“Crushing it:” Practice Guidance for Hepatitis C

Today’s post on Hepatitis C follows a few screenshots from twitter regarding the coronavirus epidemic.

Pediatric report of coronavirus in children: NEJM Full link: SARS-CoV-2 Infection in Children A recent review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that less than 1% of the cases were in children younger than 10 years of age (n=171)…3 patients required intensive care support and invasive mechanical ventilation; all had coexisting conditions. There was one death in a 10-month-old child with intussusception had multiorgan failure and died 4 weeks after admission.

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As noted yesterday, this post will review a recent practice guidance for hepatitis C

Some specific recommendations for children:

Testing:

  • “All children born to HCV-infected women should be tested for HCV infection. Testing is recommended using an antibody-based test at or after 18 months of age.”
  • “Testing with an HCV-RNA assay can be considered in the first year of life, but the optimal timing of such testing is unknown” (but can be done as early as 2 months of life).
  • “The siblings of children with vertically-acquired chronic HCV should be tested for HCV infection, if born from the same mother.”

Counseling for parents:

  • “Parents should be informed that hepatitis C is not transmitted by casual contact and, as such, children with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions.”
  • “Parents should be informed that universal precautions should be followed at school and in the home of children with HCV infection. Educate families and children about the risk and routes of HCV transmission, and the techniques for avoiding blood exposure, such as avoiding the sharing of toothbrushes, razors, and nail clippers, and the use of gloves and dilute bleach to clean up blood.”

Treatment:

  • “Direct-acting antiviral (DAA) treatment with an approved regimen is recommended for all children and adolescents with HCV infection aged ≥3 years as they will benefit from antiviral therapy, regardless of disease severity.”
  • Early treatment in childhood is expected to be cost-effective compared to treatment at later ages based on previous studies

This chart provides recommendations for pediatric patients who have not received prior direct-acting antivirals. More information at HCVguidelines.org

“Crushing it:” Two More Pediatric Hepatitis C Trials

Before today’s planned blog post, I wanted to mention a good NY Times article which highlights how long the virus which causes COVID-19 can be present on surfaces:

Full link from NY Times: How Long Will Coronavirus Live on Surfaces or in the Air Around You?

An excerpt:

The virus lives longest on plastic and steel, surviving for up to 72 hours. But the amount of viable virus decreases sharply over this time. It also does poorly on copper and cardboard, surviving four to eight hours; the latter finding suggests packages that arrive in the mail should be safe — unless the delivery person has coughed or sneezed on it or has handled it with contaminated hands.

That the virus can survive and stay infectious in aerosols is also important for health care workers.

For weeks experts have maintained that the virus is not airborne. But in fact, it can travel through the air and stay suspended for that period of about a half-hour.

The virus does not linger in the air at high enough levels to be a risk to most people who are not physically near an infected person. But the procedures health care workers use to care for infected patients are likely to generate aerosols.

The original article from NEJM:  Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

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This “C” virus was hard to cure until recently.  More good news from recently published studies for pediatric hepatitis c virus (HCV) treatment:

  • KB Schwarz et al. Hepatology 2020; 71: 422-30. 
  • MM Jonas et al. Hepatology 2020; 71: 456-62.
  • AASLD-IDSA Practice Guidance Panel. Hepatology 2020; 71: 686-721

In the first study of an all oral regimen of ledipasvir-sofosbuvir, sustained virological response at 12 weeks after dosing (SVR12) was achieved in 33 of 34 (97%) of children 3-<6 yrs of age with genotypes 1 or 4 (only 1 with type 4). No serious adverse effects were reported. Dosing: 33.75 mg/150 mg if <17 kg or 45 mg/200 mg if ≥17 kg. The one non-responder discontinued treatment due to drug taste.  Pharmokinetic studies in 13 patients confirmed appropriate medication dosing.

In the second study of glecaprevir/pibrentasvir (G/P), as part of the DORA phase 2/3 nonrandomized, open-label trial, adolescents 12-17 received the ‘adult’ regimen of 300 mg/120 mg daily for 8-12 weeks in accordance with indication duration based on adult data.  Among the 47 patients (genotypes 1, 2, 3, 4), 100% achieved SVR12. Safety profile was consistent with prior studies in adults.

The third publication, which is quite lengthy, highlights updated recommendations for HCV in adults and children (this will be reviewed in tomorrow’s post).

Related blog posts:

Ledipasvir-Sofosbuvir for Children 6-11 years

Almost two years ago, the FDA approved Ledipasvir-Sofosbuvir (aka Harvoni) for pediatric patients 12-17 years of age with hepatitis C virus (HCV) infection.  Now, a recent study (KF Murray, WF Balistreri, S Bansal et al. Hepatology 2018; 68: 2158-66) is likely to expedite approval for children ages 6-11 years of age.

In this open-label study with 92 patients, 88 had genotype 1, 89 received treatment with ledipasvir-sofosbuvir without ribavirin for 12 weeks, 97% were perinatally-infected, and 78% were treatment naive.  The median age was 9 years. The dose (determined by intense pharmacokinetics) was 45 mg-200 mg (half the adult dosage). Two patients with genotype 3 HCV received ledipasvir-sofosbuvir for 24 weeks along with ribavirin.

Key findings:

  • SVR12 was 99% (91/91).  The single patient without SVR12 had relapsed 4 weeks after completing a 12 week treatment course.
  • Ledipasvir-sofosbuvir was well-tolerated; the common adverse events reported were headache and pyrexia.

The authors note that while most children are considered to have mild symptoms or are asymptomatic, some progress to have significant fibrosis or cirrhosis, a small minority develop hepatocellular carcinoma, and HCV infection can impact both cognitive development and overall health.

My take: This study confirms that effectiveness of DAA therapy with ledipasvir/sofosbuvir in children as young as 6 years of age.

Related study: F Tucci et al. Hepatology 2018; 68: 2434-37. The authors report the successful treatment with ledipasvir/sofosbuvir of an infant with both SCID and HCV infection.

Related blog posts:

Mesquite Flat Sand Dunes, Death Valley

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.

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From Twitter Feed-Funny Church Signs

From Twitter Feed-Funny Church Signs

Liver Briefs Feb 2017

JB Schwimmer et al. Gastroenterol 2016; 151: 1141-54.  Using a double-masked trial with 169 children with NAFLD, the use of cysteamine bitartrate for 1 year did not reduce histologic activity scores, but did reduce liver aminotransferase levels.

NA Terrault et al. Gastroenterol 2016; 151: 1131-40. The authors collected data from 2099 participants in the HCV-TARGET study who mainly received ledpasvir-sofosbuvir (311 received therapy in combination with ribavirin).  The study included 25% blacks, 66% with genotype 1A, 41% with cirrhosis, 50% with prior treatment, and 30% who were receiving proton pump therapy.  Key finding: SVR12 rates varied from 95% to 97% based on duration of therapy.  Factors that predicted SVR12 included higher albumin (>3.5 g/dL), lower total bilirubin (<1.2), absence of cirrhosis, absence of proton pump inhibitor therapy.

KR Olson et al. NEJM 2017; 376: 268-78.  This case report of an 18 yo woman with acute liver failure provides a helpful review.  For Wilson’s disease, the article reviews rapid diagnostic criteria: “a screen that shows a ratio of alkaline phosphatase (IU per liter) to total bilirubin (mg per deciliter) of lower than 4.0 and then subsequently shows a ratio of aspartate aminotransferase (IU per liter) to alanine aminotransferase (IU per liter) of higher than 2.2 has been described as 100% sensitive and specific for the diagnosis of Wilson’s disease.”  Making this diagnosis quickly is crucial and allows these patients to be UNOS status 1A, “the only cause of acute liver faliure that allows a patient with preexisting liver disease to be listed as status 1A”

Among children older than 10 years of age, Wilson's disease accounted for 90% of metabolic disease.

Among children older than 10 years of age, Wilson’s disease accounted for 90% of metabolic disease.

HCV Treatment: Nearing 100% Effectiveness

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?

Glacier Nat'l Park

Glacier Nat’l Park