Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2010)

In registration trials of pegylated interferons α2a and α2b plus ribavirin, 10–14% of patients had to discontinue therapy due to a number of adverse events (AEs). Thrombocytopenia is a frequent laboratory AE in treated patients. Although baseline and treatment-induced low platelet counts are a rather common phenomenon in patients with advanced liver disease and compensated cirrhosis, treatment associated, serious bleeding episodes are rare but information on the accurate risk is limited. Yet, in anticipation of thrombocytopenia associated bleeding, product labels of pegylated interferons recommend a dose reduction when platelet counts reach <50,000/μl (as reported in 3–6% of patients) and treatment discontinuation altogether at a platelet count of ⩽25,000/μl. It is well recognized that dose reduction of anti-viral therapy significantly compromises the success rate of sustained viral response (SVR). As a result and in an era of individualized treatment, more clinicians are trying to stretch the limits of the safety margins of interferon treatment in order to improve SVR, especially in patients with compensated cirrhosis and baseline thrombocytopenia, who have frequently been excluded from clinical trials. In this issue of the Journal, Roomer and co-workers have retrospectively analyzed the correlation between baseline and iatrogenic thrombocytopenia and the risk of major bleeding during anti-viral therapy with pegylated interferons and ribavirin. Treatment was associated with a mean platelet drop of 42% as compared to 30–50% in the literature. The rate of grades 3 and 4 thrombocytopenia with platelet counts <50,000 and <25,000/μl, respectively, reached 9.3% and 2.8%. This figure is marginally higher compared to previous reports which ranged between 3% and 6%. Yet, none of the thrombocytopenic patients in this study developed serious bleeding. However, in a multivariate analysis, platelet counts <50,000/μl and cirrhosis were associated with a higher degree of minor bleeding including epistaxis, gingival bleeding, hematoma, gastrointestinal bleeding (apparently controlled), and vaginal bleeding. Finally, no serious bleeding was observed in a subset of patients who started anti-viral therapy with a baseline platelet count <80,000/μl. The authors conclude that the safety margin of treatment in chronic HCV patients with pegylated interferon and ribavirin and a platelet count <50,000/μl should be reconsidered. Based on the presented data, no definite conclusion can be drawn regarding the safety of anti-viral treatment in the presence of a platelet count <25,000/μl since the number of the nine patients studied was relatively small. The results of this study are reassuring for patients with a platelet count as low as 50,000/μl and important for clinicians who treat HCV patients, especially those with splenomegaly, advanced liver disease and compensated cirrhosis. Of special importance is the observation that platelet counts remained relatively stable between 25 and 50,000/μl in the 18 patients in whom no interferon dose reduction was performed. This information may also be relevant in view of the currently ongoing phase III study with the thrombopoietin receptor agonist Elthrombopeg. In 12/30 patients who developed a platelet count <50,000/μl, a dose reduction was performed and apparently these patients were more likely to develop a bleeding episode, although of minor clinical significance. The study has a number of limitations. The authors have made some suggestions regarding modification of interferon dosing in the presence of thrombocytopenia. However, new guidelines regarding interferon dose reduction and stopping rules must wait for a prospective study and caution must be applied in the over-interpretation of the results, especially in patients with grade 4 thrombocytopenia. Furthermore, the information provided in this report was derived from a heterogenous patient population with various HCV genotypes who were treated by different regimens. No information was presented regarding the success of anti-viral therapy in this mixed cohort of thrombocytopenic and non-thrombocytopenic patients. In conclusion, the incidence of severe thrombocytopenia in this analysis of 321 patients with chronic HCV treated with pegylated interferon and ribavirin was low and serious bleeding was not observed. In this issue of the Journal, Nae-Yun Heo and co-workers have summarized their experience with anti-viral treatment of compensated patients with chronic hepatitis B (CHB) who developed sequential resistance, initially to lamivudine and than to adefovir monotherapy. This population of 91 patients had a number of lamivudine resistant mutations rtM204v/l and or rtl180M as well as adefovir resistant mutations rtA181V/T and or rt236T (see Table 1 for a detailed description). Forty-one of these patients were treated with 100 mg lamivudine and 10 mg adefovir/day (combination group) while 50 patients received Entecavir 0.5 mg/day (monotherapy group) for at least 12 months. The most important finding of this study is the high non-response rate to anti-viral treatment observed already at 6 months of therapy in 51.2% of the combination group as compared to 16.0% in the monotherapy group. Furthermore, at 12 months of treatment, an inadequate virologic response was observed in 80.5% of the combination group and even in 36.0% in the monotherapy group. ALT normalization was similar in both groups at month 12, reaching 41.5% in the combination group and somewhat higher, but statistically non-significant in 58.0% of the monotherapy group. Virologic breakthrough developed in 3/41 patients of the combination group and in 3/50 patients in the Entecavir group in whom genotypic analysis revealed the presence of an rt184G or rtM260V mutations together with lamivudine resistant rtM204V/l and or rtl180M mutations. Without going into further details of the analysis described in this report, the results should raise a red flag regarding the currently employed algorithms for treating lamivudine and adefovir resistant CHB patients with a combination of these drugs. Thus, in resistant patients originally treated with lamivudine and then switched to adefovir, the add-on approach of these two drugs is associated with development of multidrug resistance which justifies the exploration of new combinations between more potent anti-viral agents against HBV. Finally, in this study, 6% of patients that switched to Entecavir developed resistance within 12 months of therapy. This observation suggests that despite its potent anti-viral properties in the treatment of naïve patients, switching to lamivudine and adefovir in patients resistant to Entecavir may indeed be associated with suboptimal results. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.