An internist referred a 35-year-old Vietnamese woman to a gastroenterologist after determining that she was infected with hepatitis B virus (HBV). Her routine laboratory evaluation showed elevated liver enzyme levels, including an alanine aminotransferase (ALT) level of 80 IU/mL. She had normal liver synthetic tests. The internist had evaluated her for viral hepatitis and found her to be hepatitis B surface antigen (HBsAg) positive.

Subsequent testing by the gastroenterologist documented that the patient had a serum HBV DNA level of 3 x 10⁶ IU/mL. She had a normal alpha-fetoprotein level, was hepatitis B e antigen (HBeAg) negative, and was positive for the antibody to hepatitis B e antigen (anti-HBe). The patient had a normal spleen size of 9 cm and a platelet count of 230,000/mm³. Her physician documented active liver disease by a liver biopsy and decided to start her on oral antiviral therapy.

Because lamivudine was on the formulary of the local health plan, the physician started the patient on lamivudine 100 mg/d. Over the next few years, he followed the patient every 3 months with laboratory tests including ALT and HBV DNA. At 15 months of treatment, the patient presented with an HBV DNA level of 4 x 10⁴ IU/mL. Since she had not had a 5-log decrease to undetectable HBV DNA, or a 1-log decrease every 3 months, the patient was defined as a primary treatment nonresponder; therefore, a viral resistance mutation test was performed. The INNOLiPA test showed the presence of the rtL180M and rtM204V gene mutations, which are associated with nucleoside resistance including lamivudine resistance.^1,2 The patient was switched to adefovir monotherapy, and a 2-log decrease in the serum levels of HBV DNA was seen over the next 12 months to 100 IU/mL. Since the patient still had not become HBV DNA negative, a second INNOLiPA test was performed to determine the presence of drug resistance. The rtL180M and rtM204V gene mutations were no longer present, but the rtA181V and rtN236T gene mutations were seen. These mutations are associated with nucleotide resistance, specifically adefovir resistance.^1-3 Lamivudine was reintroduced, with continued adefovir therapy. Three months later, the patient showed a rise in ALT from a nadir of 40 IU/mL to 160 IU/mL. Concurrently, HBV DNA rose by 1 x 10³ IU/mL to 1100 IU/mL. A repeat gene mutation test was performed, which showed persistence of the adefovir resistance pattern and reemergence of the lamivudine pattern.

Discussion Question: Which of the following prompts you to alter your management strategy for a patient receiving antiviral therapy for chronic HBV infection?

Discussion

Answer: (d). All of the above scenarios indicate insufficient response to, or failure of, antiviral therapy and require a change in management.

Patients started on treatment for chronic HBV infection should be monitored after 3 months to determine whether there was a ≥1-log reduction in HBV DNA.⁴ The absence of a sustained ≥1-log decrease within 3 months of initial therapy suggests primary antiviral treatment failure.⁴ If a patient has a decline of 1 log in the first 3 months, a subsequent assessment should show a further decline of HBV DNA of 1 log every 3 months thereafter until HBV DNA in the serum is undetectable. The absence of a sustained decrease warrants a switch to an alternative first-line monotherapy such as entecavir, telbivudine, or adefovir, provided that the development of a resistance mutation had not occurred.

Ultimately, the goal of therapy is to obtain complete suppression of viral replication, i.e. HBV DNA negativity by a sensitive test such as polymerase chain reaction (PCR). Patients who do not reach HBV DNA negativity are at highest risk of developing drug resistance (Fig. 1).^1,5,6 If the patient is not HBV DNA negative early in the course of treatment, practitioners should strongly consider adding or changing to an alternative therapy.^3,4

Timing of the addition or switch depends on the risk of developing resistance (Fig. 2A-D).^7-13 If a patient treated with lamivudine is not HBV DNA negative at 3 to 6 months, a change in therapeutic management is advised.^5,14 With telbivudine, one can wait until 6 months to adjust treatment.^15,16

Because adefovir and entecavir have much lower rates of resistance in the first 2 years of therapy,^8-11 the time point for treatment decision can be extended to 1 year with adefovir and 2 to 3 years with entecavir. With adefovir therapy, persistent HBV DNA at 12 months is a key predictor of resistance (Fig. 3).^6,17 However, the specific time point for changing therapy is less certain for entecavir since at 3 years over 90% to 95% of patients are HBV DNA negative by PCR, and the cumulative rate of resistance is 1.1%.⁸

Patients who do show an initial response require continued monitoring for the emergence of drug resistance. The emergence of resistance has been associated with transmission of drug-resistant mutants, formation of vaccine escape mutants, increased risk of resistance to other HBV antiviral medications, flares in liver enzymes, rapid progression of liver disease, urgent need for transplantation, and death.^1,4 There is a clearly documented association with drug resistance and rising HBV DNA levels. A ≥1-log rebound in HBV DNA compared with nadir during antiviral therapy indicates secondary antiviral treatment failure.⁴ Confirmation of drug resistance via viral genetic sequencing assays is now possible through commercial laboratories.

Once resistance develops, it is necessary to change to an alternative therapy or add a second drug. Both adefovir and entecavir are approved by the Food and Drug Administration (FDA) for use in lamivudine-resistant HBV infection. The US Treatment Algorithm³ recommends either adding adefovir or switching to entecavir, and notes that potential future management includes adding or switching to emtricitabine/tenofovir. Adding adefovir to lamivudine in the setting of lamivudine resistance is superior to a switch to monotherapy and is more effective in suppressing HBV replication and decreasing the rate of emergence of a resistant viral population.^18-21 Combining the two drugs reduces the risk of adefovir resistance.⁶ Although there is a substantial risk of entecavir resistance in patients with nucleoside resistance (ie, lamivudine resistance) compared with the treatment-naive population, entecavir remains an effective option overall for reducing viral load, normalizing ALT, and promoting histologic improvement in patients with resistance to lamivudine as a monotherapy.^22,23 When using entecavir in a lamivudine-resistant patient, lamivudine should be discontinued and entecavir should be either given alone (provided there is rapid decline in HBV DNA to undetectable levels)^1,3 or used in combination with a nucleotide analog such as adefovir or tenofovir (personal communication, RG Gish, 2006).³

Avoiding drug resistance is a key management step in treating patients with chronic HBV infection. Choose a medication or combination therapy with the lowest risk of resistance. This is particularly important for patients with advanced liver disease. Once a patient has decompensated cirrhosis, it may be too late to stop progression to liver failure by adding or changing medications to manage resistance, and flares may occur due to rising serum levels of virus that can lead to life-threatening events (eg, further liver decompensation).

Lamivudine is no longer recommended as a first-line agent due to its high rates of resistance,³ and because it may not be as effective as other available therapies.^24-26 Lamivudine also increases the risk of cross-resistance to other antivirals, as shown in this case study. Rates of resistance to adefovir monotherapy are higher in patients with preexisting lamivudine resistance than in treatment-naive patients.²⁷ Moreover, the preexistence of lamivudine-resistant mutations increases the risk of entecavir resistance and lowers the response rate to entecavir.^8,28,29

The recently updated Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States recommends adefovir, entecavir, or peginterferon alfa-2a as first-line therapy.³ These agents are effective in suppressing HBV DNA and minimizing the risk of resistance. The FDA recently approved another antiviral agent, telbivudine, for use in treatment-naive patients with chronic HBV infection, but this agent is not currently approved for patients with resistance to other antivirals. Following the model of HIV therapy, combination regimens may be used in the future to reduce the risk of drug resistance.³⁰ Other emerging anti-HBV therapies have been reviewed elsewhere.³¹

References

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