Minimal Transmission of HIV Despite Persistently High Transmission of Hepatitis C Virus in a Swedish Needle Exchange Program

From Journal of Viral Hepatitis

M. Alanko Blomé; P. Björkman; L. Flamholc; H. Jacobsson; V. Molnegren; A. Widell

Posted: 01/10/2012; J Viral Hepat. 2011;18(12):831-839. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

The aim of this study was to examine the prevalence and incidence of HIV and hepatitis B and C (HBV and HCV) among injecting drug users in a Swedish needle exchange programme (NEP) and to identify risk factors for blood-borne transmission. A series of serum samples from NEP participants enrolled from 1997 to 2005 were tested for markers of HIV, HBV and HCV (including retrospective testing for HCV RNA in the last anti-HCV-negative sample from each anti-HCV seroconverter). Prevalence and incidence were correlated with self-reported baseline characteristics. Among 831 participants available for follow-up, one was HIV positive at baseline and two seroconverted to anti-HIV during the follow-up of 2433 HIV-negative person-years [incidence 0.08 per 100 person-years at risk (pyr); compared to 0.0 in a previous assessment of the same NEP covering 1990–1993]. The corresponding values for HBV were 3.4/100 pyr (1990–1993: 11.7) and for HCV 38.3/100 pyr (1990–1993: 27.3). HCV seroconversions occurred mostly during the first year after NEP enrolment. Of the 332 cases testing anti-HCV negative at enrolment, 37 were positive for HCV RNA in the same baseline sample (adjusted HCV incidence 31.5/100 pyr). HCV seroconversion during follow-up was significantly associated with mixed injection use of amphetamine and heroin, and a history of incarceration at baseline. In this NEP setting, HIV prevalence and incidence remained low and HBV incidence declined because of vaccination, but transmission of HCV was persistently high. HCV RNA testing in anti-HCV-negative NEP participants led to more accurate identification of timepoints for transmission.

Introduction

Injecting drug use is an important route of HIV transmission worldwide,^[1,2] and hence targeting injecting drug users (IDUs) is a priority in HIV prevention. IDUs are also at risk of infection with other blood-borne pathogens, especially hepatitis B virus (HBV) and hepatitis C virus (HCV). Because these viruses share transmission routes, measures taken to prevent HIV might also be expected to reduce the spread of HBV and HCV. A wide range of strategies have been attempted to decrease blood-borne transmission among IDUs, as exemplified by harm reduction interventions such as methadone maintenance therapy (MMT) and needle exchange programmes (NEPs). Although NEPs are recommended by the World Health Organization (WHO), there is no unequivocal evidence from controlled studies demonstrating the protective efficacy of such schemes.^[3,4] Most evaluations of the effectiveness of NEPs regarding HIV compare populations or assess injection-related risk behaviour,^[5–7] and most studies of virological markers have been cross-sectional.^[8,9] HIV incidence studies among NEP participants have in general revealed low rates of seroconversion, especially when NEPs had been initiated before significant spread of HIV occurred in the target population.^[10–13] Such results agree with our earlier observations regarding NEP participants in Malmö, Sweden, in 1990–1993.^[14] However, a major concern in our Malmö NEP was ongoing transmission of HBV and HCV, which indicated blood-borne transmission despite access to clean injection equipment. We subsequently added HBV immunization to the program, as well as targeted health education concerning the risks of HCV transmission for both HCV-infected and HCV-uninfected participants.

The objective of the present study was to further investigate the recent epidemiology of HIV, HBV and HCV among new participants in the Malmö NEP, which is one of only two such programs in Sweden, and also to determine whether incident HCV infection was linked to baseline drug use–related risk factors.

Methods

Setting

In Sweden (pop. 9 million), approximately 4500 people had been diagnosed with HIV by the year 2005 (prevalence 0.04%), and, from 1995 to 2005, about 300 new cases were reported annually, with approximately 10% infected through injection drug use.^[15] The prevalence of previous HBV exposure in the general middle-aged population in urban areas was approximately 4% in 2000.^[16] Considering HCV, the prevalence in 1996–2006 was 0.5%, and injection drug use was reported to be the transmission route in 65% of the registered cases.^[17] No data are available regarding the incidence of HCV in Sweden.

The city of Malmö (pop. about 270 000) is located in Skåne County in the southernmost part of Sweden (pop. about 1 million), approximately 20 km from Copenhagen, Denmark. From 1997 to 2005, the average annual incidence of HIV in Skåne County was 39 (range 31–51), and most infections were acquired through sexual transmission. In 2005, approximately 500 people diagnosed with HIV were living in Skåne County.^[18] According to estimations,^[19] there were 1600 IDUs in Malmö in 1998 (1080 per 100 000 inhabitants aged 15–54 years). In 2006, there were 1000 HIV-infected IDUs in the entire country, and 6% of those IDUs lived in Malmö while the majority (72%) lived in the capital city of Stockholm.

The Malmö Needle Exchange Programme

The Malmö NEP was initiated in 1987, and it is located in the University Hospital compound at the Department of Infectious Diseases. The staff consists of two assistant nurses, a registered nurse, a social worker, a midwife and a physician. The NEP is open daytime during weekdays. A total of 3950 new participants enrolled in the Malmö NEP, and approximately 1150 persons were active in the programme each year during that period. Prerequisites for enrolment are self-reported injection drug use, age ≥20 years, signs of recent venipuncture and consent to HIV testing (which may be performed under code). About 140–200 new participants enrol annually. At the time of registration, structured data are collected and risk reduction counselling is given. A maximum of 20 needles and 10 syringes can be obtained per visit. Most participants who have initially chosen to be anonymous later decide to allow use of their unique national identity number (NIN) for management of data and test results, after which collected data are updated. NINs are used in all Swedish hospital and laboratory databases and in population registers.

Those susceptible to either HIV, HBV and/or HCV infection are serologically tested approximately every 3 months until seroconversion occurs. In addition, immunization against hepatitis B and A has been offered since 1994 and 1999, respectively. Educational videos aimed at both reducing infection and preventing overdose are shown in the waiting room, and participants are given barrier contraceptives, pregnancy screening and treatment for sexually transmitted infections. Basic medical care, psychosocial support and referral to detoxification or methadone/buprenorphine maintenance clinics are also offered, all free of charge.

Subjects

A total of 1661 participants registered in the Malmö NEP between 1 January 1997 and 31 December 2005 were eligible for inclusion in the present study, and a NIN was available for 1183 of those individuals. The remaining 478 subjects were mainly sporadic visitors who refused both use of their NINs and blood sampling (n = 454), or agreed only to blood sampling (n = 24), and thus identification of serological markers was not possible. Among the 1183 persons who allowed use of their NINs, 831 provided two or more samples and underwent two or more registered needle/syringe exchanges, and they were included in the analysis of incidence and risk factors prevalent at enrolment; this group is referred to as the longitudinal cohort. The 352 persons providing only one blood sample were analysed regarding prevalence of viral markers, demographics and risk profile; this group is called the baseline-only cohort.

Virological Testing

Serological Tests Virological results were retrieved from the mainframe computer at the hospital microbiology laboratory. During the study period, testing was progressively upgraded with new instruments and techniques [1997, chemiluminescence assay using avidin-coated tubes (Boehringer, Mannheim, Germany); 1998, bead-based ELISA (CobasCore; Roche, Mannheim, Germany); 2001, microparticle-based EIA (Abbott AxSym, Abbott Park, IL, USA)]. The markers studied were as follows: for HIV, anti-HIV antibodies followed by immunoblotting if needed; for HBV, hepatitis B surface antigen (HBsAg), core antibodies (anti-HBc) and surface antibodies (anti-HBs); for HCV, anti-HCV antibodies followed by immunoblotting if needed. All assays were continuously evaluated in international proficiency panels. Sera were routinely stored at −20 °C, which allowed retrospective retesting of relevant sera with the most sensitive anti-HCV assay (third generation Abbott AxSym).

Molecular Tests To define the time of HCV acquisition more exactly, all the latest available preseroconversion sera testing anti-HCV negative in the third-generation AxSym assay were retrospectively tested for HCV RNA in a Taqman48 Roche assay (Roche Diagnostics). Because the sample volumes were limited and the Taqman system requires 1 mL of starting material, participant sera were prediluted 1:10 in negative serum, which resulted in a detection limit of 150 IU/mL for HCV RNA.

Statistical Methods

Odds ratios, Mann–Whitney U-tests and Fisher's Exact tests were calculated to analyse differences between groups. Univariate and multiple logistic regression analyses were carried out to identify baseline risk factors associated for previous HCV exposure and with HCV seroconversion. Kaplan–Meier curves with log rank tests were plotted to visualize and test time to seroconversion between different year periods. The statistical tests were performed in spss 15.0 for Windows ( SPSS Inc., Chicago, IL, USA). P-values <0.05 were considered statistically significant. Odds Ratios (ORs) were considered as significant if the entire 95% confidence range either was above or below 1.0

The timepoint of seroconversion to HIV, HBV and HCV was defined as the midpoint between the last antibody-negative and the first antibody-positive sample. The timepoint of HCV infection was adjusted by the results of HCV RNA testing. The monitored follow-up period spanned from the first serum sample collected after registration in the NEP to the last sample taken before the end of 2005.

Ethical Considerations

After approval by the regional research ethics committee, the purpose and the procedure of our study were announced on posters in the NEP and in advertisements in the local press, including a widely distributed free daily newspaper. An opt-out strategy was used, assuming consent for NEP participants who did not actively object to study inclusion. All analyses were coded, with the exception of linking of the longitudinal laboratory results.

Results

Baseline Characteristics of Injecting Drug Users Who Did or Did Not Provide a National Identity Number

Participants with and without available NINs did not differ significantly with regard to gender, age or geographic origin (data not shown). However, only 50% of those with a NIN had spent time in prison prior to the enrolment in the NEP compared to 57% of those not providing a NIN (OR 0.76, CI 0.61–0.94: P = 0.013). Among those who did provide a NIN, injection of amphetamine only was less prevalent (OR 0.78, CI 0.62–0.98; P = 0.039), whereas cannabis use was significantly more common (OR 1.86, CI 1.41–2.45; P < 0.001).

Baseline Prevalence of HIV, HBV and HCV Markers in Injecting Drug Users Who Provided a National Identity Number

Longitudinal Cohort vs Baseline-only Cohort The baseline prevalence of serological markers for all identified patients was 0.34% (4/1183) for anti-HIV, 32% (380/1183) for anti-HBc and 64% (758/1183) for anti-HCV.

Markers of previous exposure to HBV and HCV were significantly more prevalent in the baseline-only cohort compared to the longitudinal cohort for HBV (OR 1.82, CI 1.40–2.37; P < 0.001) and for HCV (OR 1.85, CI 1.41–2.44; P < 0.001). The baseline-only cohort also had a significantly longer history of injecting both heroin and amphetamine before enrolling in the NEP (P < 0.001). Likewise, the use of cannabis (OR 2.01, CI 1.23–3.28; P = 0.004) and oral amphetamine (OR 2.70, CI 2.08–3.50; P < 0.001) was more prevalent in the baseline-only cohort. This group also reported having spent time in police custody more often (OR 1.69, CI 1.21–2.38; P = 0.002) or in prison (OR 1.50, CI 1.16–1.92; P = 0.002), or had been in care under the social services law (OR 1.73, CI 1.27–2.35; P = 0.001).

Longitudinal Cohort HIV. One of the 831 persons in the longitudinal cohort was anti-HIV positive at enrolment but had tested anti-HIV negative 3 months previously.

HBV. Markers of HBV exposure were detected at baseline in 236 persons (28%), 10 of whom developed chronic HBs antigenemia. Neither male gender (OR 1.30, CI 0.91–1.86) nor being born outside Sweden (OR 0.79, CI 0.54–1.14) was associated with a higher risk of HBV exposure. Exclusive use of heroin was associated with a significantly lower risk of HBV exposure compared to exclusive use of amphetamine or mixed use of those drugs (OR 0.48, 0.31–0.74; P = 0.0008). Furthermore, testing positive for HBV markers was strongly correlated with the presence of anti-HCV (OR 5.91, CI 3.97–8.80). Only seven persons had received full HBV vaccination and achieved protective levels of anti-HBs before NEP enrolment.

HCV. At baseline, anti-HCV was found in 499 (60%) participants. Univariate comparison of participants dichotomized for baseline anti-HCV status showed that presence of anti-HCV was associated with (Table 1, left section) older age (OR 1.09, CI 1.07–1.11; P < 0.001), longer duration of heroin injection (OR 1.11, CI 1.07–1.15; P < 0.001), longer duration of amphetamine injection (OR 1.11, CI 1.09–1.14; P < 0.001), parenteral use of both heroin and amphetamine (OR 1.65 CI 1.24–2.19; P = 0.001), use of oral amphetamine (OR 1.52, CI 1.13–2.04; P = 0.006), previous incarceration (OR 2.43, CI 1.82–3.25; P < 0.001), time in residential treatment centres (OR 1.39, CI 1.05–1.84; P = 0.021) and exposure to HBV (OR 5.72, CI 3.86–8.48; P < 0.001). Male gender (OR 0.68, CI 0.49–0.95; P = 0.023), intravenous heroin (OR 0.34, CI 0.24–0.48; P < 0.001) and oral heroin (OR 0.52, CI 0.33–0.82; P = 0.006) use were associated with a lower risk of anti-HCVseropositivity. By multivariate analysis, the following factors were significant: male gender (OR 0.39, CI 0.26–0.58; P < 0.001), higher age at entry (OR 1.03, CI 1.01–1.06; P = 0.007), longer duration of parenteral heroin (OR 1.06, CI 1.01–1.11; P = 0.011) and amphetamine (OR 1.06 CI 1.03–1.09; P < 0.001) use, previous incarceration (OR 1.59, CI 1.10–2.29; P = 0.013), residential treatment (OR 1.59, CI 1.01–2.51; P = 0.045) and markers of HBV exposure (OR 2.75, CI 1.76–4.32; P < 0.001).

Incidence of HIV, HBV and HCV Markers in the Longitudinal Cohort

HIV In 1999, seroconversion to anti-HIV occurred in two men (24 and 27 years of age, both anti-HCV positive). Anti-HIV were detected in one of those men 10 months after the first anti-HIV-negative registration sample; he had not visited the NEP for eight consecutive months during that period. The other man had tested anti-HIV negative 3 months prior to the first anti-HIV positive sample. Thus, the incidence of HIV was 0.082/100 pyr during a total time at risk of 2433 years (Table 2).

Hepatitis B Participants negative for HBsAg and/or anti-HBc were offered vaccination according to a standard three-dose schedule and using a postvaccination titre of anti-HBs >10 IU/mL as a criterion for protection. In the longitudinal cohort, 588 persons were susceptible to HBV. Three hundred and fifty-one of those individuals (60%) received at least three doses of vaccine, and protective levels of anti-HBs were achieved in 321 (91%).

HBV seroconversion occurred in 39 participants (21 with documented HBsAg and anti-HBc, 18 with anti-HBc only). The median interval between NEP enrolment and anti-HBc seroconversion was 17 months (range 2.0–101.0). The follow-up time was 1160 pyr, yielding a seroconversion rate of 3.36/100 pyr (Table 2). Nineteen (48%) of the incident HBV cases had begun vaccination with 11 having received only one dose and 2 two doses. Six subjects with HBV seroconversion had been fully vaccinated but had not achieved anti-HBs ≥10 IU/mL. No incident case of HBV occurred in vaccine responders. Five of the incident HBV cases developed chronic HBV infection. Thirteen (33%) of the 39 HBV seroconverters were susceptible to HCV, and 9 (69%) of those also seroconverted to anti-HCV. Drug use profiles did not differ significantly between those who were and those who were not infected with HBV during participation in the NEP.

Hepatitis C Seroconversion to anti-HCV. During 486 person-years at risk, 186 anti-HCV seroconversions occurred among 332 anti-HCV-negative individuals, resulting in an incidence of 38.3/100 pyr (Table 2). The majority of incident HCV infections occurred during the first 2 years after registration (Fig. 1a).

Figure 1. Time (years) elapsed before seroconversion to anti-HCV after enrolment in the Malmö needle exchange programme. The results are shown without (a) and with (b) adjustment for HCV viraemia in last anti-HCV-negative blood sample.

To assess potential trends over calendar time, we divided the entire cohort into three groups composed of all susceptible subjects registered in the NEP during three successive 3-year study periods. The time to event for those susceptible to HCV was calculated in Kaplan–Meier mode. Because the time of observation was shorter for the last group, events occurring later than the first 12 months after registration were censored. The corresponding time curves to HCV seroconversion are shown in Fig. 2. No significant differences were detected between these three groups.

Figure 2. Anti-HCV-free interval during the first 12 months of participation in the Malmö needle exchange programme among injecting drug users enrolled during three successive periods: 1997–1999, 2000–2002 and 2003–2005.

Risk Factors for anti-HCV Seroconversion. Univariate comparison of those who seroconverted to anti-HCV and those who remained anti-HCV negative showed that seroconversion was associated with the following (Table 1, right section): use of cannabis (OR 2.18, CI 1.02–4.65; P = 0.044), injection of both heroin and amphetamine (OR 1.60, CI 1.01–2.53; P = 0.044), and incarceration prior to enrolment (OR 1.79, CI 1.12–2.86; P = 0.015). Use of intravenous amphetamine (OR 0.55, CI 0.34–0.87; P = 0.012) only and oral amphetamine (OR 0.60, CI 0.38–0.96; P = 0.035) only was associated with a lower risk of seroconversion. Multivariate logistic regression analysis indicated that the duration of intravenous use of amphetamine before enrolment (OR 0.96 CI 0.92–1.00; P = 0.034), reported injection of both amphetamine and heroin (OR 1.87, CI 1.15–3.02; P = 0.011), and incarceration prior to enrolment (OR 1.89, CI 1.14–3.12; P = 0.013) were significant risk factors for HCV seroconversion after joining the programme.

Needle exchange programme participation was significantly longer and the number of visits significantly greater for the anti-HCV seroconverters than for those who remained anti-HCV negative. However, participants with detectable anti-HCV at baseline had a significantly lower median number of NEP visits, as well as a lower frequency of attendance than those who were anti-HCV negative at inclusion (Table 3).

HCV Incidence Adjusted for Serological Window Phase. Because anti-HCV antibodies appear months after infection, the high HCV incidence observed during the first months after enrolment might be explained by HCV infection acquired prior to registration. Among 186 persons who showed anti-HCV seroconversion following enrolment, HCV RNA was detected in the last available anti-HCV-negative sample in 67 cases (Fig. 1b). Thirty-seven of these were HCV viremic in their anti-HCV-negative enrolment sample, leading to a reclassification from incident to prevalent infection in those subjects, with an adjusted incidence of 31.5 per 100 pyr. Comparison of seroconverters who were in serological window phase at enrolment with subjects who acquired HCV after enrolment revealed no significant differences in relation to age or type or duration of drug use (data not shown).

Discussion

For more than two decades, the WHO has promoted needle exchange to prevent sharing of injection equipment and HIV transmission among IDUs. Despite this, many countries have pursued a restrictive policy and in Sweden only two NEPs exist. Furthermore, syringes and needles cannot be purchased legally without a prescription in Sweden.

Because the true efficacy of NEP cannot be demonstrated in randomized controlled trials, continuous evaluation of existing projects is critical. If the prevalence of HIV is very low in an IDU population under investigation, HIV seroconversion is not a reliable marker to detect blood-borne transmission. Like in our 1990–93 cohort, the incidence of HIV remained very low in the 1997–2005 cohort, and no new cases were detected after 1999.

We and others^[20,21] have used HBV and HCV as surrogate markers of the potential risk of spreading HIV. It is obvious that HBV immunization can confound the incidence of HBV and affect its usefulness as a surrogate marker. HCV is not effectively transmitted sexually and thus mainly reflects the injection risk, making this virus a more suitable marker of blood transmission.

Following our previous evaluation in 1990–1993, HBV immunization was introduced for unexposed NEP participants, which led to a sharp decline in HBV incidence from 11.7/100 to 3.36/100 pyr.

Our high HCV incidence is alarming (Table 2) and agrees with our previous results and those of others[22–24]. Several reasons may contribute to this phenomenon including the effects of a higher viral load and greater physical virion stability of HCV compared to HIV,^[25,26] as well as the much higher background prevalence of HCV among IDUs. Prevention of HCV transmission among IDUs is indeed a challenge, as demonstrated by a meta-analysis of 18 studies,^[27] which showed that neither NEPs nor MMT affected the incidence of HCV in IDUs. Researchers in the Netherlands recently found that only a combination of low-threshold NEPs and MMT could reduce HCV transmission among IDUs.^[28]

The majority of the participants in the Malmö NEP in 1997–2005 were already infected with HCV at baseline. Furthermore, we found that older age and longer duration of intravenous drug use was associated with HCV infection, and mixed use of heroin and amphetamine and incarceration prior to NEP enrolment were independent risk factors for HCV infection. Our data also show that most cases of HCV seroconversion occurred during the first year after enrolment, which is earlier than reported by Hagan et al.^[29]

Retrospective assessment of HCV RNA in frozen key samples from the longitudinal cohort revealed viraemia in 37/332 (12%) of the subjects who were anti-HCV negative at the time of enrolment. In an additional 30 individuals, a viraemic window-phase sample preceded anti-HCV seroconversion. Thus, it is likely that PCR analysis performed prospectively in anti-HCV-negative NEP participants would be a better method for detecting incident cases of HCV infection, permitting earlier and more effective interventions and tracing of transmission chains among such subjects.

After the initial phase of high HCV incidence following enrolment, new HCV infections became rarer in those still susceptible –a phenomenon which could be due both to behavioural and immunological factors.^[30]

Our study has limitations. Only NEP participants who were fully identified could be followed, which might have affected the results. However, demographic data reported by identifiable and nonidentifiable subjects were similar. Subjects with only one serum sample available had a higher risk profile compared to those in the longitudinal cohort, but they usually paid single or very few visits to the NEP making it questionable whether they should be regarded as NEP participants. Prospective assessment and monitoring of changes in drug injection risk profile was not consistently documented, nor were sexual risk factors. Furthermore, we were unable to objectively determine exact periods of and reasons for interruptions in NEP participation (e.g. imprisonment, travel or admission to detoxification clinics), and whether such interruptions were associated with changes in the rates of HCV seroconversion.

The effectiveness of a NEP depends on several factors, which, in addition to the number of needles and syringes exchanged,^[31] include acceptance and accessibility by the target population, as well as provision of adequate health education and medical services. In the Malmö NEP, limited opening hours and an age requirement of ≥20 years for participation may have been counterproductive, whereas the broad range of services offered probably had the opposite effect. A major advantage of NEPs is the possibility for surveillance of HIV seroepidemiology among IDUs and provide early warning as illustrated by the outbreak of HIV that occurred in 1994 in Vancouver,.^[32,33]

In conclusion, the persistently low incidence of HIV in the cohort we studied may be explained by a protective effect of the NEP combined with low background prevalence of HIV. Although NEPs conducted under these circumstances do not affect the incidence of HCV, they do contribute to surveillance and control of HIV transmission in the target population. Molecular testing focusing on participants with anti-HCV-negative samples may offer improved means of case finding.

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