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Factors associated with spontaneous clearance of hepatitis C virus among illicit drug users Grebely, Jason; Raffa, Jesse Daniel; Lai, Calvin; Krajden, Mel; Conway, Brian; Tyndall, Mark Jul 31, 2007

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Can J Gastroenterol Vol 21 No 7 July 2007 447Factors associated with spontaneous clearance ofhepatitis C virus among illicit drug usersJason Grebely BSc PhD1, Jesse D Raffa BSc MSc2, Calvin Lai MMath3, Mel Krajden MD FRCPC4, Brian Conway MD FRCPC1, Mark W Tyndall MD ScD FRCPC3,51Department of Anesthesiology, Pharmacology and Therapeutics; 2Department of Statistics; 3BC Centre for Excellence in HIV/AIDS; 4British Columbia Centre for Disease Control; 5Department of Medicine, University of British Columbia, Vancouver, British ColumbiaCorrespondence: Dr Jason Grebely, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Suite 201, 1200 Burrard Street, Vancouver, British Columbia V6Z 2C7. Telephone 604-642-6429, fax 604-642-6419, e-mail jgrebely@interchange.ubc.caReceived for publication October 5, 2006. Accepted November 28, 2006J Grebely, JD Raffa, C Lai, M Krajden, B Conway, MW Tyndall.Factors associated with spontaneous clearance of hepatitis C virusamong illicit drug users. Can J Gastroenterol 2007;21(7):447-451.BACKGROUND: Spontaneous clearance of hepatitis C virus(HCV) occurs in approximately 25% of individuals.METHODS: To better understand the characteristics associatedwith clearance, the present study evaluated HCV clearance in acommunity-based cohort study. The Community Health and SafetyEvaluation project recruited 3553 individuals via community organi-zations and door-to-door canvassing of a random sample of singleoccupancy hotels in the community to monitor uptake of health serv-ices and to estimate the incidence of communicable infections.Cohort data were linked with longitudinal laboratory databases,including HCV antibody and polymerase chain reaction assay results.RESULTS: Overall, 762 individuals had HCV antibody and RNAtesting performed between 1999 and 2005. Spontaneous HCV clear-ance was observed in 179 individuals (23.5%), while HCV persist-ence was observed in 583 individuals (76.5%). The ability to developprotective immunity against HCV, as demonstrated by viral clear-ance, occurred more often in individuals of Aboriginal ethnicity(adjusted OR [AOR] 2.9, 95% CI 2.0 to 4.3; P<0.001) and femaleindividuals (AOR 1.6, 95% CI 1.1 to 2.4; P=0.01). The rate ofspontaneous HCV clearance was reduced in individuals using anytype of illicit drugs (AOR 0.54, 95% CI 0.29 to 1.00; P=0.05) andthose with HIV coinfection (AOR 0.58, 95% CI 0.38 to 0.88;P=0.01). Of 218 HIV-infected subjects, 48 of 51 (94%) in whom theorder of HCV and HIV infection was established were infected withHCV a median of 2.4 years (range 0.2 to 10 years) before becominginfected with HIV.CONCLUSIONS: Aboriginal ethnicity and female sex were associ-ated with increased rates of HCV clearance, while HIV coinfectionand illicit drug use were associated with increased HCV persistence.Key Words: Aboriginal ethnicity; Female; Hepatitis C virus; HIV;Injection drug useLes facteurs associés à la clairance spontanéedu VHC chez les usagers de drogues illicitesHISTORIQUE : La clairance spontanée du virus de l’hépatite C (VHC)se produit chez environ 25 % des personnes atteintes.MÉTHODOLOGIE : Pour mieux comprendre les caractéristiques asso-ciées à la clairance, la présente étude a évalué la clairance du VHC au seind’une étude de cohorte communautaire. Le projet d’évaluation de la san-té et de la sécurité communautaires a recruté 3 553 personnes auprès d’or-ganismes communautaires et par la sollicitation à domicile d’unéchantillon aléatoire provenant de maisons de chambres au sein de la col-lectivité afin de surveiller la mise en application des services de santé etd’estimer l’incidence d’infections transmissibles. Les données de cohorteétaient reliées aux bases de données longitudinales de laboratoire, y com-pris l’anticorps du VHC et les résultats des dosages de la réaction enchaîne de la polymérase.RÉSULTATS : Dans l’ensemble, 762 personnes ont subi des épreuvesd’anticorps du VHC et d’ARN exécutées entre 1999 et 2005. On aobservé la clairance spontanée du VHC chez 179 personnes (23,5 %) et lapersistance du VHC chez 583 personnes (76,5 %). La capacité dedévelopper une immunité protectrice contre le VHC, démontrée par laclairance virale, se produit plus souvent chez des personnes d’ethnieautochtone (rapport de cotes rajusté [RCR] 2,9, 95 % IC 2,0 à 4,3;P<0,001) et de sexe féminin (RCR 1,6, 95 % IC 1,1 à 2,4; P=0,01). Letaux de clairance spontanée du VHC était réduit chez les personnes quiutilisaient quelque type de drogues illicites que ce soit (RCR 0,54, 95 %IC 0,29 à 1,00; P=0,05) et chez celles qui étaient co-infectées par le VIH(RCR 0,58, 95 % IC 0,38 à 0,88; P=0,01). Des 218 sujets infectés par leVIH, 48 des 51 personnes (94 %) chez qui on avait établi l’ordre d’ap-parition de l’infection au VHC et au VIH avaient été infectées par leVIH, une médiane de 2,4 ans (fourchette de 0,2 à 10 ans) avant d’êtreinfectés par le VIH.CONCLUSIONS : L’ethnie autochtone et le sexe féminin s’associaientà une augmentation des taux de clairance du VHC, tandis que la co-infection au VIH et l’usage illicite de drogues étaient reliés à la persis-tance accrue du VHC.Illicit drug use is associated with high rates of hepatitis C virus(HCV) transmission in many urban centres. Of the estimated170 million HCV prevalent cases in the world, over 50% occuramong injection drug users (IDUs), and over 75% of incidentinfections occur in the IDU population (1). Acute infectionwith HCV is characterized by the detection of viremia, subse-quent development of HCV-specific antibodies, a high likeli-hood of persistent viremia and chronic infection (2,3).Following acute infection, the overall rate of spontaneous viralclearance is estimated to be 25%, but appears to be dependenton the route of transmission, and other host and pathogen-related characteristics (4-9). Factors that have been associatedwith spontaneous clearance include female sex (10-14) andyoung age at the time of infection (15,16). Conversely, blackethnicity and coinfection with HIV (5,7,17,18) have been asso-ciated with reduced rates of HCV clearance.In 1997, studies (19-21) from the Downtown Eastside ofVancouver, British Columbia, home to over 5000 IDUs, havereported annual HCV incidence rates of over 16 cases per100 person-years between 1996 and 1999. The correspondingORIGINAL ARTICLE©2007 Pulsus Group Inc. All rights reserved9991_grebely.qxd  29/06/2007  9:45 AM  Page 447prevalences of HIV and HCV were 23% and 88%, respectively(20). This neighbourhood received international attention inthe late 1990s due to increasing visible drug use, a significantrise in overdose-related deaths, and the declaration of a publichealth emergency due to epidemic rates of HIV and HCVinfection. These outbreaks of HIV and HCV infection occurreddespite the presence of needle-exchange programs and freeaccess to medical treatment.To increase our understanding of the HCV epidemic in thispopulation, identifying the determinants of early clearance ofviremia (generally understood to represent a ‘spontaneous cure’of HCV) is essential. With this in mind, the present studymeasured the rate and characteristics of HCV clearance amonginfected individuals enrolled in a large, community-basedcohort in Vancouver.METHODSStudy populationThe Community Health And Safety Evaluation (CHASE) projectis a prospective, open cohort study designed to evaluate healthservice use in the Downtown Eastside of Vancouver. BetweenJanuary 2003 and June 2004, 3553 individuals were recruited viacommunity organizations and door-to-door canvassing of a randomsample of single occupancy hotels in the community, based oncensus information. Individuals were eligible for inclusion if theylived or used health services in the community. Study participantsreceived a $10 stipend to complete a short, interviewer-administered questionnaire to collect information about demo-graphics, health service utilization, HIV and HCV testing, andrecent illicit drug use. Subjects were requested to provide a time-limited consent for the researchers to perform linkages withprovincial health services databases. This included HCV, HIV andhepatitis B virus (HBV) testing performed at the British ColumbiaCentre for Disease Control (BCCDC) and the University ofBritish Columbia virology department. Individuals who receivedtreatment for HCV infection were excluded from the present studyto eliminate the possibility of treatment-induced viral clearance asa confounding factor. Of the CHASE cohort participants, 762 wereincluded in the study by demonstrating anti-HCV reactivity andhaving one or more commercial HCV RNA tests performed(Figure 1). The University of British Columbia’s and ProvidenceHealth Care’s (Vancouver, British Columbia) research ethicsboards approved the present study.Laboratory testingSamples from individuals with a confirmed positive test for anti-HCVantibodies were further evaluated for the presence of HCV RNA.HCV persistence was defined by the presence of one or moredetectable HCV RNA tests following a positive test for anti-HCV.HCV clearance was defined by the presence of one or moreundetectable HCV RNA tests following a positive test for anti-HCV.Individuals were suspected of having acute HCV infection basedon a single HCV RNA-positive or -negative result within sixmonths of their first anti-HCV-positive test, and were notconsidered in the present analysis because of the potentialmisclassification of spontaneous viral clearance.All HCV antibody and RNA testing was performed at two cer-tified provincial laboratories between 1992 and 2005. HCV anti-body testing was performed using second- or third-generationenzyme immunoassays (EIAs) as follows: May 1992 to September1993, UBI HCV EIA version 2.0 (Organon Teknika, USA);October 1993 to July 1994, UBI HCV EIA version 2.1 (OrganonTeknika, USA); August 1994 to March 1997, UBI HCV EIA ver-sion 4.0 (Organon Teknika, USA); and April 1997 to present,AxSYM HCV version 3.0 (Abbott Diagnostics, USA). Specimensreactive for anti-HCV antibodies were retested by the second- orthird-generation recombinant immunoblot assay (Chiron, USA)until 1999 for confirmation. Between April 1997 and July 1999,AxSYM HCV version 3.0 anti-HCV reactive specimens wereretested by UBI HCV version 4.0, and from August 1999 to pres-ent, AxSYM HCV version 3.0 reactive samples were retested byOrtho EcI (Ortho-Clinical Diagnostics, Canada). Only specimensreactive by both manufacturer’s tests were considered to be anti-HCV reactive. HCV RNA testing was performed by the qualitativeCOBAS AMPLICOR HCV Test version 2.0 (Roche DiagnosticSystems, Canada) with a limit of detection of 50 IU/mL. HBV andHIV serology test results were abstracted as recorded in the BCCDCvirology database by confidential record linkage.Statistical analysisVariables of interest in the present analysis included sex, estimatedage at infection, ethnicity, housing status, recent treatment withmethadone, recent jail time, HCV treatment history, alcohol use,injection drug use, noninjection illicit drug use, previous HBVinfection and HIV status. The duration of HCV infection in HCVseroprevalent individuals was calculated using the date of their firstrecorded positive EIA test for HCV antibodies. In 658 patientswho were seroprevalent on their first test, age at infection was esti-mated by random sampling from the age distribution of the inci-dent cases. The duration of infection in 104 individuals with HCVseroconversion between 1992 and 2005 was estimated using themidpoint of the first positive and last negative HCV antibody tests.Aboriginal ethnicity included all people with an indigenous her-itage, including the Inuit, First Nations, Native American,Alaskan Native and Métis people. Exposure to HBV was definedby current or historical anti-HBV total reactivity. Active HBVinfection was defined by the detection of HBV surface antigen.HIV status was determined by either serological testing from theBCCDC HIV testing database or subject self-reporting for individ-uals diagnosed outside the province. Unstable housing was definedas living in a shelter or living on the street. Injection and noninjec-tion illicit drug use and alcohol use in the previous six months wasevaluated as ‘frequent use’ (everyday or most days) or ‘any use’(subclassified as two to three times per week, two to three times permonth or once a month). Specific drug use included injection andnoninjection of cocaine, heroin and crystal methamphetamine use.Characteristics of individuals with and without HCV clearance werecompared using two-sample t tests for quantitative variables and χ2tests or Fisher’s exact tests, as appropriate, for testing differencesbetween proportions. A multiple logistic regression model wasthen fit comprised of all variables and subsequently reduced usingGrebely et alCan J Gastroenterol Vol 21 No 7 July 20074482117 individuals received HCV Ab testing3553 individuals with questionnaire data1315 (63.6%) HCV Ab+ individualsHCV persistence(n=583, 76.5%)(Ab+/RNA+)762 (58.0%) individuals with HCV RNA testing availableHCV clearance(n=179, 23.5%)(Ab+/RNA–)48 individuals excluded(received HCV treatment)       Figure 1) Subject disposition. Ab Antibody; HCV Hepatitis C virus9991_grebely.qxd  29/06/2007  9:45 AM  Page 448backwards elimination. Statistically significant differences wereassessed at a significance level of 0.05. All reported P values weretwo-sided.RESULTSOf the 1315 HCV antibody-positive individuals enrolled in theCHASE cohort, a total of 762 individuals received testing forHCV RNA and were subsequently followed for a median periodof 4.4 years. The mean number of HCV RNA tests per individ-ual was 1.6 (range one to 10). No significant differences wereobserved in the demographics of HCV antibody-positive indi-viduals who did and did not receive HCV RNA testing, includ-ing age (P=0.86), male sex (P=0.95), ethnicity (P=0.15),unstable housing (P=0.19), illicit drug use (P=0.42) and HIVinfection (P=0.15). However, individuals who did not receiveHCV RNA testing were more likely to engage in recent injec-tion drug use (64.3% versus 56.6%, P=0.006). Overall,583 individuals (76.5%) had persistent viremia, and 179 (23.5%)were determined to have spontaneous clearance of viremia(Figure 1). The demographic and behavioural characteristics ofindividuals with persistent viremia versus those with sponta-neous clearance are shown in Tables 1 and 2. Overall, themean age was 42 years and the estimated age at HCV infectionwas 32.2 years. There were no significant differences in themean age (41.7 years versus 42.5 years; P=0.32) or the estimatedage at infection (32.4 years versus 31.5 years; P=0.27) betweenindividuals with persistent viremia and those with spontaneousclearance.In the univariate analysis, the ability to develop protectiveimmunity to HCV, evident in the present study by spontaneousclearance of HCV infection, occurred more frequently amongindividuals of Aboriginal ethnicity (OR 2.8, 95% CI 2.0 to 4.0;P<0.001) and female sex (OR 1.8, 95% CI 1.3 to 2.6; P=0.001).Decreased rates of spontaneous HCV clearance were observedin individuals with HIV coinfection (OR 0.68, 95% CI 0.46 to1.0; P=0.06). Estimated age at infection, housing status, previ-ous methadone treatment, recent jail time, HBV infection,alcohol use, and illicit noninjection or injection drug use in thepreceding six months were not associated with HCV persist-ence or clearance (Tables 1 and 2).As shown in Table 3, after adjusting for confounding vari-ables using multiple logistic regression analysis, the factorsindependently associated with spontaneous clearance of HCVincluded Aboriginal ethnicity (adjusted OR [AOR] 2.9, 95%CI 2.0 to 4.3; P<0.001) and female sex (AOR 1.6, 95% CI 1.1to 2.4; P=0.01). Spontaneous clearance of HCV was inverselyassociated with the use (versus nonuse) of any illicit drugs(AOR 0.54, 95% CI 0.29 to 1.0; P=0.05) and HIV infection(AOR 0.58, 95% CI 0.38 to 0.88; P=0.01).To identify whether HIV infection impacts HCV clearanceor persistence, 51 subjects were identified in whom the order ofHCV and HIV infections could be established based on docu-mented timing of HCV and HIV seroconversion. In total, 48 ofSpontaneous clearance of HCV in illicit drug usersCan J Gastroenterol Vol 21 No 7 July 2007 449TABLE 1Characteristics of participants with persistent hepatitis Cvirus (HCV) versus those with HCV clearanceHCV HCVpersistence clearance(Ab+/RNA+) (Ab+/RNA–)(N=583), (N=179), ORCharacteristic n (%) n (%) (95% CI) P*SexMale 411 (70.5) 102 (57.0) – –Female 172 (29.5) 77 (43.0) 1.8 (1.3–2.6) 0.001EthnicityCaucasian 389 (66.7) 82 (45.8) – –Aboriginal 145 (24.9) 86 (48.0) 2.8 (2.0–4.0) <0.001Other 49 (8.4) 11 (6.2) 1.1 (0.53–2.1) 0.99Estimated age at infection†<30 years 236 (40.6) 81 (45.3) – –≥30 years 345 (59.2) 98 (54.7) 0.83 (0.59–1.2) 0.31Estimated age at infection≤20 41 (7.1) 16 (8.9) – –21 to 30 195 (33.6) 65 (36.3) 0.85 (0.45–1.6) 0.7531 to 40 208 (35.8) 63 (35.2) 0.78 (0.41–1.5) 0.5541 to 50 111 (19.1) 27 (15.1) 0.62 (0.31–1.3) 0.27>50 26 (4.5) 8 (4.5) 0.79 (0.30–2.1) 0.81Housing statusUnstable 434 (74.4) 124 (69.3) – –Stable 149 (25.6) 55 (30.7) 1.3 (0.89–1.9) 0.20Methadone treatmentNo 368 (63.1) 125 (69.8) – –Yes 215 (36.9) 54 (30.2) 0.74 (0.52–1.1) 0.12Jail timeNo 446 (76.5) 138 (77.1) – –Yes 137 (23.5) 41 (22.9) 0.97 (0.65–1.4) 0.95HBV coinfectionNo previous infection 559 (95.9) 170 (95.0) – –Previous infection 24 (4.1) 9 (5.0) 1.2 (0.56–2.7) 0.67HIV-1 coinfection HIV-1– 406 (69.6) 138 (77.1) – –HIV-1+ 177 (30.4) 41 (22.9) 0.68 (0.46–1.0) 0.06Percentages indicate proportion in columns. *As determined by the χ2 orFisher’s exact test as appropriate; †Age data were not obtained for two par-ticipants. – Negative; + Positive; Ab Antibody; HBV Hepatitis B virusTABLE 2Characteristics of participants with persistent hepatitis Cvirus (HCV) versus those with HCV clearance over theprevious six monthsHCV HCVpersistence clearance(Ab+/RNA+) (Ab+/RNA–)(N=583), (N=179), ORCharacteristic n (%) n (%) (95% CI) P*Alcohol useNone 323 (55.4) 94 (52.5) – –Any 260 (44.6) 85 (47.5) 1.1 (0.80–1.6) 0.55Illicit drug useNone 42 (7.2) 19 (10.6) – –Any 541 (92.8) 160 (89.4) 0.65 (0.37–1.2) 0.19Injection drug useNone 243 (41.7) 88 (49.1) – –Any 340 (58.3) 91 (50.8) 0.74 (0.53–1.0) 0.09Injection cocaine useNone 306 (52.5) 106 (59.2) – –Any 277 (47.5) 73 (40.8) 0.76 (0.54–1.1) 0.14Injection heroin useNone 388 (66.6) 128 (71.5) – –Any 195 (33.4) 51 (28.5) 0.79 (0.55–1.2) 0.25Crack cocaine useNone 162 (27.8) 56 (31.3) – –Any 421 (72.2) 123 (68.7) 0.85 (0.59–1.2) 0.42*As determined by the χ2 or Fisher’s exact test as appropriate. – Negative; + Positive; Ab Antibody9991_grebely.qxd  29/06/2007  9:45 AM  Page 44951 individuals (94%) acquired HCV infection a median of2.4 years (range 0.2 to 10 years) before being diagnosed withHIV.DISCUSSIONWe investigated the rate and characteristics associated withHCV clearance among inner-city residents in Vancouver bystudying a large, community-based cohort consisting mainly ofillicit drug users. We documented that 23.5% of individuals inwhom testing for HCV antibodies and viremia were availablespontaneously cleared their infection. This is consistent withpreviously reported clearance rates of 14% to 46% in non-IDUs(4-8). In our cohort, Aboriginal ethnicity and female sex wereassociated with an enhanced capacity to clear HCV infection.In contrast, HIV coinfection and illicit drug use were associatedwith increased persistence of HCV infection.Our findings with respect to the Aboriginal race are consis-tent with data from other centres in Canada, suggesting thatspontaneous HCV clearance may be higher in these individuals(22,23). A similar finding has recently been published in stud-ies of Alaskan Natives (24). Interestingly, other data suggestthat African Americans exhibit decreased rates of HCV clear-ance (5,7,18). The basis for the association between race andHCV clearance is not well understood.We observed that female sex was associated with increasedrates of HCV clearance. This is supported by previously pub-lished data (10-14) and a recent systematic review of 31 longi-tudinal studies evaluating the correlates of spontaneous HCVclearance (9). In a pooled analysis of 675 subjects with HCVclearance, the investigators determined that male subjects weresignificantly less likely (OR 0.43, 95% CI 0.36 to 0.53,P<0.001) to clear HCV spontaneously (19%) than female sub-jects (40%). It has been postulated that HCV clearance infemale subjects may be facilitated by estrogen (11,25).However, this difference may also be attributed to genetic orimmunological differences that have not yet been determined.The association of sex and race with spontaneous HCVclearance speaks to possible roles for host genetics and immunityin viral control. Genetic polymorphisms in a number ofimmunological proteins involved in the regulation of cellularimmune responses (such as interleukin [IL]-10, IL-19, IL-20and tumour necrosis factor-alpha), as well as in both humanleukocyte antigen class I and II molecules, are associated withreduced clearance (26-31). Immunological studies inAboriginals suggest a lower genetic tendency to produce IL-10than Caucasians and a reduced susceptibility to HCV protein-induced IL-10 immune responses, implicating a role for theimmune system in this enhanced protection (32). It has recentlybeen determined that inhibitory natural killer cells may beimportant in HCV clearance, and that differing activity ofcertain genes encoding interactions between human leukocyteantigen class I molecules and natural killer cells may play animportant role in the efficacy of this process (33). However, fur-ther research is needed to understand the associations betweenhost genetics or the immune system and HCV clearance.HIV infection was associated with reduced rates of HCVclearance. Similar observations have been found in studiesamong United States veterans (18), hemophiliacs (16) andIDUs (7). The results from our study suggest that the majorityof illicit drug users are infected with HCV a median of 2.4 yearsbefore HIV infection, which is consistent with reports fromother groups (34). Therefore, given that HCV clearancegenerally occurs within the first six to 12 months of infection,HIV is most often impacting persistence of HCV rather than itsinitial clearance in this setting. HIV infection may decreasecirculating HCV-specific CD4 and CD8 T cells that are gener-ally present in higher levels in individuals who cleared HCVinfection (35). This preservation of higher CD4 cell levels,which is associated with preserved anti-HCV lymphoprolifera-tive responses, may be reduced or eliminated on HIV infection(35). Our cohort, as currently recruited, does not provide uswith the statistical power to evaluate this hypothesis.In addition, illicit drug use was associated with dimin-ished capacity to resolve HCV infection. Relationshipsbetween specific drug use patterns and viral clearance werenot detected, although this may reflect sample size.Alternatively, the effect may be of marginal significance,because the overall rate of HCV clearance in our cohort,which included a large proportion of IDUs, approximatedthat previously reported in non-IDU populations. The lowerlevel of viral clearance among those who report injectingmay also relate to a higher risk of reinfection. It is interestingto note that data from this cohort (36) and others (37) havedemonstrated that HCV reinfection after HCV clearanceoccurs less frequently than de novo HCV infection in IDUsand non-IDUs alike, suggesting little or no effect of thisbehaviour on the virus-host relationship.The present study has a number of limitations, mostly thoseinherent to observational cohorts. Testing for anti-HCV anti-bodies and HCV RNA occurred as clinically indicated. In prac-tice, antibody testing would be performed periodically inindividuals with such high risk of HCV infection, but lesssymptomatic patients (who may be more likely to resolve infec-tion) may not be tested for HCV RNA and would be missingfrom our analysis. Moreover, the majority of HCV RNA testingwas performed in recent years because of the increased avail-ability of HCV treatment in this population. Viral clearancewas, in some cases, confirmed by a single negative test, whichmay represent fluctuating low levels of viremia rather than trueclearance. Also, given the level of detection of the assay used(less than 50 U/mL), some individuals, defined as spontaneouslyclearing HCV infection, may have had low but undetectableviremia. However, the overall rate of HCV clearance (24%) isconsistent with other studies and reassures us that our conclu-sions are valid. Additionally, not all patients received HCVRNA testing, introducing a potential selection bias againstindividuals who may not have come forward for more compre-hensive testing or who were not likely to receive follow-up care.Drug use was assessed only in the six months preceding thequestionnaire, and historical drug use information was not avail-able. However, similar demographics and HIV status betweenthe two groups suggest a relative comparability of the groups andindicate similar testing patterns. An additional limitation withthe present study is that many of the variables, such as illicitGrebely et alCan J Gastroenterol Vol 21 No 7 July 2007450TABLE 3Multiple logistic regression of factors associated withclearance of hepatitis C virus infectionCharacteristic Adjusted OR 95% CI PAboriginal ethnicity (versus Caucasian) 2.9 2.0–4.3 <0.001Female sex 1.6 1.1–2.4 0.01HIV-1-positive 0.58 0.38–0.88 0.01Any illicit drug use 0.54 0.29–1.0 0.059991_grebely.qxd  04/07/2007  2:18 PM  Page 450drug use behaviours, were based on patient self-report and maybe prone to socially desirable responses.Given the limited currently available data investigatingHCV clearance in IDUs, the results of our study provide novelinsights into this issue. Our results suggest that Aboriginalethnicity and female sex may promote clearance (perhaps byenhanced immunological control), while HIV coinfectionand illicit drug use may reduce the likelihood of clearance,presumably by a similar mechanism. Understanding themechanisms underlying our observations may be helpful in themanagement of individuals with acute infection. Moreover, theunderstanding of factors that promote or hinder the generationof protective immunity may aid in the development of vaccinesor improved treatment options for HCV infection. Further studiesare required to confirm our observations from a clinical andpathophysiological perspective. This information will be animportant step in refining our approach to HCV infection inmedical practice.ACKNOWLEDGEMENTS: The present research was partiallysupported by the Canadian Institutes of Health Research (Jesse D Raffa), the National Canadian Research Training Programin Hepatitis C (Jason Grebely) and Vancouver Coastal Health(Mark W Tyndall and Brian Conway). Mark W Tyndall is therecipient of a Senior Scholar Award from the Michael SmithFoundation for Health Research.Spontaneous clearance of HCV in illicit drug usersCan J Gastroenterol Vol 21 No 7 July 2007 451REFERENCES1. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis Cvirus infection. Lancet Infect Dis 2005;5:558-67.2. Cox AL, Netski DM, Mosbruger T, et al. Prospective evaluation ofcommunity-acquired acute-phase hepatitis C virus infection. Clin Infect Dis 2005;40:951-8.3. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus andhepatitis C virus infection. Nat Rev Immunol 2005;5:215-29.4. Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C:High rate of both spontaneous and treatment-induced viral clearance.Gastroenterology 2003;125:80-8.5. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up afteracute hepatitis C infection. Hepatology 1999;29:908-14.6. Seeff LB. 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