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Abnormal QTc Syndrome in HIV-Infected Patients: A Systematic review of Prevalence and Risk Factors

Abnormal QTc Syndrome in HIV-Infected Patients: A Systematic review of Prevalence and Risk Factors Antiviral Therapy 2019; 24:459–465 (doi: 10.3851/IMP3335) Original article Abnormal QTc syndrome in HIV-infected patients: a systematic review of prevalence and risk factors 1 2 3 Daniel B Chastain *, Michael P Veve , Jamie L Wagner Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Albany, GA, USA Department of Clinical Pharmacy and Translational Science, University of Tennessee College of Pharmacy, Knoxville, TN, USA Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, MS, USA *Corresponding author e-mail: daniel.chastain@uga.edu Background: The purpose of this review is to critically PLWH who have an increased HIV RNA viral load or analyse data regarding the prevalence and risk factors decreased CD4 T-cell count are at further risk for pro- for developing a prolonged QTc interval and subsequent gressing to sudden cardiac death (SCD). Many medica- sudden cardiac death (SCD) in persons living with HIV tions commonly prescribed in the PLWH population, such (PLWH). as antiretrovirals and antimicrobials used in opportunistic Methods: A systematic literature search using PubMed infection prophylaxis, have also been shown to promote and Google Scholar databases was performed using the QTc prolongation through inhibition of human ether-a- following search terms: ‘HIV and prolonged QTc’ and go-go potassium channels or through drug metabolism ‘managing HIV-patients with prolonged QTc’. References inhibition of other QTc prolonging drugs. within articles of interest were also evaluated. Conclusions: Due to the high number of risk factors Results/Discussion: PLWH are at an increased risk of hav- associated with QTc prolongation, clinicians should ing a prolonged QTc interval. Some risk factors for this incorporate baseline and routine ECG monitoring for include the virus itself, concomitant medications, comor- PLWH to potentially lower the increased risk of SCD bid conditions, addictions and electrolyte disturbances. in PLWH. Introduction Worldwide, over 37 million people are living with HIV have a prevalence of QTc prolongation ranging from (PLWH) [1,2]. While this number continues to rise, 5–45%, approaching one of every two PLWH, which is the number of new infections per year has plateaued, 2–3× higher compared with uninfected patients [7–9]. but this is not evenly distributed with higher incidence This prolongation can lead to the development of tor- occurring in locations such as rural areas of the US [3], sade de pointes (TdP) and ventricular fibrillation, ending Eastern Europe, Central Asia, the Middle East and in sudden cardiac death (SCD) in up to 20% of PLWH North Africa [4]. With advancements in antiretroviral [1,5,7,10,11]. Indeed, a recent study using the Veter- therapy (ART), PLWH are living longer and are at risk ans Aging Cohort Study (VACS) Virtual Cohort, HIV- of developing other chronic conditions associated with infected veterans had a 14% higher risk of SCD com- increased life expectancy, including cardiovascular dis- pared with uninfected veterans [12]. Additionally, risk of ease (CVD). In addition to advanced age, PLWH are at SCD was 4.5-fold higher among PLWH compared with further risk of developing CVD due to the effects of the the general population in San Francisco [13]. However, virus on the cardiovascular tissue [1] and the effects of the association between QTc prolongation and SCD in ART [5,6] on the body. PLWH remains poorly understood. Several studies have While a plethora of data exist describing the increased identified characteristics associated with QTc prolon- morbidity and mortality of ischaemia-related cardiovas- gation in PLWH, however, there is discordance among cular effects of HIV, there are less regarding the impact these studies [5,9,10,14,15]. Therefore, the purpose of of the virus on electrical conduction in the heart, more this review is to critically analyse data regarding the specifically, QT interval prolongation corrected for prevalence and risk factors for developing a prolonged heart rate (QTc). Available data indicate that PLWH QTc interval and subsequent SCD in PLWH. ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 459 AVT-19-RV-4555_Chastain.indd 459 AVT-19-RV-4555_Chastain.indd 459 22/11/2019 13:49:20 22/11/2019 13:49:20 DB Chastain et al. Methods (odds ratio [OR] 5.8, 95% CI 1.3, 26.4). Furthermore, QTc prolongation was more likely to occur if HIV RNA In order to compile a thorough review, a systematic viral load ≥17,900 copies/ml or CD4 T-cell count <144 literature search was performed within PubMed and cells/mm [18]. In those with both HIV RNA viral load Google Scholar using the following search terms: ‘HIV ≥17,900 copies/ml or cell count <144 cells/mm risk of and prolonged QTc’ and ‘managing HIV-patients with QTc prolongation was almost 15× higher (OR 14.74, prolonged QTc’. The articles were restricted to the Eng- 95% CI 3.84, 56.55; P<0.0001). lish language. Article titles and abstracts were screened There is discordance in previously published literature for possible inclusion, and references within articles of on the impact of ART and other HIV-associated medi- interest were assessed to capture additional sources. cations on the development of SCD in PLWH. Older literature indicates that protease inhibitor (PI)-based regimens and some opportunistic infection (OI) treat- Results/discussion ment regimens are more likely to cause a prolonged QTc In the following text, we will analyse previous studies interval than alternative regimens [10,17]; while, more that have evaluated the incidence of, and risk factors recently published literature indicates that there is no associated with QTc prolongation in PLWH. In addition, association between ART and QTc prolongation [7,15]. we will examine the mechanisms of QTc prolongation Compared with uninfected controls, mean QTc inter- associated with antiretrovirals (ARVs), antimicrobial val was significantly longer in PLWH receiving ART agents for opportunistic infections and other ‘high risk’ for a mean 1.5 ±2 years with mean CD4 T-cell count drugs due to the high prevalence of PLWH receiving one 440 ±188 cells/mm (409 ±21 versus 421 ±21  msec; or more of these medications. respectively; P=0.002)  [14]. Frequency of QTc inter- val prolongation was similar among ART-naive and QTc interval prolongation -experienced PLWH [5]. Prolonged QTc interval was Although prevalence differs among studies, QTc observed in 15.9% (22/138) of HIV-positive patients of prolongation is a common finding in PLWH [7–9,14]. which 98% were virologically suppressed with a mean + 3 The mechanism of acquired prolonged QTc syndrome is CD4 T-cell count of 602 ±360 cells/mm who had been proposed to be due to alterations in cardiac innervation infected for a mean of 15.1 ±6.7 years [11]. secondary to autonomic neuropathy [9,16], leading to Among PLWH, frequency of QTc interval prolongation dilated cardiomyopathies potentiating arrhythmias. A appears to differ between males and females. Prolonged study by Kocheril et al. [10] suggested that HIV infec- QTc was observed in 22.8% of HIV-infected males and tion may be associated with acquired prolonged QTc 6.7% of HIV-infected females from the HIV-HEART syndrome independent of electrolyte abnormalities and study, of which approximately 95% were on ART, com- medications. This is thought to be due to direct infection pared with 3.9% of uninfected matched males and 1.8% of cardiac cells by the virus [1,17]. Prolonged QTc was of uninfected matched females (OR 7.9, 95% CI 5.0, 12.6 observed in 45% (45/100) of adult patients with AIDS, for HIV-infected males versus uninfected males and OR 28% (22/78) of asymptomatic HIV-infected patients 6.7, 95% CI 1.8, 24.2 for HIV-infected females versus and 10% (8/80) of uninfected controls [9]. Mean uninfected females) [7]. Mean QTc was 424.1 ±23.3 and QTc was significantly different in patients with AIDS 435.5 ±19.6 msec in HIV-infected males and females, and (430 ±50 msec) when compared with those with asymp- 411.3 ±15.3 and 416.4 ±17.3 msec in uninfected males tomatic HIV infection (420 ±50 msec; P<0.05) and unin- and females, respectively (P<0.0001 for both sexes). In fected controls (400 ±40 msec; P<0.05). The authors the Multicenter AIDS Cohort Study (MACS), a signifi- hypothesized that this was the result of disease progres- cantly longer QTc interval was observed in HIV-infected sion in prolonged QTc syndrome given an absence of men compared with uninfected controls after adjusting QTc prolonging drugs and electrolyte abnormalities. for body mass index (BMI), alcohol consumption greater Additional data suggest that HIV disease progression, than 13 drinks per week, cumulative pack-year of smok- marked by decreasing CD4 T-cell count and increasing ing, use of opiates, systolic blood pressure, fasting blood HIV RNA viral load, are independently associated with glucose, glomerular filtration, left ventricular hypertro- the presence of and increasing degree of a prolonged phy, and receipt of anti-hypertensive, anti-diabetic or QTc QTc interval [5,9,15,17,18]. Duration of HIV infection prolonging medications [19]. has been associated with QTc prolongation [9]. Nadir Regardless of age or severity of HIV, PLWH remain + 3 or current CD4 T-cell count <200 cells/mm , but not at higher risk of QTc prolongation for a multitude of HIV RNA viral load, at the time of ECG was associ- reasons. Furthermore, QTc prolongation in PLWH is ated with prolonged QTc interval [5]. In multivariate associated with lower CD4 T-cell counts, specifically analysis, risk of QTc prolongation was increased sixfold less than 200 cells/mm [5,15], higher concentrations + 3 in PLWH with nadir CD4 T-cell count <200 cells/mm of inflammatory biomarkers [19], CVD, including 460 ©2019 International Medical Press AVT-19-RV-4555_Chastain.indd 460 AVT-19-RV-4555_Chastain.indd 460 22/11/2019 13:49:20 22/11/2019 13:49:20 Abnormal QTc syndrome in HIV-infected patients hypertension [11], chronic kidney disease (CKD) [11], was first introduced into the US market in 1998, with smoking [7] and coinfection with HCV [11]. In addi- well-documented clinical efficacy and favourable phar - tion, prolonged QTc interval predicts CVD [8]. macological properties [24]. While no longer recom- mended as an initial first-line ART since 2017, the single Antimicrobial agents associated with QTc prolongation tablet regimen (STR) of EFV combined with emtricit- PLWH are at an increased risk of QTc prolongation due abine (FTC)/tenofovir disoproxil fumarate (TDF) had to alterations in cardiac innervation [9,16] and a higher been used extensively as a preferred therapy in ART- prevalence of prescribed QTc prolonging antimicrobi- naive patients prior to development of integrase strand als used for viral suppression or as treatment and/or transfer inhibitor (INSTI)-based STRs [25]. prophylaxis against OIs [11]. QTc prolongation and TdP with EFV was first Many antimicrobials commonly prescribed to PLWH described in 2002 [26]. Subsequent reports in both can potentiate the risk of QTc prolongation through PLWH and HIV-negative healthy volunteers described the inadvertent inhibition of the human ether-a-go-go- further evidence of the relationship between EFV and related gene (hERG) potassium ion channels, which are QTc prolongation [27–29]. The extent of EFV prolong- responsible for maintaining normal cardiac conduc- ing the QT interval was recorded as >580 msec [26], tion [20]. hERG potassium channels conduct the rapid however, in HIV-negative patients, a mean increase of component of the delayed rectifier potassium current, 5.2 msec was seen [28]. Additionally, a higher prevalence I , and regulate the outward flow of potassium from of QTc prolongation was seen in patients receiving EFV- Kr myocytes. Drug-induced suppression of I results in based ART when compared with non-EFV-based regi- Kr the accumulation of intracellular potassium leading to mens (adjusted OR, 4.82; 95% CI, 1.54, 15.11)  [27]. delayed ventricular repolarization and subsequent pro- The relationship between EFV administration and QTc longed QTc interval [20,21]. Differences in drug affinity prolongation has been hypothesized to be due to EFV’s for I suppression, cytochrome P450 (CYP)-mediated long terminal half-life [26] and can occur at any point Kr drug–drug interactions, and accumulation of renally- over the course of therapy [29]. eliminated antimicrobials leading to increased drug Abdelhady and colleagues [30] hypothesized that exposures are additional factors that potentiate the risk volunteers with decreased CYP 2B6 allele expression, of QTc prolongation and TdP [20]. the main metabolic pathway of EFV, would be at higher Several antimicrobials used in PLWH have been asso- risk of QTc prolongation. EFV was found to signifi- ciated with QTc prolongation (Table 1). Relatively few cantly prolong the QTc interval at steady-state in slow data exist describing the exact mechanism of QTc pro- metabolizers with the CYP 2B6*6 allele in a direct longation in detail and are often limited to case reports concentration–response relationship (baseline 406 highlighting abnormal ECG findings or TdP. ±16.4 versus steady-state 423 ±11.8 msec; P<0.05). Results from cellular electrophysiology assessment Antiretroviral therapy found EFV to inhibit inward and outward I currents Kr While significant advancements have been made in the in a concentration-dependent manner. Based on these safety and efficacy of ART over the last decade, some data, the proposed mechanism of EFV-mediated QTc ART associated with QTc prolongation are still com- prolongation may be due to its ability to inhibit hERG monly prescribed [22]. Continued use of older, toxic I , which may be exacerbated in individuals with slow Kr ARTs is seen in developing countries where HIV is CYP2B6 metabolism. prevalent, mostly due to a lack of access to newly devel- oped agents, cost, and/or other socio-economic barri- Rilpivirine ers [23]. Literature describing the association of QTc Rilpivirine (RPV) is a second generation NNRTI first prolongation and ART is surprisingly sparse, and many introduced to the US market in 2010, and displays a data provide conflicting evidence regarding true asso- favourable side effect profile and higher genetic barrier ciations with QTc prolongation. Most data suggest spu- to resistance when compared with other NNRTIs [31]. rious associations in select populations, such as slow RPV is available in combination with nucleoside/nucle- CYP metabolizers of the primary ART metabolic path- otide reverse transcriptase inhibitors (NRTIs) and the way. Still, clinicians should consider the potential for INSTI, dolutegravir, as STRs [25]. Data examining the QTc prolongation in patients receiving other QTc pro- QTc-prolonging effects of RPV have been documented longing agents or with other comorbidities known to from clinical trials. cause arrhythmias. A summary is provided in Table 1. RPV demonstrated QTc interval prolonging effects in a dose- and concentration-dependent man- Efavirenz ner, at both therapeutic and supratherapeutic doses EFV is a commonly prescribed non-nucleoside [28,32–34], however, there is conflicting data between reverse transcriptase inhibitor (NNRTI) [22] that HIV-negative healthy volunteers and PLWH [28]. Antiviral Therapy 24.6 461 AVT-19-RV-4555_Chastain.indd 461 AVT-19-RV-4555_Chastain.indd 461 22/11/2019 13:49:20 22/11/2019 13:49:20 DB Chastain et al. Table 1. Mechanism of QTc prolongation associated with antiretrovirals, antimicrobial agents for opportunistic infections and other ‘high risk’ drugs commonly used in PLWH [15,22–24,26,46,48,50,54–61] QTc mechanism Factors associated with QTc prolongation Metabolism Inhibition of inhibited another I Dosing regimen Presence of other Documented Kr Inhibition by another blocker when prolongation QTc prolonging Extent of QTc sudden Medication class of hERG drug metabolism occurred agents prolongation cardiac death Non-nucleoside reverse transcriptase inhibitors Efavirenz + - - 600 mg daily No ≥5.2 msec No Rilpivirine + - - 25–150 mg daily No ≥11 msec No Protease inhibitors Saquinavir + +/- - 1,000 mg twice daily n/a n/a No Atazanavir + +/- - 300 mg daily n/a n/a No Lopinavir + +/- - 400 mg twice daily n/a n/a No Nelfinavir + - - 750 mg three n/a n/a No times daily Ritonavir +/- +/- + 100 mg daily to n/a n/a No twice daily Macrolides Azithromycin + +/- + 1,200 mg weekly No n/a Yes Clarithromycin + +/- + 500 mg twice daily No n/a Yes Azoles Fluconazole + + + Any dose n/a n/a No Itraconazole + + + Any dose n/a n/a No Posaconazole + + + Any dose n/a n/a No Voriconazole + + + Any dose n/a n/a No Other Pentamidine + - - 300 mg every +/- n/a No 4 weeks Primaquine +/- - - 30 mg daily No n/a No Methadone + + + Any dose No n/a No hERG, human ether-a-go-go-related gene; n/a, information not available; PLWH, persons living with HIV; +, displays mechanism; -, no evidence; +/-, inconclusive data. Additional non-clinical studies of RPV demonstrated older-generation PIs, such as saquinavir (SQV) and the drug to inhibit potassium channels involved in lopinavir (LPV) in combination with ritonavir (RTV), cardiac action potential repolarization at concentra- which were widely used and regarded as a break- tions approximately 10-fold greater than the clini- through ART class during the mid-1990s [39]. How- cal exposures. Thus, the proposed mechanism of ever, tolerability and dosing requirements led to the QTc prolongation is likely similar to EFV. The pro- refinement of newer-generation PIs, most of which are arrhythmic potential of RPV, with similarly reported available as once-daily tablets or as fixed-dose combi- QTc prolonging effects for EFV, caused subsequent nation tablets with cobicistat [25]. In 2010, the FDA Phase III studies to assess cardiac toxicity as a major issued warnings that RTV-boosted LPV and RTV- safety outcome and exclude patients with a history of boosted SQV may cause prolongation of QTc and PR prolonged QTc syndrome [33,34]. In Phase III stud- [40,41]. Atazanavir (ATV) is also commonly associ- ies, which compared RPV/FTC/TDF to EFV/FTC/TDF, ated with QTc prolongation and is recommended as investigators found an increase in QTc interval with a second-line therapy [25,42]. A study conducted in a mean change from baseline of 12.0 msec (95% CI 2005 to discover the mechanism of QTc prolongation 10.1, 13.8) [33,34]. Two patients receiving RPV expe- in PIs found LPV, nelfinavir (NFV), RTV, and SQV all rienced conduction abnormalities or rate and rhythm caused dose-dependent blockade of hERG channels, disturbances, and an additional patient discontinued and LPV was also found to block the repolarization therapy related to grade 3 QTc prolongation [33]. of I channels in neonatal mouse cardiac myocytes Kr [21]. These inconsistent observations suggest inter- Ritonavir-boosted protease inhibitors personal differences between volunteers/patients and Data describing the QT prolonging effects of the individual PI characteristics may hinder the ability to PIs are conflicting [27,35–38]. Most data are with detect associations with QTc prolongation and TdP. 462 ©2019 International Medical Press AVT-19-RV-4555_Chastain.indd 462 AVT-19-RV-4555_Chastain.indd 462 22/11/2019 13:49:20 22/11/2019 13:49:20 Abnormal QTc syndrome in HIV-infected patients Nucleoside/nucleotide reverse transcriptase inhibitors were refuted with a similar meta-analysis suggesting the NRTIs have also been linked to QTc prolongation, but incidence of arrhythmias in absence of coexisting risk these data generally include heterogeneous popula- factors is very low [61]. Despite most data surrounding tions and lack consideration for confounding variables. QTc-prolonging data and macrolides is outside PLWH A  comprehensive review in 2010 discovered that 3TC, populations, the risk remains. among other ARVs, was commonly associated with TdP, The mechanism of QTc prolongation is thought to be but no significant conclusions could be made [43]. Other blockage of the I encoded by hERG, but also through Kr data suggest 3TC and ZDV are not associated with QT CYP3A4 inhibition of other QTc-prolonging medica- prolongation [44], but conflicting data exist [27]. The tions [62,63]. Variation exists within the macrolide mechanism of NRTI-induced QTc prolongation is not family of compounds in terms of both I inhibitory Kr well understood but may be due to activation of reactive potency and CYP3A4 inhibition potential [63]. oxygen species in the heart mitochondria [45]. Invasive mycoses Antimicrobial agents for opportunistic infections Azole antifungals Pneumocystis jirovecii PLWH, particularly those with AIDS, are at increased Pentamidine risk of invasive fungal infections like oesophageal or Pentamidine is an alternative recommendation for oropharyngeal thrush and cryptococcal meningitis [46]. prophylaxis and therapy of Pneumocystis jirovecii Fluconazole is commonly used in the treatment of these pneumonia (PJP) [46]. Numerous case reports have OIs, which is also a known QTc-prolonging agent [64]. highlighted the QTc-prolonging effects associated with An increasing prevalence of fluconazole-resistant Can- inhaled or parenteral pentamidine in PLWH [47–49], dida spp. warrants an increased use of voriconazole, although these older data are limited by coadministra- posaconazole, itraconazole and isavuconazonium in tion with other QTc prolonging agents or in the set- select indications [46]. ting of electrolyte imbalances [48]. Other retrospective From 1995–2015, there were 191 cases of reported and prospective data have suggested pentamidine is not TdP with systemic azole antifungals; fluconazole was associated with QTc prolongation [50,51]. A poten- associated with the highest proportion of events [64]. tial mechanism was described by de Boer et al. [52], The proposed mechanism of QTc prolongation is due who showed pentamidine inhibits the hERG pathway to hERG inhibition of internal I pores and I protein Kr Kr in canine ventricular cardiomyocytes through I , with trafficking, as well as the inhibition of other I blocking Kr Kr internal pore blockage and protein trafficking. medication metabolism [63]. The degree of QTc prolon- gation can vary between different antifungals within the Primaquine azole class, likely due to structural differences or bind- Primaquine is a recommended alternative therapy in ing affinity to various ion pores and channels, in addi- the management of PJP, in combination with clinda- tion to variability in inhibition of CYP-enzymes [63]. mycin [46]. While related to the parent drug quinidine, which is associated with significant QTc prolongation, Other ‘high risk’ drugs the cardiovascular activity of primaquine has not been Methadone extensively studied [53]. One study found no signifi- Methadone is another well-known QTc-prolonging agent. cant effect of primaquine on the QTc interval of 16 The high prevalence of illicit substance use in the PLWH healthy volunteers [54]. Regardless, QTc prolonga- population highlights the potential risk of methadone- tion is an adverse effect listed in the package insert associated QTc prolongation. Methadone use was found of the drug, likely due to the structural relationship to be an independent predictor of QTc prolongation in an with quinidine [55]. The potential mechanism of QTc injection drug use population, as well as the methadone prolongation is through blockade of hERG via I , as dose used, presence of CYP3A4 inhibitors, potassium level Kr demonstrated in human embryonic kidney cells [56]. and liver dysfunction in PLWH [65,66]. The mechanism of methadone QTc prolongation has demonstrated a dose- Mycobacterium avium complex dependent binding to hERG potassium ion channels [67]. Macrolides Macrolide antibiotics are a mainstay in prophylaxis and Managing HIV-infected patients with prolonged QTc treatment of MAC [46]. Azithromycin and clarithro- intervals mycin are most commonly used, both of which have While the exact quantification of PLWH who have a been well documented to exhibit QTc-prolonging activ- prolonged QTc interval is unknown, clinicians can employ ity [57–59] by as much as an absolute risk increase of strategies to help prevent SCD in these patients. First, 118.1 for SCD and ventricular tachyarrhythmias related PLWH should undergo baseline and routine ECGs [1,5]. to QTc-prolonging potential [60]. However, these data Second, clinicians should monitor all medications Antiviral Therapy 24.6 463 AVT-19-RV-4555_Chastain.indd 463 AVT-19-RV-4555_Chastain.indd 463 22/11/2019 13:49:20 22/11/2019 13:49:20 DB Chastain et al. 8. Soliman EZ, Prineas RJ, Roediger MP, et al. 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Glob Cardiol Sci Pract prolongation in HIV-infected patients: a case-control study 2017; 2017:11. by 24-hour Holter ECG recording. BMC Cardiovasc Disord 65. John J, Amley X, Bombino G, et al. Torsade de Pointes due 2012; 12:124. to methadone use in a patient with HIV and hepatitis C 45. Szabados E, Fischer GM, Toth K, et al. Role of reactive coinfection. Cardiol Res Pract 2010; 2010:524764. oxygen species and poly-ADP-ribose polymerase in the 66. Vallecillo G, Mojal S, Roquer A, et al. Risk of QTc development of AZT-induced cardiomyopathy in rat. prolongation in a cohort of opioid-dependent HIV-infected Free Radic Biol Med 1999; 26:309–317. patients on methadone maintenance therapy. Clin Infect Dis 46. Panel on Antiretroviral Guidelines for Adults and 2013; 57:1189–1194. Adolescents. Guidelines for the use of antiretroviral 67. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long agents in adults and adolescents with HIV. Department QT syndrome in injection drug users receiving methadone: of Health and Human Services. 2019. (Accessed 30 April high frequency in hospitalized patients and risk factors. 2019.) Available from http://aidsinfo.nih.gov/contentfiles/ Arch Intern Med 2006; 166:1280–1287. lvguidelines/AdultandAdolescentGL.pdf Accepted 9 August 2019; published online 30 September 2019 Antiviral Therapy 24.6 465 AVT-19-RV-4555_Chastain.indd 465 AVT-19-RV-4555_Chastain.indd 465 22/11/2019 13:49:20 22/11/2019 13:49:20 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Abnormal QTc Syndrome in HIV-Infected Patients: A Systematic review of Prevalence and Risk Factors

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SAGE
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1359-6535
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Antiviral Therapy 2019; 24:459–465 (doi: 10.3851/IMP3335) Original article Abnormal QTc syndrome in HIV-infected patients: a systematic review of prevalence and risk factors 1 2 3 Daniel B Chastain *, Michael P Veve , Jamie L Wagner Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Albany, GA, USA Department of Clinical Pharmacy and Translational Science, University of Tennessee College of Pharmacy, Knoxville, TN, USA Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, MS, USA *Corresponding author e-mail: daniel.chastain@uga.edu Background: The purpose of this review is to critically PLWH who have an increased HIV RNA viral load or analyse data regarding the prevalence and risk factors decreased CD4 T-cell count are at further risk for pro- for developing a prolonged QTc interval and subsequent gressing to sudden cardiac death (SCD). Many medica- sudden cardiac death (SCD) in persons living with HIV tions commonly prescribed in the PLWH population, such (PLWH). as antiretrovirals and antimicrobials used in opportunistic Methods: A systematic literature search using PubMed infection prophylaxis, have also been shown to promote and Google Scholar databases was performed using the QTc prolongation through inhibition of human ether-a- following search terms: ‘HIV and prolonged QTc’ and go-go potassium channels or through drug metabolism ‘managing HIV-patients with prolonged QTc’. References inhibition of other QTc prolonging drugs. within articles of interest were also evaluated. Conclusions: Due to the high number of risk factors Results/Discussion: PLWH are at an increased risk of hav- associated with QTc prolongation, clinicians should ing a prolonged QTc interval. Some risk factors for this incorporate baseline and routine ECG monitoring for include the virus itself, concomitant medications, comor- PLWH to potentially lower the increased risk of SCD bid conditions, addictions and electrolyte disturbances. in PLWH. Introduction Worldwide, over 37 million people are living with HIV have a prevalence of QTc prolongation ranging from (PLWH) [1,2]. While this number continues to rise, 5–45%, approaching one of every two PLWH, which is the number of new infections per year has plateaued, 2–3× higher compared with uninfected patients [7–9]. but this is not evenly distributed with higher incidence This prolongation can lead to the development of tor- occurring in locations such as rural areas of the US [3], sade de pointes (TdP) and ventricular fibrillation, ending Eastern Europe, Central Asia, the Middle East and in sudden cardiac death (SCD) in up to 20% of PLWH North Africa [4]. With advancements in antiretroviral [1,5,7,10,11]. Indeed, a recent study using the Veter- therapy (ART), PLWH are living longer and are at risk ans Aging Cohort Study (VACS) Virtual Cohort, HIV- of developing other chronic conditions associated with infected veterans had a 14% higher risk of SCD com- increased life expectancy, including cardiovascular dis- pared with uninfected veterans [12]. Additionally, risk of ease (CVD). In addition to advanced age, PLWH are at SCD was 4.5-fold higher among PLWH compared with further risk of developing CVD due to the effects of the the general population in San Francisco [13]. However, virus on the cardiovascular tissue [1] and the effects of the association between QTc prolongation and SCD in ART [5,6] on the body. PLWH remains poorly understood. Several studies have While a plethora of data exist describing the increased identified characteristics associated with QTc prolon- morbidity and mortality of ischaemia-related cardiovas- gation in PLWH, however, there is discordance among cular effects of HIV, there are less regarding the impact these studies [5,9,10,14,15]. Therefore, the purpose of of the virus on electrical conduction in the heart, more this review is to critically analyse data regarding the specifically, QT interval prolongation corrected for prevalence and risk factors for developing a prolonged heart rate (QTc). Available data indicate that PLWH QTc interval and subsequent SCD in PLWH. ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 459 AVT-19-RV-4555_Chastain.indd 459 AVT-19-RV-4555_Chastain.indd 459 22/11/2019 13:49:20 22/11/2019 13:49:20 DB Chastain et al. Methods (odds ratio [OR] 5.8, 95% CI 1.3, 26.4). Furthermore, QTc prolongation was more likely to occur if HIV RNA In order to compile a thorough review, a systematic viral load ≥17,900 copies/ml or CD4 T-cell count <144 literature search was performed within PubMed and cells/mm [18]. In those with both HIV RNA viral load Google Scholar using the following search terms: ‘HIV ≥17,900 copies/ml or cell count <144 cells/mm risk of and prolonged QTc’ and ‘managing HIV-patients with QTc prolongation was almost 15× higher (OR 14.74, prolonged QTc’. The articles were restricted to the Eng- 95% CI 3.84, 56.55; P<0.0001). lish language. Article titles and abstracts were screened There is discordance in previously published literature for possible inclusion, and references within articles of on the impact of ART and other HIV-associated medi- interest were assessed to capture additional sources. cations on the development of SCD in PLWH. Older literature indicates that protease inhibitor (PI)-based regimens and some opportunistic infection (OI) treat- Results/discussion ment regimens are more likely to cause a prolonged QTc In the following text, we will analyse previous studies interval than alternative regimens [10,17]; while, more that have evaluated the incidence of, and risk factors recently published literature indicates that there is no associated with QTc prolongation in PLWH. In addition, association between ART and QTc prolongation [7,15]. we will examine the mechanisms of QTc prolongation Compared with uninfected controls, mean QTc inter- associated with antiretrovirals (ARVs), antimicrobial val was significantly longer in PLWH receiving ART agents for opportunistic infections and other ‘high risk’ for a mean 1.5 ±2 years with mean CD4 T-cell count drugs due to the high prevalence of PLWH receiving one 440 ±188 cells/mm (409 ±21 versus 421 ±21  msec; or more of these medications. respectively; P=0.002)  [14]. Frequency of QTc inter- val prolongation was similar among ART-naive and QTc interval prolongation -experienced PLWH [5]. Prolonged QTc interval was Although prevalence differs among studies, QTc observed in 15.9% (22/138) of HIV-positive patients of prolongation is a common finding in PLWH [7–9,14]. which 98% were virologically suppressed with a mean + 3 The mechanism of acquired prolonged QTc syndrome is CD4 T-cell count of 602 ±360 cells/mm who had been proposed to be due to alterations in cardiac innervation infected for a mean of 15.1 ±6.7 years [11]. secondary to autonomic neuropathy [9,16], leading to Among PLWH, frequency of QTc interval prolongation dilated cardiomyopathies potentiating arrhythmias. A appears to differ between males and females. Prolonged study by Kocheril et al. [10] suggested that HIV infec- QTc was observed in 22.8% of HIV-infected males and tion may be associated with acquired prolonged QTc 6.7% of HIV-infected females from the HIV-HEART syndrome independent of electrolyte abnormalities and study, of which approximately 95% were on ART, com- medications. This is thought to be due to direct infection pared with 3.9% of uninfected matched males and 1.8% of cardiac cells by the virus [1,17]. Prolonged QTc was of uninfected matched females (OR 7.9, 95% CI 5.0, 12.6 observed in 45% (45/100) of adult patients with AIDS, for HIV-infected males versus uninfected males and OR 28% (22/78) of asymptomatic HIV-infected patients 6.7, 95% CI 1.8, 24.2 for HIV-infected females versus and 10% (8/80) of uninfected controls [9]. Mean uninfected females) [7]. Mean QTc was 424.1 ±23.3 and QTc was significantly different in patients with AIDS 435.5 ±19.6 msec in HIV-infected males and females, and (430 ±50 msec) when compared with those with asymp- 411.3 ±15.3 and 416.4 ±17.3 msec in uninfected males tomatic HIV infection (420 ±50 msec; P<0.05) and unin- and females, respectively (P<0.0001 for both sexes). In fected controls (400 ±40 msec; P<0.05). The authors the Multicenter AIDS Cohort Study (MACS), a signifi- hypothesized that this was the result of disease progres- cantly longer QTc interval was observed in HIV-infected sion in prolonged QTc syndrome given an absence of men compared with uninfected controls after adjusting QTc prolonging drugs and electrolyte abnormalities. for body mass index (BMI), alcohol consumption greater Additional data suggest that HIV disease progression, than 13 drinks per week, cumulative pack-year of smok- marked by decreasing CD4 T-cell count and increasing ing, use of opiates, systolic blood pressure, fasting blood HIV RNA viral load, are independently associated with glucose, glomerular filtration, left ventricular hypertro- the presence of and increasing degree of a prolonged phy, and receipt of anti-hypertensive, anti-diabetic or QTc QTc interval [5,9,15,17,18]. Duration of HIV infection prolonging medications [19]. has been associated with QTc prolongation [9]. Nadir Regardless of age or severity of HIV, PLWH remain + 3 or current CD4 T-cell count <200 cells/mm , but not at higher risk of QTc prolongation for a multitude of HIV RNA viral load, at the time of ECG was associ- reasons. Furthermore, QTc prolongation in PLWH is ated with prolonged QTc interval [5]. In multivariate associated with lower CD4 T-cell counts, specifically analysis, risk of QTc prolongation was increased sixfold less than 200 cells/mm [5,15], higher concentrations + 3 in PLWH with nadir CD4 T-cell count <200 cells/mm of inflammatory biomarkers [19], CVD, including 460 ©2019 International Medical Press AVT-19-RV-4555_Chastain.indd 460 AVT-19-RV-4555_Chastain.indd 460 22/11/2019 13:49:20 22/11/2019 13:49:20 Abnormal QTc syndrome in HIV-infected patients hypertension [11], chronic kidney disease (CKD) [11], was first introduced into the US market in 1998, with smoking [7] and coinfection with HCV [11]. In addi- well-documented clinical efficacy and favourable phar - tion, prolonged QTc interval predicts CVD [8]. macological properties [24]. While no longer recom- mended as an initial first-line ART since 2017, the single Antimicrobial agents associated with QTc prolongation tablet regimen (STR) of EFV combined with emtricit- PLWH are at an increased risk of QTc prolongation due abine (FTC)/tenofovir disoproxil fumarate (TDF) had to alterations in cardiac innervation [9,16] and a higher been used extensively as a preferred therapy in ART- prevalence of prescribed QTc prolonging antimicrobi- naive patients prior to development of integrase strand als used for viral suppression or as treatment and/or transfer inhibitor (INSTI)-based STRs [25]. prophylaxis against OIs [11]. QTc prolongation and TdP with EFV was first Many antimicrobials commonly prescribed to PLWH described in 2002 [26]. Subsequent reports in both can potentiate the risk of QTc prolongation through PLWH and HIV-negative healthy volunteers described the inadvertent inhibition of the human ether-a-go-go- further evidence of the relationship between EFV and related gene (hERG) potassium ion channels, which are QTc prolongation [27–29]. The extent of EFV prolong- responsible for maintaining normal cardiac conduc- ing the QT interval was recorded as >580 msec [26], tion [20]. hERG potassium channels conduct the rapid however, in HIV-negative patients, a mean increase of component of the delayed rectifier potassium current, 5.2 msec was seen [28]. Additionally, a higher prevalence I , and regulate the outward flow of potassium from of QTc prolongation was seen in patients receiving EFV- Kr myocytes. Drug-induced suppression of I results in based ART when compared with non-EFV-based regi- Kr the accumulation of intracellular potassium leading to mens (adjusted OR, 4.82; 95% CI, 1.54, 15.11)  [27]. delayed ventricular repolarization and subsequent pro- The relationship between EFV administration and QTc longed QTc interval [20,21]. Differences in drug affinity prolongation has been hypothesized to be due to EFV’s for I suppression, cytochrome P450 (CYP)-mediated long terminal half-life [26] and can occur at any point Kr drug–drug interactions, and accumulation of renally- over the course of therapy [29]. eliminated antimicrobials leading to increased drug Abdelhady and colleagues [30] hypothesized that exposures are additional factors that potentiate the risk volunteers with decreased CYP 2B6 allele expression, of QTc prolongation and TdP [20]. the main metabolic pathway of EFV, would be at higher Several antimicrobials used in PLWH have been asso- risk of QTc prolongation. EFV was found to signifi- ciated with QTc prolongation (Table 1). Relatively few cantly prolong the QTc interval at steady-state in slow data exist describing the exact mechanism of QTc pro- metabolizers with the CYP 2B6*6 allele in a direct longation in detail and are often limited to case reports concentration–response relationship (baseline 406 highlighting abnormal ECG findings or TdP. ±16.4 versus steady-state 423 ±11.8 msec; P<0.05). Results from cellular electrophysiology assessment Antiretroviral therapy found EFV to inhibit inward and outward I currents Kr While significant advancements have been made in the in a concentration-dependent manner. Based on these safety and efficacy of ART over the last decade, some data, the proposed mechanism of EFV-mediated QTc ART associated with QTc prolongation are still com- prolongation may be due to its ability to inhibit hERG monly prescribed [22]. Continued use of older, toxic I , which may be exacerbated in individuals with slow Kr ARTs is seen in developing countries where HIV is CYP2B6 metabolism. prevalent, mostly due to a lack of access to newly devel- oped agents, cost, and/or other socio-economic barri- Rilpivirine ers [23]. Literature describing the association of QTc Rilpivirine (RPV) is a second generation NNRTI first prolongation and ART is surprisingly sparse, and many introduced to the US market in 2010, and displays a data provide conflicting evidence regarding true asso- favourable side effect profile and higher genetic barrier ciations with QTc prolongation. Most data suggest spu- to resistance when compared with other NNRTIs [31]. rious associations in select populations, such as slow RPV is available in combination with nucleoside/nucle- CYP metabolizers of the primary ART metabolic path- otide reverse transcriptase inhibitors (NRTIs) and the way. Still, clinicians should consider the potential for INSTI, dolutegravir, as STRs [25]. Data examining the QTc prolongation in patients receiving other QTc pro- QTc-prolonging effects of RPV have been documented longing agents or with other comorbidities known to from clinical trials. cause arrhythmias. A summary is provided in Table 1. RPV demonstrated QTc interval prolonging effects in a dose- and concentration-dependent man- Efavirenz ner, at both therapeutic and supratherapeutic doses EFV is a commonly prescribed non-nucleoside [28,32–34], however, there is conflicting data between reverse transcriptase inhibitor (NNRTI) [22] that HIV-negative healthy volunteers and PLWH [28]. Antiviral Therapy 24.6 461 AVT-19-RV-4555_Chastain.indd 461 AVT-19-RV-4555_Chastain.indd 461 22/11/2019 13:49:20 22/11/2019 13:49:20 DB Chastain et al. Table 1. Mechanism of QTc prolongation associated with antiretrovirals, antimicrobial agents for opportunistic infections and other ‘high risk’ drugs commonly used in PLWH [15,22–24,26,46,48,50,54–61] QTc mechanism Factors associated with QTc prolongation Metabolism Inhibition of inhibited another I Dosing regimen Presence of other Documented Kr Inhibition by another blocker when prolongation QTc prolonging Extent of QTc sudden Medication class of hERG drug metabolism occurred agents prolongation cardiac death Non-nucleoside reverse transcriptase inhibitors Efavirenz + - - 600 mg daily No ≥5.2 msec No Rilpivirine + - - 25–150 mg daily No ≥11 msec No Protease inhibitors Saquinavir + +/- - 1,000 mg twice daily n/a n/a No Atazanavir + +/- - 300 mg daily n/a n/a No Lopinavir + +/- - 400 mg twice daily n/a n/a No Nelfinavir + - - 750 mg three n/a n/a No times daily Ritonavir +/- +/- + 100 mg daily to n/a n/a No twice daily Macrolides Azithromycin + +/- + 1,200 mg weekly No n/a Yes Clarithromycin + +/- + 500 mg twice daily No n/a Yes Azoles Fluconazole + + + Any dose n/a n/a No Itraconazole + + + Any dose n/a n/a No Posaconazole + + + Any dose n/a n/a No Voriconazole + + + Any dose n/a n/a No Other Pentamidine + - - 300 mg every +/- n/a No 4 weeks Primaquine +/- - - 30 mg daily No n/a No Methadone + + + Any dose No n/a No hERG, human ether-a-go-go-related gene; n/a, information not available; PLWH, persons living with HIV; +, displays mechanism; -, no evidence; +/-, inconclusive data. Additional non-clinical studies of RPV demonstrated older-generation PIs, such as saquinavir (SQV) and the drug to inhibit potassium channels involved in lopinavir (LPV) in combination with ritonavir (RTV), cardiac action potential repolarization at concentra- which were widely used and regarded as a break- tions approximately 10-fold greater than the clini- through ART class during the mid-1990s [39]. How- cal exposures. Thus, the proposed mechanism of ever, tolerability and dosing requirements led to the QTc prolongation is likely similar to EFV. The pro- refinement of newer-generation PIs, most of which are arrhythmic potential of RPV, with similarly reported available as once-daily tablets or as fixed-dose combi- QTc prolonging effects for EFV, caused subsequent nation tablets with cobicistat [25]. In 2010, the FDA Phase III studies to assess cardiac toxicity as a major issued warnings that RTV-boosted LPV and RTV- safety outcome and exclude patients with a history of boosted SQV may cause prolongation of QTc and PR prolonged QTc syndrome [33,34]. In Phase III stud- [40,41]. Atazanavir (ATV) is also commonly associ- ies, which compared RPV/FTC/TDF to EFV/FTC/TDF, ated with QTc prolongation and is recommended as investigators found an increase in QTc interval with a second-line therapy [25,42]. A study conducted in a mean change from baseline of 12.0 msec (95% CI 2005 to discover the mechanism of QTc prolongation 10.1, 13.8) [33,34]. Two patients receiving RPV expe- in PIs found LPV, nelfinavir (NFV), RTV, and SQV all rienced conduction abnormalities or rate and rhythm caused dose-dependent blockade of hERG channels, disturbances, and an additional patient discontinued and LPV was also found to block the repolarization therapy related to grade 3 QTc prolongation [33]. of I channels in neonatal mouse cardiac myocytes Kr [21]. These inconsistent observations suggest inter- Ritonavir-boosted protease inhibitors personal differences between volunteers/patients and Data describing the QT prolonging effects of the individual PI characteristics may hinder the ability to PIs are conflicting [27,35–38]. Most data are with detect associations with QTc prolongation and TdP. 462 ©2019 International Medical Press AVT-19-RV-4555_Chastain.indd 462 AVT-19-RV-4555_Chastain.indd 462 22/11/2019 13:49:20 22/11/2019 13:49:20 Abnormal QTc syndrome in HIV-infected patients Nucleoside/nucleotide reverse transcriptase inhibitors were refuted with a similar meta-analysis suggesting the NRTIs have also been linked to QTc prolongation, but incidence of arrhythmias in absence of coexisting risk these data generally include heterogeneous popula- factors is very low [61]. Despite most data surrounding tions and lack consideration for confounding variables. QTc-prolonging data and macrolides is outside PLWH A  comprehensive review in 2010 discovered that 3TC, populations, the risk remains. among other ARVs, was commonly associated with TdP, The mechanism of QTc prolongation is thought to be but no significant conclusions could be made [43]. Other blockage of the I encoded by hERG, but also through Kr data suggest 3TC and ZDV are not associated with QT CYP3A4 inhibition of other QTc-prolonging medica- prolongation [44], but conflicting data exist [27]. The tions [62,63]. Variation exists within the macrolide mechanism of NRTI-induced QTc prolongation is not family of compounds in terms of both I inhibitory Kr well understood but may be due to activation of reactive potency and CYP3A4 inhibition potential [63]. oxygen species in the heart mitochondria [45]. Invasive mycoses Antimicrobial agents for opportunistic infections Azole antifungals Pneumocystis jirovecii PLWH, particularly those with AIDS, are at increased Pentamidine risk of invasive fungal infections like oesophageal or Pentamidine is an alternative recommendation for oropharyngeal thrush and cryptococcal meningitis [46]. prophylaxis and therapy of Pneumocystis jirovecii Fluconazole is commonly used in the treatment of these pneumonia (PJP) [46]. Numerous case reports have OIs, which is also a known QTc-prolonging agent [64]. highlighted the QTc-prolonging effects associated with An increasing prevalence of fluconazole-resistant Can- inhaled or parenteral pentamidine in PLWH [47–49], dida spp. warrants an increased use of voriconazole, although these older data are limited by coadministra- posaconazole, itraconazole and isavuconazonium in tion with other QTc prolonging agents or in the set- select indications [46]. ting of electrolyte imbalances [48]. Other retrospective From 1995–2015, there were 191 cases of reported and prospective data have suggested pentamidine is not TdP with systemic azole antifungals; fluconazole was associated with QTc prolongation [50,51]. A poten- associated with the highest proportion of events [64]. tial mechanism was described by de Boer et al. [52], The proposed mechanism of QTc prolongation is due who showed pentamidine inhibits the hERG pathway to hERG inhibition of internal I pores and I protein Kr Kr in canine ventricular cardiomyocytes through I , with trafficking, as well as the inhibition of other I blocking Kr Kr internal pore blockage and protein trafficking. medication metabolism [63]. The degree of QTc prolon- gation can vary between different antifungals within the Primaquine azole class, likely due to structural differences or bind- Primaquine is a recommended alternative therapy in ing affinity to various ion pores and channels, in addi- the management of PJP, in combination with clinda- tion to variability in inhibition of CYP-enzymes [63]. mycin [46]. While related to the parent drug quinidine, which is associated with significant QTc prolongation, Other ‘high risk’ drugs the cardiovascular activity of primaquine has not been Methadone extensively studied [53]. One study found no signifi- Methadone is another well-known QTc-prolonging agent. cant effect of primaquine on the QTc interval of 16 The high prevalence of illicit substance use in the PLWH healthy volunteers [54]. Regardless, QTc prolonga- population highlights the potential risk of methadone- tion is an adverse effect listed in the package insert associated QTc prolongation. Methadone use was found of the drug, likely due to the structural relationship to be an independent predictor of QTc prolongation in an with quinidine [55]. The potential mechanism of QTc injection drug use population, as well as the methadone prolongation is through blockade of hERG via I , as dose used, presence of CYP3A4 inhibitors, potassium level Kr demonstrated in human embryonic kidney cells [56]. and liver dysfunction in PLWH [65,66]. The mechanism of methadone QTc prolongation has demonstrated a dose- Mycobacterium avium complex dependent binding to hERG potassium ion channels [67]. Macrolides Macrolide antibiotics are a mainstay in prophylaxis and Managing HIV-infected patients with prolonged QTc treatment of MAC [46]. Azithromycin and clarithro- intervals mycin are most commonly used, both of which have While the exact quantification of PLWH who have a been well documented to exhibit QTc-prolonging activ- prolonged QTc interval is unknown, clinicians can employ ity [57–59] by as much as an absolute risk increase of strategies to help prevent SCD in these patients. First, 118.1 for SCD and ventricular tachyarrhythmias related PLWH should undergo baseline and routine ECGs [1,5]. to QTc-prolonging potential [60]. However, these data Second, clinicians should monitor all medications Antiviral Therapy 24.6 463 AVT-19-RV-4555_Chastain.indd 463 AVT-19-RV-4555_Chastain.indd 463 22/11/2019 13:49:20 22/11/2019 13:49:20 DB Chastain et al. 8. Soliman EZ, Prineas RJ, Roediger MP, et al. Prevalence associated with prolonged QTc intervals to determine the and prognostic significance of ECG abnormalities in HIV-infected patients: results from the Strategies risk/benefit of prescribing them to PLWH. Lastly, clinicians for Management of Antiretroviral Therapy study. should be aware of other causes of QTc prolongation, such J Electrocardiol 2011; 44:779–785. as male sex, electrolyte disturbances, kidney function, con- 9. Sani MU, Okeahialam BN. QTc interval prolongation in patients with HIV and AIDS. J Natl Med Assoc 2005; current disease states, medications and addictions [7,11]. 97:1657–1661. As the number of concurrent causes increases, so does 10. Kocheril AG, Bokhari SA, Batsford WP, Sinusas AJ. Long QTc the risk of QTc prolongation progression to SCD, which and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997; 20:2810–2816. should prompt an increase in ECG monitoring [11]. The 11. 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QT dispersion in HIV-infected patients receiving combined antiretroviral therapy. Ann Noninvasive PLWH. HIV-infection, higher viral loads, lower CD4 Electrocardiol 2014; 19:561–566. T-cell counts, higher concentrations of inflammatory 15. Gaharwar R, Molke SB, Singh AP, Jatav OP. Association biomarkers, certain antimicrobial agents, addictions, of electrocardiogram abnormalities in human immunodeficiency virus infected patients with special electrolyte imbalances, CKD and CVD all contribute reference to QTc interval. Int J Adv Med 2017; 2:4. to the risk of developing a prolonged QTc interval and 16. Villa A, Foresti V, Confalonieri F. Autonomic neuropathy and subsequent SCD. Due to the high number of risk factors prolongation of QT interval in human immunodeficiency virus infection. Clin Auton Res 1995; 5:48–52. associated with QTc prolongation in PLWH, awareness 17. McIntosh RC, Lobo JD, Hurwitz BE. 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Department QT syndrome in injection drug users receiving methadone: of Health and Human Services. 2019. (Accessed 30 April high frequency in hospitalized patients and risk factors. 2019.) Available from http://aidsinfo.nih.gov/contentfiles/ Arch Intern Med 2006; 166:1280–1287. lvguidelines/AdultandAdolescentGL.pdf Accepted 9 August 2019; published online 30 September 2019 Antiviral Therapy 24.6 465 AVT-19-RV-4555_Chastain.indd 465 AVT-19-RV-4555_Chastain.indd 465 22/11/2019 13:49:20 22/11/2019 13:49:20

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Antiviral Therapy – SAGE

Published: Aug 1, 2019

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