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EFFECTIVENESS OF ANTIRETROVAL THERAPY IN REDUCING MORTALITY AMONG HIV INFANTS
EFFECTIVENESS OF ANTIRETROVAL THERAPY IN REDUCING MORTALITY AMONG HIV INFANTS
TABLE CONTENTS
Title Page———i
Certification——–ii
Dedication———iii
Acknowledgement——-iv
Abstract ———vi
Table of Content——–vii
Chapter One
1.0 Introduction ——-1
1.1 Statement of Problem——4
1.2 Purpose of the Study——5
1.3 Significance of Study——8
1.4 Limitation——–9
1.5 Scope of Study——-11
Chapter Two
2.0 Review of Related Literature —-12
2.6 Summary of Literature Review—- 19
Chapter Three
3.0 Research Methodology and Procedure—22
3.1 Population ——–22
3.2 Sample and Sampling Technique—-22
3.3 Validation of the Instrument —-23
3.4 Reliability of the Instrument —–23
3.5 Data Analysis——-23
Chapter Four
4.0 Presentation and Discussion of Result—24
4.1 Analysis and interpretaion of Data—25
4.2 Discussion of Results——38
Chapter Five
5.0. Summary, Conclusion, and Recommendation –40
5.1 Summary——–40
5.2 Conclusion——–41
5.3 Recommendation——42
References ———45
Appendix 1——–47
Appendix ———50
Background
In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. We investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial.
Methods
HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir–ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). We report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy.
Results
At a median age of 7.4 weeks (interquartile range, 6.6 to 8.9) and a CD4 percentage of 35.2% (interquartile range, 29.1 to 41.2), 125 infants were randomly assigned to receive deferred therapy, and 252 infants were randomly assigned to receive early therapy. After a median follow-up of 40 weeks (interquartile range, 24 to 58), antiretroviral therapy was initiated in 66% of infants in the deferred-therapy group. Twenty infants in the deferred-therapy group (16%) died versus 10 infants in the early-therapy groups (4%) (hazard ratio for death, 0.24; 95% confidence interval [CI] , 0.11 to 0.51; P<0.001). In 32 infants in the deferred-therapy group (26%) versus 16 infants in the early-therapy groups (6%), disease progressed to Centers for Disease Control and Prevention stage C or severe stage B (hazard ratio for disease progression, 0.25; 95% CI, 0.15 to 0.41; P<0.001). Stavudine was substituted for zidovudine in four infants in the early-therapy groups because of neutropenia in three infants and anemia in one infant; no drugs were permanently discontinued. After a review by the data and safety monitoring board, the deferred-therapy group was modified, and infants in this group were all reassessed for initiation of antiretroviral therapy.
Conclusions
Early HIV diagnosis and early antiretroviral therapy reduced early infant mortality by 76% and HIV progression by 75%. (ClinicalTrials.gov number, NCT00102960.)
Infants with human immunodeficiency virus type 1 (HIV-1) infection have higher rates of disease progression and mortality than older children,1–3 even with a high percentage of CD4 lymphocytes (CD4 percentage).4 Whereas early initiation of antiretroviral therapy may be appropriate for infants, continuing treatment for life is problematic, given the limitations of the available drugs, the long-term toxicity of antiretroviral therapy, adherence issues, the risk of resistance to antiretroviral therapy, and limited resources. This trial addresses the optimal time of initiation and duration of antiretroviral therapy in infants with in utero or intrapartum HIV-1 infection. We hypothesized that early initiation of limited antiretroviral therapy soon after primary infection, when the immune system is most immature, would be beneficial and would delay the time to initiation of continuous antiretroviral therapy. In accordance with the recommendation, in June 2007, of the the data and safety monitoring board, we report the early outcomes for infants who were randomly assigned to receive deferred therapy as compared with those assigned to receive early antiretroviral therapy.
Methods
Study Design
The Children with HIV Early Antiretroviral Therapy (CHER) trial is a phase 3, randomized, open-label trial conducted by the Comprehensive International Program for Research in AIDS — South Africa in collaboration with the Medical Research Council Clinical Trials Unit, United Kingdom, and the Division of AIDS (DAIDS) of the National Institutes of Health (NIH). The study is being conducted in two centers in South Africa: the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, in Soweto, and the Children’s Infectious Diseases Clinical Research Unit, Tygerberg Children’s Hospital, in Cape Town.
We enrolled infants 6 to 12 weeks of age who had HIV infection (defined by a positive polymerase-chain-reaction [PCR] test for HIV-1 DNA and a plasma HIV-1 RNA level on PCR of >1000 copies per milliliter) and a CD4 percentage of 25% or more. Exclusion criteria are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org. Infants were randomly assigned to receive one of three treatments: early limited antiretroviral therapy for 96 weeks, early limited antiretroviral therapy for 40 weeks, or deferred therapy. Immunologic criteria for initiating antiretroviral therapy in the deferred-therapy group or reinitiating antiretroviral therapy in the early-therapy groups were a CD4 percentage of less than 20%5 or, in the case of children younger than 12 months, a CD4 percentage of less than 25% or a CD4 count of less than 1000 cells per cubic millimeter, according to World Health Organization (WHO) guidelines updated in 2006.6 Clinical criteria for initiating or reinitiating antiretroviral therapy7 were Centers for Disease Control and Prevention (CDC) stage C or investigator-selected (severe) stage B events (see the Supplementary Appendix), including symptomatic lymphoid interstitial pneumonitis, bronchiectasis, nephropathy, cardiomyopathy, and failure to thrive. GlaxoSmithKline provided lamivudine and zidovudine, and the South African Department of Health provided lopinavir–ritonavir. Written informed consent was obtained from the parents or legal guardians of all the infants. The authors vouch for the completeness and accuracy of the data.
Study Treatment
First-line antiretroviral therapy consisted of zidovudine at a dose of 240 mg per square meter of body-surface area twice daily and lamivudine at a dose of 4 mg per kilogram of body weight twice daily, with lopinavir–ritonavir given at a dose of 300 mg of lopinavir plus 75 mg of ritonavir per square meter twice daily until 6 months of age,8 then at a dose of 230 mg of lopinavir plus 57.5 mg of ritonavir per square meter twice daily. The second-line regimen was predefined and consisted of didanosine, abacavir, and nevirapine (or efavirenz instead of nevirapine if the child was older than 3 years of age). The criteria for switching to second-line therapy are listed in the Supplementary Appendix.
Screening, Randomization, and Follow-up
Infants who were exposed to HIV were identified from programs for the prevention of mother-to-child transmission of HIV-1 in the Western Cape and Gauteng provinces. PCR for HIV-1 DNA was performed from 4 weeks of age when cotrimoxazole prophylaxis commenced. In Gauteng, the regimen for the prevention of mother-to-child transmission of HIV-1 was single-dose nevirapine administered to both the mother and the neonate; in the Western Cape, the regimen was zidovudine administered to mothers from 34 weeks’ gestation and to neonates for 7 days and single-dose nevirapine administered to both.
The randomization schedule was prepared centrally by the trial statistician and faxed to the study sites. Randomization was stratified according to clinical center, and blocks, varying randomly in size, were used to ensure balance in the number of infants assigned to each group according to center.
After randomization, the infants were seen every 4 weeks until week 24, then every 8 weeks until week 48, and every 12 weeks thereafter. At each scheduled visit, the evaluation included documentation of any HIV-related clinical events, a complete blood count with a differential count, measurements of aminotransferase levels, and a CD4 cell count with calculation of the CD4 percentage. The pharmacist at each site measured adherence to the assigned medication by comparing the amount of drug dispensed with that returned at the subsequent visit. Toxicity was graded according to the criteria of the DAIDS9 of the National Institute of Allergy and Infectious Diseases (NIAID), at the NIH. The study was also conducted under a Food and Drug Administration investigational-new-drug application (number 71,494).
Outcomes
The primary outcome was the time to death or failure of the first-line antiretroviral therapy. The latter was defined as any of the following: failure to reach a CD4 percentage of 20% or more by week 24 of therapy or a decrease in the CD4 percentage to less than 20% after the first 24 weeks of antiretroviral therapy (immunologic failure), severe CDC stage B or stage C events (clinical failure), or toxicity requiring more than one drug substitution within the same class or a switch to a new class or requiring permanent discontinuation of treatment (i.e., regimen-limiting toxicity failure). An independent end-point review committee reviewed all deaths and CDC stage C and severe stage B events without knowledge of CD4 values, status of antiretroviral therapy, or randomized treatment assignments. Investigators at each of the two centers remained unaware of the primary and secondary outcomes at the other center.
Review and Monitoring
The trial was approved by the ethics committees of both participating institutions. According to the protocol, the study is reviewed at least annually by the independent DAIDS international data and safety monitoring board of Africa; this board can recommend termination or modification of the study because of safety or efficacy concerns. The guiding statistical criterion for “proof beyond reasonable doubt” is based on a difference of at least 3 SD in the log relative hazard (or nominal P<0.001) in any interim analysis (according to the Haybittle-Peto rule). Two such annual reviews have been conducted. In addition, a subcommittee of the data and safety monitoring board reviews all deaths according to randomized treatment assignments and can call for an unscheduled review by the full data and safety monitoring board if there are any safety concerns; the subcommittee has performed three reviews (approximately every 3 months).
At the second annual review of the data and safety monitoring board, in June 2007, by which time accrual had been completed, strong evidence of a difference in mortality emerged between infants who had been randomly assigned to receive early antiretroviral therapy and those assigned to the deferred-therapy regimen. The data and safety monitoring board recommended dissemination of these early findings and urgent evaluation of children in the deferred-therapy group who were not receiving antiretroviral therapy for possible initiation of antiretroviral therapy. The board also recommended that all three groups be continued, with modification in the deferred-therapy group as mentioned above.
Statistical Analysis
The sample size was estimated with the use of the methods previously developed for sample size and estimation of statistical power in complex clinical trials.10,11 We assumed that the cumulative probability of death or regimen failure in the deferred-therapy group would be 0.06, 0.17, 0.28, 0.39, and 0.49 by years 1, 2, 3, 4, and 5, respectively. We assumed that for the first 5 years of follow-up, the annual hazard ratio for disease progression or death would be 0.51, 0.57, 0.78, 0.85, and 0.88 in the group that received early limited antiretroviral therapy for 40 weeks and 0.51, 0.27, 0.43, 0.67, and 0.74 in the group that received early limited antiretroviral therapy for 96 weeks, as compared with the deferred-therapy group. These assumptions were based on estimates of death rates, time to initiation of antiretroviral therapy, and time to failure of antiretroviral therapy in other pediatric cohorts.4,12 Under these assumptions, the planned sample size of 375 children (125 per group), enrolled over a period of 18 months and followed for a minimum of 3.5 years, would provide 80% power to reject the null hypothesis of no difference among the three groups in the time to the primary outcome, on the basis of a global log-rank test with a two-sided alpha level of 0.05.
The planned primary analysis was to first test the null hypothesis of no difference among the three groups in the time to death or regimen failure by means of a global log-rank test with two degrees of freedom (with stratification according to site). If the null hypothesis was rejected, then each of the early-therapy groups was to be compared with the deferred-therapy group in terms of the average hazard during the follow-up period with the use of a Cox proportional-hazards model, also stratified according to site. Although pairwise comparisons of all groups were performed, we report the comparison of the deferred-therapy group with the combined early-therapy groups, preserving blinding between the early-therapy groups, as recommended by the data and safety monitoring board. All analyses are based on complete data as of June 20, 2007.
We used the intention-to-treat approach to compare the early-therapy groups combined with the deferred-therapy group. Time-to-event methods (i.e., Kaplan-Meier plots and the log-rank test stratified according to site) were used to compare the two groups for the time to the primary end point and survival. Cox proportional-hazards modeling was used to estimate a summary hazard ratio for death or treatment failure for the early-therapy groups combined as compared with the deferred-therapy group. The frequency of grade 3 or 4 adverse events in the two groups was compared with the use of a chi-square test. The time to initiation of continuous antiretroviral therapy in the deferred-therapy group was estimated with the use of Kaplan-Meier methods. Changes in the CD4 percentage and the CD4 count over time were summarized with the use of point estimates of mean changes from baseline documented at each visit. All reported P values are two-sided and have not been adjusted for multiple testing.
Results
Of 5985 infants born to mothers in programs for the prevention of mother-to-child transmission of HIV-1, 405 were HIV-positive (6.8%). The transmission rate was higher in Soweto (8.4%) than in Cape Town (5.6%), probably because of different regimens for the prevention of mother-to-child transmission of HIV-1. An additional 155 HIV-infected infants were referred from other infant diagnosis programs. Among 560 HIV-infected infants considered for the trial, 110 were ineligible because the CD4 percentage was less than 25%, and 45 were ineligible for other reasons (Fig. 1). Between August 2005 and February 2007, a total of 377 infants were enrolled; 125 infants were randomly assigned to the deferred-therapy group, and 252 infants were randomly assigned to the early-therapy groups. Two pairs of twins were enrolled: the first pair underwent randomization, and the second pair of twins were nonrandomly assigned to the same grou