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Table of Contents
ORIGINAL ARTICLE
Year : 2015  |  Volume : 14  |  Issue : 4  |  Page : 169-176  

QTCinterval prolongation in HIV-negative versus HIV-positive subjects with or without antiretroviral drugs


1 Department of Internal Medicine, Cardiac Care Centre, Federal Medical Centre, Ido Ekiti, Ekiti State, Nigeria
2 Department of Internal Medicine, Endocrinology, Diabetes and Metabolism Unit, Ladoke-Akintola University of Technology Teaching Hospital, Ogbomoso, Oyo State, Nigeria

Date of Web Publication16-Oct-2015

Correspondence Address:
Olarinde Jeffrey Ogunmola
Department of Internal Medicine, Cardiac Care Centre, Federal Medical Centre, Ido-.Ekiti, Ekiti State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1596-3519.152072

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   Abstract 

Background: QTc interval prolongation signifies an increased risk of life-threatening arrhythmia and sudden cardiac death. Cardiac manifestations of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome have become increasingly important causes of morbidity and mortality. We investigated HIV-positive patients to determine the effects of HIV infection, antiretroviral drugs, and identifiable confounders on QTc prolongation. Materials and Methods: A case-control study was conducted in a rural tertiary health center in Nigeria. Data collected included demographic variables, body mass index, blood pressure, HIV status, antiretroviral treatment (ART), duration of HIV infection and treatment, CD4 T-lymphocyte count, heart rate (HR), and QT interval. QT was corrected for HR using Bazett's formula. Results: The sample frame comprised 89 (42.4%) HIV-negative subjects (39.3% male, 60.7% female; mean age, 36.28 ± 7.03 years); 45 (21.4%) HIV-positive, ART-naïve patients (31.1% male, 68.9% female; mean age, 36.48 ± 9.12 years); and 76 (36.2%) HIV-positive patients on ART (27.6% male, 72.4% female; mean age, 39.00 ± 7.68 years). The QTc interval and resting HR were higher in HIV-positive, drug-naïve patients than in the other two groups (P < 0.001). Female sex was associated with prolonged QTc intervals in all groups. Conclusion: HIV-positive patients may be at higher risk of sudden cardiac death due to fatal arrhythmia secondary to QTc interval-related cardiac events. Healthcare providers should be aware that a prolonged QTc interval is a potential indicator of increased cardiovascular risk and should exercise caution in prescribing potentially QT-prolonging medications to HIV-positive patients.

   Abstract in French 

Résumé
Contexte: QTc interval prolongation significatives es un risque accru d'arythmie mortelle et mort subite. Manifestations cardiaques de virus cacité d'immunodefi humaine (VIH) et syndrome de cience acquise immunodefi sont devenus de plus en plus importantes causes de morbidité et de mortalité. Nous avons étudié les patients VIH-positifs pour déterminer les effets de l'infection VIH, antirétroviraux et identifiants en facteurs confondants sur QTc.
Matériels et méthodes: une étude cas-témoins a été menée dans un centre de santé tertiaires en milieu rural au Nigeria. Les données recueillies comprenaient des variables démographiques, indice de masse corporelle, la pression artérielle, séropositivité, un traitement antirétroviral (ART), durée de HIV infection et traitement, le nombre de lymphocytes T CD4, la fréquence cardiaque (HR) et de l'intervalle QT. QT a été corrigé pour les RH à l'aide de la formule de Bazett.
Résultats: Le cadre de l'échantillon composé de 89 (42,4%) Sujets séronégatifs (39,3% de garçons, 60,7% de femmes; âge moyen, ±36.28 ans 7,03); 45 (21,4%) Patients naïfs ART séropositifs, (31,1% de garçons, 68,9% de femmes; âge moyen, ±36.48 ans 9,12); et 76 (36,2%) Les patients VIH-positifs sur l'ART (27,6% de garçons, 72,4% de femmes; âge moyen, ±39,00 7,68 ans). L'intervalle QTc et HR de repos étaient plus élevées dans les VIH-positifs, drogue-naïve patients que chez les autres AQ4 deux groupes (P < 0,001). Sexe féminin a été associé à des intervalles QTc prolongés dans tous les groupes.
Conclusion: Chez les patients VIH-positifs peuvent être plus à risque de mort subite due à l'arythmie fatale secondaire pour les événements cardiaques axés sur l'intervalle QTc. Prestataires de soins doivent être conscients qu'un intervalle QTc prolongé est un indicateur potentiel d'augmentation du risque cardiovasculaire et devrait faire preuve de prudence dans la prescription potentiellement allongeant l'intervalle QT médicaments pour les patients VIH-positifs.
Mots-clés: Traitement antirétroviral, électrocardiogramme, fréquence cardiaque, virus de l'immunodéficience humaine, de l'intervalle QT

Keywords: Antiretroviral treatment, electrocardiogram, heart rate, human immunodeficiency virus, QT prolongation, torsades de pointes


How to cite this article:
Ogunmola OJ, Oladosu YO, Olamoyegun MA. QTCinterval prolongation in HIV-negative versus HIV-positive subjects with or without antiretroviral drugs. Ann Afr Med 2015;14:169-76

How to cite this URL:
Ogunmola OJ, Oladosu YO, Olamoyegun MA. QTCinterval prolongation in HIV-negative versus HIV-positive subjects with or without antiretroviral drugs. Ann Afr Med [serial online] 2015 [cited 2020 Aug 9];14:169-76. Available from: http://www.annalsafrmed.org/text.asp?2015/14/4/169/152072


   Introduction Top


Nigeria has the second-largest population of people living with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) worldwide after South Africa.[1] HIV infection and AIDS are known to cause cardiac disease.[2] The number of deaths attributable to these conditions has also increased.[2] Prolongation of the QT interval as measured by electrocardiography (ECG) has been used to predict fatal arrhythmic events.[3] Moreover, epidemiologic studies have shown an increased risk of cardiac death among those with prolonged QT intervals.[3],[4] A higher prevalence of QTc interval prolongation among HIV-infected patients than among HIV-negative subjects has been reported.[5],[6] However, the only study of this nature in Nigeria was performed in an urban hospital setting.[6] In addition, this study did not define or include an antiretroviral treatment (ART) group. Because Nigeria is predominantly rural (more rural than urban settlements), studies of this nature in rural settings would provide more accurate and complementary information. Therefore, we assessed QTc intervals in HIV-infected patients with and without ART and compared them with QTc intervals in HIV-negative subjects. We also evaluated associations between prolonged QTc intervals and identifiable confounders. This study was designed to help determine the effects of HIV infection, antiretroviral drugs, and identifiable confounders on QTc prolongation.


   Materials and Methods Top


This analytical case-control study was conducted in the HIV clinic of the Federal Medical Centre, Ido-Ekiti, Ekiti State, Nigeria, one of the few rural tertiary health centers in Nigeria. It is a referral center for primary and secondary health institutions in Ekiti State and other neighboring states. These peripheral centers usually use this center for referral because of the availability of specialists, free antiretroviral drugs, social support, and other services. However, many patients seek medical treatment in our hospital as afirst point of contact. HIV-positive patients are referred to this HIV clinic following screening with rapid assessment kits.

The participants of this study comprised HIV-positive patients on ART; HIV-positive, ART-naïve patients; and HIV-negative subjects. The latter group comprised the patients' relatives, hospital staff members, and community volunteers. The three groups were age- and sex-matched. All participants were recruited consecutively. The analytical sample for this study was limited to those who underwent conventional HIV diagnosis using enzyme-linked immunosorbent assay (ELISA) and western blot assay techniques. Exclusion criteria were conduction abnormalities or arrhythmias other than isolated premature beats, pregnancy and puerperium, history of cardiac disease, drugs other than antiretroviral drugs (except few patients already on antihypertensive drugs), cigarette smoking, alcohol intake on the day of presentation or history of abuse, electrolyte abnormalities (potassium or calcium), diabetes mellitus, and renal disease (estimated glomerular filtration rate, ≤60 mL/min 1.73 m 2). Similarly, subjects with indeterminate HIV test results or incomplete data relevant to this study were excluded. Apart from the effect of HIV infection on QTc interval prolongation, the following were considered as confounders: ART, duration of HIV infection, body mass index (BMI), and CD4 cell count.

The Ethics Committee of the Federal Medical Centre, Ido-Ekiti, Ekiti State approved the study. Individuals gave informed consent to participate. All data were anonymized.

The minimum sample size was calculated using a formula for estimating proportions in populations of <10,000: nf = n/1+ n/N, where nf is the desired sample size when the population is <10,000, N is the estimated population size (estimated as the average of 168 new HIV-positive patients seen annually in the HIV clinic), and n is obtained using the formula n = z 2 pq/d 2, where z is the standard normal deviate using a 95% confidence level of 1.96, p is the proportion of the target population estimated to have a particular characteristic (the prevalence of HIV in Nigeria is 3.6%), q is obtained using the formula 1.0−p, and d is the degree of accuracy desired, set at 0.05.

Thus,

n = (1.96)2 × 0.036 × 0.964/(0.05)2 = 53.328

and,



Therefore, the minimum sample size for this study was 40.

The analytic variables of eligible participants were age, sex, BMI, blood pressure, CD4 T lymphocyte count, heart rate (HR), QTc interval, HIV status, duration of HIV infection, type of ART, and ART duration. All participants were clinically examined. The HIV status was assessed using HIV-1/HIV-2 ELISA (Genscreen Ultra HIV Ag-Ab; Bio-Rad, Marnes la Coquette, France) with EDTA-anticoagulated blood samples at the National Blood Transfusion Service laboratory (owned by the federal government of Nigeria to provide safe blood). Reactive samples were confirmed using western blot confirmation kits (New Lav-Blot I and II; Bio-Rad).

Hypertension was considered to be present in patients already on antihypertensive drugs or with a persistently elevated blood pressure of ≥140/90 mmHg on at least two readings on separate occasions after the initial screening.[7] BMI was classified as normal at 18.5–24.9 kg/m 2, overweight at 25.0–29.9 km/m 2, and obese at ≥30.0 kg/m 2.[8],[9]

All participants underwent resting 12-lead surface ECG testing using a Schiller AT-2 ECG machine (Welch Allyn, Inc., San Diego, CA, USA; made in Switzerland). This was performed in accordance with the American Heart Association specifications.[10],[11] The ECG machine was set at a speed of 25 mm/s and gain setting of 10 mm/mV. The ECG results were interpreted automatically by the ECG machine and cross-checked for accuracy by two of the authors (consultant cardiologist and senior resident cardiologist). The QT interval was taken from the beginning of the QRS complex to the end of the downslope of the T wave (crossing of the isoelectric line); when a U wave was present and seemed to merge with the T wave, the QT interval was measured to the nadir of the curve between the T and U waves. The QT interval was measured in lead II and then corrected for HR using Bazett's formula.

Data were analyzed using sex-specific QTc interval categories (abnormal values were >440 ms for men and >460 ms for women) because the QTc interval length is typically longer in women than in men.[12],[13],[14] All data were collected by the same trained research personnel in the same laboratories using identical instruments and assays between the two groups.

Statistical analysis was performed using the Statistical Package for the Social Sciences version 16 (SPSS Inc., Chicago, IL, USA). Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as percentages. The independent t-test and Pearson's Chi-square or Fisher's exact test were used to identify group differences in means and proportions, respectively. The means of the three groups were compared using one-way analysis of variance. Multiple comparisons of the groups were performed using the post hoc Bonferroni test with 95% confidence interval (CI). Statistical significance was set at P < 0.05.


   Results Top


Overall, 210 participants were studied. All participants were black race and the ethnic groups composition were: Yoruba, 194 (92.4%); Igbo, 11 (5.2%), Hausa, 1 (0.5%); and others, 4 (1.9%). The sample comprised 89 (42.4%) HIV-negative subjects (35 [39.3%] males, 54 [60.7%] females); 45 (21.4%) HIV-positive, ART-naïve patients (14 [31.1%] males, 31 [68.9%] females); and 76 (36.2%) HIV-positive patients on ART (21 [27.6%] males, 55 [72.4%] females). Most of the HIV-positive patients on ART (97.5%) were receiving zidovudine, lamivudine, and nevirapine, while the remaining 2.5% were receiving tenofovir, lamivudine, and boosted lopinavir (lopinavir coformulated with low-dose ritonavir). Only nine subjects of this group among all the participants were receiving antihypertensive drugs. The ART duration was 3.0–149.0 months (mean, 34.2 ± 28.6 months).

[Table 1] shows that the mean ages among the three groups were not significantly different (P = 0.060, CI = 36.24–38.37), and there were no differences between any two groups. Similarly, sex was matched among the three groups (P = 0.266). There was a statistically significant difference in mean BMI among the three groups (P < 0.001, CI = 23.62–24.89). Group comparisons showed a significant difference in BMI between HIV-negative subjects and HIV-positive, ART-naïve patients (P < 0.001, CI = 1.47–5.39) and between HIV-negative subjects and HIV-positive patients on ART (P < 0.001, CI = 1.26–4.61), but not between HIV-positive, ART-naïve patients and HIV-positive patients on ART (P = 1.000, CI = −1.52–2.51). The prevalence of hypertension among the three groups was not significantly different (P = 0.363), and there were no differences between any two groups. The mean CD4 count (cells/mm 3) among the three groups showed a significant difference (P < 0.001, CI = 539.2–632.7), with a significant difference between HIV-negative subjects and HIV-positive, ART-naïve patients (P < 0.001, CI = 393.5–606.3) and between HIV-negative subjects and HIV-positive patients on ART (P < 0.001, CI = 404.6–586.3), but not between HIV-positive, ART-naïve patients and HIV-positive patients on ART (P = 1.000, CI = −104.9–113.9).
Table 1: Characteristics of study participants

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The mean resting HR differed significantly among the three groups (P < 0.001, CI = 80.8–84.3). In multiple comparisons, there were significant differences between HIV-negative subjects and HIV-positive, ART-naïve patients (P < 0.001, CI = −17.5–6.9), between HIV-negative subjects and HIV-positive patients on ART (P = 0.007, CI = −10.3–−1.2), and between HIV-positive, ART-naïve patients and HIV-positive patients on ART (P = 0.016, CI = −11.87–−0.93). There was a statistically significant difference in the mean QTc interval among the three groups (P < 0.001, CI = 0.409–0.418). This was also observed between HIV-negative subjects and HIV-positive, ART-naïve patients (P = 0.003, CI = −0.033–−0.005) and between HIV-negative subjects and HIV-positive patients on ART (P = 0.001, CI = −0.030–−0.006), but not between HIV-positive, ART-naïve patients and HIV-positive patients on ART (P = 1.000, CI = −0.015–0.013). Sex consideration with respect to the mean QTc interval among the groups showed significant differences in both males (P = 0.006, CI =0.3895–0.4028) and females (P = 0.042, CI = 0.4172–0.4274). Within-group sex differences also showed longer QTc intervals in females than in males (HIV-negative subjects, P < 0.001, CI = −0.04015–−0.01694; HIV-positive, ART-naïve patients, P = 0.013, CI = −0.04313–−0.00545; HIV-positive patients on ART, P = 0.020, CI = −0.03502–−0.00306). The mean QTc interval decreased with an increasing ART duration (P = 0.023, CI =0.4136–0.4283) [Table 2]. There was statistical significance between <1- and >5-year durations (P = 0.019, CI = 0.0032–0.0480), but not between <1- and 1- to 5-year durations (P = 0.671, CI = −0.0101–0.0304) or between 1- to 5 and >5-year durations (P = 0.371, CI = −0.0089–0.0398). [Table 2] also shows changes in the QTc interval with an increased HIV infection duration. There were no significant differences among the three groups (P = 0.208, CI = 0.4129–0.4316) or between any two groups. Similarly, no significant group differences were found in the QTc interval versus the CD4 cell count (P = 0.391, CI =0.4136–0.4283) and BMI (P = 0.134, CI =0.4136–0.4283). [Figure 1] shows the sex distribution patterns, which were similar among the three groups. Males had longer QTc intervals.
Table 2: Characteristics of HIV-positive patients

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Figure 1: Sex distribution of QTc interval according to HIV status

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   Discussion Top


The QTc has been established as a powerful independent risk factor for cardiac events (syncope or cardiac arrest).[15],[16],[17],[18] We observed that the mean QTc interval in HIV-positive, ART-naïve patients was significantly longer than that in HIV-negative subjects but not between HIV-positive, ART-naïve patients and HIV-positive patients on ART. Thus, HIV infection may be the factor contributing to this difference in the QTc interval. In addition, progressive shortening of the mean QTc interval with an increasing ART duration (progressive reduction in viral load) further confirms the possible effect of HIV infection on the QTc interval rather than ART itself. The reason for this association is unclear. Furthermore, we found that the mean QTc interval progressively lengthened with an increasing duration of HIV infection, although this was not statistically significant. The lack of statistical significance may have been due to the low number of HIV-positive patients not on ART beyond a 1-year duration of infection. Only 9 and 2 patients had a 1- to 5-year and >5-year ART duration, respectively; these numbers obviously lack statistical power for assessment when compared with 34 patients with a <1-year duration. Significant associations were previously reported by Fiorentini et al.[19] and Charbit et al.[20] They observed that a group of HIV-infected patients with prolonged QTc intervals showed a higher risk of death at follow-up than did patients with normal QTc intervals.[19] In our study, ART was not significantly associated with QTc interval prolongation. This is similar to previous findings.[19] Our analysis confirms a sex difference in the QTc interval, which was longer in females than in males. This difference in the QTc interval between the sexes has been previously reported.[21] Biologic sex is known to be a factor in that women are more sensitive to drugs that prolong the QTc interval, and they are more highly represented in reports of torsades de pointes (TdP) by the US Food and Drug Administration.[22],[23],[24],[25] QTc interval prolongation is a sign of prolonged repolarization of the ventricular myocardium. This leads to early after depolarization, which can trigger polymorphic ventricular tachycardia (TdP).[26] The mechanism of drug-induced QTc prolongation is believed to usually involve blockade of cardiac potassium channels.[27] Protease inhibitors (PIs) reportedly predispose individuals to QT prolongation.[28],[29] The impact of some PIs on hERG blockade has been documented.[28] This gene encodes the pore-forming alpha subunit of a voltage-gated potassium channel expressed in the heart and nervous tissue. hERG mutation may cause a reduction in the delayed rectifier current of myocardial repolarization, leading to long QT syndrome. Therefore, lopinavir can cause dose-dependent blockade of hERG channels, suggesting predisposition to QT prolongation and TdP. Although PIs were expected to prolong the QT interval, we did not identify prolongation in this study. However, the number of our study participants on PIs was too small to significantly impact our observation. Cytochrome P450 is known to be responsible for the metabolism of about 60% of currently known drugs.[30] Several nonnucleoside reverse transcriptase inhibitors (NNRTIs) and PIs are cytochrome P450 substrates and inhibitors of CYP3A4; thus, they may increase the risk of QTc prolongation.[29],[30],[31] Among antiretroviral agents, only the nucleoside reverse transcriptase inhibitors (NRTIs) appear to be devoid of QT and the metabolic liability.[29] However, zidovudine (an NRTI) has been shown to prolong the QT interval in rats by activating reactive oxygen species formation in cardiac mitochondria.[32] In our study, virtually all patients were on an NNRTI (nevirapine). Despite this, QTc prolongation in relation to ART was not seen. This discrepancy may be due to the fact that drug-induced QTc prolongation is not a universal phenomenon. Why some individuals are susceptible to this condition while others are not remains unclear. They may have a subclinical genetic mutation that is only revealed when they are exposed to certain drugs. In addition, previous reports of QTc prolongation and TdP in HIV-infected patients describe the effects of a combination of the HIV-specific treatment and concomitant non-HIV-specific therapy such as antifungal agents, antibiotics, methadone, and others.[31] This might explain the lack of influence of NNRTIs on the QTc interval in this study.

Independent of administered medications, QTc prolongation in HIV-infected patients is reportedly associated with cardiac innervation alterations due to autonomic neuropathy.[33] Autonomic dysfunction has been demonstrated in HIV-positive patients and in those with AIDS.[34] However, the reason for the relationship between QTc prolongation and HIV infection is not yet clear.

Human immunodeficiency virus-related adipose redistribution syndrome (HARS) is known to be associated with sympathovagal imbalance and may be accompanied by other metabolic disorders such as dyslipidemia, glucose intolerance, insulin resistance, hypertension, and high BMI.[35],[36] In the population we studied, there was no significant difference in the prevalence of hypertension among or between groups. Whether any relationships exist among BMI, HARS, and QTc prolongation remains to be established. Obesity has been cited as a risk for QTc interval prolongation.[37],[38] We did not observe a significant relationship between obesity and QTc prolongation in our study. Among all patients, we found the highest mean resting HR in HIV-positive, ART-naïve patients. This finding may be related to the theoretical possibility of an effect of HIV infection on cardiac nerves and autonomic function. It may also be related to patient anxiety due to uncertainty about the future following their newly discovered HIV status. This is unlike HIV-positive patients on ART who are longer in contact with healthcare services and are doing well; thus, HIV-positive, ART-naïve patients may be less likely than HIV-positive patients on ART to acquire better health education. However, this needs further exploration because an increased resting HR is associated with higher cardiovascular mortality and morbidity in the general population,[39],[40],[41],[42],[43] even when other cardiac risk factors are taken into consideration.[40],[42],[43] Moreover, many studies have reported that a high resting HR is associated with atherosclerosis and an elevated risk of adverse cardiovascular events.[39],[44],[45],[46] The mechanisms linking an elevated HR with cardiovascular pathology and pathophysiology are not well-understood, and the results concerning possible benefits of pharmacological HR-lowering therapies are inconsistent.[44],[47],[48],[49],[50],[51] The association has been suggested to involve sympathetic overactivity.[52],[53] In addition, both an elevated HR and reduced HR variability have been shown to accelerate the atherosclerotic process in coronary arteries through local hemodynamic changes.[54],[55] A higher resting HR has also been associated with increased pulse wave velocity, and resultant increased arterial stiffness.[56],[57],[58],[59] A high pulse wave velocity is a marker of cardiovascular aging and an acknowledged independent risk factor for cardiovascular morbidity.[60]

This study is not without limitations. Potential unmeasured confounders include serum magnesium (can affect calcium levels), 24-h Holter ECG (QTc interval varies throughout the day and can be affected by factors such as sleep or meals; the time of the day was not standardized, which could result in data variability), genetic determinants, cirrhosis, and plasma drug concentrations. In addition, interpersonal and intrapersonal errors in QT interval measurements are possibilities but, these are not likely to be significant based on the level of skills and commitment of the personnel that performed it.

A strength of this study is that it provides data based on a representative sample of a predominantly rural population setting typical of the Nigerian population. In addition, we addressed the influence of ART on the QTc interval. Previous research in Nigeria was conducted in an urban teaching hospital and did not consider the influence of ART on the QTc interval. Furthermore, to the best of the authors' knowledge and belief, this is thefirst study in Nigeria to report on the resting HR of HIV-positive patients.


   Conclusion Top


Human immunodeficiency virus infection is associated with higher QTc intervals and resting HR, but not with BMI. Long-term ART suggests possible protection from QTc interval-related adverse events secondary to HIV. Our findings suggest that HIV-positive patients may be at higher risk of sudden cardiac death as a result of the fatal arrhythmia known as TdP.[61],[62] Future genetic and molecular studies are required to better delineate the functionality of cardiac channel variants and the risk of sudden cardiac death.[63] Accurate identification of patients at risk of QTc prolongation is imperative in HIV-positive patients. It is important to assess each patient before prescribing drugs known to be implicated in QTc interval prolongation and then closely monitor them afterward. Clinicians should be alert to the increasing list of drugs that cause QTc prolongation, and to the presence of predisposing conditions.

Source of Support:

Nil

Conflict of Interest:

None declared.

 
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