Section V: Treatment, treatment services and prevention
HIV/hepatitis C virus co-infection in drug users: risk behavior and prevention
Hagan, Hollya; Thiede, Hanneb; Des Jarlais, Don Ca,c
From the aCenter for Drug Use and HIV Research, National Development and Research Institute, New York, NY, USA
bPublic Health Seattle and King County, HIV/AIDS Epidemiology Program, Seattle, WA, USA
cBaron Edmund de Rothschild Chemical Dependency Center, Beth Israel Medical Center, New York, NY, USA.
Correspondence to Holly Hagan, Center for Drug Use and HIV Research, National Development and Research Institute, 71 West 23rd Street, 8th Floor, New York, NY 10010, USA. Tel: +1 212 845 4465; fax: +1 917 438 0894.
Studies of HIV-positive patients have consistently shown that drug users, in particular injection drug users (IDU), are far more likely to have hepatitis C virus (HCV) infection than other patient groups. HIV incidence and prevalence in IDU has declined in recent years, but HCV remains endemic in this population. HCV antibody prevalence among non-injection users of drugs such as heroin and cocaine is between 5 and 30%, although there are scant data on specific transmission risk behavior. The control of HIV/HCV co-infection must address HCV prevention. Epidemiological studies have suggested that HCV prevalence in IDU is subject to various influences, some of which may be modifiable by interventions. However, studies have not shown consistent effects of various prevention strategies on HCV transmission, including studies of HCV screening and education, drug treatment or needle exchange. Although some large cross-sectional studies in regions where needle exchange is available to a large number of drug injectors have reported declining HCV prevalence, the scale of services needed is a matter of considerable debate and has not been systematically quantified. Priorities for research related to the prevention of HIV/HCV co-infection should include estimating the effect on disease occurrence of eliminating specific risk factors, and specifying the level of resources needed to alter HCV incidence.
Studies of the occurrence of HIV and hepatitis C virus (HCV) co-infection show that injection drug users (IDU) are more likely than other HIV-positive patient groups to be co-infected. This appears to be so because HCV is primarily transmitted via parenteral routes, so that the exposure risk of HIV and HCV is more highly correlated in this population than in other groups at risk of HIV. HCV is hyperendemic in IDU [1,2], and is generally acquired before exposure to other blood-borne viruses, such as hepatitis B virus or HIV. Therefore, in IDU, HIV infection is more likely to occur in HCV-positive than in HCV-negative individuals. An exception to this generalization may occur when HIV is primarily sexually transmitted in IDU; in that case, more HIV infections may be expected in HCV-negative IDU (because the association between the exposure risk of HIV and HCV may be weaker).
Much more is known about how to prevent HIV infection in IDU than for HCV; therefore, a practical strategy to reduce the prevalence of HIV/HCV co-infection could focus on simply preventing HIV transmission in IDU. However, in addition to the fact that HCV is a serious disease in its own right, the problem remains that most HIV infections in IDU will occur in HCV-positive individuals so long as HCV is hyperendemic in drug injector populations. Given this epidemiological backdrop for HIV infection in IDU, a long-term strategy for the control of HIV/HCV co-infection should encompass the prevention of both HIV and HCV. In this paper, studies of risk factors and the prevention of HCV infection in drug users are summarized, with recommendations for an overall strategy to reduce co-infection. HIV prevention is discussed here only as it relates to HIV/HCV prevention in drug users; comprehensive reviews of HIV prevention in drug users are available elsewhere [3,4].
Hepatitis C virus risk factors in injection drug users
Studies have found that factors correlated with ‘time at risk’ are associated with prevalent HCV infection among IDU, including older age, a longer duration of drug injection and a high frequency of injection (Table 1) [5–20]. A study of IDU admitted to drug treatment in six US cities reported an HCV prevalence between 66 and 93%, with a strong correlation between age and prevalence in each city . There is some debate regarding the average time to HCV seroconversion after the start of drug injection. Early studies reported a high prevalence in new injectors, including two studies reporting that at least two-thirds of IDU injecting for less than 2 years were HCV positive [18,21]. These early reports of the rapid acquisition of HCV in new injectors led to recommendations to target HCV prevention efforts towards those at risk of initiating drug injection, i.e. youth at risk of beginning drug use, and sniffers and snorters of illegal drugs . Such a policy could conceivably reduce prevention resources allocated for drug injectors, reasoning that it is ‘too late’ to prevent HCV infection in these individuals.
Other studies reported a relatively low HCV prevalence after 2–5 years of drug injection [6,9,12,14,15,23]. These include an HCV prevalence of 13% in Australian IDU injecting for less than 3 years , and 21% in UK IDU injecting for less than 5 years . In the United States, a low HCV prevalence has been reported in a number of cities, including 44% in New York City IDU aged 18–24 years , and 39% in San Francisco IDU younger than 30 years . Using life-table methods, one study estimated that the mean interval between the start of injection and the acquisition of anti-HCV is approximately 3.8 years ; the study also found a high-risk subset of new injectors (approximately 40%) who acquired HCV within one year after beginning to inject. Altogether, the research suggests that there is broad variability in the average time to HCV seroconversion from the start of injection; within a range of between one and 5 years. Variability in this interval is probably related to IDU characteristics such as the frequency of injection and the number of injection partners [8,18,20]. Estimates of HCV prevalence may thus be affected by sampling methods, with some studies including a disproportionate sample of either high or low-risk IDU.
In cohort studies, HCV seroconversion rates in drug users ranged between 10 and 40% [5–7,9,10,12,16,17,19,23]. Both HIV and HCV transmission have been reported in association with specific injection practices, such as the injection of cocaine (which may be a marker for frequent injection) and injection with a syringe previously used by another IDU [9,16,24,25], and there have been several seroincidence studies demonstrating the transmission of HCV by the shared use of other injection equipment [9,12,13]. Other studies reporting increased HIV or HCV prevalence or incidence associated with backloading (dividing drugs using a syringe) or sharing of cooker, cotton or rinse water have either not controlled for syringe sharing, or reported that the association was no longer significant after adjustment for syringe sharing [26,27]. One cross-sectional study did adjust for other injection risk behavior and found a significant association between backloading and HIV infection . In many IDU populations, syringe sharing has declined substantially since HIV was first recognized, but sharing of other injection equipment has persisted, with 50–70% of IDU reporting the recent sharing of cookers or cotton, or backloading [29,30]. Quantifying the relative risk of blood-borne viral transmission associated with individual risk factors is important, as it may be used to guide resource allocation towards providing effective prevention materials and education. The calculation of measures of attributable risk for individual risk behaviors is equally important because it approximates the proportion of infections that may be prevented by reducing or removing the risk factor in question .
Hepatitis C virus risk factors in non-injection drug users
An excess occurrence of HCV infection has been reported among individuals who smoke or inhale drugs such as heroin, cocaine or amphetamines . The etiology of HCV transmission in this population is not well understood, although it is believed that exposure to HCV-positive blood could occur from the shared use of pipes or straws to administer the drug. Epistaxis (nosebleed) is a frequent occurrence among drug sniffers, resulting from irritation to the nasal mucous membranes caused by exposure to the drug itself. Crack smoking is also associated with open sores on the lips and oral mucosa . An HCV-infectious individual could thus deposit a small amount of blood on drug equipment that may enter the bloodstream of other users through small breaks in the skin or mucosa. In non-injection drug users, a population at risk of HIV infection primarily via sexual exposure, a low HCV prevalence suggests that reducing the initiation into drug injection may contribute to HCV control . Sexual HCV transmission is believed to occur at low frequency, but its relative importance to the HCV burden may increase as drug risk practices decline.
Data to support the hypothesis of HCV transmission in non-injection drug user populations are scant, but relatively consistent. Three studies of blood donors found an elevated HCV prevalence associated with a history of intranasal cocaine use [35,36], and drug inhalation, which could include either smoking or sniffing . Other studies that recruited samples of non-injection drug users reported HCV prevalences in the range of 5–21% (Table 2) [38–47]. These studies have differed with respect to recruitment and geographical setting, but all have used a cross-sectional design, so there is weak evidence for any specific causal mechanism for HCV transmission infection in this population. Time at risk is the most commonly reported risk factor in these studies. In a New York City study of 337 heroin users who had never injected, HCV prevalence was 13% and HIV prevalence was 9%; in univariate analysis, HCV infection was associated with sharing a crack pipe or rolled bank note for drug administration . In another New York study of heroin and cocaine sniffers , seroprevalence was highest among those who sniffed or snorted heroin together with cocaine (9%) versus 3% among those who did not use these drugs together.
A recent study reported detecting HCV RNA in the nasal secretions of one HIV/HCV-co-infected individual . HIV infection is believed to play a role in sexual HCV transmission [49,50]; whether transmission of HCV via nasal secretions may also be facilitated by HIV infection remains unclear. Additional research is needed to show whether the carriage of HCV in nasal secretions differs between HIV-positive and HIV-negative individuals.
HIV and hepatitis C virus co-infection in injection drug users
A number of studies have reported the prevalence of co-infection in injection drug users; many of these have been studies of HIV-positive patients in clinical settings (Table 3) [51–62]. HCV prevalence in these samples has been high, between 52 and 92%, although many studies report an HCV prevalence above 70% [51–59]. As previously mentioned, this may be because in drug injectors the exposure risk factors for HIV and HCV are strongly correlated. Other studies have examined HIV prevalence among HCV-positive injectors and found that it is more highly variable, between 8 and 50% [60–62]. This may be due to the fact that in IDU populations there is greater geographical and temporal variability in HIV risk than for HCV.
HIV and hepatitis C virus prevention for injectors
HCV prevention programmes in many localities have been designed on the basis of an assumption that the prevention of HIV in drug users will also prevent HCV. This would seem reasonable because HCV and HIV have many characteristics in common, including the fact that both are transmitted via parenteral exposure and occur in similar populations. However, empirical studies of the effect of HIV prevention programmes on HCV transmission have reported mixed results. There are several possible reasons why programmes that prevent HIV may not have an effect on HCV transmission, including the fact that HCV is more efficiently transmitted parenterally than HIV [63,64], that with a higher HCV prevalence there are more potential IDU transmitters, and that there may be more sources of HCV exposure (cookers, cotton, water) in the injection setting. Taken together, this would suggest that the influence of HIV prevention programmes on HCV transmission may be smaller than their effect on HIV.
HIV prevention interventions evaluated for their effect on HCV include education and screening, drug treatment and syringe exchange. In Spain, HIV and HCV prevalence were examined among drug injectors attending an HIV prevention education programme between 1990 and 1996 . Among new injectors, HIV prevalence decreased from 36 to 15%, but HCV prevalence remained high and unchanged (74–72%). Results were interpreted as demonstrating that information about safe injection may reduce HIV but may not be sufficient to control HCV transmission. Several studies have examined the influence of methadone drug treatment on HCV. A study of Italian IDU showed that methadone was marginally effective against HCV infection , with seroconverters being somewhat less likely to have been in a methadone programme. Studies in Melbourne  and Seattle  showed no difference in HCV seroconversion rates between those in methadone treatment versus those out of treatment (approximately 20% in both groups, in both studies). However, eligibility criteria for participation in the two studies included recent drug injection at enrollment. With longer retention and more opportunity to become abstinent, an effect may occur. Hepatitis B infection rates were lower in Seattle IDU who remained in methadone treatment over a one-year follow-up period. HCV incidence was also lower, but the sample size of HCV-negative IDU followed up was small (n = 78) so the rate was not significantly different from that observed among those who left treatment . A survey of drug treatment programmes in the USA reported that only 68% of methadone programmes offer HCV antibody testing to all of their clients . A similar study in England and Wales reported that only 24% provided routine HCV screening to their patients . Enrollment in methadone or other drug treatment programmes does not therefore guarantee access to HCV prevention services, and any potential effect of drug treatment on HCV incidence may only be via an overall reduction in injection drug use.
Needle exchange programmes for IDU have sought to reduce the transmission of blood-borne viral infections by exchanging sterile syringes for used ones and by distributing other new equipment, such as drug cookers, used to prepare drugs for injection. Several studies have reported that IDU who participate in needle exchange programmes are less likely than others to use syringes and other equipment previously used by another injector [72–76], and are less likely to acquire HIV [77,78]. Two studies in Canada showed that exchange users were more likely to acquire HIV [79,80].
Studies of the effect of needle exchange on HCV transmission have been somewhat inconsistent. An early case–control study of needle exchange found a sevenfold lower risk of HCV among exchange users versus non-exchangers . In 1999, a longitudinal cohort study to evaluate needle exchange and HCV risk carried out in Seattle found no difference in HCV seroconversion rates between exchange users and other IDU . The lack of an effect in the Seattle study was attributed to high levels of the shared use of drug preparation equipment in both exchange users and others . A study of new injectors in New York City also found no association between exchange use and HCV incidence . Another study of IDU in Stockholm, reported 26 HCV seroconversions per 100 person-years among exchange users, although no comparison group was used in the study . Therefore, although needle exchange appears to control HIV transmission via risk reduction, greater adherence to strict safe injection practices may be needed to prevent HCV infection.
Community-level studies of HCV prevention in the UK and Australia (where needle exchange and drug treatment are provided on a relatively large scale [85,86]) have noted substantial declines in HCV prevalence in young IDU. In Edinburgh, HCV prevalence fell from 69% in 1989 to 13% in 1997, and in Glasgow, prevalence declined from 91% in 1990 to 43% in 1997 [87,88]. In IDU enrolling in Australian methadone maintenance for the first time, HCV prevalence decreased from 71% in 1991 to 50% in 1995 . In Vancouver, the expansion of syringe exchange and drug treatment programmes was temporally associated with a decline in HIV incidence (from 19% a year to 5% a year); HCV incidence also fell, although not as much (29–16%) . In Seattle, approximately 3 million syringes are exchanged each year among 10 000–12 000 drug injectors. In IDU aged 18–30 years enrolled in research studies in Seattle between 1994 and 2003, HCV prevalence declined from 68 to 27% . In New York City, there are approximately 160 000 IDU served by nine needle exchange programmes. Over the 1990–2001 period, HCV prevalence declined from 81 to 59% among injectors entering detoxification programmes . Although these studies were carried out in areas where needle exchange is available to a substantial proportion of injectors, the ‘size’ of needle exchange programmes and the level of other harm reduction services needed to affect HIV and HCV transmission on a community level is a subject of current debate and research.
Research has shown that the prevalence of HCV infection among HIV-positive drug injectors is extremely high, in the range of 50–90% [51–59]. The correlation between drug use and co-infection is consistent across studies of HIV-positive patients. Among 1634 patients enrolled in the multinational CAESAR (Canada, Australia, Europe, South Africa) studies of HIV treatment, HCV infection was 365 times more likely among IDU than homosexual men . However, there are indications from epidemiological studies suggesting that the prevalence of HCV infection may decline in HIV-positive patients over the next several years. These include studies showing relatively low HCV prevalence in some samples of young IDU [6,9,12,14,15,23], and an increase in sexual HIV transmission in IDU (thus weakening the correlation between the risk of exposure to both HIV and HCV) [94,95].
HCV prevention among IDU appears to be a daunting goal, but declining prevalence in some samples suggests that HCV infection rates may be subject to various influences, and some of these may be modifiable by prevention programmes. Furthermore, it appears that there may be substantial variability in the length of the period of susceptibility to primary HCV infection in drug injectors; the interval between the start of injection and HCV exposure. Understanding factors related to variation in this interval may identify high-risk IDU populations and potential opportunities for intervention. Nonetheless, HCV prevention may require a level of resources and a willingness to pursue its control that has not previously been brought to bear. It is conceivable that HCV prevention has failed not so much because the wrong strategy was pursued, but because efforts have been too small-scale and therefore weak in relation to the number of factors favoring HCV transmission. Several paths to HCV prevention and the control of HIV/HCV co-infection suggested by recent studies merit further research. Clearly, methods to identify recent-onset injectors and other high-risk individuals, and ways to attract them to HIV/HCV prevention programmes are needed. Ideally, these programmes would offer HCV screening, needle exchange and drug treatment to large proportions of individuals at risk, with adequate provision of prevention materials, including syringes, drug cookers, filtration cotton and condoms. Case-finding and counseling should include special emphasis paid to HCV-positive individuals, to teach and encourage the reduction of transmission risk behavior. The development and dissemination of behavioral interventions to help drug users manage both HIV and HCV risk are urgently needed. Whether and under what circumstances drug treatment may contribute to HCV control (depending on characteristics of treatment per se, or characteristics of the population being treated) is another highly important research question, given the central public health role of drug treatment to the health and well-being of drug users. Finally, priorities for research related to the prevention of HIV/HCV co-infection should include estimating the effect on disease occurrence of eliminating specific risk factors, and specifying the level of resources needed to alter HCV incidence.
The authors would like to acknowledge the research assistance provided by Roberta Scheinmann, Aundrea Woodall and Rebecca Stern of the National Development and Research Institutes (NDRI), NY, which was essential to the preparation of this paper.
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hepatitis C; injection drug use; HIV; prevention; risk factors; epidemiology
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