LAM Resistance

The selection of LAM-resistant mutants is the main limitation to LAM treatment. The most common mutation affects the tyrosine, methionine, aspartate, aspartate (YMDD) motif in the catalytic domain of the HBV DNA polymerase, resulting in a substitution from methionine to valine (M552V) or isoleucine (M552I). This mutation can occur in isolation, or in conjunction with another mutation that affects an upstream region, resulting in a substitution from leucine to methionine (L528M). These genetic changes result in a decreased capability of the virus to replicate (41), which accounts for the lower HBV DNA levels observed in patients with LAM-resistant mutants.

LAM resistance is usually manifested as breakthrough infection (defined as reappearance of HBV DNA in serum after its initial disappearance). However, breakthrough infection can also be a result of noncompliance. Unlike HIV infection, LAM-resistant HBV mutants are usually not detected until patients have been on treatment for at least 6 mo. Geno-typic resistance can be detected in 17% patients after 1 yr of treatment, increasing to 40% after 2 yr and 55% after 3 yr of treatment. In vitro studies (42) found that these mutants confer up to 10,000-fold resistance. Thus, increasing the dose cannot restore the antiviral effect of LAM on these mutants.

The clinical course of patients with LAM-resistant mutants is variable, and the long-term outcome of these patients remains to be determined. In most patients, continuation of LAM results in lower serum HBV DNA and ALT levels, compared to pretreatment. The continued benefit may be related to the suppressive effect of LAM on residual wildtype virus and the lower replication capacity of the mutants. However, some patients may develop acute exacerbations of liver disease. In a report from Taiwan (43), 13/32 patients with LAM-resistant mutants were observed to have flares in ALT, during a median follow-up period of 24 wk (range 4-94 wk). Although most of the flares were asymptomatic, three (23%) patients had hepatic decompensation. Fatal exacerbations, associated with the selection of LAM-resistant mutants, have also been reported in other studies, and appear to be more common in patients with underlying cirrhosis or recurrent hepatitis B post-liver transplantation (44,45). The Taiwan study (43) found that HBeAg seroconversion can occur after the detection of LAM-resistant mutants, and was more common in patients who had ALT flares (8/12 patients 75%), compared to no HBeAg seroconversion seen in 19 patients without ALT flares (P < 0.001). These findings support the continued use of LAM in patients who developed LAM-resistant mutants. However, longer follow-up of a larger cohort of patients is needed to determine if continued treatment is beneficial to all patients with LAM resistance. Clearly, there is a need to be prudent in the use of LAM, and an urgent demand to develop safe and effective therapy for patients with worsening liver disease caused by LAM-resistant HBV mutants. Several antiviral agents have been shown to be effective against LAM-resistant HBV mutants in in vitro studies, but only adefovir dipivoxil has been tested in vivo. The preliminary data are encouraging, but the long-term safety and efficacy of adefovir dipiv-oxil has not been determined.

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