Effects of combination antiretroviral therapies on the risk of myocardial infarction among HIV patients

Abstract

Background: Cohort studies have demonstrated greater risk of myocardial infarction (MI) associated with specific antiretroviral use, while meta-analyses of randomized controlled trials (RCTs) have not. These differences may be due to inherent biases in the observational study design or to the limited duration of randomized trials. We conducted a new-user, active-comparator cohort study emulating an RCT comparing the initiation of several antiretrovirals as part of combination antiretroviral therapy (cART) and MI.

Methods: We included North Carolina (NC) Medicaid beneficiaries infected with human immunodeficiency virus between 2002 and 2008 who were previously untreated with cART. We compared hazard ratios (HRs) and 95% confidence intervals (CIs) of MI between abacavir and tenofovir recipients, and lopinavir-ritonavir or atazanavir recipients and nonnucleoside reverse transcriptase inhibitor (NNRTI) recipients. We adjusted for confounding through inverse probability weighting methods.

Results: There were 3481 NC Medicaid new cART recipients who contributed 6399 person-years and experienced 38 MI events. Receiving abacavir compared with tenofovir as part of cART was associated with an increased rate of MI (unadjusted HR = 2.70 [95% CI = 1.24-5.91]; adjusted HR = 2.05 [0.72-5.86]). Point estimates also suggest a relationship between receipt of atazanavir or lopinavir-ritonavir compared with an NNRTI and MI, although estimates were imprecise.

Conclusions: We found an increased rate of MI among patients initiating abacavir compared with tenofovir, although the association was decreased after confounding adjustment. Without a very large prospective comparative clinical trial, a much larger observational study of patients initiating cART would be needed to better define this apparent association.

Figure 1

Strength of an unmeasured clinical factor needed to eliminate observed relationship between initiation of cART containing abacavir vs. cART containing tenofovir.

Figure 1

Active-comparator, new-user study design. HIV-positive patients who were initiators of combination antiretroviral therapy (cART) in the North Carolina Medicaid program between 2002 and 2008. A.) Comparisons of the nucleoside reverse transcriptase inhibitors abacavir and tenofovir with any anchor antiretroviral plus lamivudine/emtricitabine (standard of care; Group 1). B.) Comparisons of specific anchor antiretrovirals (the protease inhibitors atazanavir [Group 1] or lopinavir-ritonavir [Group 2] vs. any non-nucleoside reverse transcriptase inhibitor) plus lamivudine/emtricitabine and any nucleoside reverse transcriptase inhibitor.

Figure 1

Active-comparator, new-user study design. HIV-positive patients who were initiators of combination antiretroviral therapy (cART) in the North Carolina Medicaid program between 2002 and 2008. A.) Comparisons of the nucleoside reverse transcriptase inhibitors abacavir and tenofovir with any anchor antiretroviral plus lamivudine/emtricitabine (standard of care; Group 1). B.) Comparisons of specific anchor antiretrovirals (the protease inhibitors atazanavir [Group 1] or lopinavir-ritonavir [Group 2] vs. any non-nucleoside reverse transcriptase inhibitor) plus lamivudine/emtricitabine and any nucleoside reverse transcriptase inhibitor.

Figure 2

Assembly of the combination antiretroviral therapy initiator cohort.

Figure 3

Inverse probability weighted Kaplan-Meier curves for the time to a myocardial infarction event among HIV-positive persons (identified by ICD-9 code and antiretroviral use in administrative claim) initiating nucleoside reverse transcriptase inhibitors as part of a new combination antiretroviral therapy (cART) regimen. Abacavir compared with tenofovir.

Figures 4a and b

Inverse probability weighted Kaplan-Meier curves for the time to myocardial infarction event among HIV-positive persons (identified by ICD-9 code and antiretroviral use in administrative claim) initiating protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI) A. atazanavir alone or in combination with ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) B. lopinavir-ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine). Note: axes focused on 90% to 100% surviving.

Figures 4a and b

Inverse probability weighted Kaplan-Meier curves for the time to myocardial infarction event among HIV-positive persons (identified by ICD-9 code and antiretroviral use in administrative claim) initiating protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI) A. atazanavir alone or in combination with ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) B. lopinavir-ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine). Note: axes focused on 90% to 100% surviving.

Figures 5a, 5b, and 5c

Kaplan-Meier curves for the time to treatment switch or discontinuation among HIV-positive persons (identified by ICD-9 code and antiretroviral use in administrative claim) initiating combination antiretroviral therapy. A. Abacavir compared with tenofovir B. atazanavir alone or in combination with ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) C. lopinavir-ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine). Note: different time scale for part B. compared with parts A. and C.

Figures 5a, 5b, and 5c

Kaplan-Meier curves for the time to treatment switch or discontinuation among HIV-positive persons (identified by ICD-9 code and antiretroviral use in administrative claim) initiating combination antiretroviral therapy. A. Abacavir compared with tenofovir B. atazanavir alone or in combination with ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) C. lopinavir-ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine). Note: different time scale for part B. compared with parts A. and C.

Figures 5a, 5b, and 5c

Kaplan-Meier curves for the time to treatment switch or discontinuation among HIV-positive persons (identified by ICD-9 code and antiretroviral use in administrative claim) initiating combination antiretroviral therapy. A. Abacavir compared with tenofovir B. atazanavir alone or in combination with ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) C. lopinavir-ritonavir compared with non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine). Note: different time scale for part B. compared with parts A. and C.