Category Archives: Hepatology

What’s Going on with Hepatitis A and Hepatitis B?

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Despite the excitement regarding Hepatitis C, Hepatitis A and Hepatitis B remain important challenges. Here’s the latest:

1. Collier MG, et al. “Hepatitis A Hospitalizations in United States, 2002-2011” Hepatology 2015; 61: 481-85. The authors examined the changes in demographics and frequency of HAV hospitalization during the study period. Key findings:

  • Rates of hospitalization dropped from 0.72/100,000 to 0.29/100,000.
  • Average age of hospitalized patient increased from 37.6 years to 45.5 years and more comorbidities were noted.
  • No changes were noted in length-of-stay or in-hospital deaths

2. DiBisceglie AM et al. “Recent US Food and Drug Administration Warnings on Hepatitis B Reactivation with Immune-Suppressing and Anticancer Drugs: Just the Tip of the Iceberg?” Hepatology 2015; 61: 703-11. Key recommendation: “There is good evidence to support routine screening of all patients for hepatitis B prior to undergoing chemotherapy or immunosuppressive treatment; use of prompt antiviral treatment appears to diminish the risk of severe or fatal reactivation of hepatitis B. Different organizations suggest disparate screening recommendations (Table 4).  AASLD suggests HBsAg, and anti-HBc.  CDC suggests adding anti-HBs.

3. Reddy KR, et al. Gastroenterology 2015; 148: 215-19, technical review 221-44.  AGA Guideline on the Prevention and Treatment of HBV Reactivation During Immunosuppressive Therapy. Key Recommendations:

  • Screen patients with HBsAg and anti-HBc, followed by a sensitive HBV DNA test if positive
  • Treat at-risk patients with antivirals with high barrier to resistance for at least 6 months after discontinuation of immunosuppressive therapy (except in patients taking B cell depleting agents who it is recommended to treat for at least 12 months afterwards)

Reactivation risk: (For all of the specifics — Full text article link)

  • High risk of reactivation (>10%): B cell depleting agents (eg. rituximab, ofatumumab), anthracycline derivatives (eg. doxorubicin, epirubicin), and daily moderate to high dose steroids (>10 mg) for at least 4 weeks.
  • Moderate risk of reactivation (1-10%): anti-TNF therapy, integrin inhibitors (eg. ustekinimab, vedolizumab), tyrosine kinase inhibitors, low-dose steroids daily (<10 mg/day) for at least 4 weeks (if HBsAg-positive but not if only anti-HBc-positive)
  • Low risk of reactivation (<1%): azathiopurine, 6-mercaptopurine, methotrexate.  No antiviral prophylaxis required.

For those interested in a more detailed summary of the recommendations: AGA Website HBV Reactivation Recommendations

4. Corsa AC et al. “No Resistance to Tenofovir Disoproxil Fumarate Through 96 Weeks of Treatment in Patients with Lamivudine-Resistant Chronic Hepatitis B. Clin Gastroenterol Hepatol 2014; 12: 2106-12.  This study followed 280 patients–no resistance to tenofovir was observed.

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“Mutant Ninja Viruses”

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Yesterday’s post “Understanding HCV Treatment Failures with Sofusbuvir” provided a summary of why patients with hepatitis C virus (HCV) genotype 3 may not respond to therapy. Now a terrific article (Hepatology 2015; 61: 471-80, editorial, titled “Mutant Ninja Viruses” 421-23) looks at why some patients with the favorable HCV genotype 2 may fail to respond.

By using extensive genotyping data and sequencing, the authors were able to determine why some patients with genotype 2 did not respond to combination therapy with ribavirin/sofusbuvir.  These patients were characterized by as genotype 2 based on Siemens VERSANT HCV Genotype INNO-LiPA 2.0 Assay.  This assay “looks at conserved sequences in the 5′ region of the virus.” However, these patients were genotyped as well using a technique to examine the 3′ region of the virus.  From among more than 2000 samples, the two assays gave divergent results in 0.5% of the cases with the 5′ end indicating genotype 2 and the 3′ end indicating genotype 1.

What is happening?

  • Detailed analyses of these discordant viruses showed that they were hybrid viruses with a crossover point located in the NS2/NS3 region.
  • In patients with these hybrid viruses, only 3 of 11 responded to therapy, indicating that they behave like genotype 1 patients.

Bottomline: “These novel viruses are true viral Ninjas hiding a challenging array of ‘difficult-to-cure’ genotype 1 enzymes under an ‘easy-to-cure’ genotype 2 coat.

Understanding HCV Treatment Failures with Sofusbuvir

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While the new treatments for hepatitis C have improved dramatically in terms of cure rates and side effects (and pharmaceutical companies bottom-line), there are still patients who do not respond, especially those with genotype 3.  A recent study (Hepatology 2015; 61: 56-65) has provided some information into why this is happening.

A division of the FDA looked into five sofosbuvir (SOF) trials and performed sequencing to characterize potential resistance-associated substitutions.

Key findings:

  • Nonstructural protein 5B (NS5B) substitutions, L159F and V321A, emerged in 2.2%-4.4% of subjects who failed SOF treatment.
  • Baseline substitutions in 316 were associated with a reduced response in HCV genotype 1b subjects.
  • This study identified only 11 patients with genotype 3 with potentially relevant substitutions.

Bottomline: In the vast majority of patients, no resistance-associated substitution could be identified, indicating that we have a lot to learn why some patients are not responding.

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Theses Eggs Contain Eggs!

Theses Eggs Contain Eggs!  Is the “allergen information” really necessary in this case?

EXCEPTIONal Outcomes and Liver Allocation

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A recent study (Hepatology 2015; 61: 285 & editorial 28-31) takes a closer look at US liver organ allocation and outcomes.

The editorial notes that our allocation in the US is targeted towards “need.” Since February 2001, the MELD score was adopted with “the stated aim of reducing deaths on the waiting list.”  Other potential aims:

  • Equity –so any one who might benefit from a graft has an equal chance and a first-come, first-served approach is adopted
  • Utility –organs are allocated to the recipient who is likely to have the best outcomes
  • Benefit –organs are allocated to the patient who has the greatest benefit, so taking into account the risks of dying with and without a transplant
  • Fairness — ‘an ill-defined combination of all the approaches’

The editorial notes that “despite the concerns the approach has been highly effective in achieving its goal in reducing waiting list mortality.”

“Like any system, it can be manipulated and, given the life-saving nature of transplantation, it is scarcely surprising that both legal and illegal methods have been adopted to artificially raise the MELD score and distort allocation.”

The study reviewed 78,595 adult liver transplant candidates (2005-2012).  27.3% of the waiting list was occupied by candidates with exceptions.

Candidates with exceptions fared much better on the waiting list compared to those without exceptions in mean days waiting (HCC 237 versus non-HCC 426), transplantation rates (HCC 79.1% versus non-HCC 40.6%), and waiting list death rate (HCC 4.5% versus non-HCC 24.6%).

The editorialists recommend that “we should consider diverting some of the resources used to develop and implement a perfect allocation scheme into increasing the number of donors and livers used for transplant and, in the longer term, finding treatments and interventions that will render liver transplantation a treatment of historic interest.”  Now that’s a lofty goal.

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Liver Update -January 2015

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Briefly noted:

1. Gastroenterology 2014; 147: 1327-37 (editorial 1216-18).  “Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.” 66 patients received VSL#3 (9 x 10 to the 11th bacteria), 64 patients received placebo -both groups studied for 6 months. Treatment with lactulose and rifaximin were withdrawn a week prior to study entry. Key findings: ‘fewer hospitalizations for severe encephalopathy, better quality of life, and decreases in Child-Turcotte-Pugh class and Model for End-Stage Liver Disease.’  Hazard ratio for preventing hospitalization with VSL#3 was 0.52. However, the findings did not show that VSL#3 reached a statistically-significant reduction in recurrence rate for hepatic encephalopathy. No adverse events were noted.

2. NY Times: Gilead sued over cost of Sovaldi.

3. N Engl J Med 2014; 371:2375-2382.  Link to abstract: Interferon-free Antiviral Regimen for HCV after Liver Transplantation:  “Treatment with the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population.”

4. “Transplantation Traffic –Geography as Destiny for Transplant Candidates” NEJM 2014; 271: 2450-52.  Describes ongoing geographic inequality in organ distribution and obstacles to improving allocation.

5. Liver Transpl 2015; 21: 57-62. Immediate Extubation After Pediatric Liver Transplantation –feasible in 67% according to this retrospective review.

Local Law Office --Truth in Advertising?

Local Law Office –Truth in Advertising?

HCV: When to Spike the Ball

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When a team scores a touchdown in football, often one sees a player spike the ball in celebration.  The equivalent of spiking a ball rarely happens in medicine.  That being said, a recent study (Hepatology 2015; 61: 41-45) indicates that after treatment sofosbuvir regimens, you can celebrate if you have a sustained virological response (SVR) at 12 weeks (SVR12).

The authors conducted a retrospective review of five trials with 863 patients with HCV genotypes 1-6.  “Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24.” Of the patients who relapsed, most (77.6%) did so within 4 weeks of completing therapy.

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How Common is Hepatitis E in the U.S.?

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In a recent study (Hepatology 2014; 60: 815-22), data from the National Health and Nutrition Evaluation Survery (NHANES) 1988-94 was compared with the NHANES 2009-2010 with regard to Hepatitis E virus (HEV) epidemiology.  In addition, the most recent surgery coupled with a high performance HEV assay.  A total of 8,814 individuals were included in the analysis.

Key findings:

  • The seroprevalence of HEV was estimated at 6.0% in the U.S. which is only one-third as high as previous estimates.
  • Birth outside the U.S., Hispanic race, and increasing age were all factors associated with increased HEV seroprevalence.  The associations of hispanic origin and birth outside U.S. as risk factors disappear when age is taken into account.

Also noted: Hepatology 2014; 60: 1082-89.  “Liver transplantation in the management of porphyria” –useful review.

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Magnetic Resonance Elastography in Nonalcoholic Fatty Liver Disease

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A recent study (Hepatolology 2014; 60: 1920-8) shows that magnetic resonance (MR) elastography can be an accurate noninvasive tool to assess liver fibrosis.

Background: Assessing severity of liver fibrosis provides important prognostic information in patients with nonalcoholic fatty liver disease (NAFLD); however, these patients are often obese which decreases the success of transient elastography.  In addition, high hepatic fat content may alter the results of transient elastography.  Hence, an alternative noninvasive technique is desirable.

Design: Prospective study with 117 consecutive patients with biopsy-proven NAFLD who also underwent 2D-MR elastography between 2011-2013.

Results:

  • Fibrosis stage: stage 0 n=43, stage 1 n=39, stage 2 n=13, stage 3 n=12, stage 4 n=10.
  • MR elastography identified stage 3-4 with an accuracy of 0.92, with little overlap between advanced (F3-4) and non-advanced (F0-2) values.  The specificity, sensitivity, positive/negative predictive values, and cutoff values are detailed in Table 2.
  • Figure 3 provides a cool picture demonstrating the different MR elastography stiffness heat maps correlated with liver fibrosis. Link to similar web-based image from Siemens.

Bottomline: This technology allows a noninvasive measure of liver fibrosis in NAFLD patients and will probably be of use in other liver conditions.  Given the fact that a liver biopsy is more risky and often expensive, this technology and other noninvasive markers of advanced liver disease will be important tools.

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What is the Role of Ursodeoxycholic Acid in Primary Sclerosing Cholangitis?

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While previous studies of ursodeoxycholic acid (UDCA) at high doses (28-30 mg/kg/day) have been shown to have detrimental effects, a number of randomized controlled trials (RCTs) have shown that low-dose UDCA has been associated with biochemical improvements but no differences in endpoints like death, liver transplantation or cholangiocarcinoma.  Given this conflicting information, a new study (Hepatology 2014; 60: 931-40, editorial 785-88) has examined the effects of withdrawal of low-dose UDCA.

In this cohort, the median age was 34 years, “62% were male, 69% had IBD, 19% had cirrhosis, and the baseline UDCA dose was 10-15 mg/kg/day.”

Key findings:

  • “At 3 months, discontinuation of UDCA in patients with PSC causes significant deterioration in liver biochemistry and influences concentrations of bile acid metabolites.”
  • Alkaline phosphatase increased 75.6%, GGT increased 117.9%, bilirubin increased by 50%, aspartate aminotransferase increased by 45.0%, and alanine amiontransferase increased by 63.9%
  • The Mayo Risk Score for PSC (associated with PSC prognosis) also increased 0.5 points from baseline.

Conclusion (from editorial): “there may still be a role for judicious use of UDCA in patients with well-compensated disease.”  A suggested “yet unproven” algorithm for use of UDCA is noted in Figure 1 pg 787 and considers UDCA for patients with alkaline phosphatase >1.5x ULN and/or PSC-associated symptoms like pruritus.  If no clinical improvement within 6 months, then stopping UDCA is recommended.

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PEG vs Lactulose in Hepatic Encephalopathy

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In a study (JAMA Intern Med. Published online September 22, 2014. doi:10.1001/jamainternmed.2014.4746) with 50 participants, PEG was more effective than standard therapy of lactulose for hepatic encephalopathy.  PEG vs Lactulose (HELP study) Abstract.

Here’s an excerpt:

Design, Setting, and Participants  The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE.

Interventions  Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization…

Results  Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01)… The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.

Conclusions and Relevance  PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE.

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