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Combination Therapy With Tenofovir and Peginterferon May Not Be Translated Into Current Clinical Practice
Gastroenterology 2016;-:1
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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.
Combination Therapy With Tenofovir and Peginterferon May Not Be Translated Into Current Clinical Practice Dear Editor: We read with great interest the paper by Marcellin et al published in Gastroenterology.1 The authors demonstrated that combination therapy with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (Peg-IFN) for 48 weeks could result in higher rate of hepatitis B surface antigen (HBsAg) loss than either monotherapy in the multicenter international trial. However, the key question is whether the new strategy is good enough to be translated into current clinical practice. In this trial, the TDF þ Peg-IFN combination group indeed had higher rate of HBsAg loss than Peg-IFN monotherapy group (Kaplan-Meier estimate, 9.1% vs 2.8%; P ¼ .003). However, this improvement was mainly observed in genotype A patients (2.7% [5/185] in Peg-IFN monotherapy group vs 8.6% [16/186] in the combination group); a previous study had demonstrated that genotype A was associated with better response to Peg-IFN treatment than other genotypes.2 Meanwhile, for the subgroups of genotype B and C, which are the most prevalent genotypes in Asia Pacific area (also the highly endemic area), the potential benefit of TDF þ Peg-IFN on HBsAg loss, is limited. At week 72, the TDF þ Peg-IFN group only had 1 or 2 additional patients with HBsAg loss than PegIFN monotherapy among genotype B and C patients. Therefore, considering the cost of combination therapy in HBV endemic areas, the strategy may not be a suitable strategy for the majority of chronic hepatitis B patients worldwide. The proportion of patients with HBsAg loss at week 72 was estimated by Kaplan-Meier method in the trial. If we calculate the HBsAg loss rate by simply using the division method (missing ¼ failure), the average rate of HBsAg loss among hepatitis B e antigen (HBeAg)-negative patients treated with Peg-IFN based therapy (ie, TDF þ Peg-IFN group and Peg-IFN group) was 4.5% (7/157), which was actually similar to that reported in Peg-IFN phase III registration trial (3.4% [12/356]).3 Moreover, it is interesting that the rate of HBeAg seroconversion is significantly higher in TDF þ Peg-IFN group than that in Peg-IFN monotherapy group (23.1% vs 12.3%) at week 48, but the rates between the 2 groups were comparable at week 72, indicating that the combination therapy might “speed up” but not improve HBeAg seroconversion. Similarly, it is also possible that the combination therapy just speed up HBsAg clearance in the short term. Long-term follow-up studies in HBeAg-positive and -negative patients treated with Peg-IFN for 3 years showed that 11% and 8.7% could
achieve HBsAg loss during off-treatment follow-up.4,5 Therefore, based on the results of current trial, whether the short-term benefit of TDF þ Peg- IFN strategy on HBsAg clearance can be translated into long-term benefit remains unknown; long-term follow-up is warranted to clarify this important issue. In contrast, it should be mentioned that HBsAg clearance is indeed an ideal endpoint that we all dream of and make great effort to realize; however, we do have to admit that HBsAg clearance is still rare by using current available drugs, although different strategies have been tried to improve HBsAg clearance. What is more important is that sustained suppression of viral replication was demonstrated clearly to be related to the improvement of survival for chronic hepatitis B patients, where HBsAg clearance is not required. Until now, almost all the patients could achieve undetectable HBV DNA level after long-term entecavir or TDF treatment.6,7 Thus, it is more realistic to keep viral replication under control for more patients rather than seek HBsAg clearance for few patients. We will pursue HBsAg clearance with the advent of novel drugs with new targets and new mechanisms, just like the successful story of chronic hepatitis C. Q2 RONG FAN JIAN SUN JINLIN HOU State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases and Hepatology Unit Nanfang Hospital, Southern Medical University Guangzhou
References 1. 2. 3. 4. 5. 6. 7.
Marcellin P, et al. Gastroenterology 2016;150:134–144. Buster EHCJ, et al. Gastroenterology 2009;137: 2002–2009. Marcellin P, et al. N Engl J Med 2004;351:1206–1217. Buster EHCJ, et al. Gastroenterology 2008;135:459–467. Marcellin P, et al. Gastroenterology 2009;136: 2169–2179. Chang T-T, et al. Hepatology 2010;51:422–430. Marcellin P, et al. Hepatology 2014;60:313A–314A.
Conflicts of interest The authors have made the following disclosures: JLH has received grant/ research support from Roche, Novartis, and GSK. The other authors declare Q1 that they have no conflicts of interest. Funding Grant support provided by the National Science and Technology Major Project (2012ZX10002003) and President Foundation of Nanfang Hospital, Southern Medical University (2014C010).
http://dx.doi.org/10.1053/j.gastro.2015.12.046
COR 5.4.0 DTD YGAST60358_proof 26 March 2016 2:00 pm ce
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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.
Combination Therapy With Tenofovir and Peginterferon May Not Be Translated Into Current Clinical Practice Dear Editor: We read with great interest the paper by Marcellin et al published in Gastroenterology.1 The authors demonstrated that combination therapy with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (Peg-IFN) for 48 weeks could result in higher rate of hepatitis B surface antigen (HBsAg) loss than either monotherapy in the multicenter international trial. However, the key question is whether the new strategy is good enough to be translated into current clinical practice. In this trial, the TDF þ Peg-IFN combination group indeed had higher rate of HBsAg loss than Peg-IFN monotherapy group (Kaplan-Meier estimate, 9.1% vs 2.8%; P ¼ .003). However, this improvement was mainly observed in genotype A patients (2.7% [5/185] in Peg-IFN monotherapy group vs 8.6% [16/186] in the combination group); a previous study had demonstrated that genotype A was associated with better response to Peg-IFN treatment than other genotypes.2 Meanwhile, for the subgroups of genotype B and C, which are the most prevalent genotypes in Asia Pacific area (also the highly endemic area), the potential benefit of TDF þ Peg-IFN on HBsAg loss, is limited. At week 72, the TDF þ Peg-IFN group only had 1 or 2 additional patients with HBsAg loss than PegIFN monotherapy among genotype B and C patients. Therefore, considering the cost of combination therapy in HBV endemic areas, the strategy may not be a suitable strategy for the majority of chronic hepatitis B patients worldwide. The proportion of patients with HBsAg loss at week 72 was estimated by Kaplan-Meier method in the trial. If we calculate the HBsAg loss rate by simply using the division method (missing ¼ failure), the average rate of HBsAg loss among hepatitis B e antigen (HBeAg)-negative patients treated with Peg-IFN based therapy (ie, TDF þ Peg-IFN group and Peg-IFN group) was 4.5% (7/157), which was actually similar to that reported in Peg-IFN phase III registration trial (3.4% [12/356]).3 Moreover, it is interesting that the rate of HBeAg seroconversion is significantly higher in TDF þ Peg-IFN group than that in Peg-IFN monotherapy group (23.1% vs 12.3%) at week 48, but the rates between the 2 groups were comparable at week 72, indicating that the combination therapy might “speed up” but not improve HBeAg seroconversion. Similarly, it is also possible that the combination therapy just speed up HBsAg clearance in the short term. Long-term follow-up studies in HBeAg-positive and -negative patients treated with Peg-IFN for 3 years showed that 11% and 8.7% could
achieve HBsAg loss during off-treatment follow-up.4,5 Therefore, based on the results of current trial, whether the short-term benefit of TDF þ Peg- IFN strategy on HBsAg clearance can be translated into long-term benefit remains unknown; long-term follow-up is warranted to clarify this important issue. In contrast, it should be mentioned that HBsAg clearance is indeed an ideal endpoint that we all dream of and make great effort to realize; however, we do have to admit that HBsAg clearance is still rare by using current available drugs, although different strategies have been tried to improve HBsAg clearance. What is more important is that sustained suppression of viral replication was demonstrated clearly to be related to the improvement of survival for chronic hepatitis B patients, where HBsAg clearance is not required. Until now, almost all the patients could achieve undetectable HBV DNA level after long-term entecavir or TDF treatment.6,7 Thus, it is more realistic to keep viral replication under control for more patients rather than seek HBsAg clearance for few patients. We will pursue HBsAg clearance with the advent of novel drugs with new targets and new mechanisms, just like the successful story of chronic hepatitis C. Q2 RONG FAN JIAN SUN JINLIN HOU State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases and Hepatology Unit Nanfang Hospital, Southern Medical University Guangzhou
References 1. 2. 3. 4. 5. 6. 7.
Marcellin P, et al. Gastroenterology 2016;150:134–144. Buster EHCJ, et al. Gastroenterology 2009;137: 2002–2009. Marcellin P, et al. N Engl J Med 2004;351:1206–1217. Buster EHCJ, et al. Gastroenterology 2008;135:459–467. Marcellin P, et al. Gastroenterology 2009;136: 2169–2179. Chang T-T, et al. Hepatology 2010;51:422–430. Marcellin P, et al. Hepatology 2014;60:313A–314A.
Conflicts of interest The authors have made the following disclosures: JLH has received grant/ research support from Roche, Novartis, and GSK. The other authors declare Q1 that they have no conflicts of interest. Funding Grant support provided by the National Science and Technology Major Project (2012ZX10002003) and President Foundation of Nanfang Hospital, Southern Medical University (2014C010).
http://dx.doi.org/10.1053/j.gastro.2015.12.046
COR 5.4.0 DTD YGAST60358_proof 26 March 2016 2:00 pm ce
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