Clinical Findings & Diagnosis
Chronic hepatitis B afflicts 248 million people worldwide (2 billion overall have been infected; endemic areas include Asia and sub-Saharan Africa) and up to 2.2 million (predominantly males) in the United States. It may be noted as a continuum of acute hepatitis B or diagnosed because of repeated detection of HBsAg in serum, often with elevated aminotransferase levels.
Five phases of chronic HBV infection are recognized: immune tolerant phase, immune active (or immune clearance) phase, inactive HBsAg carrier state, reactivated chronic hepatitis B phase, and the HBsAg-negative phase. In the immune tolerant phase (HBeAg-positive chronic HBV infection), HBeAg and HBV DNA are present in serum and are indicative of active viral replication, and serum aminotransferase levels are normal, with little necroinflammation in the liver. This phase is common in infants and young children whose immature immune system fails to mount an immune response to HBV.
Persons in the immune tolerant phase and those who acquire HBV infection later in life may enter an immune active phase (HBeAg-positive chronic hepatitis B), in which aminotransferase levels are elevated and necroinflammation is present in the liver, with a risk of progression to cirrhosis (at a rate of 2–5.5% per year) and of hepatocellular carcinoma (at a rate of more than 2% per year in those with cirrhosis); low-level IgM anti-HBc is present in serum in about 70%.
Patients enter the inactive HBsAg carrier state (HBeAg-negative chronic HBV infection) when biochemical improvement follows immune clearance. This improvement coincides with disappearance of HBeAg and reduced HBV DNA levels (less than 105 copies/mL, or less than 20,000 international units/mL) in serum, appearance of anti-HBe, and integration of the HBV genome into the host genome in infected hepatocytes (intrahepatic covalently closed circular DNA, a surrogate marker of the transcriptional activity which has been identified in serum as hepatitis B core–related antigen). Patients in this phase are at a low risk for cirrhosis (if it has not already developed) and hepatocellular carcinoma, and those with persistently normal serum aminotransferase levels infrequently have histologically significant liver disease, especially if the HBsAg level is low.
The reactivated chronic hepatitis B phase (HBeAg-negative chronic hepatitis B) may result from infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core or core promoter region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV. HBeAg-negative chronic hepatitis B accounts for less than 10% of cases of chronic hepatitis B in the United States, up to 50% in southeast Asia, and up to 90% in Mediterranean countries, reflecting in part differences in the frequencies of HBV genotypes. In reactivated chronic hepatitis B, there is a rise in serum HBV DNA levels and possible progression to cirrhosis (at a rate of 8–10% per year), particularly when additional mutations in the core gene of HBV are present. Risk factors for reactivation include male sex and HBV genotype C as well as immunosuppression. Treatment of HCV infection with direct-acting antiviral agents has been reported to lead to instances of HBV reactivation.
In patients with either HBeAg-positive or HBeAg-negative chronic hepatitis B, the risk of cirrhosis and of hepatocellular carcinoma correlates with the serum HBV DNA level. Other risk factors include advanced age, male sex, alcohol use, cigarette smoking, HBV genotype C, and coinfection with HCV or HDV. HIV coinfection is also associated with an increased frequency of cirrhosis when the CD4 count is low. Only 1% of treated and untreated patients per year reach the HBsAg-negative phase, in which anti-HBe may remain, serum ALT levels are normal, and HBV DNA is undetectable in serum but remains present in the liver; in some cases, anti-HBs appears in serum.
Acute hepatitis D infection superimposed on chronic HBV infection may result in severe chronic hepatitis, which may progress rapidly to cirrhosis and may be fatal. Patients with long-standing chronic hepatitis D and B often have inactive cirrhosis and are at risk for decompensation and hepatocellular carcinoma. The diagnosis is confirmed by detection of anti-HDV or HDAg (or HDV RNA) in serum.
Patients with active viral replication (HBeAg and HBV DNA [105 copies/mL or more, or 20,000 international units/mL or more] in serum and elevated aminotransferase levels) may be treated with a nucleoside or nucleotide analog or with pegylated interferon. Nucleoside and nucleotide analogs are preferred because they are better tolerated and can be taken orally. For patients who are HBeAg-negative, the threshold for treatment is a serum HBV DNA level of 104 copies/mL or more, or 2000 international units/mL or more. If the threshold HBV DNA level for treatment is met but the serum ALT level is normal, treatment may still be considered in patients over age 35–40 if liver biopsy or a noninvasive assessment of liver fibrosis demonstrates a fibrosis stage of 2 of 4 (moderate) or higher. Therapy is aimed at reducing and maintaining the serum HBV DNA level to the lowest possible levels, thereby leading to normalization of the ALT level and histologic improvement. An additional goal in HBeAg-positive patients is seroconversion to anti-HBe, and some responders eventually clear HBsAg. Although nucleoside and nucleotide analogs generally have been discontinued 6–12 months after HBeAg-to-anti-HBe seroconversion, some patients (especially Asian patients) serorevert to HBeAg after discontinuation, have a rise in HBV DNA levels and recurrence of hepatitis activity, and require long-term therapy, which also is required when seroconversion does not occur and in patients with cirrhosis (at least until HBsAg clears and possibly indefinitely). HBeAg-negative patients with chronic hepatitis B also generally require long-term therapy because relapse is frequent when therapy is stopped.; a low serum HBsAg level identifies patients who are at low risk for relapse and in whom HBsAg is more likely to clear if the nucleoside or nucleotide analog is stopped after 3 years than if it is continued indefinitely.
The available nucleoside and nucleotide analogs—entecavir, tenofovir, lamivudine, adefovir, and telbivudine—differ in efficacy and rates of resistance; however, in HBeAg-positive patients, they all achieve an HBeAg-to-anti-HBe seroconversion rate of about 20% at 1 year, with higher rates after more prolonged therapy. The preferred first-line oral agents are entecavir and tenofovir. Entecavir is rarely associated with resistance unless a patient is already resistant to lamivudine. The daily dose is 0.5 mg orally for patients not resistant to lamivudine and 1 mg for patients who previously became resistant to lamivudine. Suppression of HBV DNA in serum occurs in nearly all treated patients, and histologic improvement is observed in 70% of patients. Entecavir has been reported to cause lactic acidosis when used in patients with decompensated cirrhosis. Tenofovir disoproxil fumarate, 300 mg orally daily, is equally effective and is used as a first-line agent or when resistance to a nucleoside analog has developed. Like entecavir, tenofovir has a low rate of resistance when used as initial therapy. Long-term use may lead to an elevated serum creatinine level and reduced serum phosphate level (Fanconi-like syndrome) that is reversible with discontinuation of the drug. Tenofovir alafenamide, 25 mg orally daily, is an alternative formulation of tenofovir that was approved by the FDA in 2016; it is associated with a lower rate of renal and bone toxicity than tenofovir disoproxil fumarate.
The first available nucleoside analog was lamivudine, 100 mg orally daily. No longer considered first-line therapy in the United States, it still may be used in countries in which cost is a deciding factor. By the end of 1 year of therapy with lamivudine, however, 15–30% of responders experience a relapse (and occasionally frank decompensation). As a result of a mutation in the polymerase gene (the YMDD motif) of HBV DNA that confers resistance to lamivudine. The rate of resistance reaches 70% by 5 years of therapy. Adefovir dipivoxil has activity against wild-type and lamivudine-resistant HBV but is the least potent of the oral antiviral agents for HBV and is now rarely if ever used. The standard dose is 10 mg orally once a day for at least 1 year. As with lamivudine, only a small number of patients achieve sustained suppression of HBV replication with adefovir. Resistance to adefovir occurs in up to 29% of patients treated for 5 years. Patients with underlying kidney dysfunction are at risk for nephrotoxicity from adefovir. Telbivudine, given in a daily dose of 600 mg orally, is more potent than either lamivudine or adefovir but like them is associated with resistance, particularly in patients who are resistant to lamivudine. Elevated creatine kinase levels are common in patients treated with telbivudine.
Nucleoside and nucleotide analogs are well tolerated even in patients with decompensated cirrhosis (for whom the treatment threshold may be an HBV DNA level less than 104 copies/mL and therapy should be continued indefinitely) and may be effective in patients with rapidly progressive hepatitis B (“fibrosing cholestatic hepatitis”) following organ transplantation. Combined use of a nucleoside and nucleotide analog or of peginterferon and a nucleoside or nucleotide analog has not been shown convincingly to have a substantial advantage over the use of one drug alone.
Nucleoside analogs are also recommended for inactive HBV carriers (and those positive only for anti-HBc) prior to the initiation of immunosuppressive therapy (including rituximab or anti-tumor necrosis factor antibody therapy) or cancer chemotherapy to prevent reactivation. In patients infected with both HBV and HIV, antiretroviral therapy, including two drugs active against both viruses (eg, tenofovir plus lamivudine or emtricitabine), has been recommended when treatment of HIV infection is indicated. Telbivudine and tenofovir are classified as pregnancy category B drugs, and lamivudine, a category C drug, has been shown to be safe in pregnant women with HIV infection. Antiviral therapy has been recommended, beginning in the third trimester, when the mother’s serum HBV DNA level is 200,000 international units/mL or higher to reduce levels at the time of delivery.
Peginterferon alfa-2a is still an alternative to the oral agents in selected cases. A dose of 180 mcg subcutaneously once weekly for 48 weeks leads to sustained normalization of aminotransferase levels, disappearance of HBeAg and HBV DNA from serum, and appearance of anti-HBe in up to 40% of treated patients and results in improved survival. A response is most likely in patients with a low baseline HBV DNA level and high aminotransferase levels and is more likely in those who are infected with HBV genotype A than with other genotypes (especially genotype D) and who have certain favorable polymorphisms of the IL28B gene. Moreover, many complete responders eventually clear HBsAg and develop anti-HBs in serum, and are thus cured. Relapses are uncommon in complete responders who seroconvert from HBeAg to anti-HBe. Peginterferon may be considered in order to avoid long-term therapy with an oral agent, as in young women who may want to become pregnant in the future. Patients with HBeAg-negative chronic hepatitis B have a response rate of 60% after 48 weeks of therapy with peginterferon, but the response may not be durable once peginterferon is stopped. A rapid decline in serum HBsAg titers predicts a sustained response and ultimate clearance of HBsAg. The response to peginterferon is poor in patients with HIV coinfection.
In chronic hepatitis D, peginterferon alfa-2b (1.5 mcg/kg/wk for 48 weeks) may lead to normalization of serum aminotransferase levels, histologic improvement, and elimination of HDV RNA from serum in 20–50% of patients, but relapse may occur and tolerance is poor. Nucleoside and nucleotide analogs are generally not effective in treating chronic hepatitis D; prenylation inhibitors (eg, lonafarnib) and HBV-HDV–specific receptor blockers (eg, bulevirtide [formerly myrcludex B]) are under study.
The sequelae of chronic hepatitis secondary to hepatitis B include cirrhosis, liver failure, and hepatocellular carcinoma. The 5-year mortality rate is 0–2% in those without cirrhosis, 14–20% in those with compensated cirrhosis, and 70–86% following decompensation. The risk of cirrhosis and hepatocellular carcinoma correlates with serum HBV DNA levels, and a focus of therapy is to suppress HBV DNA levels below 300 copies/mL (60 international units/mL). In patients with cirrhosis, even low levels of HBV DNA in serum increase the risk of hepatocellular carcinoma compared with undetectable levels. HBV genotype C is associated with a higher risk of cirrhosis and hepatocellular carcinoma than other genotypes. Antiviral treatment improves the prognosis in responders, prevents (or leads to regression of) cirrhosis, and decreases the frequency of liver-related complications (although the risk of hepatocellular carcinoma does not become as low as that in inactive HBV carriers and hepatocellular carcinoma may even occur after clearance of HBsAg). A risk score (PAGE-B) based on a patient’s age, sex, and platelet count has been reported to predict the 5-year risk of hepatocellular carcinoma in white patients taking entecavir or tenofovir.