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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e31821fd64f
Supplement Article

Short-Term Virological Efficacy, Immune Reconstitution, Tolerance, and Adherence of Once-Daily Dosing of Didanosine, Lamivudine, and Efavirenz in HIV-1–Infected African Children: ANRS 12103 Burkiname

Barro, Makoura MD*; Some, Jérôme MD†; Foulongne, Vincent MD‡; Diasso, Yaya PharmD§; Zouré, Emmanuelle MD‖; Hien, Hervé MD, MPH¶; François, Rouet PhD¶; Michel, Segondy PharmD, PhD†; Drabo, Aly PharmD**; Tamboura, Hassane MD‖; Ouiminga, Adama MD††; Diagbouga, Serge DVM, PhD‡‡; Hien, Alain PharmD§§; Yaméogo, Souleymane PharmD§§; Van De Perre, Philippe MD, PhD‡; Nacro, Boubacar MD, PhD‖; Msellati, Philippe MD, PhD‖‖

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From the *Department of Pediatrics, Teaching Hospital Center Sourô Sanou, Bobo-Dioulasso, Burkina Faso; †Institut de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso; ‡ Department of bacteriology-virology, INSERM U 1058, University Montpellier 1, CHU Montpellier, Montpellier, France; §Department of Laboratory, Centre Hospitalier Universitaire Sourô Sanou, Bobo-Dioulasso, Burkina Faso; ‖Department of Pediatrics, Centre Hospitalier Universitaire Sourô Sanou, Bobo-Dioulasso, Burkina Faso; ¶Centre Muraz, Unité de Recherche sur la santé de la reproduction, le VIH et les maladies associées, Bobo-Dioulasso, Burkina Faso; #Retrovirology laboratory, International Center for Medical research of Franceville (ICMRF) Franceville Gabon; **DESS biologie clinique, Centre Muraz, Unité technique/laboratoire d'analyses médicales, Bobo-Dioulasso, Burkina Faso; ††DESS biologie clinique, Centre Muraz, Unité de recherché sur la santé de la reproduction, le VIH et les maladies associées, Bobo-Dioulasso, Burkina Faso; ‡‡Programme National de Lutte contre la Tuberculose, Ouagadougou, Burkina Faso; §§Department of Pharmacy, Centre Hospitalier Universitaire Sourô Sanou, Bobo-Dioulasso, Burkina Faso; and ‖‖UMI 233, IRD Université de Montpellier I, Montpellier, France.

Supported by Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS).

Presented in part at 10th Baylor International Pediatric AIDS Initiative network meeting, September 29th to October 3rd 2008, Kampala, Uganda; and Dominique Dormont 5th International Conference, March 26-28, 2009, Val de Grâce, Paris, France.

The authors have no conflicts of interest to disclose.

This clinical trial has been registered at www.clinicaltrials.gov with the number NCT00122538.

Correspondence to: Dr Boubacar Nacro, MD, PhD, 03 BP 4150 Bobo 03 Burkina Faso (e-mail: bnacro@fasonet.bf).

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Abstract

Access to antiretroviral therapy (ART) and routine laboratory monitoring are limited for HIV-1-infected children from sub-Saharan Africa. This trial conducted in Bobo-Dioulasso, Burkina Faso, aimed to describe the biological efficacy, tolerance, and adherence of the combination of didanosine, lamivudine, efavirenz in once-daily administration among eligible HIV-1-infected children. From February 2006 to November 2007, 51 HIV-1-infected children aged from 30 months to 15 years and eligible for ART were enrolled in a phase II open clinical trial with follow-up visits every 3 months. HIV-1 genotype testing was performed in children with plasma viral load (PVL) >1000 copies per milliliter after ART initiation. Children were followed for a median of 13.4 months [interquartile range (IQR) 12.8-14.2]. At enrollment, median CD4 count was 8% (IQR = 4.5-12). PVL was 341,032 (IQR = 127,838-761,539) copies per milliliter. At 12 months, median CD4 increased significantly by +15% (P < 10-3), and median PVL decreases significantly by −290,500 copies per milliliter (P < 10-4). Hemoglobin and platelets counts increased significantly by +1.05 g/dL (P < 10-5) and 108,500 cells per milliliter (P < 10-3), respectively. Based on pill count, mean yearly adherence was 97.3%, and 48% of the children had an adherence rate ≥95% at the four quarterly visits. Adherence was better for girls than for boys independently of other sociodemographic variables or markers of HIV disease progression. Drug-resistant mutations were found in 11 children (21.6%). This once-daily drug combination is associated with excellent virological efficacy, immune reconstitution, and good adherence. However, the high prevalence of drug resistance mutations is a matter of concern.

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INTRODUCTION

Use of antiretroviral (ARV) drug combinations has brought a great clinical satisfaction and significant mortality reduction in HIV-infected children worldwide including throughout Africa.1 In developed countries, the efficacy of pediatric antiretroviral therapy (ART) has been proved excellent.2 Still children access to ART remains limited in most developing countries. One of the challenges when ART must be initiated in this context is the fear of toxicity and lack of adherence. In Senegal, a combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) in once-daily dosing improved adherence but also efficacy and tolerance in eligible adults.3 The failure rate in children is generally higher because of insufficient suppression of viral replication,4 making pediatric care more complex.5 The major risk of this residual replication is the selection of resistant viral populations, which can seriously compromise the future treatment of these children with the limited number of pediatric ARV formulations. Poor adherence is one of the major causes of residual viral replication. A study of American children on ART found that about 60% adhered to their treatment regimen.6 The greater complexity of ART regimens may be contributing to poor adherence in children, and simplification of these treatments is a major focus.7 Data on once-a-day ART in children are still lacking. The aim of the present phase II trial was to describe the evolution of biological parameters of efficacy, tolerance of and adherence to ART with ddI, 3TC, and EFV in once-daily administration in children, in Burkina Faso, West Africa.

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METHODS AND PATIENTS

Study population included HIV-1-infected children followed at the Pediatric Department of the University Teaching Hospital Souro Sanou in the city of Bobo Dioulasso from February 2006 to November 2007. This is a clinical prospective, open-label one-arm phase II trial, which included children from 30 months to 15 years naive of ARV drugs except prophylactic treatment for prevention of mother to child transmission of HIV, with a weight >10 Kg, an hemoglobin >7 g/dL, aspartate amino transferase (AST) and alanine aminotransferase (ALT) <5 times the normal values, amylasemia <2.5 times the normal value, and platelet count >50 000/mL. From inclusion, each child received a triple ARV drug combination once-a-day with ddI, 3TC, and EFV. ARV formulations and doses were summarized in Table 1.

Table 1
Table 1
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The drugs were provided to caregivers or patients (if adolescent) by a hospital pharmacist on a monthly basis. Drugs were administrated at bedtime by one of the parents, preferably the mother or the child's guardian. Sociodemographic and clinical characteristics were obtained at inclusion visit and monthly follow-up visits. Adherence to the study treatment was assessed by the trial physician and the pharmacist monthly and a quarterly caregiver questionnaire. The questionnaire characterized the child's primary caregiver, documented the caregivers' and child's knowledge of the diagnosis, the difficulties in administering the drugs, the disruption of daily life by the treatment, the importance of the treatment, the extent to which the suggested pill administration protocol was followed, and the reasons for missed doses.

A second-line treatment was proposed in case of treatment failure. The equipments used for routine biological analysis were Lisa 300 Plus for biochemical analysis, Sysmex KX-21N for blood cells counter. CD4+ T-cell counts were measured using the fluorometric FACS-count technique, and HIV RNA plasma viral load (PVL) was measured using the Generic Charge Viral kit assay (Biocentric, Bandol, France),8 with a detection threshold of 300 copies per milliliter. HIV-1 resistance testing was based on AC11 Resistance Group recommendations (French National Agency for AIDS Research, ANRS). RNA was extracted with the MagNa pure compact apparatus from samples containing >1000 HIV-1 RNA copies per milliliter. Drug susceptibility was deduced from the ANRS algorithm (http://www.hivfrenchresistance.org).

The HIV-1 genotype was determined from both the RT and protease sequences, as previously described.9 For each child, virological, immunological, and clinical parameters were collected on standardized record forms at inclusion and during the follow-up. The primary endpoint was the percentage of patients with PVL <300 copies per milliliter at month 12 and the median change in PVL between baseline, 3, and 12 months. Secondary endpoints were CD4 cell count changes of ≥25% at month 12, the median change in absolute numbers and in percentages CD4 cell count between baseline, 3, 6, and 12 months. Selected grade III serious adverse effects were those of the severity scale for children aged >3 months established by the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS): hemoglobin rate <7 g/dL, platelet count <50,000/mm3, ALAT et ASAT >10 times the upper limit, glucose <2.2 and >13.9mmol/L, creatinine >1.9 time the upper limit, total cholesterol >7.7 mmol/L, bilirubin>3 times the upper limit, and amylase >2 times the upper limit. Triglycerids and cholesterol were also monitored.

Written informed consent was obtained from a parent or caregiver. The trial protocol was approved by the institutional review board of Centre Muraz and the Ethic Committee for Health Research of the Ministry of Health of Burkina Faso. This clinical trial has been registered at www.clinicaltrials.gov with the number NCT00122538. The χ2 test and Kruskal-Wallis test were used for comparison of biological parameters. The relationship between yearly and quarterly adherence (as a continuous variable then categorized in 3 levels as follows: <80%, 80%-94%, and ≥95%) and various sociodemographic factors and markers of HIV disease was examined using t test, χ2, and Fisher exact test when appropriate. A significance level of P = 0.05 was used for all statistical analyses.

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RESULTS

Baseline Characteristics

From February 2006 to November 2007, 51 HIV-1-infected children were enrolled in the trial, and none had previously taken ART except for prevention of mother to child transmission of HIV. Mean age was 6.8 years (from 2.5 to 14.5years). Male to female sex ratio was 1.5:1. Ninety-two percent of the patients (n = 48) originated from the city of Bobo-Dioulasso. About half of the patients were in school. Fifty nine percent of these children (30 of 51) were orphan of at least a relative, and among them, 13.5% (7 of 51) had lost both parents. The mother was the primary care giver (45.1%), followed by the grandmother (15.7%) and an aunt 13.7%). Almost all children (96.1%) were presumed to be infected through mother-to-child transmission. Mean body weight was 17.6 kg (range: 11 to 37 kg). Mean height was 109.4 cm (range: from 85 to 150 cm). Five children had marasmus and two a mixed form of malnutrition.

A third of these children were at Centers for Disease Control and Prevention clinical stage A of HIV infection, 56.9% at stage B, and 9.8% at stage C. The median CD4 count was 8% (interquartile range = 4.5-12), and the median PVL was 341032 (127838-761539) copies per milliliter at baseline. The baseline biological parameters are displayed in Table 2.

Table 2
Table 2
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Virological and Immunological Responses

The median CD4+ T lymphocyte count increased significantly after ART was initiated (P = 10−4): +5%, +8%, +9%, and +15% at 3, 6, 9, and 12 months, respectively. The increase of CD4 absolute count at 6 months was 107% and 167% at 12 months. At 6 months, 74.5% of the children had an undetectable PVL and 75.5% at 12 months (P < 10−4) (Table 3). Of the 15 children in virological failure, 11 of them developed resistance, a cumulative rate of 21.6% (11 of 51) at 12 months (Table 4). Five patients changed treatment during the first year of follow-up because of resistance.

Table 3
Table 3
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Table 4
Table 4
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Evolution of Hematologic and Biochemical Parameters

Median hemoglobin was low at inclusion 9.40 (interquartile range = 8.55-10.30) g/dL increased significantly during treatment (P = 0.0001) and remained lower than normal values according to age during follow-up. No significant change was noted for biochemical parameters between the median values at baseline and M12 excepted for bilirubin (Table 5). Side effects of grade III during M12 follow-up period were as follows: anemia (4%), thrombocytopenia (4%), hyperamylasemia (10%), and hypertransaminasemia (2%).

Table 5
Table 5
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Clinical Outcomes

The respiratory and digestive events were the most frequently reported. Of all the clinical events, only 2 cases of extrapulmonary tuberculosis were recorded, fulfilling the AIDS-defining WHO criteria. Five children developed B or C stage event during the first 3 months of follow-up and another one 9 months later, a cumulative rate of change of 11.5% over the 12 months of follow-up. Ten patients were hospitalized for the following reasons: severe infectious syndromes (4), malignant chicken pox (2), bacterial pneumonia (1), pulmonary tuberculosis (1), abdominal pain (1), and genital hemorrhage (1).

Two weeks after the initiation of ART, a child developed a skin rash that required the treatment to be stopped during 2 weeks. The reintroduction after resolution of the skin signs was done uneventfully. Two children died during the period of follow-up (12-month survival rate: 96.1%).

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Adherence and Its Determinants

Based on pill counts, the average yearly adherence for all patients (n = 50) was 97.3% (range: 88.5% to 99.8%), without any marked difference over time (Fig. 1). Nearly half of the 25 patients who had adherence data for the four quarterly visits (48%) had adherence >95% for at each visit.

Figure 1
Figure 1
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Yearly average adherence was higher for girls than for boys (98.3 vs. 96.7 with P = 0.0006). Whereas, there was no measurable difference according to other sociodemographic characteristics and markers of HIV disease.

The most common reasons given by the caregiver to explain missed doses were forgetfulness, lack of control of the prescription, travel, changes in the caregiver, falling asleep before the scheduled time to take the dose, and child refusal.

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DISCUSSION

In our trial, 75.5% of the children had undetectable PVL at 12 months after ART initiation. Similar response (77%) was reported by Landman in Senegal in eligible adults treated with the same 3 ARV drugs.3 PVL decrease was more important during the 3 first months on ART than thereafter. This fact could be due to resistances developed by certain patients. The increase of CD4 number was 167% after 12 months on ART, confirming the good immune restoration conferred by this ART regimen. Similarly, Kariyo et al1 reported a gain of 158.9% in CD4 in children after 12 months of ART with a comparable regimen in Burundi.

Hemoglobin rate increased significantly between M0 and M12 (P = 0.00001) but stayed always at values lower than normal, and 4% of children developed a severe anemia during follow-up. Several studies had shown that anemia was frequently associated to HIV.10,11 In fact, multifactorial causes involved in pathogenesis of anemia: nutritional factor, direct toxic effect of HIV on the bone marrow, and erythroid progenitor cells.12

Two cases of thrombocytopenia were reported as already described. The most frequent etiology is idiopathic thrombocytopenia induced by 2 nonmutually exclusive mechanisms: peripheral destruction of platelets and central production failure.12

Hypertransaminasemia was reported in 2% of children in this 12-month period, an event that could be linked to the fact that the 3 drugs used in combination have a liver toxicity.13 Hyperamylasemia has also already been associated with administration of ddI and 3TC.13

Confirming reports by Sawadogo et al14 in 2005 in Burkina Faso and by Scherpbier in Amsterdam in 200715 but in contrast with others,13 no blood lipids disturbance was observed in our study. Low blood cholesterol can be linked to malnutrition, malabsorption, and frequent hepatic dysfunction14,16

This once-daily dose of pediatric ART combination allowed children to obtain a good average level of adherence in the first year, higher in fact than what has been reported in other studies. However, despite the high average adherence in this study, only half of children who had data for the entire study period were able to maintain ≥95% adherence at all consecutive visits, underscoring the difficulty in maintaining good adherence with long-term treatments. As has been previously reported in the literature, the proportion of children with ≥95% adherence varied over time, but we did not observe a significant trend as observed in some studies.17 This could be explained by the fact that the caregivers were regularly reminded to give the medications until the end of the trial, which is not the case in most routine circumstances.

Our study found that girls had significantly better yearly average adherence than boys, which contradicts with the report of Williams et al,18 who found that boys had better adherence than girls. For the majority of authors, there is no association between adherence and gender, and the effect of gender could be conceived only in a multifactorial system.6,19-24

A high prevalence of drug resistance mutations has been found in our sample (21.6%); In Côte d'Ivoire, we observed a similar frequency (23%) of genotypic resistance to at least one ARV drug in a large series of children on ART,25 According to the genotypic analysis, 10 and 9 children showed high-level resistance to EFV and to the 3TC, respectively; these results are consistent with the use of such drugs with low genetic barriers to the emergence of viral resistance.25 The emergence of mutations M184V and K103N conferring resistance to the NRTI (6 of 11) and NNRTI (7 of 11), respectively, was the most important virologic findings in our study.

Clotet B26 in Spain reported the same results for the mutations K103N; indeed, K103N is found in HIV strains isolated from patients experiencing a viral rebound in plasma HIV-RNA levels who have received an EFV-containing regimen.

Most of our children were infected with CRF02 strains (72.72%); this distribution of HIV-1 genetic forms is concordant with a report from Ghana27 where CRF-02 was the dominant genetic form (65.7%).

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CONCLUSIONS

Once-a-day ART combining ddI, 3TC, and EFV is highly effective in terms of virological response and immune restoration. Clinical, biochemical, and hematologic tolerance is excellent, at least for the first 12 months after treatment initiation. We observed few severe biologic grade III events noted, without clinical repercussions. However, the high prevalence of drug resistance mutations only a few months after treatment initiation is a serious matter of concern.

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ACKNOWLEDGMENTS

Special thanks to the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) for its financial support and to its Director (Pr Jean-François Delfraissy) and support team (Drs Brigitte Bazin and Claire Rekacewicz), the associations' counselors (Associations Espoir pour Demain and Association Responsabilité Espoir Vie Solidarité) for supporting the families and children. Special thanks to ANRS for financial support. Dr Elizabeth Yakes for her help in analyzing data and revising this article.

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REFERENCES

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3. Landman R, Schiemann R, Thiam S, et al. Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal. AIDS. 2003;17:1017-1022.

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11. Diack Mbaye A, Signaté Sy H, Diagne Gueye NR, et al. Aspects épidémiologiques et cliniques de l'infection à VIH de l'enfant au centre hospitalier national d'enfants d'Albert-Royer à Dakar. Arch Pédiatr (Paris). 2005;12:404-409.

12. Pryce C, Pierre RB, Steel-Duncan J, et al. Safety of antiretroviral drug therapy in Jamaican children with HIV/AIDS. West Indian Med J. 2008;57:238.

13. Nuesch R, Srasuebkul P, Ananworanich J, et al. Monitoring the toxicity of antiretroviral therapy in resource limited setting: a prospective clinical trial cohort in Thailand. J Antimicrob Chemother. 2006;58:637-644.

14. Sawadogo M, Sakandé J, Kabré E, et al. Profil lipidique au cours de l'infection par le VIH à Ouagadougou-Burkina Faso: intérêt des marqueurs lipidiques dans le suivi de l'évolution de l'infection à VIH. Annales de Biologie Clinique. 2005;63:507-512.

15. Scherpbier HJ, Bekker V, Pajkrt D, et al. Once-daily highly active antiretroviral therapy for HIV- infected children: safety and efficacy of an efavirenz- containing regimen. Pediatrics. 2007;119:705-715.

16. Lemberg DA, Palasanthiran P, Goode M, et al. Tolerabilities of antiretrovirals in paediatrics HIV infection. Drug Saf. 2002;25:973-991.

17. Muyingo SK, Walker AS, Reid A, et al. Patterns of individual and population-level adherence to antiretroviral therapy and risk factors for poor adherence in the first year of the DART Trial in Uganda and Zimbabwe. J Acquir Immune Defic Syndr. 2008;48:468-475.

18. Williams PL, Storm D, Montepiedra G, et al. Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics. 2006;118:e1745-e1757.

19. Allain L. mémoire de Master. Evaluation de l'observance au traitement antirétroviral dans une cohorte d'enfants infectés par le VIH. Contexte de l'hôpital pédiatrique Charles-De-Gaulle de Ouagadougou. Burkina Faso (1er trimestre 2005).

20. Nabukeera-Barungi N, Kalyesubula I, Kekitiinwa A, et al. Adherence to antiretroviral therapy in children attending in Mulago Hospital, Kampala. Ann Tropical Paediatrics. 2007;27:123-131.

21. Van Dyke RB, Lee S, Johnson GM, et al. Reported adherence as a determinant of response to highly active antiretroviral therapy in children who have HIV infection. Pediatrics. 2002;109:e61.

22. Arrivé E, Anaky MF, Wemin ML, et al. Assessment of adherence to highly active antiretroviral therapy in a cohort of African HIV-infected children in Abidjan, Cote d'Ivoire. J Acquir Immune Defic Syndr. 2005;40:498-500.

23. Naar-King S, Arfken C, Frey M, et al. Psychosocial factors and treatment adherence in paediatric HIV/AIDS. AIDS Care. 2006;18:621-628.

24. Simoni JM, Montgomery A, Martin E, et al. Adherence to antiretroviral therapy for pediatric HIV infection: a qualitative systematic review with recommendations for research and clinical management. Pediatrics. 2007;119:1371-1383.

25. Chaix ML, Rouet F, Kouakoussui KA, et al. Genotypic Human Immunodeficiency Virus Type 1 Drug Resistance in Highly Active Antiretroviral Therapy-Treated Children in Abidjan, Cote d'Ivoire. Ped Infect Dis J. 2005;24:1072-1076.

26. Clotet B. Efavirenz: resistance and cross-resistance. Hospital Universitari Germans Trias I Pujol, Badalona, Spain. Int J Clin Pract Suppl. 1999;103:21-25.

27. Delgado E, Ampofo WK, Sierra M, et al. High prevalence of unique recombinant forms of HIV-1 in Ghana: molecular epidemiology from an antiretroviral resistance study. J Acquir Immune Defic Syndr. 2008;48:599-606.

Keywords:

ART; biological follow-up; children; once a day dose

© 2011 Lippincott Williams & Wilkins, Inc.

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