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Association of injection drug use with incidence of HIV-associated non-AIDS-related morbidity by age, 1995-2014 / IDU Increases Comorbidities Risk: DAAs May reduce ESRD & Comorbidities Risk
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" It is possible that new direct-acting antivirals for treatment of HCV [35] will reduce incidence of ESLD for both PWID and non-IDU in the future. However, IDU may be a barrier to HCV treatment"
Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV coinfected patients - (05/16/16)
active IDU associated with immune activation.....current IDUs are at even greater risk for immune activation & inflammation & onset for & perhaps early, accelerated & premature comorbidities
Understanding the Relative Contributions of IDU and HCV on Systemic Immune Activation...... .....HCV should be aggressively treated in current IDUs even more if HIV and/or HCV positive - (04/4/16)
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Association of injection drug use with incidence of HIV-associated non-AIDS-related morbidity by age, 1995-2014
"We estimated that IDU was associated with increased risk of ESRD. .....Our finding that IDU is associated with ESLD is not surprising, given high prevalence of HCV coinfection and alcohol consumption among PWIDs [33]. Furthermore, among those with HIV/HCV coinfection, IDU is associated with increased rate of HCV disease progression [34] and liver-related mortality. It is possible that new direct-acting antivirals for treatment of HCV [35] will reduce incidence of ESLD for both PWID and non-IDU in the future. However, IDU may be a barrier to HCV treatment [36] and it will be important to assess trends in HCV treatment and liver disease progression in this population.,,,,Cause-specific hazard for non-AIDS-defining cancer was lower among PWIDs than among non-IDU in this cohort. In the ART-CC, IDU was associated with higher hazard of non-AIDS-related cancer death [2]. Few studies of cancer incidence among HIV-infected persons have specifically stratified on IDU. Investigations into incidence of specific cancers and their association with IDU could provide insight into these results, but we did not have enough incident cancers to stratify cancers further.....Although we did not observe increased risk of cardiovascular events among IDUs, PWID had a higher crude cause-specific hazard of MI and stroke. There is other evidence that PWID have a higher cause-specific hazard of cardiovascular causes of death [2]. Both heroin and cocaine use are in Baltimore, and cocaine is associated with acute MI and stroke [37]. The lack of association between IDU and risk of cardiovascular events may be because of high prevalence of noninjection illicit drug use among the non-IDU in our cohort. However, it may also be the result of appropriately accounting for competing events."
"In this cohort, cause-specific mortality hazard was approximately 50% higher among PWIDs than among non-IDU. The hazard of ESLD and ESRD were higher among PWID, which led to a higher risk of ESLD and ESRD among PWID at nearly all ages, even though fewer PWID survived to be diagnosed with a HANA comorbidity. This association remained even after standardizing on baseline covariates and potentially differential loss-to-clinic. However, PWID did not have a higher risk of all HANA comorbidities. Although the cause-specific hazard ratio for stroke comparing PWID and non-IDU was suggestive of a strong association, risk of stroke was similar in PWID and non-IDU, and possibly lower among PWIDs until age 40. The cause-specific hazard and risk of MI and non-AIDS-defining cancers was lower among PWIDs compared with non-IDU, although associations failed to reach statistical significance."
from Jules: the rates of examined comorbidities in Table 1 are higher for PWIDs including cancers & heart disease as well end-stage renal & liver disease....although authors say:
"Because some persons reporting history of IDU subsequently ceased injecting drugs (and few if any persons with no history of IDU initiated injecting drugs) results probably underestimate the association between continuous IDU and HANA comorbidity and death.
......Risk of stroke, MI, and non-AIDS-defining cancer were not significantly different among PWIDs and non-IDUs, although risk of non-AIDS-defining cancers was slightly lower among PWIDs compared with non-IDUs (risk difference at age 55 years = -4.9%, 95% CI: -11.2, 1.3%). The most common non-AIDS-defining cancers among PWIDs were lung (19%) and liver (15%), compared with skin (12%), anal (11%), and lung (11%) among non-IDU.....In this cohort, cause-specific mortality hazard was approximately 50% higher among PWIDs than among non-IDU. The hazard of ESLD and ESRD were higher among PWID, which led to a higher risk of ESLD and ESRD among PWID at nearly all ages, even though fewer PWID survived to be diagnosed with a HANA comorbidity. This association remained even after standardizing on baseline covariates and potentially differential loss-to-clinic. However, PWID did not have a higher risk of all HANA comorbidities. Although the cause-specific hazard ratio for stroke comparing PWID and non-IDU was suggestive of a strong association, risk of stroke was similar in PWID and non-IDU, and possibly lower among PWIDs until age 40. The cause-specific hazard and risk of MI and non-AIDS-defining cancers was lower among PWIDs compared with non-IDU, although associations failed to reach statistical significance.
Furthermore, 'the' effect of IDU on HANA comorbidity risk likely varies according to type of drug injected, and frequency and duration of injection. Although we had some information on use of specific drugs from medical record review, we did not have information on frequency and duration of drug use over time. Furthermore, documentation of drug use in the medical record was likely differential according to history of IDU. If we had attempted to estimate an association between time-varying use of specific drugs and HANA, such an imperfect measure of 'exposure' could lead to biased results [31]. History of IDU may be a more discriminating indicator of future HANA comorbidity risk than time-varying injecting behavior, anyway, because of the long induction period for all HANA comorbidities we investigated. Despite not distinguishing the many specific effects of IDU in this study, we believe our results are useful to HIV providers who may know patients' history of IDU but who do not have time or resources to collect current injecting behavior."
![table2](../images/060816/table2.gif)
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Association of injection drug use with incidence of HIV-associated non-AIDS-related morbidity by age, 1995-2014
AIDS June 1 2016
Lesko, Catherine R.; Moore, Richard D.; Tong, Weiqun; Lau, Bryan
aDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Healthb School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Abstract
Objective: Incidence of HIV-associated non-AIDS (HANA) related comorbidities is increasing in HIV-infected individuals. Our objective was to estimate the risk of HANA comorbidity associated with history of injection drug use (IDU) correctly accounting for higher death rates among people who inject drugs (PWID).
Design: We followed HIV-infected persons aged 25-59 years who enrolled in the Johns Hopkins HIV Clinical Cohort between 1995 and May 2014, from enrollment until HANA comorbidity diagnosis, death, age 60, or administrative censoring.
Methods: We compared cumulative incidence ('risk'), by age, of validated diagnoses of HANA comorbidities among HIV-infected PWID and non-IDU; specifically, we considered end-stage renal disease (ESRD), end-stage liver disease (ESLD), myocardial infarction, stroke, and non-AIDS-defining cancer. We used competing risk methods appropriate to account for death, standardized to the marginal distribution of baseline covariates, and adjusted for potential differential loss-to-clinic.
Results: Of 5490 patients included in this analysis, 37% reported IDU as an HIV transmission risk. By age 55 years, PWID had higher risk of ESLD [risk difference = 6.8, 95% confidence interval (CI): -1.9, 15.5] and ESRD (risk difference = 11.1, 95% CI: 1.2, 21.0) than did non-IDU. Risk of myocardial infarction and stroke were similar among PWID and non-IDU. Risk of non-AIDS-defining cancer was lower among PWID than among non-IDU (risk difference at 55 years: -4.9, 95% CI: -11.2, 1.3).
Conclusion: Not all HANA comorbidities occur with higher incidence in PWID compared with non-IDU. However, higher incidence of ESRD and ESLD among PWIDs highlights the importance of recognition and management of markers of these comorbidities in early stages among PWID.
Introduction
AIDS-related comorbidity and mortality in the modern antiretroviral therapy (ART) era has declined rapidly and non-AIDS-related causes of morbidity and death represent an increasing share of the burden of disease among HIV-infected persons [1-4]. The apparent high incidence of HIV-associated non-AIDS (HANA) comorbidities in HIV-infected persons [3,4] is thought to be associated with persistent immunodeficiency, residual inflammation caused by HIV even among people with suppressed viral load [5], direct effects of antiretroviral drugs [6,7], and with lifestyle characteristics that are more prevalent in HIV-infected persons than among uninfected persons [8], including hepatitis C virus (HCV) infection, smoking, and alcohol use [9,10].
Since early in the epidemic in the United States, injection drug use (IDU) has been an important risk factor for HIV acquisition. IDU is associated with poorer HIV-related outcomes and faster progression of HIV disease and death [11]. Furthermore, compared with persons who do not inject drugs (non-IDU) persons who inject drugs (PWID) have a higher prevalence of many risk factors for HANA comorbidities, in particular HCV coinfection, smoking, and alcohol use. Thus, a history of IDU may be an important predictor for incident HANA comorbidity. Yet, to our knowledge, the cumulative incidence of HANA comorbidities among PWIDs has not been described.
Our goal was to describe the occurrence of major HANA comorbidities among PWID compared with non-IDU, using competing risk methodologies to appropriately account for differences in survival between the two groups. Because PWID experiences higher risk of death than non-IDU, standard Cox proportional hazards models for HANA events may lead to incorrect inferences regarding the risk of HANA events (see statistical methods for more details). Competing risk methods facilitate fuller description of the risk of HANA comorbidities among PWIDs compared with non-IDU individuals.
excerpts
PWID consistently had higher risk of death prior to any HANA comorbidity diagnosis than non-IDU at all ages (Fig. 1) For example, by age 55, risk of death prior to an ESLD diagnosis was 13.1% [95% confidence interval (CI): 6.5%, 19.6%] higher among PWIDs than among non-IDU (Table 1). Risk of death before any other HANA diagnosis was similar, although not identical; risk of death before HANA diagnosis was higher for HANA comorbidities that tended to occur at older ages (data not presented). Even given higher risk of death, after standardizing on baseline covariates and adjusting for loss-to-clinic, PWID had higher risk of ESLD and ESRD than did non-IDU (Fig. 1). The risk difference at age 55 for ESLD and ESRD was 6.8% (95% CI: -1.9, 15.5%) and 11.1% (95% CI: 1.2, 21.0%), respectively, comparing PWID to non-IDU. The magnitude of the risk difference for ESLD was driven in large part by one early ESLD case when there were few other PWID in the age risk set (see the large step in Fig. 1). Deleting the early ESLD case, brought the risk difference of ESLD at age 55 down slightly to 5.0% (95% CI: -3.2, 13.2%). Risk of stroke, MI, and non-AIDS-defining cancer were not significantly different among PWIDs and non-IDUs, although risk of non-AIDS-defining cancers was slightly lower among PWIDs compared with non-IDUs (risk difference at age 55 years = -4.9%, 95% CI: -11.2, 1.3%). The most common non-AIDS-defining cancers among PWIDs were lung (19%) and liver (15%), compared with skin (12%), anal (11%), and lung (11%) among non-IDU.
Discussion
In this cohort, cause-specific mortality hazard was approximately 50% higher among PWIDs than among non-IDU. The hazard of ESLD and ESRD were higher among PWID, which led to a higher risk of ESLD and ESRD among PWID at nearly all ages, even though fewer PWID survived to be diagnosed with a HANA comorbidity. This association remained even after standardizing on baseline covariates and potentially differential loss-to-clinic. However, PWID did not have a higher risk of all HANA comorbidities. Although the cause-specific hazard ratio for stroke comparing PWID and non-IDU was suggestive of a strong association, risk of stroke was similar in PWID and non-IDU, and possibly lower among PWIDs until age 40. The cause-specific hazard and risk of MI and non-AIDS-defining cancers was lower among PWIDs compared with non-IDU, although associations failed to reach statistical significance.
In this study, we examined risk of HANA comorbidities according to history of IDU. Our results should not be interpreted as the causal effect of continuous IDU. Because some persons reporting history of IDU subsequently ceased injecting drugs (and few if any persons with no history of IDU initiated injecting drugs) results probably underestimate the association between continuous IDU and HANA comorbidity and death. Furthermore, 'the' effect of IDU on HANA comorbidity risk likely varies according to type of drug injected, and frequency and duration of injection. Although we had some information on use of specific drugs from medical record review, we did not have information on frequency and duration of drug use over time. Furthermore, documentation of drug use in the medical record was likely differential according to history of IDU. If we had attempted to estimate an association between time-varying use of specific drugs and HANA, such an imperfect measure of 'exposure' could lead to biased results [31]. History of IDU may be a more discriminating indicator of future HANA comorbidity risk than time-varying injecting behavior, anyway, because of the long induction period for all HANA comorbidities we investigated. Despite not distinguishing the many specific effects of IDU in this study, we believe our results are useful to HIV providers who may know patients' history of IDU but who do not have time or resources to collect current injecting behavior.
We estimated that IDU was associated with increased risk of ESRD. IDU was previously noted as highly prevalent among persons diagnosed with HIV-1-associated nephropathy [32]. In contrast to our results, in the ART Cohort Collaboration (ART-CC), IDU was not associated with hazard of renal-related mortality [2]. The ART-CC examined non-AIDS-related causes of death and is one of the only other studies to report cumulative incidence functions, which appropriately account for competing events by not censoring individuals experiencing a competing event. However, the ART-CC examined causes of death, not incident diagnoses, and therefore, may have been underpowered to detect an association between IDU and renal-related morbidity. We analyzed validated clinical diagnoses of HANA comorbidities rather than causes of death, which increased power (because individuals could contribute events to more than one analysis), and was more sensitive for the outcome (because a HANA comorbidity did not have to cause death to be included). Our findings suggest that IDU should be considered an important risk factor for ESRD.
Our finding that IDU is associated with ESLD is not surprising, given high prevalence of HCV coinfection and alcohol consumption among PWIDs [33]. Furthermore, among those with HIV/HCV coinfection, IDU is associated with increased rate of HCV disease progression [34] and liver-related mortality [2]. An estimate of how much of the increased risk of ESLD among PWIDs is mediated by HCV coinfection would be particularly useful in light of new, highly effective direct-acting antiviral treatment regimens for HCV. It is possible that new direct-acting antivirals for treatment of HCV [35] will reduce incidence of ESLD for both PWID and non-IDU in the future. However, IDU may be a barrier to HCV treatment [36] and it will be important to assess trends in HCV treatment and liver disease progression in this population.
Cause-specific hazard for non-AIDS-defining cancer was lower among PWIDs than among non-IDU in this cohort. In the ART-CC, IDU was associated with higher hazard of non-AIDS-related cancer death [2]. Few studies of cancer incidence among HIV-infected persons have specifically stratified on IDU. Investigations into incidence of specific cancers and their association with IDU could provide insight into these results, but we did not have enough incident cancers to stratify cancers further.
Although we did not observe increased risk of cardiovascular events among IDUs, PWID had a higher crude cause-specific hazard of MI and stroke. There is other evidence that PWID have a higher cause-specific hazard of cardiovascular causes of death [2]. Both heroin and cocaine use are in Baltimore, and cocaine is associated with acute MI and stroke [37]. The lack of association between IDU and risk of cardiovascular events may be because of high prevalence of noninjection illicit drug use among the non-IDU in our cohort. However, it may also be the result of appropriately accounting for competing events.
Our analysis has several strengths, including, first, proper accounting for death as a competing risk. Most prior studies have not used competing risk methods, which may explain some of the disagreement in the literature as to the association between IDU and HANA comorbidities or non-AIDS-related causes of death [2,38]. Second, we used validated HANA comorbidity diagnoses, rather than relying on clinical diagnoses or cause-specific mortality. Third, we allowed individuals to contribute diagnoses to more than one HANA analysis. Because older HIV-infected patients often have multimorbidity [39] this increased our power. Indeed, 49 individuals in our cohort had more than one HANA comorbidity diagnosis. Finally, by presenting cumulative incidence curves (Fig. 1) we have increased the interpretability of our results. Because not everyone enters the cohort at age 25 (i.e. we have late entries), one limitation of our analysis is that we must assume that HANA comorbidity incidence among younger PWIDs is a good substitute for the HANA incidence among older PWIDs, had we been able to observe them when they were younger. If older and younger PWID who entered our cohort were not comparable, we may have over (or under) estimated the risk of HANA comorbidities (Table 3).
In conclusion, the increased risk of ESRD and ESLD among HIV-infected PWIDs should be recognized and monitored. It will be particularly important to understand the mediating effect of HCV infection on this increased risk in light of the new treatments for HCV. Notably, we did not find evidence of an association between IDU and risk of stroke or MI, although the cause-specific hazard of stroke was slightly elevated among PWIDs. Finally, the risk of non-AIDS-defining cancers was actually lower among PWIDs than among non-IDU. PWID in our cohort have higher mortality rates than non-IDU and it will be important to understand the reasons for these higher rates. Our analysis indicates that to date, after for death as a competing event, PWID are not at increased risk compared with non-IDU for several HANA comorbidities that have become of increasing concern as HIV-infected persons survive longer.
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