HCV Treatment and “MELD Purgatory”

A recent study (A Kwong et al. Liver Transplantation 2018; 24: 735-43) and associated editorial (P Martin, pg 727-8) highlight an unintended consequence of HCV therapeutic success –“MELD purgatory.”

The study notes that with the availability of more effective direct-acting antivirals for HCV, there has been a decrease in wait-list mortality and a decrease in disease severity.  This was determined by reviewing 3 timed cohorts (2004 n=2408, 2009 n=2402, and 2014 n=2817) from the Organ Procurement and Transplantation database.

  • For example, the 2014 had a 21% lower risk of wait-list death (HR 0.79) than the 2009 cohort.  This is in contrast to other (non-HCV) disease in which there was no change in mortality.
  • Also, the MELD rate of change was 2.35 per year for the 2009 cohort compared to 1.90 for the 2014 group.
  • In their discussion, the authors note that while patients with HCV can achieve a sustained virologic response, those with advanced liver disease still need liver transplantation.  In these patient, there is a much lower prospect of attaining a high enough MELD score to receive organ offers –“leaving them with persistent complications and a decreased quality of life.”  This situation has been termed “MELD purgatory.”

The editorial notes that in the five years since the introduction of sofosbuvir, HCV has been displaced as the single commonest indication for liver transplantation by nonalcoholic fatty liver disease.  These agents have led to a decrease in advance HCV-related liver disease.  In addition, in the past, HCV infection had near universal recurrence after transplantation and this is no longer the situation.

My take: Undeniably, the advent of DAA have made a huge dent in progressive HCV liver disease. However, those with advanced liver disease may be stuck in a purgatory between good health and poor quality of life even after clearance of HCV infection.

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Interleukin 6 and Liver Disease Mortality

Briefly noted: J Remmler et al. Clin Gastroenterol Hepatol 2018; 16: 730-7.  This retrospective study with 474 patients showed that blood levels of interleukin 6 were associated with mortality.  In this cohort, those with levels in the lowest quartile (< 5.3 pg/mL) had zero fatalities within 1 year.  In those with the highest quartile (37 pg/mL or more), had a 67.7% mortality rate within 1 year.  The associated editorial (pg 630-32) notes that IL6 functions include liver regeneration, infection defense, and metabolic homeostasis.  “IL6 is synthesized during inflammatory conditions…persistent activation of the IL6 pathway may have detrimental effects in the livers and in other tissues.”

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New Treatment for Primary Biliary Cholangitis

Another treatment is emerging for biliary cholangitis (PBC):  C Corpechot et al (NEJM 2018; 378: 2171-81) shows that an inexpensive medication, bezafibrate, is effective in patients with PBC who have not responded adequately to ursodeoxycholic acid. An associated editorial (2234-35 by Elizabeth Carey) notes that this medication is not available in the U.S., though a similar medicine, fenofibrate “has shown similar efficacy” in PBC (off-label).

Comprehensive 2018 AASLD Guidance for Chronic Hepatitis B

NA Terrault et al. Hepatology 2018; 67: 1560-99. Here’s the full link: Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance

Some of the key points:

Table 4 (pg 1565): provides a refresher on interpretation of serology

Table 5 (pg 1567): Children and Adults Who Are HBsAg Positive:

  • Can participate in all activities, including contact sports
  • Should not be excluded from daycare or school participation and should not be isolated from other children
  • Can share food and utensils and kiss others

Figure 1 (pg 1571) Treatment algorithms.

  • For both HBsAg-positive/HBeAg-positive and HBsAg-positive/HBeAg-negative patients, treatment is recommended if ALT ≥2 x ULN.
  • For both groups, treatment is NOT recommended for those with ALT ≤ULN and low HBV DNA levels (<20,000 IU/mL for HBeAg-positive and <2,000 IU/mL for HBeAg-negative).
  • In those who do not fall into these categories, ongoing monitoring is recommended

Figure 1 from AASLD Guidance Link

Guidance Statements for HCC Screening in HBsAg‐Positive Persons

  • All HBsAg‐positive patients and high risk adults (see page 1574) with cirrhosis should be screened with US examination with or without AFP every 6 months.
  • There are insufficient data to identify high‐risk groups for HCC in children. However, it is reasonable to screen HBsAg‐positive children and adolescents with advanced fibrosis (F3) or cirrhosis and those with a first‐degree family member with HCC using US examination with or without AFP every 6 months.

Treatment: 

  • In adults: The AASLD recommends peg‐IFN, entecavir, or tenofovir (TDF) as preferred initial therapy for adults with immune‐active CHB
  • In children: The AASLD suggests antiviral therapy in HBeAg‐positive children (ages 2 to <18 years) with both elevated ALT and measurable HBV‐DNA levels, with the goal of achieving sustained HBeAg seroconversion.

Perinatal transmission:

  • The AASLD suggests antiviral therapy to reduce the risk of perinatal transmission of HBV in HBsAg‐positive pregnant women with an HBV‐DNA level >200,000 IU/mL..The only antivirals studied in pregnant women are lamivudine, telbivudine, and TDF. Of these 3 options, TDF is preferred to minimize the risk of emergence of viral resistance during treatment. Interim studies show high efficacy of TDF in preventing mother‐to‐child transmission.
  • The infants of all HBsAg‐positive women should receive immunoprophylaxis (HBV vaccination with or without hepatitis B immunoglobulin, per World Heath Organization and Centers for Disease Control and Prevention recommendations)

Treatment & prevention of HBV reactivation in patients receiving immunosuppressive or cytotoxic drugs (section 6 pages 1577-9)

  • HBsAg and anti‐HBc (total or immunoglobulin G) testing should be performed in all persons before initiation of any immunosuppressive, cytotoxic, or immunomodulatory therapy.
  • HBsAg‐positive, anti‐HBc–positive patients should initiate anti‐HBV prophylaxis before immunosuppressive or cytotoxic therapy.
  • HBsAg‐negative, anti‐HBc–positive patients could be carefully monitored with ALT, HBV DNA, and HBsAg with the intent for on‐demand therapy, except for patients receiving anti‐CD20 antibody therapy (e.g., rituximab) or undergoing stem cell transplantation, for whom anti‐HBV prophylaxis is recommended.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Liver Shorts May 2018

VL NG et al. J Pediatr 2018; 196: 139-47. This study with 148 children examined the neurodevelopmental outomes of young children with biliary atresia (ChiLDRen Study). Key finding: Children with their native livers were at increased risk for neurodevelopmental delays at 12 and 24 months.  This risk was more than 4-fold increased among those with unsuccessful Kasai procedure.

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WS Lee et al. J Pediatr 2018; 196: 14-20. Updated review on hepatopulmonary synddrome (HPS) and portopulmonary hypertension (POPH).  Figure 1 graphically shows the difference in pathophysiology.  HPS hallmark is intrapulmonary vascular dilatation.  POPH is characterized by progressive remodeling of the wall (thickening & vasoconstriction) of small pulmonary arteries.

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JA Woo Baidal et al. Hepatology; 2018; 67: 1339-47. This prospective cohort study with 528 children showed that increased Vitamin E intake in early childhood, based on validated food questionnaires, correlated with lower ALT values in mid-childhood.  Children with higher intakes “had lower odds of elevated mid-childhood ALT” (adjusted odds ratio of 0.62) when comparing quartiles 2-4 to the lowest quartile.  The authors note that Vitamin E is present in foods that are more often consumed in “healthful diets, such as wheat germ, almonds, spinach, and broccoli, as well as cooking oils.”

J Pfeiffenberger et al. Hepatology 2018; 67: 1261-69. The retrospective multicenter study with 282 pregnancies in 136 women with Wilson’s disease (WD), showed good outcomes. Aggravation of neurologic symptoms was rare (1%) (though tended to persist), liver test abnormalities (6%) resolved in all cases after delivery. Birth defect rate of 3% and spontaneous abortion rate of 26%; rthough, patients receiving treatment with zinc and D-penicillamine had lower spontaneous abortion rates, (10% and 17%, respectively) than those without treatment.  Chelation therapy resulted in no increase in the rate of birth defects compared to the general population.

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F Bril et al. Clin Gastroenterol Hepatol 2018; 16: 558-66. This prospective study of adults with biopsy-proven NASH (52 with diabetes and 49 with prediabetes) found that pioglitazone treatment was associated with a reduction in the primary outcome, NAFLD activity score by 2 or more points, in 48% of those with type 2 diabetes and 46% of those with prediabetes. And, with a resolution of NASH in 44% and 26% respectively.

 

Big Creek Greenway near McFarland

HBV Reactivation Risk with HCV DAA Therapy and What to Do About It

A recent prospective study (C-J Liu et al. Gastroenterol 2018; 154: 989-97) provided some reassurance about the likelihood of hepatitis B virus (HBV) reactivation during hepatitis C virus (HCV) treatment with direct-acting antivirals (DAA).

In this study with 111 patients with both HCV and HBV treated with ledpasvir/sofusbuvir, all (100%) of the patients had a sustained virologic response for their HCV infection. Other key findings:

  • Of the 37 patients with baseline HBV DNA < 20 IU.mL, 31 (84%) developed detectable HBV DNA levels through posttreatment week 12.
  • Of the 74 patients with baseline HBV DNA >20 IU/mL, 39 (53%) developed increases in HBV DNA >1 log10 IU/mL through posttreatment week 12.
  • 5 patients developed ALT >2 times ULN and 3 patients were started on HBV therapy.

The associated editorial (pgs 795-8) made the following recommendations:

  • “HBsAg-negative/HBcAb-positive patients should be monitored with ALT alone until SVR12 and should be tested with HBsAg +/- HBV DNA only if ALT increases or fails to normalize on therapy.”
  • “HBsAg-positive patients with undetectable baseline HBV DNA should be considered for preemptive anti-HBV treatment, or monitored with ALT and HBV DNA until SVR12”
  • “HBsAg-positive patients with positive baseline HBV DNA should be started on preemptive anti-HBV treatment until SVR12.”

Using the above management strategy will limit the number of HBV-infected patients who need to be treated.

My take: This study and the associated editorial provide useful information regarding DAA in coinfected HBV/HCV patients; this is important for patients and practitioners, especially given the black box warning on DAA medications.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Assessment of Organ Donation –MRI Often Precludes Need for a Liver Biopsy

A recent retrospective single-center study (J Satkunasingham et al. Liver Transplantation 2018; 24: 470-77) shows that MRI is a good tool to assess hepatic steatosis.  In total there were 144 liver donor candidates; a subset of 32 underwent liver biopsy.

When examining magnetic resonance spectroscopy (MRS) and MRI -proton pump density fat fraction (PDFF), the authors found that MRS-PDFF and MRI-PDFF had 95% and 100% negative predictive value in identifying patients with clinically  significant histologic steatosis (≥10%).

The associated editorial by James Trotter (pg 457-58) makes several important points:

  • Currently living donor transplantation in the U.S. accounts for 4% of all transplants
  • In his center (and most centers), protocol biopsy are not required prior to liver donation.  The main indications for donor liver biopsy are biochemical dysfunction or steatosis on imaging studies.

My take (borrowed from editorial): “Noninvasive estimation of hepatic steatosis is sufficiently accurate to forgo liver biopsy in most donors, although ultimately this decision will continue to rest with the individual center.”