The U.S. Food and Drug Administration today approved a supplemental application for Epclusa (sofosbuvir and velpatasvir) to treat hepatitis C virus (HCV) in children ages 6 years and older or weighing at least 37 pounds (17 kilograms) with any of the six HCV genotypes—or strains—without cirrhosis (liver disease) or with mild cirrhosis.
Review: NAFLD in China 1999-2018J Zhou et al. Hepatology 2020; 71: 1851-4.
NALFD increased by 8-9% in prevalence, to 29.1%. This means there are more than 230 million individuals with NAFLD in China.
Use of HCV-positive donors for liver transplantation to HCV-negative recipients. N Anwar et al. Liver Transplantation 2020; 26: 673-80. Key finding: HCV-positive organs had similar outcomes regarding graft function, patient survival and post-LT complications.
Recent Decline in Hepatocellular Carcinoma Rates in U.S. MS Shiels, TR O’Brien. Gastroenterol 2020; 158: 1503-5. Using SEER-21 population based cancer registries covering 37% of U.S. population, the authors found a recent decline in rates of HCC:
2000-2016: 119,078 cases of HCC in SEER-21 registries, 5.84/100,000
Rates increased b 5.6% per year from 2000-2007, then by 2.7% per year from 2007 to 2013, subsequent rate reached a plateau and declined with drop of 1.4% per year (P=.12)
Improvement could have been due in part to improvement in viral hepatitis treatment; a less favorable explanation could be that the drop occured due to a death from another cause (eg. non-HCC death due to cirrhosis, opioid-related death
Potential Treatment for Nonalcoholic SteatohepatitisN Chalasani et al. Gastroenterol 2020; 158: 1334-45. The study explored the use of Belapectin, an inhibitor of Galectin-3, in patients with nonalcoholic steatohepatitis and cirrhosis. n=162, phase 2 randomized, double-blind study. Key finding: 1 year of every 2 week infusions were safe but not associated with significant reductions in hepatic venous pressure gradient (HVPG) or fibrosis. However, in a subgroup without varices, there was lowered HVPG and lowered risk of new varices.
Treatment Options for Minimal Hepatic Encephalopathy: RK Dhiman et al. Clin Gastroenterol Hepato 2020; 18: 800-12. This meta-analysis which included 25 trials (n=1563) found the following:
For reversing minimal hepatic encephalopathy (MHE), rifaximin (OR 7.53) and lactulose (OR 5.39) were effective with moderate quality evidence. Probiotics had OR 3.89 and L-ornithine L-aspartate had OR 4.45 —both with low quality evidence.
For prevention of HE, L-ornithine L-aspartate had OR 0.19 (‘high moderate’ quality), and lactulose had OR 0.22 (moderate quality) were effective. Probiotics had OR 0.27 with low quality evidence.
The authors conlude that lactulose is the most effective agent for prevention and reversal of MHE.
NH Ebel et al. JPGN 2019; 68: 788-92. Hepatic 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.
“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.
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.
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).
While the emergence of multiple highly-active agents for Hepatitis C has been a terrific advance, there are a small subset of patients who have not responded to them in almost all clinical trials. A recent study (M Bourliere et al. NEJM 2017; 376: 2134-46) has identified a highly-effective combination regimen for this population: sofosbuvir/velpatasvir/voxilaprevir x 12 weeks
The authors conducted two phase 3 trials in patients who had not responded to a direct-acting antiviral (DAA) regimen previously. POLARIS-1 and POLARIS-4. 46% of patients had compensated cirrhosis Key findings:
POLARIS-1: 96% of combination group had a sustained virologic response (SVR) compared with 0% of patients receiving placebo
POLARIS-4: the triple combination had a SVR of 98%, whereas 90% had SVR with dual therapy (sofosbuvir-velpatasvir)
Among patients receiving active treatment, less than 1% discontinue treatment due to advers events.
My take: This triple therapy is highly effective in patients who were previously-treated with DAA for HCV.
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…
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.
While access to HCV treatment remains the biggest obstacle, recent studies show that the rates of HCV eradication, even in the toughest cases, now approaches 100%.
E Lawitz et al. Gastroenterol 2016; 151: 893-901.
EJ Gane et al. Gastroenterol 2016; 151: 902-9.
Editorial: M Buti pgs 795-8.
Most prior studies examined the use of two direct-acting antivirals (DAAs) with or without ribavirin. These DAAs targeted nonstructural (NS) proteins necessary for HCV replication: NS3 protease, NS5B polymerase, and NS5A protein.
These two new studies examined whether treatment with a DAA targeting all 3 NS proteins would be effective and possibly allow shorter treatments. It is noted that currently only treatment-naive genotype 1 (w/o cirrhosis) patients have a regimen that is recommended for only 8 weeks; these patients also should have HCV-RNA<6,000,000 IU/mL.
Lawitz et al studied the combination of sofosbuvir-velpatasvir and GS-9857 (voxilaprevir) for 6-8 weeks (one treatment group received ribavirin); n=197. Among treatment-naive patients w/o cirrhosis, SVR12 was 100% after 8 weeks of treatment and 94% of treatment-naive patients with cirrhosis. Among treatment-experienced patients treated for 12 weeks, 100% of all patients (w and w/o cirrhosis) achieved SVR12.
Gane et al studied the effectiveness of the combination of sofosbuvir-velpatasvir and GS-9857 in HCV genotypes 2, 3, 4, and 6 (as well as 1 with 1b); n=128. After 8 weeks of treatment, SVR12s were achieved in 93% of treatment-naive patients with cirrhosis. After 12 weeks, treatment-experienced patients with and without cirrhosis had SVR12s of 97% and 100% respectively.
My take: This combination of therapies should allow shorter treatment regimens in treatment-naive patients and effective rescue therapy for previous DAA failures. Now that we can cure almost everyone with HCV, how do make therapies affordable and accessible?