Spontaneous Resolution of Hepatitis C Infection: Factors and Rates

Spontaneous Resolution of Hepatitis C Infection:Factors and Rates Sutapa Roy MPH candidate at Boston University August 3, 2005

Hepatitis C: A Brief Review Hepatitis C: a brief review • Worldwide: 170 million people suffer • from chronic infection • Nationally, nearly 30,000 incident • cases of acute HCV occur each year • Genotypes 1a and 1b are the most • common in the U.S. (accounting for approximately 75%)

Acute Hepatitis C (“aHCV”) • Clinically, aHCV is marked by the appearance of HCV RNA serum, followed by alanine aminotransferase (ALT) elevations; anti-HCV tends to arise late • aHCV is usually asymptomatic, and is therefore difficult to recognize • Acute infection generally causes a mild course of disease -- but has a propensity to evolve into chronic infection • Fulminant hepatic failure is rare

Definition: Self-limited (Spontaneously Cleared) HCV Infection A self-limited course of disease is typically measured by at least 2 consecutive HCV RNA negative measurements. Generally, serum ALT levels also fall to normal

Factors associated with spontaneous viral clearance • Viral: genotype, evolution • Host: sex, age, race/ethnicity, immunological response • Clinical: response (symptoms); co-infection or co-morbidity • Exposures: behavioral, route of infection, dose

Viral factors: Genotype • aHCV infection with genotype 3 has been associated with spontaneous and sustained clearance: • a prospective German study of young anti-HCV (+) males with history of IDU showed 23% spontaneously cleared HCV RNA; genotype 3 was significantly more prevalent among HCV RNA (-) patients (86% of type 3 cleared vs. 7% of type 1) than among chronically-infected individuals (Lehmann et al., 2004) • a retrospective Italian pediatric study found a significant association between viremia clearance and genotype 3 (22% of pts with genotype 3 had self-limited disease, compared to <3% of pts with genotype 1a or 1b) (Bortolotti et al., 2005)

Viral factors: Evolution • HCV, an RNA virus, reproduces rapidly and circulates as a population of quasispecies, with individual viral genomes differing by 1% -- 5% in nucleotide sequence. • Ho: a heterogeneous viral population is likely a factor in evasion of humoral/cell mediated immune response • Consistent with the hypothesis of selective pressure by the host immune system, viral sequence changes were temporally correlated with antibody seroconversion (Farci et al., 2000)

Viral factors: Evolution Within 4-6 months after onset: • Genetic evolution of HCV quasispecies is associated with progression to chronic infection, while relative stasis is linked to spontaneous resolution (Farci et al., 2000) • High mutation rates in hypervariable regions of viral envelope genes are predictive of subsequent development of chronicity (Laskus et al., 2004)

Host factors: Gender Host factors: Sex Girl Power -- Female gender is significantly associated with spontaneous resolution • a French case-control study found that 66.6% of patients with self-limited HCV were female (Alric et al., 2000) • two prospective German studies found 70-75% of patients who spontaneously resolved infection were female (Gerlach et al., 1999; Gerlach et al., 2003)

Host factors: Gender Host factors: Sex a 9-year prospective study of anti-HCV+ Chinese blood donors showed that the rate of ALT abnormalities was significantly higher in males compared to females (Fan et al., 2004) This is consistent with studies have shown that ALT normalization is more common among those with self-limited infection(Jauncey et al., 2004; Hoofnagle, 2002)

Host factors: Gender Host factors: Age Clearance independent of age Younger current age Older current age No difference in age at seroconversion between clearers/resolvers Younger age at infection Older age at infection Eyster et al., 2004 Wawrzynowicz-Syczewska et al., 2004 Messick et al., 2001 Keating et al., 2005; Cox et al., 2005 Santantonio et al., 2003

Host factors: Gender Pediatric Studies • Most pediatric cohorts study vertically transmitted (VT) HCV; clearance rates range from 20% to 75%* (European Paedatric Hepatitis C Virus Network, 2005; Ceci et al., 2001) • a retrospective Australian study found similar HCV RNA clearance rates (19%) in pediatric subjects irrespective of route of acquisition (transfusion or VT) (Rerksuppaphol et al., 2004) • a prospective Italian study found that children with VT-HCV seemed to be at lower risk for progressive liver disease than adults (Bortolotti et al., 1997)

Host factors: Race Host factors: Gender Host factors: Race/ethnicity Odds of spontaneous clearance were 5.2:1 in non-black (36.4%) compared to black patients (9.3%)(Thomas et al., 2000) Hemophiliacs: inverse relationship between clearance and black race (Eyster et al., 2004) There are no significant differences detected between those cleared viremia and those who were persistent infected w.r.t. race (Cox et al., 2005) Black ethnicity is associated with a more robust antiviral CD4+ T-cell response (although unaccompanied with efficient IFN-γ response) than Caucasian ethnicity(Sugimoto et al., 2003)

Host factors: Ethnicity Host factors: Gender Host factors: Race/ethnicity a prospective study of seropositive donors with resolved infections (Busch et al., 2005, in press for Transfusion) Asian 8.2% Black non-Hispanic 14.4% White non-Hispanic 20.7% Hispanic 22.1% Other (mixed; unspecified) 22.1% The odds of HCV RNA negativity were significantly lower in Asians (unadjusted OR=0.34) and in Black non-Hispanic (unadjusted OR=0.64) than in White non-Hispanic donors.

Host factors: immune 1 Host factors: Gender Host factors: Immune response • There is an inverse relationship between the extent of the CTL response in early infection, and the chance of subsequent viral persistence(reviewed in Orland et al., 2000). • aHCV resolution is strongly associated with a durable appearance of HCV-specific CD8+ T-cells during the first 6 months following onset of disease(Gruner et al., 2001) • Progression to disease chronicity is also correlated with a decline in breadth of antigen recognition(Cox et al., 2005)

Host factors: Ethnicity Host factors: Gender Host factors: Immune response • Persistence of HCV-specific memory CD8+ T-cells following self-limited infection suggests that virus-specific CD4+ T-cells similarly persist • (reviewed in Orland et al., 2001) • Loss of the HCV-specific early CD4+/Th1-dominated immune response in acute hepatitis C is associated with immediate recurrence and persistence of HCV RNA. This inverse correlation was observed during follow-up in all patients who temporarily or permanently cleared the virus(Gerlach et al., 1999)

Host factors: Ethnicity Host factors: Gender Host factors: Immune response What about the innate immune response in HCV infection? NK cells, the lymphocytes which secrete cytokines and kill infected cells at the early stages of a primary viral infection, play an integral role in regulating the host response. Inhibitory NK cell interactions are important in determining antiviral immunity, and diminished inhibitory responses confer protection against HCV. NK cell activity is determined by the integration of signals from activating receptors and (constitutive) inhibitory receptors, such as KIR2DL3.

Host factors: Ethnicity Host factors: Gender Host factors: Immune response Homozygous individuals have an advantage in resolving HCV infection; they are able to activate NK cells with more ease, due to the relatively weak interaction between the HLA-C1 ligand and the KIR2DL3 inhibitory receptor However, this directly protective association was seen only in IDU, not in transfusion recipients(Khakoo et al., 2004) (Parham, 2004)

Host factors: immune 1 Host factors: Gender Host factors: Immune response • It is believed that T-reg cells may suppress HCV-specific CTL responses, contributing to chronic infection by suppressing strong protective immune responses. • In HCV, CD4+CD25+ T-reg cells suppress IFN-γ production and antigen-specific PBMC (peripheral blood mononuclear cell) proliferation. • There is a higher frequency of CD4+CD25+ T-reg cells in patients with chronic infections than in those who have cleared the infection. • T-reg function plays a special role in host regulation of chronic viral infections: they may be beneficial by maintaining a balance between efficient effectors and memory responses, minimizing the level of damaging inflammation to the host (Mills, 2004) • T-reg function may go on to be efficient and important in the progression or lack thereof of chronic infection, thus playing a role in early and late HCV infection

Host factors: immune 2 Host factors: Gender Host factors: Immune response Host factors are important determinants of aHCV infection dynamics: variability in host may be even more important than viral variability in determining outcome: • Inheritance of an extended IL-10 haplotype (-117A, -854T, and -627A alleles) significantly associated with spontaneous eradication (Mangia et al., 2004) • Chronically-infected patients significantly more likely to be homozygous for an allele associated with lower IL-12 production (IL-12 is a key cytokine in Th1 generation) (Houldsworth, 2005)

Host factors: immune 3 Host factors: Gender Host factors: Immune response MHC class II antigens also play a role in developing the immune response to HCV, and possible self-limited outcome: • In Caucasians, studies have shown that spontaneous clearance is associated with certain HLA alleles such as DQB1*0301 and DRB1*01. In African Americans, it is the DQB1*0301 allele. However, limited studies in Hispanic populations have failed to demonstrate significant associations between specific class II HLA alleles and outcome of HC infection (Alric et al., 1997; Thio et al., 2001; Azocar et al., 2003) • A French case-control study found that the odds of increased DRB1*1101 allele frequency were 3.8:1 among patients with self-limited infection, compared to those with persistent infection (Alric et al., 2000)

Host factors: symptoms Host factors: Gender Clinical: Symptoms Symptomatic aHCV is significantly associated with resolution: • a prospective German study of ID/hepatology clinic patients found that none of the subjects with asymptomatic aHCV lost HCV RNA without treatment (Gerlach et al., 2003) • During the untreated course of acute symptomatic hepatitis C in the same study, spontaneous clearance was observed in 52% (24/46) patients, usually within 12 weeks after the onset of symptoms • a prospective Italian study found a clearance rate of 60% (9/15) among symptomatic patients, 1/3 of whom resolved infection as long as 24 months after infection (Larghi et al., 2002)

Host factors: infection route Host factors: Gender Clinical: Symptoms • Icteric patients have a higher rate of spontaneous clearance than asymptomatic patients or those with milder symptoms(Wawrzynowicz-Syczewska et al., 2004) • Among HCV mono-infected IDUs, those with evidence of previously resolved infection were significantly (12:1) less likely to develop persistent infection than those not previously infected (they resolved twice!)(Mehta et al., 2002) • Does this suggest that clearance of HCV infection bestows anti-HCV immunity that affords partial protection against persistent infection, and/or reduces the severity of chronic infection (as measured by lower magnitude viremia)?(Rosen, 2003)

Co-infection Host factors: Gender Clinical: Coinfection HIV: a prospective US study of co-infected subjects found that, in contrast to the HIV-specific CD8+ T-cell response, the HCV-specific CD8+ T-cell response was markedly weaker and limited in breadth (regardless of disease stage or course of either infection). Also, a T-helper cell responses to HCV were entirely undetected in this dually infected cohort(Lauer et al., 2002) HBV: a cross-sectional study of US veterans found that chronic HBV infection was significantly associated with spontaneous HCV clearance (OR = 5.0 in univariate analysis)(Piasecki et al., 2004)

Host factors: behavioral Host factors: Gender Exposures: Behavior • Alcohol use is strongly and independently associated with reduced HCV clearance (after adjusting for race, HIV co-infection, age, and alcohol use disorder)(Piasecki et al., 2004; Wawrzynowicz-Syczewska et al., 2004) • Longer term monogamy was associated with increased clearance (AOR 1.5:1 per 10 year ) in a population of IDU (duration of monogamy could be a surrogate marker for a less frequent engagement in risky behaviors, and fewer repetitive exposures to HCV)(Quinn et al., 1999)

Host factors: infection route Host factors: Gender Exposures: Infection route • Vertical transmission and Transfusion: a retrospective Australian pediatric study found no difference in mode of acquisition (transfusion or vertical acquisition) and clinical outcome (Rerksuppaphol et al., 2004) • Parenteral / IDU: Parenteral exposure is a risk factor for persistent viremia(Quinn et al., 1999) IDU is associated with clearance in univariate analysis;(Alric et al., 2000) Duration of IDU is not associated with clearance;(Keating et al., 2005) Clearance independent of IDU;(Messick et al., 2001) The evidence is inconclusive…

Host factors: Ethnicity Host factors: Gender Exposure factors: Dose HCV transmission now occurs mainly through direct contract with infected blood: largely through IDU or accidental needle-sticks, but also through transfusion of contaminated blood products. Route of infection in turn determines expected inoculum size, which affects the quality of the immune response In a prospective study of 12 patients, 66% (8/12) experienced fast and continuous decline of viral load, ultimately clearing HCV RNA a mean of 34.7 days (± 22.1 days) after symptoms first appeared(Hofer et al., 2003) The protective effect of certain genes involved in innate immunity (NK cell activation) is visible only among patients with ‘low dose of viremia’ (nontransfused)(Khakoo et al., 2004)

IDU studies Host factors: Gender Rates of Spontaneous Clearance • Range: 10% to >60% • Variation by: • Length of observation • Measurement • Risk group (community acquired vs.blood product vs. transfusion) • Other…

Haemophiliac studies Host factors: Gender IDU studies Jauncey et al., JID 2004: Retrospective cohort of Australian IDUs (N=57, with 1 HIV+) Median time to clearance 5.9 months (IQR 1.4 – 11.2 months) Sustained clearance rate = 42% (24/57) Keating et al., Irish J Med Sci 2005 Prospective mono-infected cohort of Irish IDU (N=496) Serological evidence of clearance at baseline = 38% Sustained clearance rate (after 2-year follow-up) = 31%

IDU studies Host factors: Gender Hemophiliac populations Messick et al., Haemophilia 2001 Retrospective cohort of US hemophiliacs (N=75, 26 of whom were co-infected with HIV) Clearance rate among mono-infected = 25% (12/49) Mean time to clearance = 24 years None of the HIV+/HCV+ dually infected individuals spontaneously resolved HCV infection Eyster et al., Haemophilia 2004 Prospective follow-up of 12 hemophiliacs (one co-infected with HBV) Clearance rate = 66% (8/12) One patient had HCV RNA persistence for 5 years before clearance

Koch’s Postulates of Causality • Temporality • Plausibility • Dose-response (biological gradient) • Specificity • Strength of association • Consistency • Coherence • Experiment • Analogy

Spontaneous Resolution of Hepatitis C Infection: Factors and Rates