Expert Insight Into: Current Best Practices in Hepatitis B Treatment: Optimizing Response while Avoiding Resistance

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Clinical Insights

Currently, the primary goal of treatment is reduction of viral load, since duration of time at high viral load appears to be associated with the development of cirrhosis and HCC.
In general, treatment for chronic HBV infection should be initiated when viral load is >2000 IU/ml1 and/or when ALT increases to >30 IU/ml in men or >19 IU/ml in women.² However, patients with lower HBV DNA levels may be at risk for progressive liver disease and may require treatment as well, whereas specific groups, including younger immunotolerant patients or patients with mild CHB, may not require immediate treatment but should be carefully monitored.¹
Patients on treatment should be monitored every 3-6 months for response to therapy and for the development of viral resistance.
As recommended in this paper, first-line nucleoside analogue (NA) therapies for chronic HBV are entecavir and tenofovir, due to their potency and low rates of resistance.³ These recommended first-line NAs, together with pegylated interferon, are also listed as the first-line treatments in the recently updated guidelines established by EASL¹ and AASLD.²
In the opinion of the author, patients who show inadequate response but not resistance to one first-line NA are switched to the other; whereas, patients who become resistant to one first-line NA have the second first-line agent added to the treatment.³
Because of their high rates of resistance, lamivudine and telbivudine are considered third-line and second-line therapies, respectively; whereas, adefovir is advised as second- or add-on therapy due to its low potency in suppressing viral load.²

PLEASE NOTE: The peer-reviewed journal article reviewed in this educational activity has been selected by faculty on the scientific merits of the new data and/or information being reported, which form the building blocks for a better understanding of the disease and its management. The evidence-based clinical findings provided in these articles are important in helping clinicians improve patient care and outcomes. Each article review is one part of a larger overall curriculum mosaic that provides a full and balanced perspective on this disease and its management. We suggest that you read all of the article reviews in this series.

Although practice guidelines for the treatment of patients with hepatitis B virus (HBV) can guide treatment decisions, uncertainties relative to infection and the complexity of the guidelines can limit patient care. Among the factors hindering optimal treatment are questions about the initiation and termination of therapy, cost issues, and the development of drug resistance. A recent article by Dr. Robert G. Gish presents a set of treatment paradigms for the management of chronic HBV, based on recent guidelines formulated by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), the Asian-Pacific Association for the Study of the Liver, and the National Institutes of Health.¹

Initiation of treatment should be based on two factors - plasma concentration of HBV DNA (viral load) and serum concentration of alanine aminotransferase (ALT). EASL guidelines recommend a viral load of 2000 IU/ml as the threshold for starting therapy, in patients who are positive or negative for hepatitis B e antigen (HBeAg). Measurements of viral load are especially important, since longer time at a given HBV DNA concentration is associated with increased risks of hepatocellular carcinoma (HCC) and cirrhosis. AASLD guidelines recommend that ALT >30 IU/ml for men or >19 IU/ml for women be the threshold for initiating therapy in patients positive for HBV DNA, although Dr. Gish and others suggest a lower limit of >25 IU/ml for men.

Several barriers have been found to be associated with reluctance to initiate therapy. For example, patients may be reluctant to undergo invasive procedures, especially liver biopsy. There are also concerns about the development of drug resistance and the lack of clear guidelines to terminate therapy. In addition, costs of treatment are of concern.

The primary goal of treatment is maximum reduction of viral load, which reduces the risk of resistance and the development of cirrhosis and HCC. The increased use of potent antiviral drugs in the United States has reduced the need for liver transplantation for end-stage liver disease. It is widely acknowledged that the ultimate goal of treatment is loss of hepatitis B surface antigen (HBsAg), but it should be recognized that it occurs at a relatively low rate and hence we focus on the more immediate and achievable goal of viral load reduction.

Many drugs are currently available in the United States to treat chronic HBV, including the nucleoside analogues lamivudine, entecavir, and telbivudine; the nucleotide analogues adefovir and tenofovir; and the immunomodulator peginterferon. Due to its low rate of resistance in treatment-naïve patients, entecavir is frequently utilized as first-line treatment (Figure). Entecavir, however, is much less effective in patients who have developed lamivudine resistance. The other drug used as first-line treatment at CPMC is tenofovir, which has shown persistent virologic responses in >90% of HBeAg-negative and almost 80% of HBeAg-positive patients after 72 weeks. This drug has also been shown effective in previously treated patients, including those who are lamivudine resistant, although patients with adefovir resistance at baseline are less likely to respond.

Among the other drugs used to treat HBV, lamivudine is associated with high levels of resistance with increased treatment duration, peaking at 80% after 5 years and eventually requiring combination therapy; it is therefore considered a third line agent (Figure). Telbivudine has been associated with high rates of genotypic resistance and virologic breakthrough, making it a second-line treatment in most patients, although it is frequently used in pregnant women due to its Category B toxicity designation. Adefovir is also considered a second line agent or as an add-on drug in patients who become resistant to lamivudine.

Figure. Development of resistance over 5 years in patients treated with entecavir (treatment naïve or lamivudine resistant) or lamivudine.^1,2

^a5-year Entecavir (Lamivudine-resistant) data not available.

Patients being treated for HBV must be monitored every 3 to 6 months for adequacy of response and the development of resistance. Resistance can be assessed by virologic breakthrough (≥1 log₁₀ increase in plasma HBV DNA concentration), increased serum ALT, progression of liver disease (hepatic decompensation, HCC, need for transplantation), or resistance mutations. At CPMC, to minimize resistance, patients are started on entecavir or tenofovir as first-line therapy. Patients who show inadequate response to treatment (flat response, high viral load) to one of these agents are usually switched to the other; whereas, patients who develop resistance to one agent generally have the other first-line option added to the regimen.

In summary, the success of antiviral drug treatment in patients with HBV is dependent on the prevention of viral resistance. Long-term success can be maximized by initiating treatment when viral load is low and before the development of cirrhosis, by using the most potent antiviral agents to suppress viral load, and by long-term monitoring. The most effective first-line options currently available are entecavir and tenofovir. If patients become resistant to initial therapy, combination therapy is preferred to switching agents, due to possible cross-resistance between entecavir and tenofovir.

References

Lok AS, McMahon BJ. AASLD Practice guidelines. Chronic hepatitis B: Update 2009. Hepatology. 2009; 50: 1-36.
EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50: 227-242.
Gish RG. Hepatitis B treatment: current best practices, avoiding resistance. Cleve Clin J Med. 2009;76 Suppl 3:S14-S19.

Privacy Policy

Expert Insight Into:
Current Best Practices in Hepatitis B Treatment: Optimizing Response while Avoiding Resistance

Based on the Article:

Hepatitis B Treatment: Current Best Practices, Avoiding Resistance. Cleve Clin J Med. 2009;76 Suppl 3:S14-S19.

Medical Writer: Richard J. Alexander, PhD
Expert Faculty: Adrian M. Di Bisceglie, MD, FACP

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Privacy Policy

Expert Insight Into: Current Best Practices in Hepatitis B Treatment: Optimizing Response while Avoiding Resistance

Based on the Article: Hepatitis B Treatment: Current Best Practices, Avoiding Resistance. Cleve Clin J Med. 2009;76 Suppl 3:S14-S19.

Medical Writer: Richard J. Alexander, PhD Expert Faculty: Adrian M. Di Bisceglie, MD, FACP

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

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CE Information: Pharmacists

CME/CE Instructions

Expert Insight Into:
Current Best Practices in Hepatitis B Treatment: Optimizing Response while Avoiding Resistance

Based on the Article:

Hepatitis B Treatment: Current Best Practices, Avoiding Resistance. Cleve Clin J Med. 2009;76 Suppl 3:S14-S19.

Medical Writer: Richard J. Alexander, PhD
Expert Faculty: Adrian M. Di Bisceglie, MD, FACP