Worldwide, approximately 2 million children live with HIV infection, 90% of whom live in sub-Saharan Africa.1 Most children acquire HIV through mother-to-child transmission, and despite the scale-up of effective programs aimed at preventing mother-to-child transmission, the HIV epidemic continues to grow.1 In Côte d'Ivoire, an estimated 70,000 infants became newly infected with HIV in 2011.1 Without antiretroviral therapy (ART), as many as 50% will die by their second birthday and 60% before age 5.2,3
Since 2004, with the introduction of ART in Côte d'Ivoire, significant improvements in survival have been achieved.4,5 However, the proportion of HIV-infected children who access ART remains unacceptably low, reaching only 15% in 2010.1 Indeed, managing HIV infection in children is more difficult than in adults. First, providing a continuum of care between preventing mother-to-child transmission and early infant diagnosis and ART remains a challenge,6–8 and many children fail to be diagnosed or treated despite their mothers being followed up in HIV clinics. Second, diagnosis in children is complicated; requiring advanced and expensive polymerase chain reaction techniques still not available on a routine basis.9 Finally, ART is a life-long and daily treatment, more difficult to manage in children, where pediatric formulations and dosages are not always available.10 For these reasons, scaling up access to ART care in pediatric populations remains difficult in resource-limited settings.11,12 Furthermore, despite the benefits of ART, HIV-infected children remain at risk for many other common infections and diseases that require health care.13,14 Many studies in West Africa report increased survival of HIV-infected children on ART,4,13–16 but few describe severe morbidity patterns and related utilization of health care. In this study, we report severe morbidity and associated health care resource utilization (HCRU) in HIV-infected children on ART during the 2004–2009 scaling-up period in Abidjan, Côte d′Ivoire.
Settings and Standard of Care
The Aconda program is a nongovernmental association, whose main objective is providing care to HIV-infected patients in Côte d'Ivoire. In partnership with the Bordeaux School of Public Health (ISPED, France), in 2004, Aconda launched a 5-year program of access to HIV care and ART according to the 2006 WHO guidelines. In addition to a number of public and private health care facilities, Aconda relies mostly on 1 dedicated pediatric care facility: the Centre de Prise en Charge, de Recherche et de Formation (CePReF)—Enfant clinic. At CePReF, HIV-infected children are typically seen at least every 3 months, and CD4 counts are measured every 6 months; viral load is not routinely collected. ART, cotrimoxazole prophylaxis, and blood analyses are free of charge. However, x-rays, inpatient day care, and non-ART medications are only partially subsidized, whereas routine laboratory tests (blood smears, cultures, and microscopy) are still mostly paid for by patient families.
Study Design and Participants
This was a retrospective study conducted within a cohort of HIV-infected children followed up within the CePReF facility in the Aconda care programme in Abidjan. All children younger than 15 years, with a medical record, who initiated ART for the first time between January 1, 2004 and December 31, 2009, after a confirmed HIV diagnosis were included in the study. Children were followed from ART initiation until database closeout, death, ART interruption, or loss to follow-up (no contact for >6 months), whichever came first.
Patient data were collected retrospectively from paper-based medical records at CePReF, using a standardized data collection instrument issued specifically for this purpose. A thorough description of the data collection instrument has been described elsewhere.17
Severe morbidity was defined as any event classified as WHO stage 3 or stage 4, or any event leading to inpatient day care, hospitalization, or death. Any similar event occurring within 30 days of the previous one was considered to be a complication and not counted as an additional event. Because there was no standard diagnosis validation tool, AIDS-defining events were defined according to the 2006 WHO case definitions of HIV surveillance.18 Malaria was defined as either definite, if confirmed by a positive blood smear, or probable, if a documented fever led to a prescription for an antimalarial drug. To be consistent within the study period, immunodeficiency was defined according to the WHO recommendations issued in 2006.19
HCRU was divided into 2 categories: (1) outpatient care, defined as either a medical examination with a complementary diagnosis method (complete blood count, x-ray, or blood smear) or any drug prescription other than cotrimoxazole prophylaxis or ART. (2) Inpatient care, defined as either inpatient day care by periods of 24 hours within the CePReF “day hospital” or hospitalization >24 hours at the University Hospital of Yopougon, Abidjan.
Baseline categorical data are presented as frequencies (percentage) and continuous variables using the median and interquartile range (IQR). Incidence rates (IRs) of both severe morbidity and HCRU occurring per 100 child-years (CYs) of follow-up were computed with their 95% confidence interval (95% CI). IRs were described overall and according to age at ART initiation and CD4% strata at time of event: >15%, 15%–25%, and ≥25%.
To study the incidence of recurrent morbidity and recurrent HCRU rates since ART initiation, we used parametric frailty models, estimating the baseline hazard rates with a Weibull distribution. Frailty models are an extension of the Cox regression model; a frailty model is a random effect model for time-to-event data, accounting for intrasubject correlation.20,21 Using shared frailty models allowed us to account for the dependence between recurrent events in a given patient. Moreover, children experiencing severe morbidity are more likely to die, either in hospital or, as several studies have shown, at home, unable to access care, and therefore are lost to follow-up.22 To account for this, we also ran a joint frailty model, studying the joint evolution over time of 2 survival processes: the recurrent event (severe morbidity) and the terminal event (loss to program), considering the latter as informative censoring.23 The dependence between the 2 processes was significant, and hazard rates were computed for both the recurrent and terminal events. For HCRU, this association was not significant, and we ran shared frailty models, accounting only for dependence between recurrent events (ie, the probability for utilization of health care services depended on having already used health care services previously). In all models, we used the calendar timescale, where the start of the “at-risk” period for each event was not reset to 0 after the previous event but to the actual time since entry in the study, that is, ART initiation. We used the package frailtypack of R statistical software version 2.15.2 (The R foundation for Statistical computing, Vienna, Austria), following guidelines presented by Rondeau et al.24
Overall, 332 children initiated ART between 2004 and 2009 at the CePReF at a median age of 5.7 years (IQR: 2.6–9.3; Table 1). Of these, 54.8% were male and 29.1% were classified as CDC stage C; a significantly higher proportion of children 10 years and older were classified as CDC stage C compared with those younger than 2 years (38.7%, P < 0.0001). At ART initiation, all children were receiving cotrimoxazole prophylaxis. The median CD4% count at enrollment was 10.5% (IQR: 5.8–13.9), and 65.4% met the 2006 WHO criteria for immunodeficiency by age.19 The proportion of immunodeficient children was highest among children younger than 2 years and aged 2–3 years, reaching 100% and 94.1%, respectively, in those age groups.
The median follow-up period was 2.5 years (IQR: 0.69–4.04). Overall, 45 (13.5%) children died and 22 (6.6%) were lost to follow-up. Ninety-nine (30%) children interrupted cotrimoxazole prophylaxis during follow-up, after a median time on ART of 1.8 years (IQR: 1.2–2.6); reasons for cotrimoxazole interruption were not documented. At ART initiation, 255 (77.3%) children initiated a nonnucleoside reverse transcriptase inhibitor (NNRTI)–based therapy, the remaining 75 (22.7%) initiated a PI-based ART regimen. During follow-up, 39 (11.7%) children switched to second-line treatment, defined as the change of class of treatment, at a median time of 1.7 years (IQR: 0.5–2.3). The reasons for switching to second line were not documented; however, we report 1 switch for toxicity, 1 for nonadherence, and 2 resulting from limited medication supply. Overall, the most common ART combinations for children on PIs were azidothymidine (AZT) + Lamivudine (3TC) + Nelfinavir (36%), Stavudine + 3TC + Nelfinavir (32%), and ddI + ABC + Lopinavir/ritonavir (11%). Children on NNRTIs were most commonly on AZT + 3TC + Efavirenz (42%), Stavudine + 3TC + Efavirenz (32%), and AZT + 3TC + Nevirapine (11%).
During the study period, 228 (68.7%) children experienced severe morbidity, with a median number of 1 event per child (IQR: 0–3); the maximum number of severe events in a single patient was 8, and the total amount of events observed was 464. The median delay from ART initiation to occurrence of the first event was 2.3 months (IQR: 0.7–11).
The overall severe morbidity IR was 57.1 per 100 CYs of follow-up (95% CI: 52.1 to 62.5). The global and CD4-strata–specific IRs of selected clinical events by age group at ART initiation are given in Table 2. The overall IR was similar in children younger than 5 years and those who were 5 years and older; however, we observed higher rates in children younger than 5 years compared with children who were 5 years and older when CD4% was <25%. Event-defining WHO stages 3 and 4 were the most common, with IRs reaching 82.9/100, CYs in children younger than 5 years with CD4 <15%. Non–AIDS defining morbidity was also substantial; in addition to malaria, dermatosis, asthma, and otitis, parasitic diseases were the most commonly reported diseases. We observed high IRs of malaria and non–AIDS defining events, highest in children younger than 5 years. Overall, the severe morbidity IR was highest within the first 6 months after ART initiation and reduced considerably afterward (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/A450). We observed this trend when studying the specific IR of WHO 3/4 events; however, the IRs of tuberculosis, malaria, and non–AIDS defining event IRs did not significantly differ over time (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/A450). We observed 45 deaths, mostly from unknown causes (80%); only 8 deaths (17%) could definitely be attributed to an advanced stage of the disease.
In multivariate analyses, we observed a significant association between the incidence of recurrent severe morbidity and death or loss to follow-up. When adjusted for age, gender, ART regimen, and current CD4% strata, we observed a significant protective effect cotrimoxazole prophylaxis [adjusted hazards ratio (aHR): 0.36; 95% CI: (0.23 to 0.56)]. Children on a PI-based regimen were more likely to develop severe morbidity during follow-up (aHR: 1.83; 95% CI: 1.35 to 2.47), as were children at more advanced stages of immunodeficiency (aHR: 1.57; 95% CI: 1.1 to 2.18 and aHR: 2.53; 95% CI: 1.81 to 3.55 in moderately and severely immunodeficient children, respectively; Table 3).
Health Care Resource Utilization
Of the 464 severely morbid events, 411 (89%) led to at least 1 type of HCRU, either outpatient care (80%) or inpatient care (3.5%), yielding an estimated IR of any HCRU of 50.5 per 100 CYs of follow-up (95% CI: 45.9 to 55.7) (Table 4).
Outpatient care IR was 45.6 per 100 CYs (95% CI: 41.2 to 50.5); medication prescription was the most frequent type of care provided, with a total of 651 different medications prescribed overall (IR: 80.1/100 CYs; 95% CI: 74.1 to 86.5), mostly antibiotics (32%) and antimalarials (11%). We observed significantly higher rates of antimalarial prescriptions in children younger than 5 years, consistent with observations made when studying severe morbidity, where higher rates of malaria were observed in this age group. We recorded 185 utilizations of complementary diagnoses, the IR was 22.8/100 CYs (95% CI: 19.7 to 26.3). Consequently, fewer than half of the documented severe morbidity had confirmed diagnoses: in the case of tuberculosis, only 50% underwent further examination, which in most cases was radiology; in the case of malaria, 62% of diagnoses were confirmed by further examination.
Table 5 presents multivariate analyses. When adjusted for gender, current CD4% strata, primary caregiver, and distance from the health clinic, we observed lower outpatient care in children older than 10 years (aHR: 0.49; 95% CI: 0.31 to 0.78). Furthermore, children living beyond 20 km from the clinic were less likely to use outpatient care (aHR: 0.65; 95% CI: 0.47 to 0.90). Although outpatient care in children with CD4% between 15% and 25% did not differ significantly from those with CD4 >25%, we observed higher rates of outpatient care in the more immunodeficient children (aHR: 1.84; 95% CI: 1.32 to 2.56), consistent with higher morbidity rates.
Utilization of inpatient care was much less frequent overall than outpatient care, despite the high rates of severe morbidity. The IR of inpatient day care was 25.6/100 CYs (95% CI: 22.7 to 29.7), and we observed only 17 hospitalizations (IR: 2.1/100 CYs; 95% CI: 1.3 to 3.4). Hospitalizations occurred mostly when the disease required intravenous treatment, such as anemia (18%). In multivariate analyses (Table 5), inpatient care was more frequent in children who lived between 5 and 20 km from the clinic compared with those who lived within the same district as the CePReF (aHR: 1.8; 95% CI: 1.05 to 3.11). We also observed significantly lower hazards in children on cotrimoxazole prophylaxis (aHR: 0.29; 95% CI: 0.14 to 0.58). There was a higher hazard of inpatient care in severely immunodeficient children (HR: 2.74; 95% CI: 1.58 to 4.78), implying that severe morbidity led to this kind of care.
Overall, within the first 3 months of ART initiation, we observed similar risks for severe morbidity and HCRU (see Figure S2, Supplemental Digital Content, http://links.lww.com/QAI/A450, which shows the baseline survival functions and confidence bands estimated by our frailty models for the probability of severe morbidity and HCRU). After 3 months, survival without severe morbidity dropped significantly, whereas the risk for HCRU remained constant.
This retrospective cohort study documents severe morbidity and associated HCRU in HIV-1 infected children after ART initiation in Abidjan, Côte d'Ivoire. More than two-thirds of the children included in our study developed at least 1 incident event during the follow-up period. Although most events were AIDS-defining and occurred within the first 6 months of ART, we also observed stable and substantial rates of non–AIDS defining events throughout the study period. In addition, overall severe morbidity was reduced by more than 60% in children who were on cotrimoxazole prophylaxis. Furthermore, although 88% of severe morbidity events did lead to utilization of some healthcare services, our findings reveal many missed opportunities for care.
Despite ART, we observed high rates of WHO stage 3/4 events within the first 6 months of ART initiation, which then decreased over time. Other studies have reported similar observations in resource-limited settings, attributing this trend to the early deaths of the sickest children and the benefits of ART for the remaining patients when children access to ART at advanced stage of the disease.25 Another plausible explanation is immune reconstitution inflammatory syndrome, likely manifesting in a number of mild or serious conditions.26 Furthermore, we believe that initiation of treatment at advanced stages of HIV disease and the slow rate of immune reconstitution with ART also play important roles. Indeed, the age distribution of our cohort (median age, 5.7 years) reflects the difficulties in early diagnosis of children in resource-limited settings and the many missed opportunities for early diagnosis and ART initiation. Consequently, children initiate ART at an advanced stage of immunodeficiency and, thus, remain vulnerable to numerous severe opportunistic infections and infectious morbidity. Indeed, severe morbidity IRs were highest in those with lowest CD4% count, as in other studies, in the African setting.13,14,25,27 The overall tuberculosis IR was 1.7/100 CYs and 4 times higher in severely immunodeficient children younger than 5 years. Similar results were reported in a previous study in Abidjan in 2005,28 but our observed rate is less than that reported in South Africa, where tuberculosis IRs reached 10/100 CYs.29 Although this may be because of a higher prevalence of tuberculosis disease in South Africa, we may also explain our findings by the lower access to tuberculosis diagnosis in the West African setting; this could underestimate the prevalence of tuberculosis in HIV-infected children.30 In addition, we also observed substantial IRs of malaria, particularly in children younger than 5 years. The burden of malaria in this population is well documented,31,32 but HIV therapies interact with antimalarial drugs making the management of malaria difficult.33 Our results reaffirm the importance of tuberculosis and malaria as pathogens in HIV-infected children on ART; these conditions need to be addressed to improve the care of HIV-infected children on ART.
ART regimen was another significant factor associated with recurrent severe morbidity, with higher risks for recurrent morbidity in children initiating PI-based ART, compared to those on NNRTIs. This could be an indicator bias caused by the fact that those initiating a PI-based regimen were those with more advanced disease, initiating second-line treatment. Moreover, PI-based ART is more common in younger children, who could be more vulnerable to severe morbidity. However, our model adjusted for both age and second-line treatment and therefore this confounding effect was limited. Another explanation could be that the poor palatability and inconvenient formulation make adherence to lopinavir challenging in resource-limited settings.
AIDS-related diseases are not the only burden when managing post-ART care. Indeed, we observed, in our cohort, substantial IRs of non–AIDS defining morbidity that did not decrease over time. The lack of resources for prevention, diagnostic tools, and management of general morbidity in the African setting is a strong barrier to the establishment of effective HIV care programs. Nevertheless, we reported that cotrimoxazole prophylaxis had a significant effect in reducing severe morbidity over and above the ART effect. This observation is consistent with previous studies, describing the field effectiveness of this kind of prophylaxis.34–36 Although previous studies may question the role of cotrimoxazole prophylaxis after starting ART,37 we note that, in this context, although children continue to initiate ART at advanced stages of the disease and are vulnerable to opportunistic infections and infectious morbidity, cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-infected children.38,39 Furthermore, we observed that utilization of both outpatient and inpatient care was negatively associated with the use of cotrimoxazole prophylaxis, which supports our previous statement: cotrimoxazole prophylaxis reduces severe morbidity and therefore HCRU. Efforts in scaling-up access to such prophylaxis must continue, even in ART-treated children.
Overall, 89% of the severe morbidity in our study led to medical examinations or treatment, which is higher than that observed in pre-ART cohorts.40 Despite this apparently high proportion, our observations underline the need for more effective care and management of HIV-related diseases. Indeed, resources for diagnosis and treatment have become available through HIV/AIDS control programs, facilitating patient utilization of health care services. In particular, use of complementary diagnoses remained low. We hypothesize that costs are the major explanation for the gap that we observed between severe morbidity and HCRU. For example, the lack of use of diagnostic tools can be attributed to the high costs for patients' families when nonsubsidized or more elaborate examinations are required. In addition, outpatient care was less frequent in children living beyond 20 km from the clinic; we anticipate that the cost of transport to the clinic is a considerable factor in this observation. Similarly, inpatient day care at the CePReF is subsidized, whereas hospitalizations are not. Consequently, many patients opt for 3 or 4 consecutive days of inpatient day care, returning home every evening, rather than hospitalization, thereby delaying care.
In addition to costs, social stigmatization may also explain many missed opportunities for care.41 HIV-related stigma and discrimination continue to be present in every country and region of the world, creating major barriers to providing adequate care, support, and treatment. We observed lower use of inpatient care in children living within the clinic's district compared with those living beyond 10 km. Indeed, with the clinic being in their neighborhood, families may be afraid of stigma if seen attending an HIV clinic on a daily basis.
This study has several limitations. First, the age distribution of our cohort raises the question of a left-truncation bias: HIV-infected children younger than 2 years usually have rapidly progressive disease with high mortality,2 and the less symptomatic children are the ones most likely to survive until late ART initiation. Therefore, our study is mostly based on a population of “survivors” that is composed of children with either a less rapidly progressive disease or who may have benefited from previous health care support offered outside of the Aconda context. Second, the morbidity and HCRU data used in this study were collected retrospectively and may have resulted in underestimations of the true incidence of morbidity. Furthermore, practices may vary over time and between pediatricians, influencing the frequencies of routinely confirmed diagnoses. However, we attempted to ensure the accuracy of diagnosis by requiring all specific documentation from medical charts (clinical findings, laboratory examinations, radiographic results, or copies of prescriptions). Third, our data may be incomplete on other levels: anthropometric data were scarce, preventing assessment of malnutrition.13 Furthermore, we have no data on adherence and hence are unable to ascertain if the children presenting the most events were not taking their treatment as recommended. Fourth, the lack of comparable pre-ART data collection prevented the comparison of IRs before and after treatment and the assessment of the extent to which the declining IRs of severe morbidity that we observed were because of ART and/or care effects. Finally, although we adjusted for loss to program in our analyses, we are unable to ascertain events among children not in care and thus likely underestimated true IRs. Indeed, it is not uncommon for children to skip visits, and consequently, many severe morbid events may go unnoticed by the pediatrician. Furthermore, because good clinical outcomes depend essentially on treatment adherence, when untreated, these events are liable to lead to other comorbidities and/or death, contributing to the underestimations of our IRs. However, this limitation exists also in many other studies, which demonstrate comparable loss-to-follow-up rate.14,25,42 In the light of this trend, expanding an earlier access to ART is essential to avoid severe comorbidities in HIV-infected children. Evidence for strategies to improve access and adherence to ART for children and adolescents is lacking; however, several studies have demonstrated the benefits of decentralized HIV/AIDS and task shifting, such as nurse-initiated and nurse-managed ART.43,44 A recent study in Rwanda reported that providing ART to children in a health center/nurse-based program is both feasible and very effective.45
Despite these limitations, our study provides original data on severe morbidity and HCRU in Côte d'Ivoire for ART-treated children during a period of service scale-up, reflecting the clinical practices in this setting. Caring for children with HIV remains challenging where the burden of non-AIDS–related diseases is high. Because of operational limitations such as delays in diagnosis or presentation to care and the requirement for self-pay for a number of diagnostic and therapeutic services, we observed many missed opportunities for care.46 Cotrimoxazole prophylaxis seems to continuously reduce severe morbidity and thus HCRU in ART-treated children. Younger children are particularly vulnerable to severe morbidity despite ART, underscoring the urgent need for early identification, rapid treatment initiation, and long-term retention in care, including close monitoring, improved diagnostics, and treatment for comorbidities. Improving post-ART care remains a priority in the management of the pediatric HIV epidemic.
The authors would like to thank the children and their families who participated in the Aconda care programmes and the members of the Programme de recherche sur le vih/sida et les maladies associées - Côte d'Ivoire and Aconda teams to whom they are deeply grateful. The authors specially thank Alexandre Laurent (Inserm U897) for his helpful support when using frailtypack and Katie Kelly (CEPAC group) for her reading.
THE IeDEA WEST AFRICA COLLABORATION STUDY GROUP (AS OF MARCH 21, 2013)
Participating Sites (*Members of the Steering Committee, §Members of the Executive Committee)
Benin, Cotonou: Adults: D. M. Zannou*, C. Ahouada, J. Akakpo, C. Ahomadegbé, J. Bashi, A. Gougounon-Houéto, A. Azon-Kouanou, F. Houngbé, and J. Sehonou (CNHU Hubert Maga). Pediatrics: S. Koumakpaï*§, F. Alihonou, M. d′Almeida, I. Hodonou, G. Hounhoui, G. Sagbo, L. Tossa-Bagnan, and H. Adjide (CNHU Hubert Maga).
Burkina Faso: Adults: J. Drabo*, R. Bognounou, A. Dienderé, E. Traore, L. Zoungrana, B. Zerbo (CHU Yalgado, Ouagadougou), A. B. Sawadogo*§, J. Zoungrana, A. Héma, I. Soré, G. Bado, and A. Tapsoba (CHU Souro Sanou, Bobo Dioulasso). Pediatrics: D. Yé*, F. Kouéta, S. Ouedraogo, R. Ouédraogo, W. Hiembo, and M. Gansonré (CH Charles de Gaulle, Ouagadougou).
Côte d′Ivoire, Abidjan: Adults: E. Messou*, J. C. Gnokoro, M. Koné, G. M. Kouakou, (ACONDA-CePReF); C. A. Bosse*, K. Brou, A. I. Assi (ACONDA-MTCT-Plus); H. Chenal*, D. Hawerlander, F. Soppi (CIRBA); A. Minga*, Y. Abo, J.-M. Yoboue (CMSDS/CNTS); S. P. Eholié*§, M. D. Noelly Amego, V. Andavi, Z. Diallo, F. Ello, A. K. Tanon (SMIT, CHU de Treichville), S. O. Koule*, K. C. Anzan, and C. Guehi (USAC, CHU de Treichville). Pediatrics: E. A. Aka*, K. L. Issouf, J.-C. Kouakou, M.-S. N′Gbeche, (ACONDA-CePReF); T. Pety*, Divine Avit-Edi (ACONDA-MTCT-Plus); K. Kouakou*, M. Moh, V. A. Yao (CIRBA); M. A. Folquet*, M.-E. Dainguy, C. Kouakou, V. T. Méa-Assande, G. Oka-Berete, N. Zobo, P. Acquah, M.-B. Kokora (CHU Cocody); T. F. Eboua*, M. Timité-Konan, L. D. Ahoussou, J. K. Assouan, M. F. Sami, and C. Kouadio (CHU Yopougon).
Ghana, Accra: Pediatrics: L. Renner*§, B. Goka, J. Welbeck, A. Sackey, and S. N. Owiafe (Korle Bu TH).
Guinea-Bissau: Adults: C. Wejse*§, Z. J. Da Silva*, J. Paulo (Bandim Health Project), The Bissau HIV Cohort Study Group: A. Rodrigues (Bandim Health Project), D. da Silva (National HIV program Bissau), C. Medina (Hospital National Simao Mendes, Bissau), I. Oliviera-Souto (Bandim Health Project), L. Østergaard (Department of Infectious Diseases, Aarhus University Hospital), A. Laursen (Department of Infectious Diseases, Aarhus University Hospital), M. Sodemann (Department of Infectious Diseases, Odense University Hospital), P. Aaby (Bandim Health Project), A. Fomsgaard (Department of Virology, Statens Serum Institut, Copenhagen), C. Erikstrup (Department of Clinical Immunology), and J. Eugen-Olsen (Department of Infectious Diseases, Hvidovre Hospital, Copenhagen).
Mali, Bamako: Adults: M. Y. Maïga*§, F. F. Diakité, A. Kalle, D. Katile (CH Gabriel Toure), H. A. Traore*, D. Minta*, T. Cissé, M. Dembelé, M. Doumbia, M. Fomba, A. S. Kaya, A. M. Traoré, H. Traoré, and A. A. Toure (CH Point G). Pediatrics: F. Dicko*, M. Sylla, A. Berthé, H. C. Traoré, A. Koïta, N. Koné, C. N'Diaye, S. T. Coulibaly, M. Traoré, and N. Traoré (CH Gabriel Toure).
Nigeria: Adults: M. Charurat* (UMB/IHV), S. Ajayi*, G. Alim, S. Dapiap, Otu (UATH, Abuja), F. Igbinoba (National Hospital Abuja), O. Benson*, C. Adebamowo*, J. James, Obaseki, P. Osakede (UBTH, Benin City), and J. Olasode (OATH, Ile-Ife).
Senegal, Dakar: Adults: M. Seydi*, P. S. Sow, B. Diop, N. M. Manga, J. M. Tine§, and C. C. Bassabi (SMIT, CHU Fann). Pediatrics: H. S. Sy*, A. Ba, A. Diagne, H. Dior, M. Faye, R. D. Gueye, and A. D. Mbaye (CH Albert Royer).
Togo, Lomé: Adults: A. Patassi*, A. Kotosso, B. G. Kariyare, G. Gbadamassi, A. Komi, K. E. Mensah-Zukong, and P. Pakpame (CHU Tokoin/Sylvanus Olympio). Pediatrics: A. K. Lawson-Evi*§, Y. Atakouma, E. Takassi, A. Djeha, A. Ephoévi-gah, and S. El-Hadj Djibril (CHU Tokoin/Sylvanus Olympio).
Executive Committee*: F. Dabis (Principal Investigator, Bordeaux, France), E. Bissagnene (Coprincipal Investigator, Abidjan, Côte d′Ivoire), E. Arrivé (Bordeaux, France), P. Coffie (Abidjan, Côte d′Ivoire), D. Ekouevi (Abidjan, Côte d′Ivoire), A. Jaquet (Bordeaux, France), V. Leroy (Bordeaux, France), C. Lewden (Bordeaux, France), and A. Sasco (Bordeaux, France).
Operational and Statistical Team: D. Amani (Abidjan, Côte d′Ivoire), J.-C. Azani (Abidjan, Côte d′Ivoire), E. Balestre (Bordeaux, France), S. Bessekon (Abidjan, Côte d′Ivoire), F. Bohossou (Abidjan, Côte d′Ivoire), C. Gilbert (Bordeaux, France), S. Karcher (Bordeaux, France), J. M. Gonsan (Abidjan, Côte d′Ivoire), J. Le Carrou (Bordeaux, France), S. Lenaud (Abidjan, Côte d′Ivoire), C. Nchot (Abidjan, Côte d′Ivoire), K. Malateste (Bordeaux, France), A. R. Yao (Abidjan, Côte d′Ivoire), and B. Siloué (Abidjan, Côte d′Ivoire).
Administrative Team: G. Clouet (Bordeaux, France), M. Dosso (Abidjan, Côte d′Ivoire), A. Doring§ (Bordeaux, France), A. Kouakou (Abidjan, Côte d′Ivoire), E. Rabourdin (Bordeaux, France), and J. Rivenc (Pessac, France).
Consultants/Working Groups: X. Anglaret (Bordeaux, France), B. Ba (Bamako, Mali), J. B. Essanin (Abidjan), A. Ciaranello (Boston, MA), S. Datté (Abidjan, Côte d′Ivoire), S. Desmonde (Bordeaux, France), J.-S. Elvis Diby (Abidjan, Côte d′Ivoire), G. S. Gottlieb* (Seattle, WA), A. G. Horo (Abidjan, Côte d′Ivoire), S. N'zoré Kangah (Abidjan, Côte d′Ivoire), D. Malvy (Bordeaux, France), D. Meless (Abidjan, Côte d′Ivoire), A. Mounkaila-Harouna (Bordeaux, France), C. Ndondoki (Bordeaux, France), C. Shiboski (San Francisco, CA), B. Tchounga (Abidjan, Côte d′Ivoire), and R. Thiébaut (Bordeaux, France).
Coordinating Centre: ISPED, Univ Bordeaux Segalen, Bor-deaux, France.
Regional Office: PAC-CI, Abidjan, Côte d′Ivoire.
Methodologic Support: MEREVA, Bordeaux, France.
Web site: http://www.mereva.net/iedea.
1. World Health Organization. UNAIDS Report on the Global AIDS Epidemic 2011. Geneva, Switzerland: UNAIDS; 2011.
2. Newell ML, Coovadia H, Cortina-Borja M, et al.. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364:1236–1243.
3. Spira R, Lepage P, Msellati P, et al.. Natural history of human immunodefiency virus type 1 infection in children: a five-year prospective study in Rwanda. Pediatrics. 1999;104:e56.
4. Anaky MF, Duvignac J, Wemin L, et al.. Scaling up antiretroviral therapy for HIV-infected children in Côte d'Ivoire: determinants of survival and loss to programme. Bull World Health Organ. 2010;88:490–499.
5. Adje-Toure C, Hanson DL, Talla-Nzussouo N, et al.. Virologic and immunologic response to antiretroviral therapy and predictors of HIV type 1 drug resistance in children receiving treatment in Abidjan, Cote d′Ivoire. AIDS Res Hum Retroviruses. 2008;24:911–917.
6. Tonwe-Gold B, Ekouevi DK, Bosse CA, et al.. Implementing family-focused HIV care and treatment: the first 2 years' experience of the mother-to-child transmission-plus program in Abidjan, Côte d'Ivoire. Trop Med Int Health. 2009;14:204–212.
7. Tonwe-Gold B, Ekouevi DK, Viho I, et al.. Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: evaluation of a two-tiered approach. PLoS Med. 2007;4:e257.
8. Ciaranello AL, Park JE, Ramirez-Avila L, et al.. Early infant HIV-1 diagnosis programs in resource limited settings: opportunities for improved outcomes and more cost-effective interventions. BMC Med. 2011;9:59.
9. Nielsen K, Bryson YJ. Diagnosis of HIV infection in children. Pediatr Clin North Am. 2000;47:39–63.
10. Orne-Gliemann J, Becquet R, Ekouevi DK, et al.. Children and HIV/AIDS: from research to policy and action in resource-limited settings. AIDS. 2008;22:797–805.
11. World Health Organisation. Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector. Progress Report 2010. Geneva, Switzerland: UNAIDS; 2010.
12. Bland RM. Management of HIV-infected children in Africa: progress and challenges. Arch Dis Child. 2011;96:911–915.
13. Mubiana-Mbewe M, Bolton-Moore C, Banda Y, et al.. Causes of morbidity among HIV-infected children on antiretroviral therapy in primary care facilities in Lusaka, Zambia. Trop Med Int Health. 2009;14:1190–1198.
14. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al.. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA. 2007;298:1888–1899.
15. Arrivé E, Kyabayinze DJ, Marquis B, et al.. Cohort profile: the paediatric antiretroviral treatment programmes in lower-income countries (KIDS-ART-LINC) collaboration. Int J Epidemiol. 2008;37:474–480.
16. Fenner L, Brinkhof MWG, Keiser O, et al.. Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa. J Acquir Immune Defic Syndr. 2010;54:524–532.
17. Desmonde S, Coffie P, Aka E, et al.. Severe morbidity and mortality in untreated HIV-infected children in a paediatric care programme in Abidjan, Côte d′Ivoire, 2004-2009. BMC Infect Dis. 2011;11:182.
18. World Health Organisation. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults and Children. Geneva, Switzerland: UNAIDS; 2007.
19. World Health Organisation. Antiretroviral Therapy of HIV Infection in Infants and Children: Towards Universal Access. Recommendations for a Public Health Approach. Geneva, Switzerland: UNAIDS; 2006.
20. Cook RJ, Lawless JF. The Statistical Analysis of Recurrent Events. New York, NY: Springer Publishing Company; 2007.
21. Duchateau L, Janssen P. The Frailty Model. Paris, France: Springer-Verlag; 2008.
22. Braitstein P, Songok J, Vreeman RC, et al.. “Wamepotea” (they have become lost): outcomes of HIV-positive and HIV-exposed children lost to follow-up from a large HIV treatment program in western Kenya. J Acquir Immune Defic Syndr. 2011;57:e40–e46.
23. Rondeau V, Mathoulin-Pelissier S, Jacqmin-Gadda H, et al.. Joint frailty models for recurring events and death using maximum penalized likelihood estimation: application on cancer events. Biostatistics. 2007;8:708–721.
24. Rondeau V, Mazroui Y, Gonzalez JR. Frailtypack: an R package for the analysis of correlated data with frailty models using the penalized likelihood estimation. J Stat Softw. 2012;VV(II):4–5.
25. Curtis AJ, Marshall CS, Spelman T, et al.. Incidence of WHO stage 3 and 4 conditions following initiation of anti-retroviral therapy in resource limited settings. PLoS One. 2012;7:e52019.
26. Smith K, Kuhn L, Coovadia A, et al.. Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy. AIDS. 2009;23:1097–1107.
27. De Beaudrap P, Boulle C, Lewden C, et al.. Morbidity after antiretroviral therapy initiation in HIV-1 infected children in west Africa: temporal trends and relation to CD4 count. Pediatr Infect Dis J. 2013;32:354–360.
28. Elenga N, Kouakoussui KA, Bonard D, et al.. Diagnosed tuberculosis during the follow-up of a cohort of human immunodeficiency virus-infected children in Abidjan, Côte d'Ivoire: ANRS 1278 study. Pediatr Infect Dis J. 2005;24:1077–1082.
29. Walters E, Cotton MF, Rabie H, et al.. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. BMC Pediatr. 2008;8:1.
30. Cuevas LE, Petrucci R, Swaminathan S. Tuberculosis diagnostics for children in high-burden countries: what is available and what is needed. Paediatr Int Child Health. 2012;32(suppl 2):S30–S37.
31. Becher H, Kynast-Wolf G, Sié A, et al.. Patterns of malaria: cause-specific and all-cause mortality in a malaria-endemic area of west Africa. Am J Trop Med Hyg. 2008;78:106–113.
32. Onyenekwe CC, Ukibe N, Meludu SC, et al.. Prevalence of malaria as co-infection in HIV-infected individuals in a malaria endemic area of southeastern Nigeria. J Vector Borne Dis. 2007;44:250–254.
33. Flateau C, Le Loup G, Pialoux G. Consequences of HIV infection on malaria and therapeutic implications: a systematic review. Lancet Infect Dis. 2011;11:541–556.
34. Prendergast A, Walker AS, Mulenga V, et al.. Improved growth and anemia in HIV-infected African children taking cotrimoxazole prophylaxis. Clin Infect Dis. 2011;52:953–956.
35. Walker AS, Mulenga V, Ford D, et al.. The impact of daily cotrimoxazole prophylaxis and antiretroviral therapy on mortality and hospital admissions in HIV-infected Zambian children. Clin Infect Dis. 2007;44:1361–1367.
36. Chintu C, Bhat GJ, Walker AS, et al.. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet. 2004;364:1865–1871.
37. Mulenga V, Ford D, Walker AS, et al.. Effect of cotrimoxazole on causes of death, hospital admissions and antibiotic use in HIV-infected children. AIDS. 2007;21:77–84.
38. Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S, et al.. Randomized comparison of Stopping vs continuing cotrimoxazole prophylaxis among 758 HIV+ children on long-term ART: the anti-retroviral research for Watoto trial. Presented at: Conference on Retroviruses and Opportunistic Infections; March 3–7, 2012: Atlanta, GA. Abstract 86.
39. Mounkaïla-Harouna A, Amorassani-Folquet M, Eboua FT, et al.. Incidence of malaria in HIV+ children on pediatric ART: Côte d′Ivoire, international epidemiologic databases to evaluate AIDS, 2004-2009. Presented at: Conference on Retroviruses and Opportunistic Infections; March 3–7, 2012: Atlanta, GA. Poster 954.
40. Desmonde S, Coffie PA, Aka EA, et al.. Health care resource utilization in untreated HIV-infected children in a pediatric programme, Abidjan, Cote d'Ivoire, 2004-2009. J Acquir Immune Defic Syndr. 2013;62:e14–e21.
41. Kimani-Murage EW, Manderson L, Norris SA, et al.. “It's my secret”: barriers to paediatric HIV treatment in a poor rural South African setting. AIDS Care. 2013;25:744–747.
42. Walenda C, Kouakoussui A, Rouet F, et al.. Morbidity in HIV-1-Infected children treated or not treated with highly active antiretroviral therapy (HAART), Abidjan, Cote d′Ivoire, 2000-04. J Trop Pediatr. 2009;55:170–176.
43. Cohen R, Lynch S, Bygrave H, et al.. Antiretroviral treatment outcomes from a nurse-driven, community-supported HIV/AIDS treatment programme in rural Lesotho: observational cohort assessment at two years. J Int AIDS Soc. 2009;12:23.
44. Morris MB, Chapula BT, Chi BH, et al.. Use of task-shifting to rapidly scale-up HIV treatment services: experiences from Lusaka, Zambia. BMC Health Serv Res. 2009;9:5.
45. van Griensven J, De Naeyer L, Uwera J, et al.. Success with antiretroviral treatment for children in Kigali, Rwanda: experience with health center/nurse-based care. BMC Pediatr. 2008;8:39.
46. Leroy V, Malateste K, Rabie H, et al.. Outcomes of antiretroviral therapy in children in Asia and Africa: a comparative analysis of the IeDEA pediatric multiregional collaboration. J Acquir Immune Defic Syndr. 2013;62:208–219.