HIV-exposed uninfected infants: new global challenges in the era of paediatric HIV elimination
Ceri Evans1,2, Christine E Jones3, Andrew J Prendergast1,2,4
1Blizard Institute, Queen Mary University of London, London, UK
2Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
3Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George’s, University of London, London, UK
4Department of International Health, Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD, USA
Corresponding author: Dr Andrew J Prendergast, Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
Tel: +44 207 882 2269
Fax +44 207 882 2195
Short title: HIV-exposed uninfected infants
Word count: 4997
Abstract: 152
References: 160
Key words: HIV, infant, Africa, immune activation, mortality, infections, growth
ABSTRACT
With scale-up of interventions to achieve elimination of paediatric HIV infection, the number of HIV-infected infants is declining, but the number of uninfected infants exposed to maternal HIV is increasing. Interest in the health outcomes of HIV-exposed uninfected (HEU) infants has grown over the last decade, with several studies suggesting increased mortality, infectious morbidity and growth failure compared to HIV-unexposed infants. However, heterogeneous results may reflect the inherent challenges in studies of HEU infants, which require large populations with appropriate, contemporaneous comparison groups and repeat HIV testing throughout the period of breastfeeding. Here we review the effects of HIV exposure on mortality, morbidity and growth, discuss the immunological abnormalities so far identified, and provide an overview of interventions that may be effective in this vulnerable population. As the number of HIV-infected infants declines, the health needs of HEU infants should be prioritised further, to ensure that post-2015 Sustainable Development Goals are achieved.
INTRODUCTION
Mother-to-child transmission is one of the great tragedies of the HIV epidemic, particularly in sub-Saharan Africa, where 90% of new infections occur. Although the global target to eliminate paediatric HIV by 2015 has not been attained, there has been huge progress in reducing the number of HIV-infected infants through scale-up of prevention of mother-to-child transmission (PMTCT) programmes. In the pre-antiretroviral therapy (ART) era, up to 40% of infants acquired HIV from their mothers,1 but with increasing availability of effective PMTCT interventions, transmission rates close to 1% are possible among breastfeeding populations in developing countries,2 and <1% among non-breastfeeding populations.3 The current public health approach to PMTCT is initiation of lifelong ART for all pregnant and breastfeeding women (so-called Option B+)4 to eliminate new HIV infections among children and keep their mothers alive.5 As PMTCT coverage expands, therefore, the number of HIV-infected infants is declining, but the number of HIV-exposed uninfected (HEU) infants is increasing (Figure 1). As progress towards elimination of paediatric HIV infection accelerates, a potentially vulnerable population of HEU infants, with uncertain health needs, is growing. In this Review, we summarise the evidence regarding mortality, infectious morbidity, immune function and growth of HEU infants, and highlight research gaps that need addressing to better define interventions for this growing population.
1
MORTALITY AND MORBIDITY
The observation that infants exposed to HIV, but not infected, might have increased susceptibility to infections first emerged in 1992 when HEU infants in Kenya were found to have a high incidence of measles.6 In 1993, HEU infants in Zaire were noted to have a greater risk of persistent diarrhoea than HIV-unexposed infants;7 HEU infants were highlighted as a priority group, as few management options were available for HIV-infected infants at that time. However, despite many subsequent studies, the precise impact of vertical HIV exposure on child health outcomes remains unclear. Interpretation of published findings is complicated by several factors: first, early studies lacked HIV testing, making the impact of HIV exposure difficult to separate from infant HIV infection; second, follow-up testing of HIV-uninfected mothers and infants to ensure accurate HIV status is often lacking; third, HIV-unexposed comparison groups have either not been included, or are not demographically comparable; fourth, HEU and HIV-unexposed infants often differ in breastfeeding uptake and/or duration; and fifth, contemporary studies cannot distinguish the relative contributions of HIV and ART exposure. Despite these limitations, several large studies suggest that HEU infants have increased mortality and morbidity in early life.
Mortality in the pre-ART era
The largest HEU cohort (ZVITAMBO), which prospectively followed 14110 infants in Zimbabwe prior to availability of ART, found 3-fold higher mortality among HIV-exposed compared to HIV-unexposed infants through 2 years of follow-up; this mortality risk was higher in the first compared to the second year of life (Table 1). Infants and mothers had regular HIV testing, and sensitivity analyses showed that elevated mortality was not due to unascertained postnatal HIV transmission.8 A study from Uganda reported significantly higher mortality among HEU infants at 18 months of age, but not at 12 or 24 months.9 A Zambian study, which prospectively assessed infants from 9 months to 3 years of age, demonstrated 3-fold higher mortality in HEU compared to HIV-unexposed children (95%CI 0·7-14·0).10 Statistical power in these latter studies may have been limited by relatively small sample sizes. Studies with longer follow-up report mixed results. HEU children in Rwanda had no increase in mortality through 5 years,11 but in The Gambia, HIV-1- and HIV-2-exposed uninfected children surviving beyond 4 months of age had increased mortality through median 6 years compared to HIV-unexposed children.12
Mortality in the ART era
Where infants were exposed to limited PMTCT (single-dose nevirapine/zidovudine monotherapy), results have been heterogeneous. A large South African study showed no difference in 12-month mortality between HEU and HIV-unexposed groups; the majority of infants in both groups were exclusively breastfed, which may have partially mitigated differences.13 A smaller South African study, where HEU infants were less likely than HIV-unexposed infants to breastfeed beyond 12 weeks, showed no difference in mortality through 36 weeks,14 although approximately one-third were recruited from a wealthier area where formula feeding may have been safe. HEU infants exposed to single-dose nevirapine and 6 months of zidovudine for PMTCT in the Mashi trial in Botswana had 4-fold higher mortality than HIV-unexposed infants through 24 months.15 In a large trial in Malawi, Tanzania and Zambia, HEU infants had 50% higher 12-month mortality despite single-dose nevirapine and co-trimoxazole prophylaxis.16A small study from Mozambique, in which HIV-exposed infants received co-trimoxazole prophylaxis, single-dose nevirapine and 4 weeks of zidovudine, found a trend towards increased mortality in HEU infants (OR 3·74, 95%CI 0·41-34·3).17 In a small Ugandan study, HEU infants exposed to PMTCT and receiving co-trimoxazole prophylaxis had almost 14-fold increased mortality (OR 13·7, 95%CI 1·12-167·3), but breastfeeding duration was significantly shorter than for HIV-unexposed infants.18
Studies comparing mortality in middle- and high-income-countries are lacking, but there is a need to determine the impact of HIV exposure in these settings, particularly in the current ART era.
All-cause morbidity and hospitalisation
Prior to the availability of ART, HEU infants in the ZVITAMBO trial had more hospitalisations during the neonatal period and more all-cause sick clinic visits throughout infancy, compared to HIV-unexposed infants, particularly for pneumonia and oral thrush.19 In the ART era, a large South African study found no difference in late-onset sepsis, and a slightly lower incidence of early-onset sepsis, in HEU infants during the neonatal period. However, HEU infants receiving single-dose nevirapine and 6 months of zidovudine for PMTCT in the Mashi trial in Botswana had over 2-fold higher hospitalisation compared to HIV-unexposed infants through 24 months.15 Among infants surviving to 20 months of age in Malawi, there were no differences in hospitalisation between HEU and HIV-unexposed infants, although this study may have been limited by survival bias.20 One small study from South Africa showed that, while the frequency of infections in HEU and HIV-unexposed infants was similar, HEU infants had a trend towards more hospitalisations (RR 2·74, 95%CI 0·85-8·78).21 HEU infants in Mozambique receiving co-trimoxazole prophylaxis, single-dose nevirapine and 4 weeks of zidovudine, had fewer outpatient clinic attendances than HIV-unexposed infants at 12 months, and similar hospitalisation rates.17
The most common infections in HEU infants are skin infections, lower respiratory tract infections and oral thrush, in sub-Saharan Africa,19 Latin America and the Caribbean.22 There are reports of unusual infections in HEU infants, including invasive group A streptococcal disease, haemorrhagic varicella and recurrent oral candida. HEU infants also appear to have more severe infections and a greater risk of treatment failure, especially for pneumonia,21,23-26 and higher rates of surgical complications.27
Pneumonia
Pneumonia was more common in HEU infants through 6 months of age in Zimbabwe; in sensitivity analyses including only those surviving to the end of the interval, HEU infants had over 3-fold more hospitalisations for pneumonia during the neonatal period (OR 3.4, 95%CI 1.9-6.0).19 HEU infants in South Africa had increased incidence of invasive pneumococcal disease compared to HIV-unexposed infants, before and after introduction of pneumococcal conjugate vaccine.28,29 Several studies have described pneumonia caused by an unusually broad range of organisms in HEU infants, including Staphylococcus aureus; 24 E. coli; Pseudomonas aeruginosa and other Gram-negative bacteria;24,30 cytomegalovirus and other viruses;24,30,31 and Pneumocystis jirovecii.24,25,32-36 Differences in outcome may therefore be partly due to a different spectrum of causative organisms, which are not treated by standard first-line antimicrobial regimens, or altered pathogen-specific immune responses.
Tuberculosis
HEU infants in developing countries may be at greater risk of tuberculosis (TB). In a South African series, four of eight infants with congenital TB were HEU infants; a further two were HIV-exposed but did not undergo virological testing.37 Compared to HIV-unexposed infants in Uganda, HEU infants had a 2·6-fold increased odds of TB infection, diagnosed by tuberculin skin testing or interferon-gamma release assay.38
Diarrhoea
Studies from sub-Saharan Africa comparing the incidence of diarrhoea between HEU and HIV-unexposed infants may partly be confounded by feeding practices, due to changes over time in breastfeeding recommendations for HIV-infected mothers. A comparison between formula-fed HEU infants and breastfed HIV-unexposed infants in Uganda demonstrated a 6-fold higher risk of severe diarrhoea in HEU infants at 6-11 months of age,18 whilst in Mozambique, HEU infants had less diarrhoea and a similar frequency of diarrhoea-related hospitalisation as HIV-unexposed infants, despite a shorter duration of breastfeeding.17 Other studies not reporting breastfeeding rates had mixed results, with some showing a higher frequency of diarrhoea23 or persistent diarrhoea,24 and others showing no differences.24,30 After adjusting for feeding practices in South Africa, there were no significant associations between HIV exposure and acute, persistent or overall diarrhoea to 6 months of age,13 and in the ZVITAMBO trial, where almost all HEU infants were breastfed, HEU infants did not have more acute diarrhoea than HIV-unexposed infants.19
Morbidity in developed countries
Fewer studies have assessed morbidity among HEU infants in developed countries, where routine ART exposure, lower background infectious morbidity and a lack of appropriate HIV-unexposed control groups from similar socioeconomic backgrounds make the impact of HIV exposure harder to determine. Despite these limitations, several studies suggest elevated infectious morbidity among HEU infants. In a French study of 7638 HEU infants, a high proportion (9·3%) required hospitalisation for serious infections during the first year of life;39 however, no HIV-unexposed control group was assessed and there was potential for hospitalisation bias. The most common bacterial infection was pneumonia caused by encapsulated organisms (Streptococcus pneumoniae and Haemophilus influenzae); the risk was inversely associated with maternal CD4 count for serious bacterial, but not viral, infections. In a Belgian cohort, HEU infants had almost 20-fold increased incidence of invasive group B streptococcal disease compared to unexposed infants in the first month of life (RR 19·6, 95%CI 7·5-51·7), although the absolute number of cases was small.40 HEU infants remained at risk of infection over the first year of life, with a 13-fold increased odds of invasive group B streptococcal disease and 4-fold increased odds of invasive pneumococcal disease compared to HIV-unexposed infants.41 HEU infants born in the ART era had almost 3-fold higher morbidity that those born prior to ART availability (adjusted HR 2·93, 95%CI 1·07-8·05), whether or not mothers actually received ART. A Danish study reported increased hospitalisation among HEU compared to HIV-unexposed children over the first four years of life; however, this increase was related to haematological disorders rather than infectious diseases.42
Opportunistic infections
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection of HIV-infected infants, but was reported in two 7-week-old HEU infants from Texas in 1997;32 in each case, infection was associated with a transient drop in CD4 count. Further cases of PCP pneumonia in HEU infants below 6 months of age have been reported from France,39 South Africa24,25,43 and the USA.36 In South Africa, over half of children admitted to hospital with acute hypoxic pneumonia had PCP detected using molecular techniques; HIV exposure and malnutrition were risk factors among HIV-uninfected children.13 Infants in this study were thoroughly investigated, meaning the burden of PCP in HEU infants elsewhere may be higher than previously recognised.
Causes of excess mortality and morbidity
Despite heterogeneity in the literature, the body of evidence from multiple settings indicates increased morbidity and mortality among HEU infants, and a risk of severe, unusual and complicated infections, compared to HIV-unexposed infants. The causes of excess morbidity and mortality are likely multifactorial, and may be partly driven by adverse environmental and socio-economic conditions. However, morbidity and mortality differences remain after adjustment for socio-economic status,8,19,44 and findings are not driven purely by differences in maternal care-taking capacity due to ill health;44,45 duration of breastfeeding45 and quality of breast milk;15 or colonisation46 or vertical transmission47 of pathogens. Several studies report associations between HEU infant mortality and maternal HIV disease severity, assessed either by maternal CD4 count,8,44,45,48-50 viral load44,48,49,51 or mortality44,45,48-50 (Supplementary Table 1). Incidence of respiratory tract infection has also been associated with severity of maternal HIV disease in several studies.19,22,52,53 In Zimbabwe, increased infectious morbidity remained even at maternal CD4 counts >500 cells/uL, and only disappeared with CD4 >800 cells/uL.19 HEU infants have evidence of immunological abnormalities that may at least partly explain their poor health outcomes.
IMMUNE DYSFUNCTION
A recent review provides an excellent overview of the immunology of HEU infants.54 Here, we summarise the likely causes of immune dysfunction in HEU infants and discuss additional recent studies.