Anti-HIV Drugs for Treating Infants Who Acquired HIV Infection at Birth

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00102960
• Collaborator: (none)
• Enrollment: 377
• Arms: 3
• Duration (Months): 90.1

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the effects of anti-HIV drug courses of different lengths in infants who became HIV infected at birth.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Abacavir sulfate; Drug: Didanosine; Drug: Efavirenz; Drug: Lamivudine; Drug: Lopinavir/Ritonavir; Drug: Nevirapine; Drug: Zidovudine	Phase 3

Detailed Description

In South Africa, an estimated 250,000 infants are born to HIV-infected mothers each year. A high percentage of perinatal HIV infections are due to inadequate or absent mother-to-child transmission prophylaxis. Unfortunately, even with optimal prophylaxis, relatively large numbers of HIV-infected infants will continue to be born and will require antiretroviral therapy (ART). Determining the appropriate times for initiating and interrupting treatment to benefit long-term prognosis in infants is a significant health challenge. Evidence suggests that starting ART early during acute infection will provide long-term benefits. However, longer duration of treatment increases the chance of developing drug-resistant virus, and continuous therapy begun early leads to long-term complications in children. This study will evaluate the efficacy of two different short-course ART strategies in HIV-infected infants from South Africa.

This study will last at least 3.5 years. There are two parts to this study. In Part A, infants with a baseline CD4 percentage (CD4%) of at least 25% and HIV infection diagnosed between 6 and 12 weeks of age will be randomly assigned to one of two treatment strategy arms. Arm 2 infants will receive ART for approximately 40 weeks until their first birthday. Arm 3 infants will receive ART for approximately 96 weeks until their second birthday. Treatment in both arms of Part A will begin with first-line, continuous treatment of zidovudine, lamivudine, and lopinavir/ritonavir. Those who were initially deferred treatment in Arm 1 will be reassessed for initiation of first-line, continuous ART.

First-line ART will be started in Arm 1 or restarted after interruption in Arms 2 and 3 if the appropriate criteria as defined in the protocol is met. First-line treatment of zidovudine, lamivudine, and lopinavir/ritonavir will continue until infants reach a study endpoint; when this occurs, infants will then change to second-line therapy. Second-line ART will consist of didanosine, abacavir sulfate, nevirapine and efavirenz.

All the primary efficacy analysis for this study will focus on the children enrolled in the first phase of Part A (n=377) as proposed by the data safety and monitoring board.

Follow-up visits will take place for 3.5 to 5 years, depending on time of enrollment. All infants will receive routine immunizations and cotrimoxazole (sulfamethoxazole/trimethoprim) prophylaxis from age 6 weeks until Week 40. Study visits will occur at study entry, Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48; and every 12 weeks thereafter. At these visits, infants will have vital sign measurements, a physical exam, and a medical history evaluation. Blood and urine collection will occur at all study visits. Infants' parents or guardians will also be asked to complete an adherence questionnaire.

Participants enrolled in CIPRA-ZA Project 2 are encouraged to enroll in an observational substudy organized by the Wistar Institute (Dr. Luis Montaner, Principal Investigator), in conjunction with the CIPRA team. This study is entitled,"Pediatric Immune Correlates of Early Anti-HIV Therapy." The goal of this 5-year substudy is to evaluate 120 HIV infected children from the parent study twice a year and compare them to HIV uninfected age-matched controls. Children will be evaluated by (a) characterization and identification of the innate and adaptive immune reconstitution outcomes of early (9 or 21 months) therapy in infants infected with HIV at birth and (b) identification of immune correlate outcomes to clinical progression within a period of 2 to 3 years of follow-up after stopping therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 377 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This study had two parts: Part A where children were enrolled with CD4% ≥ 25% and Part B where children were enrolled with CD4% < 25%. Part A had three arms: ART-Deferred, ART-40W and ART-96W where ART-40W and ART-96W were the early therapy arms for 40 and 96 weeks respectively. Part B were enrolled into two Arms: ART-40W and ART-96W. The primary efficacy analysis for CHER was based on 377 children that were enrolled in Part A in the first phase of the study. The NIH African data safety and monitoring board recommended that primary analysis be focussed on 377 children enrolled in the first phase of Part A. Additionally, all the key manuscripts have been analysed using this group. Hence all the results presented in clinicaltrials.gov will be specific to this group with three arms.This study had two parts: Part A where children were enrolled with CD4% ≥ 25% and Part B where children were enrolled with CD4% < 25%. Part A had three arms: ART-Deferred, ART-40W and ART-96W where ART-40W and ART-96W were the early therapy arms for 40 and 96 weeks respectively. Part B were enrolled into two Arms: ART-40W and ART-96W. The primary efficacy analysis for CHER was based on 377 children that were enrolled in Part A in the first phase of the study. The NIH African data safety and monitoring board recommended that primary analysis be focussed on 377 children enrolled in the first phase of Part A. Additionally, all the key manuscripts have been analysed using this group. Hence all the results presented in clinicaltrials.gov will be specific to this group with three arms.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Open-Label Trial to Evaluate Strategies for Providing Antiretroviral Therapy to Infants Shortly After Primary Infection in a Resource Poor Setting
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Deferred therapy Arm Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line, once daily Nevirapine: Second Line, once daily	Drug: Abacavir sulfate; Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: ABC Ziagen ; Drug: Didanosine; Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: ddI Videx ; Drug: Efavirenz; Second Line Regimen: taken orally once daily. Dosage depends on weight. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: EFV Stocrin ; Drug: Lamivudine; First Line Regimen: 4 mg/kg taken orally twice daily; Other Names: 3TC Epivir ; Drug: Lopinavir/Ritonavir; First Line Regimen: taken orally twice daily. Dosage depends on age and weight.; Other Names: LPV/r Kaletra ; Drug: Nevirapine; Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: NVP Viramune ; Drug: Zidovudine; First Line Regimen: 240 mg/m^2 taken orally twice daily; Other Names: AZT Retrovir
Experimental: Early therapy for 40 weeks Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line, once daily Nevirapine: Second Line, once daily	Drug: Abacavir sulfate; Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: ABC Ziagen ; Drug: Didanosine; Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: ddI Videx ; Drug: Efavirenz; Second Line Regimen: taken orally once daily. Dosage depends on weight. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: EFV Stocrin ; Drug: Lamivudine; First Line Regimen: 4 mg/kg taken orally twice daily; Other Names: 3TC Epivir ; Drug: Lopinavir/Ritonavir; First Line Regimen: taken orally twice daily. Dosage depends on age and weight.; Other Names: LPV/r Kaletra ; Drug: Nevirapine; Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: NVP Viramune ; Drug: Zidovudine; First Line Regimen: 240 mg/m^2 taken orally twice daily; Other Names: AZT Retrovir
Experimental: Early therapy for 96 weeks Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line, once daily Nevirapine: Second Line, once daily	Drug: Abacavir sulfate; Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: ABC Ziagen ; Drug: Didanosine; Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: ddI Videx ; Drug: Efavirenz; Second Line Regimen: taken orally once daily. Dosage depends on weight. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: EFV Stocrin ; Drug: Lamivudine; First Line Regimen: 4 mg/kg taken orally twice daily; Other Names: 3TC Epivir ; Drug: Lopinavir/Ritonavir; First Line Regimen: taken orally twice daily. Dosage depends on age and weight.; Other Names: LPV/r Kaletra ; Drug: Nevirapine; Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.; Other Names: NVP Viramune ; Drug: Zidovudine; First Line Regimen: 240 mg/m^2 taken orally twice daily; Other Names: AZT Retrovir

Outcome Measures

Primary Outcome Measures

1. Time to Failure of First Line Therapy or Death [From date of randomization up to failure of first-line therapy or death from any cause, whichever came first, assessed up to 4.8 years]

   To compare time to failure of first line ART (due to clinical, virological or immunological disease progression, or regimen-limiting ART toxicities) or death among three randomized arms (infants who receive early ART in Arms 2 and 3 and infants in whom ART is deferred until clinical or immunological disease progression in Arm 1) during the study (up to 4.8 years). The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore we report the number of participants experiencing the events per Arm.

2. Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart) [This outcome was assessed from the date of randomization to immunological failure. Immunological failure was assessed in the entire study duration of 4.8 years.]

   This was part of the primary outcome measure above. The primary outcome was a composite endpoint. The primary outcome analysis only considered the initially enrolled children that were 377 in total (ART-Deferred n=125, Early therapy 40 weeks n=126 and Early therapy 96 weeks n=126). This was part of the primary outcome measure that was a composite endpoint.

3. Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity [Regimen limiting drug toxicity was monitored from randomization up to the entire study duration of 4.8 years.]

   Development of toxicity requiring more than one drug substitution within the same class or a switch to a new class of drugs (regimen-limiting toxicity failure) or requiring a permanent treatment discontinuation. This was part of the primary outcome measure that was a composite endpoint.

4. Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy. [Clinical failure on therapy was assessed at each visit for the entire study duration of 4.8 years.]

   This included development of severe CDC Stage B or Stage C disease.This was part of the primary outcome measure that was a composite endpoint

5. Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart) [Virological failure was assessed from randomization through the entire study duration of 4.8 years.]

   This was part of the primary outcome measure that was a composite endpoint that included confirmed HIV-1 RNA value of at least 10,000 copies per/ml recorded on two consecutive separate occasions after 24 weeks of treatment (initial therapy or restart).

Secondary Outcome Measures

1. Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years) [Occurrence of severe CDC Stage B or Stage C disease or death (cumulative after 3.5 years), whichever came first, was assessed from randomization up to at least 3.5 years.]

   The outcome measure is defined as a number because it represents the number of children that experienced severe CDC Stage B or Stage C disease or death as defined in the outcome measure title above

2. Total Occurrence of Grade 3 or 4 Clinical Events [4.8 years]

   This was a secondary outcome measure that assessed the total count of Grade 3 or 4 (clinical or laboratory) adverse events.

3. Total Occurrence of Grade 3 or 4 Laboratory Events [From randomization up to 4.8 years]

4. Time From Randomization to Starting or Needing to Start Continuous Therapy [4.8 years]

   Time from randomization to starting (deferred therapy Arm) or needing to start continuous therapy (early therapy 40 or 96 weeks)

5. Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy [4.8 years]

   Resistance testing was performed on samples with a VL≥1000 c/ml together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and protease (PI) inhibitor mutations were analysed using a validated in-house population-based sequencing assay and the IAS 2011 mutation list.

6. Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage. [4.8 years]

   This was a composite endpoint in which the number of children experiencing the events is reported. The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore, we report the number of participants experiencing the events per Arm.

7. Hospitalization Rates [4.8 years]

   Hospitalisation rates in the three arms enrolled in the CHER study

8. Duration of Hospitalisation [4.8 years, the study duration]

   This is the total number of days spent in hospital by the participants and is reported per arm

9. Time to First Hospitalization [From randomization up to 4.8 years]

   To compare time to first hospitalization in the three randomized arms (infants who received early ART in Arms 2 and 3 and those who received deferred ART in Arm 1). Not all participants were hospitalized and thus the upper limits could not be evaluated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Weeks to 12 Weeks
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria for Infants:

NOTE: Per Letter of Amendment dated 04/04/07, Part B of this study is no longer recruiting participants. Per Letter of Amendment dated 09/16/08 Arm 1 of this study is longer recruiting.

• HIV infected

• Antiretroviral naive. Infants who have previously received antiretroviral drugs used to prevent mother-to-child transmission are eligible for the study.

• Parent or legal guardian willing to provide informed consent and comply with study requirements

Exclusion Criteria for Infants:

• Any major life-threatening congenital abnormalities

• Severe CDC Stage B or C disease

• Liver enzyme, absolute neutrophil count, hemoglobin, electrolyte, creatinine, or clinical toxicity of Grade 3 or higher at screening

• Any acute or clinically significant medical event that would preclude participation in the study. Randomization can take place as soon as the incurrent illness has resolved if the child is still less than or equal to 12 weeks of age.

• Use of investigational drugs

• Require certain medications. More information on this criterion can be found in the protocol.

• Inability to tolerate oral medication

• Birth weight less than 2 kg (4.4 lbs)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: James McIntyre, MBChB, MRCOG, Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand
• Study Chair: Avy Violari, MBChB, FCPSA, Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand
• Study Chair: Mark F. Cotton, PhD, Department of Pediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch

Study Documents (Full-Text)

None provided.

More Information

Publications

• Faye A, Bertone C, Teglas JP, Chaix ML, Douard D, Firtion G, Thuret I, Dollfus C, Monpoux F, Floch C, Nicolas J, Vilmer E, Rouzioux C, Mayaux MJ, Blanche S; French Perinatal Study. Early multitherapy including a protease inhibitor for human immunodeficiency virus type 1-infected infants. Pediatr Infect Dis J. 2002 Jun;21(6):518-25.
• Faye A, Le Chenadec J, Dollfus C, Thuret I, Douard D, Firtion G, Lachassinne E, Levine M, Nicolas J, Monpoux F, Tricoire J, Rouzioux C, Tardieu M, Mayaux MJ, Blanche S; French Perinatal Study Group. Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1. Clin Infect Dis. 2004 Dec 1;39(11):1692-8. Epub 2004 Nov 5.
• Havens PL, Waters D. Management of the infant born to a mother with HIV infection. Pediatr Clin North Am. 2004 Aug;51(4):909-37, viii. Review.
• King SM; American Academy of Pediatrics Committee on Pediatric AIDS; American Academy of Pediatrics Infectious Diseases and Immunization Committee. Evaluation and treatment of the human immunodeficiency virus-1--exposed infant. Pediatrics. 2004 Aug;114(2):497-505.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00102960
• Other Study ID Numbers: CIPRA ZA 002; 10404; CHER; 5R01AI062512-02; CIPRA-SA Project 2
• First Posted: Feb 7, 2005
• Last Update Posted: Nov 2, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Infant; Perinatal; HIV; Disease Transmission, Vertical; Anti-Retroviral Agents; Treatment Interruption; Treatment Naive; Acute Infection; Mother-to-Child Transmission
• Additional relevant MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Ritonavir; Lopinavir; Lamivudine; Zidovudine; Nevirapine; Abacavir; Didanosine; Efavirenz

Study Results

Participant Flow

Pre-assignment Detail	The results are presented for only 377 participants that were enrolled into the three arms (ART-Def 125, ART-40W 126 and ART-96W 126).

Arm/Group Title	ART-Deferred	Early ART up to 40 Weeks	Early ART up to 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Period Title: Overall Study
STARTED	125	126	126
COMPLETED	95	103	98
NOT COMPLETED	30	23	28

Baseline Characteristics

Arm/Group Title	Deferred Therapy	Early Therapy up to 40 Weeks	Early Therapy up to 96 Weeks	Total
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	Total of all reporting groups
Overall Participants	125	126	126	377
Age (Weeks) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Weeks]	7.1	7.4	7.5	7.3
Sex: Female, Male (Count of Participants)
Female	70 56%	76 60.3%	74 58.7%	220 58.4%
Male	55 44%	50 39.7%	52 41.3%	157 41.6%
Region of Enrollment (Number) [Number]
South Africa	125 100%	126 100%	126 100%	377 100%

Outcome Measures

1. Primary Outcome

Title	Time to Failure of First Line Therapy or Death
Description	To compare time to failure of first line ART (due to clinical, virological or immunological disease progression, or regimen-limiting ART toxicities) or death among three randomized arms (infants who receive early ART in Arms 2 and 3 and infants in whom ART is deferred until clinical or immunological disease progression in Arm 1) during the study (up to 4.8 years). The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore we report the number of participants experiencing the events per Arm.
Time Frame	From date of randomization up to failure of first-line therapy or death from any cause, whichever came first, assessed up to 4.8 years

Outcome Measure Data

Analysis Population Description

In the analysis of failure of first-line therapy, children enrolled in the ART-Deferred group were used as the reference category in the hazard ratio analysis.

Arm/Group Title	Deferred Therapy	Early Therapy up to 40 Weeks	Early Therapy up to 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Count of Participants [Participants]	48 38.4%	32 25.4%	26 20.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks
	Comments	Statistical analysis compares early therapy 40 weeks (ART-40W) relative to deferred therapy (ART-Def)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 96 Weeks
	Comments	Statistical analysis compares early therapy 96 weeks (ART-96W) relative to deferred therapy (ART-Def)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Participants Who Experienced Immunological Failure Defined as Failure of CD4% to Reach 20% or CD4% Falls Below 20% on Two Occasions, Within 4 Weeks, at Any Time After the First 24 Weeks of Therapy (Initial Therapy or Restart)
Description	This was part of the primary outcome measure above. The primary outcome was a composite endpoint. The primary outcome analysis only considered the initially enrolled children that were 377 in total (ART-Deferred n=125, Early therapy 40 weeks n=126 and Early therapy 96 weeks n=126). This was part of the primary outcome measure that was a composite endpoint.
Time Frame	This outcome was assessed from the date of randomization to immunological failure. Immunological failure was assessed in the entire study duration of 4.8 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early ART for 40 Weeks	Early Therapy for 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily
Measure Participants	125	126	126
Count of Participants [Participants]	9 7.2%	14 11.1%	11 8.7%

3. Primary Outcome

Title	Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity
Description	Development of toxicity requiring more than one drug substitution within the same class or a switch to a new class of drugs (regimen-limiting toxicity failure) or requiring a permanent treatment discontinuation. This was part of the primary outcome measure that was a composite endpoint.
Time Frame	Regimen limiting drug toxicity was monitored from randomization up to the entire study duration of 4.8 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Count of Participants [Participants]	0 0%	0 0%	0 0%

4. Primary Outcome

Title	Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy.
Description	This included development of severe CDC Stage B or Stage C disease.This was part of the primary outcome measure that was a composite endpoint
Time Frame	Clinical failure on therapy was assessed at each visit for the entire study duration of 4.8 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Count of Participants [Participants]	8 6.4%	6 4.8%	5 4%

5. Primary Outcome

Title	Number of Participants Who Experienced Virological Failure Defined as Confirmed HIV-1 RNA Value of at Least 10,000 Copies Per/ml Recorded on Two Consecutive Separate Occasions After 24 Weeks of Treatment (Initial Therapy or Restart)
Description	This was part of the primary outcome measure that was a composite endpoint that included confirmed HIV-1 RNA value of at least 10,000 copies per/ml recorded on two consecutive separate occasions after 24 weeks of treatment (initial therapy or restart).
Time Frame	Virological failure was assessed from randomization through the entire study duration of 4.8 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Count of Participants [Participants]	10 8%	1 0.8%	1 0.8%

6. Secondary Outcome

Title	Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years)
Description	The outcome measure is defined as a number because it represents the number of children that experienced severe CDC Stage B or Stage C disease or death as defined in the outcome measure title above
Time Frame	Occurrence of severe CDC Stage B or Stage C disease or death (cumulative after 3.5 years), whichever came first, was assessed from randomization up to at least 3.5 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Count of Participants [Participants]	41 32.8%	28 22.2%	21 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks
	Comments	Relative to ART-Def, ART-40W had a 13% difference in the cumulative probability of clinical disease progression or death at 3·5 years
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Proportion test
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier Cummulative Probability
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 96 Weeks
	Comments	Relative to ART-Def, ART-96W had a 13% difference in the cumulative probability of clinical disease progression or death at 3·5 years
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Proportion test
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier Cummulative Probability
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; 0.09 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Total Occurrence of Grade 3 or 4 Clinical Events
Description	This was a secondary outcome measure that assessed the total count of Grade 3 or 4 (clinical or laboratory) adverse events.
Time Frame	4.8 years

Outcome Measure Data

Analysis Population Description

This analysis was only performed on the primary groups including a total of 377 participants

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Number [Count of events]	170	118	88

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks, Early Therapy up to 96 Weeks
	Comments	The CHER study compared Grade 3 or 4 clinical event rates per 100 person-years between the three arms using Poisson regression modeling over the study duration of 4.8 years.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This p-value compares event rates per 100 person-years across the three arms
	Method	Poisson Regression
	Comments
Method of Estimation	Estimation Parameter	Rate per 100 person years
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		The rates per 100 person-years were 33.8 (Arm 1), 21.6 (Arm 2) and 16 (Arm 3)

8. Secondary Outcome

Title	Total Occurrence of Grade 3 or 4 Laboratory Events
Time Frame	From randomization up to 4.8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Number [Count of events]	35	44	33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks, Early Therapy up to 96 Weeks
	Comments	The event rates per 100 person years were compared across the three arms
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Poisson regression
	Comments
Method of Estimation	Estimation Parameter	Rate per 100 person years
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		The laboratory events per 100 person years across the three arms were: 7 (Deferred arm), 8.1 (early therapy for 40 weeks) and 6 (early therapy for 96 weeks).

9. Secondary Outcome

Title	Time From Randomization to Starting or Needing to Start Continuous Therapy
Description	Time from randomization to starting (deferred therapy Arm) or needing to start continuous therapy (early therapy 40 or 96 weeks)
Time Frame	4.8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Median (Full Range) [Weeks]	20	33	70

10. Secondary Outcome

Title	Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy
Description	Resistance testing was performed on samples with a VL≥1000 c/ml together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and protease (PI) inhibitor mutations were analysed using a validated in-house population-based sequencing assay and the IAS 2011 mutation list.
Time Frame	4.8 years

Outcome Measure Data

Analysis Population Description

Mutations presented descriptively were 1) Protease inhibitor mutations and 2) Met184Val mutations were reported. Only 32 participants with viral load above 1,000 copies/ml at their last visit while on treatment were analysed.

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	5	14	13
PI mutations	1 0.8%	1 0.8%	0 0%
Met184Val mutations	1 0.8%	5 4%	1 0.8%
No mutations	3 2.4%	8 6.3%	12 9.5%

11. Secondary Outcome

Title	Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage.
Description	This was a composite endpoint in which the number of children experiencing the events is reported. The number of participants experiencing the events did not reach the 50% survival and thus median time-to-event is not be presented. Therefore, we report the number of participants experiencing the events per Arm.
Time Frame	4.8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Count of Participants [Participants]	34 27.2%	18 14.3%	13 10.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks
	Comments	The analysis compares ART-40W relative to the ART-Def arm.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard rate reported above compares early therapy 40 weeks relative to the deferred therapy arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 96 Weeks
	Comments	The analysis compares ART-96 Weeks relative to ART-Deferred
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.18 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio compares ART-96W relative to the ART-Def arm.

12. Secondary Outcome

Title	Hospitalization Rates
Description	Hospitalisation rates in the three arms enrolled in the CHER study
Time Frame	4.8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Number [Events per 100 person years]	27.6	16.4	14.2

13. Secondary Outcome

Title	Duration of Hospitalisation
Description	This is the total number of days spent in hospital by the participants and is reported per arm
Time Frame	4.8 years, the study duration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Number [Days]	1018	533	414

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks, Early Therapy up to 96 Weeks
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	The p-value here compares the days spent in hospital across the three arms
	Method	Poisson regression
	Comments
Method of Estimation	Estimation Parameter	Count of days
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		The total number of days/count of days: 1018 (Arm 1), 533 (Arm 2) and 414 (Arm 3) were compared across the three groups by Poisson regression analysis.

14. Secondary Outcome

Title	Time to First Hospitalization
Description	To compare time to first hospitalization in the three randomized arms (infants who received early ART in Arms 2 and 3 and those who received deferred ART in Arm 1). Not all participants were hospitalized and thus the upper limits could not be evaluated.
Time Frame	From randomization up to 4.8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferred Therapy	Early Therapy 40 Weeks	Early Therapy 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.	For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
Measure Participants	125	126	126
Median (Full Range) [Weeks]	73.1	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 40 Weeks
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.562
	Confidence Interval	(2-Sided) 95%; 0.389 to 0.811
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Deferred Therapy, Early Therapy up to 96 Weeks
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0038
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.583
	Confidence Interval	(2-Sided) 95%; 0.405 to 0.840
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	4.8 years, the study duration
Adverse Event Reporting Description	Only System Organ Class and Higher Level Terms are reported for 377 participants (ART-Def 125, ART-40W 126 and ART-96W 126)
Arm/Group Title	ART-Deferred		Early ART up to 40 Weeks		Early ART up to 96 Weeks
Arm/Group Description	For participants with a CD4% of at least 25%, ART deferred until necessary. Once ART therapy was initiated, it was taken continuously. Zidovudine: First Line Regimen: Given twice daily at a dose of 240 mg/m^2 of body surface area. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.		For participants with a CD4% of at least 25%, receive 40 weeks of ART until first birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.		For participants with a CD4% of at least 25%, receive ART for 96 weeks until second birthday Zidovudine: First Line Regimen: 10 mg/mL taken orally twice per day. Dose was adjusted by age as the children grew older. Lamivudine: First Line Regimen: 4 mg/kg taken orally twice daily Lopinavir/Ritonavir: First Line Regimen: taken orally twice daily. Dosage depends on age and weight. Ritonavir: First Line Regimen taken orally twice a day. Started at 250 mg/m^2 Abacavir sulfate: Second Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol. Didanosine: Second Line Regimen: Either 100 mg/m^2 or 120 mg/m^2 taken orally twice daily. Dosage depends on age. Efavirenz: Second Line Regimen: taken orally once daily. Dosage depends on weight. Nevirapine: Second Line Regimen: 150 - 200 mg/m^2 taken orally twice daily.
All Cause Mortality
	ART-Deferred		Early ART up to 40 Weeks		Early ART up to 96 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/125 (18.4%)		11/126 (8.7%)		11/126 (8.7%)
Serious Adverse Events
	ART-Deferred		Early ART up to 40 Weeks		Early ART up to 96 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/125 (63.2%)		60/126 (47.6%)		53/126 (42.1%)
Blood and lymphatic system disorders
Anaemia	2/125 (1.6%)	2	2/126 (1.6%)	2	1/126 (0.8%)	1
Lymphadenitis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Neutropenia	1/125 (0.8%)	1	2/126 (1.6%)	2	1/126 (0.8%)	1
Splenomegaly	0/125 (0%)	0	2/126 (1.6%)	2	0/126 (0%)	0
Thrombocytopenia	1/125 (0.8%)	1	1/126 (0.8%)	2	2/126 (1.6%)	2
Cardiac disorders
Cardiac failure	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Myocarditis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Congenital, familial and genetic disorders
Cerebral palsy	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Ear and labyrinth disorders
Hearing loss unilateral	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Gastrointestinal disorders
Gastroenteritis	11/125 (8.8%)	12	5/126 (4%)	5	2/126 (1.6%)	4
Haematemesis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Vomiting	2/125 (1.6%)	2	0/126 (0%)	0	1/126 (0.8%)	1
General disorders
Accidental death	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Apparent death	2/125 (1.6%)	2	2/126 (1.6%)	2	0/126 (0%)	0
Death	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Fever	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Oedema	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Unknown cause of death	6/125 (4.8%)	6	2/126 (1.6%)	2	5/126 (4%)	5
Hepatobiliary disorders
Hepatomegaly	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Liver failure	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Immune system disorders
HIV wasting syndrome	1/125 (0.8%)	1	1/126 (0.8%)	1	0/126 (0%)	0
Infections and infestations
Lymphadenopathy	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Abscess	1/125 (0.8%)	2	1/126 (0.8%)	1	1/126 (0.8%)	1
Bronchiolitis	5/125 (4%)	5	3/126 (2.4%)	3	3/126 (2.4%)	5
Bronchitis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Bronchopneumonia	6/125 (4.8%)	8	4/126 (3.2%)	6	3/126 (2.4%)	3
Cellulitis	1/125 (0.8%)	1	2/126 (1.6%)	2	1/126 (0.8%)	1
Chickenpox	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Croup	1/125 (0.8%)	1	1/126 (0.8%)	2	1/126 (0.8%)	1
Cytomegalovirus encephalitis	1/125 (0.8%)	2	0/126 (0%)	0	0/126 (0%)	0
Cytomegalovirus hepatitis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Dysentery	1/125 (0.8%)	1	1/126 (0.8%)	1	0/126 (0%)	0
Esophageal candidiasis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Gastroenteritis	38/125 (30.4%)	53	22/126 (17.5%)	29	27/126 (21.4%)	31
Laryngotracheo bronchitis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Lower respiratory tract infection	1/125 (0.8%)	2	0/126 (0%)	0	0/126 (0%)	0
Meningitis	6/125 (4.8%)	7	2/126 (1.6%)	2	2/126 (1.6%)	2
Miliary tuberculosis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Oesophageal candidiasis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Oral candidiasis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Osteomyelitis chronic	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Otitis media	0/125 (0%)	0	1/126 (0.8%)	2	0/126 (0%)	0
Parotitis	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Pharyngitis	1/125 (0.8%)	1	1/126 (0.8%)	1	0/126 (0%)	0
Pharyngitis bacterial	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Pneumococcal pneumonia	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Pneumococcal Sepsis	1/125 (0.8%)	1	1/126 (0.8%)	1	0/126 (0%)	0
Pneumocystis carinii pneumonia	5/125 (4%)	6	1/126 (0.8%)	1	0/126 (0%)	0
Pneumonia	26/125 (20.8%)	34	18/126 (14.3%)	25	17/126 (13.5%)	20
Sepsis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	2
Septicaemia	2/125 (1.6%)	2	0/126 (0%)	0	1/126 (0.8%)	1
Sinusitis	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
TB	4/125 (3.2%)	4	3/126 (2.4%)	3	1/126 (0.8%)	1
Tonsillitis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Tuberculous bronchopneumonia	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Urinary tract infection	3/125 (2.4%)	3	4/126 (3.2%)	4	0/126 (0%)	0
Viral meningitis	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Injury, poisoning and procedural complications
Burns	1/125 (0.8%)	1	2/126 (1.6%)	2	0/126 (0%)	0
Forearm fracture	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Fracture	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Fracture femur	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Poisoning	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Skull fracture	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Investigations
AST increased	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Gamma GT increased	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Hyperkalaemia	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Lipase increased	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Transaminases increased	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Failure to thrive	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Hyperkalaemia	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Hypernatremia	0/125 (0%)	0	2/126 (1.6%)	3	3/126 (2.4%)	3
Hypokalaemia	1/125 (0.8%)	1	0/126 (0%)	0	1/126 (0.8%)	1
Kwashiorkor	1/125 (0.8%)	1	0/126 (0%)	0	1/126 (0.8%)	1
Lactic acidosis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Obesity	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Nervous system disorders
Encephalopathy	1/125 (0.8%)	1	1/126 (0.8%)	1	0/126 (0%)	0
Febrile seizure	1/125 (0.8%)	1	2/126 (1.6%)	2	0/126 (0%)	0
Focal seizures	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Generalised tonic-clonic seizure	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Pneumococcal meningitis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Seizures	1/125 (0.8%)	1	1/126 (0.8%)	1	0/126 (0%)	0
Renal and urinary disorders
Acute renal failure	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Reproductive system and breast disorders
Rectovaginal fistula	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration	0/125 (0%)	0	1/126 (0.8%)	1	0/126 (0%)	0
Aspiration pneumonitis	0/125 (0%)	0	0/126 (0%)	0	1/126 (0.8%)	1
Pneumonia	2/125 (1.6%)	2	2/126 (1.6%)	2	0/126 (0%)	0
Pneumonitis	1/125 (0.8%)	1	0/126 (0%)	0	0/126 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis	0/125 (0%)	0	2/126 (1.6%)	2	0/126 (0%)	0
Other (Not Including Serious) Adverse Events
	ART-Deferred		Early ART up to 40 Weeks		Early ART up to 96 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	123/125 (98.4%)		122/126 (96.8%)		125/126 (99.2%)
Blood and lymphatic system disorders
Lymphadenopathy	38/125 (30.4%)	46	52/126 (41.3%)	64	39/126 (31%)	42
Neutropenia	5/125 (4%)	7	9/126 (7.1%)	10	14/126 (11.1%)	17
Splenomegaly	32/125 (25.6%)	36	23/126 (18.3%)	28	10/126 (7.9%)	14
Gastrointestinal disorders
Gastroenteritis	80/125 (64%)	160	85/126 (67.5%)	214	81/126 (64.3%)	178
Hepatobiliary disorders
Hepatomegaly	53/125 (42.4%)	72	50/126 (39.7%)	72	52/126 (41.3%)	79
Infections and infestations
AIDS encephalopathy	10/125 (8%)	10	15/126 (11.9%)	15	10/126 (7.9%)	10
Bronchiolitis	58/125 (46.4%)	83	66/126 (52.4%)	104	48/126 (38.1%)	76
Bronchopneumonia	9/125 (7.2%)	10	12/126 (9.5%)	13	12/126 (9.5%)	14
Candida nappy rash	17/125 (13.6%)	19	16/126 (12.7%)	19	14/126 (11.1%)	18
Candidiasis	29/125 (23.2%)	41	32/126 (25.4%)	38	17/126 (13.5%)	21
Gastroenteritis	52/125 (41.6%)	72	42/126 (33.3%)	61	47/126 (37.3%)	64
Impetigo	27/125 (21.6%)	37	26/126 (20.6%)	31	21/126 (16.7%)	24
Molluscum Contagiosum	9/125 (7.2%)	10	10/126 (7.9%)	11	10/126 (7.9%)	12
Mucocutaneous Herpes Simplex	8/125 (6.4%)	9	7/126 (5.6%)	8	9/126 (7.1%)	10
Oral Candidiasis	60/125 (48%)	101	46/126 (36.5%)	81	50/126 (39.7%)	58
Otitis Media	70/125 (56%)	140	81/126 (64.3%)	220	78/126 (61.9%)	154
Persistent Generalised Lymphadenopathy	13/125 (10.4%)	14	17/126 (13.5%)	19	21/126 (16.7%)	23
Pharyngitis	69/125 (55.2%)	112	65/126 (51.6%)	139	62/126 (49.2%)	118
Pneumonia	49/125 (39.2%)	81	44/126 (34.9%)	78	45/126 (35.7%)	78
Scabies	13/125 (10.4%)	15	28/126 (22.2%)	38	20/126 (15.9%)	25
TB	23/125 (18.4%)	24	28/126 (22.2%)	31	25/126 (19.8%)	25
Tinea	49/125 (39.2%)	63	50/126 (39.7%)	78	53/126 (42.1%)	81
Tonsilitis	41/125 (32.8%)	72	49/126 (38.9%)	89	39/126 (31%)	68
Urinary tract infection	10/125 (8%)	12	15/126 (11.9%)	21	6/126 (4.8%)	7
Varicella Zoster	7/125 (5.6%)	7	16/126 (12.7%)	16	5/126 (4%)	5
Investigations
ALT Increased	11/125 (8.8%)	12	8/126 (6.3%)	10	4/126 (3.2%)	5
Gamma GT Increased	7/125 (5.6%)	7	4/126 (3.2%)	6	2/126 (1.6%)	3
Metabolism and nutrition disorders
Failure to thrive	37/125 (29.6%)	41	31/126 (24.6%)	37	19/126 (15.1%)	23
Skin and subcutaneous tissue disorders
Dermatitis	103/125 (82.4%)	320	96/126 (76.2%)	223	89/126 (70.6%)	206
Nappy rash	9/125 (7.2%)	10	19/126 (15.1%)	31	7/126 (5.6%)	10

Limitations/Caveats

The CHER study did not include an early continuous therapy Arm, had not been powered to test for differences between early therapy 40 weeks vs. 96 weeks and never assessed in-utero vs. intrapartum infections.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.