HBV Treatment Fundamentals: Getting Back to Basics to Optimize Patient Outcomes CME

Individualizing Treatment in the Patient With Chronic HBV Infection: When to Start, What to Use, and When to Stop CME

Anna S. F. Lok, MD

Posted: 10/20/2011


There are 7 approved therapies for chronic hepatitis B virus (HBV) infection: 2 formulations of interferon (IFN) (standard and pegylated IFN [PEG-IFN]) and 5 nucleos(t)ide analogs (NUCs): lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. Although these therapies are effective in suppressing HBV When treplication, they do not eradicate the virus. Most patients, therefore, require a long duration of treatment and sometimes lifelong treatment to derive clinical benefit. Given that treatment is expensive and may be associated with drug resistance and adverse effects — and because not all patients with chronic HBV infection progress to cirrhosis or hepatocellular carcinoma (HCC) — questions regarding HBV treatment remain.

Guidelines from professional organizations and recommendations from consensus conferences provide a framework to guide physicians in deciding when to start treatment, which treatment to use, and when to stop treatment.[1-4] Guidelines, however, are just that, and treatment decisions should be made jointly by the patient and physician after careful consideration not only of clinical features, hepatitis B e antigen (HBeAg) status, serum HBV DNA, and alanine aminotransferase (ALT) levels, and liver histology (when available), but also individual circumstances such as family history of HCC, occupational requirements, plans for starting a family (in women), and comorbid conditions such as those that may preclude the use of IFN or increase the likelihood of adverse events. In clinical practice, other considerations, such as the patient’s perceived risk for adverse outcomes if they opt to defer treatment, cost (or copay), and willingness to undergo parenteral therapy or to adhere to many years of oral therapy, may influence a patient’s decision of both when to start treatment and the choice of therapy (Table 1). This review focuses on individualized treatment strategies.

Table 1. Factors to Consider in Treatment Decisions

Factors in disease progression
  Duration of infection
  HBV replication: HBeAg status, HBV DNA level
  Liver disease: ALT level, histology (inflammation and fibrosis), clinical evidence of portal hypertension, cirrhosis
Factors associated with treatment response
  Activity of liver disease: ALT level, histology (inflammation)
  HBV replication: HBeAg status, HBV DNA level
  HBV genotype (IFN treatment only)
Factors specific to the individual patient
  Plans to start a family in women of reproductive age
  Occupational requirements
  Family history of HCC
  Patient’s perception of risk for adverse outcomes if hepatitis B is left untreated
  Patient’s perception of likelihood of treatment response and benefit
  Cost and healthcare coverage
  Patient preference: willingness to commit to IFN therapy or a long course of oral medications

ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; IFN = interferon
Adapted from Degertekin B, et al. Hepatology. 2009;49(Suppl1):S129-S137.

Choosing Appropriate Drug Therapy

Once a decision to initiate treatment is made, the next step is to choose the appropriate drug. The decision regarding whether to use NUC or IFN is based on patient characteristics and patient preferences (Table 2).

Table 2. Comparison of Pegylated Interferon and Nucleos(t)ide Analogs

Consideration Pegylated Interferon Nucleos(t)ide Analogs
Route of administration Parenteral, SC injection Oral
Duration of treatment 1 year A few years to lifelong
Antiviral activity Modest Modest: ADV
Strong: LAM
Strongest: ETV, TDF, TBV
Drug resistance NA 0%-20% after 1 year Low: ETV, TDF
Higher: ADV, TBV
Highest: LAM
Immunomodulatory activity Yes No
HBeAg seroconversion ~ 30% after 1 year treatment ~ 20% after 1 year treatment
40%-50% after 5 years continuous treatment
HBsAg loss ~ 3% after 1 year
~ 10% after 3-5 years of post-treatment follow-up
0%-3% after 1 year
0%-8% after 4-5 years continuous treatment
Predictors of response High ALT, low HBV DNA
Genotype A (HBeAg-positive patients)
High ALT, low HBV DNA
Adverse events Frequent
(flu-like symptoms, fatigue, bone marrow suppression, depression)
(nephrotoxicity [ADV, TDF]; myositis, myalgia [TDF]; lactic acidosis [class effect])When t
Decompensated liver disease Contraindicated Indicated
Compensated cirrhosis Selected cases, use with care Indicated
Pregnancy Class C, contraindicated LAM, ADV, ETV: class C
TDF, TBV: class B
LAM, TDF: safe in humans based on registry dataWhen t

ADV = adefovir dipivoxil; ALT = alanine aminotransferase; ETV = entecavir; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; LAM = lamivudine; SC = subcutaneous; TBV = telbivudine; TDF = tenofovir disoproxil fumarate
Data from Lok AS, et al. Hepatology. 2007;5:507-539.[1]


The main advantage of IFN is that it is administered for a finite duration. IFN also seems to be associated with a higher rate of hepatitis B surface antigen (HBsAg) loss, although this benefit is seen mainly in patients with genotype A infection. Clinical trials showed that a 1-year course of IFN results in a higher rate of HBeAg seroconversion than a similar duration of lamivudine treatment,[5] but in clinical practice, NUCs are administered for longer than 1 year, and similar or higher rates of HBeAg seroconversion can be achieved after 3-5 years of continuous NUC treatment.[6-9]

Pretreatment factors that have been shown to predict IFN-related response in HBeAg-positive patients include high ALT (a surrogate for host immune response to HBV), low HBV DNA, and HBV genotype A.[10] These data have led to development of models to guide decisions regarding IFN treatment. Recently, decline in HBsAg titer at week 12 or When t24 during PEG-IFN treatment had been suggested to predict sustained response off-treatment, and it may be used to decide whether to continue treatment.[11] These algorithms have not, however, been validated prospectively, and the optimal cutoff values have not been determined.

Retrospective analysis of data from the registration trial of PEG-IFN alpha-2a with or without lamivudine in HBeAg-negative patients showed that patient age and gender, HBV genotype, and pretreatment ALT and HBV DNA levels were associated with sustained response off-treatment, but the predictive accuracy has not been validated and appears to be dependent on genotype.[12] Decline in HBsAg titer during PEG-IFN treatment had also been demonstrated to predict sustained response, and a working group suggested that suboptimal decline in HBsAg titer and HBV DNA after 12 weeks of treatment should be When tused as a stopping rule in HBeAg-negative patients, particularly those with genotype D infection.[11]

Nucleos(t)ide Analogs

Major advantages of NUCs include ease of administration (oral), potent antiviral activity, and favorable safety profile. The main disadvantages of NUCs include risk for drug resistance and the need for a long duration of treatment (often lifelong). Of the 5 approved NUCs, entecavir, tenofovir, and telbivudine have more potent antiviral activity followed by lamivudine and then adefovir dipivoxil. Entecavir and tenofovir have a higher genetic barrier to resistance (ie, lower rates of drug resistance) followed by adefovir dipivoxil, telbivudine, and then lamivudine. The most consistent predictor of response to When tNUC in HBeAg-positive patients is high pretreatment ALT.[13,14] Predictors of response to NUC in HBeAg-negative patients have not been established. Unlike IFN, response to NUC is similar across the major HBV genotypes (A-D).

Although all 5 NUC agents approved for hepatitis B are well tolerated, lactic acidosis has been reported in a case series of entecavir treatment in patients with severe liver decompensation[15]; myalgia, myositis, and peripheral neuropathy in patients receiving telbivudine[16]; and nephrotoxicity and renal tubular dysfunction in patients receiving adefovir dipivoxil or tenofovir.[17,18] Tenofovir and telbivudine are categorized as class B drugs regarding safety in pregnancy, with the other NUCs as well as IFN categorized as class C drugs. Based on data from the antiretroviral pregnancy registry, lamivudine and tenofovir appear to be safe even when used in the first trimester of pregnancy.[19]


Currently, monotherapy with a NUC or PEG-IFN is recommended as initial therapy. Although combination therapy has potential advantages, neither combination of PEG-IFN+NUC or combination of 2 NUCs had been shown to induce higher rates of sustained response. The main advantage of combination therapies is a reduction in rate of lamivudine resistance compared with lamivudine monotherapy. Given the low rate of resistance to entecavir or tenofovir, the benefit of de novo combination therapy involving either of these drugs is limited.[8,9]

IFN should not be used in patients who have decompensated cirrhosis, severe exacerbations of chronic hepatitis B, immunosuppression, or medical or psychiatric contraindications. IFN may be used with caution in patients with compensated cirrhosis provided they have normal hepatic synthetic function and no evidence of portal hypertension. IFN is most appropriate for young patients, those who are reluctant to commit to a long duration of treatment, and HBeAg-positive patients who have high pretreatment ALT levels or genotype A infection.

NUCs are most appropriate for patients who have decompensated liver disease or contraindications to IFN, and those who are willing to commit to long durations of treatment. Of the 5 approved NUCs, entecavir and tenofovir have the best profile regarding safety, efficacy, and drug resistance. Tenofovir is preferred in patients who might be contemplating pregnancy and in those who might have been exposed to lamivudine or telbivudine in the past. Tenofovir can be administered with or without food and is more convenient for patients who have difficulty in adhering to their medication regimen. Entecavir is preferred in patients who have other medical conditions, such as diabetes or hypertension that are associated with increased risk for renal insufficiency. Lamivudine and telbivudine should not be used because of the high rates of drug resistance unless cost is a limiting factor and the anticipated duration of treatment is short (eg, prophylaxis in patients who will be receiving immunosuppressive therapies). Adefovir dipivoxil should not be used because of its weak antiviral activity.

When to Discontinue Treatment

Ideally, antiviral therapy should be continued until HBsAg loss, but the likelihood of this occurring is low: HBsAg loss occurs in approximately 10% of patients 3-5 years after completing a 1-year course of PEG-IFN, and in up to 10% of patients after 4-5 years of continuous NUC therapy.[5-9]


Recommended duration of PEG-IFN treatment is 48 weeks for both HBeAg-positive and HBeAg-negative patients. Recent studies suggest that on-treatment decline in HBsAg titer may be used to define early stop rules, but this strategy must be validated in prospective clinical studies.

Nucleos(t)ide Analogs

NUCs are often administered indefinitely because of the high risk for viral relapse when treatment is discontinued. Treatment can, however, be stopped in patients who have achieved the desired endpoint. For HBeAg-positive patients with precirrhotic liver disease, treatment can be discontinued 12 months after achieving HBeAg seroconversion. Although some studies demonstrated that durability of NUC-related HBeAg seroconversion is low, many of these studies involved small numbers of patients or inadequate duration of consolidation therapy. One study found that the 5-year cumulative rate of relapse after discontinuation of lamivudine was only 9% in patients with ≥ 12 months of consolidation therapy.[20] Some experts argue that treatment should be continued indefinitely because reactivation of HBV replication and progression to HBeAg-negative hepatitis will occur in most, if not all, patients, but long-term follow-up studies showed that some patients can remain in the inactive carrier state for decades. These data indicate that if patients are well monitored, disease progression can be prevented if treatment is reinitiated when HBV DNA, ALT levels, or both become elevated. Committing all patients to lifelong treatment because of possible future reactivation would be akin to lifelong cancer chemotherapy to prevent future relapse in patients who have achieved remission.

The therapeutic endpoint is unclear for HBeAg-negative precirrhotic patients. Treatment is often continued indefinitely, but may be stopped in those who achieved HBsAg loss. Preliminary data from one small study suggest that treatment can be stopped in selected patients who maintain viral suppression for 3-5 years. These data have not, however, been validated.[21]

For patients who had decompensated liver disease or cirrhosis, lifelong treatment is recommended because of concerns about fatal flares when treatment is discontinued. Treatment may be stopped, however, in selected patients with compensated cirrhosis who have lost HBsAg or have completed an adequate duration of consolidation therapy after HBeAg seroconversion (in those who were previously HBeAg positive) provided they are closely monitored and treatment reinstituted in the presence of viral rebound or ALT elevation. This recommendation is supported by studies that demonstrate regression of cirrhosis in patients with maintained viral suppression after 3-5 years of NUC therapy.[22]

Although it has been suggested that patients with inadequate or slow decline in HBV DNA during the first 12-24 weeks of NUC monotherapy should receive an additional NUC, this approach was derived from studies of lamivudine and telbivudine. Studies of entecavir and tenofovir (which have high genetic barriers to resistance) found that HBV DNA levels continued to decline in patients with slow initial response, and rates of drug resistance were low in patients who remained on the same treatment.[9,23]


Decisions regarding when to start treatment, which therapies to use, and when to stop treatment must take into consideration not only viral or disease factors, but also individual patient circumstances and preferences to achieve optimal results.


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