The implementation of programmes aimed at preventing mother-to-child transmission (PMTCT) and providing antiretroviral therapy (ART) have dramatically improved pediatric HIV care in sub-Saharan Africa.1–4 However, in Côte d'Ivoire, as in many low-income countries in West Africa, scaling up comprehensive care for HIV-infected children still encounters many barriers.5–7
First, although PMTCT coverage has improved greatly, reaching 54% in 2009,8 mothers continue to transmit the disease to their children6–9 leading to an ongoing pediatric HIV epidemic. Second, the uptake of early infant diagnosis is poor in Côte d'Ivoire and requires routine polymerase chain reaction techniques10 that are expensive and not available to all. Consequently, children are diagnosed belatedly, at an advanced clinical and/or immunologic stage of the disease. In addition, providing a continuum of care between postnatal HIV diagnosis, pediatric care, and ART remains a challenge in Côte d'Ivoire. Without ART, HIV-infected children in Côte d'Ivoire also experience severe morbidity and mortality.11–13 The proportion of HIV-infected children with access to ART in Côte d'Ivoire remains unacceptably low; it was estimated to reach only 15% in 2010,4 despite the scaling up of ART since 2004.
Although many studies describe the effects of ART both in adults14,15 and children,5,16,17 few have assessed the utilization of health care resources in HIV-infected children before their access to ART. These data would be helpful in assessing changes in pediatric health care utilization before and after access to ART and guiding the “when to treat” question that remains unanswered in HIV-infected children aged 2 years and older.18
In this study, we analyzed health care resource utilization (HCRU) according to severe morbidity among ART-untreated HIV-1–infected children waiting for access to ART over the 2004–2009 scaling up period in Abidjan, Côte d'Ivoire.
This study was carried out in Abidjan, Côte d'Ivoire. In 2004, the estimated HIV prevalence in this setting in pregnant women was 8.3%.19,20 In 2008, PMTCT coverage was 40% and the HIV prevalence in newborn infants was 2.5%.21
The ACONDA programme is a nongovernmental association whose main objective is providing care to HIV-infected patients in Côte d'Ivoire. Children enter the ACONDA programme in one of two ways: (1) after an HIV diagnosis at a pediatric clinic after presentation with AIDS-related symptoms or (2) after referral for HIV testing because their mother was identified as HIV infected. In partnership with the Bordeaux School of Public Health (ISPED, France), ACONDA launched in 2004 a 5-year programme of access to HIV care and treatment delivering ART according to the 2006 WHO guidelines. In addition to a number of public and private health care facilities, the programme relies mostly on 2 health care facilities entirely dedicated to pediatric care: the Centre de Prise en Charge, de Recherche et de Formation (CePReF) Enfant and the MTCT-Plus programme (mother-to-child-transmission prevention programme). The CePReF provides care for one of the largest active pediatric ART cohorts in Abidjan5; the MTCT-Plus programme follows infants born to identified HIV-infected mothers.22
Standard of Care
The ACONDA programme delivers a comprehensive model of pediatric HIV care covering 3 components: psychological care (diagnosis disclosure), clinical care (diagnosis and treatment, including ART and prophylaxis of opportunistic infections), and prevention (HIV screening). In addition, clinical research studies are also conducted in the CePReF and the MTCT-Plus sites. Partly financed by the President's Emergency Plan for AIDS Relief through the Elizabeth Glaser Pediatric AIDS Foundation, ARTs, cotrimoxazole prophylaxis, and blood analyses are free of charge. However, x-rays, in-patient day care, and other medication (antibiotics and antimalarial treatment) are only partially subsidized, whereas routine medical examinations (blood smears, cultures, and microscopy) are still mostly paid for by patient families.
Study Design and Participants
Eligibility criteria for inclusion in our study included all those aged 15 years or younger, who had not initiated any form of ART other than a PMTCT intervention and who were enrolled in the ACONDA programme (CePReF and MTCT-Plus) between January 1, 2004 and December 31, 2009 after a confirmed HIV diagnosis by polymerase chain reaction or a serology if aged 18 months and older.
Data Collection and Analysis
Patient data were mainly stored in paper-based medical records at the CePReF. The data were collected retrospectively using a standardized data collection instrument issued specifically for this purpose. A thorough description of the data collection has been described elsewhere.11 We analyzed HCRU among children followed up at least once between 2004 and 2009, from their inclusion in the ACONDA programme until ART initiation or closeout date (death or lost to follow-up, defined as no clinical contact more than 6 months).
Events were classified as “severe morbidity” if they were suspected to be WHO stage 3 or 4 or if they led to inpatient day care, hospitalization, or death. Because there was no standard diagnosis validation tool, events were defined as “definite” or “probable” according to the WHO case definitions of HIV surveillance (2006).23 In addition, malaria was considered to have occurred if the diagnosis was either confirmed by a positive blood smear or suspected by the presence of a high temperature leading to a prescription for an antimalarial treatment. To be consistent with the study period, immunodeficiency was defined according to the WHO recommendation issued in 2006.24
HCRU was defined as either (1) outpatient care: (1.1) medical examination with complementary diagnosis method (such as complete blood count, x-ray, and blood smear) and (1.2) any of the following drug prescription: antibiotics, antimalarial treatments, and tuberculosis treatment not involving any kind of hospitalization or (2) inpatient care: (2.1) inpatient day care by periods of 24 hours and (2.2) hospitalization. All HCRU initiated within 24 hours of the diagnosis were considered.
Baseline categorical data are presented as frequencies (percentage) and continuous variables as median [interquartile range (IQR)]. Incidence rates (IR) of HCRU (complementary diagnosis, drug prescription, inpatient day care, and hospitalization) occurring per 100 child-years (CY) of follow-up were computed with their 95% confidence interval (95% CI). IRs were described overall and according to age groups.
Factors associated with the IR of HCRU were described with a Poisson regression approach, allowing variance adjustment for nonindependence when multiple observations were included for a single patient. Relative risks were estimated using the generalized estimating equations approach.25 Analyses were performed using PROC GEMNOD in SAS 9.2.
Overall, 405 children were included in our study: 313 from the CePReF and 92 from the MTCT-plus database. The baseline characteristics are presented in Table 1. Briefly, children were diagnosed at a median age of 4.5 years (IQR: 1.9–7.5); 46.7% were female. Overall, 12.3% were classified as CDC stage C with a significantly higher proportion in those aged 10–15 years (22.1%, P < 0.0001). Immunologic data (CD4 percent or count) were available for 308 children (76.1%), of these children, 27.7% met the 2006 WHO criteria for immunodeficiency by age. The proportion of immunodeficient children was highest among the 10–15 year olds (55%, P < 0.0001). Of the 74.1% of children eligible for cotrimoxazole prophylaxis according to the 2007 WHO recommendations for the use of cotrimoxazole,26 90.3% were under treatment. Only 36% of children aged 1 year or younger were prescribed cotrimoxazole prophylaxis.
Patient Follow-Up and Severe Morbidity
Overall 405 children were included and followed up for a median length of 11.6 months (IQR: 1.4–30.7). At baseline, 136 (33.6%) were eligible for ART initiation; of these children, 113 initiated ART (83.1%); after a median time of 0.9 months (IQR: 0.5–3.1), 8 died (5.9%) and 6 were lost to follow-up (4.4%). The remaining 268 children, not yet eligible for ART at baseline, were followed up for a median time of 16.1 months (IQR: 7.9–26.2); 127 (47.2%) initiated ART, 13 (4.8%) died and 35 (13%) were lost to follow-up. The total follow-up period was 642.31 CY of observation.
During this period, 371 severe morbid events were registered in 162 children (40%). The median time, from the date of enrolment until the occurrence of the first event was 9.1 months (IQR: 1.2–26.3). The overall observed severe morbidity IR was 60.9 per 100 CY of follow-up (95% CI: 55.1 to 67.2); this was significantly more frequent in children aged 10 years and older, varying from 29.0 per 100 CY in children aged 1 year and younger to 95.5 per 100 CY in children aged 10–15 years (P < 0.0001) (Table 2). The leading cause of severe morbidity was malaria, including clinical diagnoses of malaria (35%). Lung diseases, including bronchiectasis, and diarrhea were also frequent causes of morbidity (20% and 14%, respectively) (Table 3).
Health Care Resource Utilization
Of the 371 severe morbid events, 212 led to any outpatient care, either complementary diagnosis or a prescription, yielding an estimated IR of 33.0 per 100 CY of follow-up (95% CI: 28.9 to 37.8) (Table 2).Complementary diagnosis IR was 22.4 per 100 CY (95% CI: 19.1 to 26.4). Radiology was the most frequent diagnosis tool (15%), mostly used to investigate probable chronic lung diseases (53%) and pulmonary tuberculosis (57%). Of the 21 suspected cases of pulmonary tuberculosis, only 5 diagnoses led to complementary diagnoses by sputum culture. Although suspected malaria was the leading cause of severe morbidity, only 11% of the presumptive diagnoses were confirmed by blood smear. Consequently, less than half of the documented severe morbidity had confirmed diagnoses.
The overall estimated outpatient prescription IR was 15.3 per 100 CY (95% CI: 12.5 to 18.6); antibiotics were the most frequent (IR = 10.1/100 CY, 95% CI: 7.9 to 12.9). Age specific IRs and their 95% CI are described in Table 2. There were no records of treatment prescriptions for children aged 10 years and older. We observe the higher rates of prescriptions among children aged 2–5 years (20.4, 11.0, and 9.9 per 100 CY for overall, antibiotics, and antimalarial treatment, respectively).
Table 3 describes HCRU according to severe morbid events. Of the 135 malaria cases, 69 (51%) led to outpatient care. Chronic lung disease led to a high rate of outpatient care (96%). Moreover, the 21 suspected TB cases led to 24 different outpatient health care resources (114.3%), corresponding to 20 complementary diagnoses and 4 TB treatment prescriptions.
When adjusted for age, immunodeficiency at baseline and primary caregiver, children presenting evidence of immunodeficiency and children with no immunologic follow-up were less disposed to receive outpatient care (RR = 0.32, 95% CI: 0.18 to 0.56 and RR = 0.27, 95% CI: 0.13 to 0.56, respectively) compared with children with no evidence of immunodeficiency. Moreover, we observed lower outpatient HCRU in children primarily cared for by both parents compared with those whose primary caregiver was their mother alone (RR: 0.34, 95% CI: (0.15 to 0.77).
The overall inpatient care IR (day care and hospitalization) was 27.7 per 100 CY of follow-up, 95% CI: 23.9 to 32.1. The estimated inpatient day care rate was 21.8 per 100 CY of follow-up; the rate of hospitalization was 5.9 per 100 CY (Table 2). There were no significant differences in inpatient care IR in the difference age groups (P = 0.49).
Inpatient day care was mostly accompanied by intravenous therapy and many events led to more than 12 hours of care (percentages >100%). Overall, it was more frequent after suspected malaria or lung disease (55% and 4% with and without IV therapy, respectively) (Table 3).
We had records for 38 hospitalizations; malaria, bacterial infections, and severe anemia were the leading causes. However, 16 of these hospitalizations were for undocumented reasons and represented 94% of the unknown morbidity, most of which had already led to outpatient care or inpatient day care.
Factors associated with inpatient care are presented in Table 4. As for outpatient care, we observe significantly low inpatient HCRU in children whose primary caregivers are both parents compared with those primarily cared for by their mothers only (RR = 0.30, 95% CI: 0.14 to 0.65). On the other hand, inpatient care was significantly highest in children with no available CD4 data compared with those with documented CD4 suggesting no signs of immunodeficiency at baseline (RR = 2.91, 95% CI: 1.66 to 5.11).
This cohort study documents health care resource utilization in HIV-1–infected children who had not yet undergone ART initiation, in Abidjan, Côte d'Ivoire and who were followed up in a pediatric HIV care programme between 2004 and 2009. In this context, we make 3 main observations. First, the severe morbidity rate is high, and highest in older children, reaching 95.5/100 CY in children aged 10 years and older. Second, the overall coverage of cotrimoxazole prophylaxis at baseline is very low in children aged 1 year and younger, reaching only 36%. Third, HCRU is defined by severe morbidity and is not systematic, as only 57% of the severe morbid events led to further investigation and/or treatment. HCRU was less frequent among children whose primary caregivers were both parents compared with mother alone; outpatient care was higher in children not yet immunodeficient, whereas we observed an inverse pattern in inpatient care.
Severe morbidity in untreated HIV-infected children is early and frequent. In previous work, we showed that the risk of developing a severe morbid event was not associated with immune status, suggesting substantial morbidity attributable to other coinfections and the need for optimal prevention and care in untreated HIV-infected children.11 Indeed, these children are vulnerable to numerous serious opportunistic infections and infectious morbidity; our study showed high rates of probable malaria, lung disease, diarrheal disease, and tuberculosis. This is in agreement with well-documented high risks in sub-Saharan African HIV-infected children for malaria,27 tuberculosis,28 respiratory tract infections,12,13 and diarrheal disease.29 Prophylactic cotrimoxazole has been shown to be effective to help prevent each one of these diseases30–32 and is an affordable intervention. However, even in an HIV health care programme, it is still not available to all, despite the fact it is recommended from 6 weeks of age in HIV-exposed infants before HIV diagnosis.26 These findings highlight the need for a greater utilization of diagnostic and therapeutic services, and most importantly, the operational difficulties health care centres face in the management of pediatric HIV.
Resources for diagnosis and treatment have become available through HIV/AIDS control programmes, but there remains a deficiency in the pre-ART care of pediatric HIV; less than 50% of the severe morbidity triggered examinations or treatment. Radiology and blood analyses were the most commonly used diagnosis tools. We explain this lack of use mainly because of the costs for the families for more elaborate examinations that would not be subsidized. Consequently, diagnoses are made relying on clinical symptoms or approximate diagnosis methods. Costs of HIV care could also explain, in part, the low rate of HCRU: although both inpatient day care and HIV treatments are subsidized by the ACONDA programme, there still remains a cost for the families to access these treatments that they may not always be able to pay. Moreover, much of the inpatient day care exceeded 48 hours, comparable to hospitalization, and probably occurred in a context where actual hospitalization would have been more favorable if had been affordable. We suspect this is a common option that families may select because inpatient day care is subsidized by the care programme, limiting patient costs but delaying care. Although ART remains free, other pediatric care must be paid for in part by patients/caregivers. As such, care is often not affordable, many patients experience poor retention in care, severe avoidable morbidity, and early mortality.
Outpatient care was less frequent in children who were immunodeficient at baseline. These children were already at an advanced stage of disease and were more likely to initiate ART, leading to less observed time at risk. However, these children were already at an advanced stage of disease and faced a higher risk of death33; they may have been more likely to die at home before they could reach health care facilities. We hypothesize that these children may account for a larger proportion of undocumented deaths and lost to follow-up than nonimmunodeficient children.34
We can explain the inverse observation in inpatient care by the severity of the event. Indeed, children with no available immunologic data tend to be children with very severe clinical conditions and who die or are transferred to hospitals for long-term care.
HCRU was lower in children cared for by both parents. Indeed, having both parents as primary caregivers implies that when medical decisions are necessary, both parents should consent. Recent studies have pointed out the social barriers often encountered in pediatric HIV care programmes when disclosing the child's and mother's HIV status to the father.35,36 The results observed in the “both parents” group can be explained by this, and we hypothesize that the father of most of these children is unaware of his child's and possibly wife's HIV status.
Our model does not allow observing the effect of cotrimoxazole prophylaxis on HCRU. Indeed, coverage of cotrimoxazole prophylaxis was correlated with age and significantly less frequent in infants 1 year or younger, who constitute a too small proportion of our cohort to allow the model to converge. Nevertheless, we report incidences of severe morbidity and associated HCRU, showing substantial morbidity attributable to other coinfectious diseases and the need for pre-ART care despite cotrimoxazole prophylaxis.
There are 2 major limitations inherent in our retrospective study design. First, our cohort is exposed to a left truncation bias: the less symptomatic children are the ones more likely to still be alive and therefore our study is based on a selected population of the more healthy untreated HIV-infected children. Our study population is comprised of children diagnosed at a later age, having consequently survived many events and who have been included in an HIV programme where the health care support might have been better than that offered outside of the ACONDA context. However, this survivorship bias is existent in many other studies.37,38
Second, severe morbidity and HCRU are likely underdocumented in our data set. For example, the completion of medical charts may vary from one pediatrician to another and may vary over time, and diagnoses could not be routinely confirmed using standardized diagnosic procedures. We acknowledge that the reliability of clinical events is questionable; however, we attempted to ensure the accuracy of severe morbidity by requiring specific documentation, such as clinical findings, laboratory examinations, and radiographic results. Social stigmatization of HIV among the African population also leads to withheld information concerning events during follow-up.39
Despite these considerations, our study provides original data on pre-ART severe morbidity and health care resource utilization in a large pediatric cohort, reflecting as best as possible the current clinical practices in Côte d'Ivoire. Managing HIV in children remains challenging in an era where ART is scaling up.40,41 Free cotrimoxazole prophylaxis according to the WHO recommendations and other diagnostic and therapeutic interventions are still not available to all, leading to avoidable severe morbidity in those HIV-infected children who have not yet initiated ART. This study took place in 2004–2009, during the rollout of ART in Côte d'Ivoire. However, because of operational limitations, such as delays in diagnosis or presentation to care, stigma associated with HIV care, limited ART availability, and the requirement for self-pay for a number of diagnostic and therapeutic services that we observed, many missed opportunities to put eligible children on ART.
Although the WHO has revised its guidelines now recommending ART for all HIV-infected children 24 months or younger, the coverage in resource-limited settings remains low.8 Identifying HIV-infected infants is a challenge in West Africa. In addition to the sophisticated and expensive techniques required for early infant diagnosis of HIV, PMTCT coverage is low; PMTCT services are estimated to have reached only 54% of pregnant HIV-infected women in Côte d'Ivoire in 2009. Although PMTCT interventions are scaling up today, this emphasises the need for efforts to strengthen the link between PMTCT and childcare programmes. Improving pre-ART care remains a priority in the management of the pediatric HIV epidemic and access to cotrimoxazole must remain a priority in such a population.
Additional research must be undertaken in a pediatric population, to better understand the severe morbidity in HIV-infected children and retention in care and associated costs to guide public health interventions, as it has recently been done in developed countries.42 The data presented here represent a base case scenario against which we could compare more frequently reported outcomes for children receiving ART, and we therefore believe that these data can inform current debates about the impact of universal ART initiation (regardless of CD4) for children of various ages, particularly in those older than 2 years. Furthermore, lifetime pre-ART treatment costs will probably be overweighed after ART access, as pediatric HIV infection becomes a chronic disease leading to greater health care utilizations. This will have to be assessed and will highlight the cost effectiveness of preventing MTCT in low-income countries.
The authors would like to thank the children and their families who participated in the ACONDA care programmes. The authors are deeply grateful to all staff members of the PACCI and ACONDA teams (the CePReF and the MTCT-Plus programme) involved in the care of HIV/AIDS patients in Abidjan. Each of these people has during the postelectoral crisis in 2011 courageously continued to serve the sick, wounded, displaced, and the refugees—all victims of the war and to bring them medicine, food, water, support, and humanity. The authors would also like to thank the CEPAC group (Cost-Effectiveness for Preventing AIDS Complications) for their collaboration and input in this study. Finally, a special thank you goes to Dr X. Anglaret (INSERM U897 and Programme PACCI) for his helpful support.
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