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Prof. Man-Fung YUEN, A 22-year-old, asymptomatic, male patient presented in August 2007 with persistently elevated alanine aminotransferase (ALT) levels >2 × the upper limit of normal (ULN) and a high hepatitis B virus (HBV) DNA count of 8.7 log copies/mL. The patient was found to be hepatitis B e antigen (HBeAg) positive. The patient was started on lamivudine therapy and response to treatment was continually assessed during the following weeks. Within 4 weeks of initiating therapy there was a marked drop in HBV DNA levels to 524 copies/mL. The patient was again evaluated after 24 weeks of therapy and a further drop in HBV DNA levels to <35 copies/mL was noted, which is well below the threshold detectable by PCR assay. The patient was continued on lamivudine and during the first year of treatment the patient’s HBV DNA continued to remain undetectable by PCR assay and his liver enzyme levels normalized. As the patient‘s response to lamivudine therapy was good, treatment with lamivudine was continued and the ALT and HBV DNA levels were monitored at yearly intervals. The patient continued on lamivudine therapy for 5 years. Throughout this treatment period the patient’s ALT levels remained normal and HBV DNA remained undetected by PCR assay. With continued treatment the patient underwent HBeAg seroconversion, and shortly thereafter the patient became hepatitis B surface antigen (HBsAg) negative. Because of the exceptionally good response to lamivudine therapy, it was decided to discontinue lamivudine once the patient had achieved HBeAg seroconversion and HBsAg negative status. Regular annual follow-up was continued to monitor the virus load of the patient to enable the early detection of any re-emergence of HBV. |
In chronic hepatitis B (CHB) HBeAg-positive patients, treatment with lamivudine can be initiated when HBV DNA levels are <9 log copies/mL and ALT levels are ≥2× ULN [1]. Following initiation of lamivudine therapy, measurement of the HBV DNA levels should be performed after 4 weeks and 24 weeks of lamivudine treatment in all patients to predict long-term outcomes. Importantly, a reduction of HBV DNA level down to below 4 log copies/mL after 4 week of lamivudine therapy, and <3 log copies/mL after 24 weeks of therapy is indicative of a good response to treatment, with a strong likelihood of the patient achieving HBeAg seroconversion, normal ALT levels, and a low risk of developing YMDD mutations after 5 years of continued lamivudine treatment. Conversely, patients with HBV DNA levels ≥4 log copies/mL after 4 weeks of lamivudine treatment are less likely to achieve a favourable long-term response with continued lamivudine therapy [1,2]. Alternative treatment approaches with a more potent anti-viral agent or combination therapy with lamivudine and another anti-viral with a different mutation profile, such as adefovir or tenofovir, are strongly recommended in this scenario.
In patients who achieve HBeAg seroconversion with lamivudine, continuing on lamivudine treatment is preferred to cessation of therapy, even when ALT levels remain normal and HBV DNA becomes undetectable by PCR. This is because continuing with lamivudine in these patients has been associated with a greater likelihood of HBV DNA levels remaining undetectable and a lower number of ALT flares, when compared with those who discontinue lamivudine. Moreover, the risk of developing resistance when lamivudine therapy is continued after HBeAg seroconversion is low. In particular, older age, higher serum bilirubin, genotype C virus, shorter duration of continuous lamivudine therapy after HBeAg seroconversion, and higher pre-treatment HBV DNA levels have been associated with relapse after cessation of antiviral therapy [3].
In the present case, the patient was a young, asymptomatic, male who had achieved HBV DNA levels <4 log copies/mL after 4 weeks, and <3 log copies/mL after 24 weeks on lamivudine therapy. The patient continued on lamivudine therapy for 5 years during which time he achieved HBeAg seroconversion followed by HBsAg seroclearance. It was thus decided to discontinue lamivudine therapy in this patient while regular follow ups were used to monitor his viral replication status.
Long-term continued monitoring of CHB patients is critical even after HBsAg seroclearance. This is because HBsAg seroclearance is not indicative of total eradication of HBV, but is associated with a very low viremic phase in which the HBV persist at low replicative and transcriptional levels, which allows improvement of liver histology and liver biochemistry [4]. Monitoring of viral levels in these patients is essential for early detection and treatment of any viral flares.
| References | |
| 1. | Yuen MF, et al. Combination of baseline parameters and on-treatment hepatitis B virus DNA levels to start and continue patients with lamivudine therapy. Antivir Ther 2009;14(5):679-85. |
| 2. | Yuen MF, et al. Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response. Hepatology 2007;46(6): 1695-703. |
| 3. | Fung J, et al. The duration of lamivudine therapy for chronic hepatitis B: Cessation vs. continuation of treatment after HBeAg seroconversion. Am J Gastroenterol 2009;104(8):1940-6. |
| 4. | Yuen MF, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: Replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135(4):1192-9. |