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

In the majority of adults, the body is able to eliminate the virus without treatment. Currently, there is no treatment available for acute hepatitis B infection. Symptomatic treatment 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. Treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Chronically infected patients with persistently elevated serum alanine aminotransferase and HBV DNA levels are candidates for therapy. Treatment lasts from six months to a year, depending on the medication and genotype. Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. These include antiviral drugs Lamivudine, Adefovir, Tenofovir, Telbivudine and Entecavir, as well as immune system modulators, such as interferon alpha-2a and pegylated interferon-alpha-2a.[1][2][3][4]

Medical Therapy

Acute Hepatitis B

There is no effective treatment for acute hepatitis B. Children are often treated with supportive care alone.

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.[5]

Two treatment classes are available for chronic hepatitis B: antivirals, aimed at suppressing or destroying HBV by interfering with viral replication; and immune modulators, aimed at helping the human immune system mount a defense against the virus.[5] 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 thus prevent liver damage such as cirrhosis and/or liver cancer.[5]

Chronic carriers are encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and hepatocellular carcinoma.[6]

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 by 95%. This treatment also allows a mother to safely breastfeed her child.[6]

If an individual who has never been vaccinated is exposed to the virus, he/she may be treated with HBIg immediately following the exposure.

It does not appear that combination therapy offers any advantages.[7] However, it may help in patients with resistant viruses, or in advanced stages of liver disease.

Hepatitis B 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 tailored to suit individual patients. Considerations include:

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

Indications to start antiviral medications

Below are the curent indications to start treatment for chronic hepatits B:[8]

  1. Chronic hepatitis B (HbeAg postive and negative) with HBV DNA >2000 IU/ml and/or
  2. Elevated ALT
  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:[5]

  1. Interferon (IFN)
  2. Nucleoside analogs
  3. Nucleotide analogs
First Line Agents[9]
Drug Description Dosage Side-effects
Entecavir
  • An anti-HBV nucleoside analog
  • A 94% clearance rate after 5 years of treatment is observed in HBeAg positive patients.[10]
  • A 90% clearance rate after 48 weeks of treatment is observed in HBeAg negative patients.[11]
  • A necroinflammation improvement of 96% and fibrosis improvement of 88% is seen after treatment for 6 years.[12]
  • Adults:
  • Nucleoside-inhibitor-treatment-naïve adults and adolescents ≥16 years of age - 0.5 mg/day
  • Adults and adolescents ≥16 years of age, with a history of hepatitis B viremia while receiving lamivudine, or known lamivudine or telbivudine resistance substitutions - 1 mg/day
  • Decompensated Liver Disease - 1 mg/day
  • Children with body weight >30 kg:
  • Treatment-Naïve:
  • 0.5 mg/day (10 mL of oral solution or one 0.5 mg tablet)
  • Lamivudine-Experienced:
  • 1 mg/day (20 mL of oral solution or one 1 mg tablet)

"Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued entecavir"

"Hepatic function should be monitored closely for at least several months after discontinuation"

"Entecavir is not recommended for patients co-infected with HIV and HBV who are not also receiving HAART, due to the potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors"

"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors"

Tenofovir
  • An anti-HBV nucleotide analog
  • A 68% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg positive patients.[13]
  • A 84% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg negative patients.
  • Adults and children ≥12 years of age:
  • 300 mg/day PO
  • Children (2-12 years):
  • 8-300 mg/day PO (oral powder)
  • Renal impaired patients should have dosages adjusted to their levels of creatinine clearance

"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir, in combination with other antiretrovirals"

"Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including tenofovir."

"Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including tenefovir"

Interferon-α 2b
  • Adults:
  • Children:

"Alpha interferons cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders."

"Patients should be monitored closely with periodic clinical and laboratory evaluations."

"Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy."

PegIFNα
  • Adults:
  • Children:
  • 180 mcg/1.73 m2 × BSA/week

"May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders"

"Patients taking ribavirin: ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients"

Second Line Agents[9]
Drug Description Dosage Side-effects
Telbivudine
  • Adults:
  • 600 mg/day, PO
  • Children:
  • Safety is unknown

"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues"

"Severe acute exacerbations of hepatitis B have been reported in patients who discontinued anti-hepatitis B therapy, including Telbivudine"

"Hepatic function should be monitored closely in patients who discontinue therapy"

Adefovir
  • Adults and children >12 years:
  • 10 mg/day PO
  • Children:
  • Not recommended for use in children less than 12 years of age

"Severe acute exacerbations of hepatitis may occur in patients who discontinue adefovir. Monitor hepatic function closely in these patients"

"Chronic use of adefovir may result in nephrotoxicity in patients at risk of renal dysfunction or having underlying renal dysfunction. Monitor renal function closely in these patients. Dose adjustment may be required"

"HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection"

"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues"

Lamivudine
  • Adults and adolescents >16 years of age:
  • 300 mg/day, administered as either 150 mg 2x/day or 300 mg 1x/day
  • Children: 3 months - 16 years of age:
  • Dosage should be adjusted to body weight

"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur."

"Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV-1 and have discontinued lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment"

"Patients with HIV-1 infection should receive only dosage forms of lamivudine appropriate for treatment of HIV-1"

Recommended Treatment

Recommended Treatment of Chronic Hepatitis B[9]
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 >40 years, when:
  • Treatment should be considered when:
+ >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:
- >2 x Upper Limit of Normal >20,000 IU/mL
  • Initial therapy may include:
- [1; >2] x Upper Limit of Normal >2,000 IU/mL
- ≤ 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
  • If decompensated - Treatment should be coordinated with transplant center:
+/- Cirrhosis Untraceable

Response to Treatment According to Genotype

Despite the fact that current guidelines have yet to acknowledge the relevance of genotype to therapeutic outcomes, this identification has been increasingly recognized in recent studies. For a standard response of post-treatment HBeAg seroconversion and normalization of ALT levels, treatment with IFN-α was shown to be more effective in genotypes A and B, as opposed to C and D.[14] Being young and infected with genotype B HBV are also related to a sustained response to IFN-α.[15][16][17][18]

A study has shown that, for HBV genotype A infection, HBeAg-negative patients who were treated with pegylated IFN-α had higher clearance of HBsAg (20%), compared to 6% clearance for genotype B, 9% for genotype C, and 6% for genotype D.[19] It was also shown that:

  • Regardless of HBeAg status, patients with HBV genotype A had better response to treatment with IFN-α that those with genotype D
  • In HBeAg-positive patients, the genotype B has better response to treatment with IFN-α, than those with HBV genotype C[20]
  • In general, patients infected with HBV genotypes A and B respond better to treatment with IFN-α than those infected with HBV genotypes C and D[21]

Data from global trials on treatment with pegylated IFN-α of HBeAg-positive patients showed:[22]

  • Patients infected with HBV genotype A, with lower levels of HBV DNA and higher levels of ALT had high probability of sustained response to the treatment
  • Patients infected with HBV genotype B and C, with lower HBV DNA and higher ALT levels had high probability of sustained response to treatment
  • Regardless of levels of HBV DNA and ALT, patients with HBV genotype D had little sustained response to pegylated IFN-α.

Therefore, these data show that besides the viral genotype, host factors also play a role in the response to treatment.[23]

Regarding treatment of hepatitis B with nucleosides and nucleotides, no association has been established between the viral genotype and the response to treatment.[20]

Management of Drug Resistance

Prevention

To prevent antiviral drug-resistance, the following measures should be taken:[9]

  • 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:[9]

Treatment

In case of resistance to:[9]

Recommendations on Whom to Treat and with What Antiviral Agent: AASLD Practice Guidelines[9]

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)

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[9]

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[9]

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 [9]

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)

References

  1. 1.0 1.1 Vargas HE, Dodson FS, Rakela J (2002). "A concise update on the status of liver transplantation for hepatitis B virus: the challenges in 2002.". Liver Transpl. 8 (1): 2–9. PMID 11799479. doi:10.1053/jlts.2002.29765. 
  2. 2.0 2.1 Omata M (1990). "Significance of extrahepatic replication of hepatitis B virus.". Hepatology. 12 (2): 364–6. PMID 2202639. 
  3. 3.0 3.1 McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC; et al. (1996). "Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization.". Transplantation. 61 (9): 1358–64. PMID 8629297. 
  4. 4.0 4.1 Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W; et al. (2005). "Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence.". Liver Transpl. 11 (4): 402–9. PMID 15776431. doi:10.1002/lt.20402. 
  5. 5.0 5.1 5.2 5.3 5.4 World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016
  6. 6.0 6.1 "Hepatitis B" (PDF). 
  7. Lau GKK; et al. (2005). "Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B". N Engl J Med. 352 (26): 2682–95. PMID 15987917. 
  8. "EASL" (PDF). 
  9. 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 American Association for the Study of Liver Disease. Practice guideline for treatment of Hepatitis B{cite web | title = AASLD PRACTICE GUIDELINES | url = http://www.aasld.org/practiceguidelines/documents/bookmarked%20practice%20guidelines/chronic_hep_b_update_2009%208_24_2009.pdf }}
  10. "Chronic Hepatitis B: Integrating Long-Term Treatment Data and Strategies to Improve Outcomes in Clinical Practice". 
  11. Lai, CL.; Shouval, D.; Lok, AS.; Chang, TT.; Cheinquer, H.; Goodman, Z.; DeHertogh, D.; Wilber, R.; Zink, RC. (2006). "Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.". N Engl J Med. 354 (10): 1011–20. PMID 16525138. doi:10.1056/NEJMoa051287.  Unknown parameter |month= ignored (help)
  12. "First-line treatment of chronic hepatitis B with entecavir or tenofovir in ‘real-life’ settings: from clinical trials to clinical practice". 
  13. "Oxford Journals". 
  14. Lin CL, Kao JH (2011). "The clinical implications of hepatitis B virus genotype: Recent advances.". J Gastroenterol Hepatol. 26 Suppl 1: 123–30. PMID 21199523. doi:10.1111/j.1440-1746.2010.06541.x. 
  15. Liu CJ, Kao JH, Chen DS (2005). "Therapeutic implications of hepatitis B virus genotypes.". Liver Int. 25 (6): 1097–107. PMID 16343058. doi:10.1111/j.1478-3231.2005.01177.x. 
  16. Liu CJ, Kao JH (2008). "Genetic variability of hepatitis B virus and response to antiviral therapy.". Antivir Ther. 13 (5): 613–24. PMID 18771045. 
  17. Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS (2000). "Hepatitis B genotypes and the response to interferon therapy.". J Hepatol. 33 (6): 998–1002. PMID 11131465. 
  18. Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T; et al. (2005). "Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.". Gut. 54 (7): 1009–13. PMC 1774609Freely accessible. PMID 15951551. doi:10.1136/gut.2004.060327. 
  19. Piratvisuth T, Lau G, Chao YC, Jin R, Chutaputti A, Zhang QB; et al. (2008). "Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B.". Hepatol Int. 2 (1): 102–10. PMC 2716864Freely accessible. PMID 19669285. doi:10.1007/s12072-007-9022-5. 
  20. 20.0 20.1 Wiegand J, Hasenclever D, Tillmann HL (2008). "Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence.". Antivir Ther. 13 (2): 211–20. PMID 18505172. 
  21. Raimondi S, Maisonneuve P, Bruno S, Mondelli MU (2010). "Is response to antiviral treatment influenced by hepatitis B virus genotype?". J Hepatol. 52 (3): 441–9. PMID 20137824. doi:10.1016/j.jhep.2009.12.014. 
  22. Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW; et al. (2009). "Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa.". Gastroenterology. 137 (6): 2002–9. PMID 19737568. doi:10.1053/j.gastro.2009.08.061. 
  23. Kao JH (2007). "Appropriate use of interferon for treatment of chronic hepatitis B.". Hepatol Res. 37 (s1): S47–54. PMID 17627636. doi:10.1111/j.1872-034X.2007.00105.x. 

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