Category Archives: Hepatology

NASH Update -September 2015

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Briefly noted:

Obeticholic acid, a Farnesoid X Receptor Ligand, is being studied as a potential agent in nonalcoholic steatohepatitis (NASH).  According to a recent study (Lancet 2015; 385: 956-65), patients assigned to receive obeticholic acid were more likely to have improved liver histology compared with placebo (50/110 [45%] compared with 23/109 [21%]).  The  obeticholic group had increase serum cholesterol and LDL cholesterol. This study looked at a subgroup of patients in the FLINT study who had undergone liver biopsies.

E Vilar-Gomez et al. Gastroenterol 2015; 149: 367-78. This prospective study of 293 patients with histologically-proven NASH were followed after undergoing lifestyle changes for 52 weeks. At week 52, 88 subjects (30%) had lost ≥5% of their weight.  Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters (steatohepatitis, NAS activity score, and fibrosis.

G Lassailly et al. Gastroenterol 2015; 149: 379-88. Between 1994-2013, 109 morbidly-obese patients with histologically-proven NASH underwent bariatric surgery.  One year after surgery, NASH had disappeared from 85% of the patients.

P Angulo et al. Gastroenterol 2015; 149: 389-97. In this retrospective analysis of 619 patients with NAFLD (1979-2005), the authors noted that “fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.”

 

Days of Future Past and Declining Liver Graft Quality

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In the most recent ‘X-men’ movie (Days of Future Past), the disastrous future is averted by having Wolverine go back in time to correct a mistake. Overall, while there are a good number of movies that have used this trick, this particular movie is pretty clever. For whatever reason, this movie came to mind as I was reading a recent study: “Declining Liver Graft Quality Threatens the Future of Liver Transplantation in the United States” (ES Orman et al. Liver Transpl 2015; 21: 1040-50).  The authors extrapolate data from UNOS to assess what the liver transplantation (LT) picture may look like in 2030. Their results/conclusion:

“If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs.”  “The transplant community will need to accept inferior grafts and potentially worse post transplant outcomes and/or develop new strategies for increasing organ donation.”

The authors note that the national epidemics of diabetes and obesity will result in more cases of NAFLD-related liver failure while at the same time worsen the quality of available grafts. In the associated editorial, (RH Wiesner, pages 1011-12) the author emphasizes that the future is not quite so set.

  • the prevalence of diabetes and obesity in donors for 2030 might not be as great as feared; in addition, medical/surgical advances may diminish the complications associated with obesity
  • there will be a marked decrease in transplants due to hepatitis C virus related cirrhosis and hepatocellular cancer

His conclusion: “in the future, we will be using donor livers that we have never used before and will be achieving similar excellent results as we have today.” Which vision of the liver transplantation future is correct?

Related blog post: AASLD/NASPGHAN 2014 Guidelines for Evaluation of Pediatric …

Bison, Yellowstone

Bison, Yellowstone

Hepatitis C : New and Newer Treatments

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A recent study (KR Reddy et al. Hepatology 2015; 62: 79-86) shows that the combination of ledipasvir/sofosbuvir is a safe, effective therapy for patients with genotype 1 Hepatitis C (HCV) and compensated cirrhosis.

The authors performed a post-hoc analysis of seven clinical trials in 513 treatment-naive and previously treated patients; 69% were previously treated. Key findings:

  • Overall, 493 (96%) achieved an SVR12; 98% of treatment-naive patients achieved an SVR12.
  • However, many patients in this analysis had received ribavirin.  In those treated without ribavirin (ledipasvir/sofosbuvir alone), the SVR12 was 90%.
  • Most common adverse effects included headache (23%), fatigue (16-19%), and asthenia (14-16%).

Bottomline: While ledipasvir/sofosbuvir was effective in this population, the 90% SVR12 is not as good as 96%.  This leads to the question of whether ribavirin is needed as well.

Related & briefly noted: SA Alqahtani et al. Hepatology 2015; 62: 25-30.  Ledipasvir/sofosbuvir treatment (8-24 weeks) resulted in SVR of 97% (with or without ribavirin) among the 1952 patients treated in the ION-1, ION-2, and ION-3 studies.

Related blog posts:

From FDA (July 24th): FDA approves new treatment for chronic hepatitis C genotype 3 infections

“The U.S. Food and Drug Administration today approved Daklinza (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection….

The safety and efficacy of Daklinza in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis.”

From FDA (July 24th): FDA approves Technivie for treatment of chronic hepatitis C genotype 4

“The U.S. Food and Drug Administration today approved Technivie (ombitasvir, paritaprevir and ritonavir) for use in combination with ribavirin for the treatment of hepatitis C virus (HCV) genotype 4 infections in patients without scarring and poor liver function (cirrhosis).

Technivie in combination with ribavirin is the first drug that has demonstrated safety and efficacy to treat genotype 4 HCV infections without the need for co-administration of interferon, an FDA-approved drug also used to treat HCV infection…

The safety and efficacy of Technivie with ribavirin were evaluated in a clinical trial of 135 participants with chronic HCV genotype 4 infections without cirrhosis. Ninety-one participants received Technivie with ribavirin once daily for 12 weeks. Forty-four participants received Technivie once daily without ribavirin for 12 weeks. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 100 percent of the participants who received Technivie with ribavirin achieved a sustained virologic response. Of those who received Technivie without ribavirin, 91 percent achieved sustained virologic response.”

Garden of the Gods, Colorado Springs

Garden of the Gods, Colorado Springs

What is Driving Racial Disparities in Access to Living Donor Liver Transplants

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Recent articles highlight a huge gap in the availability of living donor liver transplants (LDLTs) when examined based on racial/ethnic background.

  • YR Nobel et al. Liver Transpl 2015; 21: 904-13.
  • A Doyle et al. Liver Transpl 2015; 21: 897-903.

What is the reason for this inequality?

The first study examined UNOS data from 2002-2014 among adult liver transplant recipients.  Of 35,401 recipients, 2171 (6.1%) received a LDLT.

Key findings:

  • Cholestatic liver disease: When compared with white patients, the odds ratios of receiving LDLT were 0.35 for African American, 0.58 for Hispanic, and 0.11 for Asian.
  • Noncholestatic liver disease: When compared with white patients, the odds ratios of receiving LDLT were 0.53 for African American, 0.78 for Hispanic, and 0.45 for Asian.
  • LDLT recipients were more likely to have private insurance

The second study did not look at racial/ethnic background but instead focused on other recipient factors.  Using a retrospective cohort of 491 consecutive patients, they determined that all of the following resulted in a lower likelihood of LDLT:

  • Single — OR 0.34
  • Divorced –OR 0.53
  • Immigrant — OR 0.38
  • Low income quintile — OR 0.44

Together these studies allow speculation on why there is such a disparity.

  • Financial costs, including lost wages, could preclude those with lower socioeconomic status from being available as donors
  • Distrust of donation system and/or fear of surgery

Bottomline: Racial/ethnic differences and financial resources are associated with significant access inequality to living donor liver transplantation.

Related blog posts:

Cascade Canyon, Grand Tetons

Cascade Canyon, Grand Tetons

 

Updated HCV Guidelines Published

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The American Association for the Study of Liver Diseases (AASLD) has published updated Hepatitis C guidelines. The complete guidance is available online at www.hcvguidelines.org.

An updated edition of Recommendations for Testing, Managing, and Treating Hepatitis C is now published in HEPATOLOGY. This condensed version of the Guidance includes a summary of recommendations regarding treatment with direct-acting antiviral drugs. Download the PDF now.

Authors are now able to cite the guidelines in their publications as an Accepted Article, doi: 10.1002/hep.27950.

Data on Drug-Induced Liver Injury

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Two recent studies provide complementary information regarding the causes and consequences of Drug-Induced Liver Injury (DILI).:

  • Chalasani N, et al. Gastroenterol 2015; 148: 1340-52.
  • Goldberg DS, et al. Gastroenterol 2015; 148: 1353-61.

The first study looked at 899 patients with DILI in the DILI Network which is a consortium of several academic institutions funded by the US National Institutes of Health.  Antimicrobials were the most commonly implicated agents (408 cases); however, dietary/herbal supplements were another common cause (145 cases).  Top 10 individual agents:

  • Amoxicillin-clavulanate (Augmentin) (n=91)
  • Isoniazid (n=48)
  • Nitrofurantoin (n=42)
  • Sulfamethoxazole/trimethoprim (n=31)
  • Minocycline (n=28)
  • Cefazolin (n=20)
  • Azithromycin (n=19)
  • Ciprofloxacin (n=16)
  • Levofloxacin (n=13)
  • Diclofenac (n=12)

Key findings:

  • Overall, 10% of patients with DILI died or required liver transplantation.
  • 18% developed chronic injury pattern; this was more common in patients with a cholestatic liver injury.
  • Mortality was high in patients with DILI and concomitant severe skin reactions.  Causative agents of DILI with either Stevens-Johnson Syndrome or Toxic epidermal necrolysis included azithromycin (n=2), lamotrigine (n=3); and one case for each of the following: moxifloxacin, diclofenac, carbamazepine, nitrofurantoin, and possible cephalexin (patient rec’d lamotrigine as well)
  • Preexisting liver disease increased the likelihood of mortality (16% versus 5%)

The second article, a retrospective cohort study using data from >5 million covered individuals over a 7-year span from Kaiser Permanente Northern California, identified 62 inpatients categorized as having definite or possible acute liver failure (ALF).  In this cohort, 32 (52%) had DILI.  Leading agents of DILI-ALF:

  • Acetaminophen n=18
  • Herbal/dietary supplement n=6. Chinese herbals (n=2), pine needle tea, saw palmetto, one unspecified herbal.
  • Antimicrobials n=2

Bottomline: Antibiotics and herbal supplements, both of which are often used without apparent benefit, can lead to liver failure

Related blog posts:

Soapes Creek, Atlanta

Soapes Creek, Atlanta

Financial Relief For Patients with Hepatitis C

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From AASLD:  AASLD Financial Help for patients with HCV

Are your patients struggling to afford the costs of Hepatitis C treatments?

A new program through the HealthWell Foundation may be able to help. The HealthWell Foundation has launched a new Hepatitis C Fund. The fund provides copayment assistance to eligible patients to ease the burden of out-of-pocket costs associated with the treatment of Hepatitis C. Since 2004, HealthWell has assisted more than 200,000 adults and children faced with medical emergencies in paying for life-changing treatments they otherwise would not be able to afford. These patients have insurance, and yet cannot afford their part. To determine eligibility and apply for assistance through the HealthWell Foundation’s Hepatitis C Fund, visit HealthWell’s website. Please lend a hand by spreading the word about the fund.

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An “Ally” For Hepatitis C Genotype 3

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A new study (Hepatology 2015; 61: 1127-35) shows that an all-oral 12 week treatment of daclatasvir (DCV) with sofosbuvir (SOF) is effective in the difficult-to-treat Hepatitis C virus (HCV) genotype 3 patients. In this study, the “Ally-3” phase III study, 101 treatment-naïve and 51 treatment experienced patients were treated with a daily regimen of DCV 60 mg and SOF 400 mg.

Key findings:

  • SVR12 was 90% in treatment-naïve, and 86% among in treatment experienced.
  • Among patients without cirrhosis, the SVR12 was 96%, compared with 63% of those with cirrhosis (based on FibroTest scores)

Related blog posts:

Bottomline: This new regimen is a promising addition to the new crop of HCV drugs which will be affordable when?

A second study (Hepatology 2015; 61: 1174-82) examined the minimum target pricing for direct-acting antivirals (DAA) for HCV.  Using data on manufacturing costs, derived in large part from experience with HIV antivirals, the authors calculate that a minimum cost for a 12-week course of combination DAA could be US $171-360 per person without genotyping and the drug costs alone from US $122-192 per person.  Of course, these costs are completely theoretical and complete fantasy, at least until 2027 when some of the patents expire.

Related post: HCV Treatments: “Sticker Shock” or “Low Value …

Briefly noted: Hepatology 2015; 61: 1261-68.  N=986 Koreans with HBsAg carrier status and 40 years of age or older.  FIB-4 is highly predictive of hepatocellular carcinoma (HCC) risk in those with chronic hepatitis B. FIB-4 was defined based on age x AST , PLTS, and ALT.  Since a high FIB-4 reflects liver fibrosis, it is not unexpected that high levels were associated with HCC. A FIB-4 >/= 2.4 showed an adjusted Hazard Ratio of 21.34.

“This Is A Stick Up — Your Money or Your Life”

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When I read a recent Hepatology editorial (Hepatology 2015; 61: 1106-8), I could not help think of the aforementioned title of this blog.

Here’s the scoop:

The two most commonly used medications for Wilson’s disease are trientine (Syprine) and D-penicillamine (Cupramine). For about 20 years, the original manufacturer of these medications kept the consumer cost at ~$1 per 250 mg tablet.  Currently the cost of Syprine is ~$200 per 250 mg tablet and Cuprimine costs ~$55 per 250 mg tablet.  This 200-fold increase translates into a yearly cost of ~$300,000.

How did this happen?

  • Little competition
  • Profit motive
  • Patients are reluctant to protest (they need this medication to be manufactured)

Why is this outrageous?

This increase in cost was not driven by any new discovery or research innovation.

Are there options?

Zinc is inexpensive and may be an option after initial period of chelation/normalization of liver biochemistries.  Zinc needs to be taken two to three times per day and “well away from meals for best absorption.”

Bottomline: These medication prices are outrageous.

Briefly noted:

  • “Molecular pathophysiology of portal hypertension”  Hepatology 2015; 61: 1406-15. Terrific review with excellent figures.
  • “Ezetimibe for the treatment of Nonacloholic Steatohepatitis” (MOZART trial) Hepatology 2015; 61: 1239-50. This randomized double-blind, placebo-controlled trial with 50 patients (biopsy-proven NASH) showed that Ezetimbe was not significantly different from placebo in histologic response rates, serum aminotransferases, or in magnetic resonance elastography findings.
  • Van Biervliet et al. “Clinical Zinc Deficiency as Early Presentation of Wilson Disease” JPGN 2015; 60: 457-9. Case report.

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Vaccine Proven Effective for Hepatitis E

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An important advance in Hepatology -more data showing efficacy of a Hepatitis E vaccine (N Engl J Med 2015; 372:914-922).

Here’s the abstract:

BACKGROUND

Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined. 

METHODS

In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years. 

RESULTS

During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups.

CONCLUSIONS

Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.)

Related blog post:

Briefly noted:

Experience with molecular adsorbent recirculating system (MARS). Lexmond WS, et al. Liver Transpl 2015; 21: 369-80. Editorial 277-78. n=20 over 10 years. From the editorial: “Although MARS therapy has been available for more than a decade, there have been no randomized controlled trials of its use in children…the time has come to get the data necessary to prove whether MARS has utility or not.” Related blog post: Living on MARS | gutsandgrowth

“Unrecognized Chronic Hepatitis C Virus Infection Among Baby Boomers in the Emergency Department.” Hepatology 2015; 61: 776-82. 102 of 1529 individuals were confirmed to have HCV infection. Interestingly, only 54% were successfully contacted by phone and of these only 21 had attended their initial visit with a liver specialist. Related blog post: Wiping out Hepatitis C | gutsandgrowth

From NY Times Twitter Feed (screenshot)

From NY Times Twitter Feed (screenshot)

Unrelated story/link (from NY Times): FDA Slow to Act on Diet Supplement Dangers