INTRODUCTION — The following topic review will summarize issues related to the management of chronic hepatitis B. These recommendations (and the data supporting them) are discussed in detail on their corresponding topic reviews. In addition, the recommendations below are generally consistent with guidelines from the European consensus statement (EASL), Asian-Pacific consensus statement, and American Association for the Study of Liver Diseases Practice Guidelines [1-4].
Specific examples of cases are described at the end, which illustrate some of the issues that may arise when making treatment decisions for patients with chronic hepatitis B. Clinical decisions regarding individual patients should be based upon patient-specific clinical information and test results. Data supporting this section are presented separately. (See "Standard and pegylated interferon for chronic hepatitis B virus infection" and "Lamivudine monotherapy for chronic hepatitis B virus infection" and "Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection" and "Entecavir in the treatment of chronic hepatitis B virus infection" and "Telbivudine in the treatment of chronic hepatitis B virus infection" and "Tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infection who do not have HIV infection".)
HEPATITIS B VIRUS — The hepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family of hepadnaviruses, which include duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. (See "Characteristics of the hepatitis B virus and pathogenesis of infection".)
HBV has traditionally been classified into eight genotypes (A to H) based upon an inter-group divergence of 8 percent or more in the complete nucleotide sequence. The prevalence of specific genotypes varies geographically. Furthermore, genotypes may correlate with clinical course and response to interferon. Genotype testing is not necessary in routine clinical practice, but it may be indicated for HBeAg-positive patients who are considering interferon therapy since patients with genotype A have a more favorable response. (See "Clinical significance of hepatitis B virus genotypes" and "Clinical significance and molecular characteristics of common hepatitis B virus variants".)
EPIDEMIOLOGY — Hepatitis B virus infection is a global public health problem. It is estimated that there are more than 300 million HBV carriers in the world, of whom approximately 500,000 die annually from HBV-related liver disease. Despite the availability of HBV vaccines, the rate of HBV-related hospitalizations, cancers, and deaths in the United States have more than doubled during the past decade. (See "Epidemiology, transmission and prevention of hepatitis B virus infection".)
WHO SHOULD BE TESTED — A number of risk factors for HBV have been identified, providing a rationale for screening (table 1) [4-7]:
Testing should include HBsAg and anti-HBs. Patients who are negative for these markers should be vaccinated. (See "Immunizations for patients with chronic liver disease" and "Serologic diagnosis of hepatitis B virus infection" and "Hepatitis B virus vaccination".)
INITIAL EVALUATION — Initial evaluation of patients with chronic HBV infection should include (table 2):
- A history and physical examination, emphasizing risk factors for coinfection with HCV and/or HIV, use of alcohol, and family history of HBV infection and liver disease.
- Laboratory tests: complete blood count with platelets, liver biochemical tests (AST, ALT, total bilirubin, alkaline phosphatase, albumin), prothrombin time, and tests for HBV replication (HBeAg, anti-HBe, HBV DNA). Testing for immunity to hepatitis A virus (HAV) with HAV IgG antibody should be considered in patients who are not known to be immune.
- Evaluation for other causes of liver disease including hepatitis C, hepatitis D, and hemochromatosis by obtaining anti-HCV, anti-HDV (in injection drug users and persons from countries where HDV is endemic, particularly Eastern Europe, Mediterranean countries, and the Amazon basin), iron, and TIBC.
- Screening for hepatocellular carcinoma. (See "Surveillance for hepatocellular carcinoma in adults with chronic liver disease".)
- Liver biopsy may be considered for patients who meet criteria for chronic hepatitis (ie, HBsAg positive for >6 months, serum HBV DNA >10(5) copies/mL or >20,000 IU/mL, persistent or intermittent elevation in ALT/AST levels). Liver biopsy is most important for patients who do not meet current criteria for treatment but have serum HBV DNA 10(4) to 10(5) copies/mL (2000 to 20,000 IU/mL) and ALT/AST levels that are normal or mildly elevated (<2x upper limit); patients with histologically active or advanced liver disease may benefit from treatment. (See "Percutaneous liver biopsy".)
- A normal serum ALT level alone in patients with active viral replication does not predict mild or normal histologic findings [8,9]. One report found that up to 37 percent of patients with persistently normal ALT and HBV DNA levels >10,000 copies/mL had significant fibrosis and inflammation on liver biopsy. On subgroup analysis, most such patients had an ALT in the high range of normal and were older than 40. By contrast, two studies in patients in the immune tolerant phase of chronic HBV infection found that despite high HBV DNA levels, most patients had no or minimal fibrosis [10,11]. Considered together, these data indicate that age or duration of infection is important in predicting severity of liver injury in patients with high HBV DNA levels.
WHO SHOULD BE TREATED AND HOW — The rationale for treatment is to reduce the risk of progressive chronic liver disease, transmission to others, and other long-term complications from chronic HBV such as hepatocellular carcinoma. (See "Epidemiology and etiologic associations of hepatocellular carcinoma".)
We recommend that treatment be considered in patients with HBeAg positive or HBeAg negative chronic hepatitis. Patients with compensated cirrhosis and HBV DNA >2,000 IU/mL and those with decompensated cirrhosis and detectable HBV DNA by PCR assay should be considered for antiviral therapy, regardless of the serum ALT level.
The following criteria for treatment were suggested in a 2008 consensus conference from the United States National Institutes of Health [12].
- Patients in whom therapy is indicated: acute liver failure, clinical complications of cirrhosis, cirrhosis or advanced fibrosis with HBV DNA in serum, or reactivation of chronic HBV after chemotherapy or immunosuppression.
- Patients for whom therapy may be indicated: patients in the immune-active phase who do not have advanced fibrosis or cirrhosis (HBeAg-positive or HBeAg-negative chronic hepatitis).
- Patients for whom immediate therapy is not routinely indicated: 1) Patients with chronic HBV in the immune tolerant phase (with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy); 2) Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels); 3) Patients who have latent HBV infection (HBV DNA without HBsAg).
Recommendations from the American Association for the Study of Liver Diseases updated in 2009 suggest an approach and considerations for treatment (algorithm 1 and table 3).
HBeAg-positive patients — Treatment is recommended for those with HBV DNA >20,000 IU/mL and ALT >2 x ULN. Treatment should be delayed for three to six months in newly diagnosed HBeAg positive patients with compensated liver disease to determine whether spontaneous HBeAg seroconversion will occur. Patients with chronic hepatitis whose serum ALT is persistently below two times the upper limit of normal can be observed, considering treatment if and when the serum ALT becomes higher. Possible exceptions to this rule are those who have recurrent hepatitis flares that fail to clear HBeAg, patients with icteric flares, those with active or advanced histologic findings (such as moderate/severe inflammation or bridging fibrosis/cirrhosis), and patients above the age of 40 with persistently high HBV DNA levels.
Treatment may also be indicated in patients with HBV-related polyarteritis nodosa. (See "Clinical manifestations and diagnosis of polyarteritis nodosa".)
Although treatment can lead to virus suppression in HBeAg positive patients with normal ALT, the likelihood of HBeAg seroconversion is low. The benefits of long-term treatment in such patients, most of whom being young Asians with perinatally acquired HBV infection, must be balanced against the risks of drug-resistance, side effects, and costs, particularly since some of these individuals will undergo spontaneous HBeAg seroconversion and remain in remission for many years afterwards.
HBeAg-negative patients — Treatment may be initiated immediately once a diagnosis of HBeAg negative chronic hepatitis (ALT >2 x ULN and HBV DNA >2000 IU/mL) is established because sustained remission is rare in the absence of treatment. Because of the fluctuating course of HBeAg negative chronic hepatitis, serial follow-up is needed to differentiate an inactive carrier state from HBeAg negative chronic hepatitis. Liver biopsy should be considered in HBeAg negative patients who have serum HBV DNA levels >2,000 IU/mL and normal or mildly elevated ALT to determine if treatment is warranted.
Choosing among the available options — Treatment strategies for chronic HBV include interferon (standard and pegylated), lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir (in countries in which it is approved) (table 4A-C). Many new treatments are undergoing testing. Thus, an approach to the care of patients with HBV is evolving rapidly. The following are general rules that can be considered when deciding upon an approach in individual settings. Specific examples are presented in the cases below:
Interferon — The advantage of interferon compared to the other options are its finite duration of treatment, the absence of selection of resistant mutants, and a more durable response. On the other hand, side effects from interferon are troubling for many patients, and (less commonly) can be severe. Furthermore, interferon cannot be used in patients with decompensated disease. The main role of interferon is primarily treatment of young patients with well compensated liver disease, who do not wish to be on long-term treatment or are planning to be pregnant within the next two to three years, and in whom drug resistance may limit their treatment options in the future. Interferon is also an attractive option for patients with HBV genotype A infection. (See "Standard and pegylated interferon for chronic hepatitis B virus infection".)
Lamivudine — The main advantages of lamivudine are its lower cost compared to the other oral agents and the many years of experience confirming its safety, including its use during pregnancy. Compared to adefovir, lamivudine has more rapid and more potent virus suppression, but entecavir, telbivudine, and tenofovir are superior to lamivudine in suppressing viral replication. The main disadvantage of lamivudine is the high rate of drug resistance. The role of lamivudine in the care of HBV is diminishing with the availability of new therapies which are associated with lower rates of drug resistance. Lamivudine may still have a role in patients coinfected with HIV (in whom lamivudine may be part of the antiretroviral regimen).
Adefovir — The main advantage of adefovir is its activity against lamivudine-resistant HBV and a lower rate of drug resistance compared to lamivudine. However, virus suppression is slow at the approved dose and up to 25 percent of patients experience minimal or no viral suppression. Adefovir at high doses has been associated with nephrotoxicity. At the approved dose of 10 mg daily, reversible increase in serum creatinine has been reported in 3 to 9 percent of patients after four to five years of treatment. Adefovir resistance was not detected after one year of treatment but the rate of drug resistance has been reported to be as high as 29 percent after five years of treatment. The most important role of adefovir is in the treatment of patients with lamivudine-resistant HBV, preferably in combination. With the approval of tenofovir, which is more potent, the role of adefovir is rapidly diminishing. In vitro data suggest that adefovir is also effective in suppressing telbivudine- and entecavir-resistant HBV but clinical data are scant.
Entecavir — The main advantages of entecavir are its potent antiviral activity and a low rate of drug resistance. Entecavir has a more important role in primary treatment of HBV than in patients with lamivudine-resistant HBV. Entecavir may also have an important role in patients with decompensated cirrhosis because of its potent antiviral activity and low rate of drug resistance but its safety in this patient population has not been well studied.
Resistance to entecavir is rare among nucleoside-naïve patients (approximately 1 percent with up to five years of treatment). By contrast, resistance has been observed in up to 50 percent of lamivudine-refractory patients after five years of treatment. Studies in rodents (that used 24 to 40 fold higher doses of entecavir than in humans) have reported increased rates of tumors; the relevance of these findings to humans is unclear.
Telbivudine — Telbivudine appears to have slightly more potent antiviral effects compared with lamivudine and adefovir but it selects for the same resistant mutants as lamivudine and is more expensive. Thus, its role as primary therapy is limited. Furthermore, there have been rare cases of myopathy and peripheral neuropathy. (See "Telbivudine in the treatment of chronic hepatitis B virus infection".)
Tenofovir — Tenofovir has more potent antiviral activity than adefovir and is effective in suppressing wild-type as well as lamivudine-resistant HBV. Tenofovir may be used as first line treatment in treatment-naïve patients, and in patients with lamivudine, telbivudine or entecavir resistance, preferably as additional treatment in these patients. Tenofovir can also be used to substitute for adefovir in patients who have inadequate viral response to adefovir. However, its efficacy in patients with adefovir-resistant HBV is limited. Tenofovir will probably replace adefovir in countries where it is approved because of its more potent antiviral activity. Preliminary data indicate that resistance to tenofovir is rare after up to two years of treatment. (See "Tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infection who do not have HIV infection".)
Prediction of response HBeAg positive patients — For HBeAg positive patients, the likelihood of response to lamivudine, adefovir, telbivudine, entecavir, interferon, and probably tenofovir depends upon the degree of elevation of the serum aminotransferases [13,14]. As a general rule, treatment with any of these drugs does not result in higher rates of HBeAg seroconversion compared to no treatment in those who have a serum ALT ≤2 X the upper limit of normal.
Prediction of response in HBeAg negative patients — For HBeAg negative patients, prediction of response is less precise. Because of the need for long-term treatment, therapy is recommended only for those with persistent or intermittent elevation in ALT and/or substantial histologic abnormalities (moderate/severe inflammation or bridging fibrosis/cirrhosis). Interferon, adefovir, entecavir, or tenofovir are generally preferred because long-term treatment with lamivudine or telbivudine is associated with diminishing response due to selection of drug-resistant mutants. Advantages of entecavir and tenofovir are more potent antiviral activity and lower rate of drug resistance compared with adefovir.
Renal insufficiency — Entecavir may be a better option than adefovir or tenofovir in patients with renal insufficiency and in those who are at risk for renal insufficiency. While all of these medications require dose reduction according to renal function, entecavir has not been reported to cause renal impairment (table 5).
Failed prior interferon therapy — Patients who failed to respond to prior interferon therapy can be treated with lamivudine, adefovir, telbivudine, entecavir, or tenofovir with the expectation of a similar response as treatment-naïve patients.
Breakthrough infection — Those who develop breakthrough infection due to antiviral drug resistance should be treated with additional antiviral therapy. Salvage therapy should be initiated promptly at the time of virologic breakthrough, prior to biochemical breakthrough, especially those with worsening liver disease, decompensated cirrhosis, recurrent HBV after transplantation, or immunosuppression. The choice of therapy in patients who developed resistance to nucleotide/side analogue depends upon which drug was used for initial treatment (table 6).
- Although data from a small study in patients with compensated liver disease showed that substitution of lamivudine for adefovir was as effective in viral suppression as addition of adefovir, patients who stopped lamivudine were more likely to have hepatitis flares during the first few months. In addition, follow-up data found that adefovir resistance was detected only in patients who stopped lamivudine but not in those who received combination therapy. These data indicate that lamivudine should be continued after the addition of adefovir. (See "Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection".)
Compensated cirrhosis — In patients with clinically and biochemically compensated cirrhosis, interferon may be used with caution but nucleosides/nucleotides are safer. Because of the need for long-term treatment, entecavir or tenofovir is preferred.
Decompensated cirrhosis — Patients with decompensated cirrhosis should be considered for treatment with lamivudine, telbivudine, adefovir, entecavir, or tenofovir. Interferon is contraindicated in these patients. In view of the need for long-term treatment, lamivudine and telbivudine are not optimal treatments unless used in combination with adefovir or tenofovir. If adefovir monotherapy is used, HBV DNA levels and liver function should be monitored closely (monthly or more often) and treatment modified by switching to tenofovir or adding lamivudine, telbivudine, or entecavir if virus suppression is slow or inadequate. Renal function (creatinine every one to three months) should be monitored closely in patients receiving adefovir or tenofovir. Entecavir may be a preferred option if ongoing studies demonstrate its safety in these patients. Treatment of such patients should be coordinated with a transplant center. (See "Liver transplantation for chronic hepatitis B virus infection".)
Chemotherapy or immunosuppression — Issues related to patients undergoing chemotherapy or receiving immunosuppression are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppression".)
Cost-effectiveness — The cost-effectiveness of various treatment strategies for chronic HBV is incompletely understood. Although several cost-effectiveness analyses have been published, all were conducted before approval of pegylated interferon, entecavir, telbivudine, and tenofovir.
DOSES — The following are recommended doses of the specific drugs:
Interferon alfa — Interferon alfa is administered by subcutaneous injection. (See "Standard and pegylated interferon for chronic hepatitis B virus infection".)
Standard interferon
- For adults: 5 MU daily or 10 MU three times a week
- For children: 6 MU/M(2) three times weekly with a maximum of 10 MU
- Treatment duration for HBeAg positive chronic hepatitis is 16 to 32 weeks
- Treatment duration for HBeAg negative hepatitis is 12 to 24 months
Pegylated interferon alfa-2a
- For adults: 180 microG once weekly
- For children: Not approved
- The manufacturer recommends 48 weeks of treatment for HBeAg positive or negative chronic HBV. However, lower dose and/or shorter treatment duration may be sufficient for some HBeAg positive chronic hepatitis B and it is not clear if a longer duration of therapy will result in a higher rate of sustained response for HBeAg negative chronic hepatitis B. The Asian-Pacific guidelines recommended 24 weeks treatment for HBeAg positive HBV based on comparable responses obtained in the phase II trial [1].
Lamivudine — Lamivudine is administered orally. (See "Lamivudine monotherapy for chronic hepatitis B virus infection".)
- The recommended dose for adults with normal renal function without concomitant HIV infection is 100 mg daily. Dose adjustment is required in those with decreased renal function.
- The recommended dose for children is 3 mg/kg per day with a maximum of 100 mg/day
- The recommended dose for those who are coinfected with HIV is 150 mg twice daily (along with other anti-retroviral drugs).
Adefovir — Adefovir is administered orally. The dose is 10 mg daily. Patients with impaired renal function should have the dosing interval adjusted. (See "Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection".)
Entecavir — Entecavir is administered orally. The recommended dose is 0.5 mg once daily for nucleoside-naïve adults and adolescents older than 16 while it is 1 mg daily for those who have lamivudine resistance. The dosage should be adjusted in patients with a creatinine clearance of <50 mL/min. (See "Entecavir in the treatment of chronic hepatitis B virus infection".)
Telbivudine — Telbivudine is administered orally. The recommended dose is 600 mg once daily. (See "Telbivudine in the treatment of chronic hepatitis B virus infection".)
Tenofovir — Tenofovir is given at a dose of 300 mg daily; the dose needs to be adjusted in renal impairment. (See "Tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infection who do not have HIV infection".)
DURATION AND TREATMENT ENDPOINTS — The optimal duration of therapy for the oral drugs is not well-established. Most patients receiving nucleoside/nucleotide analogue therapy will require at least four to five years of treatment, and some may require indefinite treatment.
HBeAg-positive chronic hepatitis — The endpoint of treatment is HBeAg seroconversion. Patients in whom HBeAg seroconversion has occurred and serum HBV DNA has become undetectable should be treated for at least six more months after HBeAg seroconversion has been confirmed (by testing on two occasions at least two months apart) to reduce the rate of relapse. Given that roughly 50 percent of patients enrolled in clinical trials (baseline ALT >1.3x ULN) achieve HBeAg seroconversion after five years of treatment, most patients with HBeAg-positive chronic hepatitis will require several years of treatment. All patients should be closely monitored after discontinuation of treatment as viral relapse may lead to hepatitis flares and hepatic decompensation.
Treatment can be continued in patients who have maintained viral suppression but have not seroconverted as HBeAg seroconversion may occur in subsequent years.
HBeAg-negative chronic hepatitis — The endpoint of treatment has not been established. Treatment may be discontinued in patients who have confirmed loss of HBsAg (by testing on two occasions at least two months apart). Given that approximately 5 percent of patients lose HBsAg after five years of continued therapy, most patients with HBeAg-negative chronic hepatitis will require many years of treatment with its associated risks of adverse events, drug resistance, and costs. Preliminary data suggest that almost 70 percent of patients had sustained biochemical remission after a five-year course of adefovir despite viral relapse in all patients. These data need to be confirmed before a recommendation on treatment discontinuation can be made.
Compensated cirrhosis — The aim of treatment is to prevent liver failure and HCC. Thus, life-long treatment is generally recommended. It is possible that treatment may be discontinued in those who have lost HBsAg. It is not clear if treatment can be discontinued in HBeAg-positive patients who have achieved HBeAg seroconversion and completed at least 12 months of consolidation therapy, or in patients who have histologic documentation of cirrhosis regression.
Decompensated cirrhosis — Life-long treatment is recommended.
EXPERIMENTAL TREATMENTS — Several new strategies for treatment of HBV continue to be developed. Investigational treatment can be considered in selected patients where such protocols are available. These compounds are currently undergoing review by the Food and Drug Administration. (See "Newer treatments of chronic hepatitis B virus infection" and "Combination therapy for chronic hepatitis B virus infection".)
COUNSELING AND PREVENTION — Heavy use of alcohol (>40 g/d), has been associated with worsening liver disease and an increased risk of HCC. The exact amount of alcohol that can be safely consumed is unclear. Thus, advising patients to be completely abstinent is reasonable in those who have substantial liver injury. (See "Clinical manifestations and natural history of hepatitis B virus infection".)
Patients with chronic HBV should receive appropriate immunizations. (See "Immunizations for patients with chronic liver disease".)
Carriers of HBV should be counseled regarding the risk of transmission to others (table 7A-B). Patients should be advised regarding prevention of sexual transmission (ie, vaccination of spouses and steady sex partners in individuals with monogamous partners, and safe sex practice including use of condoms in subjects with multiple partners), perinatal transmission, and risk of environmental exposure from blood. (See "Epidemiology, transmission and prevention of hepatitis B virus infection".)
Household members should be vaccinated if they test negative for HBV serologic markers. HBsAg positive pregnant women should inform their providers so that their infants can receive hepatitis B immune globulin and vaccine immediately after delivery. Healthcare workers who are HBeAg positive should not perform invasive procedures without prior counseling and advice from an expert review panel.
MONITORING OF PATIENTS — Periodic screening for hepatocellular carcinoma (HCC) should be performed according to the American Association for the Study of Liver Diseases (AASLD) guidelines. The AASLD guideline for the management of hepatocellular carcinoma [15], as well as other AASLD guidelines, can be accessed through the AASLD web site at http://www.aasld.org/practiceguidelines/Pages/default.aspx. (See "Surveillance for hepatocellular carcinoma in adults with chronic liver disease".)
Patients who are not deemed to be treatment candidates at presentation and those who decide to defer treatment should undergo monitoring of liver biochemical tests, HBV DNA and HBeAg status since liver disease and/or HBV replication may become active later (algorithm 1 and table 2).
CASE ONE, YOUNG ASIAN WITH ACTIVE REPLICATION — The patient is a 25 year old Asian man who is HBsAg (+) and HBeAg (+) with serum HBV DNA of 700 million copies/mL (140 million IU/mL). He has mild inflammation on biopsy. His serum ALT is 100 IU/L (upper limit of normal 40 IU/L).
Comment — This patient should be considered for therapy with entecavir, tenofovir, or interferon alfa. Lamivudine or telbivudine may be an option if cost is a consideration. Telbivudine is slightly more potent and has a slightly lower rate of drug resistance than lamivudine but it is more expensive. Adefovir at the approved dose has weak antiviral activity and has been superseded by tenofovir.
The degree of elevation of the serum ALT is particularly important in influencing the decision to treat HBeAg positive patients since it has proven to be one of the most important predictors of HBeAg seroconversion. In one study on lamivudine, for example, the rates of HBeAg seroconversion for patients with pretreatment ALT levels within normal, one to two times normal, two to five times normal, and more than five times normal were 2, 9, 21, and 47 percent, respectively [13].
As a general rule, we consider the degree of elevation of the serum ALT in three categories: normal, between one to two times normal, and more than two times normal. Treatment with any of the approved therapies is unlikely to be successful in achieving HBeAg seroconversion in those with normal or minimally elevated serum ALT. The degree of liver inflammation on liver biopsy is also useful in predicting treatment related HBeAg seroconversion. Increasing data indicate that presence of HBeAg and high serum HBV DNA, lasting four decades or longer, are associated with increased risks of cirrhosis, hepatocellular carcinoma, and liver-related deaths. As a result, treatment may also be considered in patients who remain HBeAg positive after the age of 40, regardless of ALT level.
For patients who are contemplating interferon treatment, a test for HBV genotype can be performed. Patients with HBV genotype A are more likely to achieve HBeAg as well as HBsAg seroconversion. (See "Clinical significance of hepatitis B virus genotypes".)
The pros and cons of various treatment options should be discussed with the patient. The main advantages of nucleos/tide analogues are their side effect profile and ease of administration.
The disadvantages of interferon are costs, side effects, and need for parenteral administration but the duration of treatment is finite and interferon is not associated with drug-resistant mutations. All of the oral agents can be considered as a first line therapy. The advantage of lamivudine is its excellent safety profile, but drug resistance increases with the duration of treatment. An advantage of entecavir is its greater potency and low rate of drug resistance.
In a young patient like this, the concern is the adverse consequences of drug-resistant mutants and the possibility of more restricted treatment options in the future. Entecavir, despite its higher cost, may be a better first line therapy. Tenofovir would be a reasonable alternative in countries in which it has been approved. It is less expensive than entecavir but there is a small risk of nephrotoxicity and data on drug resistance are limited. Given the young age of the patient, pegylated interferon should also be considered because of the finite duration of treatment. (See "Entecavir in the treatment of chronic hepatitis B virus infection" and "Tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infection who do not have HIV infection".)
CASE TWO, PRESUMED PRECORE VARIANT — The patient is a 20 year old woman who is HBsAg (+), HBeAg (-). Her HBV DNA is 1.2 million copies/mL (approximately 250,000 IU/mL). She has mild portal inflammation, no fibrosis. Her serum ALT is 60 IU/L (upper limit of normal 40 IU/L).
Comment — I would follow this patient without recommending treatment at this time. Although she has high HBV DNA, she is HBeAg negative, and is likely to be infected with a precore variant. All approved treatments: interferon, lamivudine, telbivudine, adefovir, entecavir, and tenofovir have a low rate of sustained response in such patients. Because she is young and has only mild histologic changes on liver biopsy, I think it is reasonable to observe her for the time being. A reasonable approach may be to repeat liver function tests every three to six months and consider performing a repeat liver biopsy in a few years.
The situation might be different if the patient is 60 years old, repeatedly had a serum ALT that is more markedly elevated or if she had moderate to severe inflammation or bridging fibrosis or cirrhosis on liver biopsy. Because HBeAg negative chronic hepatitis tends to run a fluctuant course, serial testing is needed and treatment should be recommended if she subsequently develops more marked ALT elevation. Entecavir, tenofovir, or interferon should be considered. Longer duration of treatment will be needed but the optimal duration is unknown as the end-point of treatment has not been defined. Because of the need for long-term treatment, lamivudine and telbivudine may be less desirable. Tenofovir has replaced adefovir because of its more potent antiviral activity. (See "Standard and pegylated interferon for chronic hepatitis B virus infection" and "Lamivudine monotherapy for chronic hepatitis B virus infection" and "Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection" and "Telbivudine in the treatment of chronic hepatitis B virus infection" and "Telbivudine in the treatment of chronic hepatitis B virus infection" and "Tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infection who do not have HIV infection".)
CASE THREE, CHRONIC CARRIER, NORMAL ALT, NORMAL LIVER BIOPSY — The patient is a 22 year old man who is HBsAg (+), HBeAg (+), anti-HBe (-). His HBV DNA is 71.5 million copies/mL (approximately 14 million IU/mL) and serum ALT is persistently in the range of 30 IU/L (upper limit of normal 40 IU/L). His liver biopsy is essentially normal.
Comment — I would not treat this patient at this time although his HBV DNA level is high. He is very young, has no significant inflammation on liver biopsy and serum ALT that is normal (which predicts low probability of HBeAg seroconversion to lamivudine, telbivudine, adefovir, interferon, and probably entecavir and tenofovir).
Although antiviral therapy can decrease serum HBV DNA level in this patient, there is no evidence that treating this patient at this stage will improve clinical outcome. Given the low rate of HBeAg seroconversion (<5 percent after one year of treatment), this patient will need to receive treatment for many years and even decades to derive a clinical benefit.
The feasibility of achieving this goal must be balanced against the risk of sequential drug resistance and the patient running out of treatment options. Thus, I would follow this patient and recheck ALT every three to six months. If his ALT becomes more than two times normal, I would monitor him more frequently and recommend treatment if he does not spontaneously seroconvert after three to six months. I would biopsy this patient if he was 45 years old with similarly high HBV DNA level and consider treatment if HBV DNA level is persistently high or if there is moderate/severe inflammation and/or advanced fibrosis on biopsy.
CASE FOUR, DENTAL STUDENT WITH ACTIVE REPLICATION — The patient is a 24 year old who has recently been admitted to dental school. He is HBsAg (+), HBeAg (+), anti-HBe (-). His HBV DNA is 400 million copies/mL (approximately 80 million IU/mL) and serum ALT is 45 (upper limit of normal 40 IU/L). His liver biopsy shows macrovesicular fat, no portal fibrosis. The Dean of the dental school has denied his matriculation pending your advice.
Comment — I would advise this patient to reconsider his plans to enter dental school. Under current CDC recommendations, health care workers who are HBsAg and HBeAg positive are restricted in their abilities to perform invasive procedures, an unavoidable element of dental practice. Because he has high HBV DNA and low ALT levels, the likelihood of him responding (HBeAg loss) to current treatment is low and the chance of him clearing HBsAg is even more remote. (See "Epidemiology, transmission and prevention of hepatitis B virus infection".)
An earlier switch in career is the best advice for this young man. The situation is somewhat different for medical students who can choose career paths that do not involve performance of invasive procedures.
CASE FIVE, CHRONIC CARRIER, ADVANCED HISTOLOGIC FEATURES — The patient is a 50 year old Asian man who is HBsAg (+), HBeAg (-). His serum ALT is 75 IU/L (upper limit of normal 40 IU/L). He has moderate hepatitis with bridging fibrosis on liver biopsy.
Comment — Although this patient has only a mildly elevated serum ALT, I would recommend treatment based upon the advanced histologic features on his liver biopsy if his serum HBV DNA level is more than 10,000 copies/mL (>2000 IU/mL). The threshold HBV DNA level for initiating treatment in HBeAg negative patients is unclear because these patients tend to have lower HBV DNA levels than HBeAg positive patients. The benefit of antiviral therapy in preventing adverse clinical outcome: progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma is not as clear in patients with low HBV DNA levels.
This patient highlights the importance of liver biopsy in patients with normal or mildly elevated ALT, particularly older patients and those who have been infected for many years. Assuming he has no comorbid conditions or evidence of hepatic decompensation, adefovir, entecavir, tenofovir, or interferon would be reasonable options. Interferon should not be used in patients with decompensated cirrhosis, but it may be used cautiously in patients who have bridging fibrosis and no evidence of clinical or biochemical decompensation. Because of the need for long-term treatment, entecavir or tenofovir is preferred if oral treatment is desired.
CASE SIX, DECOMPENSATED CIRRHOSIS — The patient is a 75 year old woman who is HBsAg (+) HBeAg (+), and has a serum ALT of 50 IU/L (upper limit of normal 40 IU/L). Her HBV DNA is 8000 copies/mL (approximately 1600 IU/mL). She has ascites and known esophageal varices. She is not considered to be a candidate for liver transplantation.
Comment — Treatment with interferon is not an option for this patient because she has decompensated cirrhosis. The more difficult question is whether she would benefit from lamivudine, telbivudine, adefovir, entecavir, or tenofovir. Although lamivudine has been associated with stabilization or improvement of liver disease, most of the reports so far had been on patients with detectable HBV DNA using hybridization or bDNA assays (more than 750,000 genome equivalents/ml).
The benefit of antiviral therapy in patients with lower HBV DNA levels is not established but I would treat her because there is little to lose and suppression of HBV DNA and any accompanying inflammation may be of benefit in a patient with very little hepatic reserve.
Given the need for long-term treatment, the risk of lamivudine or telbivudine resistance and the possibility of clinical deterioration due to breakthrough infection must be considered in a patient who is not a transplant candidate. On the other hand, rapid virus suppression is important in this sick patient and some (20 to 30 percent) patients have very slow response to adefovir. Furthermore, the risk of adefovir related nephrotoxicity in older patients with decompensated cirrhosis and ascites is high (up to 20 to 30 percent).
Whether deterioration in renal function in these very sick patients is related to underlying liver failure, concomitant use of diuretics, or adefovir- or tenofovir-related nephrotoxicity is difficult to determine.
An important question is whether these patients should receive de novo combination oral antiviral therapy. There are no data to support that combination of two oral antiviral agents hastens virus suppression. Several studies showed that combination of lamivudine with another oral agent such as adefovir is associated with decreased resistance to lamivudine. Given the low rate of drug resistance associated with entecavir or tenofovir, it is not clear if combination of these drugs with another agent will result in further reduction in resistance. (See "Combination therapy for chronic hepatitis B virus infection".)
With these considerations in mind, entecavir or tenofovir is preferred despite the lack of data in this patient population. Entecavir may be a better choice because patients with decompensated cirrhosis are at risk of renal failure and because this patient is 75. As an alternative, lamivudine or telbivudine can be used in combination with adefovir or tenofovir for rapid viral suppression and to reduce risk of drug resistance. There are limited data with these drugs in this setting, a point that the patient should understand when making choices among the options.
CASE SEVEN, AWAITING TRANSPLANT — The patient is a 44 year old with decompensated cirrhosis who is on the transplant waiting list. He is HBsAg (+), HBeAg (+), and has a serum ALT of 100 IU/L (upper limit of normal 40 IU/L).
Comment — The optimal approach for patients with chronic HBV who are awaiting liver transplantation has not been established. The greatest experience in this setting has been with lamivudine but it is associated with a high rate of drug resistance. Adefovir and probably tenofovir can also be used but renal function needs to be monitored closely. Although experience with entecavir in this setting is limited, it is probably the best option. Experience with telbivudine is also limited, but due to the high rate of drug resistance, it is not an optimal treatment. The antiviral effect of adefovir 10 mg is less consistent than lamivudine or entecavir, and may be slow or suboptimal in some patients. De novo combination treatment has not been studied in this patient population but may be a reasonable option if lamivudine or telbivudine are used.
CASE EIGHT, REMAINS HBeAg POSITIVE DESPITE LAMIVUDINE FOR ONE YEAR — The patient is a 40 year old man with pretreatment ALT 129 IU/L and moderate inflammation on liver biopsy. He remains HBeAg positive but HBV DNA is undetectable by PCR after one year of therapy with lamivudine.
Comment — It is important to think through the treatment plan and all its contingencies prior to beginning any type of therapy for HBV. It is reasonable to continue treatment since longer duration of treatment is associated with an increased probability of HBeAg seroconversion. A problem with longer duration of therapy is the selection of resistant mutants (M204V/I mutants). These mutants can be detected in 15 to 30 percent of patients at the end of one year of treatment, and in 70 percent of patients at the end of four years of treatment. (See "Lamivudine monotherapy for chronic hepatitis B virus infection".)
Alternative options include switching to drugs that are more potent or have lower rates of resistance such as entecavir or to add a drug that is not cross-resistant such as adefovir or tenofovir since it is possible that resistant mutants may already be selected after one year of lamivudine treatment. (See "Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection" and "Tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infection who do not have HIV infection" and "Entecavir in the treatment of chronic hepatitis B virus infection".)
Patients who have been on lamivudine and have had undetectable serum HBV DNA for many years can continue on lamivudine, especially if virus was suppressed to undetectable levels within 6 to 12 months of initiation of treatment. Patients who have only been on lamivudine for one to two years should be switched to other drugs that have lower risk of resistance. Entecavir may be used in patients who had been exposed to lamivudine for a short time and in whom serum HBV DNA is undetectable.
CASE NINE, BREAKTHROUGH INFECTION WHILE ON LAMIVUDINE — The patient is a 56 year old woman with HBeAg positive HBV and early cirrhosis on liver biopsy. Treatment with lamivudine was associated with an initial decline in HBV DNA titers to undetectable levels by PCR assay and normalization of serum aminotransferases. However, after 18 months of treatment, she developed a flare in serum aminotransferases with increasing levels of HBV DNA. She remains HBeAg positive.
Comment — It is likely that this patient has developed breakthrough infection with a lamivudine resistant mutation. If possible, specific testing to confirm resistance should be performed, as breakthrough infection may also be due to medication non-compliance. It is important to differentiate hepatitis flares associated with HBeAg seroconversion (which is accompanied by decrease in HBV DNA level) versus flares associated with emergence of drug resistance (which is accompanied by increase in HBV DNA level).
In this case, the patient was compliant with medication and had increasing HBV DNA level. Given that she has advanced histologic features, it would be reasonable to add adefovir 10 mg daily or tenofovir 300 mg daily (while continuing lamivudine). Adefovir or tenofovir is preferred to entecavir because mutations to lamivudine decrease susceptibility to entecavir and increase the risk of entecavir resistance.
CASE TEN, ACUTE INFECTION — The patient is a 68 year old man who is hospitalized with low grade fever, abdominal pain, anorexia, and jaundice. Serologic evaluation reveals that he is HBsAg positive, IgM anti-HBc positive, with serum HBV DNA level of 1.5 million copies/mL (approximately 300,000 IU/mL). Serum ALT is 2000 U/L, total bilirubin is 8.0 mg/dL, INR is 1.5. Other causes of liver disease are excluded. The patient is not known to be a carrier for HBV; however, he is bisexual and thus has potential risk factor for HBV carriage. His aminotransferases, INR and total bilirubin rise slightly during the first two days of hospitalization while awaiting the results of the above serology.
Comment — It would appear that this patient has acute HBV, although reactivation of chronic HBV infection is also possible. It can sometimes be difficult to distinguish acute HBV from exacerbation of chronic hepatitis B based upon serology alone (unless there are previous laboratory tests available). The diagnosis of acute hepatitis B is based upon the detection of HBsAg and IgM anti-HBc (table 8 and graph 1). However, IgM anti-HBc can also be seen during severe exacerbation of chronic hepatitis B. This patient is more likely to have exacerbation of pre-existing chronic hepatitis B if he has cirrhosis at diagnosis, a family history of HBV, or past history of liver disease. By contrast, acute infection is more likely in patients with a known recent exposure and no prior history of liver disease.
A question is whether the patient should be treated with antiviral therapy. The prognosis with acute infection is relatively worse in patients who are immunocompromised, have concomitant infection with hepatitis C or D virus, have preexisting liver disease, or are elderly. Thus, the patients advanced age is a risk factor for morbidity (and possibly mortality) from acute infection.
Few studies have addressed the benefits of antiviral therapy during acute infection. There are relatively more data with reactivation of infection in patients receiving immunosuppressive therapy. In this setting, prophylaxis with antiviral treatment can help prevent severe reactivation of hepatitis. (See "Clinical manifestations and natural history of hepatitis B virus infection", section on Acute hepatitis and see Hepatitis B virus reactivation associated with immunosuppression".)
We do not believe that all patients with acute HBV require antiviral treatment since the likelihood of fulminant hepatitis B is less than 1 percent, and in immunocompetent adults the likelihood of progression to chronic HBV infection is less than 5 percent [16]. As a general rule, we treat patients with a severe (such as those who develop a coagulopathy {INR >1.5}) or a protracted course (such as persistent symptoms or marked jaundice {bilirubin >10 mg/dl} for more than four weeks after presentation). We also recommend treating patients with fulminant hepatitis B to reduce the likelihood of reinfection post-liver transplant. These recommendations are consistent with a 2009 guideline issued by the American Association for the Study of Liver Diseases [4].
Treatment would be reasonable given this patient's advanced age and coagulopathy. Interferon should be avoided because of the risk of infection and further increase in hepatic necroinflammation. In patients suspected to have protracted or severe acute hepatitis, telbivudine, lamivudine, adefovir, tenofovir, or entecavir would all be acceptable options given as monotherapy as the duration of treatment should be short. Treatment can be stopped after confirmation (two consecutive tests four weeks apart) that the patient has cleared HBsAg.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Hepatitis B".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.
