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Hepatitis C virus reinfection in injection drug users Grebely, Jason; Conway, Brian; Raffa, Jesse Daniel; Lai, Calvin; Krajden, Mel; Tyndall, Mark 2006

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1  TITLE PAGE Manuscript Number: HEP-06-0444  Title: Hepatitis C Virus Re-infection in Injection Drug Users Author Names: Jason Grebely1, Brian Conway1, Jesse D. Raffa2, Calvin Lai4, Mel Krajden5 and Mark W. Tyndall3,4  1) Department of Anesthesiology, Pharmacology and Therapeutics, 2) Department of Statistics, 3) Department of Medicine, University of British Columbia, 4) BC Centre for Excellence in HIV/AIDS, 5) BC Centre for Disease Control, Vancouver, British Columbia. Keywords: hepatitis C persistence, hepatitis C re-infection, HIV, injection drug use              2  FOOTNOTE PAGE Contact Information:   Jason Grebely Department of Anesthesiology, Pharmacology and Therapeutics University of British Columbia 201-1200 Burrard Street Vancouver, BC V6Z 2C7, Canada Tel: 604-642-6429, Fax: 604-642-6419 jgrebely@interchange.ubc.ca Brian Conway – bconway@interchange.ubc.ca, Jesse D. Raffa – jraffa@stat.ubc.ca, Calvin Lai - clai@cfenet.ubc.ca, Mel Krajden – mel.krajden@bccdc.ca, Mark W. Tyndall – mtyndall@cfenet.ubc.ca List of Abbreviations: HCV, hepatitis C virus; IDU, injection drug use; IDUs, injection drug users; PEG-IFN, pegylated interferon; RBV, ribavirin; CHASE, Community Health and Safety Evaluation; CDN, Canadian; HIV, human immunodeficiency virus; HBV, hepatitis B virus; EIA, enzyme immunoassay; Ab, antibody; RNA, ribonucleic acid; RIBA, recombinant immunoblot assay; HBsAg, HBV surface antigen;  Financial Support: This research was partially supported by the Natural Sciences and Engineering Research Council of Canada (J.D.R.), the National Canadian Research Training Program in Hepatitis C (J.G.) and Vancouver Coastal Health (M.W.T., B.C.). M.W.T. is the recipient of a Senior Scholar Award from the Michael Smith Foundation for Health Research. 3  ABSTRACT (249 words) Spontaneous clearance of hepatitis C (HCV) may provide protection against re-infection. In a large, community-based cohort study of 3,553 inner city residents (consisting mainly of injection drug users), we identified HCV-infected individuals in whom virologic clearance had occurred and compared the rate of re-infection in this group to that observed in previously uninfected members of the same cohort. We identified 926 HCV uninfected and 658 infected viremic subjects at baseline, with 152/658 (23.1%) spontaneously clearing viremia over a median follow-up of 5.2 years (IQR, 2.8-7.4). At baseline, individuals with HCV clearance were more likely to be HIV co-infected (P<0.001), engaged in frequent illicit drug use (P=0.004) and injection drug use (P<0.001). The occurrence of HCV infection was lower in individuals with previous infection (14/152, 9.2%) when compared to those without previous infection (172/926, 18.6%), with incidence rates of 1.8 (95% CI, 0.9-3.0 cases/100 person-years) and 8.1 cases/100 person-years (95% CI, 6.9-9.4 cases/100 person-years), respectively, after accounting for follow-up. In a logistic regression analysis, when previous HCV infection was assessed as a covariate with other potential confounding variables (age, sex, ethnicity, HIV infection, housing status and illicit and injection drug use), individuals with previous HCV infection and viral clearance were 4 times less likely to develop infection than those infected for the first time [adjusted odds ratio, 0.23; 95% CI, 0.10-0.51, P<0.001]. In conclusion, individuals with clearance of HCV infection may have a lower risk of acquiring HCV than individuals who have never been infected, despite ongoing exposure to HCV. 4  Hepatitis C virus (HCV) infection constitutes a major public health burden, affecting over 170 million individuals throughout the world (1). Injection drug use (IDU) has emerged as the primary mode of transmission globally, accounting for over 75% of incident cases (1). In IDUs, the prevalence of HCV infection is 60-90% (2-4), with 80% of these individuals going on to develop persistent, chronic infection (5).   Pharmacologic advances have led to the development of effective treatment regimens leading to a virologic “cure” in 50% of HCV infected subjects receiving pegylated interferon (PEG-IFN) in combination with ribavirin (RBV) (6, 7). Although these outcomes have been replicated in active IDUs  (8, 9), there is still concern that the risk of HCV re-infection through recurrent parenteral exposure will negate the benefits of treatment.  Re-infection with HCV after spontaneous clearance has, in fact, been demonstrated in IDUs with ongoing risk behavior (10, 11), as well as in other groups, including polytransfused thalassaemic children (12) and subjects undergoing liver transplantation (13). In chimpanzees re-challenged with HCV after its clearance, re-infection does occur (14-17), but there is a relative resistance to subsequent HCV infection likely related to immune protection (14, 18). In humans, preliminary data from one cohort suggests that IDUs with successful clearance of HCV are less likely to develop viremia following re-exposure to HCV when compared to previously uninfected individuals (19). Given that a greater proportion of IDUs are receiving treatment for HCV, a clearer understanding of the protection from re-infection and its determinants is important. With 5  this in mind, we compared the rate of HCV re-infection among individuals who had spontaneous HCV clearance with the rate of primary HCV infection among participants in a large, observational community-based cohort. 6  PATIENTS AND METHODS Study Population The Community Health and Safety Evaluation (CHASE) project is a prospective open cohort study designed to evaluate health service use in the Downtown Eastside of Vancouver. Between January 2003 and June 2004, 3,553 subjects were recruited via community organizations and door-to-door canvassing of a random sample of single occupancy hotels in the community, based on census information. Subjects were eligible for inclusion if they lived or utilized health services in the community. Study participants received a CDN$10 stipend to complete a short, interviewer-administered questionnaire that gathered information on demographics, health service utilization, human immunodeficiency virus (HIV) testing, HCV testing and recent drug use. To acquire historical data, subjects were requested to provide a time limited consent for the researchers to perform linkages with specific provincial health services databases using names and personal health card numbers. This included HCV, HIV and hepatitis B virus (HBV) testing performed at the British Columbia Centre for Disease Control and the University of British Columbia Virology Department at St. Paul’s Hospital. The University of British Columbia /Providence Health Care Research Ethics Board approved this study.  Individuals were defined as HCV uninfected if they had a negative enzyme immunoassay (EIA) test for HCV antibodies (HCV Ab) on their first linked test result. Participants were considered HCV infected if their first recorded EIA test for HCV antibodies was positive. HCV clearance was defined as the presence of HCV antibodies followed by one subsequent negative test for HCV RNA (HCV Ab+/HCV RNA-). HCV persistence was defined by a positive test for HCV antibodies followed by at least one HCV RNA positive test with all subsequent tests remaining 7  positive (HCV Ab+/HCV RNA+). Individuals with persistent HCV RNA were excluded from analysis except for the evaluation of demographic characteristics. We then compared the incidence of HCV infection between 1992 and 2005 in individuals with (HCV Ab+/HCV RNA-) and without (HCV Ab-) previous infection to evaluate the effect of prior infection on subsequent re-infection rates.  For the purpose of this study, the index visit in the uninfected subjects was the date of the first negative HCV antibody test. The incidence of new cases of HCV infection was measured by an HCV antibody negative test and a subsequent positive test during follow-up (HCV Ab-/HCV Ab+), with the date of HCV infection estimated as the midpoint between the last HCV antibody negative test to the first HCV antibody positive test.  During the follow-up period, the incidence of HCV re-infection was determined by the detection of HCV RNA following spontaneous clearance of HCV (HCV Ab+/HCV RNA-/HCV RNA+), with the date of HCV re-infection being estimated as the midpoint between the last HCV RNA negative test and the first HCV RNA positive test after clearance. Follow-up for individuals developing viremia was defined as the time from the index visit to the date of re-infection or infection. In individuals that remained clear of viremia, this was defined as the time from the index visit to the date of the most recent negative HCV RNA test or HCV antibody test in previously infected and previously uninfected subjects, respectively.  Laboratory Testing All virology testing was performed at two certified provincial laboratories between 1992 and 2005. HCV antibody testing was performed using first-, second- or third-generation enzyme-8  linked immunosorbent assays (May 1992 to September 1993: UBI HCV EIA v2.0 (Organon Teknika, Durham, North Carolina); October 1993 to July 1994: UBI HCV EIA v 2.1 (Organon Teknika, Durham, North Carolina); August 1994 to March 1997: UBI HCV EIA v 4.0 (Organon Teknika, Durham, North Carolina); April 1997 to present: AxSYM HCV v 3.0 (Abbott Diagnostics, Chicago, Illinois). Specimens reactive for anti-HCV antibodies were retested by the second or third generation Recombinant Immunoblot Assay (Chiron, Emeryville, California) until 1999 to confirm the EIA specificity. Between April 1997 and July 1999, AxSYM HCV 3.0 anti-HCV reactive specimens were retested by UBI HCV v4.0 and from August 1999 to the present time, AxSYM HCV 3.0 reactive samples are retested by Ortho EcI (Ortho Diagnostics, Mississauga, Canada). Only specimens reactive by both manufacturer's tests were considered to be anti-HCV reactive.  The presence or absence of viremia was detected by HCV RNA testing performed when requested by a physician. Since January 1998, HCV RNA testing is performed by the qualitative COBAS AMPLICOR HCV Test v2.0 (Limit of detection: 50 IU/mL, Roche Diagnostic Systems, Mississauga, Canada). To ensure specimen integrity, HCV RNA testing was performed using dedicated serum samples separated within 4 to 6 hours of collection or EDTA plasma separated within 3 to 5 days of collection. HBV and HIV status were determined by confidential record linkage to the British Columbia Centre for Disease Control virology testing database.  Statistical Analysis Variables of interest in this analysis included age, ethnicity, housing status, alcohol use, injection drug use, non-injection illicit drug use, previous HBV infection and HIV status. The age of 9  participants was determined on the date that the questionnaire was administered. Unstable housing was defined as living in a shelter, rooming house, single occupancy hotel or living on the street/homeless. Illicit drug use behavior included injection cocaine, injection heroin, injection crystal methamphetamine, as well as the use of heroin, crack cocaine and crystal methamphetamine though inhalation. Illicit drug use, injection drug use and alcohol use in the past six months was categorized as ‘frequent’ if used everyday/most days, ‘any’ if there was any reported use in the preceding six months and “none” if no use was reported. Exposure to HBV was defined by the presence of historical positive tests for HBV surface antigen (HBsAg) and anti-hepatitis B core total. HIV status was determined by a confidential record linkage to the British Columbia Centre for Disease Control HIV testing database or by subject self-report. We compared characteristics of subjects with and without previous HCV infection using two-sample t-test for quantitative variables and 2 or Fisher’s Exact Test, as appropriate, for testing differences between two proportions. We also compared the characteristics of subjects with and without incident HCV infection using 2 or Fisher’s Exact Test, as appropriate. A multiple logistic regression model was conducted comprised of potential confounders to assess if previous HCV infection was independently associated with reductions in the incidence of HCV infection. Statistically significant differences were assessed at a significance level of 0.05 and all reported p-values are two-sided.  10  RESULTS Of the 3,553 subjects enrolled into the cohort, HCV antibody testing was performed in 2,117 (59.6%, Figure 1). Forty-eight subjects reported having previously received treatment for HCV infection and were excluded from further analysis. At baseline, we identified 926 subjects (43.7%) uninfected with HCV as documented by negative testing for HCV antibodies. The remaining 1,143 individuals (55.2%) were HCV antibody positive on their first recorded test. HCV RNA testing was available in 658 of these subjects. No significant differences were observed in the demographics among HCV antibody positive individuals that did and did not receive HCV RNA testing, including age (P=0.87), male sex (P=0.95), illicit drug use (P=0.27) and HIV infection (P=0.32). However, subjects that did not receive HCV RNA testing were more likely to engage in recent injection drug use (62.9% vs. 54.4%, P=0.004). After identifying 506 individuals with persistent HCV infection on the basis of HCV RNA positivity, we found 152 (23.1%) with spontaneous clearance of viremia.  A comparison between the participants without previous HCV infection and those with HCV clearance is shown in Table 1.  The two groups were similar with respect to gender (P=0.41) and housing status (P=0.84), however, individuals with previous HCV clearance were older (43.7 years vs. 41.2 years, P<0.001), more likely to be of Aboriginal ethnicity (50.3% vs. 29.0%, P<0.001), have previous HBV infection (5.9% vs. 1.3%, P<0.001) and be co-infected with HIV (23.5% vs. 7.3%, P<0.001) when compared to those previously uninfected with HCV. Although there was no difference in the proportion of subjects engaging in any illicit drug use (P=0.50), individuals previously infected with HCV were more likely to be engaged in frequent illicit drug use (68.0% vs. 55.2%, P=0.004) and injection drug use (any; 48.0% vs. 26.0%, P<0.001, 11  frequent; 24.8% vs. 13.9%, P<0.001). Individuals with clearance of viremia (n=152) were followed for a median of 5.2 years (IQR, 2.8-7.4) beyond the index visit as compared to 2.8 years (IQR, 1.4-5.0) in individuals without previous HCV infection (Table 2).  The overall prevalence of HCV infection in this cohort was 63.6% (1315/2069), including 172 cases acquired in previously uninfected individuals. The occurrence of HCV infection was lower in individuals with previous infection (14/152, 9.2%) when compared to those without previous infection (172/926, 18.6%). After accounting for duration of follow-up, the incidence of HCV infection was 5 times lower in those previously infected with HCV (1.8 cases/100 person-years; 95% Confidence Interval (CI), 0.9-3.0 cases/100 person-years) when compared to those without previous infection (8.1 cases/100 person-years; 95% CI, 6.9-9.4 cases/100 person-years). This occurred despite the fact that those with previous HCV infection were at an increased risk for HCV acquisition due to a higher rate of HIV co-infection, illicit drug use and injection drug use. The observed difference could not be explained by a lack of follow-up in previously infected individuals, as the absence of viremia was documented for a median of 5.4 years (range, 0-13.5 years) in this group. In a logistic regression of individuals with and without incident HCV infection, when previous HCV infection was assessed as a covariate with other potential confounding variables (age, sex, ethnicity, HIV infection, housing status and illicit and injection drug use), individuals with previous HCV infection and viral clearance were still 4 times less likely to develop incident infection than those infected for the first time [adjusted odds ratio, 0.23; 95% CI, 0.10-0.51, P<0.001].    12  We also evaluated the occurrence of recurrent HCV viremia in individuals with and without HIV infection and previous viral clearance (Table 3). The occurrence of HCV infection in HIV negative individuals with previous HCV infection was 8/117 (6.8%) as compared to 6/35 (17.1%) in HIV co-infected individuals. After accounting for follow-up, the incidence of HCV infection in HIV negative individuals with previous HCV clearance (1.4 cases/100 person-years; 95% CI, 0.7-2.9 cases/100 person-years) remained 2 times lower than HIV co-infected individuals (2.8 cases/100 person-years; 95% CI, 1.0-6.1 cases/100 person-years).  Of the 14 subjects with HCV re-infection, 13 had ongoing cocaine use, 9 by injection (Table 4), and six subjects were HIV positive. HCV viremia was cleared a second time in 4 subjects (29%), despite ongoing cocaine use in all 4 cases. None of the 4 subjects that cleared HCV a second time were co-infected with HIV at the time of clearance.  13  DISCUSSION  In this study of a large community-based cohort of inner city residents in Vancouver, we have demonstrated that individuals with successful clearance of HCV infection have a lower risk of acquiring HCV infection than individuals without previous HCV infection, despite the fact that they appear to be at higher risk of exposure. This protection was tracked over a median of five years.   The overall rate of clearance of HCV viremia was 23.1%, which is consistent with published data in non-IDUs (20). HCV re-infection with viremia occurred in only 10/152 subjects (6.6%), despite the fact that 90% continued to engage in illicit drug use, including 50% who reported injection drug use. The existence of such cases is not surprising, given that re-infection with HCV after spontaneous clearance is well described in IDUs with ongoing risk behaviors (10, 11).  After adjusting for potential confounding variables, individuals with previous clearance of HCV infection were four times less likely to acquire HCV re-infection compared with individuals infected for the first time. Therefore, we do not believe that these different rates were associated with epidemiological differences in the two populations. In fact, these data are consistent with results from another cohort of IDUs in Baltimore in which the incidence of infection over a two-year period was 6.0 cases per 100 person-years in IDUs with HCV clearance as compared to 10.5 cases per 100 person years in previously uninfected IDUs (19). Although our patient population may differ in important ways from this cohort in terms of race and ethnicity, HIV infection and injection drug use, we observed a similar protection in subjects with previous HCV infection.   14  HIV infected subjects with previous HCV clearance were two times more likely to demonstrate recurrence of HCV viremia (2.8 cases/100 person-years) than those without HIV (1.4 cases/100 person-years). Although it was not possible to definitively establish the order of HIV and HCV infections for some participants in this study, data suggest that 90-95% of HIV infections in IDUs occur after HCV infection (3). As such, this suggests that HIV may be impacting persistence of HCV rather than its initial clearance. HIV infection may decrease circulating HCV-specific CD4 and CD8 T cells that are generally present in higher levels in individuals with HCV clearance leading to either re-infection with HCV or the re-emergence of low-level viremia that may have been undetectable by conventional assays for a period of time (21).   Our data lend support to the hypothesis that previous exposure to HCV may be protective, possibly on an immunologic basis, despite repeated exposure to HCV. In chimpanzees, re-infection with HCV leads to an attenuated course of infection, with the level and duration of viremia markedly reduced and no evidence of liver disease (15-17). The level of viremia has been linked to the nature of the cellular CD4 and CD8 T-cell responses. The in vivo depletion of memory CD4 T-cells prior to re-infection results in persistent viremia with a failure to resolve HCV infection (22), despite functional memory CD8 T-cell responses in the liver. Similarly, in vivo depletion of CD8 T-cell responses results in prolonged HCV viremia that is not controlled until HCV-specific CD8 T-cells recover in the liver (17). Importantly, it seems that with a rapid, multiantigen T-cell proliferative response, chimpanzees can develop protective immunity preventing re-infection with both the same and different genotypes of HCV (16, 23). This may also be the case in humans. In one study that considered 3 IDUs with clinical evidence of HCV re-infection and subsequent clearance it was demonstrated that clearance was associated with 15  more vigorous CD4+ T-cell responses when compared to patients with acute and chronic HCV infection (24). Further data evaluating viral sequence evolution in IDUs demonstrated that despite ongoing injection drug use during the year of observation, subjects with HCV clearance and HCV persistence demonstrated protection against both re-infection with HCV and superinfection with a different viral genotype, respectively (25).   There are at least two other potential explanations for these results. It has been demonstrated that genetic polymorphisms in some HLA class I and II molecules (26, 27) and genes encoding interactions between HLA class I molecules and NK cells (28) are associated with clearance of HCV infection. Thus, it is possible that those with HCV clearance are a selected group with genetic characteristics protecting against initial HCV infection and subsequent re-infection. Alternatively, given that this study was originally designed to evaluate health utilization, there is a lack of detailed information on needle sharing, equipment sharing and historical drug use. This is important as individuals previously exposed to HCV may be more experienced and have safer injection routines, and may thus be less likely to share injection equipment with others. Such a behavioral difference (that would protect against HCV re-infection) would not be detected in this study. However, given the higher rate of HIV infection in those with previous clearance, it is more likely that those with HCV clearance remain at a higher risk of acquiring HCV infection over time.  This report has a number of limitations inherent to large, retrospective studies. Virologic test results were obtained from a historical database including antibody assays that changed and improved over time.  This is particularly relevant to the HCV antibody tests that may have been 16  less sensitive prior to 1996. In addition, testing was not performed on a systematic basis and was only conducted by physician request, so that subjects who cleared HCV viremia and were later re-infected may have been misclassified as having persistent infection. Virologic clearance was, in some cases, confirmed by a single negative test, which may represent fluctuating low levels of viremia rather than true clearance, which may have overestimated the re-infection rate. Also, some individuals with HCV clearance may have low-level viremia below the limit of detection of the assay (50 IU/mL) and may never have truly cleared their HCV infection.  The existence of such individuals would make our analysis a minimum estimate of the difference between the two groups. Additionally, not all patients received HCV RNA testing, introducing a potential selection bias. However, the similar demographics and HIV status between the two groups would indicate similar testing patterns. Further, the incidence of primary HCV infection in individuals without previous infection may also be underestimated due to non-systematic testing for viremia, once again making our analysis a minimum estimate of the difference between the two groups. All of the limitations we have raised are best addressed within the context of a prospective cohort study with systematic laboratory testing for HCV.  Treatment for HCV infection is often withheld from IDUs because of the perceived high risk of subsequent HCV re-infection after treatment, reducing the impact of treatment on the evolution of the HCV epidemic. However, our data suggest that spontaneous clearance may confer some protection against re-infection. If protection against HCV infection extends to those who have cleared their viremia following antiviral therapy, it could provide a stronger rationale for expanding treatment programs for IDUs, including those who continue to be at risk for HCV exposure. Although preliminary data suggests that lower rates of re-infection are observed after 17  the treatment-induced clearance of HCV infection in IDUs when compared to the incidence of HCV infection in uninfected individuals (29, 30), this must be confirmed in prospective cohorts. Given that re-infection can occur, it is critical to educate patients about the potential risks for HCV re-infection associated with needle and equipment sharing.    Further research is required to investigate the mechanism of the effect we describe, to define its magnitude and to establish how it applies to treated individuals. As IDUs continue to drive the HCV epidemic in developed countries, it is quite clear that any efforts at its control must include a comprehensive strategy to address the disease in this target population.  This study provides some assurance that such strategies could be successfully implemented to limit the impact of HCV in IDUs and in the general population.18   REFERENCES 1. 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Viral evolution of hepatitis C in injection drug users. J Viral Hepat 2005;12:574-583. 26. Thio CL, Thomas DL, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, O'Brien SJ, et al. Racial differences in HLA class II associations with hepatitis C virus outcomes. J Infect Dis 2001;184:16-21. 27. Thio CL, Gao X, Goedert JJ, Vlahov D, Nelson KE, Hilgartner MW, O'Brien SJ, et al. HLA-Cw*04 and hepatitis C virus persistence. J Virol 2002;76:4792-4797. 28. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, Cheng J, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004;305:872-874. 29. Backmund M, Meyer K, Edlin BR. Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users. Clin Infect Dis 2004;39:1540-1543. 30. Dalgard O. Follow-up studies of treatment for hepatitis C virus infection among injection drug users. Clin Infect Dis 2005;40 Suppl 5:S336-338.     20  TABLES Table 1. Characteristics of participants without previous infection versus those with HCV clearance.  Characteristic Previously Uninfected HCV Ab- (n=926), n (%) HCV Clearance HCV Ab+/ HCV RNA- (n=152), n (%) P*  Age (years, mean [SD]) 41.2 [11.3] 43.7 [7.7] <0.001 Male Sex 628 (67.4) 93 (60.8) 0.41 Ethnicity        White 541 (58.4) 69 (45.1) -     Aboriginal 269 (29.0) 77 (50.3) <0.001     Other 116 (12.6) 7 (4.6) 0.089 HIV-infected 68 (7.3) 35 (23.0) <0.001 Previous HBV infection 12 (1.3) 9 (5.9) <0.001 Unstable Housing  646 (69.8) 105 (68.6) 0.84 Illicit Drug Use         Any 801 (86.5) 135 (88.9) 0.50     Frequent  511 (55.2) 104 (68.0) 0.004 Injection Drug Use         Any 241 (26.0) 73 (48.0) <0.001     Frequent 129 (13.9) 38 (24.8) <0.001 *Student’s Two Sample T-Test for Age, 2 or Fisher’s exact test as appropriate for all other comparisons of associations. 21  Table 2. Occurrence of HCV viremia in all participants without previous infection versus those with HCV clearance.  Characteristic Previously Uninfected HCV Ab- (n=926), n (%) HCV Clearance HCV Ab+/ HCV RNA- (n=152), n (%) Person-years of follow-up 2127 793 Median Follow-up (years) 2.8 5.2 Occurrence of Viremia 172/926 (18.6%) 14/152 (9.2%) Incidence (/100 person-years, 95% CI) 8.1 (6.9-9.4) 1.8 (0.9-3.0)  22  Table 3. Occurrence of HCV viremia in HIV negative and HIV positive previously infected individuals with HCV clearance (n=152).  Characteristic HCV Clearance HCV Ab+/ HCV RNA- HIV negative  (n=117) HCV Clearance HCV Ab+/ HCV RNA- HIV positive (n=35) Person-years of follow-up 581 212 Median Follow-up (years) 5.0 5.4 Occurrence of Viremia 8/117 (6.8%) 6/35 (17.1%) Incidence (/100 person-years, 95% CI) 1.4 (0.7-2.9) 2.8 (1.0-6.1)    23  Table 4. Characteristics of participants with HCV re-infection. ID 1995-97 1998 1999 2000 2001 2002 2003 2004 2005 HIV Drugs 1  Ab+/RNA- RNA+  RNA+ RNA+ RNA+   Y Crack 2 Ab+    RNA- RNA-/RNA+ RNA-   Y ID Coc 3 Ab+    RNA-   RNA+/RNA+  Y Crack 4 Ab+     RNA- RNA+ RNA-/RNA-  N ID Coc/Crack 5     Ab+ RNA+/RNA-  RNA+/RNA+  N ID Coc 6 Ab+   RNA-  RNA+    Y ID Coc 7  Ab+   RNA+ RNA+ RNA- RNA-/RNA+  N ID Coc/Crack 8      Ab+/RNA-/RNA+ RNA-  RNA-  N ID Coc/Crack 9 Ab+  RNA-  RNA+  RNA-   Y Crack 10   Ab+   RNA-/RNA- RNA- RNA+/RNA- RNA+ N ID Coc 11     Ab+  RNA- RNA+  N Crack 12  Ab+      RNA-/RNA+   N ID Coc 13 Ab+ RNA-      RNA+  N None 14 Ab+      RNA- RNA+  Y ID Coc/Crack 24  FIGURES Figure 1. Subject Disposition 25    2,117 Subjects Received HCV Ab Testing 3,553 Subjects with Questionnaire Data 1,143 (54.0%) HCV Ab+ Subjects HCV  Persistence (n=506, 76.9%)  [Ab+/RNA+] 658 (57.6%) Subjects with HCV RNA Testing Available  HCV  Clearance (n=152, 23.1%) [Ab+/RNA-] 926 (43.7%) HCV Ab-  Subjects 48 Subjects Excluded         (Received HCV Treatment) 


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