Letter to the Editor: Cardiac dysfunction among youth with perinatal HIV acquisition and exposure

Introduction

We previously described subclinical cardiac dysfunction by echocardiography among 27% of children and young adults with perinatally acquired HIV (PHIV) in a large HIV treatment program in western Kenya¹. Very few reports from the sub-Saharan Africa (SSA) region have included comparator groups inclusive of those uninfected with HIV (HU) and those with HIV exposure but uninfected (HEU). As reported from the 3^rd HIV-Exposed Uninfected Child Workshop at the 9^th International AIDS Society Conference, the numbers of infants with PHIV are declining while HEU infants are increasing with at least ten times as many as PHIV infants annually². Thus, we designed a pilot study to identify whether HIV status was associated with subclinical cardiac dysfunction by comparing the prevalence of subclinical cardiac dysfunction with appropriately matched control participants.

Methods

We performed a cross-sectional study of children, adolescents and young adults receiving healthcare at the Moi Teaching and Referral Hospital (MTRH) and Academic Model Providing Access to Healthcare (AMPATH) pediatric and adolescent clinics in Eldoret, Kenya^3-5. All study procedures were approved by the institutional review boards of MTRH and Duke University. Informed consent and assent were obtained from all caregivers and participants.

Participants

Three groups (PHIV, HEU, and HU) of twenty-five participants each were recruited for participation for this pilot study from March to July 2022. PHIV were recruited from AMPATH HIV care clinics. PHIV was defined as HIV diagnosis prior to the age of 10 years and on ART for a minimum of 6 months. HEU status was defined as known maternal HIV infection during gestation by medical record data, or caregiver report if record not available, and a participant negative HIV test at screening. HU status was defined as the absence of maternal history of HIV infection by medical record or caregiver report and a negative HIV test at screening. Eligibility criteria for all participants included being 10-19 years of age. Participants were excluded if they had known congenital heart disease or rheumatic heart disease with more than mild valvular features.

Data collection

Demographic data were extracted from electronic and paper medical records for demographic, markers of HIV infection, ART regimen and duration, anthropomorphic data, and vital signs. Potentially cardiotoxic perinatal ART regimens were deemed to be those that contained zidovudine, lopinavir, and/or abacavir. World Health Organization (WHO) standards were utilized to calculate body mass index (BMI) for age Z-score and height for age Z-score⁶. Body-surface area (BSA) was calculated using the Haycock formula⁷. A blood specimen was collected either planned as per routine clinical care or study-only phlebotomy. Hemoglobin (g/dL) and creatinine (μmol/L) tests were performed at AMPATH Reference Laboratory at MTRH (KENAS ISO 15189, accredited and GCLP compliant).

Echocardiography

Each participant underwent a research-protocolized 2-dimensional transthoracic echocardiogram after enrollment by a senior, registered cardiac sonographer (MCF). The echocardiogram was performed on a Terason 3200T portable ultrasound machine (Burlington, MA, USA) using a 4V2 cardiac transducer (range 4 to 2 MHz). Echocardiogram storage and all measurements were made on a commercially available imaging database and analysis platform, DigiView, Version 3.8.7 SP4 – Build 87 (Digisonics Inc., Houston, TX, USA). All measurements were performed in triplicate by a single research sonographer and finalized by a board certified pediatric cardiologist (AWM) blinded to the exposure groups. Relevant echocardiogram values were transformed Z-scores for interpretation⁸.

Echocardiographic measurements were performed in accordance with American Society of Echocardiography recommendations⁹. The main echocardiographic outcome variable was myocardial performance index (MPI) based on our previous work identifying MPI as the most common echocardiographic abnormality among a sample of PHIV¹. MPI is a combined assessment of left ventricular (LV) systolic and diastolic function calculated by the total isovolumetric contraction and relaxation times divided by ejection time¹⁰. For this study, MPI was measured from pulsed-wave tissue Doppler tracings obtained at the lateral and septal mitral valve annulus¹¹. An MPI value of ≥ 0.5 was considered abnormal in this age-group based on prior literature. All studies were technically adequate for all research protocol measurements.

Statistical Analysis

The statistical and research analysis plan was devised and executed by the Duke Biostatistics, Epidemiology, and Research Design Methods Core (FH, HC). Descriptive statistics were summarized by HIV status categories with means with standard deviations. Comparisons of clinical and echocardiographic characteristics of the three groups (PHIV, HEU, HU) were made using the Kruskal-Wallis test for continuous variables and the Fisher exact test for categorical variables. Echocardiographic characteristics include components of MPI (i.e., isovolumic contraction time, isovolumic relaxation time, ejection time). Univariate logistic regression was conducted to assess biologically plausible variables associated with abnormal MPI as the outcome variable. For our primary outcome model, we used multivariate logistic regression to model abnormal MPI on age and HIV status group membership with the HU group as the referent group. A subsequent multivariate logistic analysis was performed with the addition of BMI-for-age z-score and hemoglobin levels.

Results

Characteristics by HIV status

Characteristics of the groups by HIV status (PHIV, HEU and HU) are presented in Table 1. For the PHIV group, 20 participants (805) were on dolutegravir/lamivudine/tenofovir; four (16%) were on dolutegravir/abacavir/lamivudine; and one was on zidovudine/lamivudine/lopinavir/ritonavir. In unadjusted analysis, a higher proportion of HEU (36%) and PHIV (28%) participants had abnormal MPI compared to the HU group (12%), but this difference did not reach statistical significance. No differences were detected in measures of LV diastolic function (i.e., pulmonary venous S/D ratio, mitral inflow deceleration time, mitral E/A ratio, and E/e’ ratio). Additionally estimates of right ventricular systolic function and pressure were normal (tricuspid valve regurgitation jet gradient and tricuspid annular plane systolic excursion) and were not significantly different between groups. No congenital heart disease was detected. One participant from the PHIV group was noted to have mild mitral valve findings associated with rheumatic heart disease (none from HU and HEU groups).

Table 1:

Characteristics of groups by HIV status

	HUU (N=25)	HEU (N=25)	PHIV (N=25)	P-value
Age (years) *	14 (10-19)	13 (10-19)	15 (11-19)
Sex
Male	17 (68.0%)	14 (56.0%)	12 (48.0%)	0.397
Female	8 (32.0%)	11 (44.0%)	13 (52.0%)
Household Monthly Income (KSH)	8400 (8440)	9700 (7240)	8340 (11100)	0.293
HIV Variables
Years from ARV initiation			12.4 (2.8)
HIV viral suppression (<200 copies/mL)			24 (96%)
Clinical Variables
Heart Rate (Beats Per Minute)	76.8 (18.2)	75.1 (10.8)	79.5 (10.6)	0.351
Systolic Blood Pressure (mmHg)	113 (13.8)	106 (11.9)	109 (11.7)	0.3
Diastolic Blood Pressure (mmHg)	73.5 (8.5)	71.0 (6.7)	71.6 (7.7)	0.614
BMI-for-age Z-Score	−0.26 (0.9)	0.14 (1.0)	0.12 (0.9)	0.269
Height-for-age Z-Score	0.11 (1.1)	0.19 (0.9)	−0.30 (0.7)	0.132
Body-Surface-Area (m2)	1.38 (0.3)	1.33 (0.3)	1.43 (0.2)	0.164
Hemoglobin (g/dL)	14.0 (1.4)	14.3 (1.1)	13.3 (1.8)	0.039
Creatinine (μmol/L)	49.3 (14.0)	51.3 (10.0)	57.1 (12.8)	0.039
Echocardiogram Variables
LVEDd Z-Score	−0.11 (1.2)	−0.13 (1.0)	0.24 (0.8)	0.234
LV Mass (grams)	97.5 (25.4)	87.7 (26.4)	93.2 (21.6)	0.276
LV Biplane ejection fraction (%)	58.5 (2.9)	58.4 (2.0)	57.5 (2.0)	0.123
Myocardial Performance Index	0.45 (0.06)	0.48 (0.08)	0.46 (0.09)	0.341
Abnormal MPI	3 (12%)	9 (36%)	7 (28%)	0.179
TVRJ gradient (mmHg)	18.5 (6.9)	19.4 (3.7)	21.7 (7.0)	0.832
TAPSE Z-score	0.08 (1.0)	−0.09 (1.1)	0.01 (0.9)	0.96

Mean (SD), Count (%)

^*Median (range)

KSH – Kenya Shillings, ARV – antiretroviral therapy, BMI – body mass index, LVEDd – left ventricular end-diastolic diameter, LV – left ventricle/ventricular, MPI – myocardial performance index, TVRJ – tricuspid valve regurgitation jet velocity, TAPSE – tricuspid annular plane systolic excursion

Associations with abnormal MPI

There were 19 individuals (25%) with abnormal MPI across all groups. Among individuals with abnormal MPI, the average age was 15±2.9 years, while among the normal MPI group average age was 14.3±2.6 years. The proportion male was 58.9% in those with abnormal MPI (52.6% among normal MPI group); and the hemoglobin level was 14.2±1.5 g/dL (13.7±1.5 g/dL among normal MPI group). With unadjusted, univariate logistic regression, no statistically significant associations were detected between abnormal MPI and BMI z-score, age, sex, hemoglobin, potentially cardiotoxic perinatal ART exposure, or HIV status group (PHIV, HEU, HU). Compared to the HU group using multivariate logistic regression adjusted for age, HEU status was associated with abnormal MPI (OR 5.32, 95%CI 1.26-29.22, p=0.033). We further explored model sensitivity with the addition of BMI-for-age Z-score and hemoglobin levels to the primary model. Adding these two covariates did not improve the model fit significantly, but it illustrated the robustness of HEU status association with abnormal MPI. In this case, HEU status remained borderline associated with abnormal MPI (OR 4.73, 95%CI 1.07-26.8, p=0.053). PHIV status was not significantly associated with abnormal MPI in either model (OR 2.41, 95% CI 0.56-12.71, p=0.256 and OR 2.60, 95% CI 0.56-14.76, p=0.242; respectively).

Perinatal Potentially Cardiotoxic ART Exposure

Thirty-six (48%) study participants had documented perinatal exposure to zidovudine, lopinavir, and/or abacavir through personal medical records and records of AMPATH Prevention of Mother to Child Transmission (PMTCT) clinics. Fifteen participants (60%) from the HEU group and 21 (84%) from the PHIV group had documented perinatal exposure to zidovudine, lopinavir, or abacavir. A numerically higher proportion of individuals with abnormal MPI had been exposed to zidovudine, lopinavir, and/or abacavir (63%) than those with normal MPI (43%).

Discussion

We sought to confirm whether HIV infection or perinatal HIV exposure was associated with subclinical cardiac dysfunction in a study of children and adolescents in an HIV care program in western Kenya. Our chief findings confirm that the prevalence of cardiac dysfunction by echocardiogram is higher than previously reported from the region and that HEU group status is associated with abnormal MPI in multivariate modeling adjusted for age^12-15. The current study adds to the literature by comparing the burden of cardiac disease in PHIV to two important comparator groups, and shows that both PHIV and HEU had a high proportion of individuals with abnormal cardiac imaging. In addition, we focused on an early measure of cardiac dysfunction – MPI – which can detect subtle abnormalities prior to overt cardiac dysfunction. Despite the modest number of participants in each arm, our findings generate hypotheses to be tested in larger studies.

We acknowledge the limitations to this study. The sample size of participants in this pilot cross sectional study limits the interpretation of the prevalence of cardiac dysfunction in the HEU and PHIV groups. Specifically, the finding of three HU youth with abnormal MPI was unexpected and warrants confirmation in future work. Secondly, there was incomplete historical data to comprehensively assess perinatal exposures of the HEU and PHIV groups.

Conclusion

Subclinical cardiac dysfunction is common among PHIV and HEU youth in western Kenya. These findings support further research priorities focused on the cardiac health of PHIV and HEU individuals including determining the clinical relevance of these echocardiographic findings.