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

• Maintenance of viral suppression [ Time Frame: through 24 and 48 weeks post randomization ] [ Designated as safety issue: No ]
  HIV RNA quantity < 50 copies/ml
• Confirmed viral rebound [ Time Frame: through 24 weeks and 48 weeks post randomization ] [ Designated as safety issue: Yes ]
  HIV RNA > 1000 copies/ml twice

• Magnitude of CD4 response, hospital admissions, new stage II or greater clinical conditions [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]
• ALT elevations, HDL, LDL, CRP, fat distribution [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]

  Drug related toxicities, Including fat distribution and metabolic parameters

  Including when co-treated for tuberculosis

• child Adherence to medication [ Time Frame: through 48 weeks ] [ Designated as safety issue: No ]
  assessed by pharmacy reconciliation of medications brought back

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.

• HIV/AIDS
• HIV Infections

• Drug: Efavirenz
  Children are assigned to begin a EFV-based antiretroviral based regimen. Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
  Other Names:

  • Lopinavir/ritonavir (LPV/r
  • D4T
  • Abacavir (ABC)
• Drug: Lopinavir/ritonavir (LPV/r)
  Children are assigned to stay on their current LPV/r-based antiretroviral regimen.Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
  Other Names:

  • Efavirenz (EFV)
  • D4T
  • Abacavir (ABC)
• Drug: D4T
  Children are assigned to stay on their current antiretroviral regimen which includes D4T. Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
  Other Names:

  • Lopinavir/ritonavir (LPV/r)
  • Efavirenz (EFV)
  • Abacavir (ABC)
• Drug: Abacavir (ABC)
  Children stop taking D4T and switch to an abacavir. Dosing of medication will follow standard guidelines based on body surface area calculations or on body weight depending on drug, and will be in accordance with the South African Treatment guidelines.
  Other Names:

  • Lopinavir/ritonavir (LPV/r)
  • Efavirenz (EFV)
  • D4T

• Active Comparator: Group 1: Lopinavir/ritonavir (LPV/r)
  Participants are assigned to remain on their current LPV/r-based antiretroviral regimen
  Intervention: Drug: Lopinavir/ritonavir (LPV/r)
• Experimental: Group 2: Efavirenz (EFV)
  Participants are assigned to switch to an EFV-based antiretroviral regimen
  Intervention: Drug: Efavirenz
• Active Comparator: Group D: D4T
  Children are assigned to remain on their current antiretroviral regimen, which includes D4T
  Intervention: Drug: D4T
• Experimental: Group A: Abacavir (ABC)
  Children stop taking D4T and switch to ABC.
  Intervention: Drug: Abacavir (ABC)

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.

• University of Witwatersrand, South Africa
• National Institutes of Health (NIH)