• Potential conflict of interest: Nothing to report.

We appreciate the valuable comments made by Dr. Lo. We agree that serum α-fetoprotein (AFP) levels sometime fluctuate during serial observations. Therefore, we used the average AFP integration value in our study,[1] as previously described,[2, 3] and an AFP fluctuation that may have occurred during our observation period was not likely to affect the average AFP result. We also agree that a 1-month interval between AFP measurements for low-risk patients is too frequent. In our study, the AFP measurement interval depended on an individual patient's risk for hepatocellular carcinoma (HCC), and in accordance with the Japanese Evidence-based Clinical Guidelines for the Diagnosis and Treatment of HCC,[4] our AFP measurement interval was every 6 months for low-risk patients.

Unlike other cross-sectional studies that examined AFP values as a tumor marker to detect current HCC,[5] our longitudinal cohort study determined the clinical significance of posttreatment AFP values and evaluated whether AFP values could be used as a predictive risk factor for “future” HCC development. We hypothesized that the AFP values during the observation period associate with the risk for “future” HCC development because elevated serum AFP is sometimes observed in patients with advanced chronic hepatitis C virus (CHC) in the absence of HCC.

The positive predictive value of AFP was low. However, the extremely high negative predictive AFP value (0.960) suggested that the postinterferon (post-IFN) treatment AFP value <6.0 ng/mL predicted a decreased likelihood of “future” HCC development. In the HALT-C study,[6] the AFP was ≤20 ng/mL in 50% of patients who developed HCC, suggesting that the AFP predictive criterion of ≤20 ng/mL is insufficient to predict a low risk for HCC development. Therefore, post-IFN treatment predictive AFP levels should be <6.0 ng/mL to suppress the risk for “future” HCC development.

The HCC incidence is largely different between Western countries and Japan (Western < Japan).[1, 6] Therefore, future studies are needed to determine whether our results are in agreement with long-term, large cohort studies that include various population subgroups. Nevertheless, we believe that our results have important clinical implications for clinicians considering an individual patient's HCC surveillance and/or treatment strategy.

We also appreciate the valuable comments made by Drs. Toyoda, Kumada, and Tada. We are also aware that there are two distinct patterns of HCC development after sustained virological response (SVR) has been achieved. Although we carefully ruled out the existence of HCC by imaging modalities,[1] we agree that the limit of detection of our imaging apparatus did not allow us to detect and completely exclude minute HCC. However, this raises the question as to whether incidences of minute HCC are capable of producing detectable AFP. We agree with Dr. Toyoda et al. that an AFP fucosylated fraction (AFP-L3) may be useful to address this question.[7] Unfortunately, pre-IFN treatment AFP-L3 levels were not available in our patients who had post-IFN AFP ≥10 ng/mL and developed HCC after achieving SVR (n = 11). AFP-L3 values were available from nine patients at the time of HCC development and were ≤10% in eight (89%) patients, suggesting that AFP production was unlikely specific to HCC in these patients. In addition, AFP levels at the time of HCC development were not higher than AFP levels during follow-up for 8 out of 11 patients. Therefore, although the possibility of minute undetectable HCC before IFN treatment existed, elevated AFP was unlikely associated with preexisting HCC in patients with post-IFN AFP ≥10 ng/mL who had HCC after SVR was achieved.

  • Yasuhiro Asahina, M.D., Ph.D.1

  • Kaoru Tsuchiya, M.D., Ph.D. 2

  • Namiki Izumi, M.D., Ph.D.2

  • 1Department of Gastroenterology and Hepatology

  • Department of Liver Disease Control

  • Tokyo Medical and Dental University

  • Tokyo, Japan

  • 2Department of Gastroenterology and Hepatology

  • Musashino Red Cross Hospital

  • Tokyo, Japan