Do guidelines preclude hepatitis B patients from receiving treatment? #
Authors: Myron John Tong, Carlos Hsien, Leeyen Hsu, Hai-En Sun, Lawrence M. Blatt
Journal: Hepatology (2008)

We thank Tilmann et al.,1 Chan,2 and Degertekin and Lok3 for their thoughtful comments and questions concerning our article.4 As they clearly point out, the decision to treat a patient with chronic hepatitis B according to guidelines remains controversial, and ultimately, the final choice to treat an individual patient should be based on inclusion in the guideline criteria along with the clinical judgment of the physician. As many of the guideline criteria are now being reevaluated, the letters by Chan and Tilmann et al. aptly raise the question of lowering the hepatitis B virus (HBV) DNA criteria in patients with cirrhosis to allow treatment in those patients who have detectable HBV DNA concentrations of ≤104 copies/mL. The clinical outcomes of the 129 patients with cirrhosis in our database by qualitative HBV DNA categories (negative, ≤104, and >104) are shown in Table 1. As shown in the table, six patients with cirrhosis who either died from a non–hepatocellular carcinoma (HCC) liver-related event or who developed HCC had detectable baseline HBV DNA concentrations that were ≤104 copies/mL. However, 11 patients had HBV DNA levels below the limit of detection and either died from a liver-related event or developed HCC. Thus, modification of the treatment guidelines to include patients who have detectable baseline HBV DNA concentrations of ≤104 copies/mL would have captured patients from our database who ultimately had a poor outcome but would not have addressed those patients who presented with HBV DNA concentrations below the limit of detection. It is important to note, as the three letters point out and as we mentioned in the discussion section of our original article, that further prospective treatments trials are required to determine if antiviral therapies will have any impact on the incidence of HCC, especially in patients with less active liver disease [i.e., low or undetectable levels of viremia and normal or nearly normal alanine aminotransferase (ALT) levels]. The letter by Tilmann et al.1 also suggests that the use of more recently developed guidelines, such as those published by Cornberg et al.,5 may have captured additional patients with poor prognosis who were not recommended for treatment by the original four guidelines assessed in our article.4 To address this question, we conducted an analysis of patients in our database using the criteria established by Cornberg et al. The initial recommendation by Cornberg et al. is to treat all patients with cirrhosis who have detectable HBV DNA. As shown in Table 1, use of these criteria would have captured the six patients who had a poor outcome and presented with baseline HBV DNA levels of ≥104 but would have excluded the 11 patients with a poor prognosis who presented with HBV DNA levels below the detectable limits. Although we agree that the utility of treatment of patients with cirrhosis and serum HBV DNA levels below the detectable limits remains unknown, it is important to point out that patients who have serum HBV DNA levels below the detectable limit of the assay still may have underlying HBV DNA replication at low levels and may benefit from antiviral therapy. The application of Cornberg et al.'s criteria5 to the population of patients without cirrhosis in our database would have captured the nine patients who developed HCC and were not identified by the original European Association for the Study of the Liver, US Panel, Asian Pacific Panel, or American Association for the Study of Liver Diseases guidelines as candidates for therapy. In our database,4 nine patients without cirrhosis who were excluded from antiviral therapy by at least one of the guidelines eventually developed HCC. Cornberg et al.'s criteria initially assess patients without cirrhosis by baseline serum HBV DNA concentrations and recommend therapy in those patients who have serum HBV DNA concentrations of >104 copies/mL and who also meet subsequent ALT, liver histology, and HCC risk factor criteria. All nine patients who were noncirrhotic and developed HCC and who were excluded from treatment by at least one guideline had a baseline serum HBV DNA concentration of >104 copies/mL. Of the nine, only two met Cornberg et al.'s criteria for ALT cutoff (>2 times the upper limit of normal). The remaining seven patients were recommended for treatment on the basis of Cornberg et al.'s guidelines as they met the requirement for HCC risk factors (all were male and >40 years old). Thus, Cornberg et al.'s criteria captured our patients without cirrhosis who were excluded from treatment by the European Association for the Study of the Liver, US Panel, Asian Pacific Panel, or American Association for the Study of Liver Diseases guidelines. Finally, the letter by Degertekin and Lok3 addresses the issue of use of serum ALT as criteria for treatment decisions. In our database, the ALT cutoff was the most frequent reason for exclusion from treatment by the four treatment guidelines in those patients who ultimately died from a liver-related event or developed HCC. Degertekin and Lok suggest that continued monitoring of ALT would have identified those patients who were excluded from treatment on the basis of the ALT criteria but who eventually died from a liver-related event or developed HCC. Although we agree that continued monitoring of patients with chronic hepatitis B would have identified some of these patients, it is important to point out that, as shown in Fig. 1B of our original article,4 the ALT levels fluctuated significantly over time, and this makes ALT an unreliable prognostic indicator at any time point. Additionally, patients who did not develop liver-related complications also had fluctuating ALT levels during follow-up. In contrast, the cutoffs that were established for platelet and serum albumin concentrations (≤130,000 mm3 and ≤3.5 g/dL, respectively) were significantly more reliable than ALT monitoring because in no case did a patient who presented with platelet and serum albumin concentrations that met the cutoff criteria have a subsequent value outside the range of the cutoff. Therefore, utilization of the platelet and serum albumin concentration cutoffs defined in our article could allow for a treatment decision to be made earlier with less variable data in comparison with ongoing monitoring of serum ALT concentrations. At present, there are no studies that validate whether the current treatment guidelines actually include patients who may die from liver-related complications or develop HCC. The goals of treatment, including hepatitis B e antigen seroconversion, normalization of ALT, and reduced HBV DNA levels in patients who meet treatment guidelines, may only be a short-term fix, and continual evaluation of criteria for including patients who develop complications must be an ongoing process. Myron John Tong Ph.D., M.D.* , Carlos Hsien B.S. , Leeyen Hsu , Hai-En Sun B.S. , Lawrence M. Blatt Ph.D.* , * Pfleger Liver Institute and Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, Liver Center, Huntington Medical Research Institutes, Pasadena, CA.