Hepatitis B medical therapy: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Hepatitis B}} | {{Hepatitis B}} | ||
{{CMG}}; {{AE}} {{chetan}} | {{CMG}}; {{AE}} {{chetan}}, {{JS}} | ||
==Overview== | ==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 [[alanine transaminase|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|interferon alpha-2a]] and [[pegylated interferon-alpha-2a]].<ref name="pmid11799479">{{cite journal| author=Vargas HE, Dodson FS, Rakela J| title=A concise update on the status of liver transplantation for hepatitis B virus: the challenges in 2002. | journal=Liver Transpl | year= 2002 | volume= 8 | issue= 1 | pages= 2-9 | pmid=11799479 | doi=10.1053/jlts.2002.29765 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11799479 }} </ref><ref name="pmid2202639">{{cite journal| author=Omata M| title=Significance of extrahepatic replication of hepatitis B virus. | journal=Hepatology | year= 1990 | volume= 12 | issue= 2 | pages= 364-6 | pmid=2202639 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2202639 }} </ref><ref name="pmid8629297">{{cite journal| author=McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC et al.| title=Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. | journal=Transplantation | year= 1996 | volume= 61 | issue= 9 | pages= 1358-64 | pmid=8629297 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8629297 }} </ref><ref name="pmid15776431">{{cite journal| author=Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W et al.| title=Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. | journal=Liver Transpl | year= 2005 | volume= 11 | issue= 4 | pages= 402-9 | pmid=15776431 | doi=10.1002/lt.20402 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15776431 }} </ref> | |||
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 [[ | |||
==Medical Therapy== | |||
===Acute Hepatitis B=== | ===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]], | * [[Nucleoside]]/[[nucleotide]] analog treatment may be considered in severe cases of [[acute hepatitis]], though trials in adults have not shown benefit | ||
* [[Liver transplant]] may be required | * [[Liver transplant]] may be required in cases of [[fulminant hepatitis]] | ||
* Unlike [[chronic hepatitis]], [[liver transplant]] in cases of acute hepatitis | * Unlike in [[chronic hepatitis]], [[liver transplant]] in cases of [[acute hepatitis]] carry a low risk of reinfection.<ref name=WHO-Guideline-Hepatitis-B> 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</ref><ref name="pmid11799479">{{cite journal| author=Vargas HE, Dodson FS, Rakela J| title=A concise update on the status of liver transplantation for hepatitis B virus: the challenges in 2002. | journal=Liver Transpl | year= 2002 | volume= 8 | issue= 1 | pages= 2-9 | pmid=11799479 | doi=10.1053/jlts.2002.29765 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11799479 }} </ref><ref name="pmid2202639">{{cite journal| author=Omata M| title=Significance of extrahepatic replication of hepatitis B virus. | journal=Hepatology | year= 1990 | volume= 12 | issue= 2 | pages= 364-6 | pmid=2202639 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2202639 }} </ref><ref name="pmid8629297">{{cite journal| author=McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC et al.| title=Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. | journal=Transplantation | year= 1996 | volume= 61 | issue= 9 | pages= 1358-64 | pmid=8629297 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8629297 }} </ref><ref name="pmid15776431">{{cite journal| author=Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W et al.| title=Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. | journal=Liver Transpl | year= 2005 | volume= 11 | issue= 4 | pages= 402-9 | pmid=15776431 | doi=10.1002/lt.20402 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15776431 }} </ref> | ||
===Chronic Hepatitis B=== | ===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. | 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.<ref name=WHO-Guideline-Hepatitis-B> 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</ref> | ||
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 | 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]].<ref name=WHO-Guideline-Hepatitis-B> 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</ref> | ||
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]]. | 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]].<ref name=WHO-Guideline-Hepatitis-B> 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</ref> | ||
[[Asymptomatic carrier|Chronic carriers]] are encouraged to avoid consuming [[alcohol]] as it increases their risk for [[cirrhosis]] and [[hepatocellular carcinoma]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref> | |||
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. | 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.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref> | ||
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.<ref>{{cite journal | author=Lau GKK ''et al'' | title=Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B | journal=N Engl J Med | year=2005 | pages=2682-95 | volume=352 | issue=26 | id=PMID 15987917}}</ref> However, it may help in patients with [[drug resistance|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 [[drug resistance|resistance]] | |||
===Indications to start antiviral medications=== | ===Indications to start antiviral medications=== | ||
Below are the curent indications to start treatment for chronic hepatits B:<ref>{{Cite web | last = | first = | title = EASL | url = http://www.easl.eu/assets/application/files/ef520780b91cf4f_file.pdf | publisher = | date = | accessdate = }}</ref> | |||
#[[Hepatitis B|Chronic hepatitis B]] ( HbeAg postive and negative ) with HBV DNA >2000 IU/ml | #[[Hepatitis B|Chronic hepatitis B]] (HbeAg postive and negative) with HBV DNA >2000 IU/ml and/or | ||
#Elevated [[ALT]] | #Elevated [[ALT]] | ||
#Severe [[necrosis]] and fibrosis on [[biopsy]] | #Severe [[necrosis]] and fibrosis on [[biopsy]] | ||
#Decompensated or compensated [[cirrhosis]] with normal [[ALT]] or HBV DNA <2000 IU/ml | #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. | *Treatment should be continued for at least 6 months after HBeAg loss/conversion. | ||
===Antiviral Medications=== | ===Antiviral Medications=== | ||
There are three types of treatment groups: | There are three types of treatment groups:<ref name=WHO-Guideline-Hepatitis-B> 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</ref> | ||
#[[Interferon]] ([[IFN]]) | #[[Interferon]] ([[IFN]]) | ||
#[[Antivirals|Nucleoside analogs]] | #[[Antivirals|Nucleoside analogs]] | ||
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{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center | {| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center | ||
|+'''''First Line Agents''''' | |+'''''First Line Agents<ref name=AASLD>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 }}</ref>''''' | ||
! style="background: #4479BA; width: 20%;" | {{fontcolor|#FFF|Drug}} | ! style="background: #4479BA; width: 20%;" | {{fontcolor|#FFF|Drug}} | ||
! style="background: #4479BA; width: 25%;" | {{fontcolor|#FFF|Description}} | ! style="background: #4479BA; width: 25%;" | {{fontcolor|#FFF|Description}} | ||
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| style="padding: 5px 5px; background: #F5F5F5;" |'''Entecavir''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''Entecavir''' | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*An anti-HBV nucleoside analog | *An anti-HBV [[nucleoside]] analog | ||
*A 94% clearance rate after 5 years of treatment is observed in HBeAg positive patients.<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Chronic Hepatitis B: Integrating Long-Term Treatment Data and Strategies to Improve Outcomes in Clinical Practice | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337661/ | publisher = | date = | accessdate = }}</ref> | *A 94% clearance rate after 5 years of treatment is observed in HBeAg positive patients.<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Chronic Hepatitis B: Integrating Long-Term Treatment Data and Strategies to Improve Outcomes in Clinical Practice | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337661/ | publisher = | date = | accessdate = }}</ref> | ||
*A 90% clearance rate after 48 weeks of treatment is observed in HBeAg negative patients.<ref name="Lai-2006">{{Cite journal | last1 = Lai | first1 = CL. | last2 = Shouval | first2 = D. | last3 = Lok | first3 = AS. | last4 = Chang | first4 = TT. | last5 = Cheinquer | first5 = H. | last6 = Goodman | first6 = Z. | last7 = DeHertogh | first7 = D. | last8 = Wilber | first8 = R. | last9 = Zink | first9 = RC. | title = Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. | journal = N Engl J Med | volume = 354 | issue = 10 | pages = 1011-20 | month = Mar | year = 2006 | doi = 10.1056/NEJMoa051287 | PMID = 16525138 }}</ref> | *A 90% clearance rate after 48 weeks of treatment is observed in HBeAg negative patients.<ref name="Lai-2006">{{Cite journal | last1 = Lai | first1 = CL. | last2 = Shouval | first2 = D. | last3 = Lok | first3 = AS. | last4 = Chang | first4 = TT. | last5 = Cheinquer | first5 = H. | last6 = Goodman | first6 = Z. | last7 = DeHertogh | first7 = D. | last8 = Wilber | first8 = R. | last9 = Zink | first9 = RC. | title = Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. | journal = N Engl J Med | volume = 354 | issue = 10 | pages = 1011-20 | month = Mar | year = 2006 | doi = 10.1056/NEJMoa051287 | PMID = 16525138 }}</ref> | ||
*A necroinflammation improvement of 96% and fibrosis improvement of 88% is seen after | *A necroinflammation improvement of 96% and [[fibrosis]] improvement of 88% is seen after treatment for 6 years.<ref name="First">{{Cite web | last = | first = | title = First-line treatment of chronic hepatitis B with entecavir or tenofovir in ‘real-life’ settings: from clinical trials to clinical practice | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489060/ | publisher = | date = | accessdate = }}</ref> | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Adults: | *Adults: | ||
:*''Nucleoside-inhibitor-treatment-naïve adults and adolescents ≥16 years of age'' - ''0.5 mg/day'' | :*''[[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'' | :*''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'' | :*''Decompensated Liver Disease'' - ''1 mg/day'' | ||
*Children with body weight >30 kg: | *Children with body weight >30 kg: | ||
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:*''Lamivudine-Experienced'': | :*''Lamivudine-Experienced'': | ||
::*1 mg/day (20 mL of oral solution or one 1 mg tablet) | ::*1 mg/day (20 mL of oral solution or one 1 mg tablet) | ||
*Renal impaired patients should have dosages adjusted to their levels of creatinine clearance | *[[Renal]] impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | ||
*Hepatic impaired patients should have dosages adjusted | *[[Hepatic]] impaired patients should have dosages adjusted | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Exacerbations of hepatitis after discontinuation of treatment | *Exacerbations of hepatitis after discontinuation of treatment | ||
*Lactic acidosis and severe hepatomegaly with steatosis | *[[Lactic acidosis]] and severe [[hepatomegaly]] with [[steatosis]] | ||
*Diarrhea | *[[Diarrhea]] | ||
*Dyspepsia | *[[Dyspepsia]] | ||
*Nausea and vomiting | *[[Nausea]] and [[vomiting]] | ||
*Headache | *[[Headache]] | ||
*Dizziness | *[[Dizziness]] | ||
*Insomnia | *[[Insomnia]] | ||
''{{fontcolor|red|"Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued entecavir"}}'' | ''{{fontcolor|red|"Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued entecavir"}}'' | ||
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| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*An anti-HBV nucleotide analog | *An anti-HBV nucleotide analog | ||
*A 68% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg positive patients.<ref name="jid.oxfordjournals.org">{{Cite web | last = | first = | title = | *A 68% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg positive patients.<ref name="jid.oxfordjournals.org">{{Cite web | last = | first = | title = Oxford Journals | url = http://jid.oxfordjournals.org/content/204/3/415.full | publisher = | date = | accessdate = }}</ref> | ||
*A 84% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg negative patients. | *A 84% clearance rate in HBV DNA after 4 years of treatment is observed in HBeAg negative patients. | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
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*Renal impaired patients should have dosages adjusted to their levels of creatinine clearance | *Renal impaired patients should have dosages adjusted to their levels of creatinine clearance | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*[[Lactic Acidosis]]/ | *[[Lactic Acidosis]]/severe [[hepatomegaly]] with [[steatosis]] | ||
*Severe | *Severe acute exacerbation of [[hepatitis]] | ||
*New | *New onset or worsening renal impairment | ||
*Decreases in | *Decreases in bone mineral density | ||
*Immune | *Immune reconstitution syndrome | ||
*[[Headache]] | *[[Headache]] | ||
*[[Fever]] | *[[Fever]] | ||
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''{{fontcolor|red|"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"}}'' | ''{{fontcolor|red|"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"}}'' | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''Interferon-α''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''Interferon-α 2b''' | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Antiviral and antiproliferative glycoprotein | *[[Antiviral]] and antiproliferative [[glycoprotein]] | ||
*No antiviral resistance | *No [[antiviral]] [[resistance]] has been noted | ||
*Best results noted with genotype A or B who are HBeAg positive | *Best results noted with genotype A or B patients who are HBeAg positive | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Adults: | *Adults: | ||
:*5 MU/day or 10 MU 3x/week subcutaneously | :*5 MU/day or 10 MU 3x/week [[subcutaneous|subcutaneously]] | ||
*Children: | *Children: | ||
:*6 MU/m<sup>2</sup> 3x/week (maximum 10 MU) subcutaneously | :*6 MU/m<sup>2</sup> 3x/week (maximum 10 MU) [[subcutaneous|subcutaneously]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*[[Flu]]-like symptoms | |||
*[[Back pain]] | |||
*[[Dry mouth]] | |||
*[[Chest pain]] | |||
*[[Malaise]] | |||
*[[Diarrhea]] | |||
*[[Anorexia]] | |||
*[[Nausea]] | |||
*[[Abdominal pain]] | |||
*[[Depression]] | |||
''{{fontcolor|red|"Alpha interferons cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders."}}'' | |||
''{{fontcolor|red|"Patients should be monitored closely with periodic clinical and laboratory evaluations."}}'' | |||
''{{fontcolor|red|"Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy."}}'' | |||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''PegIFNα''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''PegIFNα''' | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Antiviral and antiproliferative glycoprotein | *[[Antiviral]] and antiproliferative [[glycoprotein]] | ||
*No antiviral resistance | *No [[antiviral]] [[resistance]] has been noted | ||
*Best results noted with genotype A or B who are HBeAg positive | *Best results noted with genotype A or B patients who are HBeAg positive | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Adults: | *Adults: | ||
:*180 mcg/week subcutaneously | :*180 mcg/week [[subcutaneous|subcutaneously]] | ||
*Children: | *Children: | ||
:*180 mcg/1.73 m2 × BSA/week | :*180 mcg/1.73 m2 × BSA/week | ||
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*Relapse of drug abuse/overdose | *Relapse of drug abuse/overdose | ||
*[[Bacterial infections]] | *[[Bacterial infections]] | ||
*Hepatic decompensation of CHC/HIV patients | *[[Hepatic]] decompensation of CHC/HIV patients | ||
''{{fontcolor|red|"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"}}'' | ''{{fontcolor|red|"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"}}'' | ||
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{| style="border: 0px; font-size: 90%; margin: 3px; width:80%" align=center | {| style="border: 0px; font-size: 90%; margin: 3px; width:80%" align=center | ||
|+'''''Second Line Agents''''' | |+'''''Second Line Agents<ref name=AASLD>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 }}</ref>''''' | ||
! style="background: #4479BA; width: 20%;" | {{fontcolor|#FFF|Drug}} | ! style="background: #4479BA; width: 20%;" | {{fontcolor|#FFF|Drug}} | ||
! style="background: #4479BA; width: 25%;" | {{fontcolor|#FFF|Description}} | ! style="background: #4479BA; width: 25%;" | {{fontcolor|#FFF|Description}} | ||
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| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*[[Antivirals|Nucleoside analog]] | *[[Antivirals|Nucleoside analog]] | ||
* | *Affects [[resistance]] than first line agents and not indicated if resistance to other [[nucleoside]] analogs are noted. | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Adults: | *Adults: | ||
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*Renal impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | *Renal impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Lactic acidosis and severe hepatomegaly with steatosis | *[[Lactic acidosis]] and severe [[hepatomegaly]] with [[steatosis]] | ||
*Severe acute exacerbations of hepatitis after discontinuation of treatment | *Severe acute exacerbations of [[hepatitis]] after discontinuation of treatment | ||
*Myopathy | *[[Myopathy]] | ||
*Peripheral neuropathy | *[[Peripheral neuropathy]] | ||
''{{fontcolor|red|"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues"}}'' | ''{{fontcolor|red|"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues"}}'' | ||
Line 213: | Line 205: | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*[[Antivirals|Nucleotide analog]] | *[[Antivirals|Nucleotide analog]] | ||
*Worse resistance than first line agents | *Worse [[resistance]] than first line agents | ||
*Used in cases of nucleotide analog resistance | *Used in cases of [[nucleotide]] analog [[resistance]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Adults and children >12 years: | *Adults and children >12 years: | ||
Line 222: | Line 214: | ||
*Renal impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | *Renal impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Severe acute exacerbations of | *Severe acute exacerbations of [[hepatitis]] | ||
*Nephrotoxicity | *[[Nephrotoxicity]] | ||
''{{fontcolor|red|"Severe acute exacerbations of hepatitis may occur in patients who discontinue adefovir. Monitor hepatic function closely in these patients"}}'' | ''{{fontcolor|red|"Severe acute exacerbations of hepatitis may occur in patients who discontinue adefovir. Monitor hepatic function closely in these patients"}}'' | ||
Line 236: | Line 228: | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*[[Antivirals|Nucleoside analog]] | *[[Antivirals|Nucleoside analog]] | ||
*Has a high rate of resistance and | *Has a high rate of [[resistance]] and thus is not currently used | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Adults and adolescents >16 years of age: | *Adults and adolescents >16 years of age: | ||
Line 244: | Line 236: | ||
*Renal impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | *Renal impaired patients should have dosages adjusted to their levels of [[creatinine clearance]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Lactic acidosis and severe hepatomegaly with steatosis | *[[Lactic acidosis]] and severe [[hepatomegaly]] with [[steatosis]] | ||
*Severe acute exacerbations of hepatitis B | *Severe acute exacerbations of [[hepatitis B]] | ||
*Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C | *[[Hepatic]] decompensation in patients co-infected with [[HIV-1]] and [[hepatitis C]] | ||
*[[Pancreatitis]] | *[[Pancreatitis]] | ||
*[[Headache]] | *[[Headache]] | ||
Line 255: | Line 247: | ||
*[[Nausea]] and [[vomiting]] | *[[Nausea]] and [[vomiting]] | ||
*[[Neuropathy]] | *[[Neuropathy]] | ||
*Nasal signs & symptoms | *Nasal [[signs]] & [[symptoms]] | ||
*[[Musculoskeletal pain]] | *[[Musculoskeletal pain]] | ||
''{{fontcolor|red|"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."}}'' | ''{{fontcolor|red|"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."}}'' | ||
Line 266: | Line 258: | ||
==Recommended Treatment== | ==Recommended Treatment== | ||
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center | {| style="border: 0px; font-size: 90%; margin: 3px;" align=center | ||
|+'''''Recommended Treatment of Chronic Hepatitis B''''' | |+'''''Recommended Treatment of Chronic Hepatitis B<ref name=AASLD>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 }}</ref>''''' | ||
! style="background: #4479BA; width: 4%;" | {{fontcolor|#FFF|HBeAg}} | ! style="background: #4479BA; width: 4%;" | {{fontcolor|#FFF|HBeAg}} | ||
! style="background: #4479BA; width: 17%;" | {{fontcolor|#FFF|ALT}} | ! style="background: #4479BA; width: 17%;" | {{fontcolor|#FFF|ALT}} | ||
Line 276: | Line 268: | ||
| style="padding: 5px 5px; background: #F5F5F5;" |''>20,000 IU/mL'' | | style="padding: 5px 5px; background: #F5F5F5;" |''>20,000 IU/mL'' | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Low efficacy with present treatment | *Low [[efficacy]] with present treatment | ||
*Observe: treatment should be considered as ALT rises | *Observe: treatment should be considered as [[ALT]] rises | ||
*Biopsy should be considered in adults > | *[[Biopsy]] should be considered in adults >40 years, when: | ||
:*Persistence of an elevated ALT: [Normal;<2xUpper Limit of Normal] | :*Persistence of an elevated [[ALT]]: [Normal;<2xUpper Limit of Normal] | ||
:*Family history of hepatocellular carcinoma | :*Family history of [[hepatocellular carcinoma]] | ||
*Treatment should be considered when: | *Treatment should be considered when: | ||
:*HBV DNA > 20,000 IU/mL | :*HBV DNA > 20,000 IU/mL | ||
:*Signs of inflammation (moderate to severe) or fibrosis on biopsy | :*Signs of [[inflammation]] (moderate to severe) or [[fibrosis]] on [[biopsy]] | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''+''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''+''' | ||
Line 290: | Line 282: | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Observation for 3 to 6 months. Treatment should be started if no spontaneous HBeAg loss | *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 compensated, [[liver biopsy]] should be considered prior to treatment | ||
*If patient is jaundiced or decompensated, start immediate treatment | *If patient is [[jaundice|jaundiced]] or decompensated, start immediate treatment | ||
*Initial therapy may include: | *Initial therapy may include: | ||
:* | :*[[IFN-α]]/pegIFNα | ||
:*Lamivudine | :*[[Lamivudine]] | ||
:*Adefovir | :*[[Adefovir]] | ||
:*Entecavir | :*[[Entecavir]] | ||
:*Tenefovir | :*Tenefovir | ||
:*Telbivudine | :*[[Telbivudine]] | ||
*Adefovir plays a minor role due to increased resistance rate after 1 year, and weak antiviral activity | *[[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 | *[[Lamivudine]] and [[telbivudine]] play a minor role due to increased [[resistance]] rate | ||
*Treatment goal - seroconversion with production of anti-HBe to HBeAg | *Treatment goal - [[seroconversion]] with production of anti-HBe to HBeAg | ||
*Treatment duration: | *Treatment duration: | ||
:*IFN-α - 16 weeks | :*[[IFN-α]] - 16 weeks | ||
:*PegIFN-α - 48 weeks | :*PegIFN-α - 48 weeks | ||
:*Lamivudine | :*[[Lamivudine]], [[adefovir]], [[entecavir]], [[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 | :*[[Tenofovir disoproxil fumarate]] or [[entecavir]] for: absence of response to [[IFN-α]]; or when [[IFN-α]] is contraindicated | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''-''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''-''' | ||
Line 313: | Line 305: | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Initial therapy may include: | *Initial therapy may include: | ||
:*IFN-α/PegIFN-α | :*[[IFN-α]]/PegIFN-α | ||
:*Lamivudine | :*[[Lamivudine]] | ||
:*Adefovir | :*[[Adefovir]] | ||
:*Entecavir | :*[[Entecavir]] | ||
:*Tenofovir disoproxil fumarate | :*Tenofovir disoproxil fumarate | ||
:*Telbivudine | :*[[Telbivudine]] | ||
*Lamivudine and telbivudine play a minor role due to increased resistance rate | *[[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 | *[[Adefovir]] plays a minor role due to increased [[resistance]] rate after 1 year, and weak antiviral activity | ||
*Treatment end-point not defined | *Treatment end-point not defined | ||
*Treatment duration: | *Treatment duration: | ||
:*IFN-α/PegIFN-α - 1 year | :*[[IFN-α]]/PegIFN-α - 1 year | ||
:*Lamivudine | :*[[Lamivudine]], [[adefovir]], [[entecavir]], [[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 | :*Tenofovir disoproxil fumarate or [[entecavir]] for: absence of response to [[IFN-α]]; or when [[IFN-α]] is contraindicated | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''-''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''-''' | ||
Line 331: | Line 323: | ||
| style="padding: 5px 5px; background: #F5F5F5;" |''>2,000 IU/mL'' | | style="padding: 5px 5px; background: #F5F5F5;" |''>2,000 IU/mL'' | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*If signs of necroinflammation (moderate to severe) or fibrosis on liver biopsy - consider liver biopsy and treatment | *If signs of necroinflammation (moderate to severe) or fibrosis on [[liver biopsy]] - consider [[liver biopsy]] and treatment | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''-''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''-''' | ||
Line 337: | Line 329: | ||
| style="padding: 5px 5px; background: #F5F5F5;" |''≤2,000 IU/mL'' | | style="padding: 5px 5px; background: #F5F5F5;" |''≤2,000 IU/mL'' | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Observation. Treatment should be started when: ALT or HBV DNA rise | *Observation. Treatment should be started when: [[ALT]] or HBV DNA rise | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''+/-''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''+/-''' | ||
Line 345: | Line 337: | ||
*If compensated: | *If compensated: | ||
:*If HBV DNA >2,000 IU/mL - Initial therapy may include | :*If HBV DNA >2,000 IU/mL - Initial therapy may include | ||
::*Lamivudine | ::*[[Lamivudine]] | ||
::*Adefovir | ::*[[Adefovir]] | ||
::*Entecavir | ::*[[Entecavir]] | ||
::*Telbivudine | ::*[[Telbivudine]] | ||
::*Tenofovir disoproxil fumarate | ::*Tenofovir disoproxil fumarate | ||
:*Lamivudine and telbivudine play a minor role due to increased resistance rate | :*[[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 | :*[[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 HBV DNA <2,000 IU/mL - Treatment should be considered if elevated [[ALT]] | ||
*If decompensated - Treatment should be coordinated with transplant center: | *If decompensated - Treatment should be coordinated with transplant center: | ||
:*Lamivudine (or telbivudine) + adefovir or tenofovir disoproxil fumarate or entecavir( | :*[[Lamivudine]] (or telbivudine) + [[adefovir]] or tenofovir disoproxil fumarate or [[entecavir]] (preferred) | ||
:*Referal for liver transplant | :*Referal for [[liver transplant]] | ||
|- | |- | ||
| style="padding: 5px 5px; background: #F5F5F5;" |'''+/-''' | | style="padding: 5px 5px; background: #F5F5F5;" |'''+/-''' | ||
Line 362: | Line 354: | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*If compensated - observation | *If compensated - observation | ||
*If decompensated - indication | *If decompensated - indication for [[liver transplant]] | ||
|- | |- | ||
|} | |} | ||
===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 [[genotype|genotypes]] A and B, as opposed to C and D.<ref name="pmid21199523">{{cite journal| author=Lin CL, Kao JH| title=The clinical implications of hepatitis B virus genotype: Recent advances. | journal=J Gastroenterol Hepatol | year= 2011 | volume= 26 Suppl 1 | issue= | pages= 123-30 | pmid=21199523 | doi=10.1111/j.1440-1746.2010.06541.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21199523 }} </ref> Being young and infected with [[genotype]] B [[HBV]] are also related to a sustained response to [[IFN-α]].<ref name="pmid16343058">{{cite journal| author=Liu CJ, Kao JH, Chen DS| title=Therapeutic implications of hepatitis B virus genotypes. | journal=Liver Int | year= 2005 | volume= 25 | issue= 6 | pages= 1097-107 | pmid=16343058 | doi=10.1111/j.1478-3231.2005.01177.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16343058 }} </ref><ref name="pmid18771045">{{cite journal| author=Liu CJ, Kao JH| title=Genetic variability of hepatitis B virus and response to antiviral therapy. | journal=Antivir Ther | year= 2008 | volume= 13 | issue= 5 | pages= 613-24 | pmid=18771045 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18771045 }} </ref><ref name="pmid11131465">{{cite journal| author=Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS| title=Hepatitis B genotypes and the response to interferon therapy. | journal=J Hepatol | year= 2000 | volume= 33 | issue= 6 | pages= 998-1002 | pmid=11131465 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11131465 }} </ref><ref name="pmid15951551">{{cite journal| author=Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T et al.| title=Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. | journal=Gut | year= 2005 | volume= 54 | issue= 7 | pages= 1009-13 | pmid=15951551 | doi=10.1136/gut.2004.060327 | pmc=PMC1774609 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15951551 }} </ref> | |||
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.<ref name="pmid19669285">{{cite journal| author=Piratvisuth T, Lau G, Chao YC, Jin R, Chutaputti A, Zhang QB et al.| title=Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. | journal=Hepatol Int | year= 2008 | volume= 2 | issue= 1 | pages= 102-10 | pmid=19669285 | doi=10.1007/s12072-007-9022-5 | pmc=PMC2716864 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19669285 }} </ref> 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<ref name="pmid18505172">{{cite journal| author=Wiegand J, Hasenclever D, Tillmann HL| title=Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence. | journal=Antivir Ther | year= 2008 | volume= 13 | issue= 2 | pages= 211-20 | pmid=18505172 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18505172 }} </ref> | |||
*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<ref name="pmid20137824">{{cite journal| author=Raimondi S, Maisonneuve P, Bruno S, Mondelli MU| title=Is response to antiviral treatment influenced by hepatitis B virus genotype? | journal=J Hepatol | year= 2010 | volume= 52 | issue= 3 | pages= 441-9 | pmid=20137824 | doi=10.1016/j.jhep.2009.12.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20137824 }} </ref> | |||
Data from global trials on treatment with pegylated [[IFN-α]] of HBeAg-positive patients showed:<ref name="pmid19737568">{{cite journal| author=Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW et al.| title=Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. | journal=Gastroenterology | year= 2009 | volume= 137 | issue= 6 | pages= 2002-9 | pmid=19737568 | doi=10.1053/j.gastro.2009.08.061 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19737568 }} </ref> | |||
*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.<ref name="pmid17627636">{{cite journal| author=Kao JH| title=Appropriate use of interferon for treatment of chronic hepatitis B. | journal=Hepatol Res | year= 2007 | volume= 37 | issue= s1 | pages= S47-54 | pmid=17627636 | doi=10.1111/j.1872-034X.2007.00105.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17627636 }} </ref> | |||
Regarding treatment of hepatitis B with [[nucleosides]] and [[nucleotides]], no association has been established between the viral [[genotype]] and the response to treatment.<ref name="pmid18505172">{{cite journal| author=Wiegand J, Hasenclever D, Tillmann HL| title=Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence. | journal=Antivir Ther | year= 2008 | volume= 13 | issue= 2 | pages= 211-20 | pmid=18505172 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18505172 }} </ref> | |||
==Management of Drug Resistance== | ==Management of Drug Resistance== | ||
===Prevention=== | ===Prevention=== | ||
To prevent | To prevent [[antiviral]] drug-resistance, the following measures should be taken:<ref name=AASLD>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 }}</ref> | ||
*Avoidance of unnecessary treatment | *Avoidance of unnecessary treatment | ||
*Treatment should be initiated with a low [[drug resistance|resistance]] drug, or with combination therapy | *Treatment should be initiated with a low [[drug resistance|resistance]] drug, or with combination therapy | ||
Line 374: | Line 383: | ||
===Monitoring=== | ===Monitoring=== | ||
During treatment the following should be monitored: | During treatment the following should be monitored:<ref name=AASLD>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 }}</ref> | ||
*Serum HBV DNA during course of treatment, every 3 to 6 months | *Serum HBV DNA during course of treatment, every 3 to 6 months | ||
*Treatment compliance | *Treatment compliance | ||
Line 380: | Line 389: | ||
===Treatment=== | ===Treatment=== | ||
In case of [[resistance]] to: | In case of [[resistance]] to:<ref name=AASLD>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 }}</ref> | ||
*[[Lamivudine]] | *[[Lamivudine]] | ||
:*Stop [[lamivudine]] | :*Stop [[lamivudine]] and initiate [[truvada]] ([[emtricitabine]] + [[tenofovir]]) | ||
:*[[Adefovir]] or [[tenofovir]] should be added | :*[[Adefovir]] or [[tenofovir]] should be added | ||
*[[Adefovir]] | *[[Adefovir]] | ||
:*Initiate [[lamivudine]] | :*Initiate [[lamivudine]] | ||
:*Stop [[adefovir]] | :*Stop [[adefovir]] and initiate [[truvada]] ([[emtricitabine]] + [[tenofovir]]) | ||
:*Add or switch to [[entecavir]] | :*Add or switch to [[entecavir]] | ||
*[[Entecavir]] | *[[Entecavir]] | ||
:*Stop [[entecavir]] | :*Stop [[entecavir]] and initiate [[truvada]] ([[emtricitabine]] + [[tenofovir]]) or [[tenofovir]] | ||
*[[Telbivudine]] | *[[Telbivudine]] | ||
:*Initiate [[adefovir]] or [[tenofovir]] | :*Initiate [[adefovir]] or [[tenofovir]] | ||
:*Stop [[telbivudine]] | :*Stop [[telbivudine]] and initiate [[truvada]] ([[emtricitabine]] + [[tenofovir]]) | ||
==Recommendations on Whom to Treat and with What Antiviral Agent: AASLD Practice Guidelines | ==Recommendations on Whom to Treat and with What Antiviral Agent: AASLD Practice Guidelines<ref name=AASLD>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 }}</ref>== | ||
{{cquote| | {{cquote| | ||
'''1.''' Patients with HBeAg-positive chronic hepatitis B | '''1.''' Patients with HBeAg-positive chronic hepatitis B | ||
Line 449: | Line 458: | ||
'''11.''' In patients with inactive HBsAg carrier state antiviral treatment is not indicated, but these patients should be monitored.}} | '''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 | ==Recommendations for Dose Regimens: AASLD Practice Guidelines<ref name=AASLD>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 }}</ref>== | ||
{{cquote| | {{cquote| | ||
'''1.''' [[IFN-α]] and pegIFN-α are administered as subcutaneous injections. | '''1.''' [[IFN-α]] and pegIFN-α are administered as subcutaneous injections. | ||
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:'''d.''' Decompensated cirrhosis and recurrent hepatitis B post–liver transplantation — Life-long treatment is recommended. (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 | ==Recommendations for Initial Evaluation of Persons with Chronic HBV Infection: AASLD Practice Guidelines<ref name=AASLD>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 }}</ref>== | ||
{{cquote| | {{cquote| | ||
'''1.''' Initial evaluation of persons newly diagnosed with chronic HBV infection should include history, physical examination and laboratory testing. (Grade III) | '''1.''' Initial evaluation of persons newly diagnosed with chronic HBV infection should include history, physical examination and laboratory testing. (Grade III) | ||
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'''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)}} | '''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 | ==Recommendations for Treatment of Patients with Acute Symptomatic Hepatitis B: AASLD Practice Guidelines <ref name=AASLD>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 }}</ref>== | ||
{{cquote| | {{cquote| | ||
'''1.''' Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B. (Grade III) | '''1.''' Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B. (Grade III) | ||
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[[Category:Emergency mdicine]] | |||
[[Category:Disease]] | [[Category:Disease]] | ||
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[[Category:Infectious disease]] | |||
[[Category:Hepatology]] |
Latest revision as of 22:04, 29 July 2020
Hepatitis B |
Diagnosis |
Treatment |
Case Studies |
Hepatitis B medical therapy On the Web |
American Roentgen Ray Society Images of Hepatitis B medical therapy |
Risk calculators and risk factors for Hepatitis B medical therapy |
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.
- Nucleoside/nucleotide analog treatment may be considered in severe cases of acute hepatitis, though trials in adults have not shown benefit
- Liver transplant may be required in cases of fulminant hepatitis
- Unlike in chronic hepatitis, liver transplant in cases of acute hepatitis carry a low risk of reinfection.[5][1][2][3][4]
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]
- Chronic hepatitis B (HbeAg postive and negative) with HBV DNA >2000 IU/ml and/or
- Elevated ALT
- Severe necrosis and fibrosis on biopsy
- 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]
Drug | Description | Dosage | Side-effects |
---|---|---|---|
Entecavir |
|
|
"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 |
|
|
"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 |
|
|
"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 |
|
|
"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" |
Drug | Description | Dosage | Side-effects |
---|---|---|---|
Telbivudine |
|
|
"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 |
|
|
"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 |
|
|
"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
HBeAg | ALT | HBV DNA | Treatment Regimen |
---|---|---|---|
+ | ≤2 x Upper Limit of Normal | >20,000 IU/mL |
|
+ | >2 x Upper Limit of Normal | >20,000 IU/mL |
|
- | >2 x Upper Limit of Normal | >20,000 IU/mL† |
|
- | [1; >2] x Upper Limit of Normal | >2,000 IU/mL |
|
- | ≤ Upper Limit of Normal | ≤2,000 IU/mL |
|
+/- | Cirrhosis | Traceable |
|
+/- | 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]
- Serum HBV DNA during course of treatment, every 3 to 6 months
- Treatment compliance
- Drug resistance with genotyping testing
Treatment
In case of resistance to:[9]
- Stop lamivudine and initiate truvada (emtricitabine + tenofovir)
- Adefovir or tenofovir should be added
- Initiate lamivudine
- Stop adefovir and initiate truvada (emtricitabine + tenofovir)
- Add or switch to entecavir
- Stop entecavir and initiate truvada (emtricitabine + tenofovir) or tenofovir
- Initiate adefovir or tenofovir
- Stop telbivudine and initiate truvada (emtricitabine + tenofovir)
Recommendations on Whom to Treat and with What Antiviral Agent: AASLD Practice Guidelines[9]
“ |
1. Patients with HBeAg-positive chronic hepatitis B
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)
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
6. Treatment of patients with lamivudine (or telbivudine)-resistant HBV
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
8. Treatment of patients with entecavir-resistant HBV
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)
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)
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.
2. Lamivudine is administered orally.
3. Adefovir is administered orally.
4. Entecavir is administered orally.
5. Telbivudine is administered orally.
6. Tenofovir is administered orally.
7. Duration of nucleoside analogue treatment
|
” |
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)
|
” |
References
- ↑ 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. doi:10.1053/jlts.2002.29765. PMID 11799479.
- ↑ 2.0 2.1 Omata M (1990). "Significance of extrahepatic replication of hepatitis B virus". Hepatology. 12 (2): 364–6. PMID 2202639.
- ↑ 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.
- ↑ 4.0 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. doi:10.1002/lt.20402. PMID 15776431.
- ↑ 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
- ↑ 6.0 6.1 "Hepatitis B" (PDF).
- ↑ 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.
- ↑ "EASL" (PDF).
- ↑ 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 }}
- ↑ "Chronic Hepatitis B: Integrating Long-Term Treatment Data and Strategies to Improve Outcomes in Clinical Practice".
- ↑ 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. doi:10.1056/NEJMoa051287. PMID 16525138. Unknown parameter
|month=
ignored (help) - ↑ "First-line treatment of chronic hepatitis B with entecavir or tenofovir in 'real-life' settings: from clinical trials to clinical practice".
- ↑ "Oxford Journals".
- ↑ Lin CL, Kao JH (2011). "The clinical implications of hepatitis B virus genotype: Recent advances". J Gastroenterol Hepatol. 26 Suppl 1: 123–30. doi:10.1111/j.1440-1746.2010.06541.x. PMID 21199523.
- ↑ Liu CJ, Kao JH, Chen DS (2005). "Therapeutic implications of hepatitis B virus genotypes". Liver Int. 25 (6): 1097–107. doi:10.1111/j.1478-3231.2005.01177.x. PMID 16343058.
- ↑ Liu CJ, Kao JH (2008). "Genetic variability of hepatitis B virus and response to antiviral therapy". Antivir Ther. 13 (5): 613–24. PMID 18771045.
- ↑ 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.
- ↑ 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. doi:10.1136/gut.2004.060327. PMC 1774609. PMID 15951551.
- ↑ 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. doi:10.1007/s12072-007-9022-5. PMC 2716864. PMID 19669285.
- ↑ 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.
- ↑ 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. doi:10.1016/j.jhep.2009.12.014. PMID 20137824.
- ↑ 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. doi:10.1053/j.gastro.2009.08.061. PMID 19737568.
- ↑ Kao JH (2007). "Appropriate use of interferon for treatment of chronic hepatitis B." Hepatol Res. 37 (s1): S47–54. doi:10.1111/j.1872-034X.2007.00105.x. PMID 17627636.