Management of Chronic Hepatitis B: An Overview of Practice Guidelines for Primary Care Providers

Markers of HBV Infection and CHB Disease Progression

The progression of CHB depends on the interaction between the virus and the host's immune response, with the main morbidity burden resulting from long-term liver complications (cirrhosis and HCC) that can develop as a result of a persistent immune response against HBV-infected hepatocytes. A number of surrogate markers that correlate with clinical outcomes are used in clinical practice to monitor and predict disease progression.^21⇓–23 HBsAg, the main marker of HBV infection, is detectable 1 to 2 weeks after exposure, and HBsAg clearance is considered a sign of viral clearance. Hepatitis B e antigen (HBeAg) reflects active viral replication and transcription, and indicates infectivity. Serum HBV DNA is another marker of ongoing viral replication: Higher HBV DNA levels reflect increased levels of circulating virus and, importantly, are associated with poorer outcomes. For example, several landmark long-term cohort studies showed that HBV DNA more than ∼2 × 10⁴ IU/mL (∼10⁵ copies/mL) is associated with a significantly greater risk of HCC and mortality than a lower viral load.^24⇓–26 Serum ALT is a marker of liver inflammation; ALT concentrations above the upper limit of normal (ULN) are indicative of injury to hepatocytes. The status of liver disease can also be directly assessed using liver biopsy or noninvasive techniques such as transient elastography (FibroScan); in addition, a number of other noninvasive tests that measure serum markers of liver damage (FibroSpect, FibroSure) have been developed recently.^27,28

CHB typically progresses through 4 different phases (Table 1); however, the duration of the individual phases and the overall course of the disease depend strongly on the age at which the infection was acquired. In the earliest phase—the immune- tolerant phase—no immune response is raised against the virus, and the probability of HBeAg loss and seroconversion is therefore low. This phase is characterized by high levels of HBV DNA and HBeAg positivity but normal ALT and near-normal liver histology. In the absence of liver inflammation, as signified by normal ALT concentrations, liver disease is unlikely to develop. If HBV has been acquired perinatally or during early childhood (which is usually the case in regions where HBV is endemic, such as Asia), the immune-tolerant phase is long, typically lasting 2 or 3 decades; by contrast, it may be absent or very short in adult-acquired HBV. Thus, patients in the immune-tolerant phase are generally children or young adults from regions where HBV is endemic.

If an immune response is mounted against the virus, the disease progresses to the immune clearance phase. In this phase, called HBeAg-positive CHB, the probability of achieving HBeAg seroclearance (ie, the loss of HBeAg and appearance of anti-HBeAb) is higher, with annual rates of spontaneous HBeAg seroclearance ranging from 2% to 20%. As a result of viral clearance, HBV DNA levels decline, but because of the ongoing liver injury associated with the immune response, ALT concentrations are intermittently or persistently elevated and may episodically reach up to 5 times the ULN (“ALT flares”).

Patients who achieve HBeAg seroconversion may enter the inactive carrier phase, characterized by HBeAg negativity, anti-HBeAb positivity, low or undetectable HBV DNA, and normal ALT. Unless advanced liver disease has developed during the preceding immune clearance phase, the inactive carrier phase confers a favorable prognosis, with improvements in liver histology and a halt of disease progression.²⁹ HBeAg seroconversion may also be followed by HBsAg seroclearance, which is considered to be a state as close to remission as possible and is associated with a significant reduction (albeit not complete elimination) of HCC risk.³⁰ If HBeAg seroconversion occurs late in life (after the age of ∼40 years), however, the prolonged immune response may still allow liver disease to progress.³¹ Importantly, HBV reactivation may occur, either as a result of HBeAg seroreversion (ie, restored HBeAg positivity caused by reactivation of wild-type HBV), or, more frequently, as a result of the emergence of HBV mutants that no longer express HBeAg (ie, precore or basal core promoter [PC/BCP] mutants); the latter event, which results in HBeAg-negative CHB, is particularly common among patients from Asia or the Mediterranean, where the prevalence of PC/BCP mutants is high.³² HBV reactivation can occur after years or decades of the inactive carrier state and represents, especially in the case of HBeAg-negative CHB, a late stage of the infection generally associated with advanced liver disease.^21⇓–23 Annual relapse rates following HBeAg seroconversion are estimated to be 2% to 3% among Asians, with the highest rates in males, patients infected by genotype C, and those achieving HBeAg seroconversion after the age of 40 years.²²

HBV Screening

CHB in the immune-tolerant or inactive carrier phase is often asymptomatic; therefore, a considerable proportion of patients do not know they are infected, thereby increasing the risk of developing severe liver complications and spreading the virus to others. Among people affected by CHB, an estimated 65% in the United States and up to 90% in the European Union are not aware of their infection.^33,34 In Western countries, people originating from a high or intermediate endemic area (Asia, Africa, Australia, Central and South America, and the Mediterranean) account for 50% to 95% of all patients with CHB³⁵; thus, although in the United States the overall prevalence of HBV is <1%, it is 10% or even higher among Asian Americans.^35,36 HBV screening allows early diagnosis and treatment of infected individuals, as well as vaccination of their close contacts, to reduce vertical and horizontal transmission.³⁶ CHB practice guidelines, and the recently published guidelines from the US Preventive Services Task Force, recommend HBV screening among high-risk populations, which include (1) people born in high or intermediate endemic areas (for a complete list see ref. ³⁷), (2) people who were not vaccinated as infants and whose parents were born in regions with high HBV endemicity (Southeast Asia, China, sub-Saharan Africa), (3) people needing chemotherapy or immunosuppressive therapy, (4) people with multiple sexual partners or a history of sexually transmitted disease, (5) people who have ever used injecting drugs, (6) individuals infected with human immunodeficiency virus or hepatitis C virus, and (7) household contacts or sexual partners of HBV-infected people.^10,35 Testing should include a serologic assay for HBsAg, with chronic HBV infection confirmed by the persistence of HBsAg for at least 6 months.³⁵

Overview Management of CHB

The primary goal of antiviral treatment is to prevent the development and progression of HBV-related liver disease. However, not all patients need to be treated. In general, patients considered to be treatment candidates are those in the immune clearance phase (HBeAg-positive CHB), in whom treatment aims to stimulate HBeAg seroconversion and minimize liver injury, and patients with a high risk of liver-related morbidity, that is, those with HBeAg-negative CHB and/or advanced liver disease, in whom treatment aims to prevent further progression or reverse existing liver disease.^10⇓–12 In these patients, antiviral therapy has been shown to suppress HBV replication, normalize ALT concentrations, increase HBeAg seroconversion (in HBeAg-positive patients), reverse fibrosis and cirrhosis, and improve liver function in decompensated liver disease.^{10⇓–12,38⇓–40} Antiviral therapy with nucleo(s)tide analogs (NUCs) has also recently been shown to reduce the risk of HBV-related HCC and mortality.^{4⇓⇓⇓⇓–9}

Patients with persistently normal or minimally elevated ALT (eg, patients in the immune-tolerant phase) have a low risk of liver injury and tend to have a poorer response to antiviral therapy^41,42; therefore, treatment is generally not indicated unless there is evidence of advanced liver disease.^10⇓–12 Likewise, inactive carriers do not require treatment since this phase is associated with a favorable outcome.^10⇓–12 For both groups of patients, however, regular monitoring of HBV DNA and ALT is recommended to detect any changes in disease status that might require treatment initiation.^10⇓–12

A detailed summary of the criteria for CHB treatment initiation, as recommended by the current AASLD, APASL, and EASL practice guidelines, is shown in Table 2. In general, the societal recommendations are similar; however, there are minor differences with regard to the specific cut offs for HBV DNA and ALT at which antiviral therapy should be initiated. Figure 1 shows a simple treatment algorithm for HBeAg-positive, HBeAg-negative, and cirrhotic CHB, combining the recommendations by AASLD, APASL, and EASL, and incorporating our experience and opinion.

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Figure 1.

Treatment algorithm for patients with chronic hepatitis B (CHB) who have hepatitis B e antigen (HBeAg)–positive disease (A), HBeAg-negative disease (B), or cirrhosis (C). The strength of all recommendations is A (based on guidelines for management of CHB from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver^10⇓–12). Alanine aminotransferase (ALT) upper limit of normal (ULN): 19 IU/mL in women, 30 IU/mL in men. Sensitive real-time polymerase chain reaction (PCR): lower limit of detection, ∼5-10 IU/mL; lower limit of quantification, ∼30 IU/mL. *See the text for definition of patients at high risk of hepatocellular carcinoma (HCC). ETV, entecavir; HBV, hepatitis B virus; Peg-IFN-α, pegylated interferon-α; TDF, tenofovir.

In real-life practice, patients with CHB may present with coexisting morbidities such as advanced liver disease or coinfection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus, or they may have other special circumstances such as liver transplantation, undergoing immune-suppressive therapy, or pregnancy. In these cases, specific issues need to be considered, and special management strategies are required (Table 3).

For patients in whom antiviral therapy for CHB is indicated, the currently approved agents are interferons (IFNs) and NUCs (Table 4). IFNs (IFN-α and pegylated IFN-α), which historically were the first available treatments for CHB, stimulate immune-mediated suppression of HBV and achieve higher HBeAg seroconversion rates than NUCs after 1 year (∼30%)¹²; however, they have more adverse side effects than NUCs, are administered by subcutaneous injection, and are effective in a select minority (∼30%) of all patients requiring therapy (HBeAg-positive patients with high ALT and low HBV DNA at baseline).^10,11 Furthermore, IFNs are contraindicated in patients with decompensated cirrhosis, in whom there is increased risk of liver failure and sepsis; in patients with autoimmune diseases, bone-marrow disorders, or uncontrolled psychiatric disorders; and during pregnancy.^10⇓–12 For these reasons, the use of IFNs in CHB treatment has declined with the availability of NUCs.

NUCs are oral agents and generally are better tolerated than IFNs, allowing for prolonged use. Compared with IFNs, NUCs are effective in most patients and achieve higher rates of HBV DNA suppression. Compared with IFNs, HBeAg seroconversion rates with NUCs are lower after 1 year (∼20%)¹² but may reach ∼40% to 50% with continued NUC therapy.^38,44 During long-term NUC therapy, however, drug resistance may develop.^10⇓–12 Among the approved NUCs, the nucleoside analog entecavir (ETV) and the nucleotide analog tenofovir (TDF) are currently the preferred first-line agents; both are potent compounds with high barriers to resistance (≤1% during long-term therapy).^10⇓–12 Other approved NUCs include the nucleoside analogs telbivudine and lamivudine (LVD), and the nucleotide analog adefovir; however, these older NUCs have higher rates of resistance and are no longer recommended for use as first-line monotherapy.^10⇓–12 Nucleoside and nucleotide analogs generally have nonoverlapping resistance profiles, which is an important factor to consider when managing patients who develop drug resistance (see Treatment Failure and HBV Resistance on NUC Therapy).

Special Considerations and Unresolved Issues in CHB Management

Treatment Duration and Stopping Rules

For NUC-based antiviral therapy, the guidelines stipulate that treatment can be stopped after achieving certain end points that reflect the patient's HBeAg status and degree of liver fibrosis. In HBeAg-positive patients, the recommended end points are HBeAg seroconversion following sustained undetectable HBV DNA with ALT normalization; in HBeAg-negative patients or HBeAg-positive patients who do not seroconvert, the recommended end points are sustained undetectable HBV DNA with ALT normalization.^10⇓–12 Consolidation therapy is recommended in patients who achieve these end points, but there is no consensus on its optimal duration (6 or 12 months or longer).^10⇓–12 Ultimately, HBsAg loss is the ideal end point because it is associated with a significantly reduced HCC risk, although not as low as that of a person who has never been infected with HBV.³⁰

However, achievement of these end points is rare with 4 to 5 years of treatment (40% to 52% for HBeAg seroconversion,^38,44 ≤10% for HBsAg loss²³), and there is also growing evidence suggesting that it does not guarantee long-term remission. This is because of the presence of covalently closed circular HBV DNA (cccDNA) inside the nuclei of infected hepatocytes, which is the stable genetic component of HBV that may persist even after HBsAg loss has occurred, thereby allowing HBV reactivation.^21,55 Thus, even with consolidation therapy, HBV recurrence is frequent, with ∼40% to 80% of patients experiencing virologic relapse after stopping therapy.^{56⇓⇓⇓⇓–61} Therefore, in clinical practice, a considerable proportion of patients will require long-term, if not indefinite, treatment with NUCs to maintain these end points and prevent HBV reactivation.

IFN-based therapy is administered over a finite duration (usually 48 weeks), irrespective of achievement of these end points, since prolonged maintenance therapy to suppress HBV replication is not feasible with these regimens.⁶²

Role of Noninvasive Assessment of Liver Disease

The societal guidelines all recommend assessment of liver histology in certain groups of patients to guide decisions on treatment initiation^10⇓–12 (see Table 2). However, because routine assessment of liver fibrosis and cirrhosis using liver biopsy is difficult in clinical practice, other noninvasive assessments have been developed that could be used as a substitute. Transient elastography (FibroScan), which measures liver stiffness, has been shown to be an accurate tool for assessing liver disease in patients with either a very high or very low risk of fibrosis⁶³; however, it might overestimate fibrosis in patients with elevated ALT.⁶⁴ Other noninvasive tests for fibrosis are FibroSpect and FibroSure, which measure serum markers that correlate with the degree of liver damage, such as α-2-macroglobulin, total bilirubin, apolipoprotein A1, and hyaluronic acid^27,28; however, further studies are needed to evaluate these tools in CHB management.

HCC Screening and the Role of HCC Risk Scores

CHB is associated with a higher risk of HCC, and HCC incidences among untreated patients range from 0.3% to 0.6% in those without cirrhosis and 2.2% to 3.7% in those with compensated cirrhosis.⁶⁵ Recent data indicate that with the current potent NUCs, the risk of HCC risk can be reduced but not completely eliminated.⁶⁶ Thus regular HCC surveillance is recommended even in patients receiving anti-HBV treatment, and it has been shown to be a cost-effective strategy in CHB management.⁶⁷ The AASLD Practice Guidelines for Management of HCC recommend ultrasound every 6 months for HCC screening; α-fetoprotein, which has long been used for HCC diagnosis as well, has been shown to be insufficiently sensitive and specific for use as a surveillance assay.⁶⁷ The AASLD and APASL CHB Practice Guidelines recommend screening all HBV carriers at high risk of HCC, that is, Asian men >40 years and Asian women >50 years of age, patients with cirrhosis or with a family history of HCC, Africans >20 years of age, and any carrier >40 years old with persistent or intermittent ALT elevation and/or high HBV DNA level (>2,000 IU/mL).^10⇓–12 Several HCC risk calculators have recently been developed to estimate a patient's future risk of developing HBV-related HCC.^{68⇓⇓–71} These scores incorporate various combinations of established HCC risk factors (eg, age, sex, HBV DNA level, or markers of liver function), many of which can be assessed in clinical practice and might prove useful to identify patients most in need of HCC screening.

Directions for Future Research

New Treatments for CHB

Neither IFNs nor NUCs are capable of completely eliminating the virus; thus there is a need for new treatments that might provide greater benefit. The combination of 2 potent NUCs might have additive or synergistic antiviral activity, which may result in faster or more profound viral suppression. However, the antiviral efficacy of ETV plus TDF was found to be comparable to that of ETV monotherapy, although it did show an incremental benefit in HBeAg-positive patients with baseline levels of HBV DNA ≥10⁸ IU/mL.⁸⁰ The combination of IFN plus NUC may stimulate immunologic responses in patients with NUC-induced virologic suppression, thereby potentially achieving a sustained response with a finite treatment duration. Indeed, in patients with maintained undetectable HBV DNA on ETV, the addition of or switch to pegylated IFN-α resulted in significantly higher rates of HBeAg seroconversion and HBsAg clearance than continuing on ETV alone,^81,82 indicating that this may be a new treatment strategy. An alternative approach for immune-mediated treatment of CHB is therapeutic vaccination. This modality, which is different from prophylactic vaccination, aims to boost HBV-specific T-cell responses, which are generally deficient in patients with CHB, and has the potential to be a cheap and effective treatment option. A number of therapeutic vaccines based on viral envelope or capsid antigens or HBV DNA have been developed; however, so far they have demonstrated limited clinical efficacy.⁸³