Nigerian Journal of Cardiology

: 2020  |  Volume : 17  |  Issue : 1  |  Page : 1--10

Arrhythmia in people living with HIV/AIDS

Shailesh Singh1, Katyayni Singh2,  
1 Department of Cardiology, Fortis Escorts Heart Institute, New Delhi, India
2 Department of Paediatrics, Lal Bahadur Shastri Hospital, New Delhi, India

Correspondence Address:
Dr. Shailesh Singh
M-429, Ashiana Colony, Lucknow - 226 012, Uttar Pradesh


With improvement in longevity and therapy of HIV; acquired heart diseases are expected to become more and more prevalent. The electric abnormalities in HIV/AIDS are not very rare. These electrical abnormalities in HIV/ AIDS patients may result from the structural heart diseases because of accelerated atherosclerosis, or cardiac dilation as a sequela of myocarditis, or infective endocarditis or pericardial afflictions in HIV. These electrical disorders can present with a history of palpitations, missed beats or even sudden cardiac death. Both tachy- and bradyarrhythmia may be seen in people living with HIV/AIDS.

How to cite this article:
Singh S, Singh K. Arrhythmia in people living with HIV/AIDS.Nig J Cardiol 2020;17:1-10

How to cite this URL:
Singh S, Singh K. Arrhythmia in people living with HIV/AIDS. Nig J Cardiol [serial online] 2020 [cited 2020 Aug 15 ];17:1-10
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According to the WHO data in 2018, approximately 38 million people worldwide were suffering with AIDS. In 2018, approximately 1.7 million individuals were diagnosed globally as cases of human immunodeficiency virus (HIV).[1] HIV has plagued humanity since long and has significantly reduced the lifespan and the quality of life.[2] However, the widespread use of combined antiretroviral therapy has improved the lifespan of the patient by preventing opportunistic infections.[3]

With the availability of better diagnosis and treatment of opportunistic infections and malignancies, patients are living a longer life. When people living with HIV/AIDS (PLHA) were followed up 10 years after the start of highly active (triple drug) antiretroviral therapy (HAART), it was found that the most frequent causes of death were non-AIDS cancer, AIDS, cardiovascular, and liver-related diseases.[4] With continuous improvement in the longevity and therapy of HIV, acquired heart diseases are expected to become more and more prevalent.[5]

These cardiac complications usually occur late in HIV/AIDS, and they include left ventricular diastolic dysfunction, left ventricular systolic dysfunction, pulmonary arterial hypertension, dyslipidemia, premature coronary artery disease, stroke, infective endocarditis, pericardial effusion, and cardiac malignancies.[6],[7] Many of the drugs used for the patients suffering from HIV/AIDS have also been found to be etiologic factors in many of these complications.

Cardiac rhythm abnormalities in HIV/AIDS are not uncommon.[8] They may result from structural heart diseases because of accelerated atherosclerosis, or cardiac dilation as a sequela of myocarditis, or infective endocarditis or pericardial afflictions in HIV. In addition, the polypharmacy used in the management of HIV/AIDS can also lead to electrical instability because of unusually prolonged repolarization, drug-induced electrolyte abnormalities, or drug-induced conduction system slowing. These disorders can present with a history of palpitations, missed beats, or even sudden cardiac death.

 Types of Arrhythmia in People Living With Human Immunodeficiency Virus/AIDS

Both tachy- and bradyarrhythmias may be seen in PLHA. Commonly seen electrocardiogram (ECG) changes in PLHA include mild prolongation of QTc, nonspecific ST-T changes, low-voltage complexes, intraventricular conduction delay, and monomorphic as well as polymorphic ventricular ectopics. Nonsustained ventricular tachycardia (VT) is reported in 15%–23% of patients.[8] Atrial fibrillation (AF) and flutter were found to be present in 2% of patients with PLHA.[9] Other arrhythmias which can be seen in patients with HIV/AIDS include torsades de pointes (TdP) and atrioventricular blocks. Sudden cardiac death has been found to be 4.5 times higher in patients with HIV/AIDS than that in the general population.[10]


The causes of tachyarrhythmia in PLHA can be either of the following: structural heart disease including cardiac tumors, pro-arrhythmic drugs, concomitant hepatic or renal dysfunction, dyselectrolytemia, chronic inflammation, autonomic dysfunction, substance abuse, and HIV infection itself.

Structural heart diseases

Studies have found that myocarditis is common in PLHA. The myocarditis in HIV is caused by multiple factors. HIV can directly cause myocarditis; the other causes of myocarditis include an infection due to opportunistic cardiotropic viruses, for example, Coxsackie B3 virus, Epstein–Barr virus, and Cytomegalovirus, or it may result from opportunistic bacterial infection such as Mycobacterium avium – intracellulare. Cryptococcus neoformans, an opportunistic fungus, and parasites such as Toxoplasma gondii have also been found to be the causative agents. Autoimmune myocarditis is also seen.[11] Literature suggests that myocarditis can lead to arrhythmias.[12]

Although the prevalence of HIV-associated dilated cardiomyopathy has reduced with ART being freely available under various health schemes and the increasing awareness of physicians and patients, it is still seen in many patients in developing countries.[5] The various causes of dilated cardiomyopathy in PLHA are myocarditis, ischemia due to accelerated atherosclerosis, deficiency of micronutrients such as selenium, some drugs used in the treatment of HIV patients such as zidovudine, autoimmunity, erratic inflammatory pathways, etc.[11] Studies have suggested that the patients suffering from dilated cardiomyopathy have a significantly high burden of arrhythmias, which may range from including conduction defects, AF, to life-threatening ventricular arrhythmias and sudden cardiac death.[13]

It is a known fact that because of accelerated atherosclerosis, which may be because of chronic inflammatory state, arteriopathy, or drugs such as protease inhibitors (PIs),[14],[15],[16],[17],[18],[19],[20],[21] patients with HIV/AIDS are more likely to develop coronary artery disease and myocardial infarction (MI). PLHA have an increased predisposition for the development of myocarditis, dilated cardiomyopathy, and systolic dysfunction. The structural changes in the heart because of these diseases provide a substrate for the development of VT. Patients with ejection fraction <30%, due to any cause, ischemic or nonischemic in origin, have a high likelihood of developing VT.

Cardiac tumors

Opportunistic malignancies may affect the heart. Various types of cardiac arrhythmias have been reported in patients with HIV-associated cardiac tumors.[22],[23] Even benign cardiac tumors can give rise to malignant arrhythmias.[24]


Various drugs used in the treatment of AIDS or opportunistic infections associated with it may be pro-arrhythmic. It is postulated that drug-induced QT prolongation is usually caused by the blockage of HERG potassium channels. Studies have suggested that PIs by causing a dose-dependent block of the aforementioned channels could predispose PLHA to QT prolongation and TdP.[25]

Efavirenz, a nonnucleoside reverse transcriptase inhibitor, has also been found to increase QTc interval, thus increasing the predisposition for ventricular arrhythmias.[26],[27],[28]

Ganciclovir, amphotericin B,[29] and azole group of antifungals[30] may cause long QTc and TdP. TdP has also been described in patients receiving macrolide antibiotics (erythromycin and clarithromycin), which are used for treating drug-resistant tuberculosis and in the treatment and prophylaxis of nontubercular mycobacteria.

Some other drugs which can cause QTc prolongation in people living with HIV/AIDS include Pentamidine,[31] which is used for the management of Pneumocystis jiroveci infection; trimethoprim sulfamethoxazole, which is used for the prevention of P. jiroveci and T. gondii ciprofloxacin,[32] which is used in the prevention of recurrent Salmonella bacteremia; clarithromycin, which is used in the prevention of M. avium intercellulare and Bartonella infection and in the treatment of Toxoplasma encephalitis (along with pyrimethamine and leukovorin), M. avium intercellulare infection, bacterial respiratory diseases.

Many PLHA receive treatment for opioid addiction. Methadone, an opioid substitution treatment, is commonly used for this purpose. QTc prolongation and TdPs have been reported in patients with HIV receiving high doses of methadone.[33],[34],[35],[36],[37]

Some studies have found that PLHA have higher chances of having long QT interval independent of the drugs used in treatment.[38],[39]

Comorbidities such as renal and hepatic insufficiency may lead to decreased elimination of many of the drugs mentioned above, which tend to accumulate and cause prolongation of QT interval.[40],[41],[42],[43]


Diarrhea is very common in patients with HIV infection. It may be due to the virus itself, opportunistic infections, ART, or other pharmacological agents used in HIV-infected patients.[44] This can result in electrolyte imbalances. Hypokalemia, hypocalcaemia, and hypomagnesaemia are often reported in patients with this problem.

Many HIV/AIDS patients also receive anticancer and antifungal agents for opportunistic malignancies such as lymphoma/leukemia and cryptococcal meningitis. Drugs such as amphotericin B,[45] vinblastine, and tenofovir can cause hypokalemia.[46],[47],[48] Hypokalemia can also be seen in HIV/AIDS patients as a part of electrolyte abnormalities due to enteric infections.[49] Hypokalemia, in turn, can cause early-after depolarization (EAD), leading to ventricular arrhythmias.

Similarly, hypomagnesemia has been reported with pentamidine, an agent used in the prevention and treatment of P. jiroveci pneumonia, and foscarnet, an antiviral used against Cytomegalovirus, Epstein–Barr virus, and Varicella-Zoster virus.[50],[51] Studies have reported that many HIV/AIDS patients harbor hypomagnesemia.[52] In the manner similar to hypokalemia, chronic diarrhea can also cause hypomagnesemia. Hypomagnesemia, in turn, can lead to ventricular arrhythmias through increased EAD.[53]

Chronic inflammation

Chronic systemic inflammation can provoke arrhythmias both directly, by altering cardiac electrophysiology, and indirectly, by leading to dilated cardiomyopathy or coronary artery disease, which, in turn, can give rise to arrhythmias.[54],[55] Both supraventricular and ventricular arrhythmia may be seen due to chronic inflammation.[55] Various hypotheses have been proposed to explain arrhythmia due to inflammatory state, which include abnormal calcium handling[56],[57],[58],[59] and abnormal myocardial depolarization due to Na channel dysfunction.[60]

Inflammation induced ventricular vulnerability and triggered activity, have been proposed to be another mechanism for ventricular arrhythmias.[61]

Induction of QTc and Tp interval prolongation is another mechanism by which chronic systemic inflammation can lead to arrhythmias directly.[62],[63]

Studies have proven that AF is an inflammatory disorder, characterized by increased levels of inflammatory markers such as high-sensitivity-C-reactive protein and interleukin-6.[64]

Both acute and chronic HIV infection leads to a state of inflammation. HAART decreases the inflammation, but it does not completely suppress it.[65],[66],[67],[68],[69] Probably, the fibrosis and structural changes that develop as the result of inflammation predispose to AF.[5],[70],[71]

Substance abuse

Patients with HIV/AIDS are more likely to have a positive history of substance use and abuse.[72],[73],[74] It may involve the use of alcohol, smoking, cocaine, and amphetamines. Cocaine has been associated with MI and various types of cardiac arrhythmias. There are multiple mechanisms by which cocaine can cause arrhythmias, increasing the predisposition to MI is one of them.[75]

Besides this, it causes arrhythmias by two primary mechanisms: the first is by increasing the tone of the sympathetic outflow and decreasing the vagal tone, which increase the excitability of the ventricles, and the second is by blocking sodium and potassium channels, which leads to the prolongation of QTc interval. Cocaine increases the intracellular calcium levels,

which causes an increases after-depolarizations and triggered activity, which in turn can cause ventricular arrhythmias.[76]

The use of amphetamines and amphetamine-type stimulants, a group of drugs used as central nervous system stimulants, is also common in PLHA.[77],[78]

Methamphetamine is one of the most abused amphetamines; others include dextroamphetamine, methylphenidate, ephedrine, Ice, and 3,4-methylenedioxymethamphetamine, popularly known as Ecstasy. Studies have found that it is one of the risk factors for the acquisition and transmission of HIV.[79],[80],[81],[82],[83]

Amphetamines promote the release of sympathetic neurotransmitters, causing a surge. Studies have found an association between VT/sudden cardiac death and amphetamine use.[84],[85]

Both amphetamine and cocaine can predispose for MI and development of nonischemic dilated cardiomyopathy, both of which can present with VT.

Autonomic dysfunction

The electrical stability of the heart depends on the fine balance between sympathetic and parasympathetic systems. Alterations in sympathetic or parasympathetic systems influence the heart and can lead to ventricular arrhythmia and even sudden cardiac death. Heart rate variability (HRV) reflects the imbalance in the autonomic nervous system.

Reduced HRV has been proposed as a predictor of sudden cardiac death due to ventricular tachyarrhythmia in cardiac patients.[86]

PLHA have been shown to have a higher prevalence of autonomic dysfunction, as measured by HRV.[86],[87],[88],[89],[90],[91],[92]

Patients who land up in AIDS have severe cardiac autonomic dysfunction. Those HIV-positive patients who have not yet developed AIDS do not have significant autonomic dysfunction. As the HIV disease progresses, the cardiac autonomic nervous dysfunction also progresses slowly.[93]

Askgaard et al. found that moderate autonomic dysfunction is present in HIV-positive patients even with suppressed viral load due to HAART, and it correlated with HbA1c and hypercholesterolemia but not to the duration of HIV or whether the patients received PIs as part of the HAART regimen.[94]

Human immunodeficiency virus infection

Some studies have found that PLHA have higher chances of having long QT interval independent of the drugs used in treatment.[95],[96]

 Risk Factors for Bradyarrhythmia in People Living With Human Immunodeficiency Virus/AIDS

Various types of bradyarrhythmias have been reported in PLHA. First-degree heart block has been reported in PLHA. Age, body mass index, baseline heart rate, and use of drugs such as β-blockers and PIs were found to be risk factors for first-degree heart block.[97] Cases of sick sinus syndrome, sinus arrest, and Mobitz type II AV block requiring permanent pacemaker in patients started on lopinavir/ritonavir have been reported.[98],[99] Even complete heart block (CHB) has been described in a patient treated with ritonavir-boosted lopinavir.[100] Atazanavir is another PI which is used for both treatment-naïve patients and patients with treatment failure. First-degree heart block and new asymptomatic bundle branch have been reported with its use.[101],[102]

CHB has also been reported in a patient with HIV, who was found to be leptospira positive. Electrocardiogram showed CHB, which disappeared after antibiotic treatment.[103] In another case, CHB in an AIDS patient reverted to normal sinus rhythm after treatment for cardiac invasive Burkitt's lymphoma.[104]

 Atrial Fibrillation and Flutter in Human Immunodeficiency Virus

AF is the most common type of arrhythmia globally, and its prevalence increases with increasing age.[105] As patients with HIV/AIDS are expected to live longer, more and more PLHA presenting with AF is expected.[106]

Stroke is a common cause of mortality and disability in people with HIV.[107] AF is one of the most common causes of stroke, and it increases in incidence with age.[108] Conventionally, it has been said that AF can increase the risk for stroke by five times.[105],[108] In addition, it has been said that AF increases all-cause mortality and risk of heart failure.[105],[108]

Classical risk factors associated with new-onset AF include hypertension, ischemic heart disease, heart failure, diabetes mellitus, MI, obesity, cardiac surgery, obstructive sleep apnea, hyperthyroidism, and positive family history of AF. Smoking and alcoholism have also been associated with increased risk of AF. Studies have shown that HIV-positive patients are more likely to have a history of smoking[109] and alcoholism.[110]

A study by Sanders et al. have found that both AF and flutter are more common in PLHA.[9] In this study, HIV-positive patients were found to have a higher prevalence of risk factors for AF such as dyslipidemia, hypertension, diabetes, coronary artery disease, and MI. The authors found a significant difference in the prevalence of AF in PLHA (133/5052 HIV + persons had atrial fibrillation/atrial flutter (AF/AFL), whereas 208/10,121 HIV− persons had AF/AFL). The authors also found that patients with CD4+ T-cell count <200 cells/mm3 were more likely to have AF/AFL, whereas peak viral load was not associated with it. However, another study by Hsu and Waters[70] found that both low CD4(+) cell count and high viral load were independently associated with the development of AF. Various studies have suggested that HIV-positive patients are more likely to have a structural alteration in the heart, predisposing them to AF.[5],[70],[71] Another study by Elnahar et al. found that low CD4(+) cell count was associated with AF.[111]

 Management of Atrial Fibrillation in People Living With Human Immunodeficiency Virus/AIDS

There have been many published guidelines regarding the management of AF.[105],[108] The choice of therapy depends on the presence of structural heart disease, patients' hemodynamic parameters, the concomitant drugs being used, bleeding risk, and patients' preferences.

Studies have shown that HIV is a hypercaogulopathy, so patients must be considered for anticoagulation and the thresholds for initiating the anticoagulation should be low. Lip et al. remarked in their article that because HIV is an independent risk factor for stroke, anticoagulation should be considered for all the PLHA even if the CHA2 DS2-VASc score is low.[112]

Both Vitamin K antagonists (VKA) and directly acting oral anticoagulants (DOACs) can be used for anticoagulation. The VKAs have been the mainstay of anticoagulation for HIV/AIDS patients suffering from atrial fibrillation. They are inexpensive and readily available in all parts of the world; however, they have a notoriously high number of drug–drug and drug–food interactions and require periodic monitoring of prothrombin time/international normalized ratio levels. DOACs, which include factor Xa inhibitors (including apixaban and rivaroxaban) and dabigatran, a direct thrombin inhibitor, are more expensive than VKA, are a new drug group, and we will learn about them more as their use increases globally. A significant concern with the use of anticoagulants in HIV is the potential interactions between antiretrovirals and anticoagulants. Among the antiretrovirals, PIs, cobicistat, and maraviroc are considered to be potent enzyme inhibitors, whereas nevirapine and efavirenz are enzyme inducers.

The potential drug interaction between HAART and anticoagulants should be kept in mind because specific interactions may lead to failure of anticoagulation, while a few may predispose the patients to bleed. PIs, for example, atazanavir/indinavir/lopinavir/ritonavir/saquinavir, and cobicistat inhibit CYP3A4 and P-gp, which increase the plasma levels of rivaroxaban/apixaban, leading to higher chances of bleeding. On the other hand, drugs such as nevirapine and efavirenz decrease the plasma level of factor Xa inhibitors due to CYP3A4 induction. The metabolism of dabigartan is not affected much because of PIs, but cobicistat-boosted PIs can lead to increased plasma levels of dabigartan. Therefore, it is advisable to have a spacing of 2 h between the intake of dabigartan and antiretrovirals.

Warfarin is a racemic mixture of R-warfarin and S-warfarin, the latter is a more potent anticoagulant. Both enantiomers are metabolized by different enzymes; R-warfarin undergoes metabolism by CYP1A2 and 3A4, whereas S-warfarin is metabolized by CYP2C9. Drugs such as PIs or cobicistat which cause inhibition of CYP3A4 increase the serum warfarin level. Acenocoumarol undergoes degradation by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19; the PIs can decrease its plasma levels.

The drugs used for rate control include calcium channel blockers, verapamil, diltiazem, beta-blockers, and digoxin. Digoxin, like the anticoagulants, is infamously famous for numerous drug interactions. PIs can increase the serum digoxin levels, predisposing the patients to various arrhythmia and gastrointestinal adverse effects because of digoxin toxicity. Similarly, co-administration of calcium channel blockers with PI or maraviroc predisposes the patients to heart blocks. The use of nevirapine or efavirenz in patients on calcium channel blockers mandates the use of a higher dose of the latter.

The drugs commonly used for rhythm control in AF include class IA drugs which include procainamide, quinidine, and disopyramide; class IC drugs, i.e., flecainide and propafenone; and class III drugs such as sotalol, amiodarone, dofetilide, and dronedarone.

Patients who have no evidence of the underlying structural heart disease can be initiated on dofetilide, dronedarone, flecainide, propafenone, or sotalol. Amiodarone is usually a second-line drug in this subset of patients. Patients with underlying heart failure should be started on amiodarone or dofetilide. Those with coronary artery disease should be given dofetilide, dronedarone, or sotalol; amiodarone is used as a second-line drug. The patient may also choose to undergo catheter ablation for AF.

Theoretically, a number of drug interactions can occur between the anti-arrhythmics and antiretrovirals. Amiodarone, one of the commonly used drugs for the management of rhythm control in AF, is a substrate of CYP3A4. CYP3A4 is also responsible for the metabolism of dofetilide. The concomitant use of enzyme inhibitors such as PI or cobicistat can lead to an increased serum concentration, which can manifest as life-threatening ventricular arrhythmias. Similarly, the use of enzyme inducers such as nevirapine and Efavirenz may lead to lower serum levels of these drugs.

Propafenone is mainly metabolized by CYP2D6 and to a smaller extent by CYP1A2 and CYP3A4; concomitant PI administration leads to its increased serum concentration, leading to a higher risk of ventricular arrhythmia. Flecainide is metabolized mainly via CYP2D6, and its serum levels can get boosted with the use of cobicistat, which can culminate into ventricular arrhythmia.

 Ventricular Arrhythmia in People Living With Human Immunodeficiency Virus/AIDS

Ventricular rhythms are characterized by a broad QRS complex, i.e., >120 ms. Ventricular rhythms may manifest in the form of premature ventricular complexes, VT, or ventricular fibrillation.

In the general population, with a few exceptions, VT usually occurs in patients with structural heart disease. Presence of coronary artery disease, MI, and systolic dysfunction predisposes the patients to develop the ventricular ectopic, which can occur in the form of single beats, couplets, and triplets. These beats may occur occasionally, or there may be a bigeminal, trigeminal, or quadrigeminal rhythm. Such patients may develop nonsustained or sustained VT. PLHA are more likely to have these structural heart diseases, compared to the general population.[11],[13] Sustained VT is more commonly seen in the setting of severe sepsis, significant hypoxia, atypical pneumonia due to P. jiroveci, pulmonary arterial hypertension, and coronary heart disease.[8]

PLHA are likely to have a history of recreational drug abuse, such as amphetamines and cocaine.

Both these drugs of abuse can cause arrhythmia by causing sympathetic surge, and beta-blockers are cornerstones of preventing such surge once the arrhythmia has been cardioverted.

 Acquired Long Qt Syndrome and Torsades De Pointes in People Living With Human Immunodeficiency Virus/AIDS

TdPs is a special type of polymorphic ventricular arrhythmia developing in the setting of long QT interval. PLHA have been shown to have prolonged QTc. An Italian study found that 7.4% of HIV-positive patients had prolonged QTc. The prolongation of QTc interval has been studied in patients infected with HIV.[113]

In HIV-HEART study, 22.8% of HIV-positive men were found to have long QTc compared to 3.9% of HIV-negative men. Women had lower prevalence of long QTc, and 12.1% of HIV-positive women had long QT compared to 1.8% in HIV-negative women.[114] A study from South-East Nigeria found QTC prolongation in 48% of treatment-naïve patients.[115]

Long QT syndrome has been found in approximately 1/3rd of hospitalized HIV-positive patients.[116],[117] Patients who have prolonged QTc (QTc >500 ms) may remain asymptomatic, or develop syncope, complex ventricular arrhythmia, or even sudden cardiac death.

 Prevention and Management of Torsades De Pointe in People Living With Human Immunodeficiency Virus/AIDS

ECG of patients living with HIV should be routinely monitored, and patients should be screened for acquired long QT syndrome.[118],[119] QTc interval of 500 ms or more should alert the physician, and possible reversible causes should be identified.

Patients who have electrolyte imbalances such as hypokalemia should have their ECG monitored, and their electrolyte insufficiency should be identified and treated as soon as possible. Intravenous magnesium sulfate is the treatment of choice for patients with TdP. Other options include intravenous infusion of isoproterenol[120] and overdrive pacing. Mexiletine hydrochloride has also been used in PLHA and TdP patients successfully.[121]

Cases of repeated TdP necessitating Cardio-Pulmonary Resuscitation (CPR) and implantation of an automated implantable cardioverter defibrillator (AICD) have been reported.[120],[121]

Patients who are receiving methadone for opioid-use disorder and develop TdP may be switched to sustained-release oral morphine, which may be used as an alternative to methadone.[122]


Cardiac rhythm abnormalities in HIV/AIDS are not uncommonBoth tachy- and bradyarrhythmias may be seen in PLHAThe causes of tachyarrhythmia in PLHA can be either of the following: structural heart disease including cardiac tumors, pro-arrhythmic drugs, concomitant hepatic or renal dysfunction, dyselectrolytemia, chronic inflammation, autonomic dysfunction, substance abuse, and HIV infection itselfThe potential drug interaction between HAART and anticoagulants used for the management of AF should be kept in mind because specific interactions may lead to the failure of anticoagulation, while a few may predispose the patients to bleedLong QT syndrome and TdP may occur in HIV-positive patients. Routine ECG monitoring may be warranted among patients living with HIV in clinical practice to prevent TdP.

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