Think twice if you consider entecavir treatment in cases with lamivudine refractoriness
Authors: Yucel Ustundag, Omer Topalak
Journal: Hepatology (2010)

We read with interest the article by Shim et al.1 concerning the efficacy of entecavir (ETV) in patients with chronic hepatitis B resistant to both lamivudine (LAM) and adeofovir (ADV) or to LAM alone. In this study, they indicated that ETV given at 1 mg/day for 48 weeks resulted in lesser hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) reduction in the LAM/ADV-resistant group than compared with the LAM-resistant group. They also noted that HBV DNA loss was significantly higher in the LAM-resistant group compared with the LAM/ADV-resistant group (34% versus 10%). However, they showed that virological breakthrough was similar in both groups. They also underlined that virological response at 12 weeks determined the degree of HBV DNA reduction over 48 weeks of therapy, regardless of previous antiviral treatment. In their study, Shim et al. underlined the importance of multidrug resistance in cases with inappropriate use of antivirals in HBV infection. The same authors suggested, in the introduction section, that "in terms of salvage therapy for LAM-resistant or ADV-resistant chronic hepatitis B infection, the American Association for the Study of Liver Diseases (AASLD) practice guideline recommended switching to ETV" monotherapy as an optimal strategy. However, according to the current guidelines, including AASLD 2009,2 European Association for the Study of the Liver 2009,3 and Asian Pacific Association for the Study of the Liver 2008,4 what the authors did seemed to be inappropriate to suggest to the readers. The guidelines mentioned above unanimously indicated that ETV can be recommended as a rescue therapy only for ADV-resistant chronic HBV infection having Asp236-to-Thr236 (N236T) and/or Ala181-to-Thr181/Val181 (A181T/V) substitutions. Contrary to what the authors wrote in the introduction section of their article, AASLD guidelines in 20092 on HBV infection clearly indicate that ETV is not an optimal treatment for LAM-refractory HBV. It is clearly known that Leu180-to-Met180 (L180M) + Met204-to-Val204 (M204V) and L180M + M204V + Asn236-to-Thr236 (N236T) mutants behaved 6.25-fold resistant to ETV compared with wild-type HBV.5 We also know that genotypic resistance to ETV will develop at a rate of 43% at the end of 4 years.6 Expectedly, two patients in the series of Shim et al.1 developed virological breakthrough with Ser202-to-Gly202 (S202G) ETV resistance substitutions at 36 weeks of treatment, and one patient developed biochemical breakthrough in the LAM-resistant group of patients. Unfortunately, the readers were not informed in this article how the authors treated these two cases in their series. Another relevant article in this field showed that although HBV DNA suppression was achieved in a higher percentage of patients, there was an emergence of nearly 8% resistance to ETV monotherapy in cases with previous LAM resistance in year 2.7 Thus, this strategy led to selection of multidrug-resistant HBV strains with maximal viral resistance in the near future. Another concern with this article is that the authors also underlined the impact of 1 log HBV DNA reduction at 12 weeks on antiviral efficacy at 48 weeks. However, it would be more valuable if they could provide us with the threshold level of HBV DNA reduction at 12 weeks to achieve HBV undetectability in their cases. As a result, the authors in this article1 tested an approach which is absolutely not valid and nor practical at present. Currently, we believe that ETV monotherapy is not a good alternative as a rescue therapy for cases with LAM and or LAM/ADV resistance, whereas continued treatment resulted in virus suppression in a higher percentage of patients in the series of Shim and colleagues. ETV is obviously not a drug with a high genetic barrier to resistance in the setting of LAM refractoriness. In such situations, we have to admit the effectiveness of other alternative drugs, including tenofovir. Yucel Ustundag*, Omer Topalak , * Zonguldak Karaelmas University School of Medicine, Department of Internal Medicine, Gastroenterology Clinics, Zonguldak, Turkey, Dokuz Eylül University School of Medicine, Department of Internal Medicine, Gastroenterology Clinics, Izmir, Turkey.