Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response

Abstract

The best time and hepatitis B virus (HBV) DNA level during an early lamivudine treatment period for predicting the long-term outcome are unknown. We aimed to determine the optimal time and HBV DNA level during an early treatment period for the prediction of the response after a 5-year lamivudine treatment. The HBV DNA levels at the baseline, at weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 were measured in 74 hepatitis B e antigen (HBeAg)-positive chronic HBV patients receiving lamivudine treatment. Seventeen patients achieved an ideal response [HBV DNA level < 2000 copies/mL (400 IU/ mL), HBeAg seroconversion, normal alanine aminotransferase levels, and absence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations] at year 5. Receiver operating characteristic curves showed good predictions as early as week 4. The areas under the curve for weeks 4 and 16 were 0.89 and 0.94, respectively. Predictive indices revealed 4 and 3.6 log copies/mL (2000 and 800 IU/mL, respectively) to be the best cutoff HBV DNA levels for these 2 times, respectively. All patients with HBV DNA levels lower than these respective cutoff levels at the 2 times achieved an ideal response at year 5. Patients with HBV DNA levels above these cutoff values had 83.8% and 87.7% chances of not achieving an ideal response at year 5, respectively. Conclusion: The measurement of the HBV DNA levels at week 4 of lamivudine treatment should be performed in all patients to predict the long-term outcome. The treatment can be continued for those with HBV DNA levels of less than 4 log copies/mL (2000 IU/mL). The addition of or switch to alternative antiviral agents should be considered for patients who fail to achieve this early target. (HEPATOLOGY 2007;46:1695-1703 A pproximately 400 million people worldwide have chronic hepatitis B (CHB) infection, of whom 25%-40% will develop long-term sequelae of hepatocellular carcinoma (HCC) and/or cirrhotic complications. 1 The prevention of disease progression is the primary target for the treatment of CHB. Recent evidence shows that a high hepatitis B virus (HBV) DNA level is associated with a higher risk of development of HCC and cirrhosis. 2,3 Effective viral suppression by the nucleoside analogue, lamivudine, reduces the risk of complications in patients with or without advanced disease. 4,5 However, a prolonged lamivudine treatment is associated with increasing incidence of drug-resistant mutations [tyrosine-methionine-aspartate-aspartate (YMDD) mutants], which reaches more than 70% after 5 years of lamivudine treatment. 6 Despite this, lamivudine is still commonly used for several reasons. It has the longest surveillance for safety. Twenty to twenty-five percent of patients do not develop YMDD mutations and continue to have satisfactory viral suppression even after a prolonged treatment. 5 Moreover, it is the only nucleoside/nucleotide analogue proven in randomized controlled studies to reduce disease progression. 4 Therefore, identifying patients who are likely to achieve an ideal...

Early Viral Kinetics of Telbivudine and Entecavir: Results of a 12-Week Randomized Exploratory Study with Patients with HBeAg-Positive Chronic Hepatitis B

“…Yuen et al previously demonstrated the importance of HBV DNA suppression by week 24 of treatment to prevent the emergence of antiviral resistance with lamivudine (39). More recently, those authors also reported that HBV DNA levels of Ͻ2,000 copies/ml at treatment week 4 are predictive of outcomes at 5 years for lamivudine-treated patients (38). A rapid decline in HBV viral load (Ն3 log copies/ml) at week 12 was also reported to be an important predictor of the subsequent response to adefovir therapy (9).…”

On-treatment monitoring of HBV DNA levels: predicting response and resistance to oral antiviral therapy at week 24 versus week 48

“…All the patients with serum HBV DNA levels of less than 2,000 IU/ml at week 4 of lamivudine treatment had an ideal response at 5 years, including HBeAg seroconversion, ALT normalization, and serum HBV DNA levels of less than 400 IU/ml and no lamivudine resistance mutations. In contrast, 83.8% of patients who had serum HBV DNA levels of more than 2,000 IU/ml by treatment week 4 did not achieve long-term ideal response [29]. Although serum HBV DNA levels at week 24 were also predictive of outcomes at 5 years, the emergence of mutations conferring resistance to lamivudine and adefovir was detected by week 24.…”

“…In this analysis, undetectable HBV DNA levels at 12 and 24 weeks of lamivudine treatment had a 93% and 72% predictive value for maintained response at 2 and more than 4 years, respectively. Ontreatment serum HBV DNA levels as early as week 4 of lamivudine treatment were predictive of long-term outcomes at 5 years in patients with HBeAg-positive CHB [29]. In this study, serum HBV DNA levels were assessed at baseline, weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 in 74 HBeAg-positive patients with chronic HBV infection.…”

“…On-treatment serum HBV DNA levels have also been shown to be predictive of long-term virologic outcomes with lamivudine [11,12,14,28,29]. Early studies of lamivudine found that only patients with undetectable serum HBV DNA levels by week 24 of treatment achieved loss of HBeAg and HBeAg seroconversion [11,12].…”

“…Some groups have proposed practical recommendations based on experimental data. For example, in the pooled analysis of predictors of response to lamivudine therapy discussed above, Yuen et al [29] noted that HBV DNA levels at 4 and 16 weeks were the best indictors of ideal response at 5 years. On the basis of these data, the investigators recommended a continuation of lamivudine therapy in patients who achieve HBV DNA levels of less than 4 log copies/ml (\2,000 IU/ ml) at week 4.…”