Hepatitis B Điều trị

Evaluation

The evaluation of patients suspected of hepatitis B begins with a history and physical examination. Measure HBeAg, anti-HBe, HBV DNA, and ALTs, and perform a liver ultrasound. HBeAg and anti-HBe are important in determining the phase of chronic hepatitis B virus infection. HBV DNA serum level is used to diagnose, establish the phase of the infection, decide to treat, and monitor treatment. In HBeAg-positive chronic hepatitis B, HBV DNA level is >20,000 IU/mL while it is <20,000 IU/mL in HBeAg-negative chronic hepatitis B. ALT and/or AST levels may be normal or elevated in chronic hepatitis B.

CBC, PT, and serum albumin are also measured to determine disease severity. It is also essential to screen high-risk patients for HCC every 6-12 months using ultrasound and alpha-fetoprotein. 

If the patient meets the criteria for chronic hepatitis B, a liver biopsy may be done to grade the stage of liver disease as chronic hepatitis B may evolve into cirrhosis and HCC. A liver biopsy is essential in determining disease activity in cases of inconclusive biochemical and HBV markers.

Principles of therapy

Acute Hepatitis B

The main goal of treatment for acute hepatitis B is to prevent the risk of acute or subacute hepatic failure. Another relevant goal of treatment is to improve the quality of life by shortening the disease duration associated with symptoms as well as the risk of chronicity. Supportive care should be given as treatment with antivirals is generally not recommended. Consider hospitalization if there is vomiting, dehydration, or signs of hepatic decompensation. Consider treatment with nucleoside or nucleotide analogues in patients with severe acute hepatitis.

Chronic Hepatitis B

Vaccination against hepatitis B for non-immune patients is important.

Periodic screening for HCC in high-risk carriers is likewise essential. HCC may have a long asymptomatic stage lasting for 2 years or longer. Carriers of hepatitis B virus at high risk for developing HCC include Asian men >40 years, Asian women >50 years, patients with cirrhosis, coinfected with hepatitis C virus, with hepatitis B virus genotype C, with hepatitis D virus infection, persistent HBV DNA of >2000 IU/mL, or those with a family history of HCC in a first-degree relative. Screening methods are ultrasound with or without alpha-fetoprotein (AFP) determination every 6 months.

A liver biopsy may be performed to assess the degree of liver damage, rule out other causes of liver disease, and help predict the prognosis. It is also recommended for chronic hepatitis B patients who are candidates for antiviral therapy.

Hepatitis D

The aim of treatment in patients with hepatitis D is to eradicate or to achieve long-term suppression of both hepatitis D virus and hepatitis B virus. Supportive care should be given, and hospitalization should be considered if there is vomiting, dehydration, or signs of hepatic decompensation. It is essential to screen the patient for other sexually transmitted diseases in cases of sexually acquired hepatitis or if otherwise appropriate. Consideration of an expert referral is also important.

Pharmacological therapy

Severe Acute Hepatitis B

Severe acute hepatitis B is characterized by coagulopathy, persistent jaundice for >4 weeks, or signs of acute hepatic failure. More than 95% of immunocompetent individuals with symptomatic acute hepatitis B would recover spontaneously without antiviral therapy. Antiviral therapy is given only to patients with acute liver failure or with a protracted severe course (ie total bilirubin >3 mg/dL, international normalized ratio of >1.5, presence of ascites or encephalopathy).

Entecavir, Tenofovir alafenamide, or Tenofovir disoproxil fumarate may be used in these patients, while Peginterferon is contraindicated. Observational data have shown that early nucleos(t)ide analogue treatment can reduce rates of chronicity if treatment is initiated within 8 weeks of acute hepatitis B. Continue treatment until HBsAg is cleared or indefinitely if to undergo liver transplantation.

Chronic Hepatitis

In patients without clinical evidence of cirrhosis, with persistently normal ALT, HBV DNA of <2,000 IU/mL, regardless of HBeAg status or age, treatment is not recommended.

Treatment is recommended in patients who have evidence of compensated or decompensated cirrhosis regardless of HBeAg status or HBV DNA or ALT levels; those without clinical evidence of cirrhosis but with persistently abnormal ALT, HBV DNA of >20,000 IU/mL, regardless of HBeAg status; and those with chronic hepatitis B virus severe reactivation.

The primary goal of treatment in chronic hepatitis B treatment is to permanently suppress hepatitis B virus or to eliminate it. It is necessary to achieve continued viral suppression to reduce or prevent hepatic disease and disease progression. The short-term goals are to sustain the suppression of HBV DNA, ALT normalization, to prevent decompensation, and to decrease hepatic necroinflammation and fibrosis during and after therapy. The long-term goals of therapy are to avoid hepatic decompensation, reduce or prevent progression to cirrhosis and/or HCC, and prolong survival.

Endpoints used to assess response include the following:

• Biochemical response: Normalization of serum ALT
• Virological response: HBV DNA of <10⁴ copies/mL and sustained seroconversion from HBeAg to anti-HBe
• Histological response: Decrease in histology activity compared to pretreatment liver biopsy or a reduction of at least 1 point in fibrosis by Metavir staging
• Complete response: Fulfill criteria of biochemical and virological response and loss of HBsAg

Considerations Prior to Initiation of Treatment

Prior to initiation of treatment, it is important to consider the age of the patient, the severity of the liver disease, the likelihood of response, potential adverse events, and complications. HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3 to 6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment. The choice of therapy will depend on the availability, cost of medication, the necessary number of clinic visits, the expected duration of treatment, and patient or clinician preference.

There is no evidence that combination therapy of two direct antiviral agents result in better viral suppression compared to a single agent. Antiviral therapy does not remove the risk of HCC, thus HCC surveillance must continue. In treating concurrent infections such as hepatitis C virus, hepatitis D virus, and HIV infection, it is important to identify the dominant virus as this will determine the therapeutic regimen. Concurrent hepatitis C infection may be treated with the same antiviral therapy for hepatitis C virus monoinfection. All of these treatment strategies should also be considered in pharmacological therapy.

Preferred Agents

Entecavir

Entecavir is considered a first-line agent for the treatment of chronic hepatitis B virus infection. It is approved for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in ALT or AST or histologically active disease. Its use is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naive and Lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic hepatitis B virus infection with compensated liver disease after 1 year of treatment.

It appears to be superior to Lamivudine based on histologic improvement, reduction in viral load, and ALT normalization. It is also effective in the treatment of patients with Adefovir and Tenofovir resistance. It inhibits hepatitis B virus polymerase activities such as base priming, reverse transcription of the negative strand from the pregenomic messenger RNA, and synthesis of the positive strand of HBV DNA.

Studies in rodents exposed to high doses (ie 3-40 times that given to humans) of Entecavir showed an increased incidence of lung adenomas, brain gliomas, and HCC.

Tenofovir alafenamide

Tenofovir alafenamide is a phosphonamidite prodrug of Tenofovir that inhibits hepatitis B virus replication through incorporation into the viral DNA by hepatitis B virus reverse transcriptase resulting in DNA chain termination. Its potential significant side effect includes lactic acidosis; hence, it is essential to perform HIV testing prior to initiating therapy and to monitor lactic acid levels.

It is used as a first-line agent for the treatment of immune-active chronic hepatitis B virus infection in adults with compensated liver disease. It is equally effective as Tenofovir disoproxil fumarate but uses a lower dose, thus it has fewer systemic adverse effects. It should be considered in patients with or at risk of bone disease or renal dysfunction. It is approved for use in patients with HIV in combination with Emtricitabine with or without other HIV drugs. Clinical trials with follow-up at 2 years reported no resistance to Tenofovir alafenamide therapy.

Tenofovir disoproxil fumarate  

Tenofovir disoproxil fumarateIt is a prodrug of Tenofovir and it inhibits hepatitis B virus polymerase resulting in the inhibition of viral replication. Its potential significant side effects include lactic acidosis, nephropathy, Fanconi syndrome, and osteomalacia. It is essential to perform HIV testing prior to initiating therapy and to monitor renal function at baseline, within the first 4 weeks of treatment, after 3 months of treatment, and every 3-6 months thereafter; bone density at baseline and during treatment; and lactic acid levels if with clinical concern.

It is used as a first-line agent for the treatment of chronic hepatitis B virus infection and as an alternative agent in patients with suspected or confirmed resistance to Adefovir, Entecavir, Lamivudine, and Telbivudine. It is an effective antiviral agent for hepatitis B (chronic HBeAg positive or HBeAg negative) that so far has no resistance detected. It may be given to pregnant women who require treatment and is the preferred antiviral agent in the third trimester which significantly reduces perinatal transmission of hepatitis B virus.

Peginterferon alfa

Peginterferon alfa is approved in several countries as first-line agent for chronic hepatitis B for both HBeAg-positive and HBeAg-negative chronic hepatitis in adult patients with compensated liver disease, evidence of viral replication, and liver inflammation. In many countries in Asia, Peginterferon alfa 2b is approved for use in the treatment of chronic hepatitis B.

It appears to have superior efficacy compared to nucleos(t)ide analogues based on HBeAg seroconversion, HBV DNA suppression and HBsAg seroconversion. It has a longer half-life compared to Interferon alfa and it appears to impart a clinical benefit over conventional Interferon alfa. Treatment with Peginterferon is more likely to achieve loss of HBeAg and HBsAg in genotypes A and B than in other genotypes.

An inert polyethylene glycol is added to Interferon, decreasing the drug’s renal clearance and increasing its half-life. It provides sustained viral suppression with efficacy similar to or better than the standard Interferon alfa. It has a finite duration of therapy with no reported resistance. It is contraindicated in patients with decompensated cirrhosis, autoimmune disease, uncontrolled epilepsy, severe infection, retinal disease, heart failure, chronic obstructive pulmonary disease, pregnancy, history of mental illness, and other underlying diseases. Its side effects include mood swings and depression; hence, the patient’s mental health should be closely monitored by the clinician.

Other Agents

Adefovir dipivoxil

Adefovir dipivoxil is used as an alternative treatment in patients with HBeAg-positive chronic hepatitis B infection. It may be a preferred agent for patients with negative HBeAg, HBV DNA >10⁵ copies/mL, and elevated ALT. It is effective as an add-on agent in suppressing Lamivudine-resistant hepatitis B virus; resulted in HBV DNA suppression of 82-87% and lower risk of Adefovir resistance of 4-8% in 3-4 years. The 10-mg dose has a more favorable risk-benefit profile compared to the 30-mg dose.

HBeAg-positive chronic hepatitis patients may discontinue therapy after 1 year and with confirmed HBeAg seroconversion, but the durability of response is unknown. Therapy may be continued in those who did not achieve HBeAg seroconversion, but safety and efficacy have not been established. HBeAg-negative chronic hepatitis may need extended treatment (>1 year) to maintain response. Further studies are needed to determine the optimal duration of therapy. 

It works by inhibiting the reverse transcriptase and DNA polymerase activity and is incorporated into hepatitis B virus DNA causing chain termination; however, its barrier to resistance is low and can lead to drug resistance. Renal function and bone profile must be monitored every 3 months for patients with predisposition to renal insufficiency and for patients on Adefovir dipivoxil for >1 year. 

Clevudine  

A daily dose of 30 mg for 24 weeks of Clevudine has been shown in two randomized, double-blind, placebo-controlled studies to be associated with serum HBV DNA levels of <300 copies/mL in the Amplicor PCR assay in 59% of HBeAg-positive patients and in 92% of HBeAg-negative patients. It is essential to monitor for muscle symptoms and muscle weakness during therapy. This drug is already discontinued in some countries due to cases of serious myopathy leading to myonecrosis.

Interferon alfa  

Interferons have antiviral, antiproliferative, and immunomodulatory effects. Interferon alfa may be a preferred agent in the treatment of HBeAg-negative chronic hepatitis B and HBeAg-positive chronic hepatitis with elevated ALT. It suppresses hepatitis B virus replication and induces remission of liver disease. Its efficacy is limited to a small percentage of highly selected patients and relapse is a major problem in HBeAg-negative chronic hepatitis B. It also has a finite duration of therapy. For HBeAg-positive chronic hepatitis B, important predictors of response to therapy are high pretreatment ALT and lower levels of serum HBV DNA.

Prednisone priming prior to Interferon alfa therapy is not recommended. Interferon alfa is contraindicated in patients with decompensated cirrhosis and coexisting autoimmune diseases. It is not recommended for patients with compensated cirrhosis because of risk of hepatic decompensation associated with Interferon alfa-related flares of hepatitis. Side effects include mood swings and depression; hence, the patient’s mental health should be closely monitored by the clinician. Pregnancy is discouraged during Interferon therapy and if the patient becomes pregnant during therapy, Interferon should be replaced with another drug.

Lamivudine

Lamivudine is used in patients with HBeAg-positive chronic hepatitis with elevated ALT but has a high rate of drug resistance during long-term treatment. It is recommended in viremic patients (HBeAg-positive and HBeAg-negative patients) with an ALT of >5x the upper limit normal especially if there is concern regarding decompensation.

Its good safety profile and ease of administration are its advantages over Interferon alfa. Pretreatment ALT is the most important predictor of response and response is greatest in patients with an ALT that is 2-5x the normal value. Treatment with Lamivudine may be discontinued in patients who have completed 1 year of treatment and have persistent HBeAg seroconversion to anti-HBe and undetectable HBV DNA by PCR assay. Treatment may be continued in patients who have not achieved HBeAg seroconversion and have no evidence of breakthrough infection because HBeAg seroconversion may occur with continued treatment.

It causes premature termination of the viral DNA chain termination thereby inhibiting hepatitis B virus DNA synthesis. It induces histologic improvement and reduction in rate of development of hepatic fibrosis. While on therapy, it is essential to monitor liver function tests, HBeAg, and anti-HBe every 3 months. Test for HBV DNA at 3 and 6 months of therapy and every 3-6 months thereafter.

The emergence of Lamivudine-resistant hepatitis B virus is increasingly common with prolonged treatment, together with a decreasing rate of remission. It is associated with the development of Lamivudine-resistant YMDD viral mutants, which appear to be less virulent than wild-type hepatitis B virus but have been associated with rapidly progressive liver disease in some patients. Lamivudine resistance is usually manifested as a breakthrough infection with the reappearance of hepatitis B virus DNA in the serum. The benefits of continued treatment must be balanced against the risk of resistant mutants.

Telbivudine  

Telbivudine is an orally bioavailable drug with potent and specific anti-hepatitis B virus activity. Clinical trials show that Telbivudine gave more potent hepatitis B virus suppression than Lamivudine or Adefovir in both HBeAg-positive and negative patients. It also showed equal potency to Entecavir when it comes to hepatitis B virus suppression in HBeAg-positive patients but has a high rate of resistance.

It works by competitively inhibiting the viral reverse transcriptase, thereby blocking the DNA polymerase activity. It is essential to monitor for muscle symptoms and muscle weakness during therapy.

Hepatitis D

Interferon alfa is the only approved chronic hepatitis D treatment and Peginterferon is the drug of choice. Peginterferon alfa is recommended to be given for 48 weeks in patients with elevated ALT and HDV RNA levels. The endpoint of therapy is the achievement of a complete virological response (ie undetectable HBsAg with sustained suppression of HDV RNA).

Patient Education

Acute Hepatitis B

Partner notification for at-risk contacts is essential. Contact tracing should include any sexual contact (penetrative vaginal or anal or oral/anal) or needle-sharing partners within 2 weeks before the onset of jaundice until the patient becomes negative for HBsAg. All non-immune sexual and household contacts must be vaccinated.

Provide the patients with a detailed explanation of their condition and emphasize the disease’s long-term implications (eg long-term medical therapy, continuous monitoring) for their and their partners’ health. Provide clear and accurate written information for easier understanding. Advise the patients to avoid unprotected sexual intercourse and emphasize condom use. Screen patients for other sexually transmitted diseases in cases of sexually acquired hepatitis or if otherwise appropriate.

Chronic Hepatitis B

Partner notification is essential. Trace contacts as far back as any episode of jaundice or to the time when the infection is thought to have been acquired. All non-immune sexual and household contacts must be vaccinated.

Provide the patients with a detailed explanation of their condition and emphasize the disease’s long-term implications (eg long-term medical therapy, continuous monitoring) for their and their partners’ health. Provide clear and accurate written information for easier understanding. Advise patients to observe abstinence or limited use of alcohol to prevent further liver injury.

Counseling regarding the prevention of transmission of hepatitis B virus is also important. To prevent sexual transmission, protected sexual intercourse like condom use may be done. To prevent perinatal transmission, hepatitis B immune globulin (HBIg) and hepatitis B vaccine at delivery for babies of hepatitis B virus-infected mothers may be given. Counseling to prevent inadvertent transmission via environmental contamination from a blood spill may also be done.

Hepatitis D

Partner notification for at-risk contacts is essential. Provide the patient with a detailed explanation of his condition and emphasize the disease's long-term implications (eg long-term medical therapy, continuous monitoring) for their and their partner’s health. Provide clear and accurate written information for easier understanding. Advise patients to avoid unprotected sexual intercourse. 

Surgery

Liver Transplantation

Liver transplantation is indicated in patients with end-stage liver disease (cirrhosis), HCC, and acute liver failure (ie caused by viruses, drugs, and toxic agents). It is considered in patients with expected survival of ≤1 year without transplantation or if the quality of life is unsatisfactory due to liver disease. Patients with hepatitis B virus infection should be evaluated for liver transplantation despite antiviral therapy as the development of liver failure cannot be predicted.

The combination therapy with hepatitis B immunoglobulin and nucleos(t)ide analogues helps prevent hepatitis B virus recurrence in these patients undergoing liver transplantation. Recipient patients without anti-HBs should receive prophylaxis for hepatitis B virus recurrence if transplanted liver is anti-HBc positive. Hepatitis D virus replication is not a contraindication for liver transplantation.

Prevention

Prevention and Post-exposure Prophylaxis of Hepatitis B

¹Vaccination of household contacts (especially children and adolescents) of persons with acute hepatitis B virus infection is also encouraged. Consider postvaccination testing (anti-HBs) for sexual partners of persons with chronic hepatitis B virus infection. Those found to be antibody negative should receive a second, complete, vaccination series.
²Skin and wound sites exposed to blood or body fluids with hepatitis B virus infection should be washed with soap and water immediately following contact; exposed mucous membranes should be flushed with water.

Revaccination is recommended for infants born to HBsAg-positive mothers, healthcare practitioners, hemodialysis patients, and immunocompromised individuals when anti-HBs is <10 mIU/mL. Postvaccination serologic testing is recommended only for infants born to HBsAg-positive mothers, healthcare practitioners, hemodialysis patients, immunocompromised individuals (eg HIV-positive patients, stem-cell transplant recipients, cancer patients receiving chemotherapy), and sexual partners of HBsAg-positive individuals.

Hepatitis B_Follow up