This Month in Gastroenterology

This Month in

Gastroenterology By Jan Tack and John M. Carethers

Infliximab and Postoperative Recurrence of Crohn’s Disease

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large proportion of patients with Crohn’s disease require intestinal resection for stricturing or perforating disease. Most patients develop recurrence of Crohn’s disease over time, usually proximally to the surgical anastomosis. Rates of endoscopic recurrence may be as high as 90% 1 year after surgery. Clinical signs of recurrence develop in the majority of these patients over the first decade after intestinal resection, leading to a high rate of repeat operative interventions. Endoscopic recurrence is a good predictor of future clinical recurrence, development of complications, and need for reoperation. Several studies have evaluated the efficacy of drugs, including nitroimidazole antibiotics and thiopurine immunosuppressives, to prevent postoperative recurrence of Crohn’s disease, showing modest or inconsistent efficacy. It is unclear whether infliximab is able to prevent postoperative recurrence of Crohn’s disease. In this issue of GASTROENTEROLOGY, Requeiro et al report on a single-center randomized, placebo-controlled study investigating the efficacy of infliximab to prevent endoscopic, clinical, and histologic Crohn’s disease recurrence 1 year after intestinal resection. Twentyfour adult patients undergoing intestinal resection for ileal Crohn’s disease were enrolled into the trial and randomized to placebo or infliximab 5 mg/kg at 0, 2, and 6 weeks and then every 8 weeks up to 54 weeks. Concomitant immunomodulator therapy, including mesalazine, azathioprine, or 6-mercaptopurine, was kept at a stable dose throughout the study. Steroids and antibiotics were tapered over the first 12 weeks. The primary outcome variable was the proportion of endoscopic recurrence at 1 year after surgery. Secondary outcome variables included the Crohn’s Disease Activity Index and histologic activity score.

The baseline characteristics were largely comparable between both patient groups. After 1 year of treatment, only 1 of the 11 infliximab-treated patients (9%) had recurrence, compared with 11 of 13 (85%) in the placebotreated group (P ⬍ .01; Figure 1). Clinical recurrence was present in 0% of the patients in the infliximab group compared with 39% in the placebo group (P ⬍ .05). Histologic recurrence was documented in 27% of the infliximab group compared with 85% of the placebo group. The occurrence of adverse events was similar between both groups. This single-center study shows that infliximab treatment is able to prevent endoscopic, clinical, and histologic recurrence of Crohn’s disease 1 year after surgery. The positive outcome of this proof-of-concept study awaits confirmation in a larger, multicenter setting. See page 441. Telbivudine in Chronic Hepatitis B

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reatment options for chronic hepatitis B include interferons, nucleoside analogs, such as entecavir, lamivudine, and telbivudine, and nucleotide analogs, such as adefovir and tenofovir. Effective and prolonged viral suppression is a primary

treatment aim in patients with chronic hepatitis B. Lamivudine, which was the first nucleos(t)ide analog used in hepatitis B, has a high rate of resistance development during therapy. The GLOBE trial was a multicenter study designed to assess the outcomes of 2 years of treatment with telbivudine or lamivudine in chronic hepatitis B. An interim analysis after the first year of therapy demonstrated significantly greater antiviral activity and less resistance after telbivudine compared with lamivudine in both hepatitis B e antigen (HBeAg)-positive and HBeAgnegative patients. In this issue of GASTROENTEROLOGY, Liaw et al report on the 2-year results of the same trial. The study randomized a total of 1367 patients with chronic hepatitis B to telbivudine (600 mg) or lamivudine (100 mg) oral tablets once daily for 2 years. Patients were stratified according to their HBeAg status (positive [n ⫽ 921] or negative [n ⫽ 446]). The primary response endpoint was defined as a reduction of serum hepatitis B virus (HBV) DNA levels to ⬍5 log10 copies/mL, together with either normalization of alanine aminotransferase (ALT) levels or loss of serum HBeAg.

Figure 1. Percentage of patients in remission versus recurrence 1 year after intestinal resection for Crohn’s disease by random assignment to infliximab or placebo. GASTROENTEROLOGY 2009;136:369 –372

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Figure 2. Outcomes of therapy and occurrence of viral resistance during treatment with lamivudine and telbivudine in chronic hepatitis B patients who are HBeAG positive or HBeAG negative.

After 2 years, therapeutic response was significantly higher after telbivudine compared with lamivudine, both for HBeAG-positive (63% vs 48%; P ⬍ .001) and HBeAG-negative (78% vs 66%; P ⬍ .01) patients. The rate of development of resistance was significantly lower during telbivudine compared with lamivudine (25% vs 40% and 11% vs 30% for HBeAGpositive and HBeAG-negative patients, respectively; both P ⬍ .01). The differences between telbivudine and lamivudine were greater at 2 years than previously reported after 1 year. The durability of HBeAg seroconversion after discontinuation of telbivudine or lamivudine was ⬎80%. Multivariate analysis identified treatment with telbivudine as a significant, independent predictor of response after 2 years for both HBeAg-positive and HBeAg-negative patients (Figure 2). Baseline HBV DNA levels ⬍9 log10 copies/ml and ALT levels ⬎2 times the upper limit of normal were predictors of telbivudine response in HBeAg-positive patients. HBV DNA levels after 6 months of treatment were good predictors of 2-year treatment outcome. Tolerability of both drugs was good and comparable, although telbivudine was associated with a higher rate of subclinical creatine kinase elevations. The present controlled trial has shown superiority of telbivudine over 370

lamivudine in a 2-year treatment of chronic hepatitis B, both in HBeAGpositive and HBeAG-negative patients. The effects are durable after cessation of therapy, and there is a clear relationship between the magnitude of early (6 months) viral suppression and subsequent long-term outcome. See page 486. Treatment for Hepatitis C Virus Equally Effective in Mono Versus Hepatitis C and B Virus Dually Infected Individuals

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epatitis C virus (HCV) and hepatitis B virus (HBV) can cause chronic infection, and in endemic areas, many persons can be dually infected with both viruses and carry higher risk for advanced liver disease and hepatocellular carcinoma as compared with monoinfection. The current standard treatment for HCV involves pegylated interferon alfa-2a along with ribavirin, with the length of time of treatment dependent on the genotype infecting the patient. For HCV and HBV dually infected patients, there is no currently approved treatment, and occult HBV infection has been shown to reduce HCV sustained virologic response (SVR). There have been no trials using pegylated interferon therapy with ribavirin combination therapy on dually infected patients.

In the study by Liu et al, an openlabel, comparative, multicenter study of 321 consecutive Taiwanese patients (161 patients with dual infection defined as hepatitis B e antigen negative but hepatitis B surface antigen [HBsAg] positive along with HCV positive, and 160 patients with HCV infection only) was conducted to evaluate SVR at 24 weeks posttreatment in HCV monoinfected versus HCV⫹HBV dually infected patients. Patients infected with HCV genotype 1 received 48 weeks of combination therapy, and those with HCV genotype 2 or 3 received 24 weeks of combination therapy. All patients were naïve to interferon-based therapy when recruited. In patients with HCV genotype 1, the SVR for dually infected patients was 72.2%, similar to the SVR in monoinfected patients (77.3%). Likewise, in patients with HCV genotypes 2 or 3, the SVR in dually infected patients was 82.8% versus 84.0% with monoinfection (Figure 3). In dually infected patients, HBV DNA was detectable before treatment in 68 of 145 (46%); after treatment, 47 of 68 (69%) of these patients had undetectable HBV DNA levels. However, serum HBV DNA eventually appeared in 36.3% of 77 dually infected patients with undetectable pretreatment levels of HBV DNA, albeit without significant hepatitis. HBV reappearance was not different between patients with and without HCV SVR (36% vs 40%). Nineteen dually infected patients (11.8%) cleared HBsAg posttreatment with 7 of these patients showing seroconversion to anti-HBs production. Ten patients in the HCV monoinfected group were found to have occult HBV infection with detection of HBV DNA; these patients all achieved HCV SVR and their HBV DNA became undetectable posttreatment. This study indicates that HCV SVR rates for genotype 1 and genotypes 2 and 3 are similar between monoinfected and HCV⫹HBV dually infected patients treated with a combination of pegylated interferon

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Figure 3. Hepatitis C viral responses to the combination therapy of peginterferon alfa-2a and ribavirin. Intention-to-treat (ITT): analysis of patients receiving ⱖ1 dose of study treatment, including withdrawals; withdrawn cases without HCV RNA testing at 24 weeks posttreatment are counted as treatment failure. Per protocol (PP): analysis of patients completing ⱖ12 weeks of treatment. B⫹C, HBsAg-positive patients with chronic hepatitis C; C, HBsAg-negative patients with chronic hepatitis C; VR, virologic response (HCV RNA clearance at the end of treatment); SVR, sustained virologic response (HCV RNA clearance at 24 weeks posttreatment).

and ribavirin. The effect of HCV combination therapy on HBV is mixed, with an 11% HBsAg clearance rate, but with some patients reacquiring HBV DNA detection although without clinical hepatitis. The treatment of dually infected patients to achieve an HCV SVR seems to be safe. See page 496.

A Mediator for Glucocorticoid Effectiveness in a Mouse Model of Inflammatory Bowel Disease

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nflammatory bowel diseases (IBD) are most consistently treated with glucocorticoids for short-term improvement of inflammation and symptoms. In particular, glucocorticoids exert their anti-inflammatory effects by binding the glucocorticoid receptor on lymphocytes with inhibi-

Figure 4. ILZ-TG (transgenic) mice are less susceptible than WT mice to DNBS-induced colitis. Four and 7 days after DNBS administration, mice were killed and body weight (A) and macroscopic damage score (B) evaluated. Bars are the means ⫾ SE of 10 mice for each group. *P ⬍ .01 DNBS versus vehicle; oP ⬍ .01 DNBS-treated GILZ-TG versus DNBS-treated WT.

tion of nuclear factor (NF)-␬B nuclear translocation to block lymphocyte proliferation and subsequent proinflammatory cytokine release. Glucocorticoids can also induce glucocorticoid-induced leucine zipper (GILZ) protein that has also been suggested as a separate mediator to inhibit T-helper 1 cell (Th1)–induced colitis. The effects of GILZ on colitis had not been previously examined. In the study by Cannarile et al, transgenic mice that selectively overexpressed GILZ (GILZ-TG) in T cells were utilized to examine the effects of GILZ on dinitrobenzene sulfonic acid (DNBS)-induced colitis. Although wild-type (WT) mice treated with DNBS developed a severe colitis with loss of body weight and macroscopic colonic disease, GILZ-TG mice were resistant to these changes (Figure 4). DNBS-treated GILZ-TG mice, compared with WT mice, did not elevate their myeloperoxidase activity, prevented increases in adhesion molecule expression such as ICAM-1 and P-selectin, inhibited FasL up-regulation and subsequent apoptosis, had a reduced CD4⫹ T-cell infiltration in the colon, and had reduced Th1derived cytokines. Additionally, GILZ-TG mice treated with DNBS had significantly reduced NF-␬B levels compared with WT mice. Using a fusion protein containing soluble GILZ administered to DNBStreated WT mice or to established colitis in interleukin-10 knock-out mice significantly reduced the colitis and inflammatory activity, with the therapeutic effects paralleling the improved effects observed with dexamethasone treatment, which induced GILZ expression. Interestingly, mononuclear cells and CD4⫹ lamina propria cells from DNBStreated GILZ-TG mice reverted from the Th1 cytokine profile observed in DNBS-treated WT mice to a Th2 cytokine profile. Indeed, GILZ-TG mice treated with ox371

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azolone, which induces a Th2-dependent chronic inflammation of the colon, had worse inflammation than WT mice. The study indicates that GILZ,

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overexpressed in T cells or administered as a soluble protein, can significantly prevent and reduce Th1-derived colitis. Pharmacologic modulation of GILZ expression

may present a new strategy to treat IBD and may avoid the long-term effects of glucocorticoids. See page 530.