August 22, 2010

The Beginning of a New Era in Understanding Hepatitis C Virus Prevention

The Journal of Infectious Diseases 2010;202:000–000
© 2010 by the Infectious Diseases Society of America. All rights reserved.
DOI: 10.1086/656213


Josiah D. Rich and Lynn E. Taylor

Brown Medical School and Miriam Hospital Immunology Center, Brown University, Providence, Rhode Island

Received 1 July 2010; accepted 1 July 2010; electronically published 20 August 2010.

(See the article by Paintsil et al, on pages XXX–XXX.)

Reprints or correspondence: Dr Josiah D. Rich, The Miriam Hospital, 164 Summit Ave, Providence, RI 02906 (

Hepatitis C virus (HCV) infection is a staggering problem in the United States and worldwide. In the United States, HCV is responsible for 12,000 deaths each year, is the most common bloodborne pathogen, and is a leading cause of liver transplantation. Although more than 4 million people in the Unites States and 180 million worldwide (3%) are chronically infected, most are not aware of their diagnosis. The disease burden and mortality from HCV infection are predicted to increase in the United States 2‐fold to 3‐fold over the next 10–20 years as the number of persons with long duration of infection grows. This will greatly affect individual and public health and will lead to a substantial economic burden as well. Most HCV‐related mortality is occurring in men <60 years of age (and disproportionately among non‐Hispanic black men [1]), which makes HCV a leading infectious cause of years of potential life lost. Death due to HCV infection is the most frequent cause of non–AIDS‐related death for human immunodeficiency virus (HIV)–infected persons with access to highly active antiretroviral therapy [2].

Since the discovery of a reliable test for HCV antibodies in 1990 [3], we have learned a great deal about the virus—that it leads to chronic infection in 85% of exposures, that those who are infected have an average chance of 20% of developing cirrhosis after 20 years, and that those who consume alcohol, as well as those who are coinfected with HIV, are much more likely to progress to cirrhosis and death than others. Although HCV is curable, and antiviral HCV treatment leading to viral eradication reduces liver‐related morbidity and mortality, treatment with pegylated interferon plus ribavirin is burdensome, toxic, expensive, and ineffective for half of those who attempt therapy [4–6]. Treatment initiation rates are low across varied settings [7–11]. Most patients diagnosed with chronic HCV infection have not received antiviral therapy. This is due, in part, to restrictive treatment criteria excluding patients with concomitant substance use that led to the infection in the first place [12]. The treatment landscape is on the verge of a paradigm shift with the impending launch of specifically targeted antiviral therapy for HCV (STAT‐C) to inhibit HCV‐specific enzymes. Along with higher anticipated cure rates will come higher costs of therapy, increased toxicity, thrice daily pill dosing, and the introduction of resistance. The lack of an HCV vaccine and limitations of treatment highlight the imperative of developing strategies to prevent HCV transmission.

Although perinatal and sexual transmission occur (including sexual transmission among HIV‐infected men who have sex with men [13]), the HCV epidemic is predominantly driven by the injection of illicit drugs [14]. Before 1992, when widespread screening of the blood supply began in the United States, HCV was also commonly spread through blood transfusions and organ transplants. Testing of blood donors for HCV RNA by means of nucleic acid amplification was introduced in the United States as an investigational screening test in mid‐1999 to identify donations made during the window period before seroconversion [15]. In the United States, iatrogenic transmission has been almost completely eliminated with screening of the blood supply. However, there are still incidents of transmission, such as the 2007 HCV outbreak at a freestanding private endoscopy clinic in Nevada, resulting from reuse of syringes and use of single‐use medication vials on multiple patients [16, 17].

Outside of the Unites States, one of the worst iatrogenic outbreaks of HCV infection occurred in Egypt where, from the 1960s to the 1980s, a mass campaign to eradicate schistosomiasis using repeated intravenous antischistosomal therapy inadvertently infected a generation. Decades later, the overall prevalence of HCV antibody is 15%–20% of the general population [18]. Clearly, the intravenous aspect of this campaign markedly increased the transmission rate. In the absence of mass treatment campaigns using intravenous medication, similar outbreaks are not anticipated. However, acute HCV infection is typically clinically silent, and routine screening for HCV is not recommended or done, so iatrogenic transmission of HCV may be more common than we know.

During intravenous injection by injection drug users (IDUs), blood (and any bloodborne virus such as HCV) is typically drawn up into the syringe to locate the vein, thus contaminating the inside of the syringe and creating an effective tool for transmission of whatever bloodborne pathogen is then lining the syringe. IDUs often lack knowledge about safe injection practices and the need for sterility and also often lack the necessary tools (ie, sterile syringes, diluent, mixing containers [cookers], and filters [cotton]) to prevent viral transmission.

Injection drug use remains a hidden and stigmatized behavior. Addiction is a chronic relapsing disease that is highly treatable, although most people do not get the treatment that they need. Preventive efforts should focus on IDUs, but this has not transpired on the massive scale required. IDUs have been overlooked in part because of the challenges involved in working with this population, the difficulty in finding IDUs, and the underlying stigma. In the United States, society’s major response to addiction in terms of resources has been to criminalize and further drive underground the behavior, often alienating people from treatment, which then leads to negative health and social consequences. Most IDUs are incarcerated at some point, and this has contributed to an unprecedented rate of incarceration. This “intervention” is expensive and ultimately ineffective. However, while we work to redirect policies and resources toward evidence‐based prevention, treatment, and harm reduction, mass incarceration allows us to find IDUs and provides opportunities to address prevention, diagnosis, and treatment of addiction and HCV infection in the correctional setting.

HCV is much more prevalent than HIV among IDUs, and yet the reason for this has not been fully elucidated. Are key determinants the differences in viral viability in syringes, the concentration of the virus, the volume of blood remaining in the syringes, or other factors? The increased prevalence of HCV among IDUs certainly contributes to the difference (with a higher prevalence of HCV, a given syringe is more likely to have been used by someone infected with HCV than someone with HIV) but probably does not explain it completely. Answering these questions has, until very recently, been hampered by the inability to culture HCV and the lack of a small animal model of HCV transmission.

In this issue of the Journal, Paintsil et al [19] have contributed to our understanding of the biological mechanisms of HCV transmission by developing an experimental model of injection drug use by using cultured virus from HCV‐contaminated syringes. This group is the first to our knowledge to develop a microculture assay to detect viable HCV in small volumes of blood found in syringes. This work suggests that the duration of survival of HCV in used syringes and the amount of residual blood inside the syringe are important parameters for understanding transmission. The ability to use cultured virus to explore transmission mechanisms and develop prevention interventions has the potential to revolutionize the field. There has already been an improved understanding of the role played by biocides for HCV treatment [20].

Heimer’s earlier work employed similar methods to illuminate the transmission dynamics of HIV during injection drug use [21, 22]. His group demonstrated that HIV can survive in a syringe for months. This finding, along with his team’s elegant mathematical modeling studies, proved that reducing syringe circulation time could lead to reduced HIV transmission. This provided critical early evidence in support of needle exchange programs (NEPs). NEPs have had a huge impact on the reduction of HIV transmission. However, NEPs do not seem to have had as dramatic an effect on the reduction of HCV transmission among IDUs; Heimer's HCV transmission model may facilitate understanding of why this is so. Furthermore, although noninjection drug use has been epidemiologically linked to HCV transmission (perhaps through the use of contaminated drug‐sniffing implements [23, 24]), it is possible that noninjection drug use is really just a marker for illicit, undetected injection drug use. Using simulated laboratory studies with cultured virus should contribute to understanding the mechanism(s) and relative contribution of noninjection drug use to HCV transmission.

It is estimated that an individual IDU injects 1000 times a year. HCV transmission remains unrestrained among IDUs, with incidence rates ranging from 16% to 42% per year [25]. This novel investigation provides robust evidence about the dynamics of viral transmission with syringes, using simulated injecting practices. More importantly, the ability to culture HCV heralds a new era in which the combination of basic laboratory, epidemiologic, and ethnographic research should allow a much more precise understanding of HCV transmission and pave the way for designing and targeting future public health interventions to prevent HCV infection.


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Potential conflicts of interest: L.E.T. has consulted for Vertex, is on the Speakers’ Bureau for Genentech, and has received grant support from Roche.

Financial support: Partial support for this work was provided by the National Institute on Drug Abuse (NIDA) and the National Institutes of Health (NIH) (grant K23DA020383 to L.E.T. and grants K24DA022112, P30DA013868, and T32DA13911 to J.D.R.) and the NIH Center for AIDS Research (grant P30‐AI‐42853 to J.D.R. and L.E.T.).

The content is solely the responsibility of the authors and does not necessarily represent the official views of NIDA or the NIH.


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