IBD Update Feb 2019

Briefly noted:

B Feagan et al. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Alim Pharm Ther 2019 Jan;49(1):31-40. “While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios.”

MP Pauly et al. Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment with Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2018; 16: 1964-73. Using data from 8887 adults, this retrospective review found  “HBV reactivation iin 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy.”

D Lauritzen et al. Pediatric Inflammatory Bowel Diseases: Should We Be Looking for Kidney Abnormalities? Inflamm Bowel Dis 2018; 24: 2599-2605. In a cross-sectional cohort of 56 children with IBD, the authors found 25% “had either previously reported kidney disease or ultrasonographic signs of chronic kidney disease.” The authors note that plasma cystatin C is a useful biomarker for glomerular filtration as it less dependent on nutritional status; it is increased in the setteing of a decline in GFR.

L Pouillon et al. Mucosal Healing and Long-term Outcomes of Patients with Inflammatory Bowel Diseases Receiving Clinic-Based vs Trouhg Concentration-Based Dosing of Infliximab. Clin Gastroenterol Hepatol 2018; 16: 1276-83.  This retrospective study with patients who completed TAXIT maintenance phase found that patients who received trough-based infliximab dosing had a lower discontinuation rate of infliximab compared with clinic-based dosing (2 of 21 [10%]  vs. 10 of 27 [37%]).  However, both groups had >75% of patients able to continue infliximab for more than 3 years after the trial.

N Ouldali et al. Early Arthritis Is Associated With Failure of Immunosuppressive Drugs and Severe Pediatric Crohn’s Disease Evolution. Inflamm Bowel Dis 2018; 24: 2423-30. In this retrospective study with 272 patients with Crohn’s disease, 23.9% (n=65) developed arthritis and this was associated with failure of immunosuppressive drugs with OR of 6.9 after 2 years. In this study, immunosuppressive drugs refers to thiopurines and methotrexate.  By the completion of study, a much greater proportion of those with arthritis required biologic treatment (76% vs 32%, OR 4.3)

Hepatitis C Reactivation with Chemotherapy

There are a lot of reports describing the potential of adverse outcomes due to hepatitis B reactivation with chemotherapy as well as with treatment of hepatitis C; in addition, there are recommendations to prevent this occurrence (see below). With hepatitis C virus (HCV), the issue of reactivation has not garnered the same type of concern.  A recent study (HA Torres et al. Hepatology 2018; 67: 36-47) indicates that HCV can reactivate with chemotherapy, though this may not result in adverse outcomes. The authors prospectively followed HCV-infected patients receiving cancer therapy from 2012-16.  Reactivation was defined as HCV RNA increase >1 log over baseline and hepatic flare as an increase in ALT >3 times ULN.

Key finding:

  • “Reactivation occurred in 23 (23%)…No patient with reactivation experienced liver failure or liver-related death within 36 weeks after initiation of cancer treatment…most had an unremarkable clinical course.”

Related articleM Persico et al. Hepatology 2018; 67: 48-55.  In the Persico study, the authors examined the association of HCV with non-Hodgkin’s lymphoma. In this observational study, all patients underwent antiviral therapy with sofosbuvir/ledipasvir and chemotherapy.  Compared to a historical control group, the antiviral treatment group had similar overall survival but a significantly higher disease-free survival after 52 weeks.  Thus, the authors note that antiviral treatment combined with chemotherapy, “was shown to be safe and effective in influencing remission of aggressive lymphomas in HCV patients.”

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Hepatitis B Reactivation with Direct-Acting Antiviral Hepatitis C Therapy

“I refuse to accept the view that mankind is so tragically bound to the starless midnight of racism and war that the bright daybreak of peace and brotherhood can never become a reality.” Martin Luther King, Jr

——————
More information on hepatitis B virus (HBV) reactivation with direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy has been published:

  • PS Belperio et al. Hepatology 2017; 66: 27-36
  • G Chen et al Hepatology 2017; 66: 13-26
  • Editorial: RP Perrillo. G Chen et al Hepatology 2017; 66: 4-6.

In a previous post on this topic (:), it was noted that physicians need to be aware of HBV reactivation with DAAs. It appears that HCV can suppress HBV replication and that successful HCV therapy allows for HBV reactivation.

Belperio et al reviewed data from an observational study on more than 62,000 HCV-infected veterans, including 377 who had HBsAg-positivity and 7295 who had anti-HBc-positivity.

Key findings:

  • 8 of 377 HBsAg-positive had reactivation (defined as HBV DNA increase of >1000 IU/mL) of HBV during DAA treatment of HCV. Only one of these eight had a severe hepatitis (ALT 154o IU)
  • 1 of 7295 HBc-positive had HBV reactivation. This rate of reactivation is actually lower than HBV reactivation reported with ‘inactive’ disease (1-2% per year).
  • For HBV screening, the authors recommend HBsAg and anti-HBc testing

Chen et al performed a systematic review (of 28 studies included) and meta-analysis had identified overt  HBV reactivation in 12.2% of those receiving DAAs.  This was a lower rate of HBV reactivation than with interferon (14.5%); however, reactivation during DAA therapy occurred earlier (typically 4-12 weeks into treatment) and was more clinically significant. There was significant variation in the virologic and ALT criteria used to define HBV reactivation.  The authors conclude that it is “important to have HBV serology (HBsAg, anti-HBc) in all HCV patients prior to therapy.

Perillo recommends that in addition to screening, “it is my belief that anti-HBV prophylaxis be given to all HBsAg-positive patients, ” regardless of HBV DNA level.

My take: These articles help quantitate the risk of HBV reactivation during HCV therapy.

Ben Sawyer Bridge, Sullivans Island

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Hepatitis B Reactivation Due to Immunosuppressive Therapies

The topic of Hepatitis B virus (HBV) reactivation has been discussed on this blog before (see link below).  Another excellent review on this topic (R Lomba, TJ Liang. Gastroenterol 2017; 152: 1297-1309) has been published.  The authors examine the course and mechanisms of HBV reactivation.  They divide the risk of reactivation into three groups: high, moderate and low risk and proposed management.

High risk groups, which have >10% risk of reactivation) include the following

  • B-cell-depleting agents including rituximab, ofatumumab, alemtuumab, and ibritumumab
  • High-dose corticosteroids (>20 mg/day in adults)
  • Antracyclines including doxorubicin
  • Potent TNF-α inhibitors: infliximab, adalimummab, certolizumab, and golimumab
  • Local therapy ofr HCC including TACE (transarterial chemoembolization)

Moderate groups (1-10% reactivation) include cytokine-based Rx (eg. abatacept, ustekinumab, natalizumab, vedolizumab), cyclosporine, systemic chemotherapy, moderate corticosteroid dosing

Low risk groups (<1% reactivation) include thiopurines (azathioprine, 6-mercaptopurine), and methotrexate as well as short-term low-dose corticosteroids.

Management:

  • For HBV screening, the authors recommend HBsAg and anti-HBc testing
  • Prophylactic therapy with potent oral anti-HBV therapies are recommended for those at moderate or high risk of reactivation.  In those at low risk, the options include prophylactic treatment or watchful monitoring.
  • A more detailed algorithm is provided in Figure 3.  In those with HBsAg positivity, if HBV DNA is less than 2000 U/mL, this algorithm suggests monitoring labs (HBsAg, ALT, HBV DNA every 3 months)

Mechanisms of HBV reactivation are discussed.  For example, with TNF-α inhibitors “can activate a unique host antiviral pathway, the APOBEC (apolipoprotein B mRNA editing enzyme, catlytic polypeptide-like) proteins, that cause the degradation of cccDNA in HBV-infected cells. Thus, blocking this endogenous antiviral pathway may lead to a higher HBV replication state and HBV reactivation.”

My take: In pediatric gastroenterology, we do not see a lot of HBV reactivation. Nevertheless, we do use many of the medications which can trigger HBV reactivation and need to keep these recommendations in mind.

Related blog post: What HBV Testing is Needed Before TNF Inhibitor Therapy

Suntrust Park

Word of Caution with New Hepatitis C Medications

From NY Times: Are New Drugs for Hepatitis C Safe? A Report Raises Concerns

An excerpt:

Drugs approved in recent years that can cure hepatitis C may have severe side effects, including liver failure, a new report suggests. The number of adverse events appears relatively small, and the findings are not conclusive. But experts said the report was a warning that should not be ignored…

The report will be published online on Wednesday [1/25/17] by the Institute for Safe Medication Practices, a nonprofit in Horsham, Pa., that studies drug safety. Its findings are based on the group’s analysis of the Food and Drug Administration’s database of reports from doctors around the world of adverse events that might be related to medications.

In October, the F.D.A. identified the first major safety problem caused by the nine antiviral drugs. In 24 patients, the drugs wiped out hepatitis C — but also reactivated hepatitis B infections that had been dormant. Two of those patients died, and one needed a liver transplant. The agency said there were probably additional cases that had not been reported.

As a result, the agency required that a boxed warning, its most prominent advisory, be added to the labeling of the newer antivirals, telling doctors to screen and monitor for hepatitis B in all patients taking the drugs for hepatitis C. Infection with both viruses is not common, and how the reactivation occurs is not known. The problem was not detected during premarket testing of the drugs because patients who currently had hepatitis B or who had a history of it were not allowed into the studies…

The other cases of liver failure are a separate problem. He said it was important for doctors prescribing the newer drugs to test patients’ liver function thoroughly first, because liver disease can be deceptive

My take: Overall, these newer Hepatitis C medications represent a tremendous achievement.  However, as with most medications, rare serious problems can occur and in some cases may be preventable.

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What HBV Testing is Needed Before Tumor Necrosis Factor Inhibitor Therapy

As noted in a previous blog post (What’s Going on with Hepatitis A and Hepatitis B?):

Hepatitis B Reactivation risk & recommendation: (For all of the specifics — Full text article link)

  • High risk of reactivation (>10%): B cell depleting agents (eg. rituximab, ofatumumab), anthracycline derivatives (eg. doxorubicin, epirubicin), and daily moderate to high dose steroids (>10 mg) for at least 4 weeks. Recommendation: Use HBV prophylaxis
  • Moderate risk of reactivation (1-10%): anti-TNF therapy, integrin inhibitors (eg. ustekinimab, vedolizumab), tyrosine kinase inhibitors, low-dose steroids daily (<10 mg/day) for at least 4 weeks.  Recommendation: Use HBV prophylaxis if HBsAg-positive but not if only anti-HBc-positive
  • Low risk of reactivation (<1%): azathiopurine, 6-mercaptopurine, methotrexate. Recommendation: No antiviral prophylaxis required.

For those interested in a more detailed summary of the recommendations: AGA Website HBV Reactivation Recommendations

In line with the reactivation risk, a new study (and editorial) (M Barone et al. Hepatology 2015; 62: 40-6; editorial BP Perillo. Hepatology 2105; 62: 16-8) indicates that for those receiving tumor necrosis inhibitor (anti-TNF) monotherapy, hepatitis B screening requires only checking HBsAg. The study examined a total of 1218 Caucasian rheumatologic patients (receiving biologic agents) between 2001-12. In this cohort, the authors identified 179 patients who had a previously resolved HBV infection; 146 treated with anti-TNF, 14 with rituximab, and 19 with other biologic therapy. Key finding: HBV reactivation was not seen in these patients.

Bottomline: For most pediatric patients receiving anti-TNF monotherapy (eg. infliximab, adalimumab), screening with HBsAg alone should suffice.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Grand Tetons from Jackson Lodge

Grand Tetons from Jackson Lodge

What’s Going on with Hepatitis A and Hepatitis B?

Despite the excitement regarding Hepatitis C, Hepatitis A and Hepatitis B remain important challenges. Here’s the latest:

1. Collier MG, et al. “Hepatitis A Hospitalizations in United States, 2002-2011” Hepatology 2015; 61: 481-85. The authors examined the changes in demographics and frequency of HAV hospitalization during the study period. Key findings:

  • Rates of hospitalization dropped from 0.72/100,000 to 0.29/100,000.
  • Average age of hospitalized patient increased from 37.6 years to 45.5 years and more comorbidities were noted.
  • No changes were noted in length-of-stay or in-hospital deaths

2. DiBisceglie AM et al. “Recent US Food and Drug Administration Warnings on Hepatitis B Reactivation with Immune-Suppressing and Anticancer Drugs: Just the Tip of the Iceberg?” Hepatology 2015; 61: 703-11. Key recommendation: “There is good evidence to support routine screening of all patients for hepatitis B prior to undergoing chemotherapy or immunosuppressive treatment; use of prompt antiviral treatment appears to diminish the risk of severe or fatal reactivation of hepatitis B. Different organizations suggest disparate screening recommendations (Table 4).  AASLD suggests HBsAg, and anti-HBc.  CDC suggests adding anti-HBs.

3. Reddy KR, et al. Gastroenterology 2015; 148: 215-19, technical review 221-44.  AGA Guideline on the Prevention and Treatment of HBV Reactivation During Immunosuppressive Therapy. Key Recommendations:

  • Screen patients with HBsAg and anti-HBc, followed by a sensitive HBV DNA test if positive
  • Treat at-risk patients with antivirals with high barrier to resistance for at least 6 months after discontinuation of immunosuppressive therapy (except in patients taking B cell depleting agents who it is recommended to treat for at least 12 months afterwards)

Reactivation risk: (For all of the specifics — Full text article link)

  • High risk of reactivation (>10%): B cell depleting agents (eg. rituximab, ofatumumab), anthracycline derivatives (eg. doxorubicin, epirubicin), and daily moderate to high dose steroids (>10 mg) for at least 4 weeks.
  • Moderate risk of reactivation (1-10%): anti-TNF therapy, integrin inhibitors (eg. ustekinimab, vedolizumab), tyrosine kinase inhibitors, low-dose steroids daily (<10 mg/day) for at least 4 weeks (if HBsAg-positive but not if only anti-HBc-positive)
  • Low risk of reactivation (<1%): azathiopurine, 6-mercaptopurine, methotrexate.  No antiviral prophylaxis required.

For those interested in a more detailed summary of the recommendations: AGA Website HBV Reactivation Recommendations

4. Corsa AC et al. “No Resistance to Tenofovir Disoproxil Fumarate Through 96 Weeks of Treatment in Patients with Lamivudine-Resistant Chronic Hepatitis B. Clin Gastroenterol Hepatol 2014; 12: 2106-12.  This study followed 280 patients–no resistance to tenofovir was observed.

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