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

NCT00102960 | Completed Phase 3 Results DMC

• 5 other identifiers: CIPRA ZA 00210404CHER5R01AI062512-02CIPRA-SA Project 2
• Study Type: interventional
• Target: 377
• Locations: 0 countries
• Sites: N/A

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.

Conditions

HIV Infections

Keywords

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

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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

  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).

  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)

  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

  4.8 years

• Total Occurrence of Grade 3 or 4 Laboratory Events

  From randomization up to 4.8 years

• Time From Randomization to Starting or Needing to Start Continuous Therapy

  4.8 years

• Number of Participants With Indicated Viral Resistance Mutations at the Time of Failure of First Line Therapy

  4.8 years

Study Arms (3)

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

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

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

Drug: Abacavir sulfate; Drug: Didanosine; Drug: Efavirenz; Drug: Lamivudine; Drug: Lopinavir/Ritonavir; Drug: Nevirapine; Drug: Zidovudine

Interventions

Abacavir sulfate 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.

Also known as: ABC, Ziagen

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Didanosine 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.

Also known as: ddI, Videx

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Efavirenz 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.

Also known as: EFV, Stocrin

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Lamivudine DRUG

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

Also known as: 3TC, Epivir

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Lopinavir/Ritonavir DRUG

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

Also known as: LPV/r, Kaletra

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Nevirapine 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.

Also known as: NVP, Viramune

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Zidovudine DRUG

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

Also known as: AZT, Retrovir

Deferred therapy Arm; Early therapy for 40 weeks; Early therapy for 96 weeks

Eligibility Criteria

• Age: 6 Weeks - 12 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Related Publications (9)

• 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.

  PMID: 12182375 BACKGROUND

• 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.

  PMID: 15578372 BACKGROUND

• 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.

  PMID: 15275981 BACKGROUND

• 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.

  PMID: 15286240 BACKGROUND

• 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.

  PMID: 30418528 DERIVED

• 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.

  PMID: 26043884 DERIVED

• 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.

  PMID: 24209829 DERIVED

• 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.

  PMID: 22029910 DERIVED

• 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.

  PMID: 19020325 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

abacavir; Didanosine; efavirenz; Lamivudine; Lopinavir; lopinavir-ritonavir drug combination; Nevirapine; Zidovudine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Inosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Pyrimidinones; Pyridines; Thymidine

Limitations and 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.

Results Point of Contact

• Title: Dr Avy Violari and Prof Mark Cotton
• Organization: Perinatal HIV Research Unit, Johannesburg and Children's Infectious Diseases Clinical Research Unit, Cape Town all in South Africa

violari@mweb.co.za

27 11 989 9702/27 21 938 4219

Study Officials

• James McIntyre, MBChB, MRCOG

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

  PRINCIPAL INVESTIGATOR

• 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 CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 4, 2005
• First Posted: February 7, 2005
• Study Start: July 1, 2005
• Primary Completion: September 1, 2012
• Study Completion: January 1, 2013
• Last Updated: November 2, 2021
• Results First Posted: November 30, 2018

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share