- Email: [email protected]
Peginterferon add-on: an added benefit?
Comment
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Lavanchy D. The global burden of hepatitis C. Liver Int 2009; 29: 74–81. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998; 27: 209–12. Feld JJ, Jacobson IM, Hézode C, et al, for the ASTRAL-1 Investigators. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373: 2599–607. Foster GR, Afdhal N, Roberts SK, et al, for the ASTRAL-2 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373: 2608–17.
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The Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol 2016; published online Dec 15. http://dx.doi.org/10.1016/S2468-1253(16)30181-9. Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000; 355: 887–91.
With 240 million individuals infected worldwide,1 chronic hepatitis B virus (HBV) infection is a global cause of liver-related morbidity and mortality. Treatment options include pegylated interferon and nucleos(t)ide analogues. Pegylated interferon can stimulate antiviral immune mechanisms, whereas nucleos(t)ide analogues directly inhibit viral replication. These treatments are sufficient for viral suppression, but generally fail to induce functional cure, which is defined as HBs antigen (HBsAg) loss with or without formation of anti-HBs antibodies. Achievement of functional cure is associated with an improved outcome.2–4 Combination of the two treatments could lead to increased efficacy of both drugs and has been the subject of many clinical trials.5 A large randomised controlled study by Marcellin and colleagues6 analysed the efficacy of pegylated interferon and nucleotide analogue combination therapy versus pegylated interferon or nucleotide analogue therapy given alone in previously untreated HBe antigen (HBeAg)-positive or HBeAg-negative patients with chronic hepatitis B. In this landmark study, 9·1% of patients with chronic hepatitis B had a functional cure 6 months after cessation of therapy in the combination treatment group, which was significantly higher than in the pegylated interferon monotherapy group (2·8%). In patients with chronic hepatitis B, virus-specific T-cell responses are significantly impaired. Since virus-specific T-cell responses are already partly restored after long-term viral load suppression by nucleos(t)ide analogues in patients with chronic hepatitis B,7 addition of an immune modulatory agent to nucleos(t)ide analogue therapy could hypothetically be beneficial for this group of patients, leading to increased functional cure.8 In The Lancet Gastroenterology & Hepatology, Marc Bourlière and colleagues9 present data for the www.thelancet.com/gastrohep Vol 2 March 2017
PEGAN study. In this randomised, controlled, open-label trial, 185 patients with HBeAg-negative chronic hepatitis B who were on nucleos(t)ide analogue therapy for at least 1 year with undetectable HBV DNA were randomly allocated to receive pegylated interferon alfa-2a add-on therapy for 48 weeks or no additional therapy. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. Secondary endpoints included the proportion and grade of adverse events, quality of life as reported by patients, and willingness to receive pegylated interferon therapy. In the pegylated interferon group, seven (7·8%) patients had lost HBsAg at week 96 as compared with three (3·2%) in the nucleos(t)ide analogue-only control group, which was not significantly different (difference 4·6% [95% CI –2·6 to 12·5]; p=0·15). Similar to the results from Marcellin and colleagues,6 the overall proportion of patients achieving a functional cure was low, and further analyses were done to identify factors associated with functional cure. These analyses revealed a significant association between low baseline HBsAg titre and HBsAg loss, as previously reported by others.10 The authors suggest that the add-on strategy in patients with HBeAg-negative chronic hepatitis B could potentially be meaningful among patients who have an HBsAg titre of less than 3 log10 IU/mL at baseline. In this select population (representing 42% of their patients), HBsAg loss was achieved in 23% of patients who received the full dose of pegylated interferon for 48 weeks. Assuming that such a proportion of functional cure could be maintained in a prospective study, select patients might benefit from add-on pegylated interferon treatment. The authors clearly state the limitations of their study. As these patients are nucleos(t)ide analogue suppressed, no information exists about HBV genotype. Furthermore, the study was underpowered because
London School Of Hygiene & Tropical Medicine/SPL
Peginterferon add-on: an added benefit?
Published Online January 19, 2017 http://dx.doi.org/10.1016/ S2468-1253(16)30220-5 See Articles page 177
147
Comment
of a high degree of missing data and a higher than expected proportion of HBsAg loss in the control group. The absence of masking could have influenced patient behaviour, such as compliance with therapy. This patient behaviour, however, is the reality of clinical practice. The acceptability of pegylated interferon among nucleos(t)ide analogue-suppressed patients was 52%, indicating that a high barrier exists among patients with chronic hepatitis B to starting treatment with pegylated interferon. Furthermore, only 72% allocated to the pegylated interferon group received the full dose for 48 weeks. Findings from this study clearly show the importance of reporting patient-related outcomes, such as barriers to initiation of treatment, the proportion and grade of adverse events, and drug discontinuation. This study is one of few randomised controlled trials on this topic that includes a large number of patients. Considering the observed high incidence of (serious) adverse events in the pegylated interferon group and the low occurrence of HBsAg loss in this study, Bourlière and colleagues9 conclude that add-on therapy with pegylated interferon is not a therapeutic strategy to treat chronic hepatitis B to establish functional cure. Various novel HBV-specific compounds interacting with the replication cycle of HBV are under development. These direct-acting antivirals for HBV, eventually combined with less toxic immune modulators than pegylated interferon, should lead the way to treat chronic hepatitis B for achievement of functional cure in the future. In the development of new agents targeting HBV, the importance of patient-reported outcomes should be taken into consideration and critically assessed.11
Femke Stelma, *Hendrik W Reesink Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands [email protected] HWR serves as a consultant for AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, ENYO Pharma, Gilead Sciences, Janssen-Cilag, Merck, Pharmaceutical Research Associates Health Sciences, Regulus, Roche, and R-Pharm and has received grants or research support from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, ENYO, Gilead Sciences, Janssen-Cilag, Merck, PRA Health Sciences, Regulus, Replicor, and Roche. FS declares no competing interests. 1
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Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012; 30: 2212–19. Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol 2009; 50: 1084–92. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335–52. Feld JJ, Wong DKH, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. Hepatology 2009; 49: S96–102. Viganò M, Invernizzi F, Grossi G, Lampertico P. Review article: the potential of interferon and nucleos(t)ide analogue combination therapy in chronic hepatitis B infection. Aliment Pharmacol Ther 2016; 44: 653–61. Marcellin P, Ahn SH, Ma X, et al. Combination of tenofovir disoproxil fumarate and peginterferon α-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 2016; 150: 134–44. Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143: 963–73. Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B? J Hepatol 2013; 58: 205–09. Boulière M, Rabiega P, Ganne-Carrie N, et al, for the ANRS HB06 PEGAN Study Group. Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial. Lancet Gastroenterol Hepatol 2017; published online Jan 19. http://dx.doi.org/10.1016/S24681253(16)30189-3. Takkenberg RB, Jansen L, de Niet A, et al. Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with peginterferon alfa-2a and adefovir. Antivir Ther 2013; 18: 895–904. Sugarman J, Revill P, Zoulim F, et al. Ethics and hepatitis B cure research. Gut 2016; published online Nov 14. DOI:10.1136/gutjnl-2016-313009.
Understanding and management of anxiety and mood disorders in inflammatory bowel disease Published Online January 17, 2017 http://dx.doi.org/10.1016/ S2468-1253(16)30218-7 See Articles page 189
148
Anxiety and mood disorders are among the most common health problems.1 These problems are even more common among people with chronic diseases than among those without.2 Authors of a systematic review3 found that studies comparing people with inflammatory bowel disease with healthy controls had pooled prevalence estimates of anxiety disorders of
19·1% versus 9·6% in controls and of depression of 21·2% versus 13·4%. Anxiety and depression were about twice as prevalent in those with inflammatory bowel disease compared with in those without, and in those with active disease compared with those with inactive disease. Having an anxiety or mood disorder is strongly associated with disability among those with chronic www.thelancet.com/gastrohep Vol 2 March 2017
1 2
3
4
Lavanchy D. The global burden of hepatitis C. Liver Int 2009; 29: 74–81. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998; 27: 209–12. Feld JJ, Jacobson IM, Hézode C, et al, for the ASTRAL-1 Investigators. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373: 2599–607. Foster GR, Afdhal N, Roberts SK, et al, for the ASTRAL-2 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373: 2608–17.
5
6
The Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol 2016; published online Dec 15. http://dx.doi.org/10.1016/S2468-1253(16)30181-9. Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000; 355: 887–91.
With 240 million individuals infected worldwide,1 chronic hepatitis B virus (HBV) infection is a global cause of liver-related morbidity and mortality. Treatment options include pegylated interferon and nucleos(t)ide analogues. Pegylated interferon can stimulate antiviral immune mechanisms, whereas nucleos(t)ide analogues directly inhibit viral replication. These treatments are sufficient for viral suppression, but generally fail to induce functional cure, which is defined as HBs antigen (HBsAg) loss with or without formation of anti-HBs antibodies. Achievement of functional cure is associated with an improved outcome.2–4 Combination of the two treatments could lead to increased efficacy of both drugs and has been the subject of many clinical trials.5 A large randomised controlled study by Marcellin and colleagues6 analysed the efficacy of pegylated interferon and nucleotide analogue combination therapy versus pegylated interferon or nucleotide analogue therapy given alone in previously untreated HBe antigen (HBeAg)-positive or HBeAg-negative patients with chronic hepatitis B. In this landmark study, 9·1% of patients with chronic hepatitis B had a functional cure 6 months after cessation of therapy in the combination treatment group, which was significantly higher than in the pegylated interferon monotherapy group (2·8%). In patients with chronic hepatitis B, virus-specific T-cell responses are significantly impaired. Since virus-specific T-cell responses are already partly restored after long-term viral load suppression by nucleos(t)ide analogues in patients with chronic hepatitis B,7 addition of an immune modulatory agent to nucleos(t)ide analogue therapy could hypothetically be beneficial for this group of patients, leading to increased functional cure.8 In The Lancet Gastroenterology & Hepatology, Marc Bourlière and colleagues9 present data for the www.thelancet.com/gastrohep Vol 2 March 2017
PEGAN study. In this randomised, controlled, open-label trial, 185 patients with HBeAg-negative chronic hepatitis B who were on nucleos(t)ide analogue therapy for at least 1 year with undetectable HBV DNA were randomly allocated to receive pegylated interferon alfa-2a add-on therapy for 48 weeks or no additional therapy. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. Secondary endpoints included the proportion and grade of adverse events, quality of life as reported by patients, and willingness to receive pegylated interferon therapy. In the pegylated interferon group, seven (7·8%) patients had lost HBsAg at week 96 as compared with three (3·2%) in the nucleos(t)ide analogue-only control group, which was not significantly different (difference 4·6% [95% CI –2·6 to 12·5]; p=0·15). Similar to the results from Marcellin and colleagues,6 the overall proportion of patients achieving a functional cure was low, and further analyses were done to identify factors associated with functional cure. These analyses revealed a significant association between low baseline HBsAg titre and HBsAg loss, as previously reported by others.10 The authors suggest that the add-on strategy in patients with HBeAg-negative chronic hepatitis B could potentially be meaningful among patients who have an HBsAg titre of less than 3 log10 IU/mL at baseline. In this select population (representing 42% of their patients), HBsAg loss was achieved in 23% of patients who received the full dose of pegylated interferon for 48 weeks. Assuming that such a proportion of functional cure could be maintained in a prospective study, select patients might benefit from add-on pegylated interferon treatment. The authors clearly state the limitations of their study. As these patients are nucleos(t)ide analogue suppressed, no information exists about HBV genotype. Furthermore, the study was underpowered because
London School Of Hygiene & Tropical Medicine/SPL
Peginterferon add-on: an added benefit?
Published Online January 19, 2017 http://dx.doi.org/10.1016/ S2468-1253(16)30220-5 See Articles page 177
147
Comment
of a high degree of missing data and a higher than expected proportion of HBsAg loss in the control group. The absence of masking could have influenced patient behaviour, such as compliance with therapy. This patient behaviour, however, is the reality of clinical practice. The acceptability of pegylated interferon among nucleos(t)ide analogue-suppressed patients was 52%, indicating that a high barrier exists among patients with chronic hepatitis B to starting treatment with pegylated interferon. Furthermore, only 72% allocated to the pegylated interferon group received the full dose for 48 weeks. Findings from this study clearly show the importance of reporting patient-related outcomes, such as barriers to initiation of treatment, the proportion and grade of adverse events, and drug discontinuation. This study is one of few randomised controlled trials on this topic that includes a large number of patients. Considering the observed high incidence of (serious) adverse events in the pegylated interferon group and the low occurrence of HBsAg loss in this study, Bourlière and colleagues9 conclude that add-on therapy with pegylated interferon is not a therapeutic strategy to treat chronic hepatitis B to establish functional cure. Various novel HBV-specific compounds interacting with the replication cycle of HBV are under development. These direct-acting antivirals for HBV, eventually combined with less toxic immune modulators than pegylated interferon, should lead the way to treat chronic hepatitis B for achievement of functional cure in the future. In the development of new agents targeting HBV, the importance of patient-reported outcomes should be taken into consideration and critically assessed.11
Femke Stelma, *Hendrik W Reesink Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands [email protected] HWR serves as a consultant for AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, ENYO Pharma, Gilead Sciences, Janssen-Cilag, Merck, Pharmaceutical Research Associates Health Sciences, Regulus, Roche, and R-Pharm and has received grants or research support from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, ENYO, Gilead Sciences, Janssen-Cilag, Merck, PRA Health Sciences, Regulus, Replicor, and Roche. FS declares no competing interests. 1
2
3
4 5
6
7
8
9
10
11
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012; 30: 2212–19. Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol 2009; 50: 1084–92. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335–52. Feld JJ, Wong DKH, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. Hepatology 2009; 49: S96–102. Viganò M, Invernizzi F, Grossi G, Lampertico P. Review article: the potential of interferon and nucleos(t)ide analogue combination therapy in chronic hepatitis B infection. Aliment Pharmacol Ther 2016; 44: 653–61. Marcellin P, Ahn SH, Ma X, et al. Combination of tenofovir disoproxil fumarate and peginterferon α-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 2016; 150: 134–44. Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143: 963–73. Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B? J Hepatol 2013; 58: 205–09. Boulière M, Rabiega P, Ganne-Carrie N, et al, for the ANRS HB06 PEGAN Study Group. Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial. Lancet Gastroenterol Hepatol 2017; published online Jan 19. http://dx.doi.org/10.1016/S24681253(16)30189-3. Takkenberg RB, Jansen L, de Niet A, et al. Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with peginterferon alfa-2a and adefovir. Antivir Ther 2013; 18: 895–904. Sugarman J, Revill P, Zoulim F, et al. Ethics and hepatitis B cure research. Gut 2016; published online Nov 14. DOI:10.1136/gutjnl-2016-313009.
Understanding and management of anxiety and mood disorders in inflammatory bowel disease Published Online January 17, 2017 http://dx.doi.org/10.1016/ S2468-1253(16)30218-7 See Articles page 189
148
Anxiety and mood disorders are among the most common health problems.1 These problems are even more common among people with chronic diseases than among those without.2 Authors of a systematic review3 found that studies comparing people with inflammatory bowel disease with healthy controls had pooled prevalence estimates of anxiety disorders of
19·1% versus 9·6% in controls and of depression of 21·2% versus 13·4%. Anxiety and depression were about twice as prevalent in those with inflammatory bowel disease compared with in those without, and in those with active disease compared with those with inactive disease. Having an anxiety or mood disorder is strongly associated with disability among those with chronic www.thelancet.com/gastrohep Vol 2 March 2017