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  Conference on Retroviruses
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Boston, Massachusetts
March 4-7, 2018
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Recent abacavir use increases risk for Types 1 and 2 myocardial infarctions among adults with HIV
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from Jules: although reading through this I am not sure if they adjusted for history of IDU or cocaine use in the T2MI group. I'm also not sure you can adjust yourself out of potential confounders, they say this in the Discussion. I think its just difficult to analyze very well if there is a risk because of all the confounders which I think are just very difficult to completely adjust for, like drug use history.
"We acknowledge that as an observational study lacking a randomized assignment of ABC, confounding is still possible and many variables exist that could potentially be predictive not only of MI occurrence but also of the prescribing of ABC. Our methods adjusted for kidney function, which is associated with ABC and TDF prescription, and also for T1MI risk factors such as diabetes, proatherogenic hyperlipidemia, hypertension and smoking which may also impact the prescribing of ABC"
Elion, Richard A1,2; Althoff, Keri N3; Zhang, Jinbing3; Moore, Richard D4; Gange, Stephen J3; Kitahata, Mari M5; Crane, Heidi M5; Drozd, Daniel R5; Stein, James H6; Klein, Marina B7,8; Eron, Joseph J9; Silverberg, Michael J10; Mathews, William C11; Justice, Amy C12; Sterling, Timothy R13; Rabkin, Charles S14; Mayor, Angel M15; Klein, Daniel B16; Horberg, Michael A.17; Bosch, Ronald J18; Eyawo, Oghenowede19; Palella, Frank J Jr20for the North American AIDS Cohort Collaboration on Research and Design of IeDEA JAIDS Journal of Acquired Immune Deficiency Syndromes: Feb 6 2018 Ahead of Print
Background: There is persistent confusion as to whether abacavir (ABC) increases the risk for myocardial infarction (MI), and whether such risk differs by Type 1 (T1MI) or 2 (T2MI) MI in adults with HIV.
Methods: Incident MIs in NA-ACCORD participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude (HR) and adjusted hazard ratios (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham Risk Score (FRS) modified the effect of ABC on MI occurrence. Results: 8,265 adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI, 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4, 5.1) years. ABC initiators were more likely to have a history of IDU, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm3) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the prior 6 months (aHR=1.84 [1.17, 2.91]; and persisted for T1MI (aHR=1.62 [1.01,]) and T2MI (aHR=2.11 [1.08, 4.29]). FRS did not modify the effect of ABC on MI (p=0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome.
Conclusions: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk for ABC use-associated MIs.
Aging adults with HIV are at increased risk for myocardial infarction (MI)
compared to otherwise similar adults without HIV.[1, 2] This increased risk is likely the result of an amalgam of simultaneously occurring factors, including: 1) increased prevalence of traditional MI risk factors among adults with HIV;[3-6] 2) HIV-associated immune activation and dysregulation, excess inflammation and hypercoagulation[7, 8] that is blunted but not normalized with antiretroviral (ART)-induced virologic suppression and;[7, 9, 10] 3) possibly the use of specific ART drugs.[4, 11, 12]
There have been conflicting reports linking increased risks of MI and use of nucleoside reverse transcriptase inhibitor (NRTI) agents, with considerable attention focused on abacavir (ABC). Initial reports came from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D cohort); D:A:D remains the largest cohort in which this relationship has been examined systematically to date. Their analysis included 25,000 adults with HIV followed prospectively for at least 10 years and demonstrated a nearly two-fold risk of MI incidence associated with recent ABC exposure (with the prior 6 months), though more remote or cumulative ABC exposures were not associated[13]
Other observational studies have corroborated these findings[14-17]. The French Hospital Database on HIV[18] initially reported findings similar to those of D:A:D regarding recent ABC use and MI risk (OR=2.01, 95% CI 1.11-3.64) but this association did not remain significant after accounting for cocaine or intravenous drug use.[18]
Other cohorts have failed to identify such an association[19] The U.S. Food and Drug Administration (FDA) undertook a meta-analysis, including participants in randomized controlled trials, and found no increased risk of cardiovascular disease associated with ABC use.[20] However, of the 26 studies included in this analysis, only 5 reported a mean follow-up time >2 years and none reported a follow-up time of >5 years.[20] Reports from cohorts that have not demonstrated an ABC/MI association have differed widely in analytic methodology and clinical definitions used.
Tenofovir dioproxil fumarate (TDF) has been used more commonly in combination ART regimens than ABC since both became available, and ABC use has been more common among persons for whom TDF use was contraindicated, particularly because of renal impairment (calculated GFR<60 ml/min). Since renal insufficiency is an independent risk for MI, selection of ABC for use among persons with kidney disease may represent a channeling bias enriching the population of ABC users with persons who have higher MI risk compared to non-users; such bias may have influenced ABC use from 2008-onward[13, 21,22] in individuals with known cardiovascular disease (CVD) risk factors. Further, given the links between protease inhibitor use and dyslipidemia (which may increase the risk of MI), as well as the link between delayed antiretroviral therapy initiation and low CD4 counts (which have also been linked with MIs),[23] time-dependent confounding of the ABC and MI relationship is possible.
The objective of the current analysis was to determine the effect of recent ABC use on the risk of MIs overall and stratified as either a type1 MI type (T1MI) or type 2 MI (T2MI). We utilized data from the North American Cohort Collaboration on Research and Design (NA-ACCORD) and analytical methods that attempted to account for potential channeling bias and time dependent confounding of the ABC and MI relationship.
A total of 8,265 adults contributed 29,077 person years and 123 events (65 T1MI, 58 T2MI). Median follow-up time was 2.9 (interquartile range [IQR] 1.4, 5.1) years. Median follow up time was similar in ABC initiators (3.0 [IQR 1.4, 5.5] years) compared with persons who initiated other ART regimens (median= 2.9 [1.5, 5.1], p=0.27). Compared to persons who did not initiate ABC, ABC initiators were more likely to be older, female, Black, have a history of IDU and heterosexual HIV transmission risk, have HCV infection, treated hypertension, diabetes, impaired kidney function, elevated total cholesterol, elevated triglycerides, low (<200 cells/mm3) CD4 count, and a history of clinical AIDS diagnosis at study entry (Table 1). There was a decrease in ABC use (defined as ≥1 month of ABC use) from a peak of 39% of participants in 2002 to a low of 9% in 2013 (Supplement Figure 3).
The primary analysis of the combined MI outcome showed an increased risk among persons who had used ABC in the prior 6 months (p<0.0001); this difference persisted when stratifying the outcome by MI type (T1MI p<0.0001, T2MI p<0.0001, Figure 1). The proportion of MI events that were type 1 or type 2 did not vary significantly by calendar period.
After accounting for potential channeling biases and time-varying confounding in the MSM approach, persons with recent ABC exposure had an 84% increase in MI risk compared to those without recent ABC exposure (aHR=1.84 [1.17, 2.91], Table 2). Stratifying by MI type (T1MI or T2MI),[22] there was a 62% increase in the risk of T1MI with recent ABC (aHR=1.62 [1.01, 2.94]); the risk of T2MI was 2-fold with recent ABC use (aHR=2.11 [1.08, 4.29]).
To address the a priori hypothesis that cardiovascular disease risk modified the effect of ABC on MI occurrence, FRS at study entry were estimated for participants. Cumulative incidence of combined MI was highest among persons with the highest FRS (Figure 2). Stratification by MI type demonstrated that the ABC use/MI relationship persisted with T1MI, as expected, and also with T2MI. There was no statistical evidence that FRS modified the effect of ABC on the risk of combined MI (p-value of interaction=0.14). To further adjust for any differences by cardiovascular disease risk, we included FRS in the MSM approach after excluding those variables already included in the FRS; the effect of recent ABC use on combined MI remained similar (aHR=1.88 [1.20, 2.95], Supplement Table 2). In the analysis restricted to ART naïve persons who were observed to initiate ART, channeling biases that may have existed among persons with greater risk factors for T1MI were not taken into account; in this analysis, there was a 75% increase in the risk of combined MI with recent ABC use (aHR=1.76 [1.15, 2.68], Supplementary Table 3).
The results of the replicated D:A:D approach in the NA-ACCORD (aHR=1.63 [1.21, 2.18]) were remarkably similar to the D:A:D's findings (aHR=1.70 [1.17, 2.47], Supplementary Table 4). The point estimates for the relationship of ABC and MI from the main analysis, sub-group analyses, sensitivity analyses, and the D:A:D replication and original studies can be visually compared in Figure 3.
In this large, demographically diverse cohort of adults with HIV in care, we identified an increased risk of MI
associated with recent use of ABC (vs. use of ART not including ABC). This association was apparent regardless of MI type, both T1MI and T2MI. While ABC recipients were enriched for traditional risk factors for T1MI (compared to non-ABC recipients) including kidney disease, our methods accounting for channeling biases and time-dependent confounding adjusted for this potential bias. In models that included a priori stratification for FRS or specific adjustment for FRS, we observed no attenuation of the magnitude of the association between recent ABC use with MI occurrence.
Further, we were able to evaluate whether differential associations between ABC use by MI type existed. This is particularly relevant because recent work from our group has demonstrated that 45% of MIs occurring among adults with HIV are T2MI.[1] While we found that recent ABC use was associated with MI occurrence regardless of type, the magnitude of the association may be higher in T2MI. In several studies, increased MI risk has been associated with recent ABC use (within approximately 6 months of last use), implying that the pro-MI effects diminish within 6 months of ABC discontinuation. Our study purposely focused on recent and early (part of first ART regimen received) ABC exposure, with the advantage of using adjudicated MIs, a design that mimicked a clinical trial of ART initiation and included both T1 and T2MI. However, some studies have also suggested that cumulative exposure to ABC beyond 6 months may further increase MI risk,[32,33] possibly out to 24-36 months of exposure. Precise mechanisms by which ABC exposure increases the risk of MI are not currently clear. Our current understanding of potential pathophysiologic mechanisms by which ABC use may contribute to MI risk include promotion of enhanced platelet activation, aggregation and increased adhesion to vascular endothelial cells (and consequent promotion of thrombus formation) via interference with processing of purinergic mediators, resulting in an overall ABC effect that appears to involve endothelial activation.[34] While prothrombotic states probably exist for both T1MI and T2MI, ABC's effect feasibly could create an enhanced vulnerability to MI that is distinct from, but possibly additive to, MI risk from pre-existing coronary atherosclerosis or systemic inflammation or immune dysregulation. Such an effect could manifest early during ABC exposure but feasibly could also be an ongoing effect that is cumulative in nature.
While exact mechanism(s) by which ABC exerts pro-MI effects remain speculative, our results suggest that clinical screening practices for MI risk among adults with HIV focused only on more traditional T1MI risks may be insufficient. As many as 50% of the T2MIs in NA-ACCORD are related to sepsis, cocaine use or "other illicit drug-induced vasospasm[26,31], and in the current analysis we found an adjusted HR of 1.76 among IDU for T2MI. Such findings are consistent with observations from the French Hospital Database on HIV, which reported that, after adjustment for cocaine or recreational intravenous drug use, an association between recent ABC use and MI was not apparent[18]. In addition, recent work[35] demonstrated a prominent association of cocaine use with the development of MIs among adults with HIV, prompting the suggestion that treating cocaine addiction may comprise an important adjunctive measure in MI prevention for this patient group.
Our analysis identified other risk factors for T2MI, including Black race, hypertension and diabetes, traditional risk factors for T1MI, as well as a CD4 < 200 cells/mm3. It is important to note that our analysis was not focused on describing the mechanism of any ART-related causations of MI, but rather isolating the effect of recent ABC use on MI risk in the context of channeling bias and time dependent confounding. After adjusting for other factors in the model, these variables continued to be independently associated with T2MI. The identification of the prominence of T2MIs among persons living with HIV, as described by Drozd et al. (1), and our current finding of an independent association between recent ABC use and MI (both T2MI and T1MI) broaden our understanding the spectrum of potential etiologies of MIs in this population. Potential interactions between lifestyle related factors, genetics, inflammation, various causes of hypoxemia, as well as exposures to specific ARV drugs, may help to expand our understanding of the diverse etiologic factors contributing to MI among persons living with HIV.
The NA-ACCORD differs from randomized interventional ART trials from which some ABC and MI data have been analyzed previously (such as those included in the FDA meta-analysis)[20] because the NA-ACCORD analysis reflects data involving ABC utilization in clinical practice, including among adults at diverse stages of HIV disease with various types of MI risk factor profiles, and involved much longer follow-up. Our present study also represents an important improvement in verification of clinical MI events. Classification of MIs included source medical record review, standardized MI criteria and central adjudication by experts, included assignation into T1MI or T2MI categories. No MIs were included that were based only on participant self-report or on clinical ICD codes alone. Uniquely, there were a sufficient number of adults with available data from the time of ART initiation while observed in the NA-ACCORD, analysis of whom not only avoided potential analytic biases associated with prevalent ART use[36] but also enabled the use of MSM approaches that seek to overcome analytic challenges involving time-dependent confounding. The D:A:D investigators were conscientious of excluding potential mediators from the analysis[22],but in doing so, questions were raised as to whether the findings would be corroborated with alternative approaches. We note that an earlier analysis from the NA-ACCORD showed a weaker, though qualitatively similar, adjusted association between ABC exposure and MI.[37] Unlike the prior analysis, the current analysis limited the study sample to patients who were observed to initiate ART to better mimic a clinical trial. We were also able to add more recently adjudicated MIs to the sample, although the selection criteria necessary for the our approach restricted the sample and associated number of MI events in comparison with another previous NA-ACCORD study (Supplement Figure 1).[1]
We acknowledge that as an observational study lacking a randomized assignment of ABC, confounding is still possible and many variables exist that could potentially be predictive not only of MI occurrence but also of the prescribing of ABC. Our methods adjusted for kidney function, which is associated with ABC and TDF prescription, and also for T1MI risk factors such as diabetes, proatherogenic hyperlipidemia, hypertension and smoking which may also impact the prescribing of ABC. To date, we are not aware of evidence that risk factors for T2MI (sepsis, cardiac arrhythmia, recreational drug use, anemia, an impaired functional level, female sex) are associated with ABC and TDF prescribing and there is no apparent reason to suspect that ABC recipients would be enriched in T2MI risks compared to non-ABC (largely TDF) users. It should also be noted that it is possible that reverse channeling bias (i.e. the avoidance of ABC use among persons with traditional CAD risk factors) may have existed in the prescription of ABC after initial reports of its association with increased MI risk. If such a phenomenon existed it may or may not have attenuated apparent associations between recent ABC use and MI occurrence. [1] We further acknowledge that even with the large overall sample size, the number of MIs was limited and power to detect statistical evidence that FRS modified the effect of ABC on MI was limited.
In summary, in this large, diverse, North American cohort of adults with HIV in clinical care, we found that recent (within six months) ABC use significantly increased the risk of MI, both for T1 and T2 MI events. These associations persisted after adjusting for known MI risks, including kidney disease and for FRS. Our MI ascertainment and adjudication procedures were detailed, precise and involved central standardized adjudication by experts. Despite limitations, we believe that we have undertaken the most rigorous analysis possible within the limitations of our dataset, using a study population and analytic methods that better address concerns raised from previous reports evaluating ABC use and MI risk. Our findings imply that analyses seeking to ascertain factors associated with MI among adults with HIV should include routine stratification by MI type. Clinicians may struggle to identify appropriate patients for ABC therapy, integrating known risk factors for T1 MI and the less well-defined risks for T2 MI. Our evolving understanding of the prominence of T2MI among adults with HIV makes patient selection for ABC use more challenging. Future work may focus on identifying the best subset of patients who can benefit from ABC with the least amount of risk.