Liver Briefs -July 2019

NH Ebel et al. JPGN 2019; 68: 788-92Hepatic venous pressure gradient (HVPG) did not correlate with the risk of complications from portal hypertension in this pediatric cohort (n=41); this is in contrast to studies in adults showing the utility of HVPG measurements.

AG Singal et al. Gastroenterol 2019; 156: 2149-57. AGA Practice Update on Direct-Acting Antivirals for Hepatitis C and Hepatocellular Carcinoma. There are 12 best practice advice –here are the first three:

  • BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.
  • BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment.
  • BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance

N Hamdane et al. Gastroenterol 2019; 156: 2313-29. This study found that chronic HCV infection induced specific genome-wide-changes in H3K27ac which correlated with expression of mRNAs and proteins.  These epigenetic changes persisted after an SVR to DAAs or interferon-based therapies. These changes could explain some of the reason why HCC remains a risk after successful treatment with DAAs.

DT Dieterich et al. Gastroenteroloy & Hepatology 2019; 15S: 3-11 Link: “A simplified algorithm for the management of Hepatitis C Infection”  An excerpt:

“The algorithm begins with universal HCV screening and diagnosis by testing for HCV antibody with reflex to polymerase chain reaction to detect HCV RNA. The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. Unless clinically indicated, on-treatment monitoring is optional. Confirmation of cure (undetectable HCV RNA 12 weeks posttreatment) is followed by harm-reduction measures, as well as surveillance for hepatocellular carcinoma every 6 months in patients with advanced fibrosis/cirrhosis.”  My take: This algorithm is much simpler than the expanded recommendations from HCVguidelines.org website, though these agents, to my knowledge, do not yet have a pediatric indication.

 

Liver Briefs -June 2019

YH Yeo et al. Hepatology 2019; 69: 1385-97.  The prevalence of high risk individuals in the U.S. who are susceptible (not immune) to hepatitis B has decreased from 83% to 69% from 2003 to 2014.  That still leaves 64 million who would benefit from HBV vaccination.

M Sharma et al. Hepatology 2019; 69: 1657-75. This meta-analysis compared therapies for primary prevention of esophageal varices and concluded that nonselective beta-blocker (NSBB) monotherapy may decrease all-cause mortality and carried a lower risk of serious complications than variceal band ligation (VBL). However, the commentary (1382-84 by L Laine) reaches a different conclusion. “Current recommendations for primary prevention with VBL or NSBB or carvediolo still appear to be acceptable…using a shared decision-making approach” to weigh issue such as daily medication or periodic endoscopy.

J Nguyen et al. J Pediatr 2019; 207: 90-6. This study modeled the cost-effectiveness of early treatment with direct-acting antiviral therapy in adolescents with hepatitis C infection.  With pangenotypic agenst, the cost would be $10000 to $21000 per QALY gained.

S Trinh et al. Clin Gastroenterol Hepatol 2019; 17: 948-56. This retrospective hepatitis B study examined the changes in renal function between 239 tenofovir disoproxil fumarte (TDF) treated patients and 171 entecavir treated patients.  Key finding: TDF was not associated with higher risk of worsening renal function in this cohort with a mean followup of 43-46 months in patients with baseline normal renal function.  In patients with renal impairment, deterioration of renal function was noted in TDF-treated patients.  Thus, TDF should be avoided in patients with impaired renal function.

 

Rhododendrom in Sandy Springs

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December Liver Briefs

B Wildman-Tobriner et al. Gastoenterol 2018; 155: 1428-35.  This retrospective study which pooled data from 3 phase 2a trials with 370 subjects with nonalcoholic fatty liver disease (NAFLD) found that MRI iwth proton density fat fraction (PDFF) “did not accurately identify patients with NAS ≥4 (AUROC – 0.72) or fibrosis stage ≥3 (AUROC =0.66).”  Thus, this study indicates that currently liver histology remains the gold standard to determine severity of liver damage in paitents with NAFLD.

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P Nahon et al. Gastroenterol 2018; 155: 1436-1450. This study looks closer at whether direct-acting antivirals (DAA) for hepatitis C could increase the risk of hepatocellular carcinoma (HCC) in patients (n=1270) with cirrhosis. The authors found that the crude 3-year cumulative incidence of HCC were 5.9% in the DAA and 3.1% in the SVR-IFN group. However, after Cox analysis, “we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89).”  The authors indicated that patient characteristics (age, diabetes, reduced liver function) and lower screening intensity were the reasons for the increased crude rates of HCC.

Related blog post: Liver Short Takes December 2017

Love this sign –it indicates the truth of the saying:  ‘common sense is not that common’ (attributed to Voltaire)

Direct-Acting Antivirals in Patients Without Advanced Hep C Liver Disease

A recent study (LI Backus et al. Hepatology 2018; 68: 827-38, editorial 804-06) indicates that direct-acting antivirals (DAA) improve mortality in patients with hepatitis C virus (HCV) without advanced liver disease.

Using a registry from the Veterans Affairs, the authors identified 40,664 treated with interferon-free DAA regimens.  Overall there was a 96.8% sustained virologic response (SVR).  These patients were compare with 62,882 patients who did not receive DAA and without apparent advanced fibrosis.

Background: Long-term benefits have been established in patients with HCV and advanced fibrosis who have had viral eradication with DAA regimens with less hepatic decompensation and less hepatocellular carcinoma.

Key findings:

  • SVR in this cohort was associated with a 59% unadjusted reduction in all-cause mortality when compared to those who did not achieve SVR and a 69% reduction compared to the untreated cohort.
  • In absolute terms, 1-year mortality rates were reduced by 1.3% with SVR compared to treated group without SVR and by 2.9% compared to no treatments.

These declines in mortality occurred despite the fact that DAA-treated patients had more comorbid conditions and similar access to providers among the three groups.  The findings in this population of veterans will need to be replicated in other populations.

My take: This study is a big leap forward by showing that even in groups without advanced fibrosis, treatment with DAA improved a significant clinical endpoint not just a biomarker.  There are likely other unmeasured benefits in terms of health and quality of life that are likely to accrue after viral eradication

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Lake Louise, Banff

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.

An “Ally” For Hepatitis C Genotype 3

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)

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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.

A New Villain for Hepatitis C

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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