Timing Is Everything: Managing Hepatitis C Virus in Liver Transplant Candidates

Of Interest
The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017)

ILC 2017: Successful treatment for Hepatitis C in decompensated cirrhosis allows for sustained removal from the liver transplant waiting list in over 90% of patients

Timing Is Everything: Managing Hepatitis C Virus in Liver Transplant Candidates

Aronsohn, Andrew MD1
doi: 10.1097/TP.0000000000001703
Transplantation: May 2017 - Volume 101 - Issue 5 - p 898–899

Commentaries

Direct-acting antiviral regimens have revolutionized the treatment of Hepatitis C Virus (HCV) yet controversy exists regarding the optimal timing for treating HCV infected liver transplant candidates. This commentary addresses the complexities of treating these patients at the appropriate time given the unpredictable nature of liver transplant timing.

Article Outline
Direct-acting antiviral (DAA) regimens have revolutionized our approach to hepatitis C virus (HCV) management. Guidance from American Association for the Study of Liver Diseases/Infectious Diseases Society of America, European Association for the Study of the Liver, and Asian Pacific Association for the Study of the Liver1-3 now outline simple and highly effective pathways to cure for nearly all patients with HCV. Safety and efficacy of DAA regimens, even among those with decompensated cirrhosis, creates new opportunities for cure in patients who would have been previously ineligible for treatment.4 Although HCV remains a leading indication for liver transplant worldwide, there has been a paucity of data and subsequent guidance for management of liver transplant candidates with HCV. Paradoxically, we have found that simple, effective treatment regimens have spawned perhaps unanticipated complexities of HCV management in liver transplant candidates. These complexities arise because goals of therapy span beyond solely targeting viral eradication but require a comprehensive understanding of the dynamic and sometimes unpredictable nature of liver transplantation (LT) candidacy. Anticipated wait time, risk of hepatocellular carcinoma (HCC) recurrence or progression, physiologic response to cure as well as availability of HCV-positive donors all impact decisions to treat. In this issue of Transplantation, Terrault et al5 define these issues and offer much needed guidance by addressing clinical questions of interest in the International Liver Transplant Society Consensus Statement in Management of Liver Transplantation Candidates.

Data remains sparse and, at times, conflicting regarding the management of HCV in patients with HCC who are awaiting LT. In the single published study evaluating DAA-based treatment outcomes in waitlisted patients with HCV and HCC, duration of time with a negative viral load was found to be a significant predictor of HCV recurrence posttransplant.6 This concept has not yet been validated in newer DAA regimens and minimum duration of an undetectable viral load required before transplant to ensure posttreatment eradication has yet to be defined. Timing matters in HCV treatment pre-LT; however, we are still unsure of how much time we need and how much time we have. In addition, recent controversy regarding a potentially negative impact DAA treatment may play in aggressive cancer recurrence has added another wrinkle in complexity of the decision to treat waitlisted patients with HCC.7,8 Terrault et al5 describe the quality of data that associates a link between HCC recurrence and DAA therapy as low and insufficient to withhold therapy; however, pending further data, they recommend the association should at least be considered. Although the consensus statement recommends HCV treatment in waitlisted patients with HCC, severe limitations of data require this recommendation to be conditional and should be individualized based on patient characteristics and transplant center.

HCV treatment in the setting of waitlisted patients with decompensated cirrhosis is also thoughtfully addressed. Successful HCV treatment may improve survival on the waiting list and may allow for avoidance of OLT altogether.9 These benefits must be balanced with potential unintended negative consequences of treatment. This includes reduced SVR rates in CTP B and C cirrhosis with risk of resistant variant generation as well as negligible clinical benefit achieved after SVR in patients who lack hepatic regenerative capacity. Finally, it may be disadvantageous to treat and create a small improvement in Model for End Stage Liver Disease (MELD)/Child-Turcotte-Pugh (CTP) resulting in a demotion of priority on the waitlist, yet insufficient clinical improvement to avoid LT.4 What remains elusive is a true understanding of the “point of no return,” that is, the degree of liver dysfunction where HCV therapy does not yield any clinical benefit. The consensus statement frames this question based on available metrics, such as MELD, CTP, and transplant center characteristics; however, due to limitations in available data, the strength of these recommendations remain weak. Why is a point of no return so difficult to define? First, HCV treatment in patients with decompensated cirrhosis is only a recently available option, and experience remains limited. Second, the point of no return is simple in theory, but complex in practice. MELD and CTP scores were not designed to answer this question, and we may be using imprecise tools to predict a clinical outcome that relies on regenerative capacity of the liver after viral eradication. Finally, the point of no return is intrinsically related to regional transplant landscape and policy. Waitlist time, DAA availability and allocation schemes will all impact how much benefit HCV treatment will yield. The consensus statement has provided a useful foundation for consideration of this topic, but further study will be necessary to identify more precise, site-specific tools to guide us in this difficult decision to treat.

Finally, the consensus statement supports selective use of anti–HCV-positive grafts in HCV-positive recipients as well as early treatment for all LT patients with HCV.5,10 The efficacy and safety of DAA therapy post-LT has also allowed Terrault and colleagues to boldly offer consideration to use HCV-positive grafts in HCV negative recipients. The Consensus Statement stresses the need for comprehensive informed consent and defines appropriate settings for use such as high medical urgency and severe limitations in organ availability. Although data are limited and firm guidelines for use cannot yet be made, innovative thought leveraging DAA therapy such as this may significantly increase access and optimize use of available organs. However, the concept of knowingly transmitting an infectious disease into an unexposed patient is subject to some degree of moral relativism and thus may not be universally applied even though there is some precedent with infections, such as cytomegalovirus. Nonetheless, routine use of HCV-positive grafts in any recipient underscores the importance of universal access to HCV therapy post-LT.

The new era of DAA therapy has expanded candidacy for HCV treatment to include our sickest patients who are in need of LT. The consensus statement in this issue of Transplantation marks unprecedented progress in HCV therapy and also defines where our understanding is limited. Our tools to determine the optimal timing for therapy seem rudimentary in comparison to the technologically advanced DAAs, and further study to equilibrate the two is crucial. We know how to treat our patients with HCV who are awaiting transplantation, now we just need to know when to treat them.

REFERENCES
1. AASLD-IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/. Accessed February 13, 2017.
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2. European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol. 2015;63:199–236.
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3. Omata M, Kanda T, Wei L, et al. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int. 2016;10:702–726.
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PubMed
4. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373:2618–2628.
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5. Terrault NA, McCaughan GW, Curry MP, et al. International Liver Transplantation Society Consensus Statement on hepatitis C management in liver transplant candidates. Transplantation. 2017;101:945–955.
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6. Curry MP, Forns X, Chung RT, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology. 2015;148:100–107.e1.
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7. Pol S. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts. J Hepatol. 2016;65:734–740.
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8. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65:719–726.
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9. Belli LS, Berenguer M, Cortesi PA, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study. J Hepatol. 2016;65:524–531.
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10. Northup PG, Argo CK, Nguyen DT, et al. Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis. Transpl Int. 2010;23:1038–1044.
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Illegal Cancer Treatments: FDA Warning - Fraudulent Claims of Diagnosis, Treatment, Prevention or Cure

Illegal Cancer Treatments: FDA Warning - Fraudulent Claims of Diagnosis, Treatment, Prevention or Cure

AUDIENCE: Oncology, Patient, Consumer

ISSUE: FDA issued warning letters addressed to 14 U.S.-based companies illegally selling more than 65 products that fraudulently claim to prevent, diagnose, treat or cure cancer.

It is a violation of the Federal Food, Drug and Cosmetic Act to market and sell products that claim to prevent, diagnose, treat, mitigate or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses. The illegally sold products cited in the warning letters include a variety of product types, such as pills, topical creams, ointments, oils, drops, syrups, teas and diagnostics (such as thermography devices). They include products marketed for use by humans or pets that make illegal, unproven claims regarding preventing, reversing or curing cancer, killing/inhibiting cancer cells or tumors, or other similar anti-cancer claims. See the list of illegally sold cancer treatments.

BACKGROUND: The products are marketed and sold without FDA approval, most commonly on websites and social media platforms.

RECOMMENDATION: Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment. Avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult with their health care professional about proper prevention, diagnosis and treatment of cancer.

FDA News Release

warning letters

FDA takes action against 14 companies for selling illegal cancer treatments

The U.S. Food and Drug Administration today posted warning letters addressed to 14 U.S.-based companies illegally selling more than 65 products that fraudulently claim to prevent, diagnose, treat or cure cancer. The products are marketed and sold without FDA approval, most commonly on websites and social media platforms.

“Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment,” said Douglas W. Stearn, director of the Office of Enforcement and Import Operations in the FDA’s Office of Regulatory Affairs. “We encourage people to remain vigilant whether online or in a store, and avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult a health care professional about proper prevention, diagnosis and treatment of cancer.”

It is a violation of the Federal Food, Drug and Cosmetic Act to market and sell products that claim to prevent, diagnose, treat, mitigate or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses. The illegally sold products cited in the warning letters posted today include a variety of product types, such as pills, topical creams, ointments, oils, drops, syrups, teas and diagnostics (such as thermography devices). They include products marketed for use by humans or pets that make illegal, unproven claims regarding preventing, reversing or curing cancer; killing/inhibiting cancer cells or tumors; or other similar anti-cancer claims.

The FDA has requested responses from the 14 companies stating how the violations will be corrected. Failure to correct the violations promptly may result in legal action, including product seizure, injunction and/or criminal prosecution.

As part of the FDA’s effort to protect consumers from cancer health fraud, the FDA has issued more than 90 warning letters in the past 10 years to companies marketing hundreds of fraudulent products making cancer claims on websites, social media and in stores. Although many of these companies have stopped selling the products or making fraudulent claims, numerous unsafe and unapproved products continue to be sold directly to consumers due in part to the ease with which companies can move their marketing operations to new websites. The FDA continues to monitor and take action against companies promoting and selling unproven treatments in an effort to minimize the potential dangers to consumers and to educate consumers about the risks.

The FDA encourages health care professionals and consumers to report adverse reactions associated with these or similar products to the agency’s MedWatch program.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Reporting Program:
Complete and submit the report Online: www.fda.gov/MedWatch/report
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including links to the FDA news release, health fraud web page, Q&As, and Consumer Update, at:
http://links.govdelivery.com/track?

Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus

No Consistent Pattern of HBV Reactivation With Direct-acting Antivirals for HCV
NEW YORK (Reuters Health) - The largest case review to date of hepatitis B virus (HBV) reactivation associated with direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection found no consistent pattern in terms of which patients are likely to develop this adverse event.

There was also no consistency with regard to the DAA regimen most likely to lead to HBV reactivation, suggesting a potential class-effect with DAA agents, researchers from the U.S. Food and Drug Administration (FDA) report in a paper online today in Annals of Internal Medicine.

HBV reactivation associated with DAA therapy is a “newly identified safety concern in patients previously infected with HBV. Patients with a history of HBV infection require clinical monitoring while receiving DAA therapy,” write Dr. Susan Bersoff-Matcha and colleagues.

They reviewed 29 cases of HBV reactivation in patients receiving DAAs reported to the FDAs adverse event reporting system between 2013 and 2016.
Continue reading.....

Full Text Article
Annals of Internal Medicine

Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus
Susan J. Bersoff-Matcha, MD; Kelly Cao, PharmD; Mihaela Jason, PharmD; Adebola Ajao, PhD; S. Christopher Jones, PharmD, MS, MPH; Tamra Meyer, PhD, MPH; and Allen Brinker, MD, MS

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Abstract
Background:
Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV–HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis.

Objective: To assess whether HBV-R is a safety concern in patients receiving HCV DAAs.

Design: Descriptive case series.

Setting: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).

Patients: 29 patients with HBV-R receiving HCV DAAs.

Results:
The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV chacteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others.

Limitations:
The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported.

Conclusion:
Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV–HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection.

Continue to full text article.....

In The Media
Direct-acting antiviral therapy for hepatitis C virus associated with hepatitis B virus reactivation in co-infected patients
April 25, 2017 | Deepti Shroff and Evelyn Nguyen

HBV-R is a manageable adverse event, and DAAs continue to be a safe and very effective treatment for infection with HCV.

Continue reading...

Full Text Articles

I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C.

ReACH Center encourages testing and treatment for Hepatitis C to avoid cirrhosis of the liver

Published on Apr 24, 2017

Hepatitis C program helps fund treatment of Hep C through Dr. Turner's CDC grant. Brenda Westbrooks gives a testimonial on being treated for Hepatitis C and now being Hep C free.

Find out more information at http://stop-hcv-hcc.com/

Hepatitis B virus infection and alcohol consumption

World J Gastroenterol. Apr 21, 2017; 23(15): 2651-2659
Published online Apr 21, 2017.
 doi: 10.3748/wjg.v23.i15.2651

Hepatitis B virus infection and alcohol consumption

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Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and the second most common cause of cancer deaths worldwide. The top three causes of HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease. Owing to recent advances in direct-acting antiviral agents, HCV can now be eradicated in almost all patients. HBV infection and alcoholic liver disease are expected, therefore, to become the leading causes of HCC in the future. However, the association between alcohol consumption and chronic hepatitis B in the progression of liver disease is less well understood than with chronic hepatitis C. The mechanisms underlying the complex interaction between HBV and alcohol are not fully understood, and enhanced viral replication, increased oxidative stress and a weakened immune response could each play an important role in the development of HCC. It remains controversial whether HBV and alcohol synergistically increase the incidence of HCC. Herein, we review the currently available literature regarding the interaction of HBV infection and alcohol consumption on disease progression.

Vitamin D does not prevent cardiovascular disease

Vitamin D does not prevent cardiovascular disease
Monday 24 April 2017

Previous research has suggested that cardiovascular disease might be more common in people with low levels of Vitamin D.

But trials using Vitamin D as a supplement haven't shown any benefit - and it's been argued that this is because they were using too low a dose.

And now, The Vitamin D Assessment Study - a large trial of monthly, high dose supplementation - has found no benefit in preventing cardiovascular disease.

Read - Transcript

Guest
Professor Robert Scragg
School of Population Health, The University of Auckland
(view full episode)

Effectiveness and Safety of Sofosbuvir-based Regimens Plus an NS5A Inhibitor for Patients With HCV Genotype 3 Infection and Cirrhosis Results of a Multicenter Real-life

Effectiveness and Safety of Sofosbuvir-based Regimens Plus an NS5A Inhibitor for Patients With HCV Genotype 3 Infection and Cirrhosis Results of a Multicenter Real-life
Cohort S. Alonso; M. Riveiro-Barciela; I. Fernandez; D. Rincón; Y. Real; S. Llerena; F. Gea; A. Olveira; C. Fernandez-Carrillo; B. Polo; J. A. Carrión; A. Gómez; M. J. Devesa; C. Baliellas; Á. Castro; J. Ampuero; R. Granados; J. M. Pascasio; A. Rubín; J. Salmeron; E. Badia; J. M. M. Planas; S. Lens; J. Turnes; J. L. Montero; M. Buti; R. Esteban; C. M. Fernández-Rodríguez

J Viral Hepat. 2017;24(4):304-311.

Abstract and Introduction
Abstract
Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

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Management of Cirrhotic Patients After Successful HCV Eradication

Management of Cirrhotic Patients After Successful HCV Eradication
Kwok, R.M. & Tran, T.T.

Curr Treat Options Gastro (2017).

doi:10.1007/s11938-017-0134-2

First Online: 24 April 2017

Chronic hepatitis C (HCV) is a hepatotropic virus which, when untreated, can lead to progressive inflammation and fibrosis resulting in cirrhosis, hepatocellular carcinoma (HCC), and decompensations related to end-stage liver disease. The relatively recent introduction of all oral, interferon-free, direct-acting antiviral medications against HCV has transformed the management of these patients. Previous treatment regimens were prolonged, poorly tolerated, and frequently did not result in cure. Current therapies achieve sustained viral response (SVR) in the vast majority of patients including those with decompensated liver disease; a previously challenging population to treat. These successes will result in significant numbers of cirrhotic patients requiring management after SVR. Although many complications of cirrhosis are improved in this setting, regular follow-up of HCC, esophageal varices, and other sequelae of cirrhosis will be necessary. This chapter will review the management of cirrhosis in HCV patients achieving cure.

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