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

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)


HCV Guidelines

The AASLD-IDSA Recommendations for Hepatitis C Virus have been published (Hepatology 2015; 62: 932-954).  The entire report is accessible from hcvguidelines.org and from the link: HCV Guidance 2015. While having a hard copy is easy to work with, the HCVguidelines website is likely to remain more up-to-date.

A few recommendations to highlight:

  • #6. “Antiviral treatment is recommended for all patients with chronic HCV infection, except those with limited life expectancy due to nonhepatic causes (I-A)
  • #7. “If resources limit the ability to treat all infected patients immediately as recommended, then it is most appropriate to treat those at greatest risk of disease complications” (see Tables 3 and 4)
  • #8. “Use of noninvasive testing or liver biopsy is recommended in order to assess the degree of hepatic fibrosis and, hence, the urgency of immediate treatment. (I-A)”

Other Hepatology studies of interest, briefly noted:

Hepatology 2015; 62: 684-93.  Nucleos(t)ide analog “treatment does not increase the risk of renal and bone events in general.  Nucleotide analogs may increase the risk of hip fractures, but the overall event rate is low.”  This study examined 46,454 untreated chronic hepatitis B patients in comparison to 7,046 treated patients.

Hepatology 2015; 62: 715-25. This study looked at the safety of simeprevir and sofosbuvir in hepatitis C-infected patients.  “Adverse safety outcomes were similar to matched untreated controls, suggesting that safety events reflect the natural history of cirrhosis and are not related to treatment.”

Hepatology 2015; 62: 773-83. This study found that “NAFLD is independently associated with subclinical myocardial remodeling and dysfunction.”

Bruce Munro, Atlanta Botanical Gardens

Bruce Munro, Atlanta Botanical Gardens

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

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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HCV Website -No “Cat on The Roof”

A joke I heard a long time ago:

A guy asks his friend to check up on his cat while he is away on a trip.  He calls to see how kitty is doing.  His friend says, “Sorry but she died.”  In response, he tells his friend, “you should have broken me the news a lot more gently.  Maybe you could have said she was up on the roof and the next time I called it would have been easier to accept the news.”  A few years pass and he again asks his friend for a favor, this time to check up on his grandmother while he is away on a trip.  He calls to see how granny is doing.  His friend says, “Oh, she is up on the roof.”

The AASLD and “the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), announced the launch of a new website,HCVguidelines.org, that offers up-to-date recommendations for testing, managing, and treating hepatitis C virus (HCV) infection.”

The website clearly dismisses the previous established breakthrough treatments of telaprevir and boceprevir “because they are markedly inferior.”

For anyone who has been confused with the onslaught of new work on HCV, the website spells out in clear detail the best regimens for HCV treatment now that both sofusbuvir and simeprevir are available.

Bottomline: The website makes it clear that both telaprevir and boceprevir are up on the roof.

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Better HCV Treatments Approved

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.

Related blog posts:

Emerging Targets for Hepatitis C -Part 2

The best review on new therapies for HCV that I’ve read in quite a long time:

Hepatology 2013; 58: 428-38

First the abbreviations:

  • ASV -Asunaprevir
  • BOC -boceprevir
  • DAA -direct-acting antiviral
  • DCV -daclatasvir
  • DNV -danoprevir
  • NI -nucleos(t)ide inhibitor
  • NNI -nonnucleos(t)ide inhibitor
  • SIL -silibinin
  • SOF -sofosbuvir
  • TVR -telaprevir

More terminology:

  • First-generation NS3/4A protease inhibitors (TVR, BOC) are “defined as agents that display potent activity on HCV-1 but oppose a low barrier to selection of resistant viral variants and are not effective on all viral genotypes.”
  • Second generation NS3/4A protease inhibitors are “defined as agents that pose a high barrier to the development of viral resistance, retain activity against the viral variants that are resistant to first-generation compounds, and are active across all HCV genotypes.”
  • First-wave therapies are covalent linear inhibitors and second-wave therapies are either non covalent linear or macrocyclic inhibitors.

What are the weapons?

Some second-wave, first generation NS3/4A PIs: faldaprevir, asunaprevir, sovaprevir, simeprevir, danoprevir, and vaniprevir.  These agents have similar clinical efficacy as BOC and TVR but are easier to administer, usually once-a-day.  Some of these agents have better activity  against several genotypes.

MK-5172, 2nd-generation NS3/4A PI,  has pan-genotype activity & maintains antiviral activity against most mutations that confer resistance to 1st-generation PIs.

DCV, a NS5A inhibitor, has potent HCV activity but a low barrier for viral resistance; thus, it is likely to be used in combination with other agents.  Multiple NS5A inhibitors are in development.

SOF, a NS5B polymerase inhibitor, is being studied in interferon-free combinations.  Viral resistance has been rare in clinical studies with this agent.  Multiple other agents in this class are in study.

NS5B polymerase inhibitor NNIs bind to less conserved sites on HCV; thus, initial results have not been as promising.  Several NNIs, including setrobuvir and lomibuvir (& others), are being tested in combination in all-oral, interferon-free regimens.

SIL, a NS4B binding inhibitor, is an intravenous agent that has shown some efficacy in liver transplant patients.  Other oral agents, like clemizole, are being investigated.

How these agents may be useful:

  1. “The first step forward in anti-HCV therapy will be the introduction of a second-wave PI to used in combination with PEG-IFN/RBV.” Simeprevir, faldaprevir, and ritonavir-boosted danoprevir (DNV) will be easier to administer than TVR or BOC as they can be given once-daily.  In addition, these drugs are more active against genotypes 2, 4, 5, and 6.  In fact, ritonavir-boosted DNV in combination with PEG-IFN/RBV had 100% SVR efficacy for patients with HCV-4 in one trial.
  2. Next, will be NS5A and NS5B inhibitors to be used in combination with previous agents.  These agents will compete with second-wave PIs but “whether they will provide a true innovation in terms of viral cure rates, safety profile, or patient tolerability is still to be demonstrated.”  These agents work better with other DAAs.
  3. Finally, all-oral combinations will enter the market.  “The first all-oral anti-HCV regimen will be likely available in 2014 for HCV-2 and HCV-3 patients.”  SOF with RBV has had good success rates in previous studies.

Potential Problems:

  • Many of these investigational agents have been studied in easy-to-cure populations.
  • Lack of data in advanced fibrosis/cirrhosis.
  • Safety questions in post-transplant populations.
  • Affordability.  “It is possible that these innovative regimens will be confined to groups of patients in whom TVR/BOC or PEG-IFN/RBV are either ineffective or unsafe.”  Some patients may receive ‘maginally less effective and less tolerable drugs for cost-containing issues.’
  • Drug resistance.  This is likely to become a clinical problem with all oral IFN-free regimens. with TVR/BOC, resistance has limited significance due to HCV quasispecies reverting back to wild-type virus after stopping TVR or BOC.  It is unclear if this will be the case with other DAAs.



Emerging Targets for Hepatitis C -Part 1

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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