Treatment Options for Protease Inhibitor-exposed Children (NEVEREST-III)

The investigators hypothesize that switching to a regimen based on efavirenz will be as effective and safe as remaining on a regimen based on Lopinavir/ritonavir for HIV-infected children.

The investigators propose an unblinded randomized clinical trial to evaluate a simplification, protease-inhibitor (PI)-sparing treatment strategy among nevirapine (NVP)-exposed HIV-infected children treated initially with lopinavir/ritonavir (LPV/r). HIV-infected children aged 3-5 years, who have a history of exposure to NVP as part of prevention of mother-to-child HIV transmission (PMTCT), initiated LPV/r-based therapy in the first 36 months of life or who were enrolled on the control arm of Neverest 2 and who are virally suppressed with a viral load < 50 copies/ml will be included. These children will be randomized to either substitute efavirenz (EFV) for LPV/r or to continue on their LPV/r-based regimen. Eight weeks prior to the primary randomization, eligible children will also be randomized to either remain on stavudine (D4T) or switch to abacavir (ABC). Children will be followed with regular viral load and other clinical tests for 48 weeks after the primary randomization. Children in the experimental arm who have breakthrough viremia (-defined as two subsequent viral loads > 1000 copies/ml) on the EFV-based regimen will reinitiate the LPV/r regimen. The primary objective is to test whether the durability of viral suppression is equivalent when children are switched to EFV-based therapy. The primary study endpoint is failure to have HIV RNA < 50 copies/ml and/or confirmed viremia >1000 copies/ml. Secondary aims include comparison of immune preservation, toxicities, selection of resistance mutations, and adherence across the two arms. Antiretroviral drug concentrations and adherence will be investigated as possible explanations for the success and/or failure of this simplification regimen. The overall goal of the study is to contribute to the evidence base to allow expansion of treatment options for HIV-infected children in low resource settings.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV/AIDS
• Intervention / Treatment: Drug: Lopinavir/ritonavir (LPV/r); Drug: Efavirenz (EFV); Drug: Stavudine (D4T); Drug: Abacavir (ABC)

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa
      • Rahima Moosa Mother and Child Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-infected child 3 to 5 years of age at time of screening for this trial if enrolled from outside or any age if enrolled from control arm of Neverest II.
• Reliable history or documented exposure to NVP used as part of PMTCT
• Initiated antiretroviral therapy with LPV/r at age less than 36 months
• Receiving LPV/r-based ART for at least 12 months
• At least one viral load measurement less than 50 copies/ml conducted as part of screening for the study
• ALT measurement grade I or less (DAIDS Toxicity Tables 2004) (Appendix A). These may be repeated until ALTs normalize if necessary.

Exclusion criteria:

• Prior treatment with any NNRTI drug as part of a therapeutic regimen
• Substitution of other NRTI drugs (instead of 3TC and D4T which are the standard first line regimen) will be allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Group 1: Lopinavir/ritonavir (LPV/r); Participants are assigned to remain on their current LPV/r-based antiretroviral regimen. Ritonavir-boosted lopinavir syrup was given twice per day at 230 mg/m^2 per dose. Children able to swallow tablets were given 1 tablet twice per day (200 mg lopinavir/50 mg ritonavir) if body surface area was less than 0.9m^2 or 2 tablets twice per day if body surface area was 0.9m^2 or higher.	Drug: Lopinavir/ritonavir (LPV/r); Children are assigned to stay on their current LPV/r-based antiretroviral regimen.
EXPERIMENTAL: Group 2: Efavirenz (EFV); Participants are assigned to switch to an EFV-based antiretroviral regimen. Efavirenz was prescribed once daily in the evening at 200 mg for weights of 10 kg to 13.9 kg (22-30 lb) and 300mg for weights of 14 kg to 24.9 kg (31-55 lb). Efavirenz was available in 50-mg and 200-mg capsules. If children were unable to swallow capsules, caregivers were shown how to open the capsules and dissolve the contents in water.	Drug: Efavirenz (EFV); Children are assigned to begin a EFV-based antiretroviral based regimen.
ACTIVE_COMPARATOR: Group D: Stavudine (D4T); Children are assigned to remain on their current antiretroviral regimen, which includes D4T. D4T was given at 1 mg/kg twice daily	Drug: Stavudine (D4T); Children are assigned to stay on their current antiretroviral regimen which includes D4T.
EXPERIMENTAL: Group A: Abacavir (ABC); Children stop taking D4T and switch to ABC. ABC was given at 8 mg/kg twice daily.	Drug: Abacavir (ABC); Children stop taking D4T and switch to ABC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral Rebound	Probability of viral rebound defined as >=1 HIV RNA measurements >50 copies/ml using survival analysis by 48 weeks post-randomization.	48 weeks
Viral Failure	Probability of viral failure defined as >= 2 HIV RNA measurements >1000 copies/ml using survival analysis by 48 weeks post-randomization.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD4 Cell Percentage at 48 Weeks After Randomization	CD4 Cell Percentage at 48 Weeks After Randomization	48 weeks
Percentage of Participants With Elevated Total Cholesterol, Elevated LDL, Abnormal HDL, or Abnormal Triglycerides at 40 Weeks After Randomization	Percentage of participants with elevated total cholesterol, elevated LDL, abnormal HDL, or abnormal triglycerides at 40 weeks after randomization	40 weeks
Highest Grade ALT After Randomization	Highest grade ALT after randomization. Grading was determined based on the Division of AIDS (2004) Toxicity Tables to grade adverse reactions. Grading scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (potentially life-threatening).	through 48 weeks post randomization

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Witwatersrand, South Africa

Publications and helpful links

General Publications

• Coovadia A, Abrams EJ, Strehlau R, Shiau S, Pinillos F, Martens L, Patel F, Hunt G, Tsai WY, Kuhn L. Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial. JAMA. 2015 Nov 3;314(17):1808-17. doi: 10.1001/jama.2015.13631.
• Murnane PM, Strehlau R, Shiau S, Patel F, Mbete N, Hunt G, Abrams EJ, Coovadia A, Kuhn L. Switching to Efavirenz Versus Remaining on Ritonavir-boosted Lopinavir in Human Immunodeficiency Virus-infected Children Exposed to Nevirapine: Long-term Outcomes of a Randomized Trial. Clin Infect Dis. 2017 Aug 1;65(3):477-485. doi: 10.1093/cid/cix335.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: June 8, 2010
• First Submitted That Met QC Criteria: June 17, 2010
• First Posted (ESTIMATE): June 22, 2010

Study Record Updates

• Last Update Posted (ACTUAL): March 13, 2017
• Last Update Submitted That Met QC Criteria: January 31, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Ritonavir; Lopinavir; Stavudine; Efavirenz; Abacavir
• Other Study ID Numbers: AAAE1145; R01HD061255 (NIH)