Europe PMC Funders Group

Author Manuscript
J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.
Published in final edited form as:
J Acquir Immune Defic Syndr. 2015 July 1; 69(3): 348354. doi:10.1097/QAI.0000000000000603.

Europe PMC Funders Author Manuscripts

Injection drug use and Hepatitis C as risk factors for mortality in

HIV-infected individuals: the Antiretroviral Therapy Cohort
Collaboration
Writing committee and affiliations, Margaret T May, PhD,
School of Social and Community Medicine, University of Bristol, Bristol, UK
Amy C Justice, MD, PhD,
Yale University, New Haven, Connecticut, and VA Connecticut Healthcare System, West Haven,
Connecticut
Kate Birnie, PhD,
School of Social and Community Medicine, University of Bristol, Bristol, UK
Suzanne M Ingle, PhD,
School of Social and Community Medicine, University of Bristol, Bristol, UK
Colette Smit, PhD,
Stichting HIV Monitoring, Amsterdam, The Netherlands
Colette Smith, PhD,
Research Department of Infection and Population Health, University College London, London, UK

Europe PMC Funders Author Manuscripts

Didier Neau, MD, PhD,

Fdration des Maladies Infectieuses, Centre Hospitalo-Universitaire Pellegrin, Bordeaux, France
Marguerite Guiguet, PhD,
INSERM U943 and UPMC UMR-S-943, Paris, F75013 France
Carolynne Schwarze-Zander, MD,
Department of Internal Medicine, University Hospital Bonn, Germany
Santiago Moreno, MD, PhD,

Correspondence to: Dr. Margaret May, Reader in Medical Statistics, School of Social and Community Medicine, University of Bristol,
Bristol, BS8 2PS, UK, Telephone: +44 117 9287287, Fax: +44 117 928 7325, m.t.may@bristol.ac.uk.
Contribution of authors
AJ conceived the idea, KB and MM did statistical analyses, MM and AJ wrote the first draft of the paper, AJ did the literature search.
All authors contributed to study design, collection of data, data interpretation, writing the paper and approved the final version. MM
had full access to the data and acts as guarantor for the paper.
ART-CC Steering group
Andrew Boulle (IeDEA Southern Africa), Hans-Reinhard Brodt (Frankfurt), Jordi Casabona (PISCIS), Matthias Cavassini(SHCS),
Genevive Chne (Aquitaine), Dominique Costagliola (FHDH), Franois Dabis (Aquitaine), Antonella DArminio Monforte
(ICONA), Julia del Amo (CoRIS-MD), Gerd Ftkenheuer (Koln/Bonn), John Gill (South Alberta Clinic), Jodie Guest (HAVACS),
David Hans-Ulrich Haerry (EATG), Robert Hogg (HOMER), Amy Justice (VACS), Amanda Mocroft (EuroSIDA), Niels Obel
(Denmark), Heidi Crane (Washington), Fiona Lampe (Royal Free), Peter Reiss (ATHENA), Michael Saag (Alabama), Tim Sterling
(Vanderbilt-Meherry), Ramon Teira (VACH), Ard Van Sighem (ATHENA), Matthew Williams (UK-CAB), Robert Zangerle
(Austria)
Co-ordinating team
Jonathan Sterne and Margaret May (Principal Investigators), Suzanne Ingle (statistician), Adam Trickey (statistician).
Conflicts of Interest: For the remaining authors none were declared.

et al.

Page 2

Ramn y Cajal Hospital, IRYCIS, Madrid, Spain

Jodie L. Guest, PhD, MPH,
HIV Atlanta VA Cohort Study (HAVACS), Atlanta Veterans Affairs Medical Center, Decatur, GA,
USA

Europe PMC Funders Author Manuscripts

Antonella dArminio Monforte, MD, PhD,

Clinic of Infectious Diseases & Tropical Medicine, San Paolo Hospital, University of Milan, Italy
Cristina Tural, MD, PhD,
Hospital Universitari Germans Trias i Pujol, Universitat Autnoma de Barcelona, Badalona, Spain
Michael J Gill, MB,
Division of Infectious Diseases, University of Calgary, Calgary, Canada
Andrea Bregenzer, MD,
Department of Infectious Diseases, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland
Ole Kirk, MD, DMSci,
CHIP, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark
Michael Saag, MD,
Division of Infectious Disease, Department of Medicine, University of Alabama, Birmingham, USA
Timothy R Sterling, MD,
Vanderbilt University School of Medicine, Nashville, TN, USA
Heidi M Crane, MD, MPH, and
University of Washington School of Medicine, Seattle, WA, USA

Europe PMC Funders Author Manuscripts

Jonathan A C Sterne, PhD

School of Social and Community Medicine, University of Bristol, Bristol, UK

Abstract
BackgroundHIV-infected individuals with a history of transmission via injection drug use
(IDU) have poorer survival than other risk groups. The extent to which higher rates of hepatitis C
(HCV) infection in IDU explain survival differences is unclear.
MethodsAdults who started antiretroviral therapy (ART) between 2000-2009 in 16 European
and North American cohorts with >70% complete data on HCV status were followed for 3 years.
We estimated unadjusted and adjusted [for age, sex, baseline CD4 count and HIV-1 RNA, AIDS
diagnosis prior to ART, and stratified by cohort] mortality hazard ratios (HR) for IDU (versus
non-IDU) and for HCV-infected (versus HCV-uninfected).
ResultsOf 32,703 patients 3,374 (10%) were IDU; 4,630 (14%) HCV+; 1,116 (3.4%) died.
Mortality was higher in IDU compared with non-IDU (adjusted HR 2.71; 95% CI 2.32,3.16) and
in HCV+ compared with HCV (2.65; 2.31,3.04). The effect of IDU was substantially attenuated
(1.57; 1.27,1.94) after adjustment for HCV, while attenuation of the effect of HCV was less
substantial (2.04; 1.68,2.47) after adjustment for IDU. Both IDU and HCV were strongly
associated with liver-related mortality (10.89; 6.47,18.3 for IDU and 14.0; 8.05,24.5 for HCV)

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 3

with greater attenuation of the effect of IDU (2.43; 1.24,4.78) than for HCV (7.97; 3.83,16.6).
Rates of CNS, respiratory and violent deaths remained elevated in IDU after adjustment for HCV.
ConclusionsA substantial proportion of the excess mortality in HIV-infected IDU is
explained by HCV co-infection. These findings underscore the potential impact on mortality of
new treatments for HCV in HIV-infected people.

Europe PMC Funders Author Manuscripts

Keywords
HIV-1; Hepatitis C virus; injection drug use; antiretroviral therapy; cohort study; mortality

Introduction
Treated HIV-infected people with a history of injection drug use (IDU) have substantially
poorer survival than those in other transmission risk groups, both before and after
adjustment for patient characteristics at the time of starting antiretroviral therapy (ART) (1,
2). The excess mortality associated with a history of IDU varies considerably between
settings (3), suggesting that IDU may be a proxy for more direct causes of death such as
violence (4), overdose (5), higher rates of smoking (6), poorer ART adherence (7), more
frequent bacterial infections (8), or greater overall organ system injury (9, 10). Interventions
to end or reduce substance abuse may reduce excess mortality among IDU via effects on
these risk factors (11).

Europe PMC Funders Author Manuscripts

IDU is a major risk factor for chronic hepatitis C (HCV) infection, the prevalence of which
varies among injection drug using populations (12, 13). Excess mortality attributable to
HCV may not be addressed by interventions to reduce harm from substance abuse, because
the infection often persists after injection drug use has stopped. An improved understanding
of the contribution of HCV and general organ system injury to higher mortality rates among
HIV positive patients with a history IDU who are treated with ART is urgently needed, now
that highly effective treatments for HCV infection are available because this data would
inform clinical and cost-effectiveness analyses of the benefit of HCV treatment in dual
infected patients (14, 15).
Based on a collaboration of HIV cohort studies, we aimed to determine whether the
association between IDU and mortality that we previously reported (1, 16) is explained by
differential rates of HCV infection. We also examined whether IDU is independently
predictive of non-violent deaths. Our hypothesis was that, after adjustment for HCV
infection, IDU no longer has an independent association with all-cause or cause-specific
mortality.

Methods
Cohort and patient selection
The Antiretroviral Therapy Cohort Collaboration (ART-CC), which is described in detail
elsewhere (17), is an international collaboration of cohorts from North America and Europe
that combines data on HIV-infected individuals who were antiretroviral-nave when they
started ART with a combination of at least three drugs. This study was based on data from

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 4

Europe PMC Funders Author Manuscripts

sixteen cohorts that recorded history of IDU and for which data on HCV test status was
>70% complete. The included cohorts were: the AIDS Therapy Evaluation Project
Netherlands (ATHENA); French Hospital Database on HIV (FHDH); Aquitaine Cohort,
France; Departments of Internal Medicine at University of Cologne and Bonn, Germany;
Italian Cohort of Antiretroviral-Nave Patients (ICONA); CORIS, Spain; Proyecto para la
Informatizacin del Seguimiento Clnico-epidemiolgico de la Infeccin por HIV y SIDA
(PISCIS), Spain; Royal Free Hospital Cohort, London UK; Swiss HIV Cohort Study
(SHCS); The multicenter Study Group on EuroSIDA; Southern Alberta Clinic, Canada; HIV
Atlanta Veterans affairs Cohort Study (HAVACS), USA; UAB 1917 Clinic Cohort,
Birmingham, Alabama, USA; Veterans Ageing Cohort Study (VACS8),USA; VanderbiltMeharry Center for AIDS Research Nashville, Tennessee, USA; University of Washington
HIV Cohort, Seattle, WA, USA. Cohorts were checked for overlap and duplicate patients
removed. Institutional review boards from each cohort approved analysis of routinely
collected data. Eligible patients were HIV-positive, age 16 years, and initiated ART
between 2000 and 2009. All patients had CD4 cell count and HIV-1 RNA measured in the
period from three months before to one month after ART initiation. HCV+ status was
defined as a positive antibody test or positive plasma HCV-RNA viral load. IDU status
refers to HIV transmission risk group recorded by the cohort: records of ongoing active
injection drug use were not available in these data. All transmission risk groups except IDU
were categorised as non-IDU (men who have sex with men, heterosexual, blood, other/
unknown). Patients with missing HCV status were excluded from analyses. Patients were
followed up for death within 3 years of starting of ART. Causes of death were classified
using methodology adapted from the CoDe system (www.chip.dk/CoDe/tabid/55/
Default.aspx) using methods reported previously (4). The NHS Health Research Authority
South West - Cornwall and Plymouth Research Ethics Committee, UK, approved the study
(REC reference 12/SW/0253).

Europe PMC Funders Author Manuscripts

Statistical analysis
Patient demographics and clinical characteristics at start of ART were tabulated and
differences between those who were and were not HCV positive were examined using chisquared statistics and the Wilcoxon rank-sum test for medians. Kaplan-Meier estimates of
cumulative survival were plotted by HCV and IDU status and log-rank tests were used to
compare survival curves. Follow up was from initiation of ART (baseline), and was
censored at 3 years to avoid violation of the proportional hazards assumption. Cox models
were used to estimate unadjusted and adjusted [for age (16-29, 30-39, 40-49, 50-59, 60
years), sex, baseline CD4 cell count (<50, 50-99, 100-199, 200-349, 350 cells/mm3),
baseline HIV-1 RNA (<10 000, 10 000-99 999, 100 000 copies/mL), AIDS diagnosis prior
to ART] mortality hazard ratios (HR) for IDU (versus non-IDU) and for HCV+ (versus
HCV uninfected), before and after adjusting the effect of each for the other. All models were
stratified by cohort. We tested for interactions between age and both IDU and HCV status.
We repeated analyses stratifying by age (<45, 45 years). We also tested for interactions
between sex and both IDU and HCV status.
In a sensitivity analysis, we assessed the effect of possible misclassification of both IDU and
HCV status on hazard ratios. We calculated positive predictive values of IDU and HCV

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 5

status using plausible values for sensitivity and specificity which were based on consensus
expert clinician opinion of conservative estimates for these parameters, and used these to
define weights that were used to adjust for misclassification of IDU, HCV and both
variables simultaneously.

Europe PMC Funders Author Manuscripts

In a second sensitivity analyses we excluded patients with other/unknown risk

transmission group and repeated the main analysis re-estimating the crude and adjusted
mortality HR for IDU and HCV status.
We estimated adjusted hazard ratios for different causes of death [AIDS, non-AIDS
infection, liver-related, non-AIDS malignancy, myocardial infarction/ischaemic heart
disease, stroke, renal failure, violence (includes suicide and substance abuse), central
nervous system (other than stroke), other heart /vascular disease, and respiratory disease
(includes chronic obstructive pulmonary disease), other (includes infrequent causes of
death), and unknown (includes unclassifiable)]. All analyses were performed using Stata
version 12.1.

Results

Europe PMC Funders Author Manuscripts

Data on HCV status were available on 32,703/39,249 (83%) patients, of whom 1,116 (3.4%)
died within 3 years of starting ART during 931,485 person-years of follow up. 3,374
(10.3%) patients had presumed HIV transmission via IDU and 4,630 (14.2%) had tested
positive for HCV (HCV+). Compared with those in the study population, the proportion of
patients who were IDU was lower in those without HCV status recorded (8% vs. 10%).
Table 1 shows patient demographics and clinical characteristics at start of ART according to
HCV status. Compared with HCV uninfected individuals, those HCV+ were more likely to
be aged between 30-49 years old, have started ART in earlier years and to have a history of
IDU. CD4 cell counts at start of ART were similar in HCV infected and uninfected
individuals.
The prevalence of HCV among IDU was 85%: this varied from 36% to 92% between
cohorts. 38% of HCV+ were non-IDU. Figure 1 shows Kaplan-Meier survival curves by
HCV and IDU status. Survival was worst for HCV+ IDU and somewhat better for HCV+,
non IDU. Patients who were HCV uninfected had better survival than HCV+ whether or not
their transmission was via IDU, with IDU having worse survival than non-IDU within HCV
strata. The survival curves were different overall, (p <0.0001 log-rank test), and between
HCV+ and HCV uninfected in both non-IDU (p <0.0001) and IDU (p = 0.009). The survival
curves for IDU compared with non-IDU differed more amongst HCV+ (p = 0.01), than
amongst HCV uninfected patients (p = 0.08).
Table 2 shows unadjusted and adjusted mortality HR for IDU versus non-IDU and for HCV
+ versus HCV uninfected. HRs for both IDU and HCV were similar and substantially
elevated. They increased after adjustment for age, sex, and baseline CD4, HIV-1 RNA, and
AIDS diagnoses, to 2.71 (95% CI 2.32, 3.16) for IDU and 2.65 (2.31, 3.04) for HCV. When
IDU and HCV were included in the same model, attenuation of the HR for IDU (1.57; 95%
CI 1.27, 1.94) was more marked than attenuation of the HR for HCV (2.04; 1.68, 2.47).

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 6

Europe PMC Funders Author Manuscripts

There was little evidence of interaction between sex and either IDU (p = 0.07), or HCV
status (p = 0.06). There was strong evidence of interaction (P<0.001) between both IDU and
HCV status and age. In analyses stratified by age (<45, 45 years), the HRs for both IDU
and HCV were greater in younger than older patients. In both older and younger patients,
and consistent with the overall findings, attenuation of the HR for IDU was more marked
than attenuation of the HR for HCV when IDU and HCV were included in the same model.
In the sensitivity analyses allowing for misclassification of IDU and HCV, assuming a
sensitivity of 0.8 and a specificity of 0.95 for both IDU and HCV increased the mutually
adjusted mortality HR for IDU from 1.57 to 2.01 and for HCV from 2.04 to 2.51. The ratio
of HRs (HR HCV/ HR IDU), which shows the relative importance of HCV compared with
IDU, was 1.30 in the main analysis, decreased to 1.01 if only IDU was misclassified,
increased to 1.62 if only HCV was misclassified, and was 1.25 assuming both were equally
misclassified (Supplementary table 1).
In a second sensitivity analysis we excluded 2449/32703 (7.5%) patients with other/
unknown risk group of whom only 239/2449 (10%) were HCV+. Compared with the main
analysis, crude and adjusted mortality HR for both IDU and HCV were marginally stronger
albeit with wider confidence intervals, but the mutually adjusted HR were very similar
(Supplementary table 2).

Europe PMC Funders Author Manuscripts

Table 3 shows numbers of deaths from specific causes, and cause-specific mortality hazard
ratios for IDU and HCV. For most causes of death, mortality was higher in IDU compared
with non-IDU and in HCV+ compared with HCV. For both IDU and HCV, the strongest
associations were with liver-related mortality (adjusted HR 10.89; 95% CI 6.47,18.3 for
IDU and 14.0; 8.05,24.5 for HCV) and with violent death (7.53; 4.19,13.52 for IDU and
5.95; 3.39,10.44 for HCV). The HR for deaths due to substance abuse was 14.03 (5.41,
36.39) in HCV+ compared with HCV. For liver-related mortality, the effect of IDU was
substantially attenuated (HR 2.43) after adjustment for HCV, while attenuation of the effect
of HCV was less substantial (HR 7.97) after adjustment for IDU. By contrast, for CNS and
respiratory mortality attenuation in the effect of IDU was less marked than attenuation in the
effect of HCV. Rates of violent death also remained elevated in IDU after adjustment for
HCV. Supplementary table 3 provides additional information on mortality rates for specific
causes of death. Rates of all causes of death, except myocardial infarction and ischaemic
heart disease, were higher for HCV + than for HCV uninfected individuals.

Discussion
Main results
Based on a large dataset combined from 16 HIV cohort studies that recruited patients in
Europe and North America, we examined the extent to which presumed HIV transmission
via injection drug use, and HCV infection, independently predicted all-cause and causespecific mortality. The association of transmission via IDU with all-cause mortality was
attenuated after adjustment for HCV co-infection, but mortality remained more than 50%
higher in IDU than in non-IDU. Effects of both IDU and HCV were greater in patients under
45 years of age (considered more likely to be active IDU (18)) than in older individuals, but

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 7

patterns of attenuation were similar. Sensitivity analyses confirmed that error in measuring
both IDU and HCV status affects the extent of attenuation if there is greater measurement
error in one than the other risk factor. Analyses of cause-specific mortality confirmed that
HCV is a stronger predictor than IDU for liver-related mortality, but identified particular
causes of death for which associations with IDU are not explained by HCV.

Europe PMC Funders Author Manuscripts

Strengths and limitations

Europe PMC Funders Author Manuscripts

We analysed a large dataset with over 30,000 patients and over 1,000 deaths, of which 85%
had causes classified using standardised procedures. Our analysis may suffer from
ascertainment bias as individuals with HCV serostatus available were more likely to have an
injecting drug use history which may have prompted testing for HCV compared with those
excluded from the study. We did not know if IDU were chronic or past injection drug users,
as IDU status was based on self-reported likely transmission route of infection. It is likely
that some patients reporting no history of IDU were either past or current IDU, and this
possibility is consistent with our finding of a substantial prevalence of HCV among those
recorded as non-IDU: this underscores the importance of testing and treating HCV among
all individuals who are HIV-infected, particularly as incidence of HCV infection has been
reported to be increasing in men who have sex with men in some regions(19). Further work
is needed to investigate modes of HCV acquisition among HIV-positive individuals in order
to prevent re-infection after HCV treatment. We did not have information on HBV coinfection, which might differ between IDU and HCV+ and affect prognosis. Our information
on HCV infection was limited as we did not have data on active Hepatitis C viremia (20,
21). Previous research has shown that the presence of viremia increases mortality,
particularly that due to liver-related deaths. We did not have details of treatments for HCV
infection. However, during the calendar period included in our analyses, HCV treatment
rates among those with HIV infection were low (22, 23). We did not analyse longitudinal
HCV-RNA tests to see if patients had spontaneously cleared the virus or were successfully
treated. However, the proportion that spontaneously clears HCV infection is substantially
lower among HIV-infected than HIV-uninfected individuals (24-26). Furthermore, HIVinfected individuals with spontaneous control of HCV remain at significant risk for a second
episode of viremia (27). The results of the sensitivity analysis that attempted to quantify the
possible effects of misclassification bias showed that our conclusions about the relative
importance of HCV compared with IDU for predicting mortality were robust if both IDU
and HCV were equally misclassified, although hazard ratios for both risk factors may have
been under-estimated. However, if only IDU were misclassified then IDU and HCV might
have similar mutually adjusted mortality hazard ratios, which would imply that both factors
are equally important predictors of mortality. Our results were also robust to the exclusion of
the small proportion of patients with other/unknown transmission group, some of whom
may have been IDU misclassified as non-IDU in the main analysis.
Results in context with other studies
In our study, HIV-infected individuals with HCV co-infection experienced 2.5 fold greater
mortality rates than those without HCV co-infection. Most of this excess mortality was not
explained by other risks associated with IDU. Other studies have found that HCV causes
substantial morbidity from liver (28) and renal injury (29) as well as increases the risk of
J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 8

Europe PMC Funders Author Manuscripts

coronary disease (30) and diabetes (31). Our study confirmed higher rates of mortality in
HCV+ for liver-related deaths and also for AIDS and non-AIDS, non-liver related causes of
deaths. Although HCV status is likely associated with lifestyle factors, such as tobacco use,
which are associated with higher mortality rates, HCV infection may directly contribute to
non-liver related deaths via impaired immune responses to treatment for HIV infection (32).
HRs for IDU were greater in younger patients, suggesting that active injection drug use,
which is more likely at younger ages (18), has additional harms compared with historic use.
An alternative explanation is that differences in HR by age may be partly due to
diversification of causes of death in IDU at older ages, with increased risk of deaths due to
cardiovascular disease and cancer. However among older patients, for whom active injection
drug use is less likely, HCV co-infection remained strongly associated with mortality. There
may nonetheless be lifestyle factors that differ between those with and without HCV
infection, and are not captured by IDU status, for example risky sexual behaviour,
commercial sex work, or intranasal drug use, which may contribute to the higher mortality
in those with HCV infection.
Implications

Europe PMC Funders Author Manuscripts

While there is a growing consensus on the importance of treating HCV co-infection among
those living with HIV, many barriers remain. These include higher rates of contraindications
and concerns regarding decreased antiretroviral adherence and drug-drug interactions from
polypharmacy (33). Our analyses underscore the importance of overcoming these barriers if
we are to achieve better survival among those aging with HIV, many of whom no longer use
injection drugs but are continuing to suffer consequences of past use. New oral direct acting
antiviral protease inhibitor-based therapies have been shown to result in cure rates exceeding
65% and have shortened the period during which the poorly tolerated drug interferon has to
be used (34). Furthermore, interferon-free direct acting antiviral HCV treatment for HIVinfected individuals with markedly reduced toxicity, high efficacy (>90% cure), improved
dosing schedules (once or twice-daily) and shortened treatment duration (6-24 weeks) (15),
are quickly becoming more widely available. This revolution in treatment of HCV could
enable increased treatment uptake, not just amongst IDU, but also in the emerging MSM
epidemic, which could have a major preventative impact (35). However, treatment costs
may limit scale-up as new drugs are expensive.

Conclusions
HCV infection explained much of the association of IDU with mortality in a cross cohort
analysis of HIV-infected individuals initiating ART especially among those 45 years of age
and older who were considered less likely to be active IDU. This underscores the potential
of HCV treatment to impact mortality in this co-infected population, in addition to
interventions to stop substance abuse and address other lifestyle factors. Treatment for HCV
infection is now feasible in HIV-infected people with the advent of new therapies, which are
shorter, less toxic, and have higher cure rates. Future work will investigate the extent to
which treating HCV infection reduces mortality in this population and the causes of death
that are impacted.

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 9

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
Europe PMC Funders Author Manuscripts

We thank all patients, doctors, and study nurses associated with the participating cohort studies. Data from
European cohorts were pooled in July 2012 within COHERE in EuroCoord (www.cohere.org and
www.EuroCoord.net). COHERE receives funding from the European Union Seventh Framework Programme
(FP7/2007-2013) under EuroCoord grant agreement n 260694. Sources of funding of individual cohorts include
the Agence Nationale de Recherche sur le SIDA et les hpatites virales (ANRS), the Institut National de la Sant et
de la Recherche Mdicale (INSERM), the French, Italian and Spanish Ministries of Health, the Swiss National
Science Foundation (grant 33CS30_134277), the Ministry of Science and Innovation and the Spanish Network for
AIDS Research (RIS; ISCIII-RETIC RD06/006), the Stichting HIV Monitoring, the European Commission
(EuroCoord grant 260694), the British Columbia and Alberta Governments, the National Institutes of Health (NIH)
[UW Center for AIDS Research (CFAR) (NIH grant P30 AI027757), UAB CFAR (NIH grant P30-AI027767), The
Vanderbilt-Meharry CFAR (NIH grant P30 AI54999), National Institute on Alcohol Abuse and Alcoholism (U10AA13566, U24-AA020794), the US Department of Veterans Affairs, the Michael Smith Foundation for Health
Research, the Canadian Institutes of Health Research, the VHA Office of Research and Development and
unrestricted grants from Abbott, Gilead, Tibotec-Upjohn, ViiV Healthcare, MSD, GlaxoSmithKline, Pfizer, Bristol
Myers Squibb, Roche and Boehringer-Ingelheim.
Source of Funding: Colette Smith has received honoraria for preparing educational materials, attending Ad boards
or conference sponsorship from: Janssen, ViiV, Gilead and BMS. John Gill has been a member of the National HIV
Advisory Boards to Abbvie, Gilead, Janssen Merck and ViiVHealthcare.
This work was supported by the UK Medical Research Council [grant numbers G0700820, MR/J002380/1] and the
Department for International Development (DFID). Jonathan Sterne is funded by National Institute for Health
Research Senior Investigator award NF-SI-0611-10168.

References

Europe PMC Funders Author Manuscripts

1. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active
antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002; 360(9327):119
29. [PubMed: 12126821]
2. Larsen MV, Omland LH, Gerstoft J, et al. Impact of injecting drug use on mortality in Danish HIVinfected patients: a nation-wide population-based cohort study. Addiction. 2010; 105(3):52935.
[PubMed: 20402997]
3. Mathers BM, Degenhardt L, Bucello C, et al. Mortality among people who inject drugs: a
systematic review and meta-analysis. Bulletin of the World Health Organization. 2013; 91(2):102
23. [PubMed: 23554523]
4. Gill MJ, May MT, Lewden C, et al. Causes of death in HIV-1 infected patients treated with
antiretroviral therapy 1996-2006: collaborative analysis of 13 HIV cohorts. Clin Infect.Dis. 2010;
50(10):138796. [PubMed: 20380565]
5. Green TC, McGowan SK, Yokell MA, et al. HIV infection and risk of overdose: a systematic
review and meta-analysis. AIDS. 2012; 26(4):40317. [PubMed: 22112599]
6. Ferreros I, Lumbreras B, Hurtado I, et al. The shifting pattern of cause-specific mortality in a cohort
of human immunodeficiency virus-infected and non-infected injecting drug users. Addiction. 2008;
103(4):6519. [PubMed: 18339110]
7. Spire B, Lucas GM, Carrieri MP. Adherence to HIV treatment among IDUs and the role of opioid
substitution treatment (OST). International Journal of Drug Policy. 2007; 18(4):26270. [PubMed:
17689374]
8. Kohli R, Lo Y, Howard AA, et al. Mortality in an urban cohort of HIV-infected and at-risk drug
users in the era of highly active antiretroviral therapy. Clin Infect Dis. 2005; 41(6):86472.
[PubMed: 16107987]
9. Schiavini M, Angeli E, Mainini A, et al. Risk factors for fibrosis progression in HIV/HCV
coinfected patients from a retrospective analysis of liver biopsies in 1985-2002. HIV Medicine.
2006; 7(5):3317. [PubMed: 16945079]

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 10

Europe PMC Funders Author Manuscripts

Europe PMC Funders Author Manuscripts

10. Izzedine H, Sene D, Cacoub P, et al. Kidney diseases in HIV/HCV-co-infected patients. AIDS.
2009; 23(10):121926. [PubMed: 19440143]
11. Altice FL, Kamarulzaman A, Soriano VV, et al. Treatment of medical, psychiatric, and substanceuse comorbidities in people infected with HIV who use drugs. Lancet. 2010; 376(9738):36787.
[PubMed: 20650518]
12. Vickerman P, Hickman M, May M, et al. Can hepatitis C virus prevalence be used as a measure of
injection-related human immunodeficiency virus risk in populations of injecting drug users? An
ecological analysis. Addiction. 2010; 105(2):3118. [PubMed: 19922515]
13. Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in
people who inject drugs: results of systematic reviews. Lancet. 2011; 378(9791):57183.
[PubMed: 21802134]
14. Soriano V, Labarga P, Fernandez-Montero JV, et al. The changing face of hepatitis C in the new
era of direct-acting antivirals. Antiviral Res. 2013; 97(1):3640. [PubMed: 23147192]
15. Poordad F, Lawitz E, Kowdley KV, et al. Exploratory Study of Oral Combination Antiviral
Therapy for Hepatitis C. New England Journal of Medicine. 2013; 368(1):4553. [PubMed:
23281975]
16. Murray M, Hogg RS, Lima VD, et al. The effect of injecting drug use history on disease
progression and death among HIV-positive individuals initiating combination antiretroviral
therapy: collaborative cohort analysis. HIV.Med. 2012; 13(2):8997. [PubMed: 21819529]
17. May MT, Ingle SM, Costagliola D, Justice AC, de Wolf F, Cavassini M. Cohort profile:
Antiretroviral Therapy Cohort Collaboration (ART-CC). IJE. 2014; 43(3):691702. [PubMed:
23599235]
18. Green TC, Kershaw T, Lin HQ, et al. Patterns of drug use and abuse among aging adults with and
without HIV: A latent class analysis of a US Veteran cohort. Drug Alcohol Depend. 2010; 110(3):
20820. [PubMed: 20395074]
19. Wandeler G, Gsponer T, Bregenzer A, et al. Hepatitis C virus infections in the Swiss HIV Cohort
Study: a rapidly evolving epidemic. Clin Infect Dis. 2012; 55(10):140816. [PubMed: 22893583]
20. Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from
hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis.
2012; 206(4):46977. [PubMed: 22811301]
21. Uto H, Stuver SO, Hayashi K, et al. Increased rate of death related to presence of viremia among
hepatitis C virus antibody-positive subjects in a community-based cohort study. Hepatology. 2009;
50(2):3939. [PubMed: 19585614]
22. Butt AA, Justice AC, Skanderson M, et al. Rate and predictors of treatment prescription for
hepatitis C. Gut. 2007; 56(3):3859. [PubMed: 17005764]
23. Butt AA, McGinnis KA, Skanderson M, Justice AC. Hepatitis C treatment completion rates in
routine clinical care. Liver Int. 2010; 30(2):24050. [PubMed: 19889081]
24. Piasecki BA, Lewis JD, Reddy KR, et al. Influence of alcohol use, race, and viral coinfections on
spontaneous HCV clearance in a US veteran population. Hepatology. 2004; 40(4):8929.
[PubMed: 15382122]
25. Grebely J, Raffa JD, Lai C, et al. Factors associated with spontaneous clearance of hepatitis C virus
among illicit drug users. Canadian Journal of Gastroenterology. 2007; 21(7):44751. [PubMed:
17637948]
26. Schnuriger A, Dominguez S, Guiguet M, et al. Acute hepatitis C in HIV-infected patients: rare
spontaneous clearance correlates with weak memory CD4 T-cell responses to hepatitis C virus.
AIDS. 2009; 23(16):207989. [PubMed: 19710595]
27. Kim AY, Schulze zur Wiesch J, Kuntzen T, et al. Impaired hepatitis C virus-specific T cell
responses and recurrent hepatitis C virus in HIV coinfection. PLoS Med. 2006; 3(12):e492.
[PubMed: 17194190]
28. Hernando V, Perez-Cachafeiro S, Lewden C, et al. All-cause and liver-related mortality in HIV
positive subjects compared to the general population: differences by HCV co-infection. J Hepatol.
2012; 57(4):74351. [PubMed: 22709620]
29. Fischer MJ, Wyatt CM, Gordon K, et al. Hepatitis C and the risk of kidney disease and mortality in
veterans with HIV. J Acquir Immune Defic Syndr. 2010; 53(2):2226. [PubMed: 20104121]

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 11

Europe PMC Funders Author Manuscripts

30. Butt AA, Xiaoqiang W, Budoff M, et al. Hepatitis C virus infection and the risk of coronary
disease. Clin Infect Dis. 2009; 49(2):22532. [PubMed: 19508169]
31. Butt AA, Fultz SL, Kwoh CK, et al. Risk of diabetes in HIV infected veterans pre- and postHAART and the role of HCV coinfection. Hepatology. 2004; 40(1):1159. [PubMed: 15239093]
32. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery
during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss
HIV Cohort Study. Lancet. 2000; 356(9244):18005. [PubMed: 11117912]
33. Edelman E, Gordon K, Glover K, et al. The Next Therapeutic Challenge in HIV: Polypharmacy.
Drugs and aging. 2013; 30(8):16. [PubMed: 23740523]
34. Dore GJ. The changing therapeutic landscape for hepatitis C. Medical Journal of Australia. 2012;
196(10):62932. [PubMed: 22676877]
35. Martin N, Vickerman P, Grebely J, et al. HCV treatment for prevention among people who inject
drugs: modeling treatment scale-up in the age of direct-acting antivirals. Hepatology. 2013; 58(5):
1598609. [PubMed: 23553643]

Europe PMC Funders Author Manuscripts

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 12

Europe PMC Funders Author Manuscripts

Europe PMC Funders Author Manuscripts

Figure 1.

Kaplan-Meier estimate of survival probability by HCV status and IDU transmission group.

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

et al.

Page 13

Table 1

Patient demographics and clinical characteristics at start of ART by HCV status.

Europe PMC Funders Author Manuscripts

HCV uninfected N (%)

HCV infected N (%)

28073 (86%)

4630 (14%)

810 (3%)

306 (7%)

Male

18891 (67%)

3299 (71%)

<0.001

IDU

506 (2%)

2868 (62%)

<0.001
<0.001

Number of patients
Number of deaths

37 (31 - 45)

39 (34 - 44)

16-29

5811 (21%)

490 (11%)

30-39

10833 (39%)

1998 (43%)

40-49

7085 (25%)

1710 (37%)

50-59

3115 (11%)

323 (7%)

60

1229 (4%)

109 (2%)

Age (median (IQR)) years

P difference

6607 (24%)

998 (22%)

0.003

208 (93 - 312)

206 (101 314)

0.16

<50

4526 (16%)

666 (14%)

50-99

2782 (10%)

467 (10%)

100-199

6082 (22%)

1081 (23%)

200-349

9299 (33%)

1498 (32%)

AIDS before ART

CD4 (median (IQR)) cell/mm 3

350

5384 (19%)

918 (20%)

4.85 (4.12 5.36)

4.76 (3.89 5.27)

2000-2002

10827 (37%)

2100 (45%)

2003-2005

10344 (37%)

1585 (34%)

2006-2009

7442 (27%)

945 (20%)

HIV-RNA (median(IQR)) log copies/mL

<0.001
<0.001

Year of starting ART

Europe PMC Funders Author Manuscripts

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

Europe PMC Funders Author Manuscripts

223/3635

1.66

1.67

3.23

3.29

2.46

2.45

HR

(1.30, 2.11)

(1.22,2.27)

(2.74, 3.81)

(2.76, 3.92)

(2.15, 2.82)

(2.11,2.85)

95% CI

<0.001

0.001

<0.001

<0.001

<0.001

<0.001

1.91

1.76

3.18

3.13

2.65

2.71

HR

(1.50,2.43)

(1.29,2.39)

(2.69, 3.76)

(2.62, 3.74)

(2.31, 3.04)

(2.32,3.16)

95% CI

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

Controlling for age, sex, baseline

CD4, RNA and AIDS diagnosis

HCV + Hepatitis C infected; IDU assumed route of HIV transmission via injection drug use.

186/2825

83/995

HCV+

HCV+

46/549

IDU

IDU

462/8145

Age <45

654/24558

306/4630

HCV+

Age45

232/3374

1116/32703

IDU

All patients

Deaths/patients

Unadjusted

1.88

1.33

2.15

1.62

2.04

1.57

HR

(1.40, 2.54)

(0.91, 1.96)

(1.68, 2.76)

(1.24, 2.10)

(1.68, 2.47)

(1.27,1.94)

95% CI

<0.001

0.145

<0.001

<0.001

<0.001

<0.001

Additionally controlling for

IDU/HCV

Unadjusted and adjusted mortality hazard ratios for IDU (v. Non IDU) and HCV infected (v. HCV uninfected) up to three years after starting ART from
Cox models stratified by cohort: (i) all patients, (ii) patients aged <45, (iii) patients aged 45.

Europe PMC Funders Author Manuscripts

Table 2
et al.
Page 14

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.

Europe PMC Funders Author Manuscripts

22 (2.0)
10 (0.9)
12 (1.1)
52 (4.7)
16 (1.4)

MI/IHD

Stroke

Renal failure

Violence*

CNS (other than stroke)

16 (1.4)
48 (4.3)
191 (17.1)

Respiratory disease*

Other

Unknown*
3.91 (2.76,5.54)

2.38 (1.11,5.09)

5.55 (1.86,16.55)

3.08 (1.33,7.13)

6.02 (2.01,18.08)

7.53 (4.19,13.52)

2.71 (0.56,13.12)

1.74 (0.19,15.77)

1.50 (0.78,2.88)

10.89 (6.47,18.3)

3.18 (1.89,5.34)

1.40 (1.05,1.88)

2.71 (2.32,3.16)

2.45 (1.50,4.00)

1.27 (0.45,3.59)

4.64 (0.84,25.69)

1.38 (0.45,4.23)

5.35 (1.00,28.60)

3.65 (1.48,9.02)

1.59 (0.19,13.40)

0.71 (0.06,8.57)

0.72 (0.33,1.58)

2.43 (1.24,4.78)

1.86 (0.88,3.93)

1.01 (0.69,1.48)

1.57 (1.27,1.94)

additionally
adjusted for HCV

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2016 July 01.
3.19 (2.30,4.41)

2.54 (1.32,4.89)

3.56 (1.24,10.18)

3.31 (1.60,6.84)

3.45 (1.20,9.90)

5.95 (3.39,10.44)

2.52 (0.66,9.64)

1.90 (1.20,3.01)

2.21 (0.90,5.43)

1.26 (0.23,6.73)

2.78 (1.05,7.38)

1.16 (0.23,5.93)

2.52 (1.04,6.09)

1.97 (0.32,12.17)

3.15 (0.65,15.38)

0.91 (0.12,6.85)

2.58 (1.45,4.60)

7.97 (3.83,16.6)

1.99 (1.00,3.99)

1.54 (1.11,2.14)

2.04 (1.68,2.47)

Violence includes suicide, substance abuse; Respiratory includes chronic obstructive pulmonary disease (COPD); unknown includes unclassifiable.

Adjusted for age, sex, CD4 cell count, HIV-1 RNA and AIDS at baseline, stratified by cohort

0.48 (0.06,3.65)

2.22 (1.38,3.58)

14.0 (8.05,24.5)

2.92 (1.82,4.71)

1.55 (1.21,1.99)

2.65 (2.31,3.04)

additionally
adjusted for IDU

HR (95% CI)
HCV-infected v. HCV-uninfected

2.82 (0.69,11.53)

HCV+ Hepatitis C infected; IDU assumed route of HIV transmission via injection drug use.

MI Myocardial Infarction; IHD Ischaemic Heart Disease; CNS Central Nervous System

34 (3.1)

disease

Other heart/vascular

69 (6.2)
103 (9.2)

84 (7.5)

Non-AIDS infection

Non-AIDS malignancy

459 (41.1)

AIDS

Liver-related

1116 (100)

Number (%) of
deaths

All

Cause of death

HR (95% CI)
IDU v. Non IDU

Adjusted hazard ratio for specific causes of death for IDU compared with non-IDU and HCV-infected compared with HCV-uninfected

Europe PMC Funders Author Manuscripts

Table 3
et al.
Page 15