Hepatitis B medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]; João André Alves Silva, M.D. [3]

Overview

The hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously. Early antiviral treatment may be required in fewer than 1% of people, whose infection takes a very aggressive course (fulminant hepatitis) or who are immunocompromised. On the other hand, treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Chronically infected individuals with persistently elevated serum alanine aminotransferase, a marker of liver damage, and HBV DNA levels are candidates for therapy. Treatment lasts from six months to a year, depending on medication and genotype.

Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. As of 2008, there are seven medications licensed for treatment of hepatitis B infection in the United States. These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and the two immune system modulators interferon alpha-2a and Pegylated interferon-alpha-2a (Pegasys). The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting PEGylated interferon, which is injected only once weekly. However, some individuals are much more likely to respond than others, and this might be because of the genotype of the infecting virus or the person's heredity. The treatment reduces viral replication in the liver, thereby reducing the viral load (the amount of virus particles as measured in the blood). Response to treatment differs between the genotypes. Interferon treatment may produce an e antigen seroconversion rate of 37% in genotype A but only a 6% seroconversion in type D. Genotype B has similar seroconversion rates to type A while type C seroconverts only in 15% of cases. Sustained e antigen loss after treatment is ~45% in types A and B but only 25–30% in types C and D.

Medical Therapy

After infection with the hepatitis B virus, up to 95% of adults are able to eliminate the virus without treatment. Currently, there is no treatment available for acute hepatitis B. Symptomatic treatment of nausea, anorexia, vomiting, and other symptoms may be indicated.

Early antiviral treatment may only be required in fewer than 1% of patients, whose hepatitis B takes a very aggressive course, such as in cases of fulminant hepatitis.

In general, each treatment works by reducing the viral load by several orders of magnitude. In some patients, chronic hepatitis B takes a mild course and does not require immediate treatment. Treatment strategies should be individualized. Considerations include:

• Person's risk for developing complications of persistent infection
• Person's likelihood of adhering and responding to treatment
• Risks of side effects or development of viral resistance

Acute Hepatitis B

• There is no effective treatment for acute hepatitis B. Children are often treated with supportive care alone.
• Nucleoside/nucleotide analog treatment may be considered in severe cases of acute hepatitis, despite trials in adults have not shown benefit.
• Liver transplant may be required for cases of fulminant hepatitis
• Unlike chronic hepatitis, liver transplant in cases of acute hepatitis have a low risk of reinfection.

Chronic Hepatitis B

Treatment of chronic hepatitis B aims to halt the progression of liver disease, eliminate infectivity, and prevent the development of HCC. Virological changes are usually accompanied by normalization of ALT activity, resolution of hepatic inflammation and improvement of the patients’ symptoms.

Two treatment classes are available for chronic hepatitis B: antivirals: aimed at suppressing or destroying HBV by interfering with viral replication; immune modulators: aimed at helping the human immune system to mount a defense against the virus. There are currently several treatments for chronic hepatitis B. While none of the available drugs usually clears the infection, they can stop the virus from replicating, and prevent liver damage such as cirrhosis and/or liver cancer.

Chronic carriers are encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and hepatocellular carcinoma.

Infants born to mothers known to carry hepatitis B can be treated with antibodies to the hepatitis B virus (hepatitis B immune globulin or HBIg). When given with the vaccine within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This treatment also allows a mother to safely breastfeed her child.

An individual exposed to the virus who has never been vaccinated may be treated with HBIg immediately following the exposure. For instance, a health care worker accidentally stuck by a needle used in a hepatitis B carrier would qualify. Treatment must be soon after exposure, however.

Treatments are available in the form of antiviral drugs, such as lamivudine, adefovir, entecavir or telbivudine, and immune system modulators such as interferon alpha (Uniferon) or peg-interferon alpha (PEGASYS). There are several other antivirals under investigation. However, some individuals are much more likely to respond than others.

It does not appear that combination therapy offers any advantages. However, it may help in patients with resistant viruses, or in advanced stages of liver disease.

Goal of therapy

1. Eradicate the virus from the body
2. Prevent progression of end stage liver disease (ESLD)
3. Prevent progression to hepatocellular carcinoma (HCC)
4. Clear off HBV DNA
5. HBeAg and HBsAg negative
6. Normal ALT / AST
7. Normal histology

Indications to start antiviral medications

• Following are the curent indications to start treatment for chronic hepatits B:

1. Chronic hepatitis B ( HbeAg postive and negative ) with HBV DNA >2000 IU/ml and/or
2. Elevated ALT and
3. Severe necrosis and fibrosis on biopsy
4. Decompensated or compensated cirrhosis with normal ALT or HBV DNA <2000 IU/ml

• Treatment should be continued for at least 6 months after HBeAg loss / conversion.

Antiviral Medications

There are three types of treatment groups:

1. Interferon (IFN)
2. Nucleoside analogs
3. Nucleotide analogs

First Line Agents

Drug	Description
Entecavir	An anti-HBV nucleoside analog A 94% clearance rate after 5 years of treatment is observed in HBeAg positive patients. A 90% clearance rate after 48 weeks of treatment is observed in HBeAg negative patients. A necroinflammation improvement of 96% and fibrosis improvement of 88% is seen after a treatment for 6 years.
Tenofovir	An anti-HBV nucleotide analog A 68% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg positive patients. A 84% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg negative patients.
Interferons	Antiviral and antiproliferative glycoprotein. No antiviral resistance have been noted Best results noted with genotype A or B who are HBeAg positive.

Second Line Agents

Drug	Description
Telbivudine	Nucleoside analog Worse resistance than first line agents and not indicated if resistance to other nucleoside analogs are noted.
Adefovir	Nucleotide analog Worse resistance than first line agents Used in cases of nucleotide analog resistance
Lamivudine	Nucleoside analog Has a high rate of resistance and hence not used currently

Recommended Treatment

Recommended Treatment of Chronic Hepatitis B

HBeAg	ALT	HBV DNA	Treatment Regimen
+	≤2 x Upper Limit of Normal	>20,000 IU/mL	Low efficacy with present treatment Observe: treatment should be considered as ALT rises Biopsy should be considered in adults >40years, when: Persistence of an elevated ALT: [Normal;<2xUpper Limit of Normal] Family history of hepatocellular carcinoma Treatment should be considered when: HBV DNA > 20,000 IU/mL Signs of inflammation (moderate to severe) or fibrosis on biopsy
+	>2 x Upper Limit of Normal	>20,000 IU/mL	Observation for 3 to 6 months. Treatment should be started if no spontaneous HBeAg loss If compensated, liver biopsy should be considered prior to treatment If patient is jaundiced or decompensated, start immediate treatment Initial therapy may include: IFNα/pegIFNα Lamivudine Adefovir Entecavir Tenefovir Telbivudine Adefovir plays a minor role due to increased resistance rate after 1 year, and weak antiviral activity Lamivudine and telbivudine play a minor role due to increased resistance rate Treatment goal - seroconversion with production of anti-HBe to HBeAg Treatment duration: IFN-α - 16 weeks PegIFN-α - 48 weeks Lamivudine or adefovir or entecavir or telbivudine or tenofovir disoproxil fumarate - >1 year; treatment should be continued >6 months after HBeAg seroconversion Tenofovir disoproxil fumarate or entecavir for: absence of response to IFN-α; or when IFN-α is contraindicated
-	>2 x Upper Limit of Normal	>20,000 IU/mL†	Initial therapy may include: IFN-α/PegIFN-α Lamivudine Adefovir Entecavir Tenofovir disoproxil fumarate Telbivudine Lamivudine and telbivudine play a minor role due to increased resistance rate Adefovir plays a minor role due to increased resistance rate after 1 year, and weak antiviral activity Treatment end-point not defined Treatment duration: IFN-α/PegIFN-α - 1 year Lamivudine or adefovir or entecavir or telbivudine or tenofovir disoproxil fumarate - > 1 year Tenofovir disoproxil fumarate or entecavir for: absence of response to IFN-α; or when IFN-α is contraindicated
-	[1; >2] x Upper Limit of Normal	>2,000 IU/mL	If signs of necroinflammation (moderate to severe) or fibrosis on liver biopsy - consider liver biopsy and treatment
-	≤ Upper Limit of Normal	≤2,000 IU/mL	Observation. Treatment should be started when: ALT or HBV DNA rise
+/-	Cirrhosis	Traceable	If compensated: If HBV DNA >2,000 IU/mL - Initial therapy may include Lamivudine Adefovir Entecavir Telbivudine Tenofovir disoproxil fumarate Lamivudine and telbivudine play a minor role due to increased resistance rate Adefovir plays a minor role due to increased resistance rate after 1 year, and weak antiviral activity If HBV DNA <2,000 IU/mL - Treatment should be considered if elevated ALT If decompensated - Treatment should be coordinated with transplant center: Lamivudine (or telbivudine) + adefovir or tenofovir disoproxil fumarate or entecavir(prefered) Referal for liver transplant
+/-	Cirrhosis	Untraceable	If compensated - observation If decompensated - indication fro liver transplant

Management of Drug Resistance

Prevention

To prevent HBV infection antiviral drug-resistance, the following measures should be observed:

• Avoidance of unnecessary treatment
• Treatment should be initiated with a low resistance drug, or with combination therapy
• Alternative treatment should be initiated if patients fail to respond

Monitoring

During treatment the following should be monitored:

• Serum HBV DNA during course of treatment, every 3 to 6 months
• Treatment compliance

Recommendations on Whom to Treat and with What Antiviral Agent: AASLD Practice Guidelines 2009

“

1. 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. (Grade I) Treatment should be delayed for 3 to 6 months in persons with compensated liver disease to determine if spontaneous HBeAg seroconversion occurs. (Grade II-2) Patients with icteric ALT flares should be promptly treated. (Grade III) Treatment may be initiated with any of the 7 approved antiviral medications, but pegIFN-α, tenofovir or entecavir are preferred. (Grade I) b. ALT persistently normal or minimally elevated (<2 times normal). These patients generally should not be initiated on treatment. (Grade I) Liver biopsy may be considered in patients with fluctuating or minimally elevated ALT levels especially in those above 40 years of age. (Grade II-3) Treatment may be initiated if there is moderate or severe necroinflammation or significant fibrosis on liver biopsy. (Grade I) 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. (Grade I) Treatment may be initiated with IFN-α or lamivudine. (Grade I) 2. Patients with HBeAg-negative chronic hepatitis B (serum HBV DNA >20,000 IU/mL and elevated ALT >2 times normal) should be considered for treatment. (Grade I) 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. (Grade II-2) Treatment may be initiated if there is moderate/severe inflammation or significant fibrosis on biopsy. (Grade I) Treatment may be initiated with any of the 7 approved antiviral medications but pegIFN-α, tenofovir or entecavir are preferred in view of the need for long-term treatment. (Grade I for pegIFN-α, tenofovir, or entecavir and Grade II-1 for IFN-α, adefovir, telbivudine and lamivudine). 3. Patients who failed to respond to prior IFN-α (standard or pegylated) therapy may be retreated with nucleoside analogues (NA) if they fulfill the criteria listed above. (Grade I) 4. 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 or receive additional treatment. (Grade III) 5. 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. (Grade III) A confirmatory test for antiviral-resistant mutation should be performed if possible to differentiate primary nonresponse 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). (Grade III) All patients with virologic breakthrough should be considered for rescue therapy. (Grade II-2) 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. (Grade III) 6. 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. (Grade II-3 for lamivudine-resistant HBV and III for telbivudineresistant HBV) b. If tenofovir is used, continuation of lamivudine (or telbivudine) is recommended to decrease the risk of subsequent antiviral resistence. (Grade III) c. 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. (Grade II-3 for lamivudine-resistant HBV and Grade III for telbivudine-resistant HBV). Entecavir is not an optimal therapy because of increasing risk of resistance to entecavir over time. (Grade II-2) 7. Treatment of patients with adefovir-resistant HBV a. In patients with no prior exposure to other NA, lamivudine, telbivudine or entecavir may be added. Alternatively, adefovir may be stopped and tenofovir plus lamivudine or emtricitabine may be used. (Grade III) b. In patients with prior lamivudine resistance in whom lamivudine had been stopped when treatment was switched to adefovir, adefovir may be stopped and tenofovir plus lamivudine, emtricitabine (Grade II-2) or entecavir (Grade III) may be used but the durability of response to this combination is unknown. 8. Treatment of patients with entecavir-resistant HBV a. Adefovir or Tenofovir can be used as it has been shown to have activity against entecavir-resistant HBV in in vitro studies, but clinical data are lacking. (Grade II-3) 9. 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). (Grade II-2) a. Patients with compensated cirrhosis are best treated with NAs because of the risk of hepatic decompensation associated with IFN-α–related flares of hepatitis. In view of the need for long-term therapy, tenofovir or entecavir is preferred. (Grade II-3) 10. Patients with decompensated cirrhosis — Treatment should be promptly initiated with a NA that can produce rapid viral suppression with low risk of drug resistance. (Grade II-1) a. Lamivudine or telbivudine may be used as initial treatment in combination with adefovir or tenofovir to reduce the risk of drug resistance. (Grade II-2) b. Entecavir or tenofovir alone would be an appropriate treatment in this setting but clinical data documenting their safety and efficacy in patients with decompensated cirrhosis are lacking. (Grade III) c. Treatment should be coordinated with a transplant center. (Grade III) d. IFN-α/pegIFN-α should not be used in patients with decompensated cirrhosis. (Grade II-3) 11. In patients with inactive HBsAg carrier state antiviral treatment is not indicated, but these patients should be monitored.

”

Recommendations for Dose Regimens: AASLD Practice Guidelines 2009

“

1. IFN-α and pegIFN-α are administered as subcutaneous injections. a. The recommended dose of standard IFN-α for adults is 5 MU daily or 10 MU thrice weekly. The recommended dose of pegIFN-α2a is 180 mcg weekly. (Grade I) b. The recommended IFN-α dose for children is 6 MU/m2 thrice weekly with a maximum of 10 MU. (Grade I). PegIFN-α has not been approved for treatment of chronic hepatitis B in children. c. The recommended treatment duration for HBeAg-positive chronic hepatitis B is 16 weeks for standard IFN-α and 48 weeks for pegIFN-α. (Grade I) d. The recommended treatment duration for HBeAg-negative chronic hepatitis B is 48 weeks for both standard and pegIFN-α (Grade II-3). 2. Lamivudine is administered orally. a. The recommended lamivudine dose for adults with normal renal function and no HIV coinfection is 100 mg daily (Grade I). Dose adjustment is needed for patients with estimated glomerular filtration rate <50 mL/min. (Grade I) b. The recommended lamivudine dose for children is 3 mg/kg/d with a maximum of 100 mg/d. (Grade I) c. The recommended dose of lamivudine for persons coinfected with HIV is 150mg twice daily. Lamivudine should only be used in combination with other antiretroviral medications. (Grade I) 3. Adefovir is administered orally. a. The recommended adefovir dose for adults with normal renal function is 10 mg daily. (I) Dose adjustment is needed for patients with estimated glomerular filtration rate <50 mL/min. 4. Entecavir is administered orally. a. The recommended entecavir dose for adults with normal renal function is 0.5 mg daily for patients with no prior lamivudine treatment, and 1.0 mg daily for patients who are refractory/resistant to lamivudine. (Grade I). Dose adjustment is needed for patients with estimated glomerular filtration rate <50 mL/min. 5. Telbivudine is administered orally. a. The recommended dose for adults with normal renal function is 600 mg daily. (Grade I) Dose adjustment is needed for patients with estimated glomerular filtration rate <50 mL/min. 6. Tenofovir is administered orally. a. The recommended tenofovir dose for adults with normal renal function is 300 mg daily. (Grade I) Dose adjustment is needed for patients with estimated creatinine clearance <50 mL/min. 7. Duration of nucleoside analogue treatment a. HBeAg-positive chronic hepatitis B — Treatment should be continued until the patient has achieved HBeAg seroconversion and undetectable serum HBV DNA and completed at least 6 months of additional treatment after appearance of anti-HBe. (Grade I) Close monitoring for relapse is needed after withdrawal of treatment. (Grade I) b. HBeAg-negative chronic hepatitis B — Treatment should be continued until the patient has achieved HBsAg clearance. (Grade I) 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. (Grade II-3) Close monitoring for viral relapse and hepatitis flare is mandatory if treatment is stopped. (Grade II-3) d. Decompensated cirrhosis and recurrent hepatitis B post–liver transplantation — Life-long treatment is recommended. (Grade II-3)

”

Recommendations for Initial Evaluation of Persons with Chronic HBV Infection: AASLD Practice Guidelines 2009

“

1. Initial evaluation of persons newly diagnosed with chronic HBV infection should include history, physical examination and laboratory testing. (Grade III) 2. All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart. (Grade II-3)

”

Recommendations for Treatment of Patients with Acute Symptomatic Hepatitis B: AASLD Practice Guidelines 2009

“

1. Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B. (Grade III) 2. Lamivudine or telbivudine may be used when the anticipated duration of treatment is short; otherwise, entecavir is preferred. (Grade II-3) a. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo liver transplantation. (Grade II-1) b. IFN-α is contraindicated. (Grade III)

”