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HBV Reactivation/DAAs EMA/Japan Review
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Download the PDF here
Download the PDF here
Download the PDF here
EMA reviews direct-acting antivirals for hepatitis C
Review to investigate possible hepatitis B re-activation
The European Medicines Agency (EMA) has started a review of medicines known as direct-acting antivirals used for treating chronic (long-term) hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus).
Direct-acting antivirals (Daklinza, Exviera, Harvoni, Olysio, Sovaldi and Viekirax) are important medicines for the treatment of chronic hepatitis C and can be used without interferons, which are less well tolerated. Until recently, interferons were part of treatment regimens for hepatitis C. Interferons are known to act against both hepatitis B and C viruses, which may be present at the same time in some patients.
The review follows cases of hepatitis B re-activation in patients who have been infected with hepatitis B and C viruses, and who were treated with direct-acting antivirals for hepatitis C. Hepatitis B re-activation refers to a return of active infection in a patient whose hepatitis B infection had been inactive.
EMA will now assess the extent of hepatitis B re-activation in patients treated with direct-acting antivirals for hepatitis C and evaluate whether any measures are needed to optimise the treatment.
While the review is ongoing, patients should speak to their doctor or pharmacist if they have any questions or concerns.
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Japan's Pharmaceuticals and Medical Devices Agency (PMDA) is reviewing approved hepatitis C drugs in the country for links to a possible reactivation of the hepatitis B virus, which could result in label changes......http://www.fiercepharma.com/pharma-asia/japan-s-pmda-reviews-hep-b-risk-link-to-hep-c-therapies
In a notice last week, PMDA said that the review covers Gilead Sciences' ($GILD) Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) as well as AbbVie's($ABBV) Viekirax (ombitasvir and paritaprevir and ritonavir), Bristol-Myers Squibb's ($BMY) Daklinza (daclatasvir) andSunvepra (asunaprevir), Mitsubishi Tanabe's Telavic (telaprevir), Janssen Pharmaceutical K.K.'s Sovriad (simeprevir), and Merck's ($MRK) Vanihep (vaniprevir).
Related to the review, PMDA also posted a notice from BMS warning that a suspected reactivation of hepatitis B virus following the use of Daklinza and Sunvepra caused hepatic dysfunction, including one death.
On the PMDA notice, BMS called on doctors to send patients for hepatitis B virus marker tests prior to treatment.
In a statement to FiercePharmaAsia, Janssen said: "[We] are aware of the recently initiated review of Direct Acting Antivirals (DAAs) as a treatment for hepatitis C being conducted by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.Simeprevir is one of the treatments currently undergoing the review procedure by the EMA and PMDA. We believe that the safety of our medicines is paramount and we remain fully cooperative with both of these reviews."
A similar review is being conducted by the EMA, which began back in March. The Agency has recently extended its review to also look at the risk of liver cancer (hepatocellular carcinoma) coming back in patients who were treated with direct-acting antivirals for hepatitis C, after a study published in April suggested this may be the case.
- here's the PMDA
release
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Hepatol Res. 2015 Aug 22. doi: 10.1111/hepr.12578. [Epub ahead of print]
Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co-infection.
Takayama H1, Sato T1, Ikeda F2, Fujiki S1.
Abstract
Direct-acting antiviral agents (DAA) for hepatitis C virus (HCV) are not effective for hepatitis B virus (HBV), which may be suggestive of reactivation of anti-HBe hepatitis during interferon (IFN)-free DAA therapy in HBV/HCV co-infected patients with inactive HBV. A 69-year-old male patient was diagnosed with chronic hepatitis due to HBV/HCV co-infection with serum levels of alanine aminotransferase (ALT) of 94U/L, HCV RNA of 4.2logIU/mL and HBV DNA of 2.5logcopies/mL. HCV was thought to be responsible for the hepatitis activity because of low level of HBV core-related antigen (3.1logU/mL). He was treated with combination therapy of daclatasvir and asunaprevir. Serum ALT gradually increased, and reached 237U/L on day 43 in spite of undetectable HCV RNA. Serum HBV DNA was increasing to 7.0logcopies/mL at that time. The treatment was stopped due to suspicion of drug-induced liver injury and/or HBV reactivation. Administration of entecavir reduced HBV DNA levels, followed by improvement in ALT levels. This report proposes that close monitoring of HBV DNA during the anti-HCV DAA therapy and the commencement of anti-HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in patients with HBV/HCV co-infection.
® 2015 The Japan Society of Hepatology.
Introduction
THE DEVELOPMENT OF interferon (IFN)-free regimens with direct-acting antiviral agents (DAA) has led to new insights into hepatitis C virus (HCV), and recent studies of IFN-free DAA therapy resulted in greater than 80% sustained virological response in patients with genotype 1 of HCV.[1-4] The patients with co-infection of hepatitis B virus (HBV) and HCV are at a high risk of developing liver cirrhosis and hepatocellular carcinoma. They need either or both of the anti-HBV and anti-HCV treatments depending on their viral status by utilizing therapeutic regimens for HBV or HCV mono-infection.[1, 2] Because IFN can suppress both HBV and HCV replication, HBV reactivation rarely occurs during IFN-based anti-HCV therapies. By contrast, HCV-specific DAA are not effective for HBV, which may be suggestive of HBV reactivation during IFN-free DAA therapy. We experienced HBV reactivation during combination therapy with daclatasvir and asunaprevir in a patient with HBV/HCV co-infection.
Case Report
A 69-YEAR-OLD MALE patient visited our hospital for abnormal liver function test. The serum alanine aminotransferase (ALT) level was 94U/L. His HCV was genotyped as 1b with HCV RNA 4.2logIU/mL. He was also infected with HBV. He had genotype C HBV with negative hepatitis B e-antigen, HBV DNA of 2.5logcopies/mL and hepatitis B core-related antigen (HBcrAg) of 3.1logU/mL. His imaging studies with dynamic computed tomography denied liver cirrhosis and hepatocellular carcinoma. Then, he was diagnosed with chronic hepatitis due to HBV/HCV co-infection. His low levels of HBcrAg and HBV load suggested that he was classified as an inactive HBV carrier, and HBV treatment was not thought to be necessary for his inactive HBV status according to the treatment guideline of HBV.[4, 5] HCV was thought to be responsible for the hepatitis activity, and he was treated with combination therapy of daclatasvir (60mg daily) and asunaprevir (100mg twice daily), after confirming the dominance of Y93 and L31 in the HCV NS5A region on his HCV sequence results, as shown in Figure1 and Table1.
When visited on day 15, serum ALT became normal and HCV RNA had decreased to an undetectable level. Serum ALT gradually increased thereafter, and reached 237U/L on day 43. Serum aspartate transaminase was 164U/L, γ-glutamyltransferase 60U/L and bilirubin 1.5mg/dL. Serum HBV DNA was increased to 7.0logcopies/mL at that time. He did not complain about any subjective symptoms. Biliary obstruction was not obvious in his ultrasonography. The treatment was stopped due to suspicion of drug-induced liver injury and/or acute exacerbation due to HBV reactivation of anti-HBe positive hepatitis.
A liver biopsy showed chronic hepatitis with lymphocyte infiltrations and fibrous expansions of some portal areas without zone 3 necrosis (Fig. 2), indicating that the histological appearance was compatible with hepatitis flare induced by HBV reactivation, differently from drug-induced liver injury or autoimmune hepatitis. Entecavir (0.5mg daily) was started on day 50. Reduction of HBV DNA was followed by improvement in ALT levels. Serum HCV RNA remained undetectable at 12weeks after cessation of the anti-HCV treatment.
Discussion
AN ANTI-HBE POSITIVE inactive carrier is characterized by very low or undetectable serum HBV DNA levels below 2000IU/mL and normal serum aminotransferases, and patients should be considered for treatment when they have HBV DNA levels above 2000IU/mL, serum ALT levels above the upper limit of normal or moderate liver fibrosis.[5, 6] As for abnormal ALT levels in HBV/HCV co-infected patients, responsibility of hepatitis is difficult to distinguish between HBV and HCV. The patients with very low or undetectable serum HBV DNA levels below 2000IU/mL are usually diagnosed as inactive HBV carriers. It has been reported that HBcrAg, reflecting the transcriptional activity of intrahepatic cccDNA, may help to distinguish between inactive HBV carriers and those with active disease.[7] Then, the patient in the present study showed low levels of HBcrAg and HBV load, suggesting that he should be classified as an inactive HBV carrier.
Because IFN can suppress both HBV and HCV replication, HBV reactivation rarely occurs during IFN-based anti-HCV therapies.[1] However, Liu etal.reported that a considerable number of patients revealed an increase of HBV replication in the patients with sustained virological responses to the IFN-based therapy for HCV.[8] HCV-specific DAA are not effective for suppression of HBV replication, and IFN-free DAA therapy may release HBV from HCV suppressive effects, which may be suggestive of HBV reactivation during IFN-free DAA therapy. On the other hand, reactivation of HCV may be possible during and after the anti-HCV therapy in relation to suppression of HBV replication by nucleoside analogs.
The patient in this report had HBV DNA of 320IU/mL prior to anti-HCV therapy with hepatitis flare by week 6 of treatment. Collins etal. reported HBV reactivation during anti-HCV therapy with simeprevir and sofosbuvir in two patients with HBV/HCV co-infection.[9] One patient had HBV DNA of 2300IU/mL prior to anti-HCV therapy with development of severe viremia and acute hepatitis by week 8 of treatment. The other started anti-HCV therapy with HBV DNA of less than 20IU/mL, and logarithmic increases in HBV replication were detected at week 2 of treatment with initiation of anti-HBV therapy at week 4 of treatment. HBV reactivation in these patients indicated that close monitoring of HBV DNA during the anti-HCV DAA therapy and the commencement of anti-HBV therapy with nucleoside analogs after the increase of HBV DNA should be considered in HBV/HCV co-infected patients.
Further studies are needed to determine whether simultaneous administration of anti-HBV and anti-HCV drugs, as well as preemptive anti-HBV therapy before anti-HCV therapy, would be possible.
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Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: Just the tip of the iceberg?
Hepatology Jan 13 2015
Adrian M. Di Bisceglie,1Anna S. Lok,2Paul Martin,3Norah Terrault,4Robert P. Perrillo,5andJay H. Hoofnagle6
Abstract
Reactivation of hepatitis B in the context of immunosuppressive therapy may be severe and potentially fatal. The US Food and Drug Administration has recently drawn attention to the potentially fatal risk of hepatitis B reactivation in patients receiving the anti-CD20 agents ofatumumab or rituximab. This action focuses attention on the broader issue of hepatitis B virus reactivation, which may occur with a wide variety of immunosuppressive therapies in benign or malignant disease. This article summarizes the data behind this issue. These data support the recommendation that all patients undergoing chemotherapy, immunosuppressive therapy, hematopoietic stem cell transplantation, or solid organ transplantation be screened for active or prior hepatitis B viral infection by testing for hepatitis B surface antigen and the antibody to hepatitis B core antigen in serum. Those who are found to be hepatitis B surface antigen–positive should start appropriate antiviral therapy to prevent reactivation. Additionally, even those who have recovered from hepatitis B will benefit from antiviral therapy in certain circumstances because of the risks associated with a form of hepatitis B virus reactivation referred to as "reverse seroconversion." There remain many uncertain areas that warrant further study, and further advances will benefit from close interactions between various medical specialties, regulatory agencies, and researchers. Conclusions: 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. (Hepatology 2015;61:703-711)
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