Review
Chronic comorbidities in children and adolescents with perinatally acquired HIV infection in sub-Saharan Africa in the era of antiretroviral therapy

https://doi.org/10.1016/S2352-4642(20)30037-7Get rights and content

Summary

Globally, 1·7 million children are living with HIV, of which 90% are in sub-Saharan Africa. The remarkable scale-up of combination antiretroviral therapy has resulted in increasing numbers of children with HIV surviving to adolescence. Unfortunately, in sub-Saharan Africa, HIV diagnosis is often delayed with children starting antiretroviral therapy late in childhood. There have been increasing reports from low-income settings of children with HIV who have multisystem chronic comorbidities despite antiretroviral therapy. Many of these chronic conditions show clinical phenotypes distinct from those in adults with HIV, and result in disability and reduced quality of life. In this Review, we discuss the spectrum and pathogenesis of comorbidities in children with HIV in sub-Saharan Africa. Prompt diagnosis and treatment of perinatally acquired HIV infection is a priority. Additionally, there is a need for increased awareness of the burden of chronic comorbidities. Diagnostic and therapeutic strategies need to be collectively developed if children with HIV are to achieve their full potential.

Introduction

The HIV pandemic has been established for 40 years and, in 2018, 1·7 million children (aged <15 years) worldwide were estimated to be living with HIV, of which 90% were in sub-Saharan Africa. Most children with HIV have been infected by mother-to-child transmission.1 Because of the remarkable scale-up of effective interventions that prevent mother-to-child transmission, the number of perinatally acquired HIV infections decreased from 280 000 in 2010 to 160 000 in 2018.1 Additionally, access to combination antiretroviral therapy (ART; a combination of three drugs leading to durable viral suppression) has expanded globally over the past decade, resulting in a substantial decline in mortality and an increased life expectancy in children with HIV. Thus, escalating numbers of children, who would previously have died in infancy and early childhood from untreated HIV infection, are now surviving to adolescence.2 HIV has therefore changed from a life-threatening illness to a chronic, treatable, albeit incurable, condition.

In high-income countries, adults on ART with well controlled infection have shown a range of comorbidities, including cardiovascular, renal, neurocognitive, and lung disease, which have been described and termed non-AIDS-defining illnesses. These comorbidities contrast with the opportunistic infections and malignancies that occur at advanced stages of HIV disease due to HIV-mediated immunosuppression. Likewise, there is now increasing recognition that children with HIV, including those taking ART, are at risk of developing chronic multisystem comorbidities and concomitant disability.3, 4 Some reports have suggested a trend from infectious events to non-infectious morbidities associated with inflammation, immunodeficiency, and drug toxicity as these children age.5

Many of these comorbidities will be driven by underlying inflammation associated with HIV infection. The spectrum of comorbidities in children might differ from that in adults, most likely related to the timing of HIV infection or ART initiation, or both, and the absence of traditional adult risk factors such as ageing, smoking, and drinking alcohol. Furthermore, there could be differences in the epidemiology of comorbidities in children with HIV in different settings. In high-income settings, combination ART became available in 1996, whereas in much of sub-Saharan Africa, paediatric ART was introduced after 2004. Additionally, 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

Key messages

  • Despite antiretroviral therapy, long-standing HIV infection in children is associated with multisystem chronic comorbidities, particularly in sub-Saharan Africa where HIV treatment initiation is often delayed and occurs much later in childhood than in high-income settings

  • Chronic morbidities in children with HIV are driven by underlying dysregulated immune activation associated with HIV infection, or are a sequela of infections or HIV treatment, or both

  • HIV programmes have predominantly focused on delivery of antiretroviral therapy and much less attention has been paid to diagnosis and management of chronic comorbidities

  • Validated tools for screening and diagnosis and evidence-based interventions for prevention and treatment of comorbidities need to be developed

  • As well as earlier initiation of antiretroviral therapy, HIV care programmes need to identify and address the additional health needs of children with chronic complications, including educational support, rehabilitation, nutrition, psychosocial, and mental health support, if children with HIV are to have optimal health outcomes

In this Review, we discuss the spectrum of chronic morbidities in children growing up with HIV, focusing on studies in sub-Saharan Africa, the likely pathogenesis underlying the development of comorbidities, the implications for HIV care and management, and implications for HIV programmes that have largely focused on ART delivery until now.

Section snippets

Chronic lung disease

Although the incidence of acute pulmonary infections in children with HIV has declined in the past decade because of co-trimoxazole prophylaxis and ART, several studies have reported a substantial burden of chronic respiratory symptoms and signs in children growing up with HIV who are taking ART. Symptoms and signs include cough, breathlessness, reduced exercise tolerance, hypoxia,7, 8, 9 and reduced lung function (predominantly airflow obstruction with little reversibility with

Pathogenesis of chronic comorbidities

The mechanisms underlying comorbidities associated with perinatally acquired HIV infection are largely unknown. Some of the underlying mechanisms might be shared with those reported in adult HIV infection, whereas others could be unique to the paediatric age group, in keeping with the distinct clinical features observed in this age group. Pathogenic mechanisms might also differ between populations in high-income and low-income settings.

In adults, the development of comorbidities associated with

Recommendations for policy and research

Although access to paediatric ART has increased substantially in the past decade, coverage in children lags behind that in adults with about 54% of children with HIV accessing treatment in 2018 compared with about 62% of adults globally.104 Timely diagnosis and treatment of HIV infection in children remains an essential priority.

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

Search strategy and selection criteria

This is a descriptive review on comorbidities associated with HIV infection in children, informed by clinical experience and expert opinion. We searched PubMed for articles published from Jan 1, 2014, to July 31, 2019, with MeSH terms for HIV, Africa, and children and adolescents; and with MeSH and related terms for specific comorbidities (eg, cardiac disease and lung disease). We also looked for relevant publications among our personal files. We did not set any language limits. Articles

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