Faculty Bibliography

AIMS: To determine the prevalence of hepatitis A, B and C viruses in patients attending a methadone maintenance clinic in New York City. DESIGN: Cross-sectional. SETTING: The Adult Services Clinic of Weill Cornell Medical College, an urban hospital-affiliated methadone program. PARTICIPANTS: Former heroin addicted adults (n = 103) on methadone maintenance therapy. MEASUREMENTS: Markers for hepatitis A virus [HAV immunoglobulin M (IgM) and imunoglobulin G (IgG)], hepatitis B [hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb)] and hepatitis C virus (HCVAb). Serum alanine aminotransferase (ALT) and quantitative HCV RNA were also obtained. Qualitative detection of HBV DNA and HCV genotype were obtained in a subset of subjects. FINDINGS: More than 40% of subjects had markers for all three viruses. HCVAb was the most prevalent (83.5%), followed by HBcAb (65.0%), HAV IgG (46.1%) and HBsAb (41.1%). Hepatitis C RNA was detected in 70.6% of HCVAb positive subjects. While no subject had HBsAg, HBV DNA was detected in 26.4% of subjects who underwent this measure; all (n = 20) had HBcAb as their only HBV marker. The presence of HBV DNA did not influence ALT. Subjects with HCV RNA had higher ALTs than those without HCV RNA. CONCLUSIONS: Most methadone-maintained subjects had at least one marker for viral hepatitis, with 41.8% having markers for HAV, HBV and HCV. A quarter of subjects had silent HBV infection, defined as the presence of HBV DNA in the absence of HBsAg. These subjects should be considered infectious and pose a public health risk.

BACKGROUND: The authors investigated differences between how patients and providers evaluate the quality-of-life tradeoffs associated with HCV treatment in computer-assisted interviews. They interviewed 92 treatment-naive HCV patients at gastroenterology, methadone maintenance, and HIV clinics at 3 hospitals in New York City and 23 physicians or nurses experienced in treating HCV at other hospitals in New York City. Subjects completed rating scale and standard gamble evaluations of current health and hypothetical descriptions of HCV symptoms and treatment side effects on a scale from 0 (death or worse than death) to 1 (best possible health). RESULTS: . Treatment side effects were rated worse by patients than providers using the rating scale (moderate side effects 0.42 v. 0.62; severe side effects 0.24 v. 0.40) and standard gamble (moderate side effects 0.61 v. 0.91; severe side effects 0.52 v. 0.75) (all P < or = 0.01). A year of severe side effects was equivalent to 4.1 years of mild HCV symptoms avoided for patients if they returned to their current health after treatment compared with 2.0 years avoided if they achieved average population health. For patients with depression symptoms, HCV treatment with severe side effects had lower value unless it would also improve their current health. CONCLUSIONS: . Patients have more concerns about treatment side effects than providers. Further research is warranted to develop HCV decision aids that elicit patient preferences and to evaluate how improved communication of the risks and benefits of HCV treatment and more effective treatment of depression may alter these preferences.

Hepatitis C virus (HCV) is associated with B-cell lymphoproliferative disorders such as mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). The pathogenesis of these disorders remains unclear, and it has been proposed that HCV drives the pro-liferation of B cells. Here we demonstrate that certain HCV(+)MC(+) subjects have clonal expansions of immunoglobulin M (IgM)(+)kappa(+)IgD(low/-)CD21(low)CD27(+) B cells. Using RT-PCR to amplify Ig from these singly sorted cells, we show that these predominantly rheumatoid factor-encoding V(H)1-69/J(H)4 and V(kappa)3-20 gene segment-restricted cells have low to moderate levels of somatic hypermutations. Ig sequence analysis suggests that antigen selection drives the generation of mutated clones. These findings lend further support to the notion that specific antigenic stimulation leads to B-cell proliferation in HCV MC and that chronic B-cell stimulation may set the stage for malignant transformation and the development of B-NHL. The finding that these hypermutated, marginal zone-like IgM(+)CD27(+) B cells are clonally expanded in certain subjects with MC offers insight into mechanisms of HCV-associated MC and B-cell malignancy. This study was registered at www.clinicaltrials.gov as NCT00219999

UNLABELLED: CPG 10101, a synthetic oligodeoxynucleotide (ODN), is a toll-like receptor 9 (TLR9) agonist with antiviral and immunomodulatory properties that could potentially influence chronic infection with HCV. In this multicenter Phase 1b trial, 60 HCV-positive patients (50 genotype 1 HCV) were randomized and received either placebo or CPG 10101 at 0.25, 1, 4, 10, or 20 mg subcutaneously (SC) twice weekly for 4 weeks or at 0.5 or 0.75 mg/kg SC once weekly for 4 weeks. Dose-dependent cytokine induction was observed after administration of CPG 10101. At 24 hours after administering the highest dose of 0.75 mg/kg CPG 10101, interferon (IFN)-gamma-inducible protein 10 (IP-10) had a mean increase over baseline levels (+/-SD) of 15,057 (+/-9769) pg/ml (P < 0.01, compared to placebo); IFN-alpha had a 106 (+/-63.3) pg/ml increase (P < 0.01); and 2'5'-oligoadenylate synthetase (OAS) had a 163 (+/-120.6) pmol/dl increase (P < 0.01). Decreases in HCV RNA also were dose-dependent, with the greatest group geometric mean maximum reduction of 1.69 +/- 0.618 log(10) (P < 0.05) observed in the 0.75 mg/kg dose group. Decreases >/=1 log(10) were seen in 22 of 40 patients who received >/=1 mg CPG 10101, with 3 patients exceeding a 2.5-log(10) reduction. CPG 10101 was well tolerated, and adverse events were consistent with CPG 10101's mechanism of action. CONCLUSION: In this Phase 1 study, CPG 10101 was associated with dose-dependent increases in markers of immune activation and decreases in HCV RNA levels. The data support further clinical studies of CPG 10101 for treating chronic HCV infection.

Experimental studies of animals with chronic hepadnavirus infection could provide valuable insight into optimal therapeutic strategies for individuals with chronic HBV infection. In this review, we focus on the contributions of the woodchuck model to our understanding of HBV biology and on its role in the development of antiviral drug. Furthermore, we consider the implications of studies focusing on the natural history of WHV infection for the management of HBV and the capacity of treatment to prevent complications of chronic hepatitis B infection.