December 2014
2014;27:42–55.). This is reflected in the model which stratifies age into 4 categories. A maximum score of 3 is the highest of all the variables. Could the model have been limited by the exclusion of other important risk factors? Diabetes was not included in this model owing to low prevalence. Dietary information, physical activity, micronutrient status, nonsteroidal antiinflammatory drug use, and alcohol use were not measured and therefore not included in the model. Alcohol has been shown to be associated with an increased risk of colorectal neoplasia (Am J Gastroenterol 2005;100:2049–2055). Although a recent model may have achieved a higher c–statistic (0.74; Am J Epidemiol 2012;175:584–593) with inclusion of detailed dietary information, the collection of such data in practice might be too onerous and thus may limit clinical use. Another limitation of the model may be the lack of generalizability and limited use in populations, which may differ from those observed in patients undergoing screening colonoscopy in Poland. There are 3 strategies for validating models: Internal, which uses the same dataset; temporal, which uses data from the same group or center at a different periods; and external, or data from a new population. It should be noted that the authors seem to utilize an internal strategy by splitting 1 database, which may limit generalizability (Stat Med 2000;19:453–473). Although the authors make the point that the prevalence of advanced neoplasia is similar to that of the United States, the prevalence of risk factors such as diabetes may be different (BMJ 2014;348:g3962.). Finally, another factor that may limit application of the model was the narrow age range in the study sample (40–66 years). Thus, the model’s application may be limited in a typical screening population with an age range of 50–80 years. There are endoscopy-related aspects that should be examined, especially because colonoscopy was used as the gold standard for advanced adenoma prevalence in this study. All of the endoscopists participated in “the quality assurance programme,” although details are not provided. An adequate cecal intubation rate is reported (96.0%), although only 19.2% of patients had adenomas. This rate is just short of the 20% recommended by the authors in a previous study examining interval cancers (N Engl J Med 2010;362:1795–1803). However, the overall advanced adenoma detection rate of 7.1% is consistent with other screening studies (Gut 2014;63:1130–1136). The authors considered a subgroup of serrated polyps as adenomas. Serrated lesions may not share similar risk factors with conventional adenomas. For example, 1 study showed that there was a stronger association between smoking and sessile serrated adenomas/polyps than with conventional adenomas (J Clin Gastroenterol 2011;45: 694–699). In addition, while male sex was a risk for adenomas in that study, it was not for sessile serrated adenomas/polyps. Although the authors do not provide the prevalence of serrated lesions, it is likely that this number was too small to impact the outcome. Did the polyps that were excluded from the analysis impact the results? The authors treated all nonretrieved
Selected Summaries 1433
polyps 10 mm) unresected lesions were excluded, all of which were likely advanced neoplasia. Although only a small percentage (0.3%) of the overall enrollment or even of those with advanced neoplasia (4.1%) were excluded, a comparison between these excluded patients and other patients might have reassured the reader that exclusion did not impact the study. Although the discriminatory power of the current model may fall slightly short of the desirable cutoff, the authors should be commended for developing an easy-to-use tool in a large, asymptomatic population. Their results suggest that perhaps a model that includes easily measured risk factors may not be a powerful prediction tool for advanced neoplasia. Modifications such as the addition of biomarkers may be needed to realize the goal of investigators like Kaminski et al. ETHAN BORTNIKER Division of Gastroenterology and Hepatology University of Connecticut School of Medicine Farmington, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Hanover, New Hampshire
ETROLIZUMAB IN ULCERATIVE COLITIS: TIGHTENING LEUKOCYTE TRAFFIC CONTROL IN THE INFLAMED MUCOSA Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomized, controlled, phase 2 trial Lancet 2014;384:309–318. The introduction of biological agents has dramatically changed the therapeutic management of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). In the last decade, monoclonal antibodies directed against the tumor necrosis factor (TNF)-a have been shown to be effective in inducing and maintaining clinical and endoscopic remission (Clin Gastroenterol Hepatol 2008;6: 644–653). Despite their clear efficacy profile, primary failure rates (about 40%) remain high (N Engl J Med 2005; 353:2462–2476) and are associated with important side effects, such as serious infections, infusion reactions, or paradoxical inflammation (Autoimmun Rev 2014;13:15–19). The pharmacologic blockade of integrins and adhesion molecules represents a new therapeutic frontier in the management of IBD. Etrolizumab, a b7-blocker monoclonal antibody, represents one of the newer anti-integrin drugs, with a good
1434 Selected Summaries
safety profile and slightly new mechanism of action that may be unique for the treatment of IBD. Vermeire et al (Lancet 2014;384:309–318) conducted a double-blind, placebo-controlled, randomized, phase II study on 124 patients with moderately to severely active UC who had not responded to conventional therapy. Adult patients (18-75 years) with active UC, defined as a Mayo Clinic Score (MCS) of 5 points (6 points in the United States), a centrally read MCS endoscopic subscore of 2 points, with rectal bleeding, and disease extending 25 cm from the anal verge were included. Concomitant therapies for UC had to remain stable, except for immunomodulators and steroids, tapering of which was mandatory for US patients. Subjects were randomly assigned in a 1:1:1 ratio to subcutaneous etrolizumab 100 mg at weeks 0, 4, and 8, with placebo at week 2 (etrolizumab 100 mg group; n ¼ 41); etrolizumab 420 mg at week 0 followed by 300 mg at weeks 2, 4, and 8 (etrolizumab 300 mg plus loading dose group, n ¼ 40); or to placebo (n ¼ 43). Randomization was stratified according to concomitant treatment with corticosteroids, immunomodulators, previous TNF antagonist exposure, and study site. The primary end point was clinical remission at week 10, defined as the proportion of patients with MCS of 2 points with no individual subscore of >1 point. Secondary end points were clinical remission at week 6, clinical response, and the achievement of both endoscopic subscore of 0 and rectal bleeding subscore of 0 at weeks 6 and 10. Exploratory outcomes included changes from baseline in mucosal healing (endoscopic subscore of 0 or 1), histologic active disease severity score, and pharmacodynamic biomarkers in the peripheral blood (b7 occupancy and expression levels on T and B lymphocytes) and colonic tissue (b7 occupancy and expression levels on T-lymphocyte subsets, quantification of aEþ cells, and cytokine and adhesion molecule gene expression). An exploratory diagnostic analysis of gene expression and immunohistochemistry from baseline colonic biopsy samples was also done. Etrolizumab was found to be significantly more effective than placebo in inducing clinical remission at week 10 (P < .05), because none of placebo-treated subjects achieved remission compared with 21% (8/39) with etrolizumab 100 mg and 10% (4/39) in the etrolizumab 300 mg þ loading dose group. No differences were found among the 3 treatment groups for any of the secondary end points, although the proportion of patients with an MCS of 1 was numerically higher in the etrolizumab groups than in the placebo group. No differences were found in mucosal healing, histology severity, or C-reactive protein levels at week 0 among subjects treated with etrolizumab or placebo. The number of adverse events was similar for etrolizumab and placebo; 12 serious adverse events were reported with no differences between groups and no serious opportunistic infections were reported. Mild reactions site reactions were reported in 4 patients treated with etrolizumab and 2 with placebo. No adverse events related to the development of antidrug antibodies (reported in 4 patients treated with etrolizumab 100 mg), and no lower serum levels were found to be related to antidrug antibody development.
Gastroenterology Vol. 147, No. 6
In both groups treated with etrolizumab, b7 receptors were fully occupied in the circulating CD4þ and CD8þb7þ T lymphocytes both in peripheral blood and in the colonic tissue, with a corresponding specific increase in intestinal homing CD4þb7þ T lymphocytes in the peripheral blood. Higher levels of aE expression in the colonic tissue were found in patients achieving clinical remission, suggesting further research is warranted into selecting those patients most likely to respond to etrolizumab. Comment. In the last decade, the development of antiadhesion molecules has revealed new successful therapeutic targets in IBD (Expert Rev Clin Immunol 2013; 9:301–306). Integrins play a key role in the pathogenesis of chronic inflammation, both in CD and UC, by promoting the recruitment of T cells from peripheral blood and by regulating the trafficking of immune cells into the mucosa where they contribute to develop and perpetuate inflammation (Inflammopharmacology 2012;20:1–18, Expert Rev Clin Immunol 2010;6:567–72). Both a4 and b7 subunits represent important targets for new anti-adhesion molecules. The non-selective blockade of alpha4 by natalizumab has been shown to be effective in CD (N Engl J Med 2005;353: 1912–25, Ann Pharmacother 2005;39:1833–43). However, the non-selective action of natalizumab is associated with important safety concerns, such as the reactivation of the JC virus (Expert Rev Gastroenterol Hepatol 2007;1:29–39). Vedolizumab, an anti-a4b7 monoclonal antibody has good gut-selectivity, positive efficacy rates both in CD and UC, a good safety profile, and has been approved (N Engl J Med 2013;369:711–21, N Engl J Med 2013;369:699–710). Etrolizumab has potentially similar efficacy and safety profiles as vedolizumab, but can also inhibit interactions between the aE subunit and E-cadherin that play a key role in the leukocyte retention into the mucosa and block the activation of aEb7þ intestinal dendritic cells that are implicated in the activation and dysregulation of T-cells (Inflammopharmacology 2012;20:1–18, Gut 2013;62:1122–1130, Gastroenterology 2014;146:307–309). Although the blockade of aEb7 might decrease the immune response to intestinal parasites, no occurrence of opportunistic infections was reported (Gut 2013;62:1122–1130) and no cases of progressive multifocal leukoencephalopathy were recorded. Vermeire et al found that etrolizumab was more effective than placebo in achieving remission at week 10, although the remission rates were not as great as expected in either etrolizumab group. Moreover, the secondary end point results were not achieved for both etrolizumab doses. Several factors could have had an impact on these findings and need to be further evaluated in phase III trials. First, there was a significant difference in the baseline population concerning concomitant medications; subjects entering the etrolizumab groups had lower rates of current 5-aminosalicylic acid use, which suggests more severe disease. Data from the phase II study show that concomitant use of steroids and immunosuppressant and anti-TNF–naive status were significantly associated with higher remission rates. Similarly to vedolizumab, which shares an analog mechanism of action, etrolizumab seems to be more effective in
December 2014
anti-TNF–naive subjects, so that the selection of early active moderate-to-severe UC patients for further trials may probably enhance the response and remission rates to etrolizumab. Second, the MCS has important limitations in assessing clinical response since a patient with a score decreasing by 3 points and 30% from a baseline MCS from 10 to 12 still has active disease, although he fulfills all criteria for clinical response. This trial also opens new perspectives in understanding the complex interaction between integrins and E-cadherin. It is unknown whether aEb7þ cells play only a proinflammatory role or if they also have regulatory effects (Inflammopharmacology 2012;20:1–18). In the etrolizumabtreated patients, high levels of baseline aE expression on cells were associated with better response, and the decrease in aEþ cells was associated with the decrease of all proinflammatory cytokines. The increase in expression of E-cadherin, which is associated with mucosal healing, suggests that the interaction aEb7þ cells/E-cadherin plays a key role in the pathogenesis of UC. This opens a new perspective for tailoring therapy with etrolizumab and other monoclonal antibodies and for better understanding the role of adhesion molecules and different integrin subsets in the pathogenesis of UC. GIONATA FIORINO SILVIO DANESE IBD Center Department of Gastroenterology Humanitas Research Hospital, Rozzano Milan, Italy
IS ANTIVIRAL DRUG-INDUCED HEPATITIS B SURFACE ANTIGEN LOSS DURABLE? Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability? Gut 2014;63: 1325–1332. In patients with chronic hepatitis B, seroclearance of hepatitis B surface antigen (HBsAg) is an important milestone. Patients with spontaneous HBsAg seroclearance seldom experience virologic relapse and have a low risk of disease progression and hepatocellular carcinoma. Similarly, after a course of immunomodulatory treatment with interferon or peginterferon, >10% of patients may eventually develop HBsAg seroclearance, and the response is highly durable (J Hepatol 2009;50:1084–1092; Gastroenterology 2009;136:2169–2179; Hepatology 2010;51:1945–1953). The situation with oral nucleoside analogs (NUCs) is less certain. NUCs have potent antiviral activity but do not have a direct immunomodulatory effect. Because of their ease of use and favorable safety profile, NUCs have been the preferred treatment in the majority of patients. However, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, NUC-induced HBeAg seroconversion is not as
Selected Summaries 1435
durable as spontaneous HBeAg seroconversion (Hepatology 2000;32:803–806; J Antimicrob Chemother 2013;68:2332– 2338). This leads to the important question of whether NUC-induced HBsAg seroclearance is durable and translates to good clinical outcomes. In a recent paper, Kim et al reported a large, retrospective cohort of 5,409 patients with chronic hepatitis B who were initially treated with lamivudine or entecavir (Gut 2014;63:1325–1332). During a median follow-up of 6 years, 110 patients (2.0%) achieved HBsAg seroclearance (0.33% per year). The overall prognosis of patients with NUCinduced HBsAg seroclearance was good. Only 1 patient developed hepatocellular carcinoma and another required liver transplantation, but died after an unrelated surgery. None of the other patients with HBsAg seroclearance died, underwent liver transplantation, or developed hepatocellular carcinoma. Using propensity score matching, patients with HBsAg seroclearance had 90% reduction in the risk of death or liver transplantation (hazard ratio, 0.10; P ¼ .02) and hepatocellular carcinoma (hazard ratio, 0.06; P < .01). The next question is the durability of HBsAg seroclearance. Among 111 patients with HBsAg seroclearance, 8 had HBsAg reversion within 3 years. The cumulative rates of HBsAg reversion were 7.6% at 12 months and 11.7% at 36 months. However, the HBsAg level remained low (0.05-1.0 IU/mL), and 7 patients lost HBsAg again later. In addition, 17 patients had detectable hepatitis B virus (HBV) DNA despite HBsAg seroclearance. The cumulative rates of virologic reversion were 13.8% at 1 year, 18.7% at 2 years, and 29.6% at 4 years. Again, the HBV DNA remained low, at 5 times the upper limit of normal at baseline) were associated with HBsAg seroclearance. In contrast, patients with cirrhosis were less likely to achieve HBsAg seroclearance. For some reasons, the use of entecavir as opposed to lamivudine was associated with lower rate of HBsAg seroclearance (hazard ratio, 0.30; P ¼ .05). This may be partly explained by the longer treatment and follow-up duration of patients taking lamivudine. Moreover, patients with HBsAg seroclearance had lower HBsAg levels 2 years before seroclearance and had steeper slope of decline in HBsAg. Comment. The study by Kim et al answers the 2 most important questions on NUC-induced HBsAg seroclearance (Gut 2014;63:1325–1332). First, NUC-induced HBsAg seroclearance is associated with good prognosis. Second, although around 10% of patients may experience HBsAg reversion after initial seroclearance, it is mostly transient and rarely associated with significant viral activities. In other words, NUC-induced HBsAg seroclearance can be considered durable. Several Asian groups have studied the natural history of spontaneous HBsAg seroclearance. This is associated with improvement in histologic necroinflammation and fibrosis (J Hepatol 2005;42:188–194). Overall, hepatocellular carcinoma develops in 1.1%–10.2% of patients after seroclearance (Gastroenterology 2002;123:1084–1089; J Hepatol 2005;42:
2014;27:42–55.). This is reflected in the model which stratifies age into 4 categories. A maximum score of 3 is the highest of all the variables. Could the model have been limited by the exclusion of other important risk factors? Diabetes was not included in this model owing to low prevalence. Dietary information, physical activity, micronutrient status, nonsteroidal antiinflammatory drug use, and alcohol use were not measured and therefore not included in the model. Alcohol has been shown to be associated with an increased risk of colorectal neoplasia (Am J Gastroenterol 2005;100:2049–2055). Although a recent model may have achieved a higher c–statistic (0.74; Am J Epidemiol 2012;175:584–593) with inclusion of detailed dietary information, the collection of such data in practice might be too onerous and thus may limit clinical use. Another limitation of the model may be the lack of generalizability and limited use in populations, which may differ from those observed in patients undergoing screening colonoscopy in Poland. There are 3 strategies for validating models: Internal, which uses the same dataset; temporal, which uses data from the same group or center at a different periods; and external, or data from a new population. It should be noted that the authors seem to utilize an internal strategy by splitting 1 database, which may limit generalizability (Stat Med 2000;19:453–473). Although the authors make the point that the prevalence of advanced neoplasia is similar to that of the United States, the prevalence of risk factors such as diabetes may be different (BMJ 2014;348:g3962.). Finally, another factor that may limit application of the model was the narrow age range in the study sample (40–66 years). Thus, the model’s application may be limited in a typical screening population with an age range of 50–80 years. There are endoscopy-related aspects that should be examined, especially because colonoscopy was used as the gold standard for advanced adenoma prevalence in this study. All of the endoscopists participated in “the quality assurance programme,” although details are not provided. An adequate cecal intubation rate is reported (96.0%), although only 19.2% of patients had adenomas. This rate is just short of the 20% recommended by the authors in a previous study examining interval cancers (N Engl J Med 2010;362:1795–1803). However, the overall advanced adenoma detection rate of 7.1% is consistent with other screening studies (Gut 2014;63:1130–1136). The authors considered a subgroup of serrated polyps as adenomas. Serrated lesions may not share similar risk factors with conventional adenomas. For example, 1 study showed that there was a stronger association between smoking and sessile serrated adenomas/polyps than with conventional adenomas (J Clin Gastroenterol 2011;45: 694–699). In addition, while male sex was a risk for adenomas in that study, it was not for sessile serrated adenomas/polyps. Although the authors do not provide the prevalence of serrated lesions, it is likely that this number was too small to impact the outcome. Did the polyps that were excluded from the analysis impact the results? The authors treated all nonretrieved
Selected Summaries 1433
polyps 10 mm) unresected lesions were excluded, all of which were likely advanced neoplasia. Although only a small percentage (0.3%) of the overall enrollment or even of those with advanced neoplasia (4.1%) were excluded, a comparison between these excluded patients and other patients might have reassured the reader that exclusion did not impact the study. Although the discriminatory power of the current model may fall slightly short of the desirable cutoff, the authors should be commended for developing an easy-to-use tool in a large, asymptomatic population. Their results suggest that perhaps a model that includes easily measured risk factors may not be a powerful prediction tool for advanced neoplasia. Modifications such as the addition of biomarkers may be needed to realize the goal of investigators like Kaminski et al. ETHAN BORTNIKER Division of Gastroenterology and Hepatology University of Connecticut School of Medicine Farmington, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Hanover, New Hampshire
ETROLIZUMAB IN ULCERATIVE COLITIS: TIGHTENING LEUKOCYTE TRAFFIC CONTROL IN THE INFLAMED MUCOSA Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomized, controlled, phase 2 trial Lancet 2014;384:309–318. The introduction of biological agents has dramatically changed the therapeutic management of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). In the last decade, monoclonal antibodies directed against the tumor necrosis factor (TNF)-a have been shown to be effective in inducing and maintaining clinical and endoscopic remission (Clin Gastroenterol Hepatol 2008;6: 644–653). Despite their clear efficacy profile, primary failure rates (about 40%) remain high (N Engl J Med 2005; 353:2462–2476) and are associated with important side effects, such as serious infections, infusion reactions, or paradoxical inflammation (Autoimmun Rev 2014;13:15–19). The pharmacologic blockade of integrins and adhesion molecules represents a new therapeutic frontier in the management of IBD. Etrolizumab, a b7-blocker monoclonal antibody, represents one of the newer anti-integrin drugs, with a good
1434 Selected Summaries
safety profile and slightly new mechanism of action that may be unique for the treatment of IBD. Vermeire et al (Lancet 2014;384:309–318) conducted a double-blind, placebo-controlled, randomized, phase II study on 124 patients with moderately to severely active UC who had not responded to conventional therapy. Adult patients (18-75 years) with active UC, defined as a Mayo Clinic Score (MCS) of 5 points (6 points in the United States), a centrally read MCS endoscopic subscore of 2 points, with rectal bleeding, and disease extending 25 cm from the anal verge were included. Concomitant therapies for UC had to remain stable, except for immunomodulators and steroids, tapering of which was mandatory for US patients. Subjects were randomly assigned in a 1:1:1 ratio to subcutaneous etrolizumab 100 mg at weeks 0, 4, and 8, with placebo at week 2 (etrolizumab 100 mg group; n ¼ 41); etrolizumab 420 mg at week 0 followed by 300 mg at weeks 2, 4, and 8 (etrolizumab 300 mg plus loading dose group, n ¼ 40); or to placebo (n ¼ 43). Randomization was stratified according to concomitant treatment with corticosteroids, immunomodulators, previous TNF antagonist exposure, and study site. The primary end point was clinical remission at week 10, defined as the proportion of patients with MCS of 2 points with no individual subscore of >1 point. Secondary end points were clinical remission at week 6, clinical response, and the achievement of both endoscopic subscore of 0 and rectal bleeding subscore of 0 at weeks 6 and 10. Exploratory outcomes included changes from baseline in mucosal healing (endoscopic subscore of 0 or 1), histologic active disease severity score, and pharmacodynamic biomarkers in the peripheral blood (b7 occupancy and expression levels on T and B lymphocytes) and colonic tissue (b7 occupancy and expression levels on T-lymphocyte subsets, quantification of aEþ cells, and cytokine and adhesion molecule gene expression). An exploratory diagnostic analysis of gene expression and immunohistochemistry from baseline colonic biopsy samples was also done. Etrolizumab was found to be significantly more effective than placebo in inducing clinical remission at week 10 (P < .05), because none of placebo-treated subjects achieved remission compared with 21% (8/39) with etrolizumab 100 mg and 10% (4/39) in the etrolizumab 300 mg þ loading dose group. No differences were found among the 3 treatment groups for any of the secondary end points, although the proportion of patients with an MCS of 1 was numerically higher in the etrolizumab groups than in the placebo group. No differences were found in mucosal healing, histology severity, or C-reactive protein levels at week 0 among subjects treated with etrolizumab or placebo. The number of adverse events was similar for etrolizumab and placebo; 12 serious adverse events were reported with no differences between groups and no serious opportunistic infections were reported. Mild reactions site reactions were reported in 4 patients treated with etrolizumab and 2 with placebo. No adverse events related to the development of antidrug antibodies (reported in 4 patients treated with etrolizumab 100 mg), and no lower serum levels were found to be related to antidrug antibody development.
Gastroenterology Vol. 147, No. 6
In both groups treated with etrolizumab, b7 receptors were fully occupied in the circulating CD4þ and CD8þb7þ T lymphocytes both in peripheral blood and in the colonic tissue, with a corresponding specific increase in intestinal homing CD4þb7þ T lymphocytes in the peripheral blood. Higher levels of aE expression in the colonic tissue were found in patients achieving clinical remission, suggesting further research is warranted into selecting those patients most likely to respond to etrolizumab. Comment. In the last decade, the development of antiadhesion molecules has revealed new successful therapeutic targets in IBD (Expert Rev Clin Immunol 2013; 9:301–306). Integrins play a key role in the pathogenesis of chronic inflammation, both in CD and UC, by promoting the recruitment of T cells from peripheral blood and by regulating the trafficking of immune cells into the mucosa where they contribute to develop and perpetuate inflammation (Inflammopharmacology 2012;20:1–18, Expert Rev Clin Immunol 2010;6:567–72). Both a4 and b7 subunits represent important targets for new anti-adhesion molecules. The non-selective blockade of alpha4 by natalizumab has been shown to be effective in CD (N Engl J Med 2005;353: 1912–25, Ann Pharmacother 2005;39:1833–43). However, the non-selective action of natalizumab is associated with important safety concerns, such as the reactivation of the JC virus (Expert Rev Gastroenterol Hepatol 2007;1:29–39). Vedolizumab, an anti-a4b7 monoclonal antibody has good gut-selectivity, positive efficacy rates both in CD and UC, a good safety profile, and has been approved (N Engl J Med 2013;369:711–21, N Engl J Med 2013;369:699–710). Etrolizumab has potentially similar efficacy and safety profiles as vedolizumab, but can also inhibit interactions between the aE subunit and E-cadherin that play a key role in the leukocyte retention into the mucosa and block the activation of aEb7þ intestinal dendritic cells that are implicated in the activation and dysregulation of T-cells (Inflammopharmacology 2012;20:1–18, Gut 2013;62:1122–1130, Gastroenterology 2014;146:307–309). Although the blockade of aEb7 might decrease the immune response to intestinal parasites, no occurrence of opportunistic infections was reported (Gut 2013;62:1122–1130) and no cases of progressive multifocal leukoencephalopathy were recorded. Vermeire et al found that etrolizumab was more effective than placebo in achieving remission at week 10, although the remission rates were not as great as expected in either etrolizumab group. Moreover, the secondary end point results were not achieved for both etrolizumab doses. Several factors could have had an impact on these findings and need to be further evaluated in phase III trials. First, there was a significant difference in the baseline population concerning concomitant medications; subjects entering the etrolizumab groups had lower rates of current 5-aminosalicylic acid use, which suggests more severe disease. Data from the phase II study show that concomitant use of steroids and immunosuppressant and anti-TNF–naive status were significantly associated with higher remission rates. Similarly to vedolizumab, which shares an analog mechanism of action, etrolizumab seems to be more effective in
December 2014
anti-TNF–naive subjects, so that the selection of early active moderate-to-severe UC patients for further trials may probably enhance the response and remission rates to etrolizumab. Second, the MCS has important limitations in assessing clinical response since a patient with a score decreasing by 3 points and 30% from a baseline MCS from 10 to 12 still has active disease, although he fulfills all criteria for clinical response. This trial also opens new perspectives in understanding the complex interaction between integrins and E-cadherin. It is unknown whether aEb7þ cells play only a proinflammatory role or if they also have regulatory effects (Inflammopharmacology 2012;20:1–18). In the etrolizumabtreated patients, high levels of baseline aE expression on cells were associated with better response, and the decrease in aEþ cells was associated with the decrease of all proinflammatory cytokines. The increase in expression of E-cadherin, which is associated with mucosal healing, suggests that the interaction aEb7þ cells/E-cadherin plays a key role in the pathogenesis of UC. This opens a new perspective for tailoring therapy with etrolizumab and other monoclonal antibodies and for better understanding the role of adhesion molecules and different integrin subsets in the pathogenesis of UC. GIONATA FIORINO SILVIO DANESE IBD Center Department of Gastroenterology Humanitas Research Hospital, Rozzano Milan, Italy
IS ANTIVIRAL DRUG-INDUCED HEPATITIS B SURFACE ANTIGEN LOSS DURABLE? Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability? Gut 2014;63: 1325–1332. In patients with chronic hepatitis B, seroclearance of hepatitis B surface antigen (HBsAg) is an important milestone. Patients with spontaneous HBsAg seroclearance seldom experience virologic relapse and have a low risk of disease progression and hepatocellular carcinoma. Similarly, after a course of immunomodulatory treatment with interferon or peginterferon, >10% of patients may eventually develop HBsAg seroclearance, and the response is highly durable (J Hepatol 2009;50:1084–1092; Gastroenterology 2009;136:2169–2179; Hepatology 2010;51:1945–1953). The situation with oral nucleoside analogs (NUCs) is less certain. NUCs have potent antiviral activity but do not have a direct immunomodulatory effect. Because of their ease of use and favorable safety profile, NUCs have been the preferred treatment in the majority of patients. However, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, NUC-induced HBeAg seroconversion is not as
Selected Summaries 1435
durable as spontaneous HBeAg seroconversion (Hepatology 2000;32:803–806; J Antimicrob Chemother 2013;68:2332– 2338). This leads to the important question of whether NUC-induced HBsAg seroclearance is durable and translates to good clinical outcomes. In a recent paper, Kim et al reported a large, retrospective cohort of 5,409 patients with chronic hepatitis B who were initially treated with lamivudine or entecavir (Gut 2014;63:1325–1332). During a median follow-up of 6 years, 110 patients (2.0%) achieved HBsAg seroclearance (0.33% per year). The overall prognosis of patients with NUCinduced HBsAg seroclearance was good. Only 1 patient developed hepatocellular carcinoma and another required liver transplantation, but died after an unrelated surgery. None of the other patients with HBsAg seroclearance died, underwent liver transplantation, or developed hepatocellular carcinoma. Using propensity score matching, patients with HBsAg seroclearance had 90% reduction in the risk of death or liver transplantation (hazard ratio, 0.10; P ¼ .02) and hepatocellular carcinoma (hazard ratio, 0.06; P < .01). The next question is the durability of HBsAg seroclearance. Among 111 patients with HBsAg seroclearance, 8 had HBsAg reversion within 3 years. The cumulative rates of HBsAg reversion were 7.6% at 12 months and 11.7% at 36 months. However, the HBsAg level remained low (0.05-1.0 IU/mL), and 7 patients lost HBsAg again later. In addition, 17 patients had detectable hepatitis B virus (HBV) DNA despite HBsAg seroclearance. The cumulative rates of virologic reversion were 13.8% at 1 year, 18.7% at 2 years, and 29.6% at 4 years. Again, the HBV DNA remained low, at 5 times the upper limit of normal at baseline) were associated with HBsAg seroclearance. In contrast, patients with cirrhosis were less likely to achieve HBsAg seroclearance. For some reasons, the use of entecavir as opposed to lamivudine was associated with lower rate of HBsAg seroclearance (hazard ratio, 0.30; P ¼ .05). This may be partly explained by the longer treatment and follow-up duration of patients taking lamivudine. Moreover, patients with HBsAg seroclearance had lower HBsAg levels 2 years before seroclearance and had steeper slope of decline in HBsAg. Comment. The study by Kim et al answers the 2 most important questions on NUC-induced HBsAg seroclearance (Gut 2014;63:1325–1332). First, NUC-induced HBsAg seroclearance is associated with good prognosis. Second, although around 10% of patients may experience HBsAg reversion after initial seroclearance, it is mostly transient and rarely associated with significant viral activities. In other words, NUC-induced HBsAg seroclearance can be considered durable. Several Asian groups have studied the natural history of spontaneous HBsAg seroclearance. This is associated with improvement in histologic necroinflammation and fibrosis (J Hepatol 2005;42:188–194). Overall, hepatocellular carcinoma develops in 1.1%–10.2% of patients after seroclearance (Gastroenterology 2002;123:1084–1089; J Hepatol 2005;42:
