HEPATITIS C VIRUS

A ssRNA virus (flavivirus); at least 10 different strains which differ in their clinical course

I. Transmission:

  1. Mostly parenteral (transfusion, hemodialysis, IVDA)
  2. Vertical transmission
    1. Occurs though only in about 6% of cases (Peds. 102:355, 1998--JW)
    2. Highly associated w/viremia as assessed by PCR (BMJ 315:333, 1997-JW)
    3. Increased in concurrent HIV infection, and appears to be less common with c/s than vaginal deliveries (BMJ 315:333, 1997--AFP)
    4. In a prospective study of 1,479 infants and their mothers, over minimum 24mo f/u, overall transmission rate was 6.2% and was not associated independently with maternal HIV status, elective vs. emergency delivery, mode of delivery, or type of feeding.  Vertical transmission occurred in 3.3% of infants with nonviremic mothers (J. Inf. Dis. 192:1872, 2005--JW)
    5. In another prospective study in 244 infants born to HCV RNA-positive women, incidence of HCV transmission was 0% in women with negative HCV RNA and 4.7% in women with positive HCV RNA.  Risk of vertical transmission was sig. higher in women with HIV (RR 6.5%), use of internal fetal monitoring and rupture of membranes of 6h or more.  No association with breastfeeding.  None of the infected infants had clinical disease over 5y of f/u (J. Inf. Dis. 192:1880, 2005--JW)
  3. Breastfeeding
    1. No known transmission via breastfeeding as of 1999
    2. In a study of 73 HCV Ab-positive breastfeeding women & their 76 newborn infants, 60% of whom had positive serum HCV PCR, none of them had HCV RNA detectable in their breastmilk; over 10wk f/u, only one infant showed evidence of Hep C infection (positive RNA assay); mean age of loss of maternal Hep C Ab in infants was 9mos.(Clin. Inf. Dis. 29:1327, 1999--JW)
  4. Multiple sexual partners and h/o STD's sig. risk factors though evidence of sexual transmission is unclear
    1. Frequency of co-infection of spouses of pts with hepatitis C was found to be 2.5% in one study of 80 couples (QJM 92:505, 1999--JW)
  5. Household spread occurs, sig. correlated with freq. of sex. activity and sharing of toothbrushes (Am. J. Gastroent. 91:2088, 1996-JW)

II. Clinical features:

  1. Natural Hx differs according to geography, EtOH use, viral characteristics, and coinfection w/other viruses
  1. Acute infection
    1. Almost all pts show hepatocyte injury as evidenced by increase ALT an avg. of 50d after exposure
    2. 25-35% will have sx with acute infection (malaise, weakness, anorexia, sometimes jaundice)
    3. Fulminant liver failure with acute infection has been reported but is rare
    4. Acute infection in neonates: In a cohort study of 104 perinatally infected children (either had detectable HCV RNA levels after birth (98 pts) or had Ab persisting > 18mos after birth (6pts) followed till mean age 4y; only 2 pts showed hepatomegaly and none showed FTT; most had some abnormal ALT levels; 18 pts became persistently HCV RNA-negative; 4 or these eventually lost HCV Ab (J. Inf. Dis. 181:419, 2000--JW)
  1. Chronic infection
    1. Distinguishing chronic infection from resolved acute infection
      1. Chronic infection occurs in approx. 85%--initial course doesn't predict who will develop
      2. Viremia is often intermittent in chronic infection
      3. Positive Hep C Ab with negative Hep C PCR may indicate resolved infection; one strategy is to recheck Hep C PCR after 6mos to confirm no viremia (Robert Carrithers, UWMC, personal communication)
    2. Elevated ALT levels common (about 2/3 of pts) in chronic infection though can fluctuate widely
    3. No sx or physical signs in most pts for the first 20y or so, though
      1. About 20% will develop nonspecific sx, e.g. mild intermittent fatigue and malaise
    4. Histologic findings on liver biopsy
      1. Histologic findings correlate poorly with serum ALT levels
        1. In an observational study of 2,473 hepatitis C-positive pts, 10% of those with normal ALT had bridging fibrosis on baseline liver biopsy (Gastroent. Hepatol. 4:645, 2006--JW)
      2. Typical progression of histologic findings over course of disease
        1. Inflammatory cells in the portal tracts
        2. Focal hepatocyte necrosis
        3. Inflammation and necrosis at margin of parenchyma and portal tracts ("interface hepatitis")
        4. Fibrosis--initially within portal tracts & adjacent parenchyma; later, "bridging" fibrosis between portal tracts--predicts progression to...
        5. Cirrhosis (diffuse fibrosis w/fibrous septae throughout liver)
          1. Occurs in at least 20% of pts with chronic infection within 20y of infection
    5. Hepatocellular Ca
      1. Risk is increased in pts with chronic Hep C; 1-5% after 20y (varies geographically)
      2. Usually preceded by cirrhosis; once cirrhosis is established; risk is 1-4% per year
      3. More common in men than women and in older than in younger pts
      4. Recurrence rate of resected Hepatocellular Ca in pts with Hepatitis C was reduced from 80% to 33% with interferon-alfa tx in a 6y randomized trial in 30pts (Ann. int. Med. 134:963, 2001--JW)
    6. Extrahepatic manifestations
      1. Arthritis
      2. Keratoconjunctivitis sicca
      3. Lichen planus
      4. Glomerulonephritis
      5. Essential mixed cryoglobulinemia
      6. Porphyria cutanea tarda
      7. Musculoskeletal pain and fatigue were both sig. more common in pts with hep C vs. pts with other hepatic diseases in one cross-sectional study but these sx did not correlate with transaminase levels of severity of hepatitis by bx (Am. J. Gastroent. 94:1355, 1999--JW)
      8. Thrombocytopenia

        1. Can occur in pts with HCV-associated cirrhosis; Usually multifactorial; contributing factors include splenomegaly, decreased thrombopoietin production, and virus-mediated bone marrow suppression; can worsen during interferon treatment.

  1. Overall survival--384 pts (mean age 54yo) with bx-proven HCV-related hepatic cirrhosis but no cirrhotic complications were followed to determine nat. hx. (Gastroent. 112:463, 1997-JW)
  1. 5- and 10-y incidence of hepatocellular Ca 7% and 14%
  2. 5- and 10-y incidence of decompensation in those who didn't develop Ca (ascites, variceal bleed, encophalopathy) 18% and 29%
  3. 5- and 10-y survival 91% and 79%
  4. Multivariate analysis failed to show survival advantage for pts who received alpha-IFN

III. Diagnosis/surveillance

  1. Anti-HCV antibodies
    1. Anti-HCV Ab found in 90% of pts within 3mos after infection
    2. Enzyme immunoassacy
      1. Initial screen
      2. 92-95% sensitive using PCR as a gold standard
      3. Specificity unknown as of 1998 but probably not 100%
    3. Recombinant immunoblot assay (RIBA)
      1. A confirmatory test
    4. "Low-risk individuals with positive EIA should undergo supplementary RIBA testing. If the RIBA is negative, the EIA is likely to have been a false positive" (NIH Consensus Statment--see below)--Causes include autommune diseases; consider ANA, RF
    5. "In pts presenting with biochemical or clinical evidence of liver disease, a positive EIA is sufficient to diagnose hepatitis C infection, especially if risk factors are present. A qualitative PCR can be used for confirmation." (ibid.)
    6. Patients who clear the virus may revert to seronegative status after about 2y
    7. HCV RNA has been isolated from the liver tissue and peripheral blood monocytes of some patients with negative HCV serology but LFT abnormalities (J. Inf. Dis. 189:3, 2004--JW)
  1. Tests for HCV RNA by PCR
    1. Specific but insensitive; can serve as definitive confirmatory test for initial diagnosis
  1. Monitoring disease activity
    1. Serum ALT is recommended method, trends over time more accurately reflecting disease activity than single measurements
      1. May not accurately reflect findings on liver bx
        1. AST/ALT ratio > 1 had been proposed as a predictor for cirrhosis on bx but was only 56% sensitive and had positive predictive value of only 64% in one study (Am. J. Gastroent. 95:2328, 2000--JW)
      2. If transaminases are normal, Canadian guidelines (see ref. below) recommend HCV RNA level and if that's negative, should repeat @ 6mos and 1y; if transaminases normal and HCV RNA negative on all 3 occasions, then "the infection can be considered resolved"
    2. Qualitative PCR serial measurements only helpful for monitoring response to tx
    3. Quantitative PCR (or branched DNA signal amplification assay, another measure of HCV RNA level), correlates poorly with disease severity, progression, or response to tx and "is not clinically helpful"
    4. Transcription-mediated amplification (TMA)--A better predictor of sustained virologic response to treatment than PCR (J. Hepatol. 44:83, 2006--JW)
    5. Liver biopsy--"the gold standard" for assessing disease activity and ruling out other forms of liver disease
      1. See above re: common histologic findings
      2. "In general, liver biopsies should be considered helpful but not essential for the treatment of chronic HCV infections" (Canadian guidelines; see ref. below)
      3. In a cross-sectional study in 91 pts with chronic hepatitic C and persistently normal ALT levels and 94 pts with chronic hepatitis C and persistently elevated ALT levels, all of whom underwent liver bx, all liver bx results were abnormal; 12% of normal-ALT group had at least moderate necro-inflammatory changes (as opposed to 35% of the elevated-ALT group) (Am. J. Gastroent. 98:1588, 2003--JW)
      4. In a cross-sectional study of 89 pts with both HIV and Hepatitis C infection and 117 pts with Hepatitis C only, all of whom underwent liver biopsy, the incidence of advanced necroinflammation in HIV-HCV coinfected pts was not sig. diff. in those with normal vs. elevated ALT levels (as opposed to the HCV-infected-only pts, where there the incidence was sig. highe r in those with elevated ALT (J. Acq. Imm. Def. Synd. 41:582, 2006--JW)
  1. Surveillance for hepatocellular carcinoma
    1. Surveillance with periodic AFP & hepatic ultrasound was ass'd with higher resectability rate in one prospective cohort study of pts with chronic liver disease, many of whom had hepatitis C (cited in AHRQ report 2002; see ref. below)
    2. Other candidate screening tests: interleukin-2 receptor level, protein induced in vitamin K absence (PIVKA-II)

IV. Treatment

  1. Selecting patients for treatment
    1. Generally considered to be indicated for pts at greatest risk of progression to cirrhosis:
      1. Persistently elevated ALT
      2. Positive qualitative HCV RNA
      3. Liver bx w/portal or bridging fibrosis + at least moderate inflammation and necrosis
      4. Pts with essential mixed cryoglobulinemia,
      5. Concurrent HIV infection
    2. Contraindications to treatment (some are relative
      1. Recent heavy alcohol use
      2. Major depression
      3. Cytopenias
      4. Hyperthyroidism
      5. Renal transplant
      6. Autoimmune disease.
  2. Standard interferons (mainly alpha-2b 3MU SQ 3x/wk x 12-24mos; also alpha-2a, alpha-n1, alpha-n3, consensus IFN, and IFN beta--all w/similar clinical efficacy)
    1. Patient monitoring
      1. Liver bx before starting tx is advised; also LFT's, CBC, ANA, TSH, qualitative HCV PCR, and glucose
      2. Monitor serum ALT (Q2-4wks) and qualitative PCR (Q3mos) during tx to assess biochemical and virologic efficacy, respectively. Most studies have looked at these parameters rather than clinical outcomes
      3. Consider discontinuation if:
        1.  ALT rises to 2x baseline
        2. Persistent positive PCR and elevated serum ALT after 3mos of tx (unlikely to respond and tx should be d/c'd in those pts per NIH Consensus Statement--see ref. below)
    2. Efficacy-Virologic responses
      1. Alpha-IFN x 6mos produces initial responses in 30-50% and sustained responses in 10-20% of pts
      2. Increasing duration of alpha-IFN to 12mos increases rate of sustained response to 20-30%
      3. For nonresponders to alpha-IFN, repeat tx at same dose is rarely effective
      4. For responders to alpha-IFN who relapse, retreatment x 12mos ass'd with sustained response in 30-40%
    3. Efficacy-Preventing hepatocellular carcinoma
      1. In a retrospective study of 419 pts tx'd with IFN (3 diff. types; no subgroup analysis done) vs. 144 historical controls, all with pos. HCV Ab and bx-proven hepatitis or cirrhosis, 4y incidence of hepatocellular Ca sig. higher in controls (12.2% vs. 6.6%; borderline sig.) (Ann. Int. Med. 129:94, 1998--JW)
      2. Appeared to reduce incidence of hepatocellular Ca in another retrospective study (Ann. Int. Med. 131:174, 1999--JW)
    4. See section on Interferons for details on side f/x etc.
  1. Pegylated interferon alpha-2a (Pegasys)
    1. Comparisons with standard interferons
      1. Ass'd with sig. higher incidence of sustained virologic response when given Qwk c/w standard interferon alpha-2a 3x/wk (39% vs. 19% assessed at 72wks) in a randomized 48wk trial in 531 pts with chronic hepatitis C w/o cirrhosis or bridging fibrosis on liver Bx (NEJM 343:1666, 2000--JW)
      2. Similar results were seen in a comparison trial betwen pegylated & regular IFN in 271 pts with hep C AND either cirrhosis or bridging fibrosis (sustained virologic responses 30% vs. 8%; NEJM 343:1673, 2000--JW)
      3. In a 48wk randomized trial of 1121 adults with chronic HCV randomized to either PEG-IFN-alfa-2a + ribavirin, PEG-IFN-alfa-2a + placebo, or IFN-alfa-2b + ribavirin, incidence of virologic remission 24wks after cessation of therapy was as follows; all differences sig.  Among those with receiving peg-IFN + ribarvirin who had "response" at 12wks (at least 2-log decreases in HCV RNA levels), remission 24wks after cessation of therapy was seen in 65%; of those without 12wk responses, only 3% had remission 24wks after cessation of therapy (NEJM 347:975, 2002--JW)
        1. 56% in PEG-IFN-alfa-2a + ribavirin
        2. 44% in IFN-alfa-2b + ribavirin
        3. 29% in PEG-IFN-alfa-2a + placebo
      4. 1530 pts with chronic hepatitis C randomized to PEG-IFN alfa-2b vs. IFN alfa-2b x 48wks; all pts also received oral ribavirin.  SUstained virologic response was sig. more common in plain IFN group (54% vs. 47%) (Lancet 358:958, 2001--JW)
    2. Comparisons with standard interferons as part of combined IFN-Ribavirin regimens
      1. In a randomized trial in 412 pts with chronic Hep C and HIV, who received either pegylated IFN alfa-2b vs. standard IFN alfa 2b x 48wks (all pts also received ribavirin 400mg PO BID), incidence of sustained virologic response at 72wks was sig. higher in the PEG group (27% vs. 20%) (JAMA 292:2839, 2004--abst)
    3. In a 2 x 2 study in 1,311 pts with chronic hepatitis C, PEG-IFN alfa-2a 180ug/wk x 24 or 48wks plus ribavirin 800mg/d vs. 1000-1200mg/d (the latter based on weight), incidence of sustained virologic response (no detectable HCV RNA at end of tx and during 12-24wks of f/u), 48wks of IFN and higher-dose ribavirin were both sig. better than the alternatives.  In subgroup with HCV genotypes 2 or 3, these diffs werent sig.; they were, however, in the subgroup of pts with HCV-1 (Ann. Int. Med. 140:346, 2004--abst)
    4. In a study in 3,070 pts with HCV type 1 infection randomized to IFN alfa-2b (weight-based dosing) vs. IFN alfa-2a, sustained virologic response and adverse event rates were not sig. diff. between the groups (“IDEAL” study; NEJM 361:580, 2009-JW)
    5. See above re: general info on IFN's
  1. Ribavirin (Rebetol, Copegus)
    1. Increases efficacy of IFN when used in combination 
    2. Usual dose is 1000-1200mg/d divided BID
    3. Alfa-2b + Ribavirin = "Rebetron"
    4. Can cause hemolytic anemia (5-10% of incidence requiring dose reduction; responds to erythropoietin--See Am. J. Gastroent 98:2491, 2003) and is teratogenic in animals
    5. Efficacy
      1. In IFN-naive pts--6-11mo courses in combination with alpha-IFN tx increases rate of sustained responses to 40-50% in both (NEJM 339:1485, 1998 and NEJM 339:1485, 1998--JW)
      2. For pts who relapse after or don't respond to IFN monotherapy
        1. 6-11mo course w/alfa-IFN increases rate of sustained responses to 40-50% (Lancet 352:1426, 1998--JW)
        2. 400 pts not responding to or relapsing from 3-6mos of IFN alpha-2b 3 MU 3x/wk randomized to 6mos of IFN alpha-2b 6MU 3x/wk vs. IFN alpha-2b 3MU 3x/wk + Ribavirin 1000-1200mg/d, all x 6mos; Ribavirin group had sig. higher rates of normal ALT and negative HCV PCR at 24 and 48wks (Am. J. Med. 107:112, 1999--JW)
        3. In an uncontrolled study of 604 pts with chronic HCV( mostly type 1) and bridging fibrosis or cirrhosis on liver bx who hadn't respond to IFN-based therapy (with or without ribavirin) treated with PEG-IFN-alfa-2a + ribavirin, 35% had virologic response at wk 20 and 32% at wk 48 of tx; 50% of responders had sustained virologic remission at 24wks after cessation of tx (Gastroent. 126:1015, 2004--JW)
    6. Studies comparing different durations of treatment
      1. In a study in 455 treatment-naive patients with chronic Hepatitis C randomized to 48 vs. 72 wks of PEG-IFN 2a 180 ug SQ Qwk + ribavirin 800mg QD, the incidence of sustained virologic response was not sig. diff. between the groups in the overall cohort, BUT in the subroup of pts with detectable viral loads at baseline, the response rate was sig. higher in the 72-wk group (29% vs. 17%) (Gastroent. 130: 1086, 2006--JW)
      2. In a study in 283 pts with HCV genotypes 2 or 3 randomized to treatment with PEG-IFN + ribavirin of different durations ("standard" 24wk vs. "variable-duration" in which pts with negative HCV RNA at 4wks received only 12wks of tx and others received 24wks), the two groups had similar virologic response rates at 24wks (NEJM 352:2609, 2005--JW)
  1. Amantadine
    1. In a study in 152 pts with chronic HCV, positive blood HCV RNA, elevated transaminases, and abnormal liver histology, with h/o no response (or intolerance) to interferons, randomized to amantadine 100mg BID vs. placebo x 6mos, amantadine pts had sig. reduction in ALT levels at 6mos c/w no change in placebo-treated pts; no sig. diffs in quality of life (J. Gen. Int. Med. 19:662, 2004--AFP)
  2. Nitazoxanide
    1. Classified in the "thiazolide" pharmacologic category
    2. No apparent direct antiviral activity; seems to augment IFN's anti-HCV activity
    3. Studied as monotherapy for "genotype 4" HCV
    4. In a study in 96 treatment-naive pts with HCV randomized to:
      1. Standard therapy (PEG-interferon alfa-2a 180ug weekly + ribavirin daily x 48wks)
      2. Dual therapy (nitazoxanide 500mg BID x 12wks then PEG-IFN alfa-2a 180ug weekly + nitazoxanide 500mg BID x 36wks)
      3. Triple therapy (nitazoxanide 500mg BID x 12wks then nitazoxanide 500mg BID + standard therapy x 36wks)

      in an intention-to-treat analysis, sustained virologic response at 24wks post-treatment was sig. higher in triple-therapy group than standard-therapy group (79% vs. 50%); no sig. diff. between dual-therapy group and standard-therapy group.  No sig. diff. in side f/x among the groups (Gastroent. 136:856, 2009-JW)

  3. Telaprevir
    1. A protease inhibitor specific to an HCV protease

    2. Can be combined with IFN + ribavirin for HCV genotype 1

    3. Can cause skin rash
    4. In two studies (one in 1,250 pts and one in 334 pts) with chronic HCV but no cirrhosis randomized to telaprevir vs. placebo along with (PEG-interferon alfa-2a + ribavirin), telaprevir was associated with sig. higher sustained viral response rates than standard (IFN + ribavirin) therapy alone (61-67% vs. 41-46% depending on the trial and specific protocol) though telaprevir groups had sig. higher discontinuation rates, most often due to rash ("PROVE1" and "PROVE2" trials; NEJM 360:1827, 2009 and NEJM 360:1839, 2009-JW)

  4. Boceprevir (Victrelis)

    1. An NS3 protease inhibitor

    2. Associated with anemia and dysgeusia

    3. In combination with IFN + ribavirin increases virologic response (Lancet 8/9/2010, e-pub ahead of printing; http://dx.doi.org/10.1016/S0140-6736(10)60934-8)

  5. Predictors of response to treatment
    1. Negative HCV PCR after 1mo of alpha-IFN tx was more predictive of long-term (12mo) response than transaminase levels (Gastroent. 113:1647, 1997--AFP)
    2. A 2-log decrease in quantitative HCV RNA by PCR at 12wks had a positive predictive value of 72% and a negative predictive value of 100% for sustained virologic response (undetectable serum HCV RNA at 24wks) after cessation of therapy, in a 48wk study of PEG-IFN alfa-2b vs. IFN alfa-2b; all pts in that study also received oral ribavirin (Hepatology 38:645, 2003--JW)
    3. Quantitative PCR titer < 1M copies/ml
    4. No cirrhosis or advanced fibrosis on bx (AHRQ report 2002; see ref. below)
    5. HCV genotype 2 or 3 ass'd with good response to IFN
  6. Gamma-IFN, Acyclovir, Corticosteroids-No good evidence of benefit as of 2005
  7. Liver transplantation--indicated in decompensated cirrhosis--works well; 16% have hepatic problems due to reinfection of graft
  8. Immunize ALL against hepatitis A and B!!!
  9. Treatment of recent-onset hepatitis C and acute hepatitis C
    1. In a study of 44 pts with HCV thought to have been acquired in the last 4mos with positive serum HCV RNA tests and elevated ALT levels, tx'd with IFN alfa-2B 5MU QD x 4wks then 3x/wk x 20wks)--42 pts at 6mos after therapy completed had normal ALT levels and negative HCV RNA studies (NEJM 345:1452, 2001--JW)
    2. Early tx with IFN-alfa 6MU QD x 4wks (starting 8wks after onset of acute hepatitis) vs. late (after 1y) was ass'd with sig. higher incidence of sustained virologic response (87% vs. 40%) in a randomized trial of 30 pts with acute hepatitis C (Hepatology 39:1213, 2004--abst)
  10. Treatment of Hepatitis C-associated Hepatocellular Carcinoma--In a randomized trial in 46 such patients, adding adjuvant IFN therapy (to standard therapy of arterial embolization or ethanol injection) was ass'd with sig. improved 6mo survival and reduced incidence of worsening LFT"s (Hepatogastroenterology 49:724, 2002--JW)

V. Transmission prevention guidelines for known chronic HCV cases per NIH

  1. Don't donate organs, tissues, blood, or semen
  2. Use condoms if sexually active w/multiple partners
  3. Consider possible low risk of transmission in monogamous relationships
  4. Test sexual partners for HCV
  5. Avoid sharing razors or toothbrushes
  6. There is no need to avoid close contact with others or to avoid sharing meals or utensils
  7. Breastfeeding considered safe as of 1998

Sources include: