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

Abstract

Background

The purpose of this review is to critically analyse data regarding the prevalence and risk factors for developing a prolonged QTc interval and subsequent sudden cardiac death (SCD) in persons living with HIV (PLWH).

Methods

A systematic literature search using PubMed and Google Scholar databases was performed using the following search terms: ‘HIV and prolonged QTc’ and ‘managing HIV-patients with prolonged QTc’. References within articles of interest were also evaluated.

Results/Discussion

PLWH are at an increased risk of having a prolonged QTc interval. Some risk factors for this include the virus itself, concomitant medications, comorbid conditions, addictions and electrolyte disturbances. PLWH who have an increased HIV RNA viral load or decreased CD4⁺ T-cell count are at further risk for progressing to sudden cardiac death (SCD). Many medications commonly prescribed in the PLWH population, such as antiretrovirals and antimicrobials used in opportunistic infection prophylaxis, have also been shown to promote QTc prolongation through inhibition of human ether-a-go-go potassium channels or through drug metabolism inhibition of other QTc prolonging drugs.

Conclusions

Due to the high number of risk factors associated with QTc prolongation, clinicians should incorporate baseline and routine ECG monitoring for PLWH to potentially lower the increased risk of SCD in PLWH.

Introduction

Worldwide, over 37 million people are living with HIV (PLWH) [1,2]. While this number continues to rise, the number of new infections per year has plateaued, but this is not evenly distributed with higher incidence occurring in locations such as rural areas of the US [3], Eastern Europe, Central Asia, the Middle East and North Africa [4]. With advancements in antiretroviral therapy (ART), PLWH are living longer and are at risk of developing other chronic conditions associated with increased life expectancy, including cardiovascular disease (CVD). In addition to advanced age, PLWH are at further risk of developing CVD due to the effects of the virus on the cardiovascular tissue [1] and the effects of ART [5,6] on the body.

While a plethora of data exist describing the increased morbidity and mortality of ischaemia-related cardiovascular effects of HIV, there are less regarding the impact of the virus on electrical conduction in the heart, more specifically, QT interval prolongation corrected for heart rate (QTc). Available data indicate that PLWH have a prevalence of QTc prolongation ranging from 5–45%, approaching one of every two PLWH, which is 2–3x higher compared with uninfected patients [7–9]. This prolongation can lead to the development of torsade de pointes (TdP) and ventricular fibrillation, ending in sudden cardiac death (SCD) in up to 20% of PLWH [1,5,7,10,11]. Indeed, a recent study using the Veterans Aging Cohort Study (VACS) Virtual Cohort, HIV-infected veterans had a 14% higher risk of SCD compared with uninfected veterans [12]. Additionally, risk of SCD was 4.5-fold higher among PLWH compared with the general population in San Francisco [13]. However, the association between QTc prolongation and SCD in PLWH remains poorly understood. Several studies have identified characteristics associated with QTc prolongation in PLWH, however, there is discordance among these studies [5,9,10,14,15]. Therefore, the purpose of this review is to critically analyse data regarding the prevalence and risk factors for developing a prolonged QTc interval and subsequent SCD in PLWH.

Methods

In order to compile a thorough review, a systematic literature search was performed within PubMed and Google Scholar using the following search terms: ‘HIV and prolonged QTc’ and ‘managing HIV-patients with prolonged QTc’. The articles were restricted to the English language. Article titles and abstracts were screened for possible inclusion, and references within articles of interest were assessed to capture additional sources.

Results/discussion

In the following text, we will analyse previous studies that have evaluated the incidence of, and risk factors associated with QTc prolongation in PLWH. In addition, we will examine the mechanisms of QTc prolongation associated with antiretrovirals (ARVs), antimicrobial agents for opportunistic infections and other ‘high risk’ drugs due to the high prevalence of PLWH receiving one or more of these medications.

QTc Interval Prolongation

Although prevalence differs among studies, QTc prolongation is a common finding in PLWH [7–9,14]. The mechanism of acquired prolonged QTc syndrome is proposed to be due to alterations in cardiac innervation secondary to autonomic neuropathy [9,16], leading to dilated cardiomyopathies potentiating arrhythmias. A study by Kocheril et al. [10] suggested that HIV infection may be associated with acquired prolonged QTc syndrome independent of electrolyte abnormalities and medications. This is thought to be due to direct infection of cardiac cells by the virus [1,17]. Prolonged QTc was observed in 45% (45/100) of adult patients with AIDS, 28% (22/78) of asymptomatic HIV-infected patients and 10% (8/80) of uninfected controls [9]. Mean QTc was significantly different in patients with AIDS (430 ±50 msec) when compared with those with asymptomatic HIV infection (420 ±50 msec; P<0.05) and uninfected controls (400 ±40 msec; P<0.05). The authors hypothesized that this was the result of disease progression in prolonged QTc syndrome given an absence of QTc prolonging drugs and electrolyte abnormalities. Additional data suggest that HIV disease progression, marked by decreasing CD4⁺ T-cell count and increasing HIV RNA viral load, are independently associated with the presence of and increasing degree of a prolonged QTc interval [5,9,15,17,18]. Duration of HIV infection has been associated with QTc prolongation [9]. Nadir or current CD4⁺ T-cell count <200 cells/mm³, but not HIV RNA viral load, at the time of ECG was associated with prolonged QTc interval [5]. In multivariate analysis, risk of QTc prolongation was increased sixfold in PLWH with nadir CD4⁺ T-cell count <200 cells/mm³ (odds ratio [OR] 5.8, 95% CI 1.3, 26.4). Furthermore, QTc prolongation was more likely to occur if HIV RNA viral load ≥17,900 copies/ml or CD4⁺ T-cell count <144 cells/mm³ [18]. In those with both HIV RNA viral load ≥17,900 copies/ml or cell count <144 cells/mm³ risk of QTc prolongation was almost 15x higher (OR 14.74, 95% CI 3.84, 56.55; P<0.0001).

There is discordance in previously published literature on the impact of ART and other HIV-associated medications on the development of SCD in PLWH. Older literature indicates that protease inhibitor (PI)-based regimens and some opportunistic infection (OI) treatment regimens are more likely to cause a prolonged QTc interval than alternative regimens [10,17]; while, more recently published literature indicates that there is no association between ART and QTc prolongation [7,15]. Compared with uninfected controls, mean QTc interval was significantly longer in PLWH receiving ART for a mean 1.5 ±2 years with mean CD4⁺ T-cell count 440 ±188 cells/mm³ (409 ±21 versus 421 ±21 msec; respectively; P=0.002) [14]. Frequency of QTc interval prolongation was similar among ART-naive and -experienced PLWH [5]. Prolonged QTc interval was observed in 15.9% (22/138) of HIV-positive patients of which 98% were virologically suppressed with a mean CD4⁺ T-cell count of 602 ±360 cells/mm³ who had been infected for a mean of 15.1 ±6.7 years [11].

Among PLWH, frequency of QTc interval prolongation appears to differ between males and females. Prolonged QTc was observed in 22.8% of HIV-infected males and 6.7% of HIV-infected females from the HIV-HEART study, of which approximately 95% were on ART, compared with 3.9% of uninfected matched males and 1.8% of uninfected matched females (OR 7.9, 95% CI 5.0, 12.6 for HIV-infected males versus uninfected males and OR 6.7, 95% CI 1.8, 24.2 for HIV-infected females versus uninfected females) [7]. Mean QTc was 424.1 ±23.3 and 435.5 ±19.6 msec in HIV-infected males and females, and 411.3 ±15.3 and 416.4 ±17.3 msec in uninfected males and females, respectively (P<0.0001 for both sexes). In the Multicenter AIDS Cohort Study (MACS), a significantly longer QTc interval was observed in HIV-infected men compared with uninfected controls after adjusting for body mass index (BMI), alcohol consumption greater than 13 drinks per week, cumulative pack-year of smoking, use of opiates, systolic blood pressure, fasting blood glucose, glomerular filtration, left ventricular hypertrophy, and receipt of anti-hypertensive, anti-diabetic or QTc prolonging medications [19].

Regardless of age or severity of HIV, PLWH remain at higher risk of QTc prolongation for a multitude of reasons. Furthermore, QTc prolongation in PLWH is associated with lower CD4⁺ T-cell counts, specifically less than 200 cells/mm³ [5,15], higher concentrations of inflammatory biomarkers [19], CVD, including hypertension [11], chronic kidney disease (CKD) [11], smoking [7] and coinfection with HCV [11]. In addition, prolonged QTc interval predicts CVD [8].

Antimicrobial agents associated with QTc prolongation PLWH are at an increased risk of QTc prolongation due to alterations in cardiac innervation [9,16] and a higher prevalence of prescribed QTc prolonging antimicrobials used for viral suppression or as treatment and/or prophylaxis against OIs [11].

Many antimicrobials commonly prescribed to PLWH can potentiate the risk of QTc prolongation through the inadvertent inhibition of the human ether-a-go-go-related gene (hERG) potassium ion channels, which are responsible for maintaining normal cardiac conduction [20]. hERG potassium channels conduct the rapid component of the delayed rectifier potassium current, I_Kr, and regulate the outward flow of potassium from myocytes. Drug-induced suppression of I_Kr results in the accumulation of intracellular potassium leading to delayed ventricular repolarization and subsequent prolonged QTc interval [20,21]. Differences in drug affinity for I_Kr suppression, cytochrome P450 (CYP)-mediated drug–drug interactions, and accumulation of renallyeliminated antimicrobials leading to increased drug exposures are additional factors that potentiate the risk of QTc prolongation and TdP [20].

Several antimicrobials used in PLWH have been associated with QTc prolongation (Table 1). Relatively few data exist describing the exact mechanism of QTc prolongation in detail and are often limited to case reports highlighting abnormal ECG findings or TdP.

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
Medication class	Inhibition of hERG	Metabolism inhibited by another drug	Inhibition of another I_Kr blocker metabolism	Dosing regimen when prolongation occurred	Presence of other QTc prolonging agents	Extent of QTc prolongation	Documented sudden 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 times daily	n/a	n/a	No
Ritonavir	+/-	+/-	+	100 mg daily to twice daily	n/a	n/a	No
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 4 weeks	+/-	n/a	No
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.

Antiretroviral therapy

While significant advancements have been made in the safety and efficacy of ART over the last decade, some ART associated with QTc prolongation are still commonly prescribed [22]. Continued use of older, toxic ARTs is seen in developing countries where HIV is prevalent, mostly due to a lack of access to newly developed agents, cost, and/or other socio-economic barriers [23]. Literature describing the association of QTc prolongation and ART is surprisingly sparse, and many data provide conflicting evidence regarding true associations with QTc prolongation. Most data suggest spurious associations in select populations, such as slow CYP metabolizers of the primary ART metabolic pathway. Still, clinicians should consider the potential for QTc prolongation in patients receiving other QTc prolonging agents or with other comorbidities known to cause arrhythmias. A summary is provided in Table 1.

Efavirenz

EFV is a commonly prescribed non-nucleoside reverse transcriptase inhibitor (NNRTI) [22] that was first introduced into the US market in 1998, with well-documented clinical efficacy and favourable pharmacological properties [24]. While no longer recommended as an initial first-line ART since 2017, the single tablet regimen (STR) of EFV combined with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) had been used extensively as a preferred therapy in ART-naive patients prior to development of integrase strand transfer inhibitor (INSTI)-based STRs [25].

QTc prolongation and TdP with EFV was first described in 2002 [26]. Subsequent reports in both PLWH and HIV-negative healthy volunteers described further evidence of the relationship between EFV and QTc prolongation [27–29]. The extent of EFV prolonging the QT interval was recorded as >580 msec [26], however, in HIV-negative patients, a mean increase of 5.2 msec was seen [28]. Additionally, a higher prevalence of QTc prolongation was seen in patients receiving EFV-based ART when compared with non-EFV-based regimens (adjusted OR, 4.82; 95% CI, 1.54, 15.11) [27]. The relationship between EFV administration and QTc prolongation has been hypothesized to be due to EFV's long terminal half-life [26] and can occur at any point over the course of therapy [29].

Abdelhady and colleagues [30] hypothesized that volunteers with decreased CYP 2B6 allele expression, the main metabolic pathway of EFV, would be at higher risk of QTc prolongation. EFV was found to significantly prolong the QTc interval at steady-state in slow metabolizers with the CYP 2B6*6 allele in a direct concentration-response relationship (baseline 406 ±16.4 versus steady-state 423 ±11.8 msec; P<0.05). Results from cellular electrophysiology assessment found EFV to inhibit inward and outward I_Kr currents in a concentration-dependent manner. Based on these data, the proposed mechanism of EFV-mediated QTc prolongation may be due to its ability to inhibit hERG I_Kr, which may be exacerbated in individuals with slow CYP2B6 metabolism.

Rilpivirine

Rilpivirine (RPV) is a second generation NNRTI first introduced to the US market in 2010, and displays a favourable side effect profile and higher genetic barrier to resistance when compared with other NNRTIs [31]. RPV is available in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and the INSTI, dolutegravir, as STRs [25]. Data examining the QTc-prolonging effects of RPV have been documented from clinical trials.

RPV demonstrated QTc interval prolonging effects in a dose- and concentration-dependent manner, at both therapeutic and supratherapeutic doses [28,32–34], however, there is conflicting data between HIV-negative healthy volunteers and PLWH [28]. Additional non-clinical studies of RPV demonstrated the drug to inhibit potassium channels involved in cardiac action potential repolarization at concentrations approximately 10-fold greater than the clinical exposures. Thus, the proposed mechanism of QTc prolongation is likely similar to EFV. The pro-arrhythmic potential of RPV, with similarly reported QTc prolonging effects for EFV, caused subsequent Phase III studies to assess cardiac toxicity as a major safety outcome and exclude patients with a history of prolonged QTc syndrome [33,34]. In Phase III studies, which compared RPV/FTC/TDF to EFV/FTC/TDF, investigators found an increase in QTc interval with a mean change from baseline of 12.0 msec (95% CI 10.1, 13.8) [33,34]. Two patients receiving RPV experienced conduction abnormalities or rate and rhythm disturbances, and an additional patient discontinued therapy related to grade 3 QTc prolongation [33].

Ritonavir-boosted protease inhibitors

Data describing the QT prolonging effects of the PIs are conflicting [27,35–38]. Most data are with older-generation PIs, such as saquinavir (SQV) and lopinavir (LPV) in combination with ritonavir (RTV), which were widely used and regarded as a breakthrough ART class during the mid-1990s [39]. However, tolerability and dosing requirements led to the refinement of newer-generation PIs, most of which are available as once-daily tablets or as fixed-dose combination tablets with cobicistat [25]. In 2010, the FDA issued warnings that RTV-boosted LPV and RTV-boosted SQV may cause prolongation of QTc and PR [40,41]. Atazanavir (ATV) is also commonly associated with QTc prolongation and is recommended as a second-line therapy [25,42]. A study conducted in 2005 to discover the mechanism of QTc prolongation in PIs found LPV, nelfinavir (NFV), RTV, and SQV all caused dose-dependent blockade of hERG channels, and LPV was also found to block the repolarization of I_Kr channels in neonatal mouse cardiac myocytes [21]. These inconsistent observations suggest interpersonal differences between volunteers/patients and individual PI characteristics may hinder the ability to detect associations with QTc prolongation and TdP.

Nucleoside/nucleotide reverse transcriptase inhibitors

NRTIs have also been linked to QTc prolongation, but these data generally include heterogeneous populations and lack consideration for confounding variables. A comprehensive review in 2010 discovered that 3TC, among other ARVs, was commonly associated with TdP, but no significant conclusions could be made [43]. Other data suggest 3TC and ZDV are not associated with QT prolongation [44], but conflicting data exist [27]. The mechanism of NRTI-induced QTc prolongation is not well understood but may be due to activation of reactive oxygen species in the heart mitochondria [45].

Antimicrobial agents for opportunistic infections

Pneumocystis jirovecii Pentamidine

Pentamidine is an alternative recommendation for prophylaxis and therapy of Pneumocystis jirovecii pneumonia (PJP) [46]. Numerous case reports have highlighted the QTc-prolonging effects associated with inhaled or parenteral pentamidine in PLWH [47–49], although these older data are limited by coadministration with other QTc prolonging agents or in the setting of electrolyte imbalances [48]. Other retrospective and prospective data have suggested pentamidine is not associated with QTc prolongation [50,51]. A potential mechanism was described by de Boer et al. [52], who showed pentamidine inhibits the hERG pathway in canine ventricular cardiomyocytes through I_Kr, with internal pore blockage and protein trafficking.

Primaquine

Primaquine is a recommended alternative therapy in the management of PJP, in combination with clindamycin [46]. While related to the parent drug quinidine, which is associated with significant QTc prolongation, the cardiovascular activity of primaquine has not been extensively studied [53]. One study found no significant effect of primaquine on the QTc interval of 16 healthy volunteers [54]. Regardless, QTc prolongation is an adverse effect listed in the package insert of the drug, likely due to the structural relationship with quinidine [55]. The potential mechanism of QTc prolongation is through blockade of hERG via I_Kr, as demonstrated in human embryonic kidney cells [56].

Mycobacterium avium complex Macrolides

Macrolide antibiotics are a mainstay in prophylaxis and treatment of MAC [46]. Azithromycin and clarithromycin are most commonly used, both of which have been well documented to exhibit QTc-prolonging activity [57–59] by as much as an absolute risk increase of 118.1 for SCD and ventricular tachyarrhythmias related to QTc-prolonging potential [60]. However, these data were refuted with a similar meta-analysis suggesting the incidence of arrhythmias in absence of coexisting risk factors is very low [61]. Despite most data surrounding QTc-prolonging data and macrolides is outside PLWH populations, the risk remains.

The mechanism of QTc prolongation is thought to be blockage of the I_Kr encoded by hERG, but also through CYP3A4 inhibition of other QTc-prolonging medications [62,63]. Variation exists within the macrolide family of compounds in terms of both I_Kr inhibitory potency and CYP3A4 inhibition potential [63].

Invasive mycoses Azole antifungals

PLWH, particularly those with AIDS, are at increased risk of invasive fungal infections like oesophageal or oropharyngeal thrush and cryptococcal meningitis [46]. Fluconazole is commonly used in the treatment of these OIs, which is also a known QTc-prolonging agent [64]. An increasing prevalence of fluconazole-resistant Candida spp. warrants an increased use of voriconazole, posaconazole, itraconazole and isavuconazonium in select indications [46].

From 1995–2015, there were 191 cases of reported TdP with systemic azole antifungals; fluconazole was associated with the highest proportion of events [64]. The proposed mechanism of QTc prolongation is due to hERG inhibition of internal I_Kr pores and I_Kr protein trafficking, as well as the inhibition of other I_Kr blocking medication metabolism [63]. The degree of QTc prolongation can vary between different antifungals within the azole class, likely due to structural differences or binding affinity to various ion pores and channels, in addition to variability in inhibition of CYP-enzymes [63].

Other ‘high risk’ drugs

Methadone

Methadone is another well-known QTc-prolonging agent. The high prevalence of illicit substance use in the PLWH population highlights the potential risk of methadone-associated QTc prolongation. Methadone use was found to be an independent predictor of QTc prolongation in an injection drug use population, as well as the methadone dose used, presence of CYP3A4 inhibitors, potassium level and liver dysfunction in PLWH [65,66]. The mechanism of methadone QTc prolongation has demonstrated a dose-dependent binding to hERG potassium ion channels [67].

Managing HIV-infected patients with prolonged QTc intervals

While the exact quantification of PLWH who have a prolonged QTc interval is unknown, clinicians can employ strategies to help prevent SCD in these patients. First, PLWH should undergo baseline and routine ECGs [1,5]. Second, clinicians should monitor all medications associated with prolonged QTc intervals to determine the risk/benefit of prescribing them to PLWH. Lastly, clinicians should be aware of other causes of QTc prolongation, such as male sex, electrolyte disturbances, kidney function, concurrent disease states, medications and addictions [7,11]. As the number of concurrent causes increases, so does the risk of QTc prolongation progression to SCD, which should prompt an increase in ECG monitoring [11]. The increased vigilance and monitoring of the ECG and other causes will enable clinicians to identify prolonged QTc intervals early and reduce the associated morbidity and mortality; however, the cost effectiveness of routine ECG monitoring must still be evaluated [8].

Conclusion

Prolonged QTc interval is a common finding among PLWH. HIV-infection, higher viral loads, lower CD4⁺ T-cell counts, higher concentrations of inflammatory biomarkers, certain antimicrobial agents, addictions, electrolyte imbalances, CKD and CVD all contribute to the risk of developing a prolonged QTc interval and subsequent SCD. Due to the high number of risk factors associated with QTc prolongation in PLWH, awareness of QTc through baseline and follow-up ECG monitoring may aid in reducing the increased risk of SCD.

Footnotes

Acknowledgements

The authors received no financial support for the research, authorship and/or publication of this article.

The authors declare no competing interests.

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