Tag Archives: hepatitis C

Progression of Hepatitis C in Children

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A retrospective study (Hepatology 2013; 58: 1580-86) of liver biopsies from treatment-naive children enrolled in the PEDS-C study confirm the perception that hepatitis C histologic progression is typically slow.

This study examined 35 pediatric patients (84% genotype 1) who had at least two liver biopsies more than a year a part at eight different centers.  For this study, all of the liver histology was scored by a single pathologist.  Mean age at first and final biopsy were 8.6 and 14.5 years.  Mode of transmission: 57% vertical and 39% transfusion.

Results:

  • Inflammation was minimal in about 50% at both timepoints.
  • Fibrosis was absent in 16% at both timepoints.  Fibrosis was limited to portal/periportal in 73% at first biopsy and 64% at second.
  • Proportion of patients who had bridging fibrosis/cirrhosis at second timepoint increased from 11% to 20%.  Overall, 29.5% (n=13) showed an increase in severity of fibrosis.
  • In aggregate, “this cohort did not show significant histologic progression of liver disease over 5 years.”

Implications for treatment per authors: “It may be argued that treatment of a slowly progressing disease in an asymptomatic child may be deferred given the side effects and limitations of the currently available therapy. On the other hand, some might favor early treatment…a liver biopsy …may influence decisions regarding therapy.”

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Better HCV Treatments Approved

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Both Simeprevir and Sofusbuvir have been approved unanimously by FDA panel.

Excerpt from AP report on simeprevir  (full link: ow.ly/qarKM from AGA twitter feed):

All 19 members of the Food and Drug Administration’s panel of virus experts voted in favor of approving J&J’s simeprevir, a daily pill designed to eliminate the most common form of hepatitis C.  The FDA is not required to follow the group’s recommendations, though it often does. A decision on the drug is expected next month.

Roughly 3.2 million people in the U.S. have hepatitis C, a blood-borne disease that causes liver damage and is blamed for 15,000 deaths a year…

New Brunswick, N.J.-based J&J is seeking approval to combine its pill with the long-established drug cocktail used to treat the most common form of the virus.

Despite the unanimous vote Thursday, the panel’s endorsement came with a number of conditions.

The panelists stressed that the drug is less effective in patients with a common genetic mutation called Q80K, and that people with the abnormality should be screened out so they can receive other drugs. The group also said the drug’s label should warn patients and doctors that sunburn is a common side effect. Finally, panelists said that the FDA should require J&J to conduct additional studies of the drug’s effectiveness in minorities, especially African-Americans who are disproportionately infected…

The FDA meeting comes as federal health officials urge all baby boomers to get tested for the virus…

J&J’s simeprevir appears to be slightly more effective than the standard of care, curing 80 percent of patients who had not previously been treated for the disease, according to studies submitted to the FDA. More significantly, the drug helped most patients cut the amount of time they had to take the traditional drug cocktail, with its unpleasant side effects, to six months rather than one year. Additionally, panelists said the drug’s once-a-day dosage should be far more manageable for patients than the current drugs from Merck and Vertex, which require taking 12 pills or six pills a day, respectively.

And for Sofusbuvir from Reuters (FDA panel backs Gilead hepatitis C drug sofosbuvir)

The FDA advisory panel voted 15 to 0 in favor of approval of the drug in patients with two variants of the liver-damaging disease – genotype 2 and genotype 3 – in combination with an existing treatment, ribavirin.

If approved, it will be the first all-oral treatment for genotypes 2 and 3, obviating the need for the injectable drug interferon, which can cause debilitating side effects. Panelists called the vote “historic” and a “game-changer.”

“Our patients have been waiting for this for a long time,” said Dr. Curt Hagedorn, chief of medicine service at the Central Arkansas Veterans Healthcare Service.

The panel also voted unanimously to approve the drug in patients with genotype 1 and genotype 4 variants in combination with ribavirin and interferon in patients who have not received prior therapy.

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Update on Hepatitis B & C -Postgraduate Course

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Update on Hepatitis B –Jean Pappas Molleston

Hepatitis B: Who to Treat:

  • Immune active Hepatitis B with active disease: HBeAg+ (> 6 months), HBV DNA > 20,000 IU/ml, ALT > 1.5 x normal or > 60 IU/L, &  moderate/severe inflammation/fibrosis
  • Reactivated Hepatitis B with active disease: HBeAg‐ (> 12 months), HBV DNA > 2000 IU/ml, ALT > 1.5 x normal or > 60 IU/L

Hepatitis B: Who to Not Treat:

  • Immunotolerant Hepatitis B: HBeAg+, HBV DNA > 20,000 IU/ml, Normal ALT
  • Inactive carrier: HBe Ag, HBV DNA < 2000

What to Use to Treat Children with Hepatitis B and When:

  • Only children with active disease should be treated
  • Many would suggest IFN as a first line drug, especially for younger children
  • Nucleoside analogues can now be considered in older children: Tenofovir is licensed for over age 12,  Entecavir is licensed for over age 16

What’s Exciting?

  • NCT01519960 Peg‐IFN monotherapy for children with chronic active hepatitis B
  • NCT01368497 Peg‐IFN and Entecavir for treatment of Hepatitis B in immunotolerant children
  • New drugs
  • New ways to predict who will have worse disease and who will respond
  • Direct Acting Antivirals

Treating HCV: 2013 and Beyond… Regino P. González-Peralta, M.D.

Standard of Care HCV Therapy: Children

  1. IFN/PEG-IFN-α-2a (PEG-2a):  ‘‘Branched’’ 40-kDa PEG moiety, Dose: 104 μg/m2 SQ once weekly, Available: prefilled syringes or as vials
  2. PEG-IFN-α-2b (PEG-2b): ‘‘Linear’’ 12-kDa PEG, Dose: 60 μg/m2 SQ once weekly, Available: Measured vials/ready-use pens

Other pointers:

  • Discussed IL-28 B Polymorphism –No pediatric data yet
  • Close monitoring for those who are treated
  • PEG-RBV is standard of care for children though with suboptimal efficacy and significant toxicity
  • Warp-speed evolution of HCV therapies
  • All ORAL’ regimen on horizon
  • Yearly evaluation: CBC, liver tests, HCV RNA and PT/INR (cirrhosis)

HCV Rx in Children: to treat or not:

IN FAVOR…

  • Avoid disease progression
  • Remove social stigma
  • Decrease HCV burden
  • Children ‘better’ candidates

…AGAINST

  • Benign disease
  • Efficacy
  • Toxicity
  • Direct Acting Antivirals (in the pipeline)

Full slides available on postgraduate Course Syllabus (posted with permission): PG Syllabus

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Big Interferon-free Hepatitis C Study

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Every week there is more information on clinical trials for hepatitis C; I am waiting for this to translate into improvements for the pediatric population.

This week’s biggest publication: NEJM 2013; 369: 630-9.  This was a phase 2b randomized open-label trial of faldaprevir (a NS3/4A protease inhibitor) in combination with deleobuvir (a non nucleoside NS5B polymerase inhibitor).  In total, 5 different regimens were examined, most in combination with ribavirin.  The authors recruited 362 HCV genotype 1 patients who were randomized into these treatment groups & he sustained virologic response 12 weeks after completion of therapy

  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 16 weeks (TID16W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 28 weeks (TID28W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 40 weeks (TID40W) –>52%
  • Faldaprevir 120 daily, deleobuvir 600 two times a day, and ribavirin for 28 weeks (BID28W) –>69%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, without ribavirin for 28 weeks  (TID28W-NR) –>39%

Rates of SVR were higher among genotype 1b, 56-85%, compared with 1a, 38-43% (when excluding non-ribavirin group).  Genotype 1a patients with IL28B CC had similar response (58-84%) to genotype 1b patients.  Genotype 1a patients were much more likely to relapse if not treated for at least 28 weeks.

Adverse effects were common and reported in 94% of participants; 9% had severe adverse reactions.  Gastrointestinal and dermatologic advents events were the most frequent.  Also, faldaprevir resulted in jaundice (unconjugated hyperbilirubinemia) in many patients (16-28% of patients who took ribavirin in their regimens).

This large study showed that when these oral antiviral are used in combination with ribavirin that results are similar to current standard of care treatments for adult patients.  For telaprevir or boceprevir, along with pegylated interferon and ribavirin, phase 3 trials showed SVRs between 68-75%.

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Emerging Targets for Hepatitis C -Part 1

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The latest advances in hepatitis C are related in several recent publications:

  1. Hepatology 2013; 57: 2143-54.
  2. Hepatology 2013; 57: 2155-63.
  3. Clin Gastroenterol Hepatol 2013; 11: 612-619.

The first two studies provide specific information about the effectiveness of Faldaprevir combined with peginterferon alfa-2a/ribavirin (PEG/RBV) in treatment-naive patients and patients with prior nonresponse respectively.  The third reference provides the big picture regarding all of the emerging treatments.

In the first study, the “SILEN-C1” phase 2 trial, 429 patients without cirrhosis were randomized to several treatment arms.  423 of the 429 patients were genotype 1.  This large study involved 89 centers in 15 countries.  All of the treatment groups received PEG/RBV along with either placebo, faldaprevir 120 mg with lead-in (LI), faldaprevir 240 mg LI and faldaprevir 240 mg without LI.   Faldaprevir is a NS3/4A protease inhibitor which can be administered orally once a day.  Results: SVR achieved in 56% (placebo), 72% (faldaprevir 120mg LI), 72% (faldaprevir 240 mg LI), and 84% (faldaprevir 240 mg without LI).  Discontinuation rates were 1%, 4%, 11%, and 5% for the aforementioned treatment groups.

In the second study, the “SILEN-C2” trial, 290 non cirrhotic genotype 1 patients with either no response or partial response to previous treatment underwent a 48 week treatment trial with a similar design as the SILEN-C1. Results: SVR rates among partial responders were 32% (faldaprevir 240 mg LI), 50% (faldaprevir 240 mg without LI), and 42%(faldaprevir 240 mg BID/LI).  Among null responders, SVR rates were 21% (faldaprevir 240 mg LI), 35% (faldaprevir 240 mg without LI), and 29% (faldaprevir 240 mg BID/LI).  Adverse reactions were higher in those on higher doses and included anemia, rash, indirect hyperbilirubinemia, and nausea. Discontinuation rates were 6%, 4%, and 23% for the aforementioned treatment groups.

The third study provides a landscape of current treatment and emerging treatments.  Given the improvement in SVR among genotype 1 patients, the use of either telaprevir or boceprevir in combination with PEG/RBV is the “new standard of care” among adult patients with HCV.  Studies supporting telaprevir include the ADVANCE study, the REALIZE trial, and the OPTIMIZE study.  For boceprevir, its effectiveness was demonstrated with SPRINT-2, and RESPOND-2.

Both boceprevir and telaprevir, are NS3/4A serine protease inhibitors and are considered direct acting antivirals (DAAs). On the horizon:

  • Simeprevir -NS3/4A protease inhibitor.  Studies: PILLAR, ASPIRE.  SVR: 75-86% in treatment-naive patients. Once daily, no rash or increased anemia.  Hyperbilirubinemia can occur.
  • Faldaprevir -see above studies.
  • Danoprevir -NS3/4A protease inhibitor. Study: DAUPHINE. For genotypes 1 and 4. 100% SVR in genotype 4.  Rates of withdrawal with danoprevir were similar to placebo.
  • Daclatasvir -NS5A replication inhibitor. Study: COMMAND-1. For genotypes 1 and 4.
  • Sofosbuvir -NS5B polymerase inhibitor. Studies: PROTON, ATOMIC. For genotypes 1, 4, and 6.
  • Multiple DAAs in combination. Studies: MATTERHORN, INFORM-SVR, AVIATOR, ELECTRON, SOUND-2

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Top Cited 100

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In a recent commentary, the authors provide a list of the most commonly cited digestive disease articles from 1967-2007.  (Gastroenterol 2013; 144: 673-76)

The top three:

  1. Manns, M, et al. Lancet 2001; 358: 958-65. This study compared peginterferon alfa-2b with ribavirin against interferon with ribavirin for hepatitis C
  2. Fried M, et al. NEJM 2002; 347: 975-82. This study examined the use of peginterferon alfa-2a with ribavirin for hepatitis C
  3. Marshall B, Warren J. Lancet 1984; 1: 1311-15.  This study identified a bacteria (now called Helicobacter pylori) as a cause of ulcers and gastritis.

http://dx.doi.org/10.1053/j.gastro.2013.02.013

Tattoos: a marker for Hepatitis C

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A recent study has found that tattooing was independently associated with hepatitis C virus (HCV) infection, even in those without traditional risk factors (Hepatology 2013; 57: 2117-23).

The authors of this large, multicenter, case-control study analyzed demographics and risk factors for HCV among 3,871 patients including 1,930 who had chronic HCV infection.  As in previous studies, a history of injection drug use (IDU) and blood transfusion prior to 1992 were associated with an increased risk of HCV.

After excluding patients with these risk factors, there were 465 patients with HCV and 1,421 controls.  Among these individuals, after controlling for age, sex and ethnicity, HCV-positive patients had an OR of 5.17 of having had one or more tattoos compared to the control patients.

Previous studies have not been definitive about whether tattoos represent a specific risk factor or an epiphenomenon.  That is, tattoos are known to be more common among individuals with IDU.  And, this study does not really settle the question either.  “Underrepresentation due to self-reporting of intravenous drug use is a concern that could confound our result.”  In addition, the authors note that commercial parlors have not been implicated in HCV transmission.

Bottomline: Individuals with tattoos are more likely to have HCV.  For individuals who insist on tattoos, avoid nonprofessional settings to limit the risk of HCV acquisition.

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More HCV options -phase 3 for Sofosbuvir

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The pace of research for HCV is incredible.  Two months ago phase 2 data for Sofosbuvir were reported and noted on this blog (More options for Hepatitis C | gutsandgrowth).  Now phase 3 data from multiple trials have emerged indicating the effectiveness of sofosbuvir for all HCV genotypes.

In the first study, NEJM 2013; 368: 1867-77, data from two trials (POSITRON and FUSION) of patients with HCV genotypes 2 and 3 are reported.  The POSITRON trial (63 sites, n=278 received treatment) was a blinded placebo-controlled study that evaluated 12 weeks of sofosbuvir/ribavirin compared with placebo in patients who discontinued interferon due to unacceptable adverse events or could not take interferon due to contraindications (most commonly psychiatric disorder or autoimmunity). Results: sustained virological response (SVR) in 78% of treatment group compared with 0% of placebo patients.  In addition, there was “complete concordance (100%) between rates of SVR at 12 weeks and at 24 weeks.”

The FUSION study (67 sites, n=201 received treatment) was a blinded, active-control study in patients who did not respond to a previous interferon-based regimen; one of two treatment regimens were administered: 12 weeks of sofosbuvir/ribavirin followed by placebo or 16 weeks of sofosbuvir/ribavirin. Results: 93% of genotype 2 patients had SVR and 61% of genotype 3 patients had SVR.  Among cirrhotic patients, 61% had SVR (94% of genotype 2, 21% of genotype 3); for those without cirrhosis, there was an 81% SVR (92% with genotype 2, 68% with genotype 3).  Thus, it is easy to conclude that genotype 3 patients with cirrhosis responded much less favorably.

Other important findings: rates of discontinuation among the treatment groups were similar to the placebo groups.  The most common adverse effect was anemia in the treatment groups.

In the second study, NEJM 2013; 368: 1878-87, an additional two phase 2 trials (NEUTRINO and FISSION) are reported from previously untreated chronic HCV patients.  The first trial (NEUTRINO) was an open-label study examining a 12-week regimen of sofosbuvir, peginterferon alfa-2a, and ribavirin in 327 HCV patients (98% genotypes 1 or 4).  Results: SVR noted in 90%. The second trial (FISSION) enrolled 499 patients with genotypes 2 and 3 who randomly received either peginterferon alfa-2a/ribavirin for 24 weeks or sofosbuvir/ribavirin for 12 weeks. Results: SVR noted to be 67% in both groups.  Genotype 2 patients again fared better than genotype 3 among the sofosbuvir/ribavirin group (97% versus 56%).  Some adverse events like fatigue, headache and nausea were common.  Overall, side effects were much lower in those not receiving peginterferon (see Table 3).

Take home message: From the editorial (pg 1931-32 in same issue): “a radical change in clinical practice is imminent…the low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drugs are strong selling points of a sofosbuvir-ribavirin regimen and will probably lower the threshold for HCV treatment for both patients and physicians.”

Hopefully, we will see pediatric studies soon.

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Microtargeting HCV

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“Where there is no vision, the people perish.” –King Solomon, Proverbs

A recent study (NEJM 2013; 368: 1685-94) sheds light on a new vision of potential therapies, using microRNAs designed to interfere with the pathogenesis intracellularly.  While this study used this technology to target the Hepatitis C virus (HCV), the same technology has already received FDA approval for a medication (mipomersen) used to treat familial hypercholesterolemia.

With familial hypercholesterolemia, antisense oligonucleotides were developed which inhibit the expression of apolipoprotein B-100 in the liver.  For HCV, miravirsen is a 15-nucleotide antisense oligonucleotide microRNA (miR-122) which binds two highly conserved sites in HCV RNA.  The liver-expressed miR-122 protects HCV from degradation. Thus, the antisense oligonucleotide miravirsen causes degradation of HCV.  All strains of HCV depend on miR-122. (This aspect is reiterated in an associated editorial: NEJM 2013; 368: 1741-43.)

This study enrolled 36 patients from 2010 to 2011 in a randomized, double-blind, placebo-controlled, sequential series, ascending multiple dose-ranging study (7 study sites).  All HCV patients had not received previous therapy and were genotype 1.  Patients received five weekly subcutaneous injections of miravirsen at 3 mg/kg, 5 mg/kg, 7 mg/kg or placebo injections.

Results: In the miravirsen groups, the mean maximum log reduction in HCV RNA level was related to dose: 1.2 in 3 mg/kg cohort, 2.9 in 5 mg/kg cohort, and 3.0 in 7 mg/kg cohort compared with a 0.4 reduction in the placebo cohort.  During 14 weeks of follow-up after completing treatment, HCV RNA was not detected in one patient in the 5 mg/kg group and in four patients in the 7 mg/kg group.

There were no dose-limiting toxic effects or treatment discontinuations because of adverse events.  However, cholesterol levels did decrease by ~25%. No viral resistance was identified.  In addition, during treatment with miravirsen, a sustained decrease in serum alanine aminotransferase was evident.

The authors note that the pharmacologic data from this study indicate that once-monthly regimen would be feasible.  Because miravirsen is not a substrate for P-450, it is not expected to have significant drug-drug interactions.  Further studies are underway.

Potential drawbacks of treatment: miR-122 is a tumor-suppressor gene for hepatocellular carcinoma (HCC).  Thus, treatment with miravirsen could increase the risk of HCC.  Also, in mice that lack miR-122, there is a high risk of fatty liver and fibrosis.

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