Liver Shorts: May 2019

ED Bethea et al. Clin Gastroenterol Hepatol 2019; 17: 739-47. Using a Markov-based mathematical model, the authors “found transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy to a cost-effective strategy that could improve health outcomes.”

A Villanueva. NEJM 2019; 1450-62. This is a succinct review of hepatocellular carcinoma (HCC). Some points:

  • More than 1 million patients will die from liver cancer in 2030.
  • The rate of death from liver cancer increased 43% from 2000 to 2016,.  The 5-year survival rate is grim at only 18%.  Only pancreatic cancer is more lethal.
  • HCC is rare among patients without preexisting liver disease.  Cirrhosis is the main risk factor, though hepatitis B has direct oncologic effects even in the absence of cirrhosis.
  • The authors note that cancer surveillance has no “high-quality randomized controlled trials.” However, this may be due to difficulties with enrollment. In one study, 99%of patients declined to assume the risk of being randomly assigned to the nonsurveillance group. Nonetheless, mathematical models, and lower quality studies all show survival benefits of surveillance.

Related blog post:

  • Liver Shorts April 2019 Obesity/NAFLD and alcoholic liver disease are driving an increase in HCC and liver cancer mortality

Expanding Organ Transplantation with Hepatitis C-Positive Donors

A recent study (AE Woolley et al NEJM 2019; 380: 1606-17) highlighted the outcomes of heart and lung transplant (uninfected) recipients of organs from HCV-infected donors (“DONATE HCV” trial).

In this study, 44 patients (36 lung transplant recipients, 8 heart transplant recipients) were treated preemptively with 4 weeks of sofosbuvir-velpatasvir to block viral replication.

Key findings:

  • 42 of 44 (95%) had a detectable viral load immediately after transplantation.
  • The first 35 (who have all completed 6 months of folllowup) all cleared HCV viremia –undetectable HCV at 6 months post-transplantation
  • No treatment-related complications were noted

In the associated editorial by EA Blumberg (1669-70), it is noted that organs for transplantation are in short supply for the more than 113,000 persons on waiting lists in the U.S.  “In 2018, only 36,500 persons received transplants…and 12,225 persons were removed from the waiting list because of death or progressive illness than rendered them” too sick for transplantation.

HCV donors will expand the donor pool substantially (up to one-third more donors) and these donors are typically younger and with fewer coexisting conditions.

My take: With the high response rate of the newer direct-acting antivirals (100% in this study) along with the (cost) effectiveness of a shorter course, this study shows how promising HCV-positive donors are for improving outcomes in patients in need of organ transplantation.  Long term data are still needed to determine if there are unforeseen problems (eg. late severe relapse of HCV, increased cardiovascular disease).

Related blog post: Increased Organ Availability Related to Opioid Epidemic

How Hepatitis C Therapy Affects Cardiovascular Outcomes

Briefly noted: A recent retrospective study (AA Butt et al. Gastroenterol 2019; 156: 987-96) utilized a Veterans HCV database (n=242,680) and determined that HCV therapy improved cardiovascular outcomes.

Key finding: Treatment with a direct-acting antiviral regimen lowered the risk of cardiovascular events by more than 40% (hazard ratio of 0.57) compared to no treatment.

This finding is limited based on the reliance of a retrospective study and not being able to control for factors that may have led some patients to not receive treatment.

Related blog posts:

Tackling High Drug Costs -Lessons from Australia and Brazil

In two related commentaries referenced below, the authors detail how Australia and Brazil managed to provide a blockbuster hepatitis C virus (HCV) medication without following the going-broke example of Blockbuster video stores.

  • Australia: S Moon et al. NEJM 2019; 380: 607-9
  • Brazil: EM da Fonseca et al. NEJM 2019; 605-6.

Australia provided a lump-sum payment of approximately 770 million dollars (in U.S.) over 5 years in exchange for an unlimited volume of direct-acting antivirals (DAAs). As a result of this approach, Australia managed to treat many more patients at a much lower cost.  “The government would have to spend …U.S. $4.92 billion more to treat the same number or it could treat 93,000 fewer patients with a fixed budget” of approximately U.S. $766 million.

With the Australian approach, the authors note that it is analogous to a patent buyout and works if the ongoing drug manufacturing cost is low and the manufacturer is able to meet growing volume demand.

Brazil’s approaches for DAAs relied on either threatening loss of patent protections and/or enabling local generic production of sofosbuvir.  This resulted in ~90% price discount. Patent protection in Brazil is granted only if a medication is approved by both INPI (Instituto Nacional da Propriedade Industrial) and ANVISA (Brazilian Health Regulatory Agency).

My take: Given the rising costs of medicines, examining how other countries surmount these financial barriers is important.  In my view, the often arbitrary and exorbitant pricing by pharmaceutical companies will erode the support of protective policies in the U.S. which thus far has helped produce many advances.

Skull Rock, Joshua Tree National Park

 

December Liver Briefs

B Wildman-Tobriner et al. Gastoenterol 2018; 155: 1428-35.  This retrospective study which pooled data from 3 phase 2a trials with 370 subjects with nonalcoholic fatty liver disease (NAFLD) found that MRI iwth proton density fat fraction (PDFF) “did not accurately identify patients with NAS ≥4 (AUROC – 0.72) or fibrosis stage ≥3 (AUROC =0.66).”  Thus, this study indicates that currently liver histology remains the gold standard to determine severity of liver damage in paitents with NAFLD.

Related blog posts

P Nahon et al. Gastroenterol 2018; 155: 1436-1450. This study looks closer at whether direct-acting antivirals (DAA) for hepatitis C could increase the risk of hepatocellular carcinoma (HCC) in patients (n=1270) with cirrhosis. The authors found that the crude 3-year cumulative incidence of HCC were 5.9% in the DAA and 3.1% in the SVR-IFN group. However, after Cox analysis, “we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89).”  The authors indicated that patient characteristics (age, diabetes, reduced liver function) and lower screening intensity were the reasons for the increased crude rates of HCC.

Related blog post: Liver Short Takes December 2017

Love this sign –it indicates the truth of the saying:  ‘common sense is not that common’ (attributed to Voltaire)

Genotyping Still Matters with Hepatitis C

A recent study (R Esteban et al. Gastroenterol 20018; 155: 1120-7) evaluated the efficacy of sofosbuvir and velpatasvir in patients with hepatitis C genotype 3.

Overall, the study shows good efficacy of this regimen with and without ribavirin, though with higher SVR12 and lower relapse with the addition of ribavirin.

The difference in response was driven almost entirely based on whether there were pretreatment NS5A resistance-associated substitutions (RASs) present.

  • In those with NS5A RASs the difference in response with added ribavirin compared to without was 96% vs 84%.
  • In those without NS5A RASs the difference in response with ribavirin compared to without was 99% vs. 96%.

My take:

  • If RAS testing is available and baseline Y93H is absent, then ribavirin is not likely needed
  • Genotyping is still important.  The associated editorial (pg 969-71) labeled genotype 3 ‘the problem child in the era of direct-acting antivirals.”   That is, there are still differences in treatment recommendations based on HCV genotype.

Related blog posts:

Changing Liver Mortality Trends Since 2007

A recent study (D Kim et al. Gastroenterol 2018; 155: 1154-63) used a CDC database which captures >99% of deaths in the U.S. to analyze mortality trends from 2007 through 2016.  Full text link available online: Changing Trends in Etiology-Based Annual Liver Mortality

When looking at all-cause mortality, there has been a significant decline in deaths associated with hepatitis C (HCV) but not in deaths associated with alcoholic liver disease (ALD).  The image below shows the trend and the impact of direct-acting antivirals.  Deaths associated with nonalcholic fatty liver disease (NAFLD) and due to hepatitis B (HBV) are described in this study as well, though both together account for less than 1/4th deaths associated with ALD.  Interestingly, mortality related to NAFLD was increasing slowly over the study period.

Related blog posts: