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Chronic comorbidities in children and adolescents with perinatally acquired HIV infection in sub-Saharan Africa in the era of antiretroviral therapy
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Body Changes for Young Adults Acquiring HIV at Early Age & Perinatally - (01/06/22)
Among PLWH with longitudinal follow-up, the prevalence of overweight increased (27.5% to 52.5%) as did obesity (12.5% to 25%); waist-hip and trunk-limb fat ratios also increased(p<.0001).
individuals who acquired HIV in early childhood were more likely to demonstrate central obesity compared with those without HIV. Using DEXA scans and anthropometrics, we measured body fat distribution over an average of 7 years. We also identified associations between body composition and metabolic parameters as well as the duration of exposure to certain ARVs. These findings underscore the long-term persistence and associated risk factors of central adiposity among PLWH who have life-long ARV exposure
Increased neurocognitive impairment and white matter damaged in young adults with perinatal HIV infection. A case-control study - (11/06/21)<
Participants with pHIV showed significant worse neurocognitive scores: long-term memory (p=0,001), and verbal fluency (p=0,02) compared with sHIV. No significant differences were observed in GM and WM between groups using conventional MRI. Tract-based spatial statistics analysis found significant WM damage in several tracts in the pHIV group compared to sHIV.
April 30, 2020 Lancet
children with HIV in sub-Saharan Africa start ART much later than those in high-income settings. In a global meta-analysis of children who entered HIV care before 10 years of age, the age at ART initiation in Africa was 7·8 years compared with 0·9 years in the USA.6
In summary, comorbidities in children with HIV are likely to reflect persistent immune activation and premature ageing of the immune system, potentially driven by infection in early life with cytomegalovirus and exacerbated by vitamin D deficiency in low-income settings (figure 4). Interventions aimed at reducing inflammation, cytomegalovirus suppression, or vitamin D supplementation, or a combination, could have potential for control or even reversal of comorbidities and merit further study.
In sub-Saharan Africa, there is a large cohort of children with HIV entering adolescence and adulthood that have had delayed ART initiation, and are at increased risk of multisystem impairments and earlier onset of comorbidities than are usually associated with ageing. To date, HIV care has mainly focused on delivery and sustainment of adherence to ART and there is an underappreciation of the burden of multisystem comorbidities associated with HIV in children. Additionally, complex clinical issues place heavy demands on already overstretched health-care systems, and optimum screening and management strategies are not well defined. In response to these issues, WHO convened two scoping meetings in 2014 and in 2019 to review available data and policies on management of major comorbidities associated with HIV, and evidence gaps in clinical management and programming.
Comprehensive HIV care should include diagnosis and management of comorbidities and consequent disability. The panel outlines suggestions for interventions and research priorities aimed at addressing comorbidities associated with HIV in children. In Africa, dedicated HIV services for children and adolescents are the exception rather than the rule. Provision of comprehensive HIV care will need to extend beyond centres of excellence to low-level health-care settings, integrate within existing HIV and maternal, newborn and child health platforms, and consider the physiological and psychosocial changes through childhood. Importantly, inclusion of guardians, teachers, and communities as equal partners will be crucial to optimally support children with HIV to achieve their full potential.>
Availability of diagnostic modalities for chronic lung disease, such as spirometry and high-resolution CT, is scarce in low-income settings. Therefore, chronic respiratory symptoms are often empirically treated with repeated antibiotics and antituberculosis therapy in settings where there is a high prevalence of HIV and tuberculosis is common. The pathogenesis of chronic lung disease associated with HIV is poorly understood and the disease is without specific management guidelines. However, prevention of pulmonary infections can mitigate the burden of chronic lung disease in children with HIV and optimise lung health. Pulmonary infections can be prevented by ensuring routine vaccinations (including pneumococcal conjugate vaccine and annual influenza vaccine),
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early ART initiation, continued co-trimoxazole prophylaxis and use of isoniazid prophylactic therapy, avoidance of exposure to tobacco smoke and indoor air pollution, and optimisation of nutrition.
Cardiovascular disease
Studies from low-income countries have reported a high burden of cardiac abnormalities associated with HIV in children with HIV taking ART. Prevalence estimates from these studies are wide, ranging between 14% and 89%, most likely reflecting differences in measurements and in the selection of participants.23, 24, 25 The spectrum of abnormalities includes left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, left atrial dilatation, isolated right ventricular dilatation, conduction abnormalities, and in some cases, pericardial thickening or effusion (figure 3).24, 25, 26 In a South African cohort of adolescents with HIV (aged 9–14 years), right ventricular dysfunction was the most common form of cardiopulmonary dysfunction; cardiopulmonary dysfunction was associated with lower body-mass index, height, and previous history of pulmonary tuberculosis compared with adolescents who did not have HIV. 27 Notably, in most studies, children were paucisymptomatic. A prospective study in Zimbabwean children with HIV on ART reported the incidence of left and right echocardiographic abnormalities as 3·52 and 5·64 per 100 person-years, respectively. 28 This study also reported that most abnormalities persisted at 18 month follow-up but children were either asymptomatic or their symptoms had not worsened. 28
Much less attention has been given to assessment of vascular disease in children with HIV than the attention given to cardiac disease in these children, although there is evidence from high-income countries that HIV and ART, particularly regimens that are protease inhibitor based, are associated with subclinical atherosclerosis even in young individuals.29 A South African study reported an increased risk of endothelial dysfunction in adolescents with perinatally acquired HIV compared with their age-matched peers who were HIV-negative. 30
Traditional risk factors for cardiovascular disease, including age, hypertension, smoking, and lipid abnormalities, do not play a substantial role in this age group, and HIV or ART, or both, might therefore play a larger role in the pathogenesis of cardiovascular disease.
The natural history and clinical significance of cardiovascular abnormalities are not clear. In contrast to findings from sub-Saharan Africa, a study from the USA reported a decline in rates of cardiomyopathy in the era of ART. 31
The underlying mechanistic pathways of cardiovascular abnormalities are not understood and the abnormalities reported could reflect impairment acquired before ART initiation. Surveillance and studies to investigate pathogenesis and progression are needed to understand whether these abnormalities are likely to result in an increased risk of premature cardiovascular disease as adolescents with HIV enter adulthood.
Renal and metabolic disease
Microalbuminuria is an early marker of glomerular injury and predicts further proteinuria development. Two studies from Tanzania and South Africa reported a variable prevalence of 20% (49 of 240) and 8% (43 of 511), respectively, for microalbuminuria in children with HIV.32, 33 The children in the Tanzanian study were younger and more immunosuppressed than the children in the South African study, and microalbuminuria was strongly associated with immunosuppression and haematuria. 32 Notably, African people often carry APOL1 variants G1 and G2, which are associated with increased odds of early renal disease, with HIV infection substantially augmenting the risk.34 Tenofovir disoproxil fumarate is associated with an adverse effect on renal function and wasting of low molecular weight proteins, phosphate, and glucose. Although slowly progressive, chronic kidney disease is uncommon.35 Hyperphosphaturia secondary to tubular dysfunction can disturb renal-bone metabolic regulation, leading to progressive bone loss and hypophosphataemic osteomalacia, as observed in Fanconi syndrome.35 Older ART drugs, such as stavudine, didanosine, and early generation protease inhibitors, were associated with abnormal fat distribution (lipodystrophy or lipo-atrophy). Although the newer ART regimens are less toxic, children with HIV with established lipid abnormalities or abnormalities in fat distribution show little improvement from switching to newer, less toxic ART.36
ART is also associated with dyslipidaemia and insulin resistance; however, data are sparse for children with HIV in sub-Saharan Africa. A South African study of children who attended HIV clinics on either a lopinavir and ritonavir or efavirenz based ART regimen (with 90 [90%] of 100 having taken stavudine previously) reported a 10% (10 of 96) prevalence of insulin resistance using the homoeostatic model assessment of insulin resistance (HOMA-IR) index, and similar prevalence of dyslipidaemias.
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Overall, 40% (38 of 96) had either insulin resistance or at least one lipid abnormality. The adjusted mean LDL cholesterol increased by 0·24 mmol/L for each year of cumulative lopinavir and ritonavir exposure. Notably, the median body-mass index of participants was only 15·1 kg/m2 (IQR 14·4–16·0) in children on lopinavir and ritonavir and 15·5 (IQR 14·6–17·0) in children on efavirenz where the healthy range is 18·0–24·9 kg/m2. In a trial comparing three different regimens based on nucleoside reverse transcriptase inhibitors in children starting ART in Uganda, HOMA-IR score increased significantly in all three groups 48 weeks after ART initiation, and this increase correlated with monocyte activation. 38
Similarly, in another study, abacavir was associated with increased HOMA-IR score in adolescents.39 Although the long-term effects of the renal and metabolic abnormalities reported in cross-sectional studies are not known, insulin resistance, dyslipidaemias, and abnormal fat distribution are recognised risk factors for cardiovascular disease, hence monitoring is required. Switching to newer protease inhibitors, such as atazanavir or darunavir, in children taking lopinavir might improve lipid profiles.40
Several studies report a high prevalence of mental health disorders in children and adolescents with HIV. A large, Ugandan study that recruited more than 1300 children and adolescents with HIV reported a 17·4% (233 of 1339) prevalence of any psychiatric disorder and a 9·6% (128 of 1339) prevalence of a behavioural disorder, most commonly attention deficit hyperactivity disorder. These disorders were more common in adolescents than in children and commonly occurred concurrently with each other.66
Similarly, a South African study reported that adolescents with HIV had poorer functional competence, self-concept, and motivation; and higher levels of depression, disruptive behaviour, attention-deficit hyperactivity disorder symptoms, and clinically significant anger, compared with their peers who were HIV-negative.67
Malignancy
As children with HIV reach adolescence and become sexually active, they are at risk of acquiring human papillomavirus (HPV) infection, with certain subtypes (for example, HPV 16 and HPV 18) known to cause cervical cancer. The risk might be higher in those with HIV; in an Asian study in Thailand and Vietnam, perinatally infected adolescent girls had a higher prevalence of high-risk HPV and abnormal cervical cytology than adolescents who were not infected, after adjusting for age, sexual history, and pregnancy.71In a Kenyan study, the quadrivalent HPV vaccine was safe and highly immunogenic in boys and girls with HIV.72
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