HIV InfectionsPhase 3NCT00102960

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

A Phase 3 study testing Abacavir sulfate, Didanosine and Efavirenz in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID).

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 6 to 12 weeks
Conditions the study is for: HIV Infections
What is being tested?: Abacavir sulfate, Didanosine and Efavirenz
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 377 participants
Where: No sites listed yet
Study dates: Jul 2005to Jan 2013
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 6 to 12 weeks
All sexes
No healthy volunteers
Child

Who may be able to join

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

Who cannot join

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)

About this study

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

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.

Read the 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.

Conditions: HIV Infections
Being tested: Abacavir sulfate, Didanosine, Efavirenz, Lamivudine, Lopinavir/Ritonavir
Keywords: Infant, Perinatal, HIV, Disease Transmission, Vertical, Anti-Retroviral Agents, Treatment Interruption, Treatment Naive, Acute Infection, Mother-to-Child Transmission
Medical subject headings: HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Abacavir sulfateDrug
Also called ABC, Ziagen
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.
DidanosineDrug
Also called ddI, Videx
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.
EfavirenzDrug
Also called EFV, Stocrin
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.
LamivudineDrug
Also called 3TC, Epivir
First Line Regimen: 4 mg/kg taken orally twice daily
Lopinavir/RitonavirDrug
Also called LPV/r, Kaletra
First Line Regimen: taken orally twice daily. Dosage depends on age and weight.
NevirapineDrug
Also called NVP, Viramune
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.
ZidovudineDrug
Also called AZT, Retrovir
First Line Regimen: 240 mg/m^2 taken orally twice daily

Study groups in NCT00102960
Study group	Role	What they receive
Deferred therapy Arm	Experimental	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 Receives: Drug: Abacavir sulfate; Drug: Didanosine; Drug: Efavirenz; Drug: Lamivudine; Drug: Lopinavir/Ritonavir; Drug: Nevirapine; Drug: Zidovudine
Early therapy for 40 weeks	Experimental	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 Receives: Drug: Abacavir sulfate; Drug: Didanosine; Drug: Efavirenz; Drug: Lamivudine; Drug: Lopinavir/Ritonavir; Drug: Nevirapine; Drug: Zidovudine
Early therapy for 96 weeks	Experimental	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 Receives: Drug: Abacavir sulfate; Drug: Didanosine; Drug: Efavirenz; Drug: Lamivudine; Drug: Lopinavir/Ritonavir; Drug: Nevirapine; Drug: Zidovudine

What is being measured

The primary outcome is the main question the study is designed to answer.

Time to Failure of First Line Therapy or Death
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.
Measured: 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
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 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.
Measured: 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.
Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity
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.
Measured: Regimen limiting drug toxicity was monitored from randomization up to the entire study duration of 4.8 years.
Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy.
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
Measured: Clinical failure on therapy was assessed at each visit for the entire study duration of 4.8 years.
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)
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).
Measured: Virological failure was assessed from randomization through the entire study duration of 4.8 years.

Secondary outcomes (9)

Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 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
Measured: 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.
Total Occurrence of Grade 3 or 4 Clinical Events
This was a secondary outcome measure that assessed the total count of Grade 3 or 4 (clinical or laboratory) adverse events.
Measured: 4.8 years
Total Occurrence of Grade 3 or 4 Laboratory Events
Measured: From randomization up to 4.8 years
Time From Randomization to Starting or Needing to Start Continuous Therapy
Time from randomization to starting (deferred therapy Arm) or needing to start continuous therapy (early therapy 40 or 96 weeks)
Measured: 4.8 years
Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy
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.
Measured: 4.8 years
Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage.
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.
Measured: 4.8 years
Hospitalization Rates
Hospitalisation rates in the three arms enrolled in the CHER study
Measured: 4.8 years
Duration of Hospitalisation
This is the total number of days spent in hospital by the participants and is reported per arm
Measured: 4.8 years, the study duration
Time to First Hospitalization
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.
Measured: From randomization up to 4.8 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 2005Jan 2013

First posted7 Feb 2005 (estimated)
Study startJul 2005
Primary completionSep 2012
Study completionJan 2013

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (9)Papers the sponsor has linked to this study.
Other trials for HIV InfectionsStudies of the same condition, open and under way.
More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
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.
Masking: None (open label)
Enrolment: 377 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00102960
Sponsor's protocol ID: CIPRA ZA 002
Other IDs: 10404, CHER, 5R01AI062512-02, CIPRA-SA Project 2
Status last verified: Oct 2021
First submitted: 4 Feb 2005
Last updated: 2 Nov 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: No: Data may be made available through a formal request to the protocol team

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. doi: 10.1097/00006454-200206000-00008.
PubMed 12182375
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. doi: 10.1086/425739. Epub 2004 Nov 5.
PubMed 15578372
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. doi: 10.1016/j.pcl.2004.03.004.
PubMed 15275981
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. doi: 10.1542/peds.114.2.497.
PubMed 15286240
Mutsaerts EAML, Nunes MC, van Rijswijk MN, Klipstein-Grobusch K, Otwombe K, Cotton MF, Violari A, Madhi SA. Measles Immunity at 4.5 Years of Age Following Vaccination at 9 and 15-18 Months of Age Among Human Immunodeficiency Virus (HIV)-infected, HIV-exposed-uninfected, and HIV-unexposed Children. Clin Infect Dis. 2019 Aug 1;69(4):687-696. doi: 10.1093/cid/ciy964.
PubMed 30418528
Payne H, Mkhize N, Otwombe K, Lewis J, Panchia R, Callard R, Morris L, Babiker A, Violari A, Cotton MF, Klein NJ, Gibb DM. Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis. Lancet Infect Dis. 2015 Jul;15(7):803-9. doi: 10.1016/S1473-3099(15)00087-0. Epub 2015 Jun 1.
PubMed 26043884
Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, Josipovic D, Liberty A, Lazarus E, Innes S, van Rensburg AJ, Pelser W, Truter H, Madhi SA, Handelsman E, Jean-Philippe P, McIntyre JA, Gibb DM, Babiker AG; CHER Study Team. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. Lancet. 2013 Nov 9;382(9904):1555-63. doi: 10.1016/S0140-6736(13)61409-9.
PubMed 24209829
Hainline C, Taliep R, Sorour G, Nachman S, Rabie H, Dobbels E, van Rensburg AJ, Cornell M, Violari A, Madhi SA, Cotton MF. Early Antiretroviral Therapy reduces the incidence of otorrhea in a randomized study of early and deferred antiretroviral therapy: Evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. BMC Res Notes. 2011 Oct 26;4:448. doi: 10.1186/1756-0500-4-448.
PubMed 22029910
Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008 Nov 20;359(21):2233-44. doi: 10.1056/NEJMoa0800971.
PubMed 19020325

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Study at a glance

From the registry record, last updated by the sponsor on 2 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT00102960
Acronym / sponsor ID: CIPRA ZA 002
Conditions: HIV Infections
Keywords: Infant, Perinatal, HIV, Disease Transmission, Vertical, Anti-Retroviral Agents, Treatment Interruption, Treatment Naive, Acute Infection
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 377 participants (actual)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
Study start: Jul 2005
Primary completion: Sep 2012 (actual)
Study completion: Jan 2013 (actual)
First posted: 7 Feb 2005 (estimated)
Results: Posted 30 Nov 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 3
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.

Arm	Type	Receives
Deferred therapy Arm	Experimental	Drug: Abacavir sulfate, Drug: Didanosine, Drug: Efavirenz, Drug: Lamivudine, Drug: Lopinavir/Ritonavir, Drug: Nevirapine, Drug: ZidovudineZidovudine: 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
Early therapy for 40 weeks	Experimental	Drug: Abacavir sulfate, Drug: Didanosine, Drug: Efavirenz, Drug: Lamivudine, Drug: Lopinavir/Ritonavir, Drug: Nevirapine, Drug: ZidovudineZidovudine: 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
Early therapy for 96 weeks	Experimental	Drug: Abacavir sulfate, Drug: Didanosine, Drug: Efavirenz, Drug: Lamivudine, Drug: Lopinavir/Ritonavir, Drug: Nevirapine, Drug: ZidovudineZidovudine: 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

Who may qualify

Ages: 6 to 12 weeks
Sex: All
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (4 listed)

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

Key exclusion criteria (8 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Abacavir sulfateAlso: ABC, ZiagenSecond Line Regimen: 8 mg/kg taken orally twice daily. Guidelines for switching from first line to second line therapy are available in the protocol.	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks
DidanosineAlso: ddI, VidexSecond 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.	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks
EfavirenzAlso: EFV, StocrinSecond 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.	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks
LamivudineAlso: 3TC, EpivirFirst Line Regimen: 4 mg/kg taken orally twice daily	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks
Lopinavir/RitonavirAlso: LPV/r, KaletraFirst Line Regimen: taken orally twice daily. Dosage depends on age and weight.	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks
NevirapineAlso: NVP, ViramuneSecond 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.	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks
ZidovudineAlso: AZT, RetrovirFirst Line Regimen: 240 mg/m^2 taken orally twice daily	Drug	Deferred therapy Arm, Early therapy for 40 weeks, Early therapy for 96 weeks

Primary outcome

Time to Failure of First Line Therapy or Death
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
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.
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)
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.
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.
Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity
Time frame: 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.
Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy.
Time frame: 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
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)
Time frame: 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).

9 secondary outcomes

Number of Children Experiencing Severe CDC Stage B or Stage C Disease or Death (Cumulative After 3.5 Years)
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.
Total Occurrence of Grade 3 or 4 Clinical Events
Time frame: 4.8 years
Total Occurrence of Grade 3 or 4 Laboratory Events
Time frame: From randomization up to 4.8 years
Time From Randomization to Starting or Needing to Start Continuous Therapy
Time frame: 4.8 years
Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy
Time frame: 4.8 years
Time to Death Alone or Death Plus Life Threatening Stage C Events or HIV Events Associated With Permanent End-organ Damage.
Time frame: 4.8 years
Hospitalization Rates
Time frame: 4.8 years
Duration of Hospitalisation
Time frame: 4.8 years, the study duration
Time to First Hospitalization
Time frame: From randomization up to 4.8 years

Results and safety

Results posted to the registry on 30 Nov 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
ART-Deferred	125	95
Early ART up to 40 Weeks	126	103
Early ART up to 96 Weeks	126	98

Primary outcome: Time to Failure of First Line Therapy or Death

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. Count of participants. Unit: Participants

Measure	Deferred Therapy n = 125	Early Therapy up to 40 Weeks n = 126	Early Therapy up to 96 Weeks n = 126
Value	48	32	26

Deferred Therapy vs Early Therapy up to 40 Weeks: Hazard Ratio (HR): 0.59 (95% CI 0.38 to 0.93), p = 0.02, Regression, Cox
Deferred Therapy vs Early Therapy up to 96 Weeks: Hazard Ratio (HR): 0.47 (95% CI 0.27 to 0.76), p = 0.002, Regression, Cox

Population analysed: 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.

Primary outcome: 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)

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.. Count of participants. Unit: Participants

Measure	Deferred Therapy n = 125	Early ART for 40 Weeks n = 126	Early Therapy for 96 Weeks n = 126
Value	9	14	11

Primary outcome: Number of Participants Who Experienced Regimen-limiting ART Drug Toxicity

Time frame: Regimen limiting drug toxicity was monitored from randomization up to the entire study duration of 4.8 years.. Count of participants. Unit: Participants

Measure	Deferred Therapy n = 125	Early Therapy 40 Weeks n = 126	Early Therapy 96 Weeks n = 126
Value	0	0	0

Primary outcome: Number of Participants Who Experienced Clinical Failure (Defined as Development of Severe CDC Stage B or Stage C Disease.) on Therapy.

Time frame: Clinical failure on therapy was assessed at each visit for the entire study duration of 4.8 years.. Count of participants. Unit: Participants

Measure	Deferred Therapy n = 125	Early Therapy 40 Weeks n = 126	Early Therapy 96 Weeks n = 126
Value	8	6	5

9 secondary outcomes are reported in the full results.

Adverse events

Time frame: 4.8 years, the study duration. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
ART-Deferred	79 of 125 (63.2%)	123 of 125 (98.4%)	23 of 125
Early ART up to 40 Weeks	60 of 126 (47.6%)	122 of 126 (96.8%)	11 of 126
Early ART up to 96 Weeks	53 of 126 (42.1%)	125 of 126 (99.2%)	11 of 126

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 2 Nov 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 12182375Faye 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. doi: 10.1097/00006454-200206000-00008.
Background: PubMed 15578372Faye 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. doi: 10.1086/425739. Epub 2004 Nov 5.
Background: PubMed 15275981Havens 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. doi: 10.1016/j.pcl.2004.03.004.
Background: PubMed 15286240King 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. doi: 10.1542/peds.114.2.497.
Derived from this study: PubMed 30418528Mutsaerts EAML, Nunes MC, van Rijswijk MN, Klipstein-Grobusch K, Otwombe K, Cotton MF, Violari A, Madhi SA. Measles Immunity at 4.5 Years of Age Following Vaccination at 9 and 15-18 Months of Age Among Human Immunodeficiency Virus (HIV)-infected, HIV-exposed-uninfected, and HIV-unexposed Children. Clin Infect Dis. 2019 Aug 1;69(4):687-696. doi: 10.1093/cid/ciy964.
Derived from this study: PubMed 26043884Payne H, Mkhize N, Otwombe K, Lewis J, Panchia R, Callard R, Morris L, Babiker A, Violari A, Cotton MF, Klein NJ, Gibb DM. Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis. Lancet Infect Dis. 2015 Jul;15(7):803-9. doi: 10.1016/S1473-3099(15)00087-0. Epub 2015 Jun 1.
Derived from this study: PubMed 24209829Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, Josipovic D, Liberty A, Lazarus E, Innes S, van Rensburg AJ, Pelser W, Truter H, Madhi SA, Handelsman E, Jean-Philippe P, McIntyre JA, Gibb DM, Babiker AG; CHER Study Team. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. Lancet. 2013 Nov 9;382(9904):1555-63. doi: 10.1016/S0140-6736(13)61409-9.
Derived from this study: PubMed 22029910Hainline C, Taliep R, Sorour G, Nachman S, Rabie H, Dobbels E, van Rensburg AJ, Cornell M, Violari A, Madhi SA, Cotton MF. Early Antiretroviral Therapy reduces the incidence of otorrhea in a randomized study of early and deferred antiretroviral therapy: Evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. BMC Res Notes. 2011 Oct 26;4:448. doi: 10.1186/1756-0500-4-448.
Derived from this study: PubMed 19020325Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008 Nov 20;359(21):2233-44. doi: 10.1056/NEJMoa0800971.
Individual participant dataSharing planned: No. Data may be made available through a formal request to the protocol team

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

James McIntyre, MBChB, MRCOG principal investigator

Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand

Avy Violari, MBChB, FCPSA study chair

Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand

Mark F. Cotton, PhD study chair

Department of Pediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Abacavir sulfate, Didanosine and Efavirenz in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID).

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Time to Failure of First Line Therapy or Death (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). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00102960, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Nov 2021.