Abstract
Background:
Human immunodeficiency virus (HIV) affects many organ systems in the body including the cardiovascular system, often manifesting as a subclinical left ventricular (LV) systolic dysfunction that may progress to heart failure.
Aim:
This study assessed the prevalence of LV systolic dysfunction in children on highly active antiretroviral therapy (HAART) with established clinical stage 1 HIV-disease.
Materials and Methods:
The study was a cross-sectional comparative study conducted in Aminu Kano Teaching Hospital from April to August 2019 on 200. It involved study participants comprising 100 WHO clinical stage 1 HIV-infected children and 100 control subjects, aged between 1 and 18 years selected using systematic sampling method. Echocardiography was carried out on the study participants who had already completed a pretested questionnaire.
Results:
Out of 100 HIV-infected children studied, 49 were males and 51 females (Male: Female ratio; 0.96:1.0). The mean age at diagnosis of HIV infection was 2.6 (±2.6 years) and the median viral load was 35 copies/ml. The mean ejection and shortening fractions in HIV-infected children were 59.0% and 31.0%, respectively, compared to 64.4% and 34.0% in control subjects, respectively, and were statistically significant (P = 0.000). The prevalence of LV systolic dysfunction was 8.0% (8 out of 100) in HIV-infected children while the control groups had zero prevalence (P = 0.002). The age at diagnosis correlated negatively with LV systolic dysfunction (r = 0.23, P = 0.02).
Conclusion:
This study found a subclinical LV systolic dysfunction in an HAART-established clinical stage 1 HIV-infected children. The age at diagnosis was negatively correlated with the LV systolic function. This study, therefore, support the inclusion of routine echocardiography into the evaluation of HIV-infected children.
Keywords: Age at diagnosis, human immunodeficiency virus, systolic dysfunction highly active antiretroviral therapy (HAART)
INTRODUCTION
The global burden of people living with human immunodeficiency virus (HIV) was estimated to be 39.7 million. An estimated 1.7 million new infection were recorded including children in same year of 2019. Majority (70%) of these new infections were in sub-Saharan Africa.[1] HIV affects many organs in the body including the heart with associated increased morbidity and mortality among HIV-infected children. These cardiac complications are under reported in sub-Saharan Africa.[2] Of the several reports on HIV and cardiovascular abnormalities, however, the left ventricular (LV) systolic dysfunction has been found to be predominant.[3,4] The effect of HIV on cardiac function could be due to nutritional deficiency, HIV-associated autoimmune disease, opportunistic infections, and antiretroviral drugs.[5] LV systolic dysfunction is the most important prognostic indicator in HIV disease.[6] Early commencement of highly active antiretroviral therapy (HAART) has been reported to prevent HIV disease progression and the development of LV systolic dysfunction.[7] Similarly, a long duration of HAART has been documented to reduce the risk of LV systolic dysfunction.[7-9] Pongprot et al.[10] in Thailand reported a prevalence of 37% of systolic dysfunction among the HAART-naïve, symptomatic HIV-infected children. Furthermore, Lubega et al.[11] in Uganda studied HIV-infected children with congenital heart diseases, reported a 17% prevalence of LV systolic dysfunction mostly in subjects with a severe immunodeficiency. The comparative studies in Nigeria, by Ige et al.[2] in Jos, Arodiwe et al.[4] in Enugu and Okoromah et al.[12] in Lagos reported a 30% prevalence of diastolic dysfunction, 27.0% and a 33% prevalence of systolic dysfunction in HIV-infected children, respectively. In addition, LV dysfunction was found to be associated with decreasing CD4 counts. The relationship between CD4 count and LV systolic function (LVSF) has been widely studied.[13] Some studies found an association between LVSF and the progression of HIV infection and low CD4 counts (acquired immunodeficiency syndrome)[2,4] However, the association between HIV viral load, age at diagnosis, and LVSF has not been widely documented in children who are, in HIV clinical stage 1 disease. This study assessed the prevalence of LV systolic dysfunction by two-dimensional (2D)-guided M-mode echocardiography in the WHO clinical stage 1 HIV-infected children who are on HAART, aged 1–18 years. The correlation between the age at diagnosis, duration on HAART, HAART regimen, viral load, and the LVSF were also determined. This study used viral load which is better and reliable marker of disease progression compared to CD4 count used in other studies. The use of the latter have been reported to have some limitations in accurately determining the disease progression and response to HAART.[10,13,14] The clinical stage 1 HIV disease has been limitedly studied and couple with a dearth of data on the left systolic function in HIV-infected children in sub-Saharan African. This study would create awareness and possibly provide evidence that will support the need for routine echocardiography evaluation in children that are clinically stable, with WHO clinical stage 1 HIV disease.
MATERIALS AND METHODS
The study was a cross-sectional comparative study and was conducted in Aminu Kano Teaching Hospital from April to August 2019. It involved 200 study participants comprising 100 (already diagnosed) WHO clinical stage 1 HIV infected children and 100 control and confirmed HIV negatives subjects (screened by Rapid diagnostic test). They were aged between 1 and 18 years. The participants were selected by the systematic sampling method. The control subjects were also selected by systematic sampling method. The HIV-infected children had already been clinically classified into different WHO clinical stages. In confirmation of this, the WHO clinical staging of HIV was used to further exclude those in clinical stages 2, 3, and 4, respectively, as documented in their electronic database.[15,16] The viral loads of the HIV study participants were determined by nucleic acid extraction and amplification with the use of COBAS Ampliprep and COBSA Taqman 48 following appropriate blood volume sampling and processing.
The study subjects who had been diagnosed with congenital or acquired heart disease including those on digoxin, caffeine, and cancer chemotherapy medications were excluded from the study. Informed consent and assent were sought from the parents and children. The consent and assent forms were filled out as appropriate. The age at diagnosis of HIV disease, duration on HAART and HAART regimen were also determined from electronic data of HIV-infected children, and only HIV-infected patients who had been on HAART for at least 3 months were recruited. The HAART regimen with their backbone bases was identify for which HIV patients on HAART for at most 3 months were classified into a zidovudine and non-zidovudine groups. Those on Abacavir and zidovudine base backbone were selected since they are the majority in the clinical stage 1. The blood pressure, pulse, and respiratory rate of each of the study participants were measured.
Echocardiography (Sonoscape 1800 i machine) with a probe 5HZ was used to carry out echo study on the participants who had already completed a pre-tested questionnaire. LVSF was determined by 2D-guided M-mode following guideline of the American Society for Pediatric Echocardiography.[17] Echocardiographic values and other variables were defined as follows:
Age at diagnosis is the age at which HIV infection was confirmed using age-appropriate diagnostic methods (HIV RNA polymerase chain reaction [PCR], rapid diagnostic test, and confirmation by RNA PCR)[12]
Stage 1 HIV disease is asymptomatic or having persistent generalized lymphadenopathy[15]
HAART is highly active antiretroviral Therapy[18]
Duration on HAART is the total duration a subject had been on HAART following the diagnosis of HIV infection excluding the medication-free period (documented in electronic data)
HIV viral load of <1000 copies/ul was defined as suppressed, viral load <20 copies/ml defined as undetectable, and the value above 1000 copies/ul was defined as unsuppressed viral load[18]
LVSF connotes the fractional shortening (LVSF) and LV ejection fraction (LVEF) that measure the overall LV systolic performance which could be affected by contractility, pre-load, after-load, and heart rate. Normal ejection fraction (EF) and systolic function (SF) were defined as are >50% (50%–80%) and 28% (28%–44%), respectively
LVSF <28% and LVEF <50% defined as systolic dysfunction
The (EF%) was determined by this formula = LVEDV – LVESV/LVEDV ×100.[4]
SF% = LVEDD – LVSD/LVESD ×100.[4]
The statistical analysis was done using SPSS software for Windows version 20 (IBM Corp., Armonk, NY, USA). The age and sex of the study population were summarized in proportion and percentages. The quantitative variables were summarized as mean, standard deviation and median depend on their normality distribution. Viral load was log10 transformed twice and normality was determined before being used for further analysis. Fisher exact test was used to compare the proportion of age grouping, prevalence of LV systolic dysfunction between HIV-infected children and the control groups. The mean echocardiographic parameters were compared using an independent student test after determining the normality distribution. At the bivariate level, Person correlation was used to determine the correlation between systolic function and the age at diagnosis, viral load, duration of HAART in HIV-infected children. P value < 0.05 was considered statistically significant for all statistical tests.
RESULTS
Table 1 describes baseline socio-demography of the study population. There was no statistically significant difference in age and sex of the study population (P = 0.77 and = 0.88 respectively). The mean age at diagnosis of HIV infection was 2. 6 months (±2.6) while mean duration of HAART among the HIV subjects was 78.2 months (±47.1). The median viral load was 35 (interquartile range 17–2400) copies/mL. Six of the HIV-infected children with systolic dysfunction had suppressed viral load with 40 of them having undetectable viral load. Table 2 shows the relationship between age at diagnosis of HIV infection, viral load, and duration on HAART. Majority of HIV-infected children were diagnosed age at < 12 months while those diagnosed 1–5 and 6–10 years constitute 32% and 18%, respectively. The proportion of systolic dysfunction cumulatively was higher in those with age at diagnosis above 1 year respectively compared to the subjects with a lower age at diagnosis of HIV infection (6.3% and 22%). P = 0.045. Furthermore, in our data, we observed that 6 out of 8 (75%) of the subjects with systolic dysfunction were diagnosed at age later than 5 years. Five of the HIV infected with a low EF had undetectable viral particle in the serum. Table 3 shows the use of HAART and the association with the LVSF. Sixty subjects of HIV children were on non-zidovudine combinations ABC/3TC/LVP, ABC/3TC/NVP, ABC/3TC/DRG) while 40 HIV-infected subjects were on Zidovudine-baseed combination (AZT/3TC/LVPr …) Used of HAART was not associated with the low EF (P = 0.88 and 0.33 5, respectively).
Table 1.
Baseline sociodemographic, clinical, and laboratory features of the study population
| Variables | HIV (n=100), n (%) | Control (n=100), n (%) | f/t | P |
|---|---|---|---|---|
| Age of subjects (years) | ||||
| Mean±SD | 10±3.9 | 9.8±3.9 | 1.2 | 0.77 |
| 1-5+ | 14 (14) | 15 (12) | ||
| 6-10+ | 41 (41) | 40 (40) | ||
| 11-15+ | 41 (41) | 42 (43) | ||
| ≥16 | 4.0 (4) | 3 (3) | ||
| Sex | ||||
| Male | 49 (49) | 48 (48) | 0.2 | 0.88 |
| Female | 51 (51) | 52 (52) |
f=fisher exact test, t=unpaired t-test, P=value, HIV=human immunodeficiency virus
Table 2.
Relationship between the factors associated with low ejection fraction in human immunodeficiency virus infected children
| Variables | Systolic dysfunction | F/P | |
|---|---|---|---|
|
| |||
| No | Present (EF) (%) | ||
| Age at diagnosis of HIV infection (years) | |||
| <1 | 50 | 1 (2) | 15.4/0.045 |
| 1-5+ | 32 | 3 (6.3) | |
| ≥6-10+ | 18 | 4 (22) | |
| Duration on HAART (months) | |||
| <3 | 3 | 0 | 7.78/0.19 |
| 3-6 | 2 | 1 (33) | |
| >6 | 95 | 7 (7.4) | |
| Viral load (copies/ml) | |||
| <1000 | 63 | 5 (7.9) | 0.61/0.94 |
| >1000 | 37 | 3 (8.1) | |
f=fisher exact test, P=P value, HARRT=Highly active anit-retroviral therapy, EF=Ejection fraction
Table 3.
Association between left ventricular systolic function and highly active antiretroviral therapy regimens
| Variables | Low EF present | Fisher’s exact test | P |
|---|---|---|---|
| Non-AZT | 6 (60) | 10.2 | 0.33 |
| AZT | 2 (40) | 55.8 | 0.88 |
AZT=Zidovudine, EF=Ejection fraction
Table 4 indicates a comparison of echocardiographic parameters in HIV-infected children and the control group. There was statistically significant difference in the mean ejection and shortening fraction between HIV-infected children and the control group (P = 0.00), similarly, HIV-infected children had high left atrial and aortic diameters compared to the control group (P = 0.00). Although mean ejection and shortening fractions were within normal defined values in both the HIV and the control groups. Furthermore, majority of the HIV-infected subjects had normal LVSF and only 8 out of 100 of them had low EF/SF, while some subjects had EF above 80%. EF above 80%. Table 5 shows that the prevalence of LV systolic was higher in older age HIV-infected children. Table 6 presents the comparison of the prevalence of systolic dysfunction between HIV-infected children and the control groups. There was statistically significant difference in prevalence between HIV group (8%) and the control (0%) P = 0.002. Table 7 presents the relationship between age at diagnosis of HIV and systolic function. Age at diagnosis of HIV infection shows a negative correlation with the LVSF (EF) r = −0.23, P = 0 02 and R2 = 0.052. Which means more than 50% of the subjects responsible the correlation observed EF = 81 + 0.83 (age at diagnosis [months] ±0.3). This also indicated that, as the age at diagnosis increase, there is decrease in LVSF (EF). Figure 1 shows scatter plot depicting a negative correlation of age at diagnosis of HIV disease with the LVSF (EF).
Table 4.
Comparison of echocardiography parameters of human immunodeficiency virus-infected children and human immunodeficiency virus-uninfected controls
| Variables | HIV group (n=100) | Control (n=100) | t | P |
|---|---|---|---|---|
| EF % | 59.00 (8.5) | 64.4 (6.3) | −4.3 | 0.00 |
| SF % | 31.00 (5.7) | 34.0 (4.7) | −3.9 | 0.00 |
| LVEDD (mm) | 36.5 (4.2) | 35.9 (3.7) | 0.6 | 0.78 |
| LVESV (mm) | 28 (5.6) | 27.2 (4.1) | 0.8 | 0.10 |
| AO (mm) | 20 (2.9) | 18.8 (3.2) | 1.6 | 0.00 |
| LA (mm) | 25 (4.2) | 22.9 (3.5) | 2.7 | 0.00 |
HIV=Human immunodeficiency virus, EF=Ejection fraction, LVEDD=Left ventricular end diastolic diameter, LVESV=Left ventricular end-systolic volume, AO=Aortic diameter, LA=Left atrial diameter
Table 5.
Chronological age and prevalence of left ventricular systolic dysfunction in human immunodeficiency virus children
| Age (years) | Mean EF (%) | Systolic dysfunction present (EF) |
|---|---|---|
| 1-5 | 60 | 0 |
| 6-10 | 59 | 1 (1) |
| 11-15 | 45 | 6 (5) |
| ≥16 | 55 | 1 (1) |
EF=Ejection fraction
Table 6.
Comparison of the prevalence of left ventricular systolic dysfunction in human immunodeficiency virus-infected children and human immunodeficiency virus-uninfected controls
| Variables | HIV groups (%) | Control groups | Fisher’s exact test | P |
|---|---|---|---|---|
| EF and SF | 8 | 0 | 15.53 | 0.002 |
HIV=Human immunodeficiency virus
Table 7.
Correlation of left ventricular systolic function (ejection fraction), age at diagnosis, duration on highly active antiretroviral therapy, packed cell volume, and the viral load in human immunodeficiency virus-infected children
| r (correlation coefficient) P<0.05 | r | P |
|---|---|---|
| Age at diagnosis (years) | −0.23 | 0.02 |
| Viral load (copies/ml) | 0.07 | 0.49 |
| Duration on HAART (months) | 0.03 | 0.76 |
HAART=Highly active antiretroviral therapy
Figure 1.
Shows scatter plot depicting a negative correlation between age at diagnosis of HIV disease with the left ventricular systolic function (ejection fraction). HIV = Human immunodeficiency virus
DISCUSSION
Systolic dysfunction was present in 8% of HIV-infected children but was not observed in any of the control subjects. The mean ejection and shortening fraction were within normal defined limits between HIV subjects and control groups because the majority of HIV study population had normal LVSF which could not cause a large mean difference in our study population. LV end-diastolic and end-systolic dimensions were not significantly different between HIV-infected children and the control. Our prevalence of systolic dysfunction was in agreement with the reports by Duru and Paul[19] Valilo et al.[9] Although higher values were documented in Okoromah et al.[12] and Arodiwe et al.[4,12] studies.
A greater percentage of HIV-infected children study population were on HAART for more than 6 months’ duration with a suppressed viral load in majority. The longer duration on HAART could have offered a cardioprotective effect[7] which could explained the low prevalence of systolic dysfunction observed in this study.
The adolescents’ HIV-infected children contribute to a significant proportion of those with systolic dysfunction and they were observed to have a higher age at diagnosis (≥5 years). A cumulative frequency of systolic dysfunction was lower in those with age at diagnosis less than 12 months compare to the proportion with higher age at diagnosis. Of note, a significant negative correlation was observed between the age at diagnosis and LVSF however, our finding is contrary to what was reported by Sainz et al.[20] No correlation was observed between LVSF, viral load, and the duration of HAART. Similarly, HAART regimens were not associated with low EF. The implication of delay in detecting subclinical LV systolic dysfunction is progression into a severe dilated cardiomyopathy, recurrent heart failure, or life-threatening cardiac arrhythmia which could be associated with increase mortality or a severe cardiac status that may require the not readily available and expensive cardiac transplant. Our findings suggest that age at diagnosis later than 12 months could be associated with decrease systolic function.
CONCLUSION
This study found LV systolic dysfunction in HIV-infected children WHO clinical stage 1 HIV disease on HAART. Age at diagnosis of HIV disease correlated negatively with LVSF (EF). LV systolic dysfunction was subclinical in this study. However, it may progress to over heart failure or be associated with life-threatening cardiac arrhythmia. This study, therefore, supports routine echocardiographic evaluation in the children with clinical stage 1 HIV disease and most especially children who were diagnosed late (age at diagnosis >5 years).
Contribution of this study to the research
Echocardiography has never been used for screening, diagnosis or follow-up visits in pediatrics infectious disease clinic because. There was no data on the prevalence of LV dysfunction in HIV-infected children at AKTH. This study has generated an epidemiological data that would enhance change of practice and policy in HIV-infected children.
Limitation of this study
The inability of the researchers to recruit HIV-infected children aged ≤6 months as was proposed, which was due to no newly diagnosed newly infected HIV infant at the time study was conducted.
Ethical statement
The study was approved by the institutional ethics committee of AKTH (Approval No NHREC/21/08/2008/AKTH/EC/2074).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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