Lamivudine is the first anti-HBV agent approved in China, and it has been used in therapy of CHB patients for more than one decade. Thus, there are many CHB patients who have been treated with lamivudine, but the control of HBV DNA is not ideal because of the high rate of HBV resistance. Considering different mechanisms of anti-HBV and no cross-resistance to NAs, PegIFNα-2a also has been applied for salvage therapy of patient with resistance to lamivudine. Additionally, there was no data showed the existence of resistance to NAs could decrease the efficacy of interferon to HBV. In this study, though we found that 12-month PegIFNα-2a treatment resulted to 67.4% (31/46) undetectable HBV DNA, 78.3% (36/46) ALT normalization, and higher to 50% (23/46) HBeAg seroconversion, the combined response (ALT normalization combined with HBV DNA negativity and HBeAg seroconversion) was just 26.1%. So the salvage therapy of PegIFNα-2a for CHB patients with prior NAs exposure was not ideal, and how to optimize the existing treatment strategies and early predict long-term responses was necessary and important for the management of CHB.
In past decade, many evidence indicated that the intrahepatic cccDNA decreasing would be probably an ideal prognostic variable in predicting long-term outcomes of antiviral treatment , but it was still a research procedure, dependent on a liver biopsy, and hardly available to the practicing hepatologist. Though the use of quantitative HBV DNA is well established in monitoring antiviral effect of NAs and predicting long-term risk of hepatocellular carcinoma, its value in reflecting the immune control of HBV was extremely limited. Recently, quantification of serum HBsAg in naïve CHB patients has been recommended as an alternative marker for monitoring and evaluating efficacy of treatment [8–10]. And several independent studies have shown that the decline of serum HBsAg level during interferon treatment mimics that of intrahepatic cccDNA, suggesting that a decline or loss of serum HBsAg is correlated with a more effective immune control of HBV [3, 4]. Moreover, the quantification of serum HBsAg has also been recommended as a useful index to guide interferon individualized treatment .
As we know, current therapeutic agents cannot completely remove HBV from liver; and the goal of antiviral treatment is just to slow down the progression of liver disease to cirrhosis and hepatocellular carcinoma, with the ultimate goal of improving survival. The HBsAg loss and eventual seroconversion would signify the best outcome possible for patients with CHB . It has been reported that quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to PegIFNa-2b in HBeAg-positive patients; and quantitative serum HBsAg level at 3 months of treatment could be used for the early prediction of a sustained response to PegIFN therapy in HBeAg-negative CHB patients . In our study, among 12 responders with ALT normalization, HBV DNA negativity and HBeAg seroconversion, the serum HBsAg levels decreased consistently during treatment and remained at low levels during the post-treatment follow-up. Conversely, serum HBsAg in non-responders just showed a relative slight decrease during both treatment and post-treatment follow-up. Thus our findings further suggested that monitoring of serum HBsAg levels may predict ideal responses towards interferon treatment earlier. And this finding was also consistent with the findings of other published reports [5, 12]. Additionally, we also found that the cutoff of 6000 IU/mL of serum HBsAg at months 6 had a PPV of 73.3% and an NPV of 96.8% for predicting combined responses of ALT normalization, HBV DNA negativity and HBeAg seroconversion.
In summary, the percentage of responders toward PegIFNα-2a in CHB patients with prior lamivudine exposure is not high; but the early decrease of serum HBsAg (< 6000 IU/mL at months 6) could be used as a predictor of sustained combined response. Due to the limitation of relatively small sample size, longer follow-up and larger sample size prospective trials should be required to confirm our findings.