Liver Briefs -July 2019

NH Ebel et al. JPGN 2019; 68: 788-92Hepatic venous pressure gradient (HVPG) did not correlate with the risk of complications from portal hypertension in this pediatric cohort (n=41); this is in contrast to studies in adults showing the utility of HVPG measurements.

AG Singal et al. Gastroenterol 2019; 156: 2149-57. AGA Practice Update on Direct-Acting Antivirals for Hepatitis C and Hepatocellular Carcinoma. There are 12 best practice advice –here are the first three:

  • BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.
  • BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment.
  • BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance

N Hamdane et al. Gastroenterol 2019; 156: 2313-29. This study found that chronic HCV infection induced specific genome-wide-changes in H3K27ac which correlated with expression of mRNAs and proteins.  These epigenetic changes persisted after an SVR to DAAs or interferon-based therapies. These changes could explain some of the reason why HCC remains a risk after successful treatment with DAAs.

DT Dieterich et al. Gastroenteroloy & Hepatology 2019; 15S: 3-11 Link: “A simplified algorithm for the management of Hepatitis C Infection”  An excerpt:

“The algorithm begins with universal HCV screening and diagnosis by testing for HCV antibody with reflex to polymerase chain reaction to detect HCV RNA. The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. Unless clinically indicated, on-treatment monitoring is optional. Confirmation of cure (undetectable HCV RNA 12 weeks posttreatment) is followed by harm-reduction measures, as well as surveillance for hepatocellular carcinoma every 6 months in patients with advanced fibrosis/cirrhosis.”  My take: This algorithm is much simpler than the expanded recommendations from HCVguidelines.org website, though these agents, to my knowledge, do not yet have a pediatric indication.

 

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

Hepatitis C -New Studies & New Recommendations (2017)

Briefly noted:

EJ Gane et al. Gastroenterol 2017; 152: 1366-71.  This phase 2, open-label study (n=53) examined the efficacy of ledipasvir plus sofusbuvir for 8 or 12 weeks for Hepatitis C virus (HCV) genotype 2.  An SVR was noted in 96% with 12 weeks of treatment and 74% with 8 weeks of treatment.  The only patient in the 12 week group without an SVR did not complete treatment.  Overall, this study stands in contrast with the ION-3 study which showed that 8 weeks of therapy led to an SVR of 94% among genotype 1.  Thus, this study is consistent with ledpasvir having more potency against genotye 1 and the need for a 12 week course with genotype 2 HCV.

IM Jacobson et al. Gastroenterol 2017; 152: 1372-82. This retrospective study examined 402 patients with HCV genotypes 1, 4 or 6 with Child-Pugh A compensated cirrhosis who were treated with Elbasvir/GrazoprevirKey finding: SVR12 was 98% and 89% for treatment-naive and treatment-experienced patients after 12 weeks of therapy. The authors noted that baseline tests were done to look for resistance-associated substitutions (RASs).  They recommend: “GT1a patients with RASs require extension of therapy to 16 weeks and addition of ribavirin.”

IM Jacobson et al. Gastroenterol 2017; 152: 1378-87. This AGA clinical practice update makes recommendations for patients have achieved an SVR after HCV therapy. These recommendations are mainly expert opinion given the recent advent of newer treatments for HCV and lack of data regarding long-term outcomes after these treatments. Recommendations from authors:

  • SVR should be confirmed by undetectable HCV RNA at 12 weeks after treatment regimen
  • Reconfirmation of SVR at 48 weeks after treatment is recommended.
  • Surveillance for HCC with liver imaging ± AFP should be pursued twice annually for an indefinite duration in all patients with stage 3 fibrosis or liver cirrhosis post-SVR.  Surveillance is “not recommended for patients with stages 0-2 fibrosis post SVR.”
  • Endoscopic screening for varices is recommended for all patients with cirrhosis, independent of SVR. Repeat screening should be considered if no varices or small varices are noted 2-3 years later.  If there are still no varices at 2-3 years, no further endoscopic screening is recommended.

Related blog posts:

If this picture and reports are accurate, this man’s family urged him to come inside. He said he was keeping an eye on it.

 

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.

Related blog posts:

From Twitter Feed-Funny Church Signs

From Twitter Feed-Funny Church Signs

Optimistic Results for Hepatitis C plus Hepatology Update

The August issue of Hepatology had several articles on Hepatitis C confirming the efficacy of newer agents:

  • LI Backus et al Hepatology 2016; 64: 405-14.  This “real-world” observational study from the VA Clinical registry with 4,365 genotype 1 treatment-naive patients who received ledipasvir/sofosbuvir showed SVR rates of 91.3% (w/o ribavirin) and 92% (w ribavirin).
  • P Kwo et al. Hepatology 2016; 64: 370-80 (OPTIMIST-1) This study showed that 12 weeks of simeprevir+sofusbuvir for 12 weeks was highly effective (97% SVR) and that 8 weeks of this therapy was inferior (83% SVR).  N=310 with genotype 1 (w/o cirrhosis).  No patients stopped therapy due to adverse effects.
  • E Lawitz et al. Hepatology 2016; 64: 360-69 (OPTIMIST-2) This study showed that simeprevir+sofusbuvir for 12 weeks was effective in genotype 1 patients (n=103) with cirrhosis.  For treatment-naive, the SVR was 88% and for treatment-experienced patients, the SVR was 79%.

Also in Hepatology:

  • S Heibani et al Hepatology 2016; 64: 549-55. This study looked at 1-week versus 2-week intervals for endoscopic ligation.  While 1-week ligation eradicated varices more quickly, neither approach was associated with differences in number of endoscopies, complications (including rebleeding) or other clinical outcomes.
From earlier study of "real-world" treatment of Genotype 1. Gastroenterol 2016; 150: 419-29.

From earlier study of “real-world” treatment of Genotype 1. Gastroenterol 2016; 150: 419-29. (Full text link)

 

Quick Take: How to Cure HCV in 99%!!

A new study shows an HCV sustained virological remission of 99% in a study of genotypes 1, 2, 4, 5, and 6.

ORIGINAL ARTICLE
Published Online: November 16, 2015

Here’s a terrific 2 minute summary from NEJM.

 

Does it really cost $2.6 billion to bring a new drug to market?

A recent editorial (Avorn J. NEJM 2015; 372: 1877-79) helps provide some perspective on a recent unpublished study that “it costs pharmaceutical companies $2.6 billion to develop a new drug.”  (http://csdd.tufts.edu/files/uploads/cost_study_backgrounder.pdf)

Dr. Avorn notes that when this study is published scrutiny over the methods is needed; however, the authors of the study note that their methods are unchanged from a previous 2003 study (NEJM 2015; 372: 1972). Apparently the analysis was based on data from 10 drug makers regarding compounds that they had ‘self-originated.’

Some preliminary criticisms:

  • Nearly half the costs were attributed to the cost of capitol rather than direct spending. This cost indicates that the money being used for drug development was not available for other purposes (“opportunity costs”); however, the capital costs were assessed at a very generous 10.6% per year, compounded.
  • The analysis did not include the large public subsidies provided to pharmaceutical companies in the form of research-and-development tax credits.
  • Pharmaceutical companies remain highly profitable and only spend a small fraction of their revenues on truly innovative research.
  • Many of the drugs brought to market are not “self-originated.”
  • Many drug costs are borne by the public via research at university-affiliated centers with the pharmaceutical companies taking the new discovery the last mile.  “Gilead Sciences did not invent its blockbuster treatment for hepatitis C, sofosbuvir (Sovaldi)…it acquired the product from a small company founded by the drug’s inventor, a faculty member at Emory University, much of whose work on the usefulness of nucleoside viral inhibitors was federally-funded.”

Bottomline: While pharmaceutical companies invest heavily in new drug development, the huge numbers often attributed to research costs may be overestimates; these type of analysis likely underestimate how much taxpayers have paid in subsidizing the foundation for new treatments.

Related blog post: The Difficulty with Drug Development | gutsandgrowth