Several studies have reported dramatic reductions in mortality and hospitalization among HIV-infected children following the introduction of antiretroviral therapy (ART) [1–4]. However, the long-term trends in hospitalization of children on ART are less well described, particularly in resource-limited settings in which children often initiate therapy at advanced disease stage [5–7]. As HIV-infected children survive into adolescence, hospitalization represents an important outcome measure, as an indicator of morbidity and healthcare utilization. Furthermore, there are scant data on hospitalization costs from the healthcare provider's perspective – essential to inform program financing and decision analytic models for optimal allocation of resources .
In this study, we analyzed data from a large prospective observational treatment cohort of HIV-infected children in Thailand (Clinicaltrials.gov NCT00433030). The objectives were to describe the rates of hospitalization, their primary causes, outcomes, and cost over time on ART. We assessed risk factors of hospitalization and admission frequency. We hypothesized that children who initiated ART at advanced disease stage were at higher risk of hospitalization and repeated admissions.
HIV-infected children received ART in a network of 40 public hospitals as part of the national scale-up efforts, as described elsewhere . Children aged less than 18 years, antiretroviral naive (except prophylaxes for prevention of mother-to-child transmission of HIV) who initiated ART (defined as ≥2 drugs) between January 1999 and January 2009, were included in this analysis. ART initiation was based upon clinical and immune criteria: US Centers of Disease Control and Prevention (CDC) HIV clinical disease stage B or C or CD4 T-cell percentage less than 20% if less than 2 years of age, and CD4 less than 15% if 2 years of age or above [10,11]. ART and laboratory monitoring were provided free of charge. Parents/guardians provided written informed consent at study entry, and from December 2006, assent was requested from children aged 8 years or above. The study was approved by the Thai Ministry of Public Health and local Ethics Committees.
At monthly visits, nurses/physicians asked the child/caregiver about the child's well being, including any hospitalizations in the previous month at the site or any other hospital. All serious adverse events (SAEs), defined as life threatening, requiring/prolonging hospitalization, or resulting in disability or death , were reported by the attending physician. If hospitalization occurred in another hospital, the nurse/physician interviewed the caregiver for the details.
All SAEs involving hospitalization, defined as admission for inpatient care for any duration and cause, were included in this analysis. The following data were extracted (through 31 August 2010): date of admission and discharge, primary cause of hospitalization, and outcome. The primary causes were categorized based on an organ and disease system coding scheme; diseases not within these categories were coded as ‘other’ (Supplementary Table 1, http://links.lww.com/QAD/A242). One child may contribute multiple events. Hospitalizations prior to ART initiation were excluded as they represented patients in a natural history state. When children initiated ART during hospitalization, the admission date was set at start of therapy (11 cases). Children who were discharged or died on the date of admission were assigned a stay of 0.5 days.
Costs of hospitalization were based on WHO unit cost estimate of inpatient care per day in Thailand, assuming an 80% occupancy rate, excluding drug costs, and expressed in international dollars (Int$ 2000): $47.13, $61.38, and $83.71 per day in primary, secondary, and tertiary hospitals, respectively . These cost estimates were based on an extensive literature review and modeling inpatient cost as a ratio of outpatient visit costs. The use of international dollars, based on purchasing power parity exchange rates, is recommended for nontraded goods such as inpatient day to allow for comparisons across settings . The 40 hospitals in this study were categorized by specialist services provided and bed capacity [(14 primary, 15 secondary, and 11 tertiary hospitals). Primary hospital is defined as few clinical specialities with 30–200 beds; secondary hospital: 5–10 clinical specialities with 200–800 beds; tertiary hospital: highly specialized staff and equipment and may have teaching activities with 300–1500 beds] and corresponding costs were applied .
Number of hospital admissions per 100 person-years of observation was calculated for the overall period and by 6-month and 12-month intervals. Children were at risk from start of ART to last follow-up or death.
Cost per hospitalization was the duration of admission multiplied by daily cost of inpatient care according to the hospital category. The mean and total cost of hospitalization was calculated per 6-month interval, and the cost per patient-month calculated based on total cost divided by person-month of follow-up.
Risk factors of hospitalization
The outcome of interest was number of hospitalizations per child during two time periods: less than 12 months after start of ART (early hospitalization) and over 12 months (late hospitalization). This cut off was based on the median time to all admissions and previous studies showing markedly different hospitalization rates before and after 12 months of therapy .
Potential risk factors for early and late hospitalization were baseline characteristics at start of ART with less than 20% of missing data: sex, age, CD4%, viral load, CDC disease stage, weight-for-age z-score (WAZ), height-for-age z-score (HAZ) and weight-for-height for age z-score (WHZ) based on Thai reference curves [16,17], initial regimen, calendar year of initiation, and duration of follow-up. All baseline characteristics included in the analysis had less than 10% missing data, except for viral load (16% missing). Baseline hemoglobin was excluded due to excess missing (26%); WAZ was correlated to WHZ and, therefore, only the latter was included. Analysis of late hospitalization was restricted to children on follow-up at 12 months and includes early hospitalization as a potential risk factor.
More than 50% of children were never hospitalized resulting in a large proportion with an outcome of zero, thus violating the normal distribution assumptions of standard regression models . Zero-inflated models address this issue and are increasingly used for analysis of health resource utilization [19–23]. We compared four regression models: Poisson, negative binomial, zero-inflated Poisson (ZIP), and zero-inflated negative binomial (ZINB) model. Residuals of the predicted versus observed values were compared using the Long and Freese method to assess the best fit .
The ZIP model was chosen for the final model, with the best fit to the observed data [The ZIP model was preferred due to over dispersion of data and preponderance of zero events: 77% of children were never hospitalized in the first 12 months of ART, and 77% never hospitalized after 12 months (Vuong test P <0.001 for ZIP versus Poisson model). The ZINB model was unstable with high standard errors and not pursued (data not shown).] (Supplementary Figure 1, http://links.lww.com/QAD/A242). The ZIP model addresses two questions simultaneously; first, what predicts the dichotomous outcome of never versus ever hospitalized? To ease interpretation, coefficients were transformed into odd ratios of being hospitalized. Second, among hospitalized children, what predicts the frequency of admissions? The latter is expressed as incidence rate ratios (IRRs). In univariable analysis, variables associated with each outcome at P value less than 0.2 were included in their respective components of the multivariable analyses using backward selection, and associated variables with P value 0.2 or less were kept in the final model. Data were analyzed using STATA version 11 (Stata Corp., College Station, Texas, USA).
A total of 578 children were included in the analysis. At ART initiation, the median (interquartile range, IQR) age was 7 years (2–10), CD4% 7% (2–16) and 52% of children were in CDC disease stage B or C (Table 1). The median duration of follow-up was 64 months (IQR, 43–82), with a total of 2918 person-years of follow-up.
Overall 211 (37%) children were hospitalized with 451 separate admissions (Table 2). Their median time to first admission was 4 months (IQR, 1–22) after start of ART. Among hospitalized children, 116 (55%) had one admission, 49 (23%) had two, 22 (10%) had three, and 24 (11%) had four or more (range 1–23). The mean duration of hospitalization was 8.6 days (SD 10.5 days). Outcomes were documented in all but one event: 400 (89%) were resolved, 15 (3%) voluntary discharged, 23 (5%) died during hospitalization, and 12 (3%) were resolved/discharged but died within 3 months.
Hospitalization rates, costs, and primary cause
The overall hospitalization rate was 15.4 per 100 person-years. Rates varied significantly with time: 62.9 per 100 person-years at less than 6 months of ART; 22.8 at 6–12 months; and stabilized around 10 hospitalization per 100 person-years after 2 years (Table 2, Fig. 1a). Thirty-eight percent (n = 172) of hospitalizations occurred within the first 6 months of therapy, and 51% (n = 231) within the first year. In the first 6 months, one of the highest hospitalization rates was in children with baseline CD4 cell percentage less than 5%: 90 per 100 person-years [95% confidence interval (CI) 73.3–110.3] as compared to 49 (95% CI 35.7–68.1) per 100 person-years in children with baseline CD4 cell percentage of 15% and above. However, after 6 months, the rates began to converge and by 18 months, children with baseline CD4 cell percentage less than 5% had less than 20 admissions per 100 person-years, comparable to children with higher baseline CD4% (Fig. 1b).
The mean cost of hospitalization was $580 per admission (SD 726, range $24–5902), although this varied with time, peaking at $650–750 during the first 18 months on ART and gradually declining thereafter (Table 2). The hospitalization cost for the cohort declined from $35 per patient-month during the first 6 months of ART to less than $5 per patient-month after 2 years (Fig. 1a).
The primary cause of hospitalization was infectious disease-related in 317 (71%) admissions, with pneumonia as the leading cause accounting for 30% of all admissions (Table 3). Noninfectious causes accounted for 94 (21%) admissions, including 15 (2.6%) for cardiovascular diseases. Ten admissions (2%) were classified as antiretroviral drug related (Supplementary Table 1, http://links.lww.com/QAD/A242). The primary causes of hospitalization were similar before and after 12 months of ART.
Risk factors of early and late hospitalization
Overall 133 children (23%) experienced early hospitalization in the first 12 months of ART with 231 admissions (range 1–8). Early hospitalization was independently associated with young age, stunting, and advanced disease stage at ART initiation. Children aged less than 2 years had five times the odds of early hospitalization as compared to those aged 8 years and over (P = 0.007); CDC stage B/C had two times the odds of early hospitalization as compared to stage N/A (P = 0.05); and low baseline HAZ had 1.4 odds of early hospitalization per z-score decrease (P = 0.001; Table 4). Among children with early hospitalization, CD4 cell percentage less than 5% and low WHZ at ART initiation were independently associated with higher incidence of early admissions, as well as initiation on dual therapy, late calendar year, and female sex (all P < 0.02).
At 12 months of ART, 511 (88%) children were on follow-up (31 died, 17 lost to follow-up, and 19 transferred out of the study) and included in analysis of late hospitalization: 115 (22.5%) were hospitalized with 220 admissions (range 1–21). There was no significant predictor of late hospitalization. However, among children hospitalized, higher incidence of late admissions was associated with low baseline WHZ (IRR 1.2 admissions per z-score decrease, P = 0.004), and early hospitalization (IRR 3.5, P < 0.001). Conversely, baseline age 2–7 years was associated with lower incidence of late admissions as compared to children aged 8 years and over (P < 0.0001). There appeared to be an effect of efavirenz-based regimen, but this was no longer observed when two outlier cases (with 11 and 21 late hospitalizations) were excluded (P = 0.15).
One in three children required hospitalization in 5 years of follow-up on ART. The overall hospitalization rate was 15.4 per 100 person-years, but varied with time, peaking at 63 per 100 person-years at 6 months and falling to approximately 10 per 100 person-years after 2 years of ART. Similar findings were reported in a smaller cohort of 129 children in northern Thailand, with 35% of children hospitalized, mostly during the first 6 months of therapy. Their overall hospitalization rate of 23.0 per 100 person-years was higher than that in our cohort, most likely due to their shorter follow-up time of 2 years . Recent studies in Africa and India have been restricted to cause-specific hospitalizations or focused on HIV-exposed rather than infected children and, therefore, were not comparable [25,26].
Studies in the United States and western Europe have reported extremely low hospitalization rates of less than 1 admission per 100 person-years in the HAART era [1,2,27,28]. However, those estimates were based on hospitalizations per calendar year rather than time since start of therapy and included a mixed population of children on HAART and those not yet requiring treatment. Furthermore, the treated children often initiated therapy during infancy prior to disease progression.
Studies in adults on ART have reported a decline in infectious disease-related hospitalizations accompanied by a rise in non-AIDS-related admissions over time [29,30]. In contrast, pediatric studies in Italy and Thailand suggest that infections, particularly pneumonia and bacterial infections, still constitute a large proportion of hospitalizations [2,15]. Indeed, in our study, 71% of hospitalizations were due to infections, mostly pneumonia and this proportion did not decrease even after 12 months of ART. Ten admissions were reported as antiretroviral drug-related, although 43 admissions due to hematological diseases (mainly anemia) and six admissions for metabolic diseases could have been partly antiretroviral drug-related. With only one admission due to immune reconstitution syndrome (IRIS), the IRIS incidence was lower than that in previous studies , most likely due to our classification based on the underlying illness.
Previous studies suggest that hospitalization constitute 15–49% of total cost of HIV care with highest costs incurred in the first year of treatment and/or patients at most advanced disease stage [4,31,32]. Our findings are consistent with those reports with highest costs peaking at $35 per patient-month during the first 6 months of therapy and high incidence of early hospitalization was associated with advanced disease progression at initiation. Hospitalization cost then declined to less than $5 after 2 years of ART, and less than $2 per patient-month after 4 years. This suggests that children on ART incur very low inpatient care costs as treatment programs mature, reducing the burden on healthcare services and releasing resources for other competing illnesses.
There are few costing studies to compare with. Studies in resource-limited setting have been restricted to adults and do not report disaggregated hospitalization costs [32,33]. Two pediatric studies, both in the United States, reported hospitalization costs of approximately $180 per patient-month in the HAART era [4,31]. This is over five times our highest cost estimate, despite the US cohorts reporting very low hospitalization rates of 0.28 admissions per 100 person-years  and shorter duration of admission , suggesting their costs were mainly driven by higher cost of inpatient care.
We assessed risk factors for early and late hospitalization using the ZIP model, which allows for the excess number of children with zero events. The model also utilizes the richness of the available data, with analysis of predictors of hospitalization as well as frequency of admissions. This approach departs from previous studies using only the binary outcome of ever versus never hospitalized, which fails to distinguish patients with single versus multiple admissions and the potential differences in risk factors [2,27,34].
In our cohort, children initiating ART at less than 2 years were at highest risk of early hospitalization. Similar trends have been reported in Europe and the United States [1,27], and reflects the high morbidity and mortality during infancy, particularly when therapy was initiated when immunocompromised [9,35]. CDC disease stage B/C and stunting at baseline were independent predictors of early hospitalization, whereas CD4% was not. However, among hospitalized children, low baseline CD4% and wasting were associated with higher incidence of early admissions. These findings support WHO recommendations for immediate initiation of therapy in young children less than 2 years and timely initiation of therapy in older children prior to advanced disease progression .
Initiation on dual therapy, late calendar year, and female sex were also associated with frequent early admissions. The effect of dual therapy may reflect suboptimal viral suppression associated with such combinations before availability of HAART. The effect of late calendar year of initiation may reflect increased experience of healthcare providers more readily admitting children with complications. It is unclear why female sex was associated with higher incidence of early hospitalization, although this trend has been reported in adult studies [29,32].
There were no predictors of late hospitalization, suggesting that children who survive the first year of therapy have similar risk of long-term hospitalization regardless of their baseline characteristics. However, among those hospitalized, children with early hospitalization had 3.5 times higher incidence of late admissions, which may reflect vulnerability to health problems or unresolved underlying conditions.
These results were comparable with the Poisson and negative binomial models, although those models did not differentiate predictors of hospitalization as compared to frequency of admissions; therefore, the effect of some associated variables was diluted as compared to the ZIP model (data not shown).
There are several study limitations to consider. First, hospitalizations occurring outside the study sites may have been underreported, although this is likely to be rare due to the monthly visits and free provision of care. However, our cohort has reported lower mortality rates as compared to the national treatment program [6,9], most likely due to the close monitoring and experienced care team. It is unclear whether these factors would also reduce the risk of hospitalization. Importantly, the proportion of children hospitalized was very similar to the northern Thailand cohort , the characteristics of children at start of ART are comparable to the national program , and the HIV care teams also implement the national program at their sites, and, therefore, the benefits of their experience would extend beyond our cohort.
Second, hospitalization costs were calculated based on WHO generic unit cost of inpatient care in Thailand because patient-level cost data were not available. The WHO unit costs are not specific to HIV disease or a pediatric population but do represent a standardized estimate, which allows for comparisons across populations and diseases. Third, the diagnosed causes of hospitalization may include misclassification, in particular those related to IRIS or ART toxicities. Fourth, risk factors of hospitalization were limited to baseline characteristics at start of ART, whereas time-updated variables such as current treatment, CD4%, and viral load were not included; the latter two have been reported as predictive of hospitalization in cross-sectional studies [2,27].
In summary, one in three children was hospitalized on ART, with highest risk in the first year of therapy. Young age and clinical indicators of advanced disease progression at start of ART were associated with early hospitalization, frequent admissions, and consequently higher costs to the healthcare system. Implementation of the WHO revised guidelines for immediate therapy in HIV-infected infants less than 2 years regardless of clinical or immune status [37,38], is likely to reduce mortality and hospitalization among the youngest children. Further studies on hospitalization trends and costs are warranted to evaluate the impact of the new guidelines, forecast the long-term costs of ART provision, and assess the evolving needs of HIV-infected children entering into adolescents and adulthood.
The authors would like to thank all the children, their families, and all members of the hospital teams of the participating sites involved in the PHPT pediatric cohort study.
Participating sites and principal investigators are as follows:
Chiangrai Prachanukroh: R. Hansudewechakul, K. Preedisripipat, C. Chanta; Nakornping: S. Kanjanavanit; Prapokklao: C. Ngampiyaskul, N. Srisawasdi; Chonburi: S. Hongsiriwan; Bhumibol Adulyadej: P. Layangool, J. Mekmullica; Phayao Provincial: P. Techakunakorn, S. Sriminiphant; Samutsakhon: P. Thanasiri, S. Krikajornkitti; Kalasin: S. Srirojana; Lamphun: P. Wannarit, K. Pagdi, R. Kosonsasitorn, R. Somsamai; Mae Chan: S. Buranabanjasatean; Sanpatong: N. Akarathum; Somdej Prapinklao: N. Kamonpakorn, M. Nantarukchaikul; Phan: S. Jungpichanvanich; Phaholpolphayuhasena: P. Attavinijtrakarn; Samutprakarn: A. Puangsombat, C. Sriwacharakarn; Rayong: W. Karnchanamayul; Buddhachinaraj: N. Lertpienthum, W. Ardong; Nakhonpathom: S. Bunjongpak; Health Promotion Region 6 Khon Kaen: S. Hanpinitsak, N. Pramukkul; Somdej Pranangchao Sirikit: T. Hinjiranandana; Mae Sai: S. Kunkongkapan; Chacheongsao: R. Kwanchaipanich; Chiang Kham: V. Wanchaitanawong, P. Jittamala; Pranangklao: P. Lucksanapisitkul, S. Watanayothin; Health Promotion Region 10 Chiang Mai: W. Jitphiankha, K. Jittayanun; Hat Yai: B. Warachit, T. Borkird; Mahasarakam: S. Na-Rajsima, K. Kovitanggoon; Ratchaburi: C. Sutthipong, O. Bamroongshawkaseme.
PHPT Clinical Trial unit
Sites monitoring: P. Sukrakanchana, S. Chalermpantmetagul, C. Kanabkaew, R. Peongjakta, J. Chaiwan, Y. S. Thammajitsagul, R. Wongchai, N. Kruenual, N. Krapunpongsakul, W. Pongchaisit, T. Thimakam, R. Kaewsai, J. Wallapachai, J Thonglo, S. Jinasa, J Khanmali, P. Chart, J. Chalasin, B. Ratchanee, N. Thuenyeanyong, P. Krueduangkam, P. Thuraset, S. Thongsuwan, W. Khamjakkaew; Laboratory: P. Tungyai, J. Kamkorn, W. Pilonpongsathorn, P. Pongpunyayuen, P. Mongkolwat, L. Laomanit, N. Wangsaeng, S. Surajinda, W. Danpaiboon, Y. Taworn, D. Saeng-ai, A. Kaewbundit, A. Khanpanya, N. Boonpleum, P. Sothanapaisan, P. Punyathi, P. Khantarag, R. Dusadeepong, T. Donchai, U. Tungchittrapituk, W. Sripaoraya; PHPT Data center: S. Tanasri, S. Chailert, R. Seubmongkolchai, A. Wongja, K. Yoddee, K. Chaokasem, P. Chailert, K. Suebmongkolchai, A. Seubmongkolchai, C. Chimplee, K. Saopang, P. Chusut, S. Suekrasae, T. Yaowarat, B. Thongpunchang, T. Chitkawin, A. Lueanyod, D. Jianphinitnan, J. Inkom, N. Naratee, N. Homkham, T. Thasit, W. Wongwai, W. Chanthaweethip, R. Suaysod, T. Vorapongpisan, N. Jaisieng; Administrative support: N. Chaiboonruang, P. Pirom, T. Thaiyanant, T. Intaboonma; S. Jitharidkul, S. Jaisook, D. Punyatiam, L. Summanuch, N. Rawanchaikul, P. Palidta, S. Nupradit, T. Tankool, W. Champa; Tracking & Supplies: K. Than-in-at, M. Inta, R. Wongsang; D. Chinwong, C.Sanjoom, P. Saenchitta, P. Wimolwattanasarn, N. Mungkhala,
I.J.C. contributed to the study design, conducted the analyses, writing and revision of the article. I.J.C., J.C., G.J., F.F., and M.L. contributed to the study design, interpretation of data, and critical revisions of the article. M.N., N.L., P.W., P.A., P.L., and S.L. contributed to the study design, data collection, and critical revisions of the article.
The present work was supported by the Global Fund to fight AIDS, Tuberculosis and Malaria (Thailand Grant Round 1 sub recipient PR-A-N-008); Ministry of Public Health, Thailand; Oxfam Great Britain, Thailand; Institut de Recherche pour le Développement (IRD), France; Institut National d’Etudes Démographiques, France; Department of Technical and Economic Cooperation, Thai International Cooperation Agency; International Maternal Pediatric Adolescents Aids Clinical Trials Group (IMPAACT), The National Institutes of Health, US (R01 HD 33326; R01 HD 39615). United Kingdom Medical Research Council Doctoral Training Account Studentship for I.C.
Conflicts of interest
There are no conflicts of interest.
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