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1.  Toward a More Accurate Estimate of the Prevalence of Hepatitis C in the United States 
Hepatology (Baltimore, Md.)  2015;62(5):1353-1363.
Data from the 2003-2010 National Health and Nutrition Examination Survey (NHANES) indicate that about 3.6 million people in the United States have antibodies to the hepatitis C virus, of whom 2.7 million are currently infected. NHANES, however, excludes several high-risk populations from its sampling frame, including people who are incarcerated, homeless, or hospitalized; nursing home residents; active-duty military personnel; and people living on Indian reservations. We undertook a systematic review of peer-reviewed literature and sought out unpublished presentations and data to estimate the prevalence of hepatitis C in these excluded populations and in turn improve the estimate of the number of people with hepatitis C in the United States. The available data do not support a precise result, but we estimated that 1.0 million (range 0.4 million-1.8 million) persons excluded from the NHANES sampling frame have hepatitis C virus antibody, including 500,000 incarcerated people, 220,000 homeless people, 120,000 people living on Indian reservations, and 75,000 people in hospitals. Most are men. An estimated 0.8 million (range 0.3 million-1.5 million) are currently infected. Several additional sources of underestimation, including nonresponse bias and the underrepresentation of other groups at increased risk of hepatitis C that are not excluded from the NHANES sampling frame, were not addressed in this study.
Conclusion
The number of US residents who have been infected with hepatitis C is unknown but is probably at least 4.6 million (range 3.4 million-6.0 million), and of these, at least 3.5 million (range 2.5 million-4.7 million) are currently infected; additional sources of potential underestimation suggest that the true prevalence could well be higher.
doi:10.1002/hep.27978
PMCID: PMC4751870  PMID: 26171595
2.  Comparison of Functional Variants in IFNL4 and IFNL3 for Association with Hepatitis C Virus Clearance 
Journal of hepatology  2015;63(5):1103-1110.
Background & Aims
Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls generation of the IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the ‘IL28B variant’). An IFNL3 3′ untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability.
Methods
We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach.
Results
Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r2=0.89–0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048).
Conclusion
IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.
doi:10.1016/j.jhep.2015.06.035
PMCID: PMC4615534  PMID: 26186989
genetics; IL28B; IFNL3; IFNL4; innate immunity; interferon lambda; treatment; viral clearance
4.  Test and treat this silent killer 
Nature  2011;474(7350):S18-S19.
doi:10.1038/474S18a
PMCID: PMC4751873  PMID: 21613999
5.  Hepatitis C Screening: Getting It Right 
Hepatology (Baltimore, Md.)  2012;57(4):1644-1650.
Hepatitis C is the most prevalent bloodborne viral disease in the United States and the deadliest. This year, the U.S. Preventive Services Task Force (USPSTF) will update its 2004 hepatitis C guideline, which recommends against screening asymptomatic adults for hepatitis C. This guideline has hampered public health efforts to encourage screening and identify and refer infected persons for care by declaring that such interventions were not supported by the evidence. A draft revision of the guideline, released on November 26, 2012, concludes that testing persons born between 1945 and 1965 probably has at least a small net benefit, but stops short of definitively recommending that this cohort be screened. This article examines the Task Force’s process for writing its guidelines. It recommends that the Task Force adopt a balanced approach to evaluating the benefits and harms of screening; use the preponderance of the evidence as a standard for evaluating interventions that target serious public health problems; be transparent about the value judgments that go into its decisions; consider the wide variation in disease prevalence in diverse patient populations; and recommend screening asymptomatic adults for hepatitis C.
Conclusion
By taking a broader view of the evidence, the Task Force can write new guidelines that will serve efforts to curb the hepatitis C epidemic, rather than frustrate them.
doi:10.1002/hep.26194
PMCID: PMC4751877  PMID: 23239521
6.  Seroprevalence of Hepatitis C Virus and Hepatitis B Virus Among San Francisco Injection Drug Users, 1998 to 2000 
Hepatology (Baltimore, Md.)  2007;46(3):666-671.
Previous studies suggest that most injection drug users (IDUs) become infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) soon after initiating drug use. The Urban Health Study (UHS) recruited serial cross-sections of IDUs in the San Francisco Bay area from 1986 to 2005. In the current study, we determined the prevalence of antibody to HCV and HBV (core) among UHS participants during 1998 to 2000. To examine whether the time from onset of injection to acquisition of viral hepatitis has increased, we also compared the findings among recent (<10 years) initiates to drug use who participated during 1998-2000 with those who participated in 1987. Of 2,296 IDUs who participated during 1998-2000, 91.1% had antibody to HCV and 80.5% to HBV. The number of years a person had injected drugs strongly predicted infection with either virus (Ptrend < 0.0001). HCV seroprevalence among recent initiates in 1998-2000, by years of injection drug use, was: ≤ 2, 46.8%; 3 to 5, 72.4%; 6 to 9, 71.3%. By comparison, HCV seroprevalence among 1987 participants was: ≤ 2 years, 75.9%; 3 to 5, 85.7%; 6 to 9, 91.1% (P < 0.0001). A consistent pattern was observed for HBV (P < 0.0001), and these findings were not explained by demographic differences between 1987 and 1998-2000 participants. During 1987, however, 58.7% of recent initiates had shared syringes within the past 30 days compared with 33.6% during 1998-2000 (P < 0.0001).
Conclusion
HCV and HBV seroprevalence among newer initiates to injection drug use in the San Francisco Bay area decreased markedly between 1987 and 1998-2000. This decrease coincided with the implementation of prevention activities among this population.
doi:10.1002/hep.21765
PMCID: PMC4751875  PMID: 17657818
7.  The Inverse Relationship between Chronic HBV and HCV Infections among Injection Drug Users is Associated with Decades of Age and Drug Use 
Journal of viral hepatitis  2008;15(9):690-698.
Summary
Infection with hepatitis C virus (HCV) may suppress co-infection with HBV during acute or chronic HBV infection. We examined relationships between HBV infection, HCV infection and other factors among injection drug users (IDUs) with antibodies to both viruses. Participants enrolled in a cross-sectional study during 1998–2000 were considered to have been infected with HBV if they had core antibody, to be chronically infected if they had HBV surface antigen (HBsAg), to have been infected with HCV if they had HCV antibody, and to be chronically infected if they had HCV RNA. Among 1,694 participants with antibody to both viruses, HBsAg prevalence decreased with increasing age among those positive for HCV RNA [from 4.55% in those 18–29 years to 1.03% in those ≥ 50 years old (ptrend=0.02)], but not among those who were negative for HCV RNA. Chronic HBV infection was less common overall among those with chronic HCV infection (odds ratio [OR], 0.25; p<0.0001), but this inverse relationship was much stronger in the oldest (> 50 years; OR= 0.15) than the youngest (18–29 years; OR=0.81) participants (ptrend=0.03). Similar results were obtained when duration of injection drug use was substituted for age (ptrend= 0.05). Among IDUs who have acquired both HBV and HCV, chronic HBV infection is much less common among those with chronic HCV infection, but this inverse relationship increases markedly with increasing years of age and injection drug use. Co-infection with HCV may enhance the resolution of HBsAg during the chronic phases of these infections.
doi:10.1111/j.1365-2893.2008.01005.x
PMCID: PMC4751881  PMID: 18507757
epidemiology; hepatitis B virus; hepatitis C virus; injection drug use; United States; viral suppression
8.  Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes 
PLoS ONE  2015;10(10):e0138827.
IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women’s Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)–infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV–1 and HSV–2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV–2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV–1 and 79.0% were positive for HSV–2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV–1 or HSV–2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV–2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV–2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.
doi:10.1371/journal.pone.0138827
PMCID: PMC4592222  PMID: 26431156
9.  Managing Hepatitis C in Users of Illicit Drugs 
Current hepatitis reports  2007;6(2):60-67.
Persons who inject illicit drugs are the group most severely affected by the hepatitis C epidemic but the least likely to receive treatment. Controlling the epidemic will require developing strategies for effectively treating drug users. A growing number of reports have shown that a substantial proportion of drug users treated for hepatitis C can achieve sustained virologic responses even if they have psychiatric comorbidity and even if they continue to use drugs while receiving hepatitis C treatment. Successfully treating hepatitis C in injection drug users requires collaboration between those with expertise in hepatitis and those with expertise in caring for substance users. Careful attention to management of adverse effects and strong links with mental health services are important. Further research is needed to better define which patients can be successfully treated and the program elements that are critical for success. In the meantime, substantial progress can be made using current knowledge if appropriate resources are brought to bear.
PMCID: PMC3690289  PMID: 23801897
10.  Prevention and Treatment of Hepatitis C in Injection Drug Users 
Hepatology (Baltimore, Md.)  2002;36(5 Suppl 1):S210-S219.
Injection drug users constitute the largest group of persons infected with the hepatitis C virus (HCV) in the United States, and most new infections occur in drug users. Controlling hepatitis C in the U.S. population, therefore, will require developing, testing, and implementing effective prevention and treatment strategies for persons who inject drugs. Fortunately, a substantial body of research and clinical experience exists on the prevention and management of chronic viral diseases among injection drug users. The need to implement interventions to stop the spread of HCV among drug users is critical. The capacity of substance-use treatment programs need to be expanded to accommodate all who want and need treatment. Physicians and pharmacists should be educated in how to provide access to sterile syringes and to teach safe injection techniques, both of which are lifesaving interventions. The treatment of hepatitis C in drug users requires an interdisciplinary approach that brings together expertise in treating hepatitis and caring for drug users. Treatment decisions should be made individually by patients with their physicians, based on a balanced assessment of risks and benefits and the patient's personal values. Physicians should carefully assess, monitor, and support adherence and mental health in all patients, regardless of whether drug use is known or suspected. Research is needed to better understand how best to prevent and treat hepatitis C in substance users. In the meantime, substantial progress can be made if existing knowledge and resources are brought to bear.
doi:10.1053/jhep.2002.36809
PMCID: PMC1629041  PMID: 12407596
12.  Infrequent Reinfection after Successful Treatment for Hepatitis C Virus Infection in Injection Drug Users 
We followed-up 18 injection drug users for a mean of 33.8 months (range, 4–55 months) after successful treatment for hepatitis C virus (HCV) infection. Fifteen (83%) of the patients remained HCV RNA–negative, 1 patient was not tested, and 2 patients had test results positive for HCV RNA. The estimated rate of reinfection as a result of injection drug use was 0–4.1 cases per 100 person-years (cumulative incidence, 0%–12.6% at 48 months after completion of treatment). Of 50 patients originally treated, 15 (30%) were HCV RNA–negative 3 years later.
doi:10.1086/425361
PMCID: PMC1510898  PMID: 15546094
14.  A variant upstream of IFNL3 (IL28B) creating a novel interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus 
Nature genetics  2013;45(2):164-171.
SUMMARY
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
doi:10.1038/ng.2521
PMCID: PMC3793390  PMID: 23291588
15.  Genome wide association study of spontaneous resolution of hepatitis C virus infection 
Annals of internal medicine  2013;158(4):235-245.
Background
Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood.
Objective
To evaluate the host genetic basis for spontaneous resolution of HCV infection.
Design
Two-stage genome wide association study (GWAS).
Setting
13 international multicenter study sites.
Patients
919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence).
Measurements
Frequencies of 792,721 SNPs.
Results
Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015).
Limitations
Epigenetic effects were not studied.
Conclusions
IL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.
doi:10.7326/0003-4819-158-4-201302190-00003
PMCID: PMC3638215  PMID: 23420232
16.  HCV RNA Levels in a Multi-Ethnic Cohort of Injection Drug Users: Human Genetic, Viral and Demographic Associations 
Hepatology (Baltimore, Md.)  2012;56(1):86-94.
In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV EIA were tested for HCV viremia by a bDNA assay. HCV genotype was determined by sequencing the HCV NS5B region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). HIV-1 prevalence was 13.9%. The overall median HCV RNA level was 6.45 log10 copies/ml. In unadjusted analyses, higher levels were found with older age, male gender, African American ancestry, HBV infection, HIV-1 infection and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotype 3 or genotype 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype and IL28B rs12979860 genotype were all independently associated with HCV RNA. Conclusion: The level of HCV viremia is influenced by a large number of demographic, viral and human genetic factors.
doi:10.1002/hep.25652
PMCID: PMC3369001  PMID: 22331649
epidemiology; genetics; HCV; IL28B; viremia
17.  Racial/Ethnic Differences in Spontaneous HCV Clearance in HIV Infected and Uninfected Women 
Digestive diseases and sciences  2012;58(5):1341-1348.
Background/Aims
Among individuals without human immunodeficiency virus (HIV), African Americans have lower spontaneous clearance of hepatitis C virus (HCV) than Caucasians, and women have higher clearance than men. Few studies report racial/ethnic differences in acute HCV in HIV infected, or Hispanic women. We examined racial/ethnic differences in spontaneous HCV clearance in a population of HCV mono- and co-infected women.
Methods
We conducted a cross sectional study of HCV seropositive women (897 HIV infected and 168 HIV uninfected) followed in the US multicenter, NIH-funded Women's Interagency HIV Study (WIHS), to determine the association of race/ethnicity with spontaneous HCV clearance, as defined by undetectable HCV RNA at study entry.
Results
Among HIV and HCV seropositive women, 18.7 % were HCV RNA negative, 60.9 % were African American, 19.3 % Hispanic and 17.7 % Caucasian. HIV infected African American women were less likely to spontaneously clear HCV than Hispanic (OR 0.59, 95 % CI 0.38–0.93, p = 0.022) or Caucasian women (OR 0.57, 95 % CI 0.36–0.93, p = 0.023). Among HIV uninfected women, African Americans had less HCV clearance than Hispanics (OR 0.18, 95 % CI 0.07–0.48, p = 0.001) or Caucasians (OR 0.26, 95 % CI 0.09–0.79, p = 0.017). There were no significant differences in HCV clearance between Hispanics and Caucasians, among either HIV infected (OR 0.97, 95 % CI 0.57–1.66, p = 0.91) or uninfected (OR 1.45, 95 % CI 0.56–3.8, p = 0.45) women.
Conclusions
African Americans were less likely to spontaneously clear HCV than Hispanics or Caucasians, regardless of HIV status. No significant differences in spontaneous HCV clearance were observed between Caucasian and Hispanic women. Future studies incorporating IL28B genotype may further explain these observed racial/ethnic differences in spontaneous HCV clearance.
doi:10.1007/s10620-012-2486-8
PMCID: PMC3663918  PMID: 23179159
African American; Hispanic; Acute hepatitis C; Female
18.  Spontaneous Clearance of Chronic Hepatitis C Virus Infection Is Associated With Appearance of Neutralizing Antibodies and Reversal of T-Cell Exhaustion 
The Journal of Infectious Diseases  2012;205(5):763-771.
Background. Hepatitis C virus (HCV) readily establishes chronic infection with exhaustion of HCV-specific T cells and escape from neutralizing antibodies. Spontaneous recovery from chronic infection is rare and has never to our knowledge been studied immunologically.
Methods. We prospectively studied, from prior to infection through >2 years of follow-up, cytokines, HCV-specific T cells, and antibodies, as well as viral sequence evolution in a white male who spontaneously cleared HCV genotype 1a after 65 weeks.
Results. Significant alanine aminotransferase and plasma cytokine elevation and broad HCV-specific T-cell responses did not result in HCV clearance in the acute phase. Frequency and effector function of HCV-specific T cells decreased thereafter, and HCV titers stabilized as is typical for the chronic phase. HCV clearance after 65 weeks followed the appearance of neutralizing antibodies at week 48 and was associated with reversal of HCV-specific T-cell exhaustion, as evidenced by reduced programmed death–1 (PD-1) expression and improved T-cell function. Clearance occurred without inflammation or superinfection with hepatitis B virus, human cytomegalovirus virus, influenza, and Epstein-Barr virus.
Conclusions. T-cell exhaustion is reversible at least in the first 2 years of chronic HCV infection, and this reversion in conjunction with neutralizing antibodies may clear HCV. These findings are relevant for immunotherapy of chronic infections.
doi:10.1093/infdis/jir835
PMCID: PMC3274373  PMID: 22293431
19.  IL28B rs12979860 Genotype and Spontaneous Clearance of Hepatitis C Virus in a Multi-Ethnic Cohort of Injection Drug Users: Evidence for a Supra-Additive Association 
The Journal of Infectious Diseases  2011;204(12):1843-1847.
Among 1369 Urban Health Study participants, we evaluated genetic models for the association of IL28B genotype (rs12979860 and rs8099917) with hepatitis C virus (HCV) clearance. For rs12979860, adjusted odds ratios for spontaneous HCV clearance were as follows: IL28B-CC, 3.88 (P < .001); IL28B-CT, 1.48 (P = .08). On the basis of Akaike information criteria values and χ2 tests, a supra-additive (quadratic) model fit these data best. Models based on rs8099917 provided poorer fit. Evidence that a supra-additive rs12979860-based model best fits the association of IL28B-genotype with HCV clearance may improve clinical prediction models and foster a better understanding of functional mechanisms underlying this association.
doi:10.1093/infdis/jir647
PMCID: PMC3209810  PMID: 22013224
20.  Induction of CXCR3- and CCR5-associated Chemokines during Acute Hepatitis C Virus Infection 
Journal of hepatology  2011;55(3):545-553.
Background and Aims
Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms.
Methods
Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during ten acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of over-all changes. Residuals were analyzed to characterize short-term fluctuations.
Results
CXCL9-11 induction began 38–53 days and peaked 72–83 days after virus acquisition. Increases in ALT levels followed a similar pattern. Substantial negative autocorrelations of chemokine levels at one week lags suggested substantial week-to-week oscillations. Significant correlations were observed between CXCL10 and HCV RNA as well as ALT and CXCR3-associated chemokines measured in the preceding week, CCL3-4 expression levels did not change appreciably during acute HCV infection.
Conclusions
Elevation of CXCR3-associated chemokines late during acute HCV infection suggests a role for cellular immune responses in chemokine induction. Week-to-week oscillations of HCV RNA, chemokines, and ALT suggest frequent, repeated cycles of gain and loss of immune control during acute hepatitis C.
doi:10.1016/j.jhep.2010.12.033
PMCID: PMC3094733  PMID: 21256906
CXCL9; CXCL10; CXCL11; CCL3; CCL4; inflammation
21.  Genetic Variation in CLDN1 and Susceptibility to Hepatitis C Virus Infection 
Journal of viral hepatitis  2009;17(3):192-200.
Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a ‘whole gene association study’ among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n=658) to those in IDUs who had cleared HCV (n=199) or remained HCV-uninfected (n=68). Analyses were controlled for racial ancestry (African American or European American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; p=0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; p=0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; p=0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; p=0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African American and European American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection.
doi:10.1111/j.1365-2893.2009.01166.x
PMCID: PMC2921226  PMID: 19674288
claudin-1; epidemiology; genetic; susceptibility; viral receptor
22.  HCV-Specific T-Cell Immune Responses in Seronegative Injection Drug Users 
Journal of viral hepatitis  2008;16(1):10-20.
Background/Aims
T-cell responses to HCV antigens have been reported in high-risk HCV seronegative persons, suggesting that an effective cellular immune response might be able to clear infection without the development of antibodies. Such findings, however, could be explained by waning antibody or cross-reactivity to other antigens. To address these issues, we assessed T-cell responses in high-risk, seronegative, young IDUs to multiple peptide mixes spanning the entire HCV genome.
Methods
We evaluated HCV-specific T-cell responses in 26 young (age 18-33 years) aviremic, seronegative IDUs (median duration of injection, 6 years) by interferon-γ ELISpot assay using 429 overlapping HCV peptides pooled in 21 mixes. Seventeen aviremic, seropositive IDUs (spontaneous resolvers) and 15 healthy people were used as positive and negative controls, respectively.
Results
The percentage of patients with HCV-specific cellular immune responses was similar in seronegative and seropositive aviremic IDUs (46% versus 59%, p=0.4), while these responses were not detected in any of the negative controls. Among the seronegative IDUs, 6 (23%) had intermediate to very strong responses to 10-20 peptide mixes and another 6 (23%) had moderately strong responses to 2 to 6 mixes. The 12 seronegative IDUs with HCV-specific T-cell responses had higher demographic and behavioral risk profiles than the 14 IDUs without T-cell responses (estimated risk of HCV infection, 0.47 vs. 0.26, p <0.01).
Conclusions
HCV-specific T-cell responses are common among high-risk, seronegative IDUs. The responses are broad and are associated with risk factors for HCV exposure, suggesting that they reflect true exposure to HCV in seronegative persons.
doi:10.1111/j.1365-2893.2008.01016.x
PMCID: PMC2997348  PMID: 18647233
23.  Hepatitis C Patients' Self-reported Adherence to Pegylated Interferon and Ribavirin 
Background
Prior research on adherence to Hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence.
Aims
To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings.
Methods
180 patients on treatment for Hepatitis C (23% co-infected with HIV) completed a cross-sectional survey at the site of their Hepatitis C care.
Results
Seven percent of patients reported missing at least one injection of pegylated interferon in the last four weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load.
Conclusions
Self-reported dose nonadherence to Hepatitis C treatment occurs frequently. Further studies of dose nonadherence (assessed by method other than self-report) and its relationship to HCV virologic outcome are warranted.
PMCID: PMC2891196  PMID: 19086329
Adherence; HCV; HIV; co-infection; interferon; ribavirin
24.  Naturally occurring dominant resistance mutations to HCV protease and polymerase inhibitors in treatment-naïve patients 
Hepatology (Baltimore, Md.)  2008;48(6):1769-1778.
Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir, the NS5B polymerase inhibitor AG-021541, and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.6% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses in vivo.
Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous non-response to peginterferon and ribavirin.
doi:10.1002/hep.22549
PMCID: PMC2645896  PMID: 19026009
NS3 protease inhibitor; NS5B polymerase inhibitor; Telaprevir; Boceprevir
25.  Hepatitis C Virus (HCV)–Specific Immune Responses of Long-Term Injection Drug Users Frequently Exposed to HCV 
The Journal of infectious diseases  2008;198(2):203-212.
Background
Injection drug users (IDUs) who successfully clear hepatitis C virus (HCV) have a reduced risk of developing chronic reinfection, despite their continuing exposure to the virus. To identify immunological correlates for this apparent protection, we studied HCV-specific immune responses in long-term IDUs (duration, >10 years).
Methods
HCV-specific T cell responses were assessed in proliferation, enzyme-linked immunospot (ELISPOT), interferon (IFN)–γ secretion, and cytotoxicity assays, whereas HCV-specific antibodies were assessed in enzyme immunoassays (EIAs), chemiluminescent assays, and in vitro neutralization assays.
Results
HCV-specific T cell proliferation and IFN-γ production were more common in nonviremic EIA-positive IDUs (16 [94%] of 17 IDUs) than in viremic EIA-positive IDUs (9 [45%] of 20 IDUs) (P = .003). They were also noted in 16 (62%) of 26 nonviremic EIA-negative IDUs. In contrast, 19 (90%) of 21 viremic IDUs displayed neutralizing antibodies (nAbs), compared with 9 (56%) of 16 nonviremic EIA-positive IDUs (P = .04) and 0 of 24 nonviremic EIA-negative IDUs. Nonviremic IDUs with nAbs were older (P = .0115) than those without nAbs, but these groups did not differ in terms of either injection drug use duration or HCV-specific T cell responses.
Conclusion
The reduced risk of HCV persistence in IDUs previously recovered from HCV infection correlated with T cell responses, and prolonged antigenic stimulation appears to be required to maintain humoral responses.
doi:10.1086/589510
PMCID: PMC2699613  PMID: 18505381

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