|Year : 2014 | Volume
| Issue : 2 | Page : 61-65
The QT interval in human immunodeficiency virus-positive Nigerian children
Olukemi Ige, Stephen Oguche, Christopher Yilgwan, Halima Abdu, Fidelia Bode-Thomas
Department of Paediatrics, University of Jos, Jos, Nigeria
|Date of Web Publication||18-Aug-2014|
Dr. Fidelia Bode-Thomas
Department of Paediatrics, Jos University Teaching Hospital, PMB 2076, Jos
Source of Support: None, Conflict of Interest: None
Introduction: The human immunodeficiency virus (HIV) and drugs taken for this infection are known to cause QTc interval prolongation which in turn can lead to severe arrhythmias. The prevalence and associated factors of prolonged QTc in HIV-positive children in sub- Saharan Africa have not been described.
Objectives: To compare the mean QTc interval and prevalence of QTc prolongation in HIV-positive children and HIV-negative controls, and to determine the factors associated with prolonged QTc in HIV-positive children.
Methodology: In a cross-sectional comparative study, the corrected QT intervals (QTc) of 100 HIV-positive children were compared with those of age- and sex-matched HIV-negative healthy controls. QTc > 0.46 seconds was regarded as prolonged.
Results: Subjects were aged 9 months to 14 years. Mean QTc was significantly longer-43.31 (95% CI 43.30, 43.32) seconds in HIV-positive children (62% of whom were on anti-retroviral therapy) compared with controls-41.43 (41.42, 41.44) seconds (P < 0.0001). Mean QTc was also significantly longer in subjects receiving zidovudine (ZDV) - [0.46 (0.45, 0.47) versus 0.43 (0.42, 0.44) seconds] - P = 0.007 and efavirnez (EFV) - [0.45 (0.43, 0.47) versus 0.43 (0.42, 0.44) seconds] - P = 0.047 in subjects not on these drugs. Prolonged QTc was significantly more frequent in HIV-positive children (18.0%) compared with controls (0%) - P = 0.0001. There was no significant relationship between either the mean QTc or the frequency of prolonged QTc, and the subjects' mean age, sex, clinical or immunological stage of disease.
Conclusion: Mean QTc is significantly longer in HIV-positive children (especially those receiving ZDV or EFV), compared with controls. Prolonged QTc is also significantly more frequent in subjects. Baseline and periodic ECG screening of HIV-positive children may facilitate early detection of QTc prolongation and help prevent fatal arrhythmias.
Keywords: Highly active anti-retroviral therapy, human immunodeficiency virus infection in children, acquired immune deficiency syndrome in children, prolonged QT interval
|How to cite this article:|
Ige O, Oguche S, Yilgwan C, Abdu H, Bode-Thomas F. The QT interval in human immunodeficiency virus-positive Nigerian children. J Med Trop 2014;16:61-5
|How to cite this URL:|
Ige O, Oguche S, Yilgwan C, Abdu H, Bode-Thomas F. The QT interval in human immunodeficiency virus-positive Nigerian children. J Med Trop [serial online] 2014 [cited 2021 May 10];16:61-5. Available from: https://www.jmedtropics.org/text.asp?2014/16/2/61/139049
| Introduction|| |
Human immunodeficiency virus (HIV) infection is an ongoing global epidemic with its high rate of morbidity and mortality.  The virus and drugs taken for this infection are known to affect the cardiovascular system and therefore can lead to cardiac diagnostic and therapeutic challenges. ,,
QTc interval prolongation can cause severe arrhythmias such as torsades de pointes (TdP), a polymorphic ventricular tachycardia and ventricular fibrillation.  Studies have shown that drugs such as Pentamidine/Pyrimethamine and Trimethoprim-Sulfamethoxazole (Co-trimoxazole) used in the treatment of toxoplasmosis and the treatment/prevention of Pneumocystis jiroveci pneumonia (PCP) respectively and certain antiretroviral drugs - protease inhibitors (PIs), zidovudine (ZDV) and efavirnez (EFV) - can cause significant QT prolongation. ,, Autonomic dysfunction as a result of HIV-associated neuropathy and HCV co-infection have also been shown to prolong the QTc in HIV-positive patients. , Prolonged QTc is an important cause of cardiovascular related mortality and has been shown to be more common in HIV-positive individuals compared with the general population.  There are no known studies in children in sub-Saharan Africa. 
With the increased use of highly active anti-retroviral therapy (HAART) and co-trimoxazolein HIV-positive children in sub-Saharan Africa, the prevalence and associated factors of prolonged QTc interval should be determined as it may be responsible for some of the mortalities attributed to HIV infection.
| Methodology|| |
This cross-sectional comparative study was carried out in 2008 in Jos, north-central Nigeria. The subjects were HIV-positive children on follow-up at the AIDS Prevention Initiative in Nigeria (APIN) clinic of the Jos University Teaching Hospital (JUTH). All children attending that clinic routinely have their HIV-positive status confirmed either by the polymerase chain reaction (PCR) if aged less than 18 months or by western blot for those aged 18 months and above. All children attending the Pediatric Infectious Diseases Clinic (PIDC) were eligible for selection and formed the sampling frame from which 100 HIV-positive children were recruited into the study by systematic sampling. A sampling interval of every other child which was obtained by dividing the total number of clinic attendees children by the calculated sample size, was used in selecting the subjects. An equal number of age- and sex-matched HIV-negative healthy controls were also enrolled from the Pediatric Out Patients Department. Parents of all the study participants gave informed written consent. The Ethics Committee of JUTH approved the study.
Subjects' sociodemographic data were obtained by interviewing the parents. Socioeconomic status was determined using the method described by Olusanya et al.  For HIV-positive children, information on their clinical and immunological stages of disease [according to World Health Organization (WHO) criteria]  and their current medications, were retrieved from their clinic records. Pulse rate (PR) and blood pressure (BP) were measured manually in all subjects and controls using standard methods. ,
A 12-lead electrocardiogram (ECG) was performed on each child using the Cardiette ® ar600 adv Electrocardiograph 2004. The heart rate was determined manually using standard methods. Sinus tachycardia was regarded as a sinus rhythm with a heart rate faster than 120 beats/minute.  The QT interval was measured manually in lead II, from the beginning of the QRS complex to the end of the T wave. The measured QT interval was corrected for heart rate using Bazette's formula.  A corrected QT interval (QTc) exceeding 0.46 seconds was regarded as prolonged. 
Data was analyzed using Epi Info version 3.5.1 (CDC, Atlanta, Georgia, USA). Student t-test or it's variant, the Wilcoxon two-sample test were used to compare means of continuous variables. Chi-square was used to test the association between categorical variables, but its variant, the Fisher's exact test, was used when any cell value was less than 5. A P < 0.05 was considered significant.
| Results|| |
Subjects and controls were aged 9 months to14 years - mean 6.53 (5.81, 7.25) and 6.53 (5.80, 7.26) years, respectively, P = 0.90. The sex distribution was also similar in both groups [Table 1]. A significantly higher proportion of the HIV-positive children belonged to the middle and lower income strata, P < 0.0001. The two groups were similar with respect to their mean pulse rates (PR) and diastolic blood pressures (DBP), but systolic blood pressure (SBP) was significantly higher in HIV-positive subjects [Table 1].
|Table 1: Comparison of socio-economic status and some clinical parameters of 100 HIV-positive children and 100 age- and sex-matched controls|
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Clinical Characteristics of Subjects
According to WHO clinical staging of disease, 69 (69.0%) of the HIV-positive children had clinical stage 1 disease, 14.0% were in stage 2, and 17 (17.0%) in stage 3. None had stage 4 disease. Using WHO immunological staging criteria, 57 of the 100 children infected with HIV had no significant immune deficiency. Mild immune deficiency was present in 10%, advanced immune deficiency in 8.0% and severe immune deficiency in the remaining 25.0% of HIV-infected children. Co-trimoxazole was being used by 98 (98.0%) of the patients, HAART by 62% and anti-tuberculous therapy (ATT) by 16.0% [Table 2].
Heart Rate, QT and QTC In Subjects and Controls
Sinus tachycardia was present on the ECGs of 9 (9.0%) subjects but none of the controls, P = 0.002, while mean heart rates were similar in subjects and controls, P = 0.49 [Table 3].
|Table 3: Mean heart rates, QT intervals and prevalence of prolonged QTc in 100 HIV-positive subjects and 100 controls|
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The mean QT and QTc intervals were however significantly longer in HIV-positive children [34.83 (34.82, 34.84) and 43.31 (43.30, 43.32) seconds, respectively] compared with controls [33.10 (33.01, 33.19) seconds and 41.43 (41.42, 41.44) seconds, respectively]. Prolonged QTc was significantly more frequent in the HIV-positive children being present in18 (18.0%) subjects but none of the controls (P = 0.0001) [Table 3]. No significant relationship was found between the mean QTc interval and the subjects' age, blood pressure, sex, presence of sinus tachycardia, clinical and immunological stages of disease, and the use of co-trimoxazole.
QTc and Associated Factors
Mean QTc interval was significantly longer in subjects receiving HAART compared with those not on such treatment [Table 4]. Specifically, mean QTc interval was significantly longer in subjects receiving ZDV - [0.46 (0.45, 0.47) versus 0.43 (0.42, 0.44) seconds] - P = 0.007 and EFV - [0.45 (0.43, 0.47) versus 0.43 (0.42, 0.44) seconds] - P = 0.047 but not in those receiving PIs - [0.44 (0.43, 0.45) versus 0.44 (0.43, 0.45) seconds] - P = 0.88 [Table 4].
|Table 4: Mean QTc in relation to various characteristics of 100 HIV-positive children|
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HAART was being used by 13 (72.2%) of the 18 subjects with prolonged QTc compared with 49 (59.8%) of 82 with normal QTc. This difference was not statistically significant, P = 0.32. None of the subjects with prolonged QTc interval were receiving protease inhibitors (PIs). Twelve (92.3%) were on zidovudine (ZDV) and 5 (38.4%) on efavirenz (EFV) while 4 (30.8%) were on a combination the two. Neither the use of EFV nor ZDV were significantly associated with prolonged QTc - P = 0.28 and 0.07, respectively [Table 5].
|Table 5: Prolonged QTc in relation to various characteristics of 100 HIV-positive children|
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The presence of prolonged QTc was also not significantly associated with age, blood pressure, sex, presence of sinus tachycardia, clinical and immunological stage of disease, or the use of co-trimoxazole [Table 5].
| Discussion|| |
This study reveals a longer mean QTc interval and a higher prevalence of prolonged QTc in HIV-positive children compared with controls. Saidi et al. also reported longer mean QTc intervals in HIV-infected children compared with controls.
Prolonged QTc interval occurred in 18% of our subjects as opposed to only 1% of controls. Even though there are no ready prevalence studies in children for comparison, our finding is similar to the 19.8% reported by Reinsch et al. in a study of HIV-positive adults in Germany. Prolonged QTc interval was defined in that study as any value exceeding 0.44 seconds in males and 0.46 seconds in females. Sani et al.,  who had earlier studied adults in our locality, reported much higher prevalence rates of 28.0% and 40.0% in HIV-positive but non-AIDS and in AIDS patients, respectively. Their definition of prolonged QTc as > 0.44 seconds, as opposed to 0.46 seconds in the present study may have accounted for the difference.
Similar to other studies in adults, prolonged QTc interval was not significantly associated with the use of HAART in this study. , Twelve (66.7%) of the 18 subjects with prolonged QTc interval were on ZDV compared with 41 (50.0%) of the 82 subjects with a normal QTc interval. Although the difference was not statistically significant, this finding is similar to that of Fiorentini et al. who found that adults on ZDV were at increased risk of prolonged QTc but not at a statistically significant level. ZDV is a drug which has been shown to prolong the QTc interval in rats by the activation of oxygen free radical formation in the mitochondria of the cardiac myocytes. 
There was no significant relationship between the use of protease inhibitors (PIs) and the mean QTc interval in this study and none of the three subjects with prolonged QTc interval were receiving protease inhibitors, which are second-line anti-retroviral agents that are only used when the first-line agents are not effective. Protease inhibitors have been shown to block the in vitro human ether-a-go-go-related gene (hERG) current-a pathway central to the pathophysiology of all drug-induced QTc interval prolongation. , Charbit et al. also did not find any independent association between the use of PIs and QTc interval prolongation in adults. The reason for this was attributed to the fact that the hERG blockade of PIs is dose dependent and that the dose used was not high enough to cause QTc interval prolongation.  Charbit et al. further suggested that the well-documented discrepancy between in vitro and in vivo studies may be another reason why no association was found between the use of PIs and prolongation of the QTc interval. 
We found no significant association between prolonged QTc and the use of co-trimoxazole (TMZ-SMZ), a drug also known to prolong the QT interval,  and which was being administered to 98% of the subjects in this study. This may be because our subjects were receiving the drug at low dose, for prophylaxis against PCP. It has been shown that at this lower dose, the risk of prolonged QTc interval and TdP is low. 
As has been reported by other authors, we found sinus tachycardia to be significantly associated with HIV infection.  Autonomicneuropathy with unopposed sympathetic stimulation and left ventricular systolic dysfunction, both of which have been documented in children with HIV infection, could be possible reasons for this. , The latter has been explained both on the basis of an immune-mediated mechanism and a direct cytotoxic effect on myocardial cells, while the former is thought to be possibly related to injury to the suprachiasmatic nucleus within the hypothalamus, with a resulting increase in sympathetic activity. ,
In conclusion, this study demonstrates that HIV-positive children have longer mean QTc and much higher prevalence of prolonged QTc than HIV-negative controls and that the mean QTc interval is significantly longer in those receiving zidovidine and efavirnez. These findings were not found to be related to the duration or stage of disease. Hence, baseline ECG screening before commencement of HAART and periodic evaluations thereafter may facilitate the early detection of drug-induced QTc prolongation and the adoption of appropriate steps to prevent the occurrence of fatal arrhythmias.
| References|| |
|1.||Joint United Nations Programme on HIV/AIDS (UNAIDS) WHO. 2012 Global report: UNAIDS Report on the global AIDS epidemic 2012. Available from: http://www.unaids.org/en/resources/publications/2012. [Last accessed in 2013 Sep 20]. |
|2.||Lipshultz SE, Williams PL, Wilkinson JD, Leister EC, Van Dyke RB, Shearer WT, et al. Cardiac status of children infected with Human Immunodeficiency Virus who are receiving long -term combination antiretroviral therapy: Results from the adolescent master protocol of the multicenter pediatric HIV/AIDS cohort study. JAMA Pediatr 2013;167:520-7. |
|3.||Barbaro G. Cardiovascular Manifestations of HIV infection. Circulation 2002;106:1420-5. |
|4.||Shah I, Prabhu SS, Sumitra V, Shashikiran HS. Cardiac dysfunction in HIV infected Children: A pilot study. Indian Pediatr 2005;42:146-9. |
|5.||Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363-72. |
|6.||Vittecoq D, Escaut L, Chironi G, Teicher E, Monsuez JJ, Andrejak M, et al. Coronary heart disease in HIV-infected patients in the highly active antiretroviral treatment era. AIDS 2003;17 Suppl 1:70-6. |
|7.||Chiang CE. Congenital and acquired long QT syndrome. Current concepts and management. Cardiol Rev 2004;12:222-34. |
|8.||Sani MU, Okeahialam BN. QTc interval prolongation in patients with HIV and AIDs. J Natl Med Assoc 2005;97:1657-61. |
|9.||Villa A, Foresti V, Confalonieri F. Autonomic neuropathy and prolongation of QT interval in human immunodeficiency virus infection. Clin Auton Res 1995;5:48-52. |
|10.||Nordin C, Kohli A, Beca S, Zaharia V, Grant T, Leider J, et al. Importance of hepatitis C coinfection in the development of QT prolongation in HIV-infected patients. J Electrocardiol 2006;39:199-205. |
|11.||Tseng ZH, Secemsky EA, Dowdy D, Vittinghoff E, Moyers B, Wong JK, et al. Sudden cardiac death in patients with human immunodeficiency virus infection. J Am Coll Cardiol 2012;59:1891-6. |
|12.||Okoromah CA, Ojo OO, Ogunkunle OO. Cardiovascular dysfunction in HIV- infected children in a sub-saharan country: Comparative cross-sectional observational study. J Trop Paediatr 2012;58:3-11. |
|13.||Olusanya O, Okpere E, Ezimokhai M. The importance of social class in fertility control in a developing country. West Afr J Med 1985;4:205-12. |
|14.||World Health Organization. WHO Case Definitions of HIV Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Diseases in Children Younger than 15 years of Age. 2006. |
|15.||Levick D. Examination of the cardiovascular system. J Clinical Examination 2007;3:8-14. |
|16.||Perloff D, Grim C, Flack J, Frolich ED, Hill M, McDonald M, et al. Human blood pressure determination by sphygmomanometry. Circulation 1993;88:2460-70. |
|17.||Park MK. Electrocardiography. In: Park MK, George R, Troxler M, editors. 4 th ed. Paediatric Cardiology for Practitioners. St. Louis: Mosby; 2002. p. 34-51. |
|18.||Goldenberg I, Moss AJ, Zareba W. QT Interval: How to measure it and what is "normal". J Cardiovasc Electrophysiol 2006;17:333-6. |
|19.||Saidi AS, Moodie DS, Garson A Jr, Lipshultz SE, Kaplan S, Lai WW, et al. Electrocardiography and 24-hour electrocardiographic ambulatory recording (Holter monitor) studies in children infected with human immunodeficiency virus type 1. The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV-1 Infection Study Group. Pediatr Cardiol 2000;21:189-96. |
|20.||Reinsch N, Buhr C, Krings P, Kaelsch H, Neuhaus K, Wieneke H, et al. Prevalence and risk factors of prolonged QTc interval in HIV-infected patients: Results of the HIV-HEART study. HIV Clin Trials 2009;10:261-8. |
|21.||Benchimol-Barbosa PR. Circadian cardiac autonomic function in perinatally HIV-infected preschool children. Braz J Med Biol Res 2009;42:722-30. |
|22.||Busti AJ, Tsikouris JP, Peeters MJ, Das SR, Canham RM, Abdullah SM, et al. A prospective evaluation of the effect of atazanavir on the QTc interval and QTc dispersion in HIV positive patients. HIV Med 2006;7:317-22. |
|23.||Fiorentini A, Petrosillo N, Di Stefano A, Cicalini S, Borgognoni L, Boumis E, et al. QTc interval prolongation in HIV-infected patients: A case-control study by 24-hour Holter ECG recording. BMC Cardiovasc Disord 2012;12:124. |
|24.||Szabados E, Fisher GM, Toth K, Csete B, Nemeti B, Trombitas K, et al. Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat. Free Radic Biol Med 1999;26:309-17. |
|25.||Anson BD, Weaver JG, Ackerman MJ, Akinsete O, Henry K, January CT, et al. Blockade of HERG channels by HIV protease inhibitors. Lancet 2005;365:682-6. |
|26.||Fantoni M, Autore C, Del Borgo C. Drugs and cardiotoxicity in HIV and AIDS. Ann N Y Acad Sci 2001;946:179-99. |
|27.||Charbit B, Rosier A, Bollens D, Boccara F, Boelle PY, Koubaa A, et al. Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: A cross- sectional study. Br J Clin Pharmacol 2009;67:76-82. |
|28.||Chinello P, Lisena FP, Angeletti C, Boumis E, Papetti F, Petrosillo N. Role of antiretroviral treatment in prolonging QTc interval in HIV-positive patients. J Infect 2007;54:597-602. |
|29.||Committee for Medicinal Products for Human Use. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005. CHMP/ICH/2/04 November. Available from: http://www.emea.europa.eu/pdfs/human/ich/000204en.pdf. [Last accessed on 2013 Jul 26]. |
|30.||Lopez JA, Harold JG, Rosenthal MC, Oseran DS, Schapira JN, Peter T. QT Prolongation and Torsades de Pointes after Administration of Trimethoprim- Sulphamethoxazole. Am J Cardiol 1987;59:376-7. |
|31.||Van der Sijs H, Kowlesar R, Klootwjik APJ, Nelwan SP, Vulto AG, van Gelder T. Clinically relevant QTc prolongation due to overridden drug-drug interaction alerts: A retrospective cohort study. Br J Clin Pharmacol 2009;67:347-54. |
|32.||Lubega S, Zirembuzi GW, Lwabi P. Heart Disease among Children with HIV/AIDS attending the Paediatric Infectious Disease Clinic at Mulago Hospital. Afr Health Sci 2005;5:219-26. |
|33.||Moldovan L, Branzan O, Nechita O, Adreleanu C, Teodorescu M, Geamai A. Clinical diagnosis of cardiac involvement in HIV infection. J Med Life 2012;5:297-303. |
|34.||Ige OO, Oguche S, Bode-Thomas F. Left ventricular systolic function in Nigerian children with human immunodeficiency virus infection. Congenit Heart Dis 2012;7:417-22. |
|35.||Kawai C. From myocarditis to cardiomyopathy: Mechanisms of inflammation and cell death. Learning from the past for the future. Circulation 1999;99:1091-100. |
|36.||Yun AJ, Lee PY, Bazar KA. Modulation of host immunity by HIV may be partly achieved through usurping host autonomic functions. Med Hypotheses 2004;63:362-6. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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