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Early Triple Therapy vs Mono or Dual Therapy for Children With Perinatal HIV Infection
To the Editor: The time at which antiretroviral therapy (ART) should be initiated in children with perinatal human immunodeficiency virus (HIV) infection remains controversial. In a cohort study, Berk et al1 reported clinical benefit from mono/dual ART started before 60 days of life in 10 children compared with treatment administered at 61 to 120 days of life in 16 children. The 23 children who received early triple ART were not investigated because none of them progressed to category C diagnosis by 3 years of age. We performed a similar analysis in a cohort study of a larger data set of children with a longer follow-up to evaluate the outcomes of early and very early triple ART.
Methods
This was a post hoc analysis of data collected by the Italian Register for HIV Infection in Children, a network of 106 pediatric clinics distributed throughout Italy that is highly representative of the Italian population of perinatally HIV-infected children; details are described elsewhere.2 Approval for the study was granted from the University of Florence and the ethics committees of the participating institutions, and written informed consent was obtained from children's parents or legal guardians.
Children infected with HIV born in 1988-2001 who received early ART treatment ( 120 days of life) with at least 3 years of follow-up or earlier death were included. Treatments were considered if they were given continuously for at least 1 month in children who remained free of category C diagnoses for 1 month after initiating therapy.1 Children who progressed to triple ART after starting mono/dual ART were excluded from the analysis because of potential modification of the effect of the triple therapy.
The following comparisons were performed using Kaplan-Meier analysis with the log-rank test: (1) mono/dual ART vs triple ART at age 120 days or younger; (2) very early (60 days) vs early (61-120 days) mono/dual ART; and (3) very early vs early triple ART. Cox regression analysis was performed to evaluate the risk of progression to category C diagnosis adjusted for the year of study entry (before 1996 vs 1996 or later) and baseline CD4+ T-cell percentage. The sample size had a power of 80% to detect a 50% difference between triple vs mono/dual ART and between very early vs early ART, with a 2-sided  = .05 and an assumption that 69% of children receiving only mono/dual therapy and no subsequent triple ART would progress to category C diagnosis.1 Statistical analyses were performed using SPSS software, version 11.5 (SPSS Inc, Chicago, Ill). P<.05 was considered statistically significant.
Results
Forty-one children received mono/dual ART and 22 children received triple ART (Table). The proportion progressing to category C diagnosis was significantly higher in children receiving mono/dual ART than in children receiving triple ART (28/41 [69.3%; 95% confidence interval {CI}, 61.9%-75.5%] vs 1/22 [4.5%; 95% CI, 0.2%-8.9%]; P<.001) (Figure). Death occurred in 18 of 41 (43.9%; 95% CI, 36.7%-51.6%) vs 0 of 22 children (P<.001), respectively, at a median (interquartile range) age of 20 (10-27) months. After adjusting for year of study entry and baseline CD4+ T-cell percentage, the risk of progression to category C diagnosis remained significantly greater for children receiving mono/dual ART (hazard ratio, 2.34; 95% CI, 1.16-23.14; P = .04).
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Table. Characteristics of the Study Participants
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Figure. Kaplan-Meier Curves for Category C Diagnosis–Free Survival in Children With Perinatal Human Immunodeficiency Virus Infection Receiving Early or Very Early ART
P values are from log-rank test. ART indicates antiretroviral therapy. Very early indicates treatment at age 60 days or younger. Early indicates treatment at age 61 to 120 days.
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Progression occurred in 14 of 22 (63.6%; 95% CI, 54.9%-73.8%) children receiving very early mono/dual ART vs 14 of 19 (73.6%; 95%CI, 65.7%-83.8%) children receiving early mono/dual ART (P = .52); death occurred in 7of 22 (31.8%; 95% CI, 22.6%-41.7%) vs 11 of 19 (57.9%; 95% CI, 48.2%-69.2%) children, respectively (P = .12). Progression occurred in 1 of 10 (10.0%; 95% CI, 1.0%-19.5%) children receiving very early triple ART vs 0 of 12 children receiving early triple ART (P = .28) and no child died (Figure).
Comment
Triple ART at age 120 days or younger was associated with reduced HIV progression and improved survival compared with mono/dual ART at age 120 days or younger. Conversely, no difference in rates of disease progression was shown comparing very early vs early mono/dual or triple ART, suggesting that very early ART may not be of value in treatment of perinatally infected children.1
Benefit from ART during primary infection3 vs deferred ART has been reported in several observational studies.4-5 Very early ART might be of benefit in infants with intrauterine infection, who may be more vulnerable to rapid disease progression than children infected intrapartum.6
Limitations of our study include that, as a cohort study, there is a potential that unmeasured confounders caused the observed differences. Small sample size and few outcomes in some of the subgroups also limit the ability to reach definitive conclusions and may account for some of the differences in results compared with Berk et al.1 As a post hoc analysis, the findings should be considered hypothesis generating. Given these factors, there is a need for randomized trials of treatment for perinatal HIV infection to understand the optimal methods of preventing disease progression. Consideration must also be given to treatment in countries where triple therapy is not available.
Access to Data: Dr de Martino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosures: None reported.
Funding/Support: This work was supported by the Italian Ministero della Salute, Istituto Superiore di Sanità, 5th AIDS Project, 2003 (grant number:20F.15).
Role of Sponsor: The sponsor had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data as well as in preparation, review, or approval of the manuscript.
A complete list of the members of the Italian Register for HIV Infection in Children was published in reference 4.
Acknowledgment: We are grateful to Dr Catiuscia Lisi, Department of Statistics, University of Florence, Italy, for help with the statistical analyses.
Elena Chiappini, MD, PhD;
Luisa Galli, MD
Department of Pediatrics
University of Florence
Florence, Italy
Clara Gabiano, MD;
Pier-Angelo Tovo, MD
Department of Pediatrics
University of Turin
Turin, Italy
Maurizio de Martino, MD
maurizio.demartino{at}unifi.it
Department of Pediatrics
University of Florence
Florence, Italy
For the Italian Register for HIV Infection in Children
1. Berk DR, Falkovitz-Halpern MS, Hill DW, et al, California Pediatric HIV Study Group. Trends in early clinical manifestations of perinatal HIV infection in a population-based cohort. JAMA. 2005;293:2221-2231.
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2. de Martino M, Tovo PA, Balducci M, et al, Italian Register for HIV Infection in Children; Italian National AIDS Registry. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. JAMA. 2000;284:190-197.
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3. Kassutto S, Rosenberg ES. Primary HIV type 1 infection. Clin Infect Dis. 2004;38:1447-1453.
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4. Chiappini E, Galli L, Tovo PA, et al, Italian Register for HIV Infection in Children. Virologic, immunologic, and clinical benefits from early combined antiretroviral therapy in infants with perinatal HIV-1 infection. AIDS. In press.5. Faye A, Le Chenadec J, Dollfus C, et al, French Perinatal Study Group. Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1. Clin Infect Dis. 2004;39:1692-1698.
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6. Smith R, Malee K, Charurat M, et al, Women and Infant Transmission Study Group. Timing of perinatal human immunodeficiency virus type 1 infection and rate of neurodevelopment. Pediatr Infect Dis J. 2000;19:862-871.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2006;295:626-628.
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