New pediatric treatment guidelines recommend starting all HIV-infected infants on antiretroviral treatment regardless of their immunologic or clinical profile. Treatment initiation with Lopinavir/ritonavir (LPV/r) is recommended because of concerns about resistance to non-nucleoside reverse transcriptase-inhibitors (NNRTI) following use of nevirapine (NVP) in prevention of mother-to-child HIV transmission (PMTCT). Guidelines offer no specific advice about whether LPV/r-based therapy (usually recommended as a second- line regimen but here recommended as first-line) should be continued life-long for all HIV-infected children starting therapy at a young age. There are several risks associated with indefinite, long-term use of LPV/r- based therapy, including its poor palatability (raising adherence challenges in toddlers and older children), interactions with rifampicin used for co-treatment for tuberculosis, the lack of any suitable second-line regimens, and uncertainty about its long-term metabolic toxicities when used in developing children. We propose an unblinded randomized clinical trial to evaluate a simplification, protease-inhibitor (PI)-sparing treatment strategy among NVP-exposed HIV-infected children treated initially with LPV/r. The primary objective is to test, among children suppressed on LPV/r-based therapy, whether the durability of viral suppression is equivalent when children are switched to efavirenz (EFV)-based therapy. EFV-based therapy is an attractive alternative as it is already recommended for treatment of children >3 years, is widely used, palatable with once daily pediatric formulations, a low, well-described toxicity profile, and is recommended for co-treatment with rifampicin. We propose to recruit 300 HIV-infected children aged 3 to 5 years at a clinical site in Johannesburg, South Africa. Inclusion criteria will include exposure to NVP as part of PMTCT, initiation of LPV/r-based therapy in the first 36 months of life and a viral load <50 copies/ml. These children will be randomized to either substitute EFV for LPV/r or to continue on their LPV/r-based regimen. Children will be followed with regular viral load and other clinical tests for 48 weeks after randomization. Children in the experimental arm who have breakthrough viremia on the EFV-based regimen will promptly reinitiate the LPV/r regimen. 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 effects 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.

Public Health Relevance

We propose a randomized clinical trial to evaluate, among nevirapine-exposed, HIV-infected children initiated and suppressed on lopinavir/ritonavir-based antiretroviral therapy, whether switching to efavirenz-based therapy at the age of 3 to 5 years leads to comparable maintenance of virologic suppression as continuation of lopinavir/ritonavir-based therapy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD061255-01A2S1
Application #
8124226
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Shirazi, Yasaman
Project Start
2010-04-09
Project End
2012-02-28
Budget Start
2010-09-01
Budget End
2012-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$444,690
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Shiau, Stephanie; Strehlau, Renate; Shen, Jing et al. (2018) Biomarkers of Aging in HIV-Infected Children on Suppressive Antiretroviral Therapy. J Acquir Immune Defic Syndr 78:549-556
Shiau, Stephanie; Strehlau, Renate; Technau, Karl-Günter et al. (2017) Early age at start of antiretroviral therapy associated with better virologic control after initial suppression in HIV-infected infants. AIDS 31:355-364
Abrams, Elaine J; Woldesenbet, Selamawit; Soares Silva, Juliana et al. (2017) Despite Access to Antiretrovirals for Prevention and Treatment, High Rates of Mortality Persist Among HIV-infected Infants and Young Children. Pediatr Infect Dis J 36:595-601
Murnane, Pamela M; Strehlau, Renate; Shiau, Stephanie et al. (2017) 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 65:477-485
Pinillos, Francoise; Dandara, Collet; Swart, Marelize et al. (2016) Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation. BMC Infect Dis 16:56
Coovadia, Ashraf; Abrams, Elaine J; Strehlau, Renate et al. (2015) Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial. JAMA 314:1808-17
Kuhn, Louise; Schramm, Diana B; Shiau, Stephanie et al. (2015) Young age at start of antiretroviral therapy and negative HIV antibody results in HIV-infected children when suppressed. AIDS 29:1053-60
Salimo, Anna T; Ledwaba, Johanna; Coovadia, Ashraf et al. (2015) The use of dried blood spot specimens for HIV-1 drug resistance genotyping in young children initiating antiretroviral therapy. J Virol Methods 223:30-2
Shiau, Stephanie; Kuhn, Louise; Strehlau, Renate et al. (2014) Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment. BMC Pediatr 14:39
Technau, Karl-Günter; Kalk, Emma; Coovadia, Ashraf et al. (2014) Timing of maternal HIV testing and uptake of prevention of mother-to-child transmission interventions among women and their infected infants in Johannesburg, South Africa. J Acquir Immune Defic Syndr 65:e170-8

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