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Using hepatitis C virus and herpes simplex virus-2 to track HIV among injecting drug users in New York City
Drug and Alcohol Dependence 101 (2009) 88–91
Contents lists available at ScienceDirect
Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep
Using hepatitis C virus and herpes simplex virus-2 to track HIV among injecting drug users in New York City Don C. Des Jarlais a,∗ , Kamyar Arasteh a , Courtney McKnight a , Holly Hagan b , David Perlman a , Samuel R. Friedman b a b
Beth Israel Medical Center, United States National Development and Research Institutes, Inc., 71 W. 23rd Street, 8th Floor, New York, NY 10010, United States
a r t i c l e
i n f o
Article history: Received 12 June 2008 Received in revised form 22 September 2008 Accepted 6 November 2008 Available online 23 December 2008 Keywords: Hepatitis C Herpes simplex virus-2 HIV Injecting drug users Substance abuse AIDS
a b s t r a c t Objective: To explore the potential utility of hepatitis C virus (HCV) seroprevalence as a biomarker for injection risk, and herpes simplex virus-2 (HSV-2) as a biomarker for sexual risk among injecting drug users (IDUs). We examined the relationships between HCV and HIV and between HSV-2 and HIV among injecting drug users in New York City relative to the large-scale implementation of syringe exchange in the mid-1990s. Methods: 397 injecting drug users were recruited from a drug detoxification program in New York from 2005 to 2007. Informed consent was obtained, a questionnaire covering demographics, drug use and HIV risk was administered. Blood samples were tested for antibody to HIV, HCV and HSV-2. Results: Among all subjects, HIV prevalence was 17%, HCV prevalence 72% and HSV-2 prevalence 48%. Among IDUs who began injecting before 1995, HIV was 28%, HCV serostatus was strongly associated with HIV serostatus (AOR = 8.96, 95% CI 1.16–69.04) and HSV-2 serostatus was not associated with HIV serostatus (AOR = 1.31, 95% CI 0.64–2.67). Among subjects who began injecting in 1995 or later, HIV was 6%, HCV was not associated with HIV (AOR = 1.04, 95% CI 0.27–4.08) and HSV-2 serostatus was strongly related to HIV serostatus (AOR = 10.71, 95% CI 1.18–97.57). Conclusions: HCV and HSV-2 HCV and HSV-2 may provide important new tools for monitoring evolving HIV epidemics among IDUs. Reconsideration of the current CDC hierarchical transmission risk classification system may also be warranted. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Injecting drug users (IDUs) are at risk for HIV through both multi-person use (sharing) of needles and syringes and through unprotected sexual intercourse. Sharing of needles and syringes is a relatively efficient means for transmitting HIV, and extremely rapid transmission of HIV has occurred in IDU populations (Des Jarlais et al., 1989; Kaplan, 1989). When provided with good access to sterile injection equipment, however, IDUs will greatly reduce injection risk behavior, leading to substantial reductions in HIV incidence (Des Jarlais et al., 2000). Sexual transmission of HIV among IDUs then increases in importance (Kral et al., 2001; Lindenberg et al., 2006; Strathdee and Sherman, 2003). Knowing the relative importance of injecting versus sexual transmission among IDUs is critical to understanding evolving HIV epidemics and allocating prevention resources.
∗ Corresponding author at: Beth Israel Medical Center/CDI, 160 Water Street, 24th Floor, New York, NY 10038, United States. Tel.: +1 212 256 2549; fax: +1 212 256 2570. E-mail address: [email protected] (D.C. Des Jarlais). 0376-8716/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2008.11.007
There are, however, considerable difficulties in studying the relative importance of HIV transmission through injecting versus sexual behavior among IDUs. The CDC surveillance transmission risk classification system is hierarchical, and all persons who report both injecting drug use and high-risk heterosexual activity are grouped into the injecting drug use category (Centers for Disease Control and Prevention, 2008). Research studies require very large numbers of incident HIV infections to statistically test for changes in the importance of injection-related versus sexual transmission of HIV over time, and it is important that data collection methods do not change over the relevant time period. In this report, we examine the potential utility of using hepatitis C virus (HCV) and herpes simplex virus type 2 (HSV-2) prevalence as biomarkers for injecting and sexual risk among IDUs. As HCV is transmitted predominantly through sharing of drug injection equipment (Hagan and Des Jarlais, 2000) and HSV-2 is transmitted virtually entirely through sexual activity (Freeman et al., 2006), these can be considered relatively specific biomarkers for injecting and sexual risk. Thus, the strength of the relationship between HCV and HIV in a population of IDUs will be a valid measure of the importance of injecting related HIV transmission in that popula-
D.C. Des Jarlais et al. / Drug and Alcohol Dependence 101 (2009) 88–91
tion, and the strength of the association between HSV-2 and HIV in that population will be a valid measure of the importance of sexual HIV transmission. HSV-2 also facilitates sexual acquisition and transmission of HIV (Freeman et al., 2006; Wald and Corey, 2003), so that HSV-2 infection is not only a biomarker for sexual risk, but also a causal factor in sexual transmission of HIV. We explore the potential utility of HCV and HSV-2 as biomarkers for HIV risk in relation to the large-scale expansion of syringe exchange programs in New York City that occurred in the mid1990s. This expansion was temporally associated with a dramatic reduction in HIV incidence among IDUs (from 4/100 person-year to <1/100 person-years at risk) (Des Jarlais et al., 2005). 2. Methods The data reported here are a part of studies of drug users entering the Beth Israel Medical Center drug detoxification program in New York City. The methods were previously described in detail (Des Jarlais et al., 1989; Maslow et al., 2002), so only a summary will be presented here. The Beth Israel detoxification program serves the city as a whole; approximately half of its patients live in Manhattan, one quarter in Brooklyn, one fifth in the Bronx, and the rest (5%) elsewhere. Patients enter the program on a voluntary basis. Both injecting and non-injecting drug users are eligible to participate in the study. For this report, however, we used data only from persons who reported injecting heroin, cocaine or other drugs in the 6 months prior to the interview. Within gender, patients are admitted on an “open bed” basis, so that there should not be any bias in terms of assignment to specific wards in the detoxification unit. Research staff visit the general admission wards of the program in a pre-set order. Research staff examine all intake records of a specific ward and construct a list of patients admitted within the past 3 days. All of the patients on the list for the specific ward were then asked to participate in the study. Among patients approached by our interviewers, willingness to participate was over 95%. After all of the patients admitted to a specific ward in the 3-day period had been asked to participate and interviews had been conducted with those who agreed to participate, the interviewer moves to the next ward in the pre-set order. As there is no relationship between assigning patients to wards and the order that the staff rotate through the wards, these procedures should produce an unbiased sample. Data reported here were collected from August 2005 to April 2007. A structured questionnaire covering demographics, drug use, sexual risk behavior, and use of HIV prevention services was administered by a trained interviewer. The questionnaire included items on date of birth and age at first illicit drug injection, so that it was possible to calculate the year of first injection. After completion of the interview, the participant was referred to an HIV counselor for pre-test counseling and serum collection. HIV testing was conducted at the New York City Department of Health Laboratory using repeated enzyme-linked immunosorbent assays (ELISA) testing with Western blot confirmation. HCV testing was also conducted at the New York City Department of Health Laboratory, using the Abbott HCV enzyme immunoassay (EIA) 2.0 test. HSV-2 testing was conducted by Bio-Reference Laboratories using the HerpeSelect HSV-1 and HSV-2 ELISA (Focus Technologies, Cypress, CA). We used the chi-square test to assess the differences in the prevalence of HIV, HCV, and HSV-2. To test the strength of the association between HIV and HCV/HSV-2 we estimated odds ratios using the Mantel-Haenszel method. Multivariate logistic regression was used to model the association of HCV and HSV-2 with HIV. In order to adjust for the effect of demographic variables we included age, gender, and race/ethnicity as covariates in the models. The study was approved by the Beth Israel Institutional Review Board.
reported smoking crack cocaine in the 6 months prior to the interview. Among the 62 female subjects, 11 (18%) reported exchanging sex for drugs and 21 (34%) reported exchanging money for drugs in the 6 months prior to the interview. Among the 301 male subjects, 42 (14%) reported giving drugs for sex and 37 (12%) reported giving money for sex in the 6 months prior to the interview. 3.2. HIV, HCV and HSV-2 seroprevalence Table 1 shows HIV, HCV and HSV-2 seroprevalences for the entire sample and within demographic subgroups (gender, age, race/ethnicity). In the sample as a whole, HIV prevalence was 17% (95% CI 13–21%), HCV seroprevalence was 72% (95% CI 67–77%) and HSV-2 prevalence was 48% (95% CI 43–53%). Older subjects were more likely to be seropositive for all three viruses. Female subjects and African-American subjects were significantly more likely to be seropositive for HIV and for HSV-2. Other than the age difference, none of the differences in HCV seroprevalence by demographic characteristics were statistically significant. Twenty-two males reported male-with-male sex (MSM) in the 5 years prior to the interview. Compared to the 279 males who did not report MSM behavior, the 22 MSM subjects were significantly more likely to be HIV seropositive (36% vs. 13%, p < .05), slightly more likely to be HSV-2 seropositive (55% vs. 40%, p = .17), and there was no difference in HCV seroprevalence (72% vs. 64%, p = .43). For the sample as a whole, there were highly significant associations between HCV seroprevalence and HIV seroprevalence (odds ratio = 5.34, 95% CI 2.08–13.75, p < .0001) and between HSV2 seroprevalence and HIV seroprevalence (odds ratio = 2.91, 95% CI 1.62–5.23, p < .001), and a modest association between HCV and HSV-2 seroprevalence (OR = 1.65, 95% CI 1.03–2.62, p < .05). 3.3. Associations between HCV and HIV for IDUs who began injecting prior to 1995 and 1995 or later Syringe exchange programs expanded greatly in New York during the mid 1990s, leading to a large reduction in HIV incidence among IDUs in the city, from 3.5/100 person-years to 0.8/100 person-years (Des Jarlais et al., 2005). We examined the relationships between HCV and HIV and HSV-2 and HIV separately for IDUs who began injecting prior to 1995 and IDUs who began injecting in 1995 or later (IDUs who began injecting in 1995 or later would have spent their entire injection careers in an environment with legal access to sterile syringes.) (see Table 2). HIV seroprevalence was 32% among IDUs beginning to inject before 1995 and 6% (11 HIV seropositives) among those beginning Table 1 HIV, HCV and HSV-2 seroprevalence among IDUs entering detoxification treatment, New York City, 2005–2007.
3. Results 3.1. Demographics, drug use and sexual behavior Three hundred and sixty-six injecting drug users participated in the study from August 2005 to April 2007 and provided complete HIV, HCV, and HSV-2 data. (Antibody test results were not obtained or indeterminate for an additional 50 IDUs.) The subjects with complete test results had a mean age of 39 (S.D. = 9.1), 199 (54%) were under age 40; 301 (82%) were male, 62 (17%) were female; 77 (21%) were white, 72 (20%) were Black, and 205 (56%) were Hispanic. The drugs most commonly injected in the 6 months prior to the interview were heroin (injected by 89%), cocaine (injected by 42%), and speedball (combined heroin and cocaine, injected by 48%). The subjects also reported substantial non-injecting drug use: 48% reported intranasal heroin use, 17% reported intranasal cocaine use and 39%
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HIV (n+/N (%))
HCV (n+/N (%))
HSV2 (n+/N (%))
Total sample (n = 366)
62/366 (17%)
264/366 (72%)
176/366 (48%)
Gender Male (n = 301) Female (n = 62)
44/301 (15%)* 17/62 (27%)
213/301 (71%) 48/62 (77%)
122/301 (41%)** 52/62 (84%)
Race/ethnicity White (n = 77) Black (n = 72) Hispanic (n = 205)
8/77 (10%)* 20/72 (28%) 33/205 (16%)
48/77 (62%) 53/72 (74%) 153/205 (75%)
27/77 (35%)* 47/72 (65%) 96/205 (47%)
Age <40 (n = 199) 40 or older (n = 167)
17/199 (9%)** 45/167 (27%)
125/199 (63%)** 139/167 (83%)
79/199 (40%)* 97/167 (58%)
All comparisons are demographic characteristics with each virus (comparisons are vertical within each virus). * p < .05. ** p < .0001.
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Table 2 Associations between HCV and HSV-2 prevalence with HIV prevalence by date of first injection among IDUs in New York City. Date of first injection
HIV−
HIV+
OR (95% CI)
Before 1995
HCV+ HCV−
111 (83%) 23 (17%)
51 (98%) 1 (2%)
10.57 (1.39–80.41)*
1995 of later
HCV+ HCV−
96 (56%) 74 (44%)
6 (60%) 4 (40%)
1.16 (0.32–4.25)
Before 1995
HSV-2+ HSV-2−
71 (53%) 63 (47%)
34 (65%) 18 (35%)
1.68 (0.86–3.26)
HSV-2+ HSV-2−
62 (36%) 108 (64%)
9 (90%) 1 (10%)
1995 or later* * **
Table 3a HIV seropositive status among IDUs in New York City by their HCV and HSV-2 status and year of first injection.
Total HCV and HSV-2 negative HCV positive, HSV-2 negative** HSV-2 positive, HCV negative HCV and HSV-2 positive* * **
First injection, pre-1995
First injection, 1995 or later
52/186 = 28% 0/12 = 0% 18/69 = 26% 1/12 = 8% 33/93 = 35%
10/180 = 6% 1/50 = 2% 0/59 = 0% 3/28 = 11% 6/43 = 14%
p < .05. p < .0001 (Fisher’s exact test for difference by year of first injection).
15.68 (1.94–126.68)**
p < .05. p < .0001.
to inject in 1995 or later (p < .001). HCV seroprevalence was 87% among IDUs who began injecting prior to 1995 and 57% among those who began injecting in 1995 or later (p < .001). HSV-2 prevalence was 57% among those who began injecting before 1995 and 39% among those who began injecting in 1995 or later (p < .01). The association between HCV and HIV seroprevalence was extremely strong among IDUs who began injecting prior to 1995 (OR = 10.57, 95% CI 1.39–80.41), and not significant among IDUs who began injecting in 1995 or later (OR = 1.16, 95% CI 0.32–4.25). In contrast, the association between HSV-2 and HIV was not significant among those who began injecting before 1995 (OR = 1.68, 95% CI 0.86–3.26) and very strong among those who began injecting in 1995 or later (OR = 15.68, 95% CI 1.94–126.68). We conducted separate multivariate logistic regression analyses for subjects who began injecting prior to 1995 and subjects who began injecting in 1995 or later, controlling for race/ethnicity, gender and age (40 and older). Among subjects who began injecting prior to 1995, HCV serostatus was associated with HIV serostatus (AOR = 8.96, 95% CI 1.16–69.04) and HSV-2 serostatus was not associated with HIV serostatus (AOR = 1.31, 95% CI 0.64–2.67). Among subjects who began injecting in 1995 or later, HCV was not associated with HIV (AOR = 1.04, 95% CI 0.27–4.08) and HSV-2 serostatus was strongly related to HIV serostatus (AOR = 10.71, 95% CI 1.18–97.57). We also conducted multivariate analyses by combining time periods. The latter approach produced similar results. There was a significant interaction between time period and HCV such that subjects who began injecting before 1995 and were HCV positive were more likely to be HIV positive than subjects who began injecting in 1995 or later and were HCV negative (AOR = 11.08, 95% CI 2.4–51.22). We also observed a significant interaction between time period and HSV-2 on HIV. Subjects who began injecting in 1995 or later and were HSV-2 positive were more likely to be HIV positive than subjects who began injecting before 1995 versus and were not HSV-2 positive (AOR = 4.79, 95% CI 1.03–22.27). Numbers of subjects by combinations of HCV and HSV-2 serostatus and HIV prevalence by date of first injection (prior to 1995 and 1995 or later) are presented in Table 3a. HIV prevalence among the total samples, the HCV positives, and the HCV, HSV-2 double positives was clearly lower among IDUs who began injecting in 1995 or later. The difference in lower HIV prevalence among HCV seropositive/HSV-2 seronegatives is particularly dramatic. There was only a single HIV seropositive who was positive on neither of the two biomarkers. This subject reported male-with-male (MSM) behavior in the 5 years prior to the interview and that he had begun injecting only 1 month prior to the interview. Thus it is very likely that he became infected with HIV through MSM activity prior to beginning to inject, and it is not surprising that he was HCV negative.
Table 3b presents the percentages of HIV seropositives among the different combinations of HCV and HSV-2 serostatus by date of first injection. Even with the modest number of HIV seropositives among the IDUs who began injecting in 1995 or later, there are still significant differences in the distribution of HIV seropositives by HCV/HSV-2 serostatus. IDUs who began injecting in 1995 or later are significantly less likely to be HCV seropositive/HSV-2 seronegative, and significantly more likely to be HSV-2 seropositive/HCV seronegative. 4. Discussion In this report, we explored whether using HCV as biomarker for injection-related risk and HSV-2 as a biomarker for sexual risk might provide useful information about the continuing HIV epidemic among IDUs in New York City. Our analyses indicated that the large-scale expansion of syringe exchange programs in New York was temporally associated with a decrease in the relative importance of injecting-related HIV transmission and an increase in the importance of sexual transmission among IDUs. These findings are consistent with cohort studies of HIV transmission among IDUs after expansion of syringe exchange programs in Baltimore (Strathdee and Sherman, 2003), San Francisco (Kral et al., 2001) and Amsterdam (Lindenberg et al., 2006). The findings in this report are also consistent with the previously reported reduction in HCV among IDUs in New York following the expansion of syringe exchange (Des Jarlais et al., 2005). We do not claim that the consistency of the results reported here with cohort studies validates the use of HCV and HSV-2 as biomarkers for injecting and sexual risk. We do, however, believe that the consistency indicates that the use of HCV and HSV-2 should be considered as a promising new tool for research on evolving HIV epidemics among IDUs. We would suggest that the use of HCV and HSV-2 as biomarkers is most likely to be productive under the following conditions: (1) there are extremely few HIV seropositives who are not also HCV and/or HSV-2 seropositive, and (2) there is sufficient variation among the combinations of HCV, HSV-2 and HIV serostatus to permit statistical testing (as in Tables 3a and 3b). Table 3b Percentages of HIV seropositives by HCV/HSV-2 serostatus by year of first injection among IDUS in New York City.
Total HIV seropositives HCV and HSV-2 negative HCV positive, HSV-2 negative HSV-2 positive, HCV negative HCV and HSV-2 positive
First injection, pre-1995
First injection, 1995 or later
52 0/52 = 0% 18/52 = 35% 1/52 = 2% 33/52 = 64%
10 1/10 = 10%a 0/10 = 0%** 3/10 = 30%*** 6/10 = 60%
All comparisons are by date of first injection. a HIV positive subject reported MSM behavior. ** p = .027 by Fisher’s exact test for difference by year of first injection. *** p = .01 by Fisher’s exact test for difference by year of first injection.
D.C. Des Jarlais et al. / Drug and Alcohol Dependence 101 (2009) 88–91
Research using HCV and HSV-2 as biomarkers could be conducted at a small fraction of the cost of traditional cohort studies, and it should be possible to incorporate HCV and HSV-2 testing into HIV surveillance systems without great difficulties. There are a several limitations in this study. There are potential differences between IDUs who began injecting prior to 1995 versus IDUs who began injecting in 1995 or later that we were not able to “control for” in our analyses. For example, it is very likely that there was a much greater loss of HIV seropositives to death, illness or ceasing to inject drugs among the IDUs who began injecting prior to 1995 than among IDUs who began injecting in 1995 or later. In this cross-sectional study, we cannot be certain of the order of HCV, HSV-2 and HIV infections. (Though the very small number of HIV infections among IDUs who were HCV and HSV-2 negative suggests that these infections generally precede HIV infection among IDUs.) We also cannot be certain of the order of beginning to inject and infection with the three viruses. (Given the high rates of HSV-2 and HIV among non-injecting drug users in New York; Des Jarlais et al., 2007, it is highly likely that some drug users are infected with HSV2 and HIV before they move from non-injecting to injecting drug use.) Despite the limitations and need for additional research, we do believe that our findings can be used for targeting prevention efforts in New York City. Female IDUs (85% of whom are HSV-2 seropositive) and African-American IDUs (67% of whom are HSV2 seropositive) are clearly at high risk for sexual acquisition of HIV. Our findings also raise important questions about the current CDC hierarchical classification system for HIV transmission. The CDC hierarchical classification system for HIV/AIDS transmission places injecting drug use above high-risk heterosexual activity. Persons who report both injecting drug use and heterosexual activity with a high-risk partner are placed only in the injecting drug use category. The CDC classification system is widely used for policy, resource allocation and research decisions in the US and worldwide. While additional research is needed, it may be appropriate to consider a combined category of injecting drug use and high heterosexual risk, similar to the male-sex-with-males/injecting drug use category (MSM-IDU). An HIV seropositive person reporting injecting drug use, heterosexual but not MSM risk behavior, and who is HSV-2 seropositive could be placed in an IDU-high heterosexual risk (IDU-HHR) transmission category. In cities like New York with good legal access to sterile syringes, use of an IDU-high heterosexual risk category may better reflect recent HIV transmission patterns among IDUs than the current CDC classification system. Role of funding source This research was funded by grant R01 DA 03574 from the National Institute on Drug Abuse (NIDA). NIDA was not involved
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in conceptualization, design or content of this manuscript, only for funding the research study. Contributors Don C. Des Jarlais designed the study, wrote the protocol, and wrote the first draft of the manuscript. Kamyar Arasteh undertook the statistical analysis and Courtney McKnight directed the research study from which the data for the manuscript was derived. All authors contributed to the intellectual content of the paper, read and edited all drafts and approved the final manuscript. Conflict of interest None of the authors have any conflicts of interest related to this manuscript. References Centers for Disease Control and Prevention, 2008. HIV/AIDS Surveillance Report: Cases of HIV Infection and AIDS in the United States and Dependent Areas, 2006. Retrieved September 15, 2008, 2008, from http://www. cdc.gov/hiv/topics/surveillance/basic.htm#def. Des Jarlais, D.C., Hagan, H., Arasteh, K., McKnight, C., Perlman, D., Friedman, S.R., 2007. Herpes simplex virus-2 and HIV among non-injecting drug users in New York City. Sex Transm. Dis. 34 (11), 923–927. Des Jarlais, D.C., Friedman, S.R., Novick, D.M., Sotheran, J.L., Thomas, P., Yancovitz, S., Mildvan, D., Weber, J., Kreek, M.J., Maslansky, R., Bartelme, S., Spire, T., Marmor, M., 1989. HIV-1 infection among intravenous drug users in Manhattan, New York City, from 1977 through 1987. JAMA 261, 1008–1012. Des Jarlais, D.C., Perlis, T., Arasteh, K., Torian, L.V., Beatrice, S., Milliken, J., Mildvan, D., Yancovitz, S., Friedman, S.R., 2005. HIV incidence among injection drug users in New York City, 1990 to 2002: use of serologic test algorithm to assess expansion of HIV prevention services. Am. J. Public Health 95, 1439–1444. Des Jarlais, D.C., Perlis, T., Friedman, S.R., Chapman, T., Kwok, J., Rockwell, R., Paone, D., Milliken, J., Monterroso, E., 2000. Behavioral risk reduction in a declining HIV epidemic: injection drug users in New York City, 1990–1997. Am. J. Public Health 90, 1112–1116. Freeman, E., Weiss, H., Glynn, J., Cross, P., Whitworth, J., Yayes, R., 2006. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20, 73–83. Hagan, H., Des Jarlais, D.C., 2000. HIV and HCV infection among injecting drug users. Mt. Sinai J. Med. 67, 423–428. Kaplan, E., 1989. Needles that kill: modeling human immunodeficiency virus transmission via shared drug injection equipment in shooting galleries. Rev. Infect. Dis. 11, 289–298. Kral, A.H., Bluthenthal, R.N., Lorvick, J., Gee, L., Bacchetti, P., Edlin, B.R., 2001. Sexual transmission of HIV-1 among injection drug users in San Francisco, USA: riskfactor analysis. Lancet 357, 1397–1401. Lindenberg, C., Krol, A., Smit, C., Buster, M., Coutinho, R., Prins, M., 2006. Decline in HIV incidence and injecting, but not in sexual risk behaviour, seen in drug users in Amsterdam: a 19-year prospective cohort study. AIDS 20, 1771–1775. Maslow, C.B., Friedman, S.R., Perlis, T.E., Rockwell, R., Des Jarlais, D.C., 2002. Changes in HIV seroprevalence and related behaviors among male injection drug users who do and do not have sex with men: New York City, 1990–1999. Am. J. Public Health 92, 382–384. Strathdee, S.A., Sherman, S.G., 2003. The role of sexual transmission of HIV infection among injection and non-injection drug users. J. Urban Health 80, iii7–iii14. Wald, A., Corey, L., 2003. How does herpes simplex virus type 2 influence human immunodeficiency virus infection and pathogenesis? J. Infect. Dis. 187, 1509–1512.
Contents lists available at ScienceDirect
Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep
Using hepatitis C virus and herpes simplex virus-2 to track HIV among injecting drug users in New York City Don C. Des Jarlais a,∗ , Kamyar Arasteh a , Courtney McKnight a , Holly Hagan b , David Perlman a , Samuel R. Friedman b a b
Beth Israel Medical Center, United States National Development and Research Institutes, Inc., 71 W. 23rd Street, 8th Floor, New York, NY 10010, United States
a r t i c l e
i n f o
Article history: Received 12 June 2008 Received in revised form 22 September 2008 Accepted 6 November 2008 Available online 23 December 2008 Keywords: Hepatitis C Herpes simplex virus-2 HIV Injecting drug users Substance abuse AIDS
a b s t r a c t Objective: To explore the potential utility of hepatitis C virus (HCV) seroprevalence as a biomarker for injection risk, and herpes simplex virus-2 (HSV-2) as a biomarker for sexual risk among injecting drug users (IDUs). We examined the relationships between HCV and HIV and between HSV-2 and HIV among injecting drug users in New York City relative to the large-scale implementation of syringe exchange in the mid-1990s. Methods: 397 injecting drug users were recruited from a drug detoxification program in New York from 2005 to 2007. Informed consent was obtained, a questionnaire covering demographics, drug use and HIV risk was administered. Blood samples were tested for antibody to HIV, HCV and HSV-2. Results: Among all subjects, HIV prevalence was 17%, HCV prevalence 72% and HSV-2 prevalence 48%. Among IDUs who began injecting before 1995, HIV was 28%, HCV serostatus was strongly associated with HIV serostatus (AOR = 8.96, 95% CI 1.16–69.04) and HSV-2 serostatus was not associated with HIV serostatus (AOR = 1.31, 95% CI 0.64–2.67). Among subjects who began injecting in 1995 or later, HIV was 6%, HCV was not associated with HIV (AOR = 1.04, 95% CI 0.27–4.08) and HSV-2 serostatus was strongly related to HIV serostatus (AOR = 10.71, 95% CI 1.18–97.57). Conclusions: HCV and HSV-2 HCV and HSV-2 may provide important new tools for monitoring evolving HIV epidemics among IDUs. Reconsideration of the current CDC hierarchical transmission risk classification system may also be warranted. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Injecting drug users (IDUs) are at risk for HIV through both multi-person use (sharing) of needles and syringes and through unprotected sexual intercourse. Sharing of needles and syringes is a relatively efficient means for transmitting HIV, and extremely rapid transmission of HIV has occurred in IDU populations (Des Jarlais et al., 1989; Kaplan, 1989). When provided with good access to sterile injection equipment, however, IDUs will greatly reduce injection risk behavior, leading to substantial reductions in HIV incidence (Des Jarlais et al., 2000). Sexual transmission of HIV among IDUs then increases in importance (Kral et al., 2001; Lindenberg et al., 2006; Strathdee and Sherman, 2003). Knowing the relative importance of injecting versus sexual transmission among IDUs is critical to understanding evolving HIV epidemics and allocating prevention resources.
∗ Corresponding author at: Beth Israel Medical Center/CDI, 160 Water Street, 24th Floor, New York, NY 10038, United States. Tel.: +1 212 256 2549; fax: +1 212 256 2570. E-mail address: [email protected] (D.C. Des Jarlais). 0376-8716/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2008.11.007
There are, however, considerable difficulties in studying the relative importance of HIV transmission through injecting versus sexual behavior among IDUs. The CDC surveillance transmission risk classification system is hierarchical, and all persons who report both injecting drug use and high-risk heterosexual activity are grouped into the injecting drug use category (Centers for Disease Control and Prevention, 2008). Research studies require very large numbers of incident HIV infections to statistically test for changes in the importance of injection-related versus sexual transmission of HIV over time, and it is important that data collection methods do not change over the relevant time period. In this report, we examine the potential utility of using hepatitis C virus (HCV) and herpes simplex virus type 2 (HSV-2) prevalence as biomarkers for injecting and sexual risk among IDUs. As HCV is transmitted predominantly through sharing of drug injection equipment (Hagan and Des Jarlais, 2000) and HSV-2 is transmitted virtually entirely through sexual activity (Freeman et al., 2006), these can be considered relatively specific biomarkers for injecting and sexual risk. Thus, the strength of the relationship between HCV and HIV in a population of IDUs will be a valid measure of the importance of injecting related HIV transmission in that popula-
D.C. Des Jarlais et al. / Drug and Alcohol Dependence 101 (2009) 88–91
tion, and the strength of the association between HSV-2 and HIV in that population will be a valid measure of the importance of sexual HIV transmission. HSV-2 also facilitates sexual acquisition and transmission of HIV (Freeman et al., 2006; Wald and Corey, 2003), so that HSV-2 infection is not only a biomarker for sexual risk, but also a causal factor in sexual transmission of HIV. We explore the potential utility of HCV and HSV-2 as biomarkers for HIV risk in relation to the large-scale expansion of syringe exchange programs in New York City that occurred in the mid1990s. This expansion was temporally associated with a dramatic reduction in HIV incidence among IDUs (from 4/100 person-year to <1/100 person-years at risk) (Des Jarlais et al., 2005). 2. Methods The data reported here are a part of studies of drug users entering the Beth Israel Medical Center drug detoxification program in New York City. The methods were previously described in detail (Des Jarlais et al., 1989; Maslow et al., 2002), so only a summary will be presented here. The Beth Israel detoxification program serves the city as a whole; approximately half of its patients live in Manhattan, one quarter in Brooklyn, one fifth in the Bronx, and the rest (5%) elsewhere. Patients enter the program on a voluntary basis. Both injecting and non-injecting drug users are eligible to participate in the study. For this report, however, we used data only from persons who reported injecting heroin, cocaine or other drugs in the 6 months prior to the interview. Within gender, patients are admitted on an “open bed” basis, so that there should not be any bias in terms of assignment to specific wards in the detoxification unit. Research staff visit the general admission wards of the program in a pre-set order. Research staff examine all intake records of a specific ward and construct a list of patients admitted within the past 3 days. All of the patients on the list for the specific ward were then asked to participate in the study. Among patients approached by our interviewers, willingness to participate was over 95%. After all of the patients admitted to a specific ward in the 3-day period had been asked to participate and interviews had been conducted with those who agreed to participate, the interviewer moves to the next ward in the pre-set order. As there is no relationship between assigning patients to wards and the order that the staff rotate through the wards, these procedures should produce an unbiased sample. Data reported here were collected from August 2005 to April 2007. A structured questionnaire covering demographics, drug use, sexual risk behavior, and use of HIV prevention services was administered by a trained interviewer. The questionnaire included items on date of birth and age at first illicit drug injection, so that it was possible to calculate the year of first injection. After completion of the interview, the participant was referred to an HIV counselor for pre-test counseling and serum collection. HIV testing was conducted at the New York City Department of Health Laboratory using repeated enzyme-linked immunosorbent assays (ELISA) testing with Western blot confirmation. HCV testing was also conducted at the New York City Department of Health Laboratory, using the Abbott HCV enzyme immunoassay (EIA) 2.0 test. HSV-2 testing was conducted by Bio-Reference Laboratories using the HerpeSelect HSV-1 and HSV-2 ELISA (Focus Technologies, Cypress, CA). We used the chi-square test to assess the differences in the prevalence of HIV, HCV, and HSV-2. To test the strength of the association between HIV and HCV/HSV-2 we estimated odds ratios using the Mantel-Haenszel method. Multivariate logistic regression was used to model the association of HCV and HSV-2 with HIV. In order to adjust for the effect of demographic variables we included age, gender, and race/ethnicity as covariates in the models. The study was approved by the Beth Israel Institutional Review Board.
reported smoking crack cocaine in the 6 months prior to the interview. Among the 62 female subjects, 11 (18%) reported exchanging sex for drugs and 21 (34%) reported exchanging money for drugs in the 6 months prior to the interview. Among the 301 male subjects, 42 (14%) reported giving drugs for sex and 37 (12%) reported giving money for sex in the 6 months prior to the interview. 3.2. HIV, HCV and HSV-2 seroprevalence Table 1 shows HIV, HCV and HSV-2 seroprevalences for the entire sample and within demographic subgroups (gender, age, race/ethnicity). In the sample as a whole, HIV prevalence was 17% (95% CI 13–21%), HCV seroprevalence was 72% (95% CI 67–77%) and HSV-2 prevalence was 48% (95% CI 43–53%). Older subjects were more likely to be seropositive for all three viruses. Female subjects and African-American subjects were significantly more likely to be seropositive for HIV and for HSV-2. Other than the age difference, none of the differences in HCV seroprevalence by demographic characteristics were statistically significant. Twenty-two males reported male-with-male sex (MSM) in the 5 years prior to the interview. Compared to the 279 males who did not report MSM behavior, the 22 MSM subjects were significantly more likely to be HIV seropositive (36% vs. 13%, p < .05), slightly more likely to be HSV-2 seropositive (55% vs. 40%, p = .17), and there was no difference in HCV seroprevalence (72% vs. 64%, p = .43). For the sample as a whole, there were highly significant associations between HCV seroprevalence and HIV seroprevalence (odds ratio = 5.34, 95% CI 2.08–13.75, p < .0001) and between HSV2 seroprevalence and HIV seroprevalence (odds ratio = 2.91, 95% CI 1.62–5.23, p < .001), and a modest association between HCV and HSV-2 seroprevalence (OR = 1.65, 95% CI 1.03–2.62, p < .05). 3.3. Associations between HCV and HIV for IDUs who began injecting prior to 1995 and 1995 or later Syringe exchange programs expanded greatly in New York during the mid 1990s, leading to a large reduction in HIV incidence among IDUs in the city, from 3.5/100 person-years to 0.8/100 person-years (Des Jarlais et al., 2005). We examined the relationships between HCV and HIV and HSV-2 and HIV separately for IDUs who began injecting prior to 1995 and IDUs who began injecting in 1995 or later (IDUs who began injecting in 1995 or later would have spent their entire injection careers in an environment with legal access to sterile syringes.) (see Table 2). HIV seroprevalence was 32% among IDUs beginning to inject before 1995 and 6% (11 HIV seropositives) among those beginning Table 1 HIV, HCV and HSV-2 seroprevalence among IDUs entering detoxification treatment, New York City, 2005–2007.
3. Results 3.1. Demographics, drug use and sexual behavior Three hundred and sixty-six injecting drug users participated in the study from August 2005 to April 2007 and provided complete HIV, HCV, and HSV-2 data. (Antibody test results were not obtained or indeterminate for an additional 50 IDUs.) The subjects with complete test results had a mean age of 39 (S.D. = 9.1), 199 (54%) were under age 40; 301 (82%) were male, 62 (17%) were female; 77 (21%) were white, 72 (20%) were Black, and 205 (56%) were Hispanic. The drugs most commonly injected in the 6 months prior to the interview were heroin (injected by 89%), cocaine (injected by 42%), and speedball (combined heroin and cocaine, injected by 48%). The subjects also reported substantial non-injecting drug use: 48% reported intranasal heroin use, 17% reported intranasal cocaine use and 39%
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HIV (n+/N (%))
HCV (n+/N (%))
HSV2 (n+/N (%))
Total sample (n = 366)
62/366 (17%)
264/366 (72%)
176/366 (48%)
Gender Male (n = 301) Female (n = 62)
44/301 (15%)* 17/62 (27%)
213/301 (71%) 48/62 (77%)
122/301 (41%)** 52/62 (84%)
Race/ethnicity White (n = 77) Black (n = 72) Hispanic (n = 205)
8/77 (10%)* 20/72 (28%) 33/205 (16%)
48/77 (62%) 53/72 (74%) 153/205 (75%)
27/77 (35%)* 47/72 (65%) 96/205 (47%)
Age <40 (n = 199) 40 or older (n = 167)
17/199 (9%)** 45/167 (27%)
125/199 (63%)** 139/167 (83%)
79/199 (40%)* 97/167 (58%)
All comparisons are demographic characteristics with each virus (comparisons are vertical within each virus). * p < .05. ** p < .0001.
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Table 2 Associations between HCV and HSV-2 prevalence with HIV prevalence by date of first injection among IDUs in New York City. Date of first injection
HIV−
HIV+
OR (95% CI)
Before 1995
HCV+ HCV−
111 (83%) 23 (17%)
51 (98%) 1 (2%)
10.57 (1.39–80.41)*
1995 of later
HCV+ HCV−
96 (56%) 74 (44%)
6 (60%) 4 (40%)
1.16 (0.32–4.25)
Before 1995
HSV-2+ HSV-2−
71 (53%) 63 (47%)
34 (65%) 18 (35%)
1.68 (0.86–3.26)
HSV-2+ HSV-2−
62 (36%) 108 (64%)
9 (90%) 1 (10%)
1995 or later* * **
Table 3a HIV seropositive status among IDUs in New York City by their HCV and HSV-2 status and year of first injection.
Total HCV and HSV-2 negative HCV positive, HSV-2 negative** HSV-2 positive, HCV negative HCV and HSV-2 positive* * **
First injection, pre-1995
First injection, 1995 or later
52/186 = 28% 0/12 = 0% 18/69 = 26% 1/12 = 8% 33/93 = 35%
10/180 = 6% 1/50 = 2% 0/59 = 0% 3/28 = 11% 6/43 = 14%
p < .05. p < .0001 (Fisher’s exact test for difference by year of first injection).
15.68 (1.94–126.68)**
p < .05. p < .0001.
to inject in 1995 or later (p < .001). HCV seroprevalence was 87% among IDUs who began injecting prior to 1995 and 57% among those who began injecting in 1995 or later (p < .001). HSV-2 prevalence was 57% among those who began injecting before 1995 and 39% among those who began injecting in 1995 or later (p < .01). The association between HCV and HIV seroprevalence was extremely strong among IDUs who began injecting prior to 1995 (OR = 10.57, 95% CI 1.39–80.41), and not significant among IDUs who began injecting in 1995 or later (OR = 1.16, 95% CI 0.32–4.25). In contrast, the association between HSV-2 and HIV was not significant among those who began injecting before 1995 (OR = 1.68, 95% CI 0.86–3.26) and very strong among those who began injecting in 1995 or later (OR = 15.68, 95% CI 1.94–126.68). We conducted separate multivariate logistic regression analyses for subjects who began injecting prior to 1995 and subjects who began injecting in 1995 or later, controlling for race/ethnicity, gender and age (40 and older). Among subjects who began injecting prior to 1995, HCV serostatus was associated with HIV serostatus (AOR = 8.96, 95% CI 1.16–69.04) and HSV-2 serostatus was not associated with HIV serostatus (AOR = 1.31, 95% CI 0.64–2.67). Among subjects who began injecting in 1995 or later, HCV was not associated with HIV (AOR = 1.04, 95% CI 0.27–4.08) and HSV-2 serostatus was strongly related to HIV serostatus (AOR = 10.71, 95% CI 1.18–97.57). We also conducted multivariate analyses by combining time periods. The latter approach produced similar results. There was a significant interaction between time period and HCV such that subjects who began injecting before 1995 and were HCV positive were more likely to be HIV positive than subjects who began injecting in 1995 or later and were HCV negative (AOR = 11.08, 95% CI 2.4–51.22). We also observed a significant interaction between time period and HSV-2 on HIV. Subjects who began injecting in 1995 or later and were HSV-2 positive were more likely to be HIV positive than subjects who began injecting before 1995 versus and were not HSV-2 positive (AOR = 4.79, 95% CI 1.03–22.27). Numbers of subjects by combinations of HCV and HSV-2 serostatus and HIV prevalence by date of first injection (prior to 1995 and 1995 or later) are presented in Table 3a. HIV prevalence among the total samples, the HCV positives, and the HCV, HSV-2 double positives was clearly lower among IDUs who began injecting in 1995 or later. The difference in lower HIV prevalence among HCV seropositive/HSV-2 seronegatives is particularly dramatic. There was only a single HIV seropositive who was positive on neither of the two biomarkers. This subject reported male-with-male (MSM) behavior in the 5 years prior to the interview and that he had begun injecting only 1 month prior to the interview. Thus it is very likely that he became infected with HIV through MSM activity prior to beginning to inject, and it is not surprising that he was HCV negative.
Table 3b presents the percentages of HIV seropositives among the different combinations of HCV and HSV-2 serostatus by date of first injection. Even with the modest number of HIV seropositives among the IDUs who began injecting in 1995 or later, there are still significant differences in the distribution of HIV seropositives by HCV/HSV-2 serostatus. IDUs who began injecting in 1995 or later are significantly less likely to be HCV seropositive/HSV-2 seronegative, and significantly more likely to be HSV-2 seropositive/HCV seronegative. 4. Discussion In this report, we explored whether using HCV as biomarker for injection-related risk and HSV-2 as a biomarker for sexual risk might provide useful information about the continuing HIV epidemic among IDUs in New York City. Our analyses indicated that the large-scale expansion of syringe exchange programs in New York was temporally associated with a decrease in the relative importance of injecting-related HIV transmission and an increase in the importance of sexual transmission among IDUs. These findings are consistent with cohort studies of HIV transmission among IDUs after expansion of syringe exchange programs in Baltimore (Strathdee and Sherman, 2003), San Francisco (Kral et al., 2001) and Amsterdam (Lindenberg et al., 2006). The findings in this report are also consistent with the previously reported reduction in HCV among IDUs in New York following the expansion of syringe exchange (Des Jarlais et al., 2005). We do not claim that the consistency of the results reported here with cohort studies validates the use of HCV and HSV-2 as biomarkers for injecting and sexual risk. We do, however, believe that the consistency indicates that the use of HCV and HSV-2 should be considered as a promising new tool for research on evolving HIV epidemics among IDUs. We would suggest that the use of HCV and HSV-2 as biomarkers is most likely to be productive under the following conditions: (1) there are extremely few HIV seropositives who are not also HCV and/or HSV-2 seropositive, and (2) there is sufficient variation among the combinations of HCV, HSV-2 and HIV serostatus to permit statistical testing (as in Tables 3a and 3b). Table 3b Percentages of HIV seropositives by HCV/HSV-2 serostatus by year of first injection among IDUS in New York City.
Total HIV seropositives HCV and HSV-2 negative HCV positive, HSV-2 negative HSV-2 positive, HCV negative HCV and HSV-2 positive
First injection, pre-1995
First injection, 1995 or later
52 0/52 = 0% 18/52 = 35% 1/52 = 2% 33/52 = 64%
10 1/10 = 10%a 0/10 = 0%** 3/10 = 30%*** 6/10 = 60%
All comparisons are by date of first injection. a HIV positive subject reported MSM behavior. ** p = .027 by Fisher’s exact test for difference by year of first injection. *** p = .01 by Fisher’s exact test for difference by year of first injection.
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Research using HCV and HSV-2 as biomarkers could be conducted at a small fraction of the cost of traditional cohort studies, and it should be possible to incorporate HCV and HSV-2 testing into HIV surveillance systems without great difficulties. There are a several limitations in this study. There are potential differences between IDUs who began injecting prior to 1995 versus IDUs who began injecting in 1995 or later that we were not able to “control for” in our analyses. For example, it is very likely that there was a much greater loss of HIV seropositives to death, illness or ceasing to inject drugs among the IDUs who began injecting prior to 1995 than among IDUs who began injecting in 1995 or later. In this cross-sectional study, we cannot be certain of the order of HCV, HSV-2 and HIV infections. (Though the very small number of HIV infections among IDUs who were HCV and HSV-2 negative suggests that these infections generally precede HIV infection among IDUs.) We also cannot be certain of the order of beginning to inject and infection with the three viruses. (Given the high rates of HSV-2 and HIV among non-injecting drug users in New York; Des Jarlais et al., 2007, it is highly likely that some drug users are infected with HSV2 and HIV before they move from non-injecting to injecting drug use.) Despite the limitations and need for additional research, we do believe that our findings can be used for targeting prevention efforts in New York City. Female IDUs (85% of whom are HSV-2 seropositive) and African-American IDUs (67% of whom are HSV2 seropositive) are clearly at high risk for sexual acquisition of HIV. Our findings also raise important questions about the current CDC hierarchical classification system for HIV transmission. The CDC hierarchical classification system for HIV/AIDS transmission places injecting drug use above high-risk heterosexual activity. Persons who report both injecting drug use and heterosexual activity with a high-risk partner are placed only in the injecting drug use category. The CDC classification system is widely used for policy, resource allocation and research decisions in the US and worldwide. While additional research is needed, it may be appropriate to consider a combined category of injecting drug use and high heterosexual risk, similar to the male-sex-with-males/injecting drug use category (MSM-IDU). An HIV seropositive person reporting injecting drug use, heterosexual but not MSM risk behavior, and who is HSV-2 seropositive could be placed in an IDU-high heterosexual risk (IDU-HHR) transmission category. In cities like New York with good legal access to sterile syringes, use of an IDU-high heterosexual risk category may better reflect recent HIV transmission patterns among IDUs than the current CDC classification system. Role of funding source This research was funded by grant R01 DA 03574 from the National Institute on Drug Abuse (NIDA). NIDA was not involved
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in conceptualization, design or content of this manuscript, only for funding the research study. Contributors Don C. Des Jarlais designed the study, wrote the protocol, and wrote the first draft of the manuscript. Kamyar Arasteh undertook the statistical analysis and Courtney McKnight directed the research study from which the data for the manuscript was derived. All authors contributed to the intellectual content of the paper, read and edited all drafts and approved the final manuscript. Conflict of interest None of the authors have any conflicts of interest related to this manuscript. References Centers for Disease Control and Prevention, 2008. HIV/AIDS Surveillance Report: Cases of HIV Infection and AIDS in the United States and Dependent Areas, 2006. Retrieved September 15, 2008, 2008, from http://www. cdc.gov/hiv/topics/surveillance/basic.htm#def. Des Jarlais, D.C., Hagan, H., Arasteh, K., McKnight, C., Perlman, D., Friedman, S.R., 2007. Herpes simplex virus-2 and HIV among non-injecting drug users in New York City. Sex Transm. Dis. 34 (11), 923–927. Des Jarlais, D.C., Friedman, S.R., Novick, D.M., Sotheran, J.L., Thomas, P., Yancovitz, S., Mildvan, D., Weber, J., Kreek, M.J., Maslansky, R., Bartelme, S., Spire, T., Marmor, M., 1989. HIV-1 infection among intravenous drug users in Manhattan, New York City, from 1977 through 1987. JAMA 261, 1008–1012. Des Jarlais, D.C., Perlis, T., Arasteh, K., Torian, L.V., Beatrice, S., Milliken, J., Mildvan, D., Yancovitz, S., Friedman, S.R., 2005. HIV incidence among injection drug users in New York City, 1990 to 2002: use of serologic test algorithm to assess expansion of HIV prevention services. Am. J. Public Health 95, 1439–1444. Des Jarlais, D.C., Perlis, T., Friedman, S.R., Chapman, T., Kwok, J., Rockwell, R., Paone, D., Milliken, J., Monterroso, E., 2000. Behavioral risk reduction in a declining HIV epidemic: injection drug users in New York City, 1990–1997. Am. J. Public Health 90, 1112–1116. Freeman, E., Weiss, H., Glynn, J., Cross, P., Whitworth, J., Yayes, R., 2006. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20, 73–83. Hagan, H., Des Jarlais, D.C., 2000. HIV and HCV infection among injecting drug users. Mt. Sinai J. Med. 67, 423–428. Kaplan, E., 1989. Needles that kill: modeling human immunodeficiency virus transmission via shared drug injection equipment in shooting galleries. Rev. Infect. Dis. 11, 289–298. Kral, A.H., Bluthenthal, R.N., Lorvick, J., Gee, L., Bacchetti, P., Edlin, B.R., 2001. Sexual transmission of HIV-1 among injection drug users in San Francisco, USA: riskfactor analysis. Lancet 357, 1397–1401. Lindenberg, C., Krol, A., Smit, C., Buster, M., Coutinho, R., Prins, M., 2006. Decline in HIV incidence and injecting, but not in sexual risk behaviour, seen in drug users in Amsterdam: a 19-year prospective cohort study. AIDS 20, 1771–1775. Maslow, C.B., Friedman, S.R., Perlis, T.E., Rockwell, R., Des Jarlais, D.C., 2002. Changes in HIV seroprevalence and related behaviors among male injection drug users who do and do not have sex with men: New York City, 1990–1999. Am. J. Public Health 92, 382–384. Strathdee, S.A., Sherman, S.G., 2003. The role of sexual transmission of HIV infection among injection and non-injection drug users. J. Urban Health 80, iii7–iii14. Wald, A., Corey, L., 2003. How does herpes simplex virus type 2 influence human immunodeficiency virus infection and pathogenesis? J. Infect. Dis. 187, 1509–1512.