| Background and aimsIt is estimated that at least 350 million people around the world are still in the status of chronic hepatitis B virus (HBV) infection. Chronic HBV infection is an important public health problem especially in Asia, including China, about 100 million people there are in chronic infection. Chronic hepatitis B (CHB) is a kind of progressing disease, which can develop to cirrhosis and hepatocellular carcinoma (HCC) that has serious damage to life. The goal of the CHB treatment is to reduce or eliminate HBV as durable as possible, reduce liver inflammation and necrosis, delay and prevent disease progression, decrease and prevent hepatic decompensation, HCC and their complications. In recent years the treatment strategies to CHB improve constantly, the ordinary interferon has given way to the pegylated interferon, and several nucleoside analogues come out in succession. However, the effect of treatment is still unsatisfied. How to enhance the response and reduce resistance in the existing conditions is a challenge to the hepatologists and clinicians.Adefovir Dipivoxil (ADV) is still the only nucleotide analogue without cross resistance to other nucleoside analogues to date in China. Compared with lamivudine and telbivudine, ADV correlated resistance develops less frequently but ADV has less potent activity against HBV, which highlights an urgent need to identify the predictors that will help to find candidates who may likely benefit from ADV. Recently, It has been reported that baseline and on-treatment serum markers were significant predictors for sustained viral response in CHB patients with pegylated interferon(Peg-IFN), lamivudine and telbivudine treatment. However, the association of these predictors with effect of long term ADV treatment has rarely been reported.The aim of this study is to assess baseline and on-treatment serum markers in prediction of long term response in the early phase of treatment with ADV so as to identify the most beneficial patients from ADV treatment and optimize the therapy.MethodsTwo groups of patients were included in the study.48 HBeAg-positive CHB patients who enrolled in the study were treated with ADV (provided by GlaxoSmithKline) and followed up for 5 years. All patients were followed up at weeks 4,12,24,52 and every 12-16 weeks after week 52. Another group include 48 HBeAg-negative CHB patients who treated with ADV for 2 years and followed up at 13,26,52 and 104 weeks. Serum biochemical parameters, serum viral load (Roche COBAS Amplicore HBV Monitor PCR assay, lower limit of detection 300 copies/ml) and HBV markers (micro particle enzyme immunoassay with ABBOTT reagents) were detected. DNA sequencing and phylogenetic analysis of HBV genome were evaluated at baseline in HBeAg positive patients. Serum samples at first time point from subjects who experienced a breakthrough of HBV DNA were assessed for the development of ADV-associated mutations (rtA181V and rtN236T) in the HBV polymerase. HBsAg was quantified retrospectively by Archtect method (ABBOTT reagents). The baseline and on-treatment factors were analysed in prediction of response using SAS 9.2 (SAS Institute, Inc, Cary, North Carolina).Results1. Baseline characteristics of demographic, clinical and laboratory data All of the HBeAg positive patients are positive for HBV genotype C.85% of them are male, with an average age of 31.7 years, ALT 216.3±169.7 IU/I, baseline HBV DNA 8.5±0.8 log10 copies/ml; Of HBeAg negative patients 84.1% were male with an average age of 35.2 years, ALT143.2 IU/I, baseline HBV DNA 6.57 log 10 copies/ml.2. Virological、serological and biochemical response The rates of VR, accumulative HBeAg loss, HBeAg seroconversion and ALT normalization in the end of the fifth year were 66.0%,59.6%,23.4% and 70.2%, respectively in HBeAg positive patients while in HBeAg negative patients the rates of viral response and ALT normalization after 104 week were 77.27% and 88.64% respectively.3. Relationship between baseline parameters and endpoints The baseline ALT was a potential predictor of outcome in HBeAg positive patients. Patients with baseline ALT≥5×ULN were more likely to have HBeAg seroconversion, HBeAg loss and VR than patients with ALT<5×ULN, while in patients with HBeAg<800s/co or HBsAg<5000IU/ml higher rates of HBeAg loss were achieved. The baseline HBeAg level predicted VR too, as 88.9% patients with baseline HBeAg<800 s/co became HBV DNA negative. There was a trend that the rate of VR in the 5 years decreased with the higher levels of baseline viral load. Withiln the patients with baseline HBV DNA< 109copies/ml, the rate of HBeAg seroconversion was significantly higher in patients with ALT≥3×ULN when compared to the patients with ALT<3x×ULN (40.9% vs.8.7%, p=0.012).HBeAg negative patients with baseline HBV DNA≤7log10copies/ml had a higher viral response than patients with HBV DNA>7log10copies/ml. Baseline ALT may have no effect on response. The patients with viral response had lower baseline HBsAg than no responders but there was no statistical signiggicance.4. Impact of on-treatment markers on endpointsHBeAg positive patients with serum HBV DNA level<4 log10copies/ml at week 24 had higher rates of HBeAg seroconversion, HBeAg loss and VR compared to the patients with serum HBV DNA≥4 log10copies/ml. The drop of the serum HBV DNA≥>3 log10copies/ml at week 4 and HBV DNA undetectable at week 52 can predict VR and HBeAg loss while the drop of the serum HBV DNA≥4log10copies/ml at week 12 was significantly associated with the increased rates of HBeAg loss and HBeAg seroconversion.HBeAg negative patients with HBV DNA lower than 4 log10copies/ml or undetectable at week 26, HBV DNA undetectable at week 52 had higher rate of viral response at week 104. HBV DNA lower than 4 log10copies/ml had higher negative predictive value and HBV DNA undetectable at week 104 had higher positive predictive value. HBV DNA lower than 4 log10copies/ml was more superior to HBV DNA undetectable at week 26 in amount of patients and HBV DNA undetectable at week 52 in timing advantage.HBeAg level in HBeAg positive patients decreased with time during the treatment and HBeAg loss occurred in 28 patients at year 5. HBeAg decreased 1.22 log10s/co from baselie in patients with HBeAg remained positive in the end of year 5. Patients with HBeAg lower than 25s/co at week 24 had much higher rates of viral response and HBeAg seroconversion (91.67% vs 53.33%, P=0.006; 41.67% vs 6.7%, P=0.014, respectively).The drop of HBsAg in HBeAg positive patients depended much on the baseline HBsAg and had no predictive value to viral response and HBeAg seroconversion. In HBeAg negative patients no decrease in HBsAg level was found during 2 years of ADV therapy.Conclusions1. ADV treatment may be initiated to HBeAg positive patients with baseline ALT≥5×ULN or patients with ALT≥3×ULN and HBV DNA<109 copies/ml, lower level of HBeAg(<800s/co) or HBsAg (<5000IU/ml) may be regarded as referenced factors. For HBeAg negative patients adaptation to ADV is HBV DNA<107 copies/ml.2. Patients will be followed up regularly and long term outcome may be predicted according to on-treatment HBV DNA and HBeAg. For patients with HBV DNA level<104copies/ml at week 24 (or 26) or HBeAg<25 s/co (in HBeAg positive patients) therapy should continue and favorable outcomes may be achieved in long term therapy. For others with HBV DNA≥104copies/ml at week 24(or 26) or HBeAg≥25 s/co(in HBeAg positive patients), some modifications for the therapeutic regimen such as addition or switch to another agent should be considered to enhance the long term response.3. On treatment HBsAg may have predictive value in ADV treatment with neither HBeAg positive nor negative patients. |
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