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Antiretroviral Therapy for HIV-1—Infected Children in Haiti

  1. Eric George1,
  2. Francine Noël3,
  3. Gyrlande Bois3,
  4. Rachelle Cassagnol3,
  5. Louise Estavien3,
  6. Patricia De Matteis Rouzier3,
  7. Rose I. Verdier3,
  8. Warren D. Johnson1,
  9. Jean W. Pape3,
  10. Daniel W. Fitzgerald1 and
  11. Peter F. Wright2
  1. 1 Department of Medicine, Division of International Medicine and Infectious Diseases, Weill Medical College of Cornell University, New York, New York
  2. 2 Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee
  3. 3 Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, Port-au-Prince, Haiti
  1. Reprints or correspondence: Dr. Erik George, Dept. of Medicine, Div. of International Medicine and Infectious Diseases, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021 (erikgeorge{at}yepmail.net).
 
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Abstract

Background. Data are limited about the effectiveness of pediatric antiretroviral therapy (ART) in low-income countries.

Methods. We report the outcomes of consecutively treating 236 human immunodeficiency virus type 1 (HIV-1)—infected treatment-naive children with triple ART in Port-au-Prince, Haiti, between 1 May 2003 and 30 April 2006.

Results. Kaplan-Meier survival analysis at follow-up demonstrated that 191 children (81%) remained in care, 21 (9%) were dead, and 24 (10%) were lost to follow-up. Independent baseline predictors of mortality were age <18 months, CD4+ T cell percentage ≤5%, and weight-for-age Z score (WAZ) less than −3. Twelve months into ART, 56% of tested subjects had undetectable HIV-1 RNA loads. Median CD4+ T cell percentages at 12 months increased by 15%, 11%, and 5% in children with baseline percentages of ≤5%, 6%–24%, and ≥25%, respectively (P<.01 ). The median WAZ at 12 months increased by 1.0, 0.6, and 0.2 in children with baseline WAZ less than −2, −2 to −1.1, and −1 or more, respectively (P<.01 ).

Conclusion. With continuous donor support, trained providers, and the availability of pediatric antiretroviral drug formulations, it proved feasible to deliver pediatric ART in Haiti. The effectiveness of this program should encourage efforts to make ART available for HIV-infected children in poor countries.

Pediatric antiretroviral therapy (ART) has dramatically improved the survival of HIV-1—infected children treated in the United States and Europe [1–3]. The vast majority of the 2.3 million HIV-infected children live in low- and middle-income countries, where there is limited access to antiretroviral drugs [4]. In 2003, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) jointly launched the “3 by 5” initiative to facilitate the delivery of ART globally [5]. By March 2006, 1.3million people had received ART [6]. Fewer than 5% of the recipients were children, and the majority of these lived in middle-income countries (e.g., Brazil and Thailand). Pediatric ART delivery has been hampered by the shortage of trained providers, lack of diagnostic techniques, and limited availability of pediatric drug formulations.

The rapidity of disease progression and death ofHIVinfected infants in poor countries is alarming. Two-year mortality without intervention is >50% [7, 8]. There are few published data on the effectiveness of pediatric ART in areas with high rates of poverty, illiteracy, malnutrition, and tropical diseases [9–13].

In Haiti, 78% of the people live in extreme poverty (per-capita income, <$2/day), and the delivery of health-care services is weak. The latest national sentinel surveillance surveys estimated the HIV prevalence at 3.1% among pregnant women attending antenatal clinics [14]. Vertical transmission of HIV has been reported to be 27%–37% [15, 16]. A nationwide expansion of adult AIDS services is presently being staged by the Ministry of Health (MOH) in Haiti, and preparations are being made for scaling up pediatric AIDS care as well. The Groupe Haiïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), a Haitian nongovernmental organization, has provided free primary health care, including voluntary counseling and HIV testing (VCT), to communities surrounding Port-au-Prince since 1985 [17, 18]. Since 2003, ∼2500 HIV-infected adults and children have received ART [19], and 700 women have been enrolled in prevention of mother-to-child transmission (PMTCT) services.We report the clinical outcomes of consecutively treating 236 HIV-infected children with ART. This initiative was launched in collaboration with the MOH and was supported by the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the President's Emergency Plan for AIDS Relief. The present article complements a previously published study by GHESKIO [19], in which initial data on the first 94 children to receive ART were reported.

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Subjects, Materials, and Methods

Study objective and study population. The objective of this observational study conducted at the GHESKIO centers was to evaluate the effectiveness of treating HIV-1—infected children with ART in Haiti. Data were collected by reviewing clinic charts and electronic records. The effectiveness of the intervention was assessed by analyzing survival, HIV-1 RNA responses, CD4+ T cell responses, child weight gain, and ART tolerance [20].

During the study period, between 1 May 2003 and 30 April 2006, 622 children with HIV infection attended the pediatric clinic to receive medical attention. The children had either been transitioned to the clinic from the GHESKIO PMTCT services or had been referred by public or private health-care providers. Many children also presented to our clinic on the initiative of a caregiver. HIV status was confirmed after caregiver consent for HIV testing was obtained.

The study population consisted of the 236 vertically HIV-infected children (0–18 years old) who were consecutively started on triple ART during the study period. Subjects were excluded from the analysis if they had previously received ART or if <3 antiretroviral drugs were initiated at the onset of therapy. Children who did not meet treatment indications for ART continued to be monitored.

The pediatric AIDS clinic was composed of 3 pediatricians, 1 nurse, 1 psychologist, 1 pharmacist, and 2 community health workers. The physicians received training in comprehensive pediatric AIDS care in the United States and were supported by the National Institutes of Health Fogarty International Center.

HIV therapy and other services. The decision to start children on ART was based on WHO pediatric ART guidelines [21]. ART was initiated in patients with WHO clinical stage 3–4 disease. ART was considered in children with stage 1–2 disease and a CD4+ T cell percentage <25% (<12 months old) or <15% (≥12 months old). Before the initiation of ART, all children underwent a psychosocial evaluation to identify social services needs. During the first month receiving ART, doctor visits were scheduled on a weekly basis. Thereafter, visits were scheduled on a monthly basis. Children were also evaluated and treated for concurrent illnesses.

Antiretroviral medications were dispensed at each clinic visit. First- and second-line antiretroviral regimens and drug dosing followed WHO guidelines (table 1). Adherence to ART was continuously assessed. Attendance records in the clinic were documented, and the pharmacy kept electronic records of clinic visit dates, regimens, dosing, and quantity of formulations dispensed. Families that had difficulty complying with treatment recommendations were further assisted with standardized drugadherence strategies. Caregivers were routinely offered VCT services, psychosocial counseling, family planning, and screening for TB and sexually transmitted infections.

Table 1
Table 1

Pediatric antiretroviral therapy (ART) in Haiti.

Nutritional interventions included nutritional counseling and provision of micronutrients, as well as targeted strategies such as caloric supplementation (rice/corn and vegetable oil) for HIV-infected children who displayed signs of malnutrition. Severely malnourished children were hospitalized for nutritional rehabilitation.

Pneumocystis prophylaxis in the form of cotrimoxazole (oral daily dose, 6 mg/kg) was given to all HIV-infected children. Standard immunizations—including Haemophilus influenzae type B conjugate, hepatitis B virus, and 23-valent pneumococcal polysaccharide vaccine—were administrated in accordance with national recommendations [22].

If clinical tuberculosis (TB) was suspected, a tuberculin skin test and chest radiography were arranged. Microscopic examination and culture for mycobacterial species were performed if adequate sputum or other specimen was obtained. The decision to initiate TB treatment was based on WHO guidelines [23, 24]. Four-drug TB regimens in combination with 3-drug ART with abacavir or efavirenz (EFV) were favored.

HIV diagnosis and clinical measurements. The diagnosis of HIV-1 infection was established on the basis of WHO guidelines [25]. In children <18 months old, the detection of HIV-1 nucleic acid with the NucliSens EasyQ HIV-1 RNA assay (BioMérieux) in 2 consecutive plasma specimens was considered to be diagnostic. Alternatively, the detection of HIV-1 RNA in 1 plasma specimen and detection of p24 antigen in a second plasma specimen with the VIDAS HIV p24 II Assay (BioMérieux) including the heat-dissociation technique was considered to be diagnostic. In children <18 months old, a positive rapid ELISA HIV test confirmed by a complementary HIV test was considered to be diagnostic.

Baseline laboratory testing included hemoglobin, white blood cell count with differential, absolute CD4+ T cell count, creatinine, and liver function tests. CD4+ T cell percentages were calculated from T cell sorting using the FACSCount device (Becton Dickinson) and from absolute lymphocyte counts using the Cell-Dyn 1400 device (Abbott Laboratories). A complete blood count and CD4+ T cell count were repeated every 6 months. For subjects with sufficient plasma samples available at 0, 12, and 24 months of follow-up, HIV-1 RNA concentrations were quantified using the NucliSens EasyQ assay (lower limit of detection, 50 viral copies/mL). Antiretroviral drugresistance testing was not routinely performed.

Body weight was measured at each visit. The weight-for-age Z score (WAZ) was calculated by subtracting the median weight of a reference population at the child's age from the child's weight and dividing by the SD of the reference population at that age [26]. Body height and head circumference were not routinely measured.

Data collection and statistical analysis. Institutional review boards at GHESKIO and Weill Medical College of Cornell University (New York, NY) approved the study. Demographic data were collected during the initial VCT visit. Standardized visit forms were completed by physicians at each visit. Information on anthropometric data, antiretroviral drug changes, and adverse drug events were continuously updated in the electronic record, as were pharmacy and laboratory data.

The data were analyzed using R software (version 2.3.1; University of California, Berkeley) and Epi-Info (version 6.0; Centers for Disease Control and Prevention). Age stratification in the analysis corresponded to strata used in WHO guidelines. Medians and means were compared using the Wilcoxon ranksum test and Student's t test, respectively. Kaplan-Meier survival analysis was applied to estimate survival time probabilities after the introduction of ART. Data were censored at the date of the last visit for patients who failed to reach the end point. Cox proportional hazard models were used for multivariate analysis. Variables included were removed formthe model by a backward selection procedure if α < .05. Confounders causing a 10% change in other predictors were left in the model.

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Results

Enrollment. Between 1 May 2003, and 30 April 2006, 622 children with HIV infection received medical attention at the GHESKIO centers, of whom 285 (46%) were started on ART (figure 1). Two hundred thirty-six subjects met criteria for entry into our analysis. Nineteen children (7%) with a history of previous ART were excluded from the review. Thirty children (11%) started on 2-drug ART, because of anticipated drug-drug interaction with concomitant rifampin-based TB treatment, were also excluded from the analysis. The baseline characteristics of the study cohort of 236 HIV-1-infected treatment-naive children receiving ART are shown in table 2.

Table 2
Table 2

Baseline characteristics of 236 children with HIV-1 infection receiving antiretroviral therapy.

Outcome at the time of analysis. At analysis, the 236 patients had been monitored for 0–36 months (median, 20 months). One-hundred ninety-one children (81%) were still being monitored, 21 (9%) had died, and 24 (10%) had been lost to follow-up. Malnutrition was frequently encountered in subjects who were lost to follow-up (median WAZ, −3.0; interquartile range [IQR], −3.7 to −1.8). There were no other significant differences in baseline characteristics between patients who were lost and those who remained in care.

Survival. By Kaplan-Meier survival analysis, 80% of children were alive and under care at 24 months follow-up (figure 2). Of the 21 deaths, 15 (71%) occurred within 6 months of starting ART (median, 48 days), 18 of these children (86%) had clinical stage 3–4 disease, and 6 (29%) were <18 months old. The causes of death included 9 (43%) children with respiratory failure, 4 (19%) with gastroenteritis and hypovolemic shock, 3 (14%) with severe anemia, and 5 (24%) with unknown etiology.

Table 3
Table 3

Multivariate analysis (Cox model) of baseline characteristics associated with death in children with HIV-1 infection placed on antiretroviral therapy.

Table 4
Table 4

Mean changes in weight-for-age Z scores (WAZ) from baseline, by weight strata.

Figure 1
View larger version:
Figure 1

Profile of the study cohort. GHESKIO, Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes.

Figure 2
View larger version:
Figure 2

Kaplan-Meier survival curve with 95% confidence interval demonstrating the probability of HIV-1—infected children remaining in care. Vertical ticks denote censored observations.

In multivariate analysis, 3 independent baseline predictors of death were identified: age <18 months (hazard ratio [HR], 2.26 [95% confidence interval {CI}, 1.34–3.82]; P < .01), CD4+ T cell percentage ≤5% (HR, 1.78 [95% CI, 1.38–2.83]; P < .01), and WAZ less than −3 (HR, 2.07 [95% CI, 1.39–3.10]; P < .01) (table 3). Variables such as chronic diarrhea, TB, and HIV-1 RNA loads were not included in the Cox model. Chronic diarrhea as a clinical entity could not be substantiated retrospectively. Isolation of Mycobacterium tuberculosis was infrequently achieved in cases of suspected TB, and only a subgroup of subjects had HIV-1 RNA loads determined.

Confirmed and presumed cases of TB. A total of 48 children (20%) had symptoms and/or signs of active TB and were placed on multidrug TB treatment before, during, or after the initiation of 3-drug ART. Six of these patients had confirmed TB (M. tuberculosis isolated), 33 had probable TB (tuberculin skin test and/or chest radiography indicating TB), and 9 had suspected TB (only signs and/or symptoms indicating TB). At the time of analysis, 20 children had completed TB treatment during ART, 6 had incomplete TB treatment, 10 had recurrent TB, 3 were lost to follow-up, and 9 were dead.

Viral load, CD4+ T cell percentage, and body weight outcomes. Beginning 1 July 2004, plasma HIV-1 RNA loads were measured in children at 0, 12, and 24 months of follow-up. At baseline, plasma was available from 50 (41%) of 122 children; at 12 months, from 100 (58%) of 171 children; and at 24 months, from 60 (69%) of 87 children. The median viral load at baseline was 5.30 log10 HIV-1 RNA copies/mL. The median viral load was in the undetectable range at 12 and 24 months of follow-up. At 12 months of follow-up, 56 patients had undetectable viral loads, and 44 patients had detectable viral loads (IQR, 6875−112,500 log10 HIV-1 RNA copies/mL). Baseline characteristics (e.g., age, sex, clinical stage, ART regimen, maternal death, and caregiver education) of these 2 groups were indistinguishable.

For those in follow-up for 11 year, CD4+ T cell percentages at baseline and 12 months were documented in 167 children (98%). Patients with severe immunosuppression (CD4+ T cell percentage ≤5%) had the largest median increase in T cell responses at 12 months of follow-up (CD4+ T cell percentage increase, 15%, 11%, and 5% for children with pre-ART percentages of ≤5%, 6%–24%, and ≥25%, respectively; P < .01).

For those in follow-up for 11 year, weight at baseline and at 12 months was documented in 163 (95%) children. The median WAZ for the entire cohort at 0, 6, 12, and 24 months of follow-up increased from −2.0 (IQR, −2.9 to −1.3), to −1.4 (IQR, −2 to −0.6), to −1.3 (IQR, −1.9 to −0.4), and finally to −1.2 (IQR, −1.8 to −0.3). Subjects with evidence of malnutrition at baseline had a more-significant weight gain at 12 and 24 months of follow-up than subjects without malnutrition (table 4). Equally dramatic weight gain was noticed in subjects with moderate (WAZ between −3 and −2.1) and severe (WAZ less than −3) malnutrition.

Compliance and change in first-line regimens. Compliance with ART, defined as obtaining antiretroviral drug supply covering >90% of the time in the study, was noted in 175 patients (74%). Antiretroviral drug adherence was not systematically assessed in the present study.

Seventy-one children (30%) changed their first-line regimens. The reasons for change were adverse drug events in 26 children (11%), anticipated drug interaction (i.e., nevirapine [NVP]/rifampin) in 25 (11%) children, disruption in the medication supply in 10 (4%) children, subjective drug intolerance in 8 (3%) children, and other reasons in 2 (1%) children. Of the adverse drug events, 20 (8%) were drug toxicity, and 6 (3%) were severe immune reconstitution inflammatory syndrome (IRIS) requiring hospitalization. The cases of treatment-limiting drug toxicity were zidovudine (AZT)—induced anemia (8 cases) during 317 treatment years; NVP-induced rash (2 cases) during 86 treatment years; and EFV-induced central nervous system adverse effects (4 cases), acute hepatitis (2 cases), generalized maculopapular rash (2 case), and gynecomastia (2 cases) during a total of 267 treatment years. The cases of severe IRIS were miliary TB (1 case), TB meningitis (1 case), pulmonary TB (2 cases), and pneumonia (2 cases). Several cases of IRIS were observed that did not require the discontinuation of ART.

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Discussion

The purpose of the present study was to critically evaluate the effectiveness of treating HIV-infected children with ART in urban Port-au-Prince. The communities served had high rates of poverty, malnutrition, and TB, such as those seen in many countries where AIDS is endemic. Considerable sociopolitical unrest in Haiti further complicated the provision of services. However, with donor support, trained providers, and the availability of pediatric antiretroviral drug formulations, it proved feasible and highly effective to deliver ART and associated comprehensive pediatric AIDS services in Haiti. Three years into the program, 93% of live patients remained in care, and complete HIV-1 RNA suppression was recorded in more than half of the patients tested. These observations are comparable to the outcomes observed in high-income countries [27, 28] and provide strong evidence in support of wider availability of ART to HIV-infected children living in resource-constrained settings.

We acknowledge several limitations of our study. When conducting a population-based study, inequalities in access to services may affect the selection of subjects. The majority of patients enrolled at GHESKIO were self-referred—a category of patients that might have a better prognosis than patients referred from inpatient-care facilities, for instance. Survivor treatment-selection bias may also affect analysis. The median time from enrollment to the initiation of ART was 10 weeks in our clinic, and a number of patients died before intervention could be introduced. Furthermore, ethics were considered when the program was designed. Thus, in assessing the effectiveness of the program, the control references used were historical data from GHESKIO and data reported in the literature.

Improved survival rates were particularly striking in symptomatic infants receiving ART. In the early 1990s, the 6-month survival of infants presenting with AIDS was ∼50% at GHESKIO [16]. In our cohort, 15 (83%) of 18 infants with clinical stage 3–4 disease (median, age 8 months; IQR, 6–12 months) were alive 6 months into ART (P < .01)—corresponding to a 60% reduction in mortality. Various interventions (social services, immunization, nutritional intervention, and pneumocystis prophylaxis) have sequentially been introduced at GHESKIO to improve clinical outcomes. However, improved survival only became apparent in 2004, when viral diagnostic testing enabled the earlier initiation of ART [29, 30].

Mortality rates were dramatically higher during the first 6 months (median, 48 days) of ART [31]. Independent predictors of mortality at baseline were age <18 months, CD4+ T cell percentage ≤5%, and WAZ less than −3. Patients diagnosed with TB had significant mortality. However, TB was not included in the Cox analysis, because most cases were diagnosed clinically Accurate estimations of age and CD4+ T cell percentage might be difficult to determine in many settings, whereas most clinics can reliably obtain and document anthropometric data. Severe malnutrition might well represent a surrogate for unidentified confounders, such as underlying chronic infections (i.e., TB, M. avium complex, or cryptosporidiosis) that are exacerbated by acute illness. Programs committed to pediatric AIDS care have to carefully consider indications for pediatric ART at the local level, weighing in prevalence figures of malnutrition and TB and resources available, such as services for nutritional rehabilitation, outreach activities, and inpatient care.

In a subgroup of 100 children, 56% had undetectable HIV-1 RNA loads after having received 12 months of ART. Baseline characteristics were not different in those who had detectable versus undetectable viral loads. Large cohort studies will have to investigate potential predictors of virologic treatment failure related to the patient (e.g., age, sex, clinical status, and drug refill for <90% of time in the study), caregiver (e.g., maternal mortality, economic status, and literacy), ART regimen (e.g., antiretroviral drug combination, dose, and twice-daily vs. 3 times/daily dosing), and provider (e.g., the doctor:patient ratio).

Significant and sustained immune reconstitution was observed in our cohort. Children with low baseline CD4+ T cell percentages (≤5%) had the most dramatic increase in percentage points over time, consistent with data reported by Soh et al. [32].

Children with evidence of malnutrition at baseline had the greatest increase in WAZ (median WAZ at 0, 12, and 24 months: −2.9, −1.9, and −1.7, respectively; P < .01) at GHESKIO. In a study conducted in Côte D'Ivoire, weight gain was also recorded in a population with high rates of malnutrition [9]. The weight gain documented in our clinic was more substantial than that noted in cohorts treated in the United States, where rates of malnutrition are lower [33, 34].We believe that chances of favorable outcomes in malnourished children are greater if ART is introduced at an early stage. Our experience suggests that nutritional supplementation with carbohydrates (rice/corn), fats (vegetable oil), and proteins (high-protein biscuits) is critical. Future studies will have to validate the significance of malnutrition in the interplay between AIDS disease progression and clinical responses to ART.

One-third of the children at GHESKIO required a change in their first-line regimen. Treatment-limiting toxic effects were noted in 8% of the children. This frequency of drug toxicity was consistent with previous reports from Europe [35, 36]. Providers should be made aware of potentially serious adverse events associated with ART, including the phenomena of IRIS [37]. Higher rates of treatment interruptions due to EFV toxicity observed elsewhere in adult Haitians [19] were not observed in our children.

The greatest challenge to the program was to secure funding and a reliable drug supply. To bring the pilot study to scale, long-term funding and effective coordination of donor support need to be established [38, 39]. A national program adopting a family-oriented approach that is free of charge has the greatest chances of reaching populations in need and ensuring longterm success [31]. To dramatically increase patient recruitment rates, paramedical officers should be trained in the management of HIV-exposed children and ART. Standardized procedures for counseling, diagnosis, case finding, treatment, monitoring, and drug procurement should be further simplified. Local ART sites should independently generate cohort data to accurately estimate drug ordering and improve national drug procurement. Decentralization of pediatric HIV testing with improved low-cost diagnostic tools is essential [40]. Laboratory monitoring should be kept to a minimum.

There will continue to be a role for a model programs such as that at GHESKIO in which innovations in staff training, infrastructure development, and therapeutic options can be explored. Such centers of excellence may play a key role in the success of a national AIDS program. The promising results of this large-scale comprehensive pediatric AIDS program raise optimism about extending services in Haiti, as well as other parts of the world. We believe that gains in the survival of HIV-infected children achieved in high-income countries can be realized in poor countries, provided that donor support is secured, pediatric AIDS care is integrated with adult care and PMTCT activities, and ART becomes universally accessible.

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Acknowledgments

We are indebted to Johanne Charlemagne, Suzette Fleury, Adeline Bernard, Byron Boussicaut, Olitho Noël, Natalie Coicou, Kathia Henrys, Emilio Brignoli, Marie-Eugenie Beaulieu, Maryse Thimothee, Carole Anne Beauharnais, Massiano St.-Cyr, Abdias Marcelin, Reginald Ossi, Sonya Jean, Gabriel Thimothee, and R. Shi Jian.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Fondation Rodolphe Mérieux; Global Fund to Fight AIDS, Tuberculosis, and Malaria; President's Emergency Plan for AIDS Relief; National Institute of Allergy and Infectious Diseases (grants AI64021, AI58257, and AI07613); Fogarty International Center (grants TW006896, TW006901, and TW00018); Elisabeth Glaser Pediatric AIDS Foundation.

  • Received September 14, 2006.
  • Accepted September 16, 2006.
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  1. J Infect Dis. (2007) 195 (10): 1411-1418. doi: 10.1086/514823
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