Gastroenterology 2014;147:1185–1187
CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
What Is the Contribution of Protease Inhibitors to the High Mortality of Patients With Cirrhosis Receiving HCV Treatment? Dear Editor: Nearly a decade has passed since the licensing of peginterferon (PEG), followed by the development of new and more effective therapies. Studies published in 2011 introduced the directly-acting antivirals (DAAs), providing a promising new therapeutic approach for treating chronic hepatitis C genotype 1 (HCV-1) patients.1–5 Presently, we are in the DAAs era, and the use of protease inhibitor (PI) associated with PEG and ribavirin (RIBA) for the treatment of HCV-1 patients has increased the rates of sustained virological response (SVR). These new medications, in addition to their benefits, reveal new challenges such as the emergence of resistant virus to new therapies, interaction with other medications, or a higher rate of serious adverse effects (SAE). The current major barrier seems to be the SAE, sometimes leading to death. In the issue, Hezode C et al presented the results of CUPIC study6 and showed a high SAE and mortality rate associated with triple therapy with PEG-RIBA and PI in cirrhotic patients. Our experience7 evaluating patients with chronic liver disease treated with PEG-RIBA in a real-life context found that the SVR rate was lower than the ones in registered trials (35.3%). Moreover, when we evaluated 257 cirrhotic patients treated with PEG-RIBA in a public health program in southern Brazil, besides the lower SVR rates, we observed a mortality rate of 4.3%. The low SVR and high mortality rates in this difficult-to-treat population have been likewise described by Fernández–Rodríguez CM et al,8 when using double therapy (PEG-RIBA) in a real-life context. Thus, physicians should be careful when treating patients with advanced liver disease using triple therapy, even with the second wave DAAs, because therapy will still be associated with PEG-RIBA. In conclusion, the high SAE rate in patients with cirrhosis observed in the CUPIC study receiving triple therapy must be mainly due to the use of PEG-RIBA, and not to PI. Thereby, we anxiously await the establishment of new IFN-free therapies soon. CRISTIANE V. TOVO Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) Rio Grande do Sul, Brazil and Hospital Nossa Senhora da Conceição (HNSC) Rio Grande do Sul, Brazil
ANGELO A. MATTOS Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) Rio Grande do Sul, Brazil PAULO R. L. ALMEIDA Hospital Nossa Senhora da Conceição (HNSC) Rio Grande do Sul, Brazil
References 1. 2. 3. 4. 5. 6. 7. 8.
Poordad F, et al. N Engl J Med 2011;364:1195–1206. Jacobson IM, et al. N Engl J Med 2011;364:2405–2416. Bacon BR, et al. N Engl J Med 2011;364:1207–1217. Zeuzem S, et al. N Engl J Med 2011;364:2417–2428. Sherman KE, et al. N Engl J Med 2011;365:1014–1024. Hezode C, et al. Gastroenterology 2014;147:132–142. de Almeida PR, et al. Hepatogastroenterology 2009;56: 223–226. Fernández-Rodríguez CM, et al. Am J Gastroenterol 2010;105:2164–2172.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.07.057
Risky Business—the Real Life of the Unresolved HCV Therapy Dear Editor: We read with great interest the manuscript on the CUPIC cohort study by Hezode C et al in the July issue of Gastroenterology.1 The authors investigated the effectiveness and safety of first generation protease inhibitors in a population that was underrepresented in the phase III clinical trials:2–5 patients with genotype 1 HCV infection, compensated liver cirrhosis and previous non-response to pegylated interferon and ribavirin (PR). This study was a real-life multicenter (56 centers), prospective cohort study performed in France including a total of 511 patients. This study has several very important messages for hepatologists. One of the most striking points for us was the inclusion of older patients (aged to 83-years-old) and patients with very low platelet counts at baseline, as low as 18,000 platelets/mm3. This is quite impressive and we believe it probably represents the motivation of these patients and the faith that both patients and physicians had in these new agents at first, even though thrombocytopenia was already a considerable problem for PR treatment. On the effectiveness side, there was an expected decrease in sustained virologic response (SVR) rates compared with the clinical trials, which is explained by the presence of cirrhosis, that may be accountable for a decrease in viral susceptibility, host tolerance to the drugs (higher incidence
1186 Correspondence
Gastroenterology Vol. 147, No. 5
and severity of adverse events), and adherence to the treatment regimen. The authors report a slightly higher overall response rate on the Telaprevir group (51.8% vs 42.9%), especially on the null responders subgroup (19.4% vs 0%), but the generalizability of this data is limited by the low sample size (10 patients in the Boceprevir null responders group) and by the observational study design that renders it susceptible to systematic biases that are best avoided in randomized clinical trials, namely indication bias. Still, in this study the overall SVR rate was 49% and having in consideration the kind of patients that were included we think this is a good result, even though there was a strikingly high incidence (49.9%) of severe adverse events (SAE), most patients (70%-83%) were able to go on complete the treatment. It is reasonable to admit that adverse events are part of these treatments, even more so in cirrhotic patients. There seems to be, however, a subgroup of patients with more advanced liver disease that can be identified by low platelet count (
CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
What Is the Contribution of Protease Inhibitors to the High Mortality of Patients With Cirrhosis Receiving HCV Treatment? Dear Editor: Nearly a decade has passed since the licensing of peginterferon (PEG), followed by the development of new and more effective therapies. Studies published in 2011 introduced the directly-acting antivirals (DAAs), providing a promising new therapeutic approach for treating chronic hepatitis C genotype 1 (HCV-1) patients.1–5 Presently, we are in the DAAs era, and the use of protease inhibitor (PI) associated with PEG and ribavirin (RIBA) for the treatment of HCV-1 patients has increased the rates of sustained virological response (SVR). These new medications, in addition to their benefits, reveal new challenges such as the emergence of resistant virus to new therapies, interaction with other medications, or a higher rate of serious adverse effects (SAE). The current major barrier seems to be the SAE, sometimes leading to death. In the issue, Hezode C et al presented the results of CUPIC study6 and showed a high SAE and mortality rate associated with triple therapy with PEG-RIBA and PI in cirrhotic patients. Our experience7 evaluating patients with chronic liver disease treated with PEG-RIBA in a real-life context found that the SVR rate was lower than the ones in registered trials (35.3%). Moreover, when we evaluated 257 cirrhotic patients treated with PEG-RIBA in a public health program in southern Brazil, besides the lower SVR rates, we observed a mortality rate of 4.3%. The low SVR and high mortality rates in this difficult-to-treat population have been likewise described by Fernández–Rodríguez CM et al,8 when using double therapy (PEG-RIBA) in a real-life context. Thus, physicians should be careful when treating patients with advanced liver disease using triple therapy, even with the second wave DAAs, because therapy will still be associated with PEG-RIBA. In conclusion, the high SAE rate in patients with cirrhosis observed in the CUPIC study receiving triple therapy must be mainly due to the use of PEG-RIBA, and not to PI. Thereby, we anxiously await the establishment of new IFN-free therapies soon. CRISTIANE V. TOVO Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) Rio Grande do Sul, Brazil and Hospital Nossa Senhora da Conceição (HNSC) Rio Grande do Sul, Brazil
ANGELO A. MATTOS Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) Rio Grande do Sul, Brazil PAULO R. L. ALMEIDA Hospital Nossa Senhora da Conceição (HNSC) Rio Grande do Sul, Brazil
References 1. 2. 3. 4. 5. 6. 7. 8.
Poordad F, et al. N Engl J Med 2011;364:1195–1206. Jacobson IM, et al. N Engl J Med 2011;364:2405–2416. Bacon BR, et al. N Engl J Med 2011;364:1207–1217. Zeuzem S, et al. N Engl J Med 2011;364:2417–2428. Sherman KE, et al. N Engl J Med 2011;365:1014–1024. Hezode C, et al. Gastroenterology 2014;147:132–142. de Almeida PR, et al. Hepatogastroenterology 2009;56: 223–226. Fernández-Rodríguez CM, et al. Am J Gastroenterol 2010;105:2164–2172.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.07.057
Risky Business—the Real Life of the Unresolved HCV Therapy Dear Editor: We read with great interest the manuscript on the CUPIC cohort study by Hezode C et al in the July issue of Gastroenterology.1 The authors investigated the effectiveness and safety of first generation protease inhibitors in a population that was underrepresented in the phase III clinical trials:2–5 patients with genotype 1 HCV infection, compensated liver cirrhosis and previous non-response to pegylated interferon and ribavirin (PR). This study was a real-life multicenter (56 centers), prospective cohort study performed in France including a total of 511 patients. This study has several very important messages for hepatologists. One of the most striking points for us was the inclusion of older patients (aged to 83-years-old) and patients with very low platelet counts at baseline, as low as 18,000 platelets/mm3. This is quite impressive and we believe it probably represents the motivation of these patients and the faith that both patients and physicians had in these new agents at first, even though thrombocytopenia was already a considerable problem for PR treatment. On the effectiveness side, there was an expected decrease in sustained virologic response (SVR) rates compared with the clinical trials, which is explained by the presence of cirrhosis, that may be accountable for a decrease in viral susceptibility, host tolerance to the drugs (higher incidence
1186 Correspondence
Gastroenterology Vol. 147, No. 5
and severity of adverse events), and adherence to the treatment regimen. The authors report a slightly higher overall response rate on the Telaprevir group (51.8% vs 42.9%), especially on the null responders subgroup (19.4% vs 0%), but the generalizability of this data is limited by the low sample size (10 patients in the Boceprevir null responders group) and by the observational study design that renders it susceptible to systematic biases that are best avoided in randomized clinical trials, namely indication bias. Still, in this study the overall SVR rate was 49% and having in consideration the kind of patients that were included we think this is a good result, even though there was a strikingly high incidence (49.9%) of severe adverse events (SAE), most patients (70%-83%) were able to go on complete the treatment. It is reasonable to admit that adverse events are part of these treatments, even more so in cirrhotic patients. There seems to be, however, a subgroup of patients with more advanced liver disease that can be identified by low platelet count (
