Category Archives: Hepatology

Have You Heard of Harvoni?

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The U.S. Food and Drug Administration on 10/10/14 approved Harvoni (ledipasvir and sofosbuvir) to treat chronic hepatitis C virus (HCV) genotype 1 infection.

“Harvoni is the first combination pill approved to treat chronic HCV genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection.”

Full FDA press release –includes data supporting approval.

Related blog post: The Future is Now (for Hepatitis C) | gutsandgrowth

Understanding the Costs and Benefits of HCV Treatment

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A useful editorial in JAMA (available free online –) provides a useful overview of HCV treatments in terms of costs and strategies for using new therapies.

A couple of useful points

  • Given the cost of medications, many are using the newer therapies in those who absolutely need treatment now and waiting for costs to improve in others
  • “The ultimate approach to cost will be lower prices, which will occur as more products create competition.”
  • “This fall, an oral combination of sofosbuvir and ledipasvir will be introduced that inhibits both the NS5B polymerase and NS5A polymerase and has been shown to reduce treatment to an 8-week course with cure rates of more than 95%.2 Now, a chronic disease that affects millions of Americans can be cured by well-tolerated oral medications.”
  • Because of the large number of potential patients, “the simple math is that treatment of patients with HCV could add $200 to $300 per year to every insured American’s health insurance premium for each of the next 5 years.”

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Hepatology Update (Part 2) -Summer 2014

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Hepatology 2014; 60: 715-33.  This publication is the AASLD Practice Guideline for Hepatic Encephalopathy in Chronic Liver Disease.  The recommendations are too extensive to summarize.  Here’s one: despite concerns about efficacy, “lactulose is the first choice for treatment of episodic” overt hepatic encephalopathy.  Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence. AASLD Guidelines Website

Hepatology 2014; 60: 679-86. Using the Drug-Induced Liver Injury Network between 2004-2012, the authors identified 22 cases of hepatotoxicity attributed to statins.  Median age was 60 years.  The latency to onset of symptoms varied from 34 days to 10 years with a median of 155 days. Nine patients had a cholestatic hepatitis pattern and 12 had hepatocellular injury, including six with an autoimmune phenotype. Severity: nine required hospitalization, four had evidence of hepatic failure and one died.

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HCV Guidelines Updated

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For those trying to stay up-to-date, a headline from The Onion: “Nation’s Third-Graders Now Eating At A Ninth-Grade Level”   .

And, from American Association for the Study of Liver Diseases (AASLD):

AASLD and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), released the latest section of www.hcvguidelines.org.

The new section, “When and in Whom to Initiate HCV Therapy,” offers clinicians information on:

  • How to prioritize patients who will derive the most benefit, or will have the greatest impact on limiting further HCV transmission.
  • When to treat patients with complications such as advanced fibrosis, compensated cirrhosis, liver transplant, or severe extra-hepatic complications.
  • Additional conditions that warrant prioritization of treatment.

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A New Villain for Hepatitis C

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A recent article (Hepatology 2014; 59: 2403-12) notes a changing perception for Hepatitis C (HCV) genotype 3.  Previously, HCV genotype 3 was considered easy-to-treat with pegylated interferon and ribavirin.  Along with genotype 2, treatment for genotype 3 was given for half the duration as treatment for genotype 1; in addition, the response was much better than genotype 1 (~70-80% compared with ~50%).

With new treatments, the situation has changed.  In the U.S., genotype 1 accounts for about 70% of all infections and worldwide about 60% of all HCV infections.  In contrast, genotype 3 accounts for 10-15% of the world HCV reservoir.

Specific problems (alluded to by the authors) with genotype 3:

  • Increased steatosis
  • Increased liver fibrosis progression
  • Increased risk of hepatocellular carcinoma (HCC)
  • Increased risk of end-stage liver disease
  • Reduced sustained virological response (SVR) after direct-acting antiviral therapies

While the newest therapies have dramatically increased SVR rates for genotype 1 and improved treatment for genotype 2, this is not the case with genotype 3 thus far.  Instead of being a good genotype, genotype 3 is now a villain.

Another article provides additional data on HCV genotype 3 (Hepatology 2014; 60: 98-105).  In this study of U.S. Veterans with HCV (n=110,484), there were 8,337 with genotype 3.  In this group, despite being younger, they had a higher risk of cirrhosis (HR 1.40) and hepatocellular carcinoma (HCC) (HR 1.66) in comparison to HCV genotype 1.

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Probiotics for Hepatic Encephalopathy

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A recent open-label, randomized prospective study (Clin Gastroenterol Hepatol 2014; 12: 1003-08) indicates that probiotics (VSL#3) can be effective as primary prophylaxis of hepatic encephalopathy (HE) in at risk patients with cirrhosis.

While cirrhosis-related HE is an uncommon problem in pediatric gastroenterology/hepatology, there are few effective therapeutic options.  This study randomly assigned the 160 patients to groups given probiotics three times daily or to controls (no test article).  These patients were studied extensively including psychometric analysis, glucose hydrogen breath tests, critical flicker fusion, and lactulose hydrogen breath tests to assess orocecal transit time.

Key result: Three months of probiotics reduced HE scores.  Seven probiotic subjects developed overt HE which was significantly lower than the 14 patients in the control group (P<.05).

Bottomline: Probiotics may reduce the development of overt HE in patients with cirrhosis.

Does Chemotherapy Cause Hepatitis C Viral Relapse?

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A recent study (Clin Gastroenterol Hepatol 2014; 12: 1051-54) examined whether a sustained virological response (SVR) to hepatitis C (HCV)can be undermined by chemotherapy.

In this study with 30 patients who had an SVR before cancer diagnosis, chemotherapy, started at a median of 72 months after SVR, did not induce a viral relapse in any patient.

 

The Future is Now (for Hepatitis C)

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Three more impressive hepatitis C (HCV) studies have been published (in print):

  1. NEJM 2014; 370: 1973-82
  2. NEJM 2014; 370: 1983-92
  3. NEJM 2014; 370: 1993-2001

In the commentary on these three studies (pages 2043-47), the authors note that only a year ago, they had “speculated that highly effective interferon-free regimens would be available and should revolutionize the treatment of HCV infection…Now, we would have to say that the future is here.”

In the first study, “TURQUOISE-II,” 380 patients with Child-Pugh class A cirrhosis received either 12 weeks or 24 weeks of ritonavir (ABT-450/r), ombitasvir (ABT-267), dasabuvir (ABT-333) and ribavirin.  In the 12 week group, the sustained virologic response (SVR) was 91.8% whereas the 24 week group had an SVR of 95.9%.

In the second study, “PEARL-III and PEARL-IV,” 419 patients with genotype Ib and 305 patients with genotype 1a received 12 weeks of ritonavir, ombitasvir, dasavuvir, and ribavirin (or placebo) for 12 weeks.  For genotype 1b, SVR were 99.5% with ribavirin and 99% without ribavirin.  For genotype 1a, SVR were 97% and 90.2% respectively.

In the third study, “VALENCE,” among 419 patients with genotype 2 or 3 (21% with cirrhosis, and 58% previous interferon-based treatment), patients were treated with sofusbuvir-ribavirin or placebo for 12 weeks; the genotype 3 patients treatment was extended to 24 weeks (unblinded) after data emerged indicating a need for longer treatment course.  For the genotype 2 patients, SVR was met in 93%.  For genotype 3 patients, 85% who received a 24 week course had an SVR.

Key Points (from editorial):

  • In the first two studies, SVR was approximately 96% in untreated and treated patients without cirrhosis.
  • Patients with cirrhosis had a response rate of approximately 90%.
  • Ethnicity, IL28B, and baseline HCV RNA were not important factors in predicting response.
  • “In the era of potent DAA (direct-acting antivirals), …response-guided therapy is no longer necessary” because by week 4 of treatment, 99% of patients had non-quantifiable HCV RNA.
  • Drug resistance against these DAAs is common in preclinical studies; therefore, combination regimens are important.  “In the case of sofosbuvir and ledipasvir, a two-drug combination is sufficient…Sofosbuvir seems to have a high genetic barrier to resistance.”
  • “Perhaps the more important achievement of these interferon-free regimens is the lower rate and severity of side effects.”

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Treating HCV Helps Diabetics

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There is more data confirming that HCV treatment helps diabetic patients (Hepatology 2014; 59: 1293-1302).

Using a large National Health Insurance Research Database with more than 2.2 million Taiwanese residents diagnosed with diabetes, the authors were able to identiy 1411 HCV-treated patients, 1411 untreated patients, and 5644 uninfected/untreated controls.

Key results:

The risk of end-stage renal disease (ESRD), ischemic stroke and acute coronary syndrome (ACS) were all lower in the HCV-treated patients compared to untreated patients and compared to uninfected/untreated controls:

  • 84% reduction in the risk of ESRD
  • 47% reduction in the risk of ischemic stroke
  • 36% reduction in the risk of ACS

Why does HCV treatment reduce these diabetic complications? While the mechanisms have not been fully elucidated, it is “most likely mediated via viral clearance” which subsequently improves insulin resistance.

While this study has several limitations inherent to a study using a database, the design took efforts to minimize bias and confounding.

HCV Treatments: “Sticker Shock” or “Low Value”

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Two more commentaries/articles on hepatitis C virus treatments help with the perspective of cost.

In the first (Hepatology 2014; 59: 1246-49), the authors note that costs with HCV treatment have escalated along with improvements in SVR rates.  And, though the new 12-week therapy costs will exceed $84,000, they point out that current total cost of “therapy to achieve SVR…including management of complications, the price of treatment actually increases to $172,889 to $188,859 per SVR.”  They also note that HIV therapy averages $2000-$5000 a month and due to lifelong need, this exceeds more than one-half million dollars in treatment cost.  In addition, they note that gents like interferon have side effects that can be life-threatening. “Still, it remains unanswered if the new [HCV] agents are worth their price.”

In the second from GI Hep News, Panel calls new hepatitis C drug ‘low value.’

Here is an excerpt:

A panel of California medical experts says two new, once-daily drugs for hepatitis C represent low-value treatment alternatives for the condition because of their high price tags.

The drugs, Gilead Sciences’ sofosbuvir (Sovaldi) and Johnson & Johnson’s simeprevir (Olysio), cost more than $1,000 per pill, pushing the price for the recommended 12-week course of treatment of sofosbuvir to close to $90,000 and treatment with simeprevir to around $66,000, according to the California Technology Assessment Forum (CTAF), an independent group originally convened by the insurance industry to evaluate costs and benefits of treatments….

Replacing current care with sofosbuvir-based regimens would increase drug expenditures by $18-$29 billion per year in California alone, the report estimated. Gilead Sciences has maintained that the drug’s up-front costs are justified given that it could decrease the number of patients who ultimately suffer liver failure and need transplants. However, CTAF said it would take 20 years for payers to recoup two-thirds of the drug’s cost.

Take-home message: The newest and best HCV treatments are costly.  These drugs may really boost medical tourism where these drugs will be sold a lot more cheaply.

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