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

NCT ID: NCT00102960

Last Updated: 2021-11-02

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

377 participants

Study Classification

INTERVENTIONAL

Study Start Date

2005-07-31

Study Completion Date

2013-01-31

Brief Summary

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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

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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

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HIV Infections

Keywords

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Infant Perinatal HIV Disease Transmission, Vertical Anti-Retroviral Agents Treatment Interruption Treatment Naive Acute Infection Mother-to-Child Transmission

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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

Group Type EXPERIMENTAL

Abacavir sulfate

Intervention Type DRUG

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

Intervention Type DRUG

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.

Efavirenz

Intervention Type DRUG

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.

Lamivudine

Intervention Type DRUG

First Line Regimen: 4 mg/kg taken orally twice daily

Lopinavir/Ritonavir

Intervention Type DRUG

First Line Regimen: taken orally twice daily. Dosage depends on age and weight.

Nevirapine

Intervention Type DRUG

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.

Zidovudine

Intervention Type DRUG

First Line Regimen: 240 mg/m\^2 taken orally twice daily

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

Group Type EXPERIMENTAL

Abacavir sulfate

Intervention Type DRUG

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

Intervention Type DRUG

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.

Efavirenz

Intervention Type DRUG

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.

Lamivudine

Intervention Type DRUG

First Line Regimen: 4 mg/kg taken orally twice daily

Lopinavir/Ritonavir

Intervention Type DRUG

First Line Regimen: taken orally twice daily. Dosage depends on age and weight.

Nevirapine

Intervention Type DRUG

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.

Zidovudine

Intervention Type DRUG

First Line Regimen: 240 mg/m\^2 taken orally twice daily

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

Group Type EXPERIMENTAL

Abacavir sulfate

Intervention Type DRUG

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

Intervention Type DRUG

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.

Efavirenz

Intervention Type DRUG

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.

Lamivudine

Intervention Type DRUG

First Line Regimen: 4 mg/kg taken orally twice daily

Lopinavir/Ritonavir

Intervention Type DRUG

First Line Regimen: taken orally twice daily. Dosage depends on age and weight.

Nevirapine

Intervention Type DRUG

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.

Zidovudine

Intervention Type DRUG

First Line Regimen: 240 mg/m\^2 taken orally twice daily

Interventions

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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.

Intervention Type 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.

Intervention Type 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.

Intervention Type DRUG

Lamivudine

First Line Regimen: 4 mg/kg taken orally twice daily

Intervention Type DRUG

Lopinavir/Ritonavir

First Line Regimen: taken orally twice daily. Dosage depends on age and weight.

Intervention Type 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.

Intervention Type DRUG

Zidovudine

First Line Regimen: 240 mg/m\^2 taken orally twice daily

Intervention Type DRUG

Other Intervention Names

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ABC Ziagen ddI Videx EFV Stocrin 3TC Epivir LPV/r Kaletra NVP Viramune AZT Retrovir

Eligibility Criteria

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Inclusion Criteria

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

* 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)
Minimum Eligible Age

6 Weeks

Maximum Eligible Age

12 Weeks

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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James McIntyre, MBChB, MRCOG

Role: PRINCIPAL_INVESTIGATOR

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

Avy Violari, MBChB, FCPSA

Role: STUDY_CHAIR

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

Mark F. Cotton, PhD

Role: STUDY_CHAIR

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

Countries

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South Africa

References

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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.

Reference Type BACKGROUND
PMID: 12182375 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15578372 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15275981 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15286240 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30418528 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26043884 (View on PubMed)

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.

Reference Type DERIVED
PMID: 24209829 (View on PubMed)

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.

Reference Type DERIVED
PMID: 22029910 (View on PubMed)

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.

Reference Type DERIVED
PMID: 19020325 (View on PubMed)

Other Identifiers

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10404

Identifier Type: REGISTRY

Identifier Source: secondary_id

CHER

Identifier Type: REGISTRY

Identifier Source: secondary_id

5R01AI062512-02

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CIPRA-SA Project 2

Identifier Type: OTHER

Identifier Source: secondary_id

CIPRA ZA 002

Identifier Type: -

Identifier Source: org_study_id