovir.
• HBIG is usually given intravenously as a 10,000 IU bolus dose during the anhepatic phase followed by daily doses during the first week.
• Subsequent doses are either given monthly or in accordance with anti-HBs titers.
• A trough anti-HBs titer of at least 100 IU/ L is thought to be protective.
• However, some studies have suggested that the rate of reinfection can be reduced further in patients with anti-HBs titers consistently above 500 IU/l [41, 42].
• Active immunization using standard hepatitis B vaccines has been studied to reduce the need for life-long HBIG prophylaxis.
• Combination of HBIG and antiviral therapy has reduced recurrent hepatitis B to less than 10 percent with resultant improvement in patient and graft survival