The effect of perinatal HIV and antiretroviral therapy on vascular structure and function in young people: A systematic review and meta-analysis

BACKGROUND AND AIMS: Perinatal HIV infection (PHIV) and prolonged use of antiretroviral therapy (ART) may increase the likelihood of developing subclinical vascular dysfunction at an early age. We conducted a systematic review to assess the effect of PHIV and ART on intima-media thickness (IMT), arterial stiffness and endothelial function in individuals aged 6–25 years. METHODS: Medline, Embase and Web of Science were searched, and studies screened by two independent reviewers. We performed a meta-analysis on selected studies reporting on IMT. RESULTS: A total of 680 studies were retrieved from the databases, with 21 studies deemed eligible for qualitative analysis. There were few studies assessing IMT, arterial stiffness and endothelial function. More than half of the studies found either increased IMT, stiffer arteries or impaired endothelial function in PHIV compared to uninfected controls. A minority of the studies reported that the two groups had similar vascular parameters, a conflicting finding. There was a lack of standardisation for IMT assessment and reporting in numerous studies. In a meta-analysis of seven studies with matching methodologies, IMT was higher in PHIV compared to uninfected controls, (mean difference, 0.05 (0.01–0.09; p = 0.01) but heterogeneity between the studies was substantial (I2, 96.7%; p < 0.001). CONCLUSIONS: PHIV may affect vascular structure and function. Existing studies are generally small, often contradictory, and predominantly cross-sectional in design. Further studies are required to understand vascular health in PHIV to identify cardiovascular disease risk and improve interventional strategies aimed at prevention and treatment of early vascular changes in this population

Human Immunodeficiency Virus-Associated Chronic Lung Disease in Children and Adolescents in Zimbabwe: Chest Radiographic and High-Resolution Computed Tomographic Findings.

Background: Chronic respiratory symptoms are common among children living with human immunodeficiency virus (HIV). We investigated the radiological features of chronic lung disease in children aged 6-16 years receiving antiretroviral therapy for ≥6 months in Harare, Zimbabwe. Methods: Consecutive participants from a HIV clinic underwent clinical assessment and chest radiography. Participants with an abnormal chest radiograph (assessed by a clinician) and/or those meeting a clinical case definition for chronic lung disease underwent high-resolution computed tomography (HRCT). Radiological studies were scored independently and blindly by 2 thoracic radiologists. Relationships between radiological abnormalities and lung function were examined. Results: Among 193 participants (46% female; median age, 11.2 years; interquartile range, 9.0-12.8 years), the median CD4 cell count was 720/µL (473-947/µL), and 79% had a human immunodeficiency virus (HIV) load of <400 copies/mL. The most common chest radiographic finding was ring/tramline opacities (55 of 193 participants; 29%). HRCT scans were evaluated in 84 participants (69%); decreased attenuation (present in 43%) was the dominant abnormality seen. The extent of decreased attenuation was strongly correlated with both the severity and extent of bronchiectasis (rs = 0.68 and P < .001 for both). The extent of decreased attenuation was also negatively correlated with forced expiratory volume in first second of expiration (rs = -0.52), forced vital capacity (rs = -0.42), and forced expiratory flow, midexpiratory phase (rs = -0.42) (P < .001 for all). Conclusions: The HRCT findings strongly suggest that obliterative bronchiolitis may be the major cause of chronic lung disease in our cohort. Further studies to understand the pathogenesis and natural history are urgently needed

A novel full-length two-domain KIR2DL5A allele isolated in Zimbabwean samples: KIR2DL5A*0010104.

The novel allele KIR2DL5A*0010104 differs from that of KIR2DL5A*0010101 with eight single intronic nucleotide changes

Racial Variation in Echocardiographic Reference Ranges for Left Chamber Dimensions in Children and Adolescents: A Systematic Review.

Echocardiography plays a critical role in the assessment of cardiac disease. Important differences in echocardiographically derived cardiac chamber dimensions have been previously highlighted in different population groups in adult studies, but this has not been systematically studied in children, whose body size changes throughout childhood. The aim of this study was to review the distribution of available reference ranges for the left cardiac chamber dimensions in older children and adolescents. The following electronic data bases were searched: Medline, Embase and Web of Science were searched to identify studies which have established echocardiographic reference ranges of left heart parameters in children and adolescents from 1975 to December 2017. There was no geographical limitation. All results were imported into Endnote. Retrieved articles were screened and data extracted by two independent reviewers. A total of 4398 studies were retrieved, with 36 studies finally included in this review. 29 (81%) references were from North America and European (Caucasians) populations, with only one study each from Africa and South America. Two-dimensional and M-mode techniques were the most commonly used echocardiography techniques. There were methodological variations in techniques and normalisation of references. Comparison of selected cardiac measures showed significant differences for interventricular septal thickness among Black African, Indian, German and US American children. Available echocardiographic references cannot be generalised to all settings and therefore, there is need for locally relevant reference ranges. Africa and South America are particularly under-represented. Future studies should focus on developing comprehensive echocardiographic reference ranges for children from different racial backgrounds and should use standardised techniques

Shorter Granulocyte Telomeres Among Children and Adolescents With Perinatally Acquired Human Immunodeficiency Virus Infection and Chronic Lung Disease in Zimbabwe.

BACKGROUND: Chronic lung disease (CLD) has been reported among African children with perinatally acquired human immunodeficiency virus (HIV) infection (C-PHIV), despite combination antiretroviral therapy (cART). In adults, shorter telomere length (TL) has been reported in association with both CLD and HIV. As little is known in children, our objective was to compare TL in HIV-positive (cART-naive or -treated) and HIV-negative children with and without CLD. METHODS: Participants included Zimbabwean C-PHIV, aged 6-16, who were either newly diagnosed and cART-naive, or on cART for >6 months, and HIV-negative controls of similar age and sex. Packed blood cell (granulocyte) TLs from 621 children were compared cross-sectionally between groups. For a subset of newly diagnosed C-PHIV, changes in TL following cART initiation were evaluated. RESULTS: C-PHIV had shorter granulocyte TL compared with uninfected peers, regardless of cART. Among 255 C-PHIV without CLD, TL was shorter in cART-naive participants. In multivariable analyses adjusted for age, sex, CLD, and HIV/cART status, shorter TL was independently associated with older age, being HIV positive, and having reduced forced vital capacity (FVC). Last, cART initiation increased TL. CONCLUSIONS: In this cohort, C-PHIV and those with reduced FVC have shorter granulocyte TL, possibly the result of increased immune activation and cellular turnover due to longstanding HIV infection with delayed cART initiation

Echocardiographic reference ranges in older children and adolescents in sub-Saharan Africa.

BACKGROUND: Echocardiographic reference ranges are important to identify abnormalities of cardiac dimensions. Reference ranges for children in sub-Saharan Africa have not been established. The aim of this study was to establish echocardiographic z-score references for Black children in sub-Saharan Africa. METHODS: 282 healthy subjects aged 6-16years (143 [51%] males) with no known history of cardiac disease were enrolled in the study in Harare, Zimbabwe between 2014 and 2016. Standard M-mode echocardiography was performed and nine cardiac chamber dimensions were obtained. Two non-linear statistical models (gamma weighted model and cubic polynomial model) were tested on the data and the best fitting model was used to calculate z-scores of these cardiac chamber measures. The reference ranges are presented on scatter plots against BSA. RESULTS: Normative data for the following cardiac measures were obtained and z-scores calculated: right ventricular diameter at end diastole (RVEDD); left ventricular diameter at end diastole (LVEDD) and systole (LVESD); interventricular septal wall thickness at end diastole (IVSd) and systole (IVSs); left ventricular posterior wall thickness at end diastole (LVPWd) and systole (LVPWs); left atrium diameter at end systole (LA) and tricuspid annular plane systolic excursion (TAPSE). Girls had higher values for BMI and heart rate than boys (p=0.048 and p=0.001, respectively). Mean interventricular septal and left ventricular posterior walls thickness was higher than published normal values in predominantly Caucasian populations. CONCLUSION: These are the first echocardiographic reference ranges for children from sub Saharan Africa and will allow accurate assessment of cardiac dimensions in clinical practice

Disability, social functioning and school inclusion among older children and adolescents living with HIV in Zimbabwe.

OBJECTIVE: Increasing numbers of children with HIV are surviving to adolescence and encountering multiple clinical and social consequences of long-standing HIV infection. We aimed to investigate the association between HIV and disability, social functioning and school inclusion among 6- to 16-year-olds in Zimbabwe. METHODS: HIV-infected children receiving antiretroviral therapy from a public-sector HIV clinic and HIV-uninfected children attending primary care clinics in the same catchment area were recruited. Standardised questionnaires were used to collect socio-demographic, social functioning and disability data. Multivariable logistic regression was used to assess the relationship between HIV status and disability and functioning. RESULTS: We recruited 202 HIV-infected and 285 HIV-uninfected children. There was no difference in age and gender between the two groups, but a higher proportion of HIV-infected children were orphaned. The prevalence of any disability was higher in HIV-infected than uninfected children (37.6% vs. 18.5%, P < 0.001). HIV-infected children were more likely to report anxiety (adjusted odds ratio (aOR) 4.4; 95% CI 2.4, 8.1), low mood (aOR 4.2; 2.1, 8.4) and difficulty forming friendships (aOR 14.8; 1.9, 116.6) than uninfected children. Children with HIV also reported more missed school days, repeating a school year and social exclusion in class. These associations remained apparent when comparing children with HIV and disability to those with HIV but no disabilities. CONCLUSIONS: Children with HIV commonly experience disabilities, and this is associated with social and educational exclusion. Rehabilitation and support services are needed to facilitate educational attainment and social participation in this group

Incidence and Progression of Echocardiographic Abnormalities in Older Children with Human Immunodeficiency Virus and Adolescents Taking Antiretroviral Therapy: A Prospective Cohort Study.

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. RESULTS: Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10-14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03-6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities

Effect of antiretroviral therapy on longitudinal lung function trends in older children and adolescents with HIV-infection.

INTRODUCTION: Chronic respiratory disease is a common cause of morbidity in children with HIV infection. We investigated longitudinal lung function trends among HIV-infected children, to describe the evolution of lung disease and assess the effect of anti-retroviral therapy (ART). METHODS: Prospective follow-up of two cohorts of HIV-infected children, aged 6 to 16 years, in Harare, Zimbabwe; one group were ART-naïve at enrolment, the other established on ART for a median of 4.7-years. Standardised spirometric assessments were repeated over a 2-year follow-up period. Forced expiratory volume (FEV1) and forced vital capacity (FVC) were expressed as Global Lung Initiative defined z-scores (FEV1z and FVCz). Linear mixed-effects regression modelling of lung function was performed, with co-variate parameters evaluated by likelihood ratio comparison. RESULTS: We included 271 ART-naïve and 197 ART-established children (median age 11 years in both groups) incorporating 1144 spirometric assessments. Changes in FEV1 and FVC were associated with age at ART initiation and body mass index for both cohorts. Our models estimate that ART initiation earlier in life could prevent a deterioration of 0.04 FVCz/year. In the ART-naïve cohort, likelihood ratio comparison suggested an improvement in 0.09 FVCz/year during the two years following treatment initiation, but no evidence for this among participants established on ART. CONCLUSION: Early ART initiation and improved nutrition are positively associated with lung function and are important modifiable factors. An initial improvement in lung growth was seen in the first 2-years following ART initiation, although this did not appear to be sustained beyond this timeframe

The effect of azithromycin for management of HIV-associated chronic lung disease on right heart function : results from the BREATHE trial

BACKGROUND : Right heart abnormalities and pulmonary hypertension (PH) may be secondary to chronic lung disease. Chronic lung disease is common in children with HIV. In the BREATHE trial (Trial registration: NCT02426112), azithromycin (AZM) reduced the risk of acute respiratory exacerbations in children aged 6–19 years with HIV-associated chronic lung disease (HCLD) taking antiretroviral therapy. We assessed the possible effect of AZM on right heart dysfunction and/or PH in the trial. METHODS : A standardised transthoracic echocardiogram using M-mode, two-dimensional and Doppler was performed, at baseline and at completion of weight-based AZM given weekly for 48 weeks. Linear regression was used to compare trial arms. RESULTS : A total of 169 participants (82 AZM arm; 87 placebo arm) were included. Participants in the placebo arm were older, median age 16.2 (13.0–18.2) vs 15.3 (12.9–17.4) years, p = 0.184 in the AZM arm. At baseline, right heart abnormalities (right ventricular systolic dysfunction (RVSD), dilatation, or PH) were observed in 7(4%). Following treatment, there was no difference in prevalence of RVSD between arms (p = 0.761). There was one incident case of suspected PH, and overall, no difference in pulmonary pressures. CONCLUSION : In children with HCLD, there was evidence of secondary cardiac effects, but AZM had no effect on right heart function. Long-term follow-up in children with HIV should be part of future research to understand the clinical implications of right heart abnormalities.The Global Health and Vaccination Programme of the Norwegian Research Councilhttps://www.sciencedirect.com/journal/ijc-heart-and-vasculatuream2022School of Health Systems and Public Health (SHSPH