Mortality rates in injecting drug users (IDU) are much higher than in the general population [1–3] and HIV and hepatitis infection rates are very high [4–7]. In Spain, the HIV epidemic has been characterized by high proportions of these infections among IDU; prevalences have been close to 45% for HIV [8–11], 80% for hepatitis B virus (HBV)  and 85% for hepatitis C virus (HCV) . In consequence, prevalence of HIV/HCV coinfections in IDU is very high: 30–50% [14–16].
The natural history of HCV varies by HIV status . In HIV/HCV-positive patients, liver disease develops after approximately 10 years [18,19] whereas it takes approximately 15 to 20 years in subjects monoinfected by HCV [20,21].
The introduction of HAART (in Spain, free of charge and available since 1997 ) has profoundly increased the survival of HIV-infected people [23–25], although this effect is less strong in IDU than in other groups because of the higher non-AIDS deaths, poorer uptake and compliance of HAART and worse socioeconomic conditions [26–29]. Nevertheless, a marked population effectiveness of HAART has been shown in IDU [30,31]. In this context, diseases with incubation periods exceeding that of AIDS, such as HCV infection, might emerge as competing causes of death [32,33].
Cohort studies with a long follow-up are of particular use to assess the effect of HCV infection on mortality rates at the population level and to monitor time trends. We have analysed data from a well-characterized population-based cohort, set up in the late 1980s to evaluate the impact of HIV and HCV infections on long-term mortality in IDU, and to evaluate changes in the risk of death attributable to these infectious in the pre-HAART and HAART periods.
Data were collected for IDU who attended Centres for AIDS Information and Prevention (CIPS) in Spain from 1990 to December 1996. Detailed descriptions of this cohort have been reported previously [9,13].
A total of 3247 IDU were tested for HCV, HIV and HBV. Informed consent was obtained from all individuals. Given the likelihood of false-negative results in the first-generation HCV assays, with lower sensitivity [34,35], the 124 (3.8%) HIV-positive/HCV-negative subjects were incorporated into the HIV/HCV-positive group as they showed similar sociodemographic characteristics and mortality rates. The subjects were not tested for HCV antibodies at each visit.
All subjects were given an anonymous identification code and information was collected through a structured questionnaire. Causes of death were ascertained from death registries and classified as AIDS-related deaths, violence related deaths (drug-use related, accidents, suicides and homicides) and others (liver disease, cardiovascular disease, tumours, others and unknown).
A first-generation enzyme-linked immunoassay for HCV infection was used in 1990–1991 and a second-generation assay from 1992 onwards (UBI HCV EIA 3.0 and 4.0, respectively, Organon Teknika, Boxtel, the Netherlands). A supplementary test (Recombinant Immunoblot Assay, Ortho Diagnostic Systems, Seattle, Washington, USA) was used to confirm HCV-positive results. Determination of HIV antibodies used an enzyme-linked immunoassay (Enzygnost HIV1/HIV2; Dade Behring, Deerfield, Illinois, USA) and positive results were confirmed by Western blot (Novopath HIV-1 Immunoblot, Bio-Rad Hercules, California, USA). Markers of HBV infection were determined using an enzyme-linked immunoassay technique (Dade Behring).
Follow up and censoring strategy
Entry date was the first visit to the centres after 1990, except for 84 (2.6%) subjects who seroconverted to HIV during follow-up; their entry dates were their first HIV-positive result. Follow-up was conducted in the CIPS and referral hospitals. Linkage with the Regional Mortality Registry was periodically carried out. Any coincidence between birth dates and names was checked with medical records and hospital registers in order to obtain the maximum sensitivity. Last record linkage was conducted on March 2004 and data were censored on December 2002 to allow for reporting delay.
Descriptive analysis were carried out using frequency distribution or median and interquartile range (IQR) when appropriate. For each subject the number of person-years of follow-up was calculated, considering time from entry to death or December 2002. Calendar period was divided before and after 1997, year of introduction of HAART in our setting . Multivariate Poisson regression was used to estimate HIV-positive/HCV-positive impact on global mortality. Likelihood ratio tests were used to derive P values. A significance level of 0.05 was chosen and adjusted relative risks (RR) were computed with 95% confidence intervals (CI). Stata 8 (Stata Corp., College Station, Texas, USA) was used for the analyses.
The analyses included 3247 IDU. Median follow-up was 8.6 years, (IQR, 7.0–10.1). At baseline, 1381 (42.5%) subjects tested HIV positive, 2759 (85.0%) HCV positive, 1465 (45.1%) were HIV/HCV positive and 149 (4.6%) were positive for HBV surface antigen (HBsAg) (Table 1).
Mortality rates for injection drug users: univariate analysis
During 26 772 persons-years of follow-up, there were 585 deaths (48.0% AIDS-related deaths, 31.3% violence-related and 20.7% other causes). The overall mortality rate was 2.19/100 person-years. HIV/HCV-positive subjects had a four-fold increase in death rates compared with those negative for both (RR, 4.0; 95% CI, 2.7–5.8). A 40% increase in borderline statistically significant in mortality was observed in HIV-negative/HCV-positive IDU (RR, 1.4; 95% CI, 0.9–2.1) compared with HIV/HCV-negative IDU. A 10% decrease in global mortality was seen after 1997 (RR, 0.9; 95% CI, 0.7–1.0) (Table 2).
Female IDU had a lower risk of death compared with men (RR, 0.7, 95% CI, 0.5–0.8), as did those with the highest education (RR, 0.4; 95% CI, 0.2–0.8) or secondary education (RR, 0.6; 95% CI, 0.4–0.8) compared with those with primary studies or less. Testing HBsAg positive at entry increased the risk of death by 60% (RR, 1.6; 95% CI, 1.1–2.2).
Multivariable analyses included HIV/HCV status, calendar period and age at first visit. Age at first visit was the only confounder of the risk of death in HIV/HCV-positive subjects, and the one that accounted for the largest change of the estimate of interest.
A statistically significant interaction (P = 0.033) was detected between HIV/HCV status and calendar period. The introduction of HAART altered the difference in mortality risk between HIV/HCV-positive and HIV/HCV-negative subjects. Before 1997, HIV/HCV-positive subjects had a five-fold increase in their risk of death (RR, 5.4; 95% CI, 2.5–11.4) compared with HIV/HCV-negative subjects; after 1997, only a three-fold increase was observed (RR, 2.7; 95% CI, 1.7–4.2). Being HCV positive/HIV negative was not associated with an increase in the risk of death either before 1997 (RR, 1.3; 95% CI, 0.6–2.9) or after 1997 (RR, 1.2; 95% CI, 0.8–1.9) compared with HIV/HCV-negative subjects. Comparing mortality rates between the two calendar periods (1990–1996 and 1998–2002), increases in the risk of death were seen in the later period in HIV/HCV-negative IDU (RR, 1.6; 95% CI, 0.7–3.7) and HIV-negative/HCV-positive IDU (RR, 1.5; 95% CI, 1.0–2.1), while a 20% reduction was seen in HIV/HCV-positive IDU (RR, 0.8; 95% CI, 0.6–0.9) (RR, 1.00).
Mortality rates in HIV/HCV-positive IDU were extremely high, four times higher than mortality rates in HIV/HCV-negative IDU, but HCV infection alone did not increase the risk of death after 8 years of follow-up. While mortality rates in HIV/HCV-positive IDUs have decreased since 1997, statistically significant increases have been observed in HIV-negative/HCV-positive subjects.
This is the first cohort study that reports long-term mortality rates and evaluates the effect of HIV/HCV coinfection in our setting, allowing for a comparison of coinfected and non-coinfected individuals before and after the introduction of HAART. Information about mortality in HIV/HCV coinfected IDUs in the HAART period is scarce and few studies have performed these comparisons [36–38].
We have found a strong effect of calendar period and a clear interaction with HIV/HCV coinfection status. Since 1997, mortality rates have decreased in HIV/HCV-positive subjects. This improvement in survival is coincident with the previously reported population effectiveness of HAART in IDU in our setting , which is also likely to be attributable to other health interventions aimed at IDU, such as harm reduction programmes.
Even though the changes in mortality before and after 1997 in HIV-negative/HCV-positive IDU are statistically significant, we expected a greater effect of HCV monoinfection. Liver disease takes from 15 to 20 years to develop in subjects solely infected by HCV [20,21] and median follow-up of this cohort was 8.6 years. (IDU had already been using drugs for a median of 6 years at the time of recruitment.) The minor changes in mortality in the HCV-positive/HIV-negative group could also be explained because not all individuals with HCV antibodies are chronically infected.
Infection with HBV at study entry was associated with a 60% increase in the risk of death in the univariate analyses, but this disappeared after adjusting for HCV infection as in other studies .
Some of the sociodemographic characteristics were associated with mortality in the univariate analysis. Low educational level was closely related to poor socioeconomic status and both have been related to worse health outcomes in the general population [40,41] and in HIV-positive subjects [42,43]. As regards the lower mortality in female IDU, previous studies have also reported slower HIV progression in female IDU, and higher uptake of antiretroviral therapy, compared with male IDU .
Several methodological limitations of this study have to be addressed. One of them is the loss of follow-up, which has been extensively reported in cohorts of IDU. Consequently, we combined the record linkage with the Registry of Mortality and the follow-up in CIPS and area hospitals. Although some losses to follow-up are inevitable, we do not think that they were related to HCV status. The date of HCV seroconversion was not available, but these subjects did have information on the duration of drug use, which can be considered as a reliable indicator of the duration of HCV disease [45,46]. Certain bias may have taken place, as HIV/HCV-negative subjects at entry might have become HIV/HCV positive during follow-up. This misclassification would tend to ascribe an increased risk of death to HIV/HCV-negative IDU, biasing the results towards the null. In spite of this bias, a clearly differing mortality between the groups was detected, emphasizing the large impact that being positive for both HIV and HCV has on mortality in IDU. In addition, it would have been appropriate to include a group whose serology was HIV-positive/HVC-negative to analyse its different mortality. However, this situation is extremely uncommon as most IDU who acquire HIV through sharing infected drug use equipment already have HCV. The very high prevalence of HCV infection at first visit also indicates that, although the use of different HCV assays over time may have caused some degree of misclassification bias, the misclassification error would be small.
These results show the large population impact on long-term mortality of HIV and HCV coinfection in IDU in Spain, and illustrate the changes that have taken place in mortality rates in groups with different serological status. For subjects infected by both HIV and HCV, we are observing decreases in mortality after the introduction of HAART in our setting, but in those HIV negative/HCV positive, mortality rates have increased since 1997.
Sponsorship: This work was financed through grants from Fundación La Marató de TV3: 02/1330; Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Ayudas para contratos post Formación Sanitaria Especializada); Red de Trastornos Adictivos RTA G03/005; Fundación Barcelona SIDA 2002 and ISCIII, Red de Centros RCESP C03/09.
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