Tag Archives: hepatitis C

Can Hepatitis C really be cured?

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While many have equated a sustained virologic response (SVR) as a cure for hepatitis C virus (HCV), there have been concerns about “occult” hepatitis C.  A new study indicates that in the vast majority of patients with an SVR, there is “no evidence of ongoing HCV replication…and no evidence that HCV replicates in PBMCs of chronically infected patients” (Hepatology 2013; 57: 483-91, editorial 438-40).

There has been no disagreement that an SVR is associated with improved liver histology, improved clinical symptoms, often a reversal of fibrosis, and lower risk of hepatocellular carcinoma.  However, the study and the accompanying editorial summarize the disparity in studies about the potential for occult HCV and how the virus has been identified in the peripheral blood mononuclear cells (PBMCs) and livers of patients who have had an SVR.

The study examined 67 chronic HCV carriers and examined the liver and other tissues of 2 spontaneously recovered chimpanzees.

Key findings:

  • The authors confirm that HCV RNA can be detected in PBMCs in chronic HCV carriers, but only as nonreplicating virus; therefore, it is probably not harmful to the host or to others.
  • Healthy controls had HCV passively adsorbed to PBMCs in vitro becoming indistinguishable from the HCV RNA in PBMCs of chronic HCV carriers
  • HCV RNA could not be detected in the PBMCs of 59 presumed recovered subjects using a highly sensitive nested PCR assay (measure down to 10 IU)
  • In total, this study and others support the likelihood of absolute HCV clearance in most patients with either spontaneous or treatment-induced recovery

Editorialist recommendation: “it seems appropriate to perform virology and biochemical screening annually…particularly if…there was histologic evidence of fibrosis or cirrhosis”

Related blog entries:

Understanding IL28B

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Interleukin-28B (IL28B) has been a phenomenal discovery in the field of hepatitis C (HCV); yet, with the emergence of direct-acting antiviral (DAA) agents, its importance has been overshadowed.  While the long-term significance of IL28B is unclear, for now, it has significant clinical utility.  Three reviews/commentaries help elucidate its role:

▪                Hepatology 2012; 56: 361-66. IL 28B Genetics and Biology

▪                Hepatology 2012; 56: 367-372 Clinical Utility of IL28B

▪                Hepatology 2012; 56:  373-380 Relevance of IL28B in age of DAAs

Key points from these references:

African-Americans are less likely to respond to treatment with pegylated interferon (PEGIFN) (and ribavirin [RBV]) in large part due to a low frequency of favorable alleles (C/C genotype) to IL28B.

Predictors of response to treatment with PEGIFN/RBV:

▪                CC IL28B genotype: OR 5.9 (compared to non-CC genotype)

▪                HCV RNA level ≤600,000 IU/mL: OR 3.1 (compared to >600,000 IU/mL)

▪                Degree of fibrosis, metavir F0-2: OR 2.7 (compared with F3-F4)

▪                Rapid virological response: OR 9.1 (compared with non-RVR non CC genotype)

Overall CC genotype is associated with double the sustained virological response (SVR).

Vitamin D also plays an important role in innate immunity and deficiency is associated with lower SVR.

Algorithm for use of IL28B (applicable to patients ≥18 years):

▪                Consider obtaining IL28B in all genotype 1 patients:  

▪                If CC genotype and does not have risk factors for poor response (including cirrhosis, high viral load), then likely to treat with PEGIFN/RBV and monitor for RVR.  In patients without RVR, addition of DAA would be reasonable.

▪                If risk factors for poor response or if non-CC genotype (C/T or T/T), then consider use of DAA at onset of therapy

DAAs are expensive.  Boceprevir (BOC) costs $26,000 for 24 weeks & $48,000 for 44 weeks.  Telaprevir (TVR) costs $49,000 for 12 weeks.  These costs are in addition to costs for PEGIFN/RBV which is approximately $30,000.  The cost of testing IL28B status is approximately $300.

In patients with CC IL28B genotype, the main advantage of DAAs may be to shorten treatment course by increasing the likelihood of RVR; though with TVR, the SVR was improved even among CC genotype patients in the “ADVANCE” trial (90% compared with 64%).  In non-CC IL28B genotype, TVR or BOC is associated with > 2-fold increase in SVR.  The specific response rates for both TVR and BOC are available in these references.

Related blog entries

Pediatric HCV Guidelines

Increased ferritin predicts poor response in Hepatitis C

Unknown unknowns for Hepatitis C

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Unknown unknowns for Hepatitis C

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“ [T]here are known knowns; there are things we know that we know.
There are known unknowns; that is to say there are things that, we now know we don’t know.
But there are also unknown unknowns – there are things we do not know, we don’t know.		 ”
—United States Secretary of Defense, Donald Rumsfeld February 2002

Reading a recent epidemiology article reminded me of the preceding referenced quote  (Hepatology 2012; 55: 1652-61).  This study took a close look at knowledge of being infected with hepatitis C virus (HCV) and what HCV infection may indicate.

The study identified 30,140 participants through the National Health and Nutrition Examination Survey (NHANES) conducted from 2001-2008.  The Centers for Disease Control (CDC) obtains nationally representative data on the health and nutritional status of noninstitutionalized civilians across the U.S.  NHANES uses a ‘complex, stratified, and mulitstage probability sampling design and collects information from approximately 5,000 persons per year using standardized household interviews, physical examinations, and testing of biologic samples.’

Participants 6 years of age or older who tested positive for anti-HCV antibodies were sent a report.  Out of the 30,140 participants, 393 (1.4%) had evidence of past or current HCV infection; 170 were available for the study investigators.  Only 49.7% were aware of HCV status prior to receiving NHANES letter.  Furthermore, only 3.7% were first tested for HCV because they or their doctor thought they were at risk for infection; most were tested as part of a routine exam (perhaps detected after elevated ALT values) (46.7%), due to symptoms (15.9%), or blood donation (9.7%).

Another aspect of the study was determining the participants’ understanding of HCV infection.  Correct responses to the HCV survey were more likely in individuals between 40-59 years of age, white non-Hispanics, and patients who had seen a doctor about their HCV infection.  Specific questions often answered incorrectly included the following:

  • whether HCV could be contacted by kissing –only 68% knew this was false
  • whether HCV could be transmitted sexually –only 64% knew this was true
  • whether HCV could be acquired during birth if mother had HCV –only 57% knew this was true

Take home points:

  • Risk-based screening for HCV will continue to fail.  Physicians may not elicit adequate information and patients may deny risky behaviors even if asked.
  • Approximately half of patients in this cohort were unaware of HCV infection.
  • Many misconceptions about HCV persist even among those who had received counseling.

Related blog posts:

Pediatric HCV Guidelines

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Additional resource:

http://www.cdc.gov/hepatitis/RiskAssessment/  This website allows individuals to assess their risk for hepatitis.

Pediatric HCV Guidelines

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A useful recent article, ‘NASPGHAN Practice Guidelines for pediatric HCV’ (JPGN 2012; 54: 838-55) needs to be a handy reference.  However, given the rapid changes in the HCV field, it is likely that this reference will need to be updated soon to incorporate new information (eg. IL28b) as well as emerging therapies.

Highlights:

Epidemiology: 0.2% of children & 0.4% of adolescents are HCV-infected; primary mode is mother to child (vertical) transmission which occurs in 5-7% if mother not coinfected with HIV

Testing: For infants of HCV-infected mothers, check HCV antibody after 18 months or HCV RNA at younger ages.  Need two negative HCV RNAs to exclude infection (guidelines suggest checking 6 months apart).  Most individuals should be screened with antibody testing and confirmed with RNA test.

Screening for HCC (U/S, AFP): suggested only “for those with significant liver disease (ie. cirrhosis)” due to rarity of HCC in pediatric HCC.

Treatment:

  • Not if patient younger than 3 years
  • Probably Pegylated-interferon with ribavirin –references for pediatric studies indicate response rates of about 50% for genotype 1 and about 80% for types 2 & 3.
  • Who should be treated? Not always clear.  Probably those with elevated aminotransferases or progressive disease based on liver biopsy.  Possibly those with mild disease to eradicate virus.
  • Dosing: ribavirin  15/kg/day divided twice daily; weekly PEG-IFN-α-2a 180 microgram/1.73 m2 or weekly PEG-IFN-α-2b 60 microgram*m2

Treatment monitoring (Table 8):

  • CBC/diff, Hepatic panel, glucose 0, 1, 2, 4, 8, 12 weeks, then every  4-8 weeks
  • T4/TSH 0, 12, 24, 36, 48 weeks
  • Urine HCG 0, 24 weeks (if female >12 years)
  • Prothrombin, Urinalysis at week 0
  • HCV RNA 0, 24, 48, 72 weeks

Anticipatory Guidance: “no legal requirement” to disclose HCV infection in U.S.; however, CDC suggests revealing this information to sexual partners (http://www.cdc.gov/hepatitis/hcv/)

  • Avoid sharing toothbrush, shaving equipment with household contacts, unprotected sexual activity with multiple partners, tattooing/piercing
  • Do not need to screen household or casual contacts

Special issues:

  • Vaccines: HCV patients should receive all standard vaccines
  • Obesity and alcohol both can worsen the outcome
  • Fetal scalp probes and prolonged rupture of membranes but not route of delivery may increase risk of HCV transmission
  • Breastfeeding is not contraindicated but should be avoided during mastitis/bleeding

Additional related blog links:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Increased ferritin predicts poor response in Hepatitis C

Curing Hepatitis C without interferon

Looking for trouble

Additional references:

  • –Hepatology 2011; 54: 1433. AASLD guidelines.  See teleprevir & boceprevir as well.-http://www.aasld.org/eweb/docs/hepatitisc
  • -Hepatology 2011; 53: 1468. PEG/RBV have minimal effect on QOL/cognitive/emotional outcomes, n=114.
  • -Gastroenterology 2011; 140: 389, 450-58. HEP-C STUDY. Comb RBV (15mg/kg div BID) & PEG-2a (180mcg/1.73m2 body surface q week) is better than PEG monotherapy. 53% SVR in combo group. Neutropenia in 40% –needed to reduce dose see below). “The Combination of Ribavirin and Peginterferon Is Superior to Peginterferon and Placebo for Children and Adolescents With Chronic Hepatitis C.”
  • -Hepatology 2009; 49: 1335. Comprehensive review and guidelines
  • -J Hepatology 2010; 52: 501-07. n=107. Pediatric study. Wirth et al. Efficacy of PEG alfa-2b (1.5/g/d) & RBV (15/kg/day): Genotypes 2/3 96% SVR, genotype 1 55%.
  • -JPGN 2006; 43: 499.  Study of PEG-IFN-α-2a in children.  dose BSA m2/1.73 x 180microgm weekly x 48 weeks.  6/14 (43%) had sustained response.  all genotype 1.  Article states that IFN (3/week) + RBV has now been approved by FDA for those over 3 years

PEG-Interferon Dosing:

Dosing adjustment from hep C study in children –needed in ~40%

PEG -2a
original: 180mcg/1.73m2
1. level 1: 135 mcg, level 2: 90mcg, level 3: 45 mcg

If ANC 750-999 week 1-2: level 1 adjustment, weeks >3: no adjustment
If ANC 500-749: week 1-2: hold dose ’til >750, then level 1; weeks >3, level 1 adjustment
If ANC 250-499: week 1-2, hold until >750, then level 2 adjustment, weeks >3, then hold ’til 750, then level 1 adjustment
If ANC <250, stop drug

If PLTs 35-49K, hold til >50, then level 1
If PLTs 25-34, hold til >50, then level 2
If PLTs <25, stop drug

If Hgb <10, reduce RIBA dose by 1/2 & increase dose when hgb>10
If hgb <8.5, stop RIBA

If indirect bili >5, stop drug.  If <2.5, restart dose at one-half and if remains less than 2.5, can resume full dose after 4 weeks.

IF ALT 5-10 ULN, recheck in 1 week.  If stays high, level 1 adjustment.
IF ALT10 ULN for more than 1 week, then if drops to 5-10, level 1 but if remains >10 ULN, then stop drug.

Side effect frequency:
flu symptoms: 91%, h/a, 62%, GI symptoms 56%, injection pain 45%, muscle aches 36%, irritable 31%, fatigue 27%, rash 20%, itching 15%, anorexia 13%, trouble sleeping 11%, depression 4-12%

Increased ferritin predicts poor response in Hepatitis C

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Serum ferritin levels were independently shown to be a risk factor for poor response to treatment in hepatitis C virus (HCV) infection (Hepatology 2012; 55: 1038-47).  This article adds additional information to previous work which has shown that increased iron can be a comorbid factor in chronic viral hepatitis and other liver diseases.

This study used the Swiss Hepatitis C Cohort Study (SCCS) (n=3648).  In this group, the success of treatment with pegylated interferon alpha and ribavirin were correlated with clinical and histological features.

Ferritin levels ≥ the sex-specific median values was one of the strongest pretreatment predictors of treatment failure (OR 0.45). It had a similar predictive effect as the IL28B genotype.  In addition, higher ferritin levels were associated with severe liver fibrosis (OR 2.67) and steatosis (OR 2.29).  For women the sex-specific median for ferritin level was 85 μg/L and for men it was 203 μg/L.  The authors note that these cutoffs are quite close to the upper limits of normal of the general population (150 and 300 respectively).

Mechanistically, HCV interferes with the host’s iron metabolism leading to iron accumulation in the liver.  Part of this is explained by down-regulation of hepcidin (Help with hepcidin).  Part is due to ferritin acting as an acute phase reactant to inflammation.  Ultimately, excess iron promotes liver inflammation, oxidative stress and mitochondrial dysfunction.

How important ferritin will be with newer therapies is not clear.  It is likely that patients that are less responsive to dual therapy (pegylated interferon/ribavirin) will have poorer response as well to triple or quadruple therapies.

Additional references/previous related posts:

HCV now more deadly than HIV

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Hepatitis C virus (HCV) now kills more people in the United States than HIV (Ann Intern Med 2012; 156: 271-78).  Data from the CDC followed the mortality burden of Hepatitis B (HBV), HCV, and HIV from 1999 to 2007.    The data were derived from death certificates & a limitation was that these are often completed by individuals other than the primary physician.  Sometimes the exact cause is difficult to discern.  However, this is more likely to result in underreports of deaths from viral hepatitis compared with those from HIV.

In total, 21.8 million death certificates were analyzed.

  • HBV death rate stayed relatively constant –in 2007: 1815 deaths*
  • HCV death rate increased steadily –in 2007: 15106 deaths*
  • HIV death rate improved –in 2007: 12734 deaths*

*When infection was cause or underlying contributor of death

One in 33 baby boomers are infected with HCV; most do not know they are infected.  Three-fourths of the deaths for HCV are in this age group as well.  In addition, it is expected that mortality from HCV will grow over the next 10-15 years without a major intervention. http://www.ajc.com/health/hepatitis-c-deaths-up-1356460.html

Given the increasing HCV disease burden, this strengthens the rationale for more aggressive case finding and the use of more effective & more expensive therapies (see previous blog: The cost of progress in treating Hepatitis C.  Among patients with HCV with advanced disease/cirrhosis, monitoring for HCC is important (Looking for trouble).

Additional references:

  • -Hepatology 2011; 54: 1547. Excess mortality (6x gen population) in those who achieve SVR
  • -Gastroenterology 2010; 138: 513. Predicts peak cirrhosis due to HCV in year 2020; peak HCV prevalence was year 2000.
  • -Clin Gastro Hep 2010; 8: 924. Epidemiology 2010.
  • -Hepatology 2010; 52: 1543. Visceral adiposity is associated with increased histological findings and higher viral loads.
  • -Gastroenterology 2010; 138: 136. Predicting clinical outcomes: plt<99, Alb <3.5, AST/ALT ratio >1.2, & TB>2 all assoc with 40-50% risk of developing ‘clinical outcome’ in next 3.5yrs. Outcomes: ascites, variceal hemorrhage, decompensation according to CTP (66%), peritonitis, death (2%), encephalopathy
  • -Hepatology 2009; 49: 729. 5-yr f/u after successful HCV RX, n=150. 2 developed HCC.
  • -Gastroenterology 2009; 136: 138, 39(ed). HCC occurring c HCV ~1%/yr in HALT-C study. prolonged Rx -not helpful. n=1005
  • -Hepatology 2008; 47: 1128. Increasing mortality of HCV between 1995-2004. Due to aging of infected individuals.
  • -Hepatology 2008; 47: 1371. Genotype 4 review.
  • -Hepatology 2008; 47: 836. 2/121 bx of children had cirrhosis.
  • -J Pediatr 2007; 150: 168. n=60. Looked at two populations: look back after transfusion and referrals. mean age at infection 7 months, mean time with infection 13yrs. 12% developed significant fibrosis.
  • -Hepatology 2007; 45: 1076. Large study: Lancet 2006; 368: 938. 39,109 c HBV, 75,834 c HCV, 2,604 c both. death rate: 3.2%, 5.3%, 7.1% respecively. Increased rate of dying c HCV due to drug use rather than liver dz.
  • -Clin Gastro & Hep 2006; 4: 1190-1191, 1271-78, 1278-1282. slow progression of HCV in 184 untreated women infected in 1977 (mean 27 years) — 2.1% developed cirrhosis. genotype 1B ALT values correlated with change in histology.
  • -JPGN 2006; 43: 209. Review of 91 cases; 7 c cirrhosis at presentation (mean 11.7yrs)
  • -Clin Gastro & Hep 2005; 3: 910. cirrhosis in 71% after 60 years in Asian patients; 25% in Caucasian pts 61-80 who presumably had disease for shorter interval.
  • -Gastroenterology 2003; 125: 1695. obesity/insulin resistance worsens fibrosis in HCV
  • -Gastroenterology 2002; 123: 483-491. IFN Rx improved survival; n=2889. retrospective study.
  • -JPGN 2001;33: 22A. spontaneous clearance in 30% during short f/u; n=145.
  • -Hepatology 2000; 32: 91-96. Low likelihood of progression in cohort followed for 20yrs.

Drink Up!

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Green tea and coffee have a lot of advocates and a number of articles suggest that each can have beneficial effects for the liver.  This month’s Hepatology describes how a green tea component, epigallocatechin-3-gallate (EGCG), inhibits hepatitis C viral (HCV) entry. ECGC acts by blocking viral attachment to target cells with all HCV genotypes; it does not affect viral replication.  Other components of green tea do not have this effect.  A complete description of green tea components is described in the discussion of the article, Hepatology 2012: 54: 1947-55.  Also, there have been preliminary dosing studies in healthy volunteers which have shown that EGCG is safe at doses of 800mg daily for four weeks.  This would be the equivalent of drinking 8-16 cups of green tea per day (Clin Cancer Res 2003; 9: 3312-19).  In order to eliminate HCV, however, even higher amounts of EGCG would be likely.

 

Coffee also has been studied and has been associated with decreasing liver fibrosis.  In addition, coffee may enhance response to HCV treatments.  To my knowledge, there have not been extensive studies of either coffee or green tea for pediatric patients.

Additional References:

  • -Gastroenterology 2011; 140: 1961. Coffee (3 cups/day) increases response to PEG/RBV in HCV
  • -Hepatology 2009; 51: 201. Coffee decreases fibrosis. n=177.
  • -Hepatology 2009; 50: 1360. Coffee intake associated with slower progression of HCV liver disease
  • -Hepatology 2009; 50: 970. Coffee -2 cups per day decreases risk of liver fibrosis & HCC. Coffee has methylxanthin which inhibits connective tissue growth factor.

The cost of progress in treating Hepatitis C

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Background information on Hepatitis C (HCV):

  • —170 million people worldwide infected with HCV, 2.7 milllion people in U.S. infected
  • —27% of worldwide cases of cirrhosis are due to HCV
  • —25% of cases of hepatocellular carcinoma are due to HCV
  • —Established treatment with pegylated interferon (PEG IFN) and ribavirin have ~40% response rates in genotype 1 (74% of HCV in U.S.) and relapses are not uncommon among responders

New treatments for Hepatitis C (in combination with previous treatments):

  • —Two new drugs: Boceprevir (BOC) & Telaprevir (TVR)
  • —Overall sustained viral response (SVR) with BOC combination 63-66% vs 73-79% with TVR combination treatment
  • —Both trials demonstrate marked improvement over previous
  • Mechanism of action: —Protease inhibitor binding to NS3 HCV target
  • —BOC: Wholesale cost $1100/week (20-44 weeks)
  • —TVR: 12weeks cost: $49,000
Previous treatments for hepatitis C typically cost about $5000 per month (http://www.familydrugguide.com/family/ub/view/Consumer_Reports_Health/526033/4/hepatitis_c_drugs).  The addition of these newer drugs could add another $50,000 to the cost of treatment.  In some cases which respond well to the newer treatments, shorter treatment periods will lower the increase in cost.  Although these drugs are expensive, they may be lifesaving and may obviate the need for liver transplantation.  Due to the potential complications of HCV, more medications are in the pipeline.  They may be easier to take but are likely to be expensive as well.  The safety & effectiveness of these medications have not been demonstrated in published pediatric studies.
Article References:
  • Hepatology 2011; 54: 1433.  Updated AASLD HCV treatment guidelines
  • NEJM 2011; 364: 1195-206, Editorial pg. 1272. Addition of boceprevir, in 1097 previously untreated pts increased SVR. In whites, 40%–>67% & in blacks from 23% –>42%. Medication given after lead-in of 4 weeks. More frequent anemia in boceprevir-treated patients (SPRINT-2 study).Boceprevir dosing: 800mg (4 capsules) TID with food. (trying to space out doses evenly).
  • NEJM 2011; 365: 1014. n=540. Telaprevir study: extended SVR 72%. In pts with rapid viral response (RVR) at 4 & 12 weeks (no detectable HCV), Telaprevir12weeksPegRbv24 was as effective as Telprevir12weeksPegRbv48. Dosing for study: Teleprevir 750mg TID, PEGalfa-2a 180mcg/wk, RBV1-1.2gm per day.  Rash in 37% (severe in 5%), anemia in 39% (severe in 6%).
  • NEJM 2011; 364: 2405, 2417, 2429 (review). Telaprevir addition:  up to 75% response in HCV genotype 1 pts. n=1095 in 1st study, n=833 in 2nd study (re-treatment study)
  • Gastroenterology 2011; 140: 746. Summary of results of boceprevir (used with IFN -alfa 2b 1.5/kg) & telaprevir (used with IFN -alfa 2a 180mcg). “Similar effectiveness” thus far. Telaprevir used for 12 weeks without lead-in period.  TVR: most frequent problem -rash & then anemia.  In practice, dosing in adults: Telaprevir will be used at 750mg TID in combination with IFN-2a 180mcg & RBV 1-1.2g/d. & used for 1st 12 weeks of Rx. This will allow ~50% of patients to have shorter Rx duration:  if HCV RNA RVR –>24week total vs 48week total in those w/o RVR.  Both drugs best for genotype 1.