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- Patients and methods
- Supporting Information
Chronic hepatitis B (CHB) is one of the most important health issues, affecting more than 350 million people worldwide. In the natural history of CHB, hepatitis B e antigen (HBeAg) seroconversion usually leads to resolution of clinical hepatitis activity. However, some patients develop hepatitis B virus (HBV) reactivation at various intervals following HBeAg seroconversion and evolve into HBeAg-negative CHB.[1, 2] Reactivation of HBV is a significant predictor of progression to liver cirrhosis.[1, 2]
The treatment options for HBeAg-negative CHB patients include oral nucleos(t)ide analogues and interferon.[3-6] Although nucleos(t)ide analogues are potent inhibitors of HBV replication, easy to administer and without significant side effects, long-term maintained viral suppression is generally believed to be required for effective control of disease progression.[3-7] Interferon functions through both immunomodulatory and antiviral activities. Although interferon is commonly associated with side effects, interferon only requires treatment for a finite duration.[3-6] Studies on peginterferon alfa-2a have shown that approximately 25% of patients remained in remission, 3 years after the cessation of 48 weeks of therapy.[8, 9] Moreover, peginterferon alfa-2a therapy can achieve hepatitis B surface (HBsAg) seroclearance in 8% of patients, which is the desirable parameter closest to a clinical cure of CHB and associated with a reduced incidence of cirrhosis and hepatocellular carcinoma (HCC) and better survival.[3-6]
Recently, the quantitative serum HBsAg level or the magnitude of decline in serum HBsAg level during peginterferon therapy has been shown to be predictive of a sustained response (SR) to peginterferon therapy in HBeAg-negative CHB patients.[10-12] A combination of serum HBsAg and HBV DNA levels was further proposed as a strong negative predictor to peginterferon therapy in HBeAg-negative CHB patients. However, these studies were conducted in CHB patients mostly infected with genotype A or D. HBV genotypes have been shown to influence serum HBsAg kinetics during peginterferon therapy in HBeAg-negative CHB patients. The predictive roles of serum HBsAg and HBV DNA levels in patients infected with genotype B or C are less clear.
The purpose of this study was to determine the roles of early on-treatment serum HBsAg and HBV DNA levels in the prediction of a SR to peginterferon alfa-2a therapy in HBeAg-negative CHB patients infected with genotype B or C.
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- Patients and methods
- Supporting Information
Peginterferon alfa-2a is an established therapy for HBeAg-negative CHB. The current study demonstrated that 52% and 31% of patients achieved serum HBV DNA levels <10 000 and <312 copies/mL, respectively, at 24 weeks after 48 weeks of therapy, which was superior to the initial registration trial in which 43% and 19% of patients achieved serum HBV DNA levels <20 000 and <400 copies/mL, respectively, at 24 weeks after 48 weeks of therapy. Sixty-one per cent of patients enrolled in the global registration trial were Asian. Among them, 50% achieved serum HBV DNA levels <10 000 copies/mL, which was comparable to our results. Therefore, our results support the notion that peginterferon is one therapeutic option for HBeAg-negative patients who seek to treat the disease with a finite course of therapy.
According to the REVEAL study, a serum HBV DNA level at 10 000 copies/mL is regarded as a threshold level above which long-term progressive liver diseases, such as cirrhosis and HCC, can occur.[18, 19] Further analysis showed that the risk of liver-related mortality is increased, even in patients with serum HBV DNA levels between 300 and 10 000 copies/mL, when compared with patients with serum HBV DNA levels <300 copies/mL. Therefore, sustained suppression of serum HBV DNA to below detectable levels appears to be the most desirable therapeutic endpoint one should aim for when treating HBeAg-negative patients.
An analysis of the 315 HBeAg-negative patients with long-term follow-up following peginterferon therapy showed that younger age, high baseline ALT and low baseline HBV DNA were significant predictors of a SR (HBV DNA <10 000 copies/mL) at 24 weeks post-treatment.[9, 21] The ORs associated with the predictors were mild. In this study, we identified the baseline HBV DNA as a significant predictor of SR and the baseline HBV DNA and HBsAg as significant predictors of achieving HBV DNA <10 000 copies/mL at 24 weeks post-treatment. Furthermore, we identified the on-treatment serum HBsAg and HBV DNA levels as even better predictors of achieving SR or HBV DNA <10 000 copies/mL at 24 weeks, after 48 weeks of peginterferon therapy in HBeAg-negative patients infected with genotype B or C. It would be desirable if a baseline predictor such as HBsAg or HBV DNA can be used to identify potential responders before treatment is initiated. However, the predictive value of serum HBsAg only became moderate early during treatment (AUC = 0.50 at baseline vs. 0.75 at week 12). Early on-treatment HBsAg level is a more clinically useful predictor of treatment response.
Recently, serum HBsAg levels were shown to positively correlate with the transcriptional activity of the intrahepatic HBV covalently closed circular DNA (cccDNA) and serum HBV DNA levels in HBeAg-positive, but not in HBeAg-negative CHB patients.[22, 23] Synthesis of HBsAg from integrated HBV genomic sequences and/or dissociation of HBsAg transcription/secretion from viral replication are proposed as possible causes of this dissociation in HBeAg-negative patients.[22, 23] Intrahepatic cccDNA levels declined in parallel with the reduction of serum HBsAg levels during antiviral therapy and intrahepatic cccDNA levels at the end of antiviral therapy were shown to predict a SR after the cessation of therapy.[24, 25] Despite the imperfect correlation between serum HBsAg and intrahepatic cccDNA levels in HBeAg-negative CHB, it was shown that the end-of-treatment HBsAg level correlated strongly with a SR (HBV DNA <400 copies/mL) at 6 months post-treatment in HBeAg-negative patients undergoing peginterferon therapy, which is in agreement with our observation. More importantly, we demonstrated that the early on-treatment serum HBsAg level serves as a better predictor for SR in HBeAg-negative patients undergoing peginterferon therapy.
Moucari et al. showed that a decline of 0.5 and 1.0 log10 IU/mL in serum HBsAg levels at weeks 12 and 24 of therapy, respectively, had high predictive values for SR (NPV [90%], PPV [89%] for week 12; and NPV [97%], PPV [92%] for week 24) in a cohort of 48 HBeAg-negative patients (56% for genotype A or D). They concluded that early on-treatment serum HBsAg levels can be used as a useful marker for predicting a sustained off-treatment response. However, Rijckborst et al. showed that the on-treatment decline in HBsAg alone was of limited value in the prediction of achieving HBV DNA <10 000 copies/mL and normal ALT at 24 weeks post-treatment, but the combination of a decline in serum HBsAg and HBV DNA at week 12 gave a better prediction in 102 HBeAg-negative patients (93% for genotype A or D). An absence of a decline in serum HBsAg and HBV DNA (<2 log10 copies/mL) at week 12 of therapy provided a strong discontinuation criterion for HBeAg-negative patients. In this study consisting of 61 HBeAg-negative patients infected with genotype B or C, we found that the absolute value of the on-treatment serum HBsAg level was a better predictor of SR, achieving HBV DNA <10 000 copies/mL or achieving HBV DNA <10 000 copies/mL and normal ALT at 24 weeks post-treatment than the magnitude of the decline in HBsAg, suggesting that the remaining cccDNA level is the more critical determinant of a sustained response. The serum HBsAg level at week 12 of therapy had a moderate predictive value for SR, but a lower predictive value for achieving HBV DNA <10 000 copies/mL or for achieving HBV DNA <10 000 copies/mL and normal ALT at 24 weeks post-treatment. Combining the serum HBsAg and HBV DNA levels at week 12 of therapy yielded a limited further increase in predictive accuracy. Furthermore, the algorithm proposed by Rijckborst et al. did not perform well in our patient cohort. Therefore, although the general concept of monitoring the serum HBsAg levels during peginterferon therapy is useful, the predictive rule and value may vary depending on the patient population studied.
One major limitation of the current study was its relative small sample size, which might create the possibility of model overfitting. Further studies enrolling a larger cohort of patients from the Asia-Pacific region are warranted to validate our findings before this predictive rule can be applied universally to patients infected with genotype B or C.
There are advantages associated with the early identification of potential sustained responders to peginterferon therapy. First, it allows us to persuade candidate patients to remain on therapy. Secondly, it guides us to terminate therapy in patients with a poor early response, particularly in those who experienced troublesome side effects associated with interferon therapy. Thirdly, it provides a strategy whereby we can use serum HBsAg levels to stratify patients for further clinical studies investigating the potential roles of combination therapy with oral antiviral agents to improve therapeutic outcomes. Therefore, our study provides evidence supporting the routine use of quantitative serum HBsAg measurement in therapeutic monitoring of HBeAg-negative patients infected with genotype B or C who undergo peginterferon therapy. Although we only demonstrated the predictive value of early serum HBsAg measurement for SR 24 weeks post-treatment, all the 19 sustained responders had serum HBV DNA <312 copies/mL at 48 weeks post-treatment. Therefore, the predictive value for a SR derived from our study can be extended to 1 year post-treatment. Nonetheless, we need a larger patient cohort and a longer follow-up to assess the predictive value for a long-term SR or HBsAg seroclearance.
In conclusion, peginterferon alfa-2a therapy showed efficacy for HBeAg-negative CHB with 52% and 31% of patients achieving serum HBV DNA levels <10 000 and <312 copies/mL, respectively, at 24 weeks after 48 weeks of therapy. Serum HBsAg levels at 12, 24 and 48 weeks of therapy and HBV DNA levels at baseline, 12 and 24 weeks of therapy were independent predictors of SR at 24 weeks post-treatment. The serum HBsAg levels were significantly different during treatment between patients with SR and relapse. A quantitative serum HBsAg level at week 12 can be used for early prediction of a sustained off-treatment response to peginterferon therapy to optimise management in HBeAg-negative CHB patients infected with genotype B or C.