Frequent Longitudinal Sampling of Hepatitis C Virus Infection in Injection Drug Users Reveals Intermittently Detectable Viremia and Reinfection

University of California San Francisco, San Francisco, CA.
Clinical Infectious Diseases (Impact Factor: 8.89). 10/2012; 56(3). DOI: 10.1093/cid/cis921
Source: PubMed


Detection of hepatitis C virus (HCV) reinfection and intercalation (ie, intermittent recurrent bouts of viremia with homologous virus interspersed with aviremic periods) requires extensive and frequent evaluation and viral sequencing.

HCV infection outcomes were studied prospectively in active injection drug users with recurrent HCV RNA-positive tests after serial negative results. HCV viremia and viral sequences (Core/E1) were assessed from monthly blood samples.

Viral clearance, reinfection, and intercalating infection were all detected. Among 44 participants with apparently resolved HCV (26 incident HCV clearers and 18 enrolled with already resolved infection), 36 (82%) remained persistently HCV RNA negative, but 8 demonstrated intermittent recurrent viremia. Four of these (50%) had confirmed reinfection with a heterologous virus; 3 demonstrated viral intercalation, and 1 was not classifiable as either. Estimated incidence of first reinfection was 5.4 per 100 person-years (95% confidence interval, 2.0-14.5). Six (75%) participants, including 3 of 4 with reinfection, demonstrated sustained viral clearance for a median of 26 months since last HCV RNA test.

These results show that frequent monitoring and viral sequencing are required to correctly assess HCV outcomes and estimate incidence of reinfection (which was previously overestimated). Sustained clearance may take many months and occur after episodes of reinfection and viral intercalation. Three of 4 subjects who had confirmed reinfection showed evidence of long-term clearance. Viral intercalation occurs with significant frequency. Further studies of these events, especially immunological, are needed to inform HCV clinical care and vaccine development.

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Available from: Michael P Busch, Jan 21, 2015
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    • "Treating 8%–15% of HCV-infected active PWIDs annually for HCV would reduce HCV prevalence by 75% over 15 years according to a conservative model that assumed that reinfection rates post-treatment were the same as initial infection rates.46 Cohort studies, however, estimate the reinfection rate at 4%–6% per year,2,47 which is about half the rate assumed for initial infection,48 and those trained in safer injection practices may have even less risk of reinfection. Interferon-free therapies may, if widely available, prove viable for mass treatment of active PWIDs. "
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    ABSTRACT: The US faces at least two distinct epidemics of hepatitis C virus infection (HCV), and due largely to revised screening recommendations and novel therapeutic agents, corresponding opportunities. As only 49%-75% of HCV-infected persons in the US are aware of their infection, any chance of addressing HCV in the US is dependent upon screening to identify undiagnosed infections. Most HCV in the US consists of longstanding infections among persons born during 1945-1965 who are suffering escalating rates of liver-related morbidity and mortality. Mathematical modeling supports aggressive action to reach and treat these persons to minimize the subsequent burden of advanced liver disease on patients and the health care system. Incident infection is primarily among persons who inject drugs, less than 10% of whom have been treated for HCV. Expanded screening and treatment of active persons who inject drugs raises the prospect of utilizing "treatment as prevention" to stem the tide of incident HCV infections in this population. HIV-positive men who have sex with men (MSM) represent a population at risk for sexually transmitted HCV who may also benefit from adjusted screening guidelines to identify both acute and chronic infections. Prisoners also represent a critical population for aggressive screening and treatment. Finally, the two-stage testing algorithm for HCV diagnosis is problematic and difficult for patients and providers to navigate. While emerging therapeutics raise the prospect of reducing HCV-related morbidity and mortality, as well as eliminating new infections, major barriers remain with regard to identifying infections, improving access to treatment, and ensuring payer coverage of costly new therapeutic regimens.
    Full-text · Article · Jul 2014 · Hepatic Medicine: Evidence and Research
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    • "Even for subjects with access to a NEP, continuing injection drug use poses repeated risks of exposure to HCV, as both the previously observed incidence data from the Malmö NEP and other reports indicate [25], [32], [33]. Another recent longitudinal study among young PWID with ongoing risk behaviour found that several subjects with signs of spontaneous viral clearance had subsequent detectable viremia with the original viral strain (suggesting recurrence rather than reinfection) [34]. Both re- and superinfection were however quite frequent among active PWID in the Amsterdam Cohort [35]. "
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    ABSTRACT: To assess HCV viremia levels just before, during and one year after anti-HCV seroconversion in people who inject drugs (PWID). PWID enrolling into a needle exchange program in Malmö, Sweden, 1997-2005 constituted the source population. Sera were obtained at enrolment and at approximately 3-4 monthly intervals afterwards, and were initially tested for anti-HIV, HBsAg/anti-HBc and anti-HCV and thereafter for markers previously negative. Seroconversion to anti-HCV had occurred during the study period in 186 out of 332 seronegative subjects. In these anti-HCV seroconverters, quantitative HCV RNA PCR was retrospectively performed on frozen sera to determine viremia levels in the last anti-HCV negative, the first anti-HCV positive and in one year follow-up samples. Among 150 subjects seroconverting to anti-HCV with samples available from all three defined time-points, eight different patterns of viremia were observed. Spontaneous clearance at one year was noted in 48 cases (32%) and was associated with female gender (p = 0.03, CI 0.17-1.00). In 13 cases HCV-RNA was not detected in any study sample. Among 61 subjects with pre-seroconversion viremia, viral load was significantly higher in the pre-seroconversion samples compared to subsequent samples. For the whole group, viral load declined to undetectable levels at seroconversion in 28% of cases (but with recurrent viremia in 15%). Different patterns of HCV RNA kinetics were observed among PWID with documented seroconversion to anti-HCV. The frequently observed absence of detectable HCV RNA in the first anti-HCV positive sample (irrespective of subsequent viremia) demonstrates the importance of repeated sampling and RNA testing for determination of the outcome of acute infection.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Reinfection rates may be overestimated by misclassifying fluctuations in viral load as reinfection [20]. However, this study found a very high rate of confirmed reinfection using a rigorous definition that required reinfections to be genetically distinct from previous infections. "
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    ABSTRACT: Hepatitis C virus reinfection and spontaneous clearance of reinfection were examined in a highly characterised cohort of 188 people who inject drugs over a five-year period. Nine confirmed reinfections and 17 possible reinfections were identified (confirmed reinfections were those genetically distinct from the previous infection and possible reinfections were used to define instances where genetic differences between infections could not be assessed due to lack of availability of hepatitis C virus sequence data). The incidence of confirmed reinfection was 28.8 per 100 person-years (PY), 95%CI: 15.0-55.4; the combined incidence of confirmed and possible reinfection was 24.6 per 100 PY (95%CI: 16.8-36.1). The hazard of hepatitis C reinfection was approximately double that of primary hepatitis C infection; it did not reach statistical significance in confirmed reinfections alone (hazard ratio [HR]: 2.45, 95%CI: 0.87-6.86, p=0.089), but did in confirmed and possible hepatitis C reinfections combined (HR: 1.93, 95%CI: 1.01-3.69, p=0.047) and after adjustment for the number of recent injecting partners and duration of injecting. In multivariable analysis, shorter duration of injection (HR: 0.91; 95%CI: 0.83-0.98; p=0.019) and multiple recent injecting partners (HR: 3.12; 95%CI: 1.08-9.00, p=0.035) were independent predictors of possible and confirmed reinfection. Time to spontaneous clearance was shorter in confirmed reinfection (HR: 5.34, 95%CI: 1.67-17.03, p=0.005) and confirmed and possible reinfection (HR: 3.10, 95%CI: 1.10-8.76, p-value=0.033) than primary infection. Nonetheless, 50% of confirmed reinfections and 41% of confirmed or possible reinfections did not spontaneously clear. Conclusions: Hepatitis C reinfection and spontaneous clearance of hepatitis C reinfection were observed at high rates, suggesting partial acquired natural immunity to hepatitis C virus. Public health campaigns about the risks of hepatitis C reinfection are required.
    Full-text · Article · Nov 2013 · PLoS ONE
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