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The provision of paediatric HIV care in resource-limited settings has expanded significantly over the last decade. At the end of 2010, 456 000 children were receiving combined antiretroviral therapy (ART) in low- and middle-income countries. However, treatment coverage amongst children requiring therapy remains low. In 2010, UNAIDS estimated that, globally, only 23% of children in need of ART received it, compared with 47% of adults (WHO 2011). Factors limiting the access of HIV-infected children to ART are multiple and include poor integration of HIV care with maternal and child health services, insufficient access to early infant diagnosis, implementation of strategies inefficient for retaining HIV-infected mothers and their children in care, and staff and caregivers who have often lacked of confidence and training to deal with children infected with HIV, especially during the early years of care provision when no adapted paediatric galenic antiretroviral formulations were available. Whilst progress in addressing these factors has been made over the last 10 years with initiatives, such as the development and commercialisation of paediatric fixed-dose combinations of antiretroviral drugs, the writing up of specific and increasingly simplified guidelines for the management of paediatric HIV infection training of health workers and, more recently, roll out of improved diagnostic technologies such as HIV deoxyribonucleic acid polymerase chain reaction (DNA PCR) using dried blood spot, substantial gaps in implementation exist.
Reassuringly, an increasing number of studies have reported treatment outcomes in children who are diagnosed and initiated on ART that are comparable, if not better than those of children treated in North America or Europe (Sutcliffe et al. 2008). Médecins Sans Frontières (MSF) began providing HIV care to adults in resource-limited settings in 2000 and to children in 2001. In this study, we examine the first 10 years of experience in treating paediatric HIV infection in sub-Saharan Africa by describing the clinical characteristics of children who enrolled in HIV care during this period and reporting treatment and programme outcomes 2 years after programme inclusion. Differences in patient mortality by age group and associations with other individual-level factors are also investigated to optimise patient management.
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In this study conducted amongst 6261 paediatric patients who were receiving HIV care in four large HIV programmes in sub-Saharan Africa over a 10-year period, fewer than 5% had a history of PMTCT prophylaxis use and medical referral was the mode of entry in two of five patients. Mortality and attrition during the first two years of follow-up in HIV care were two times higher amongst the youngest children than amongst those aged five to fourteen years. Advanced clinical disease presentation, underweight and tuberculosis diagnosis were strongly associated with poor patient outcomes. Higher rates were observed in earlier years of programme activity and during the first six months of ART use and lower in the following 18 months of therapy.
In our study, patients aged <2 years represented 27% of the total number of children accessing HIV care. This figure is lower than proportions reported in other studies, where patients aged <2 years represented almost 40% of the total number of children accessing HIV care (Sutcliffe et al. 2011; Munyagwa et al. 2012). And this highlights the limited access that young children have to HIV testing and counselling in the study area. Poor access is likely to be related to a combination of inadequate access to PMTCT services, limited diagnostic capacity, especially during early years of programme activity and/or poor linkage to HIV services after diagnosis.
Besides the technological barriers to earlier enrolment of children into HIV care, the poor integration of HIV and maternal child health services means that opportunities to detect infected mothers and their infants are often missed. Almost half of the total number of children included in our analysis entered HIV care via medical referral. This finding suggests that new strategies to expand access to early HIV testing are needed to bring children into care before they are sick. Approaches that engage maternal and child health services, integration of VCT in outpatient services to facilitate HIV testing of sick children, or community-based testing need to be further developed and evaluated. As new more effective PMTCT interventions such as the option B+ (provision of uninterrupted ART to pregnant women irrespective of patient eligibility for therapy) are implemented, it is expected that a minority of children born to mothers attending PMTCT services will acquire HIV infection, and therefore, most infants diagnosed with HIV will no longer be identified in PMTCT programmes.
The low proportion of children with documented exposure to prophylaxis for PMTCT of HIV in the programmes evaluated may reflect underreporting of prophylactic use, low rates of HIV infection amongst PMTCT users and/or sub-optimal access to PMTCT care. It also reflects the important challenges faced by care providers to implement effective PMTCT programmes in Africa. Given that, in the absence of ART use, approximately half of perinatally infected children die before the age of 2 years(Newell et al. 2004; Penazzato et al. 2012), it is likely that in areas covered by the programmes evaluated, many HIV-infected children died without ever being recognised as infected with HIV.
Mortality and attrition observed in these cohorts of children was higher than amongst older patients, a finding consistent with previous studies (Raguenaud et al. 2009; Sutcliffe et al. 2011; McNairy et al. 2012). It is now well accepted that there are significant benefits in terms of mortality and morbidity reduction and improved general psychomotor development associated with early rather than deferred ART (Violari et al. 2008; Goetghebuer et al. 2012; Laughton et al. 2012). However, as the results of this study show, in reality, there continues to be many missed opportunities or gaps to access, diagnose and treat young children with HIV early enough to achieve this reduction in risk. Globally, in 2010, data from 65 low- and middle-income countries showed that only an estimated 28% of HIV exposed infants had access to early infant diagnosis (WHO 2011). Improving access to point of care testing at 6 weeks of age as recommended by WHO would be a significant step forward and could lead to earlier treatment initiation and reduced mortality of infants infected in utero (Sherman 2012).
As for adults, studies have shown that a large proportion of children lost to follow-up (12–87% in African settings) may be unrecorded deaths (McGuire et al. 2012). Besides reflecting mortality, the particularly high lost to follow-up rate amongst infants is likely to reflect the difficulties faced by HIV-infected women with young children who need to deal with their own status and that of their child. Financial family constraints and parental disease or death related to HIV infection are also likely to lead to delays in paediatric care and contribute to increased mortality and dropouts. Adapted counselling strategies and support structures for women and their families are often not sufficiently in place (Hassan et al. 2012).
Children aged 5–14 years constitute an important group amongst those enrolled in HIV care. These ‘long-term survivors’ have particular needs that are usually not adequately met in resource-limited settings. Whilst they do not have the same mortality risk as younger children as shown by this study and others (Charlebois et al. 2010; Fenner et al. 2010), they face significant morbidities, including risk of poor physical and neurodevelopmental growth, poor sexual maturation and risk of chronic lung disease (Smith et al. 2012). Furthermore, from a social perspective, this group of children has a higher likelihood of being orphaned and often struggles with challenges in their home life as well as at school, which has implications for their adherence to treatment (Williams et al. 2006).
The observed decrease in mortality over time amongst children may be attributed to progressive enrolment of children at younger ages and at earlier stages of disease. In addition, it may also reflect improvement in clinical management as clinicians acquire more experience and as new guidelines including updated recommendations are published and implemented. In the early 2000s, there was little guidance on how to best care for children infected with HIV infection. The first WHO guideline specifically concerning the care of HIV positive children was published in 2006. After the publication of results from the CHER study, in 2008, WHO recommended treating all infants before the age of 1 year, regardless of clinical or immunological status (Violari et al. 2008; Puthanakit & Bunupuradah 2010; WHO 2010). The findings of our study show that, despite the achievements of recent years, there is still a need to reduce deaths and lost to follow-up amongst children through earlier HIV diagnosis, proper screening and treatment for opportunistic infections such as tuberculosis, earlier start of ART and adequate education and counselling for children and their caregivers to maximise retention in care. Progressively increasing the age threshold for the systematic initiation of therapy of children older than one year might be a pragmatic strategy to simplify paediatric HIV care provision and improve patient outcomes by reducing delays in ART start, mortality and lost to follow-up rates.
Finally, advanced clinical disease, underweight and tuberculosis diagnosis at enrolment were strongly associated with increased risk of mortality or attrition. These findings are similar to those of previous studies (Munyagwa et al. 2012; Sutcliffe et al. 2011; Raguenaud et al. 2009; Fenner et al. 2010; Cross Continents Collaboration for Kids (3Cs4kids) Analysis & Writing Committee 2008; Wamalwa et al. 2012). Tuberculosis is an opportunistic infection frequently associated with HIV infection in adults and children and associated with increased mortality (Kyeyune et al. 2010; Bakeera-Kitaka et al. 2011). However, the burden of tuberculosis in both HIV-infected and HIV-uninfected children is significantly underestimated due to the difficulties of diagnosis (Kyeyune et al. 2010; Bakeera-Kitaka et al. 2011). Paediatric HIV infection is associated with a 20-fold increased risk of developing active tuberculosis (Hesseling et al. 2009). In our analysis, 9.8% of all children were diagnosed with tuberculosis at the time of enrolment in HIV care. Based on results from other studies conducted amongst adults and children living in the same geographical areas, this figure is likely to underestimate the true burden of disease amongst children (Shah et al. 2009; Bakeera-Kitaka et al. 2011). Published research (Bakeera-Kitaka et al. 2011; Marais et al. 2011) suggests that undiagnosed tuberculosis is likely to have contributed to the high mortality observed before and in the 6 months following ART start.
Several limitations need to be considered when interpreting the results of this evaluation. First, we used electronic health records with missing CD4 counts for most of the children and probable underreporting of PMTCT exposure. Nevertheless, the results obtained in the complete case data analysis, although generally of smaller size, were consistent with those estimated in primary analyses. Second, as shown in previous studies (McGuire et al. 2010; Desmonde et al. 2011), it is likely that many of the children lost to follow-up were unreported deaths, resulting in underestimation of mortality. However, competing risk analyses and those examining the association between baseline factors and retention in care were consistent with results of primary analyses. Third, we cannot exclude residual confounding by unmeasured factors such as information on family support and caregiver, which are likely to be associated with mortality (Sutcliffe et al. 2011). Finally, we excluded 6% of patients who had a unique clinic visit and were more likely to have advanced clinical disease, be underweight and to have died (Table S1). This might have resulted in some underestimation of study effects.