Referred by his primary care physician, a 40-year-old Chinese man presented to his gastroenterologist for further evaluation after detection of elevated liver enzyme levels on routine laboratory evaluation. The patient had a serum alanine aminotransferase (ALT) level 90 U/L and normal liver synthetic tests. The gastroenterologist evaluated the patient for viral hepatitis and found him to be HBsAg positive. Subsequent testing documented that the patient had a serum HBV DNA level 3 x 10⁸ IU/mL, platelet count 130,000/mm³, and normal alpha-fetoprotein level, and that he was HBeAg positive and anti-HBe negative. On physical examination, the patient's spleen was 13 cm in height.

The gastroenterologist suspected early cirrhosis and decided to start the patient on oral antiviral therapy using lamivudine 100 mg/d, since this medication was the only treatment that was on the patient's formulary list. The physician followed the patient sporadically with laboratory tests over the next few years. At 28 months of treatment, the patient presented with jaundice and serum HBV DNA level 2 x 10⁷ IU/mL. The patient had prolonged International Normalized Ratio (INR) and, on examination, ascites. He subsequently developed rapidly progressive liver disease, despite the addition of adefovir to the lamivudine regimen, and required an urgent liver transplant 2 months later. His hospital course was complicated, with hospital charges for his peritransplant care ultimately amounting to more than US$400,000.

In your opinion, is lamivudine still an appropriate choice for first-line therapy in patients with hepatitis B virus (HBV) infection?

Discussion

As illustrated by this case study, drug resistance is an important concern in patients treated with oral antiviral agents for hepatitis B. Resistance has been associated with the formation of vaccine escape mutants, increased risk of resistance to other antiviral medications for hepatitis B, disease flare, rapid progression of liver disease, need for urgent liver transplantation, and death.^1,2 As has been seen clinically, patients with drug-resistant mutations can transmit the infection to other individuals. Therefore, an important objective of disease management in hepatitis B is to prevent and detect development of resistance.

The choice of first-line therapy greatly affects a patient's risk of developing resistance. Some agents, particularly lamivudine, not only have a higher risk of resistance during initial therapy, but also predispose to cross-resistance against other oral antivirals used to treat HBV infection. For this reason, in the latest revision of the US Treatment Algorithm, lamivudine is no longer recommended for use as first-line therapy.³ Agents recommended for primary therapy in treatment-naive patients include peginterferon, entecavir, and adefovir. Peginterferon has not been shown to be associated with resistance, and (based on 2-year data) entecavir resistance appears to occur only in the presence of preexisting lamivudine mutations (9%) and not in treatment-naive patients (0%).^4,5 Adefovir has much lower rates of resistance (29% at 5 years in HBeAg negative patients⁶ and 42% in HBeAg positive patients⁷) than lamivudine (70% at 4 years overall).⁸

Select patients are candidates for peginterferon (ie, those who lack psychiatric/medical contraindications or decompensated cirrhosis, particularly if they have intermediate or low baseline HBV DNA [10^4-8 IU/mL] and high ALT levels [>80 U/mL]⁹). For such patients, peginterferon may be considered before nucleos(t)ide therapy since it has defined treatment intervals and high HBeAg seroconversion rates. In HBeAg positive patients, response is better in genotype A than in B, and equivalent in B and C, which, in turn, respond better than genotype D.^10,11 In HBeAg negative patients, peginterferon is modestly effective (20% virologic response as defined by long-term off-treatment HBV DNA negativity by PCR), with no specific benefit in one genotype over another.¹²

Oral antivirals—adefovir and entecavir—are alternatives for primary therapy. In a placebo-controlled trial, after nearly 3 years of adefovir, HBeAg positive patients showed good response (56% virologic, 43% HBeAg seroconversion, and 81% normalized ALT).¹³ In a similar trial, 79% of HBeAg negative patients achieved undetectable HBV DNA, and 88% had a normalized ALT level.¹⁴ Entecavir, the newest nucleoside option for treating HBV, has shown consistent superiority over lamivudine in inducing histologic improvement, reducing HBV DNA levels, and normalizing ALT.^15-17 Recently reported 2-year data on entecavir show that 93% of treatment-naive patients reached undetectable (<300 copies/mL) HBV DNA levels, with no genotypic or clinical evidence of resistance.⁵

Regardless of the agent selected for treatment, it is necessary to monitor for resistance. Rising HBV DNA level is the first clinical sign of resistance and has independently been associated with progression of liver disease, cirrhosis, cirrhosis-related complications, and hepatocellular carcinoma.^18-21 Moreover, patients who do not reach HBV DNA negativity are at the highest risk of developing drug resistance on therapy, as mutation is dependent on HBV DNA replication.²² Monitoring for HCC is also important and considered standard of care in patients at risk for liver cancer, specifically those patients with cirrhosis and men over the age of 40.

After establishing a baseline level, clinicians should monitor HBV DNA at 3 months after initiation of treatment to document that there is at least a 1-log₁₀ IU/mL reduction in HBV DNA.²³ If the patient does not achieve a ≥1-log decrease at each 3-month interval in which HBV DNA should be measured (considered primary treatment failure),²³ change to an alternative therapy such as entecavir or adefovir. Continue monitoring at least every 3 to 6 months after a documented response to identify any ≥1-log₁₀ IU/mL increase from nadir following an initial response, which indicates the presence of medication resistance (ie, breakthrough [rebound], or secondary treatment failure)²³ and the need to change to an alternative therapy or add a second drug.

The addition of adefovir to lamivudine has been shown to be an effective treatment for lamivudine-resistant patients.^24-26 There is some evidence that adefovir resistance is more common in lamivudine-resistant patients than in treatment-naive patients when adefovir monotherapy is used (ie, when lamivudine is discontinued).²⁷ Switching to entecavir has also been found to be an effective option for lamivudine-resistant patients, improving histologic, biochemical, and virologic outcomes.^28,29 Lamivudine resistance somewhat increases the risk of entecavir resistance such that viral rebound has been observed in 9% of patients by week 96.⁵ Note that once a patient has decompensated liver disease, it may be too late to stop progression to liver failure by adding or changing medications. Such patients should be referred immediately for liver transplant.³⁰

Commercial resistance assays are now available through commercial laboratories to monitor for drug resistance by identifying point mutations that are associated with both genotypic and phenotypic resistance. Use of such testing is not mandatory but may be useful to rule out noncompliance in patients with virologic breakthrough during infection. Since mutations are detectable before emergence of clinical resistance, testing may allow for early alterations in treatment to prevent disease flare in patients at particular risk for complications from progression.

In summary, drug resistance is an important clinical concern in patients with HBV infection. HBV DNA monitoring is critical in detecting lack of response and breakthrough during treatment. Strategies to minimize the risk of resistance include selection of a first-line therapy that has a low risk of resistance and cross-resistance and prompt change in treatment regimens for patients who do not respond or who experience virologic rebound.

References

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2. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105-117.
3. Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. In press. August 2006.
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