Association between exposure to Efavirenz and substrates of dysrhythmia in HIV‐infected young adults

Abstract Background Dysrhythmia and sudden cardiac arrest occur more likely in HIV patients than healthy subjects. Thus, we need to examine dysrhythmias adverse effects of medications including Efavirenz as early as possible especially in young subjects. Hypothesis Efavirenz might have contributed to increased risk of developing common types of dysrhythmia in young HIV infected patients. Methods We performed a retrospective cohort study among 62 patients on Efavirenz and 38 controls. All participants were under 40 years old without cardiovascular disease. Total significant dysrhythmia in 24‐hour ECG monitoring was the primary endpoint determined as the composite of high premature ventricular contraction (PVC) (>500 beats per 24 hours), high premature atrial contraction (PAC) (>500 bp24h), sinus pause, atrioventricular blocks, ventricular tachycardia, prolonged QTc, and low heart rate variability (HRV). Modified composite dysrhythmia consisted of low HRV (SD of normal‐to‐normal [SDNN]), high PVC and prolonged QT. Results Mean heart rate, Efavirenz regimen, male gender, and CD4 count predicted total dysrhythmia. Odds ratios were 1.108, 2.90, 4.36, and 0.96, respectively. The incidence of total dysrhythmia, high PVC, high PAC, low HRV(SDNN), and prolonged QTc were 54.8%, 41.85%, 9.71%, 45.2%, and 12.9% in patients on Efavirenz against 42.11%, 31.64%, 0%, 34.2%, and 7.91% in controls, respectively (p‐values: .031, .001, <.0001, .063, and .043 respectively). Modified composite dysrhythmia was also more frequent in Efavirenz group than that of control group (69.42% vs. 52.60%, respectively p = .032). Conclusions We found that patients with Efavirenz had higher prevalence of frequent PVC, frequent PAC, total significant dysrhythmia, Low HRV and prolonged QTc than controls.

An optimal therapeutic protocol usually consists of two NRTIs combined with one drug from the remaining categories. 4,5 Efavirenz is still one the most commonly used NNRTIs suggested as a first-line option. 4 There is a wide variety of cardiovascular potential adverse effects related to ART medications. 6 However, evidence about increased cardiovascular events or dysrhythmia in patients receiving NNRTIs especially Efavirenz is not enough. 7,8 Meanwhile we do not have sufficient publications about different types and mechanisms of dysrhythmia in those under Efavirenz treatment. Thus, as a first step we need to evaluate surrogate outcomes such as prolonged QT, which may be precursors of dysrhythmic events. Sudden cardiac death in HIV-infected patients is linked to previous myocardial infarction, cardiomyopathy, dysrhythmia, and structural heart disease.
Of these etiologies, dysrhythmias particularly ventricular tachycardia, may lead to sudden cardiac death in those without evident cardiovascular disease. 3,9 This study investigates all electrocardiographic features attributable to regimens with and without Efavirenz in patients with no apparent prior cardiovascular disease.  center. Viral load (as copy numbers) and CD4 counts are markers that help to evaluate the efficacy of treatment and to adjust for the effect of the disease phase. All patients underwent echocardiographic evaluation at baseline and after Holter-monitoring in order to detect any considerable structural heart disease.

| Definitions
Primary endpoint of the study was total significant dysrhythmia. It was defined as a composite of frequent premature ventricular contraction (PVC) (>500 bp24h), high premature atrial contraction (PAC) burden (>500 bp24h), sinus arrest, atrioventricular blocks, ventricular and supraventricular tachycardia, prolonged QTc, and low heart rate variability (HRV) (low SD of the average normal-to-normal [SDANN]). In addition, we defined another modified composite endpoint which consisted of low SD of normal-to-normal (SDNN), prolonged QT, and frequent PVC. These components seem to have greater clinical relevance with Efavirenz. High burden of ectopic beats (>500 bp24h) was determined according to prior studies. 10 We. Decreased adjusted HRV was determined as SDNN under 50 ms or SDANN values below the fifth percentile. 11

| RESULTS
The mean age of the patients was 34.22 ± 5.11 years and the median treatment length (follow-up) was 6.31 years. Sixty-two participants were on treatment with Efavirenz-containing regimens and 38 subjects received non-Efavirenz regimens. Table 1  Ejection fractions were identical on follow-up (median values were 55 for both groups with a p-value of .85). Table 2 shows the significance of different predictors of the composite endpoint, that is, total significant dysrhythmia, regarding multiple adjustments, which resulted in two models. Table 3 presents the cumulative prevalence of primary and secondary endpoints according to subgroups of gender and treatment duration. There were two cases with uncommon dysrhythmias, which were found incidentally. One had asymptomatic intermittent manifestation of a delta wave. The other patient had prominent alterations in the amplitude and direction of T waves known as T-wave alternans. No episodes of sustained or nonsustained VT occurred, not even in the subgroup of patients with prolonged QT intervals. Prolonged QT interval was more frequent in patients who did not use PIs although the difference was not significant (10% vs. 6.2%, p = .24). Treatment with PIs tended to be associated with fewer events of total dysrhythmia (54% vs. 42%, p = .065). Table 4 presents univariate and multivariate analysis pertaining to the predictors of modified composite endpoint. Furthermore, Figure 1 illustrates the differences between the two composite endpoints according to observed frequencies in subgroups. Nevertheless, most studies such as the one by Charbit et al., found that prolonged QT is associated with conventional factors as well as chronicity of HIV infection rather than with ART drugs. 20 We found that Efavirenz regimen increased the length of corrected QT interval overall and in males while females were not affected. Indeed, male subjects on Efavirenz were more likely to have prolonged QT (9.80% vs. 0%) as compared to non-Efavirenz men. Impact of Efavirenz on QT is not well established. Few studies have noticed about that Efavirenz might prolong QT interval, which is in line with our results. 21 Conversely, prolonged QTc was more frequent in females than in males irrespective of Efavirenz use. Different regulation of potassium channels called Ikr (rapidly activating delayed rectifier) is well established in women compared with men. This is concordant with many reports such as the study by Hreiche and co-workers. 22 The pathophysiology underlying QT prolongation by ART drugs is not well understood. However, decreased outward potassium, currents over the second phase of action potential has been proposed.

| DISCUSSION
Low expression of the human Ether-a'-go-go related gene (HERG) might control these potassium-rectifier channels which leads to extended repolarization. 23 Then, prolonged QTc may serve as a preliminary state to trigger premature ventricular beats (PVB) as well as ventricular tachyarrhythmia (VT). 24 Regarding vulnerable genotypes, studies have shown that risk of Efavirenz -mediated long QT markedly increased in homozygous carriers of the CYP2B6*6 allele. 9,18 In addi- General metabolic disturbance either due to HIV infection or to medications may contribute to low parasympathetic activity and low SDANN. 26 Moreover, lipodystrophy occurs commonly in patients receiving Efavirenz. 27 Some researchers declared that hypercholesterolemia, and hyperglycaemia diminish the HRV regardless of the duration of ART, which is discordant with our findings. 28 In fact, we observed greater prevalence of low HRV (SDNN) and prolonged QT in Efavirenz patients (against non-Efavirenz group) who were treated for more than 5 years. Their controlled trial found improvement of maximal volume of oxygen uptake (VO2max) and incremental values of HRV after 16 weeks. 30 Recent studies have shown an inverse relationship between biomarkers of inflammation such as IL-6, CRP, and tumor necrosis factor, and HRV. 31 Similar associations have been shown for the coagulation cascade factors like D-dimer in HIV patients. 32,33 In the present study, Efavirenz affected male subjects more than females. In fact, total significant dysrhythmia and most of the components except AV block and sinus pause were more frequent in males A greater PAC burden (>500 bp24h) was found in male HIV-AIDS patients who received Efavirenz-containing regimens. This finding was not mentioned in any of the prior studies, which evaluated ARTassociated dysrhythmia. We did not detect any cases with complete AV block, but second-degree blocks were similar in the two groups.
Therefore, as described in prior studies, Efavirenz may not contribute to an increased rate of blocks and other conduction disturbances in HIV-infected patients. [36][37][38] Despite general similarity of the two groups at baseline, a higher proportion of non-Efavirenz patients received PI. Treatment with PIs was not associated with dysrhythmia or significant ECG changes. This is in accordance with studies by Charbit et al. 20 and Fiorentini et al. 17 Despite case reports and initial studies 39 supporting such an effect, cumulative evidence has shown that QTc prolongation is not directly related to PIs. 17,20,40,41 Multivariate model in our study showed a trend toward significant decrease of dysrhythmia with greater CD4 counts which was close to previous reports. 42 This may underline the role of optimal treatment for reducing dysrhythmias particularly prolonged QT.
We excluded patients with a history of diabetes, hypertension, coronary artery disease, current smoking, dysrhythmia, chronic kidney disease, and family history of sudden cardiac death, since these factors might increase susceptibility to ischemic heart disease, which could lead to dysrhythmias. Therefore, included patients constituted a relatively homogeneous population of young to middle-aged HIV patients who were apparently free of cardiovascular disease. Although the pathogenesis of dysrhythmia involves multiple pathways and aetiologies, we aimed to restrict underlying risk factors, particularly overt structural heart diseases.
Since potential confounding factors were eliminated, we could demonstrate effects attributable to antiretroviral regimens.

| STUDY LIMITATIONS
The present investigation was a single-center study. However, it was conducted in a tertiary referral hospital with specialized facilities for HIV 6 | CONCLUSION Patients exposed to Efavirenz had higher prevalence of high PVC, high PAC, and total significant dysrhythmia but similar proportions of low HRV (SDANN). However, Efavirenz group had lower HRV as measured via SDNN with a borderline significance. Efavirenz regimen, mean heart rate, male gender and lower CD4 counts were independent predictors of total dysrhythmia. Efavirenz regimen increased QT, which was prominent in subgroup of males while females were not affected. Furthermore, majority of impacts exerted via Efavirenz were predominantly observed in males rather than females. Use of ambulatory electrocardiographic monitoring may improve screening and diagnosis of at risk individuals. However, the subgroup of HIV-infected patients who may benefit most from screening of dysrhythmia, the appropriate time intervals, methods, cost-effectiveness, follow-up protocols, and management algorithms are unclear.

ACKNOWLEDGMENTS
The authors wish to show their appreciation to staff of infectious disease ward as well as those facilitating the access to HIV registry in Imam Khomeini medical center.