- • What is the risk of hepatitis C reinfection after successful treatment?
Key take-home messages
- HCV reinfection rates vary widely. Reinfection depends on the extent to which an individual engages in high risk activities after having achieved sustained virologic response through treatment.
- The risk of HCV reinfection among patients who do not engage in higher-risk activities appears to be negligible (1).
- Some studies suggest that the risk of HCV reinfection among people who inject drugs is low but the quality of this evidence has been assessed as very low (2;3). Conversely, a recent systematic review and meta-analysis estimated that, among patients that engage in “high-risk” behaviour (e.g. people who inject drugs), the likelihood of being reinfected over a five-year period was 11% (1).
- The risk of HCV reinfection through sexual contact among men who have sex with men appears to be high (4-6).
- The risk of HCV reinfection among HIV co-infected patients is high (1).
The issue and why it’s important
Hepatitis C virus (HCV) is a major public health problem: approximately 185 million people worldwide are infected (7). In Canada, the overall prevalence of chronic HCV infection in 2011 was 0.6% or 220,697 people (8).
Traditionally, HCV treatment has consisted of pegylated-interferon and ribavirin (9). However, this therapy was associated with poor sustained virologic response (SVR) rates – a surrogate marker for cure – which is defined as undetectable HCV RNA 24 weeks after the completion of therapy (10). Early therapeutic approaches were followed by protease inhibitors boceprevir and telaprevir combined with pegylated interferon and ribavirin – a change that improved overall rates of sustained virologic response (9). Most recently, highly efficacious interferon-free regimens of direct acting antiviral agents (DAAs) (including sofosbuvir, ledipasvir and others) have fundamentally transformed the treatment landscape (9). The high sustained virologic response rate with the newer medications has been found in populations typically considered difficult-to-treat, such as those with advanced fibrosis or co-infection with HIV (10- 12).
Despite these recent successes in HCV treatment, clinicians and health systems continue to be concerned about the risk of HCV recurrence — either due to reinfection following treatment or to late relapse after having had a sustained virological response for 24 weeks (1). HCV reinfection is a particular concern in patients, including people with HIV/HCV co-infection, who continue to engage in highrisk behaviours such as injection drug use. (1).
What we found
Studies of HCV reinfection among people who inject drugs
Since intravenous drug use remains the leading cause of HCV infection and reinfection, several studies have addressed HCV reinfection following treatment-induced clearance among people who inject drugs (3).
According to the authors of the systematic review, reinfection can occur after successful HCV treatment but the rate is low even among persons who continue to inject drugs during and after treatment (3). The authors did note that the risk of reinfection may vary depending on the local HCV epidemic among people who inject drugs and be higher in communities with higher prevalence. For example, in Vancouver, the incidence of first HCV infection was 7.3 cases per 100 person years (20) and the risk of reinfection after HCV treatment was 3.2 cases per 100 person years (16). In Amsterdam, thelocal incidence of first HCV infection of 0.35 cases per 100 person years (17) – significantly lower than in Vancouver — and the risk of reinfection after HCV treatment was 0.76 cases per 100 person years.
These data suggest a relatively low risk of reinfection following successful treatment. However, the total number of person years of observation across the five studies was very low, creating considerable uncertainty about this estimate. There was also uncertainty related to the number of participants lost to followup, which was only mentioned by one study in the review (20). In addition, the inclusion of former drug users in the study population and the fact that some studies incorporated harm reduction programs may have reduced the observed risk of HCV reinfection (2).
In other studies that were not part of the systematic review, there is considerable evidence that HCV reinfection rates among people who inject drugs is high. For example:
- In a prospective Australian cohort study of people who inject drugs, the incidence rate of HCV infection was high in patients who had previously cleared HCV, even surpassing the rate seen in previously HCV-uninfected individuals (22).
- In another Australian study, incidence of potential HCV reinfection among participants with HCV clearance with 42 per 100 person years (95% CI, 25–61/100 PY) was comparable to the incidence of initial HCV infection among HCV negative participants (23).
- A study from Spain followed 118 prisoners (81% injection drug users) treated for HCV who had achieved a sustained virologic response between 2003 and 2009 (24) and found that the incidence of reinfection was high, especially among those who reported ongoing injection drug use (24). At follow-up, HCV reinfection was identified in nine former injection drug users — seven with an HCV genotype switch — for an overall reinfection rate of 5.27 cases per 100 person years. The incidence of reinfection was significantly higher among people who were actively using drugs (hazard ratio HR = 12.47; 95% CI: 2.90–53.71), people who were HIV co-infected (HR = 9.95; 95% CI: 1.73–57.34) and those engaging in more than one risk behaviour after treatment (HR = 7.47; 95% CI: 1.19–46.89).
HCV reinfection among men who have sex with men
Men who have sex with men — in particular HIV-positive men who have sex with men — demonstrate a different dynamic of HCV infection and reinfection risk:
- Researchers in London UK analyzed retrospectively reinfection rates among 145 HIV-HCV co-infected men who have sex with men with sexually acquired HCV who subsequently spontaneously cleared or underwent successful HCV treatment between 2004 and 2012 (6). Among individuals successfully treated for a primary infection, as many as 25% were re-infected within two years.
- Another retrospective study – this time in the Netherlands – found comparably high rates of HCV reinfection rate following treatment of 96. Per 100 person year among men who have sex with men of 9.6/100 person years (95% CI 6.6–14.1) (5) and higher rates of 15.2 per 100 person years among HIV-positive men who have sex with men (95% CI 8.0–26.5) (5).
- In a German study that examined 402 HIV-positive patients attending four HIV and hepatitis care centres between 2001 and 2013, about 75% of those with acute HCV infection (302 patients) were cured and therefore at risk for reinfection. Over the 12 year observation period, 48 of the 302 had at least one further HCV episode for a reinfection rate of 16% (4).
Comparison of reinfection rates between groups
The latest and most comprehensive systematic review and metaanalysis of long-term treatment outcomes of patients infected with HCV evaluated the risk of post-treatment reinfection among three populations: (a) mono-HCV infected patients with no recognized risk factors for reinfection; (b) mono-HCV infected patients engaging in activities that are higher risk (i.e. people who inject drugs, prisoners or men who have sex with men); (c) HIV/HCV coinfected patients (1). The findings were as follows:
- In HCV mono-infected patients with no recognized risk factors, the pooled estimate of reinfection rate and summary 5-year reinfection risk were zero.
- In HCV mono-infected patients engaging in activities that are higher risk, the pooled reinfection rate was 19.06/1000 person years (95% CI, 11.42–28.16) leading to a summary five-year risk of 10.67% (95% CI, 6.38%–15.66%).
- In HIV/HCV co-infected patients, the pooled reinfection rate was 32.02/1000 person years (95% CI, 0.00–123.49) leading to a summary five-year risk of 15.02% (95% CI, 0.00%–48.26%).
The review concluded that most patients continue to have a sustained virologic response (i.e. no reinfection) five years post-treatment (1). In the authors’ view, the greater reinfection risk among people engaging in higher risk activities and among people with HIV-HCV co-infection highlight the need for prevention campaigns specifically targeted at these groups (1).
It should be noted that the majority of included studies analyzed reinfection after treatment with interferon-based therapies – which have now been replaced with interferon-free regimens. Although there is no evidence that reinfection rates may differ with new the treatments, it is possible that this will be the case, particularly if the consequences of reinfection are perceived to be lower than with the old regimens (1).
To minimize the risk and rate of reinfection among individuals who engage in higher risk activities or who are at higher risk because of the presence of HIV (e.g. people who inject drugs, HIV-positive men who have sex with men, people with HIV/ HCV co-infection), health systems should develop intensive targeted harm reduction and sexual education programs for and with these groups.
What we did
We searched Medline using a combination of [Hepatitis C or HCV (text terms) or Hepatitis C or Hepatitis C, Chronic (MeSH terms)] AND [reinfection or re-infection or HIV or Sexually Transmitted Disease* or Sexually Transmitted Infection* or Sexually Transmitted or STD* (text terms) or Sexually Transmitted Diseases or Sexually transmitted Infections (MeSH terms)]. Reference lists of identified literature reviews and systematic reviews were also searched. All searches were conducted on February 2, 2016 and results limited to English articles published from 2005 to present in high income countries. The search yielded 486 references from which 24 studies were included. Sample sizes of primary studies ranged from nine to 402.
Factors that may impact local applicability
All studies cited in this review were conducted in high income countries in Western Europe (U.K., Germany, The Netherlands, Spain, Norway) as well as in the U.S., Canada and Australia. Because of similar HIV and HCV epidemics among people who inject drugs and among men who have sex with men across these countries, the findings in this review are highly relevant and transferable to the Canadian context.
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- Aspinall EJ, Corson S, Doyle JS, Grebely J, Hutchinson SJ, Dore GJ, et al. Treatment of hepatitis C virus infection among people who are actively injecting drugs: A systematic review and metaanalysis. Clinical Infectious Diseases 2013;57(Suppl 2):S80-S89.
- Grady BP, Schinkel J, Thomas XV, Dalgard O. Hepatitis C virus reinfection following treatment among people who use drugs. Clinical Infectious Diseases 2013;57(Suppl 2):S105-S110.
- Ingiliz P, Krznaric I, Stellbrink HJ, Knecht G, Lutz T, Noah C, et al. Multiple hepatitis C virus (HCV) reinfections in HIV-positive men who have sex with men: No influence of HCV genotype switch or interleukin-28B genotype on spontaneous clearance. HIV Medicine 2014;15(6):355-61.
- Lambers FA, Prins M, Thomas X, Molenkamp R, Kwa D, Brinkman K, et al. Alarming incidence of hepatitis C virus re-infection after treatment of sexually acquired acute hepatitis C virus infection in HIV-infected MSM. AIDS 2011;25(17):F21-F27.
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- Grady BP, Vanhommerig JW, Schinkel J, Weegink CJ, Bruisten SM, Lindenburg CE, et al. Low incidence of reinfection with the hepatitis C virus following treatment in active drug users in Amsterdam. European Journal of Gastroenterology & Hepatology 2012;24(11):1302-7.
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Rapid Response Service.Hepatitis C reinfection after successful treatment. Toronto, ON: Ontario HIV Treatment Network; May, 2016.
David Gogolishvili and Jason Globerman
Photo credit: Elenchos (modified)