Clinical Relevance of Transient Nevirapine Resistance

Summary

Principal Investigator: Louise Kuhn
Abstract: [unreadable] DESCRIPTION (provided by applicant): Nevirapine (NVP) is a simple, effective and relatively safe antiretroviral drug now widely used in low resource settings around the world to prevent mother-to-child transmission of HIV. NVP is also a useful drug to use as part of treatment regimens. Concern has been raised that exposure to this drug for prevention may compromise its use in treatment. The concern has arisen because viral mutations which confer resistance to NVP appear to be common among HIV-infected women and children after exposure to even single dose NVP. A study is proposed to test whether or not exposure to NVP for prevention of mother-to-child HIV transmission, and the resulting NVP resistance mutations associated with its use, will adversely influence response to a subsequent treatment regimen which includes NVP. The study will recruit HIV-infected women and their children, NVP-exposed and unexposed, in Johannesburg, South Africa, who meet criteria for starting antiretroviral treatment and will start them on a treatment regimen which includes NVP. HIVinfected women and children exposed to NVP prophylaxis will be compared to similar unexposed women and children. Further, among those exposed to NVP prophylaxis, those with NVP resistance mutations at 6 weeks post-NVP exposure will be compared to those exposed to NVP but who do not have detectable mutations. The primary study outcome is treatment failure defined on the basis of virologic outcomes at 6 months after starting treatment. Secondary objectives of the study are to characterize the nature of viral resistance mutations associated with NVP prophylaxis (including the specific mutations present, their occurrence in plasma and/or PBMCs, their frequency if the threshold of detection is lowered to detect mutations present at low frequencies in the viral population) and to investigate whether these characteristics of viral resistance explain treatment failure. The study will generate empirical data essential for formulation of evidence-based treatment policies for the hundreds of thousands of HIV-infected women and children living in low resource settings who are likely to have had prior exposure to NVP. [unreadable] [unreadable]
Funding Period: 2004-09-01 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Decay of K103N mutants in cellular DNA and plasma RNA after single-dose nevirapine to reduce mother-to-child HIV transmission
    Shayne Loubser
    AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
    AIDS 20:995-1002. 2006
  2. pmc Impact of antiretroviral drugs in pregnant women and their children in Africa: HIV resistance and treatment outcomes
    Roger Paredes
    IrsiCaixa AIDS Research Institute, Badalona, Catalonia, Spain
    J Infect Dis 207:S93-100. 2013
  3. pmc Initiation of antiretroviral therapy before 6 months of age is associated with faster growth recovery in South African children perinatally infected with human immunodeficiency virus
    Stephanie Shiau
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
    J Pediatr 162:1138-45, 1145.e1-2. 2013
  4. ncbi Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy
    Stephen Arpadi
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, Columbia University Medical Center, 630 W 168th Street, New York, NY 10032, USA
    Arch Dis Child 98:258-64. 2013
  5. pmc Lipid profiles in young HIV-infected children initiating and changing antiretroviral therapy
    Renate Strehlau
    Empilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
    J Acquir Immune Defic Syndr 60:369-76. 2012
  6. pmc Adherence and viral suppression among infants and young children initiating protease inhibitor-based antiretroviral therapy
    Chloe A Teasdale
    ICAP Columbia University, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
    Pediatr Infect Dis J 32:489-94. 2013
  7. ncbi Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial
    Louise Kuhn
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Columbia University, New York, NY 10032, USA
    Lancet Infect Dis 12:521-30. 2012
  8. ncbi HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine
    Gillian M Hunt
    AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
    AIDS 25:1461-9. 2011
  9. pmc Antiretroviral therapy responses among children attending a large public clinic in Soweto, South Africa
    Tammy M Meyers
    Department of Paediatrics, Harriet Shezi Children s Clinic, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
    Pediatr Infect Dis J 30:974-9. 2011
  10. pmc Adherence and virologic suppression during the first 24 weeks on antiretroviral therapy among women in Johannesburg, South Africa - a prospective cohort study
    Ziad El-Khatib
    Nordic School of Public Health NHV, Gothenburg, Sweden
    BMC Public Health 11:88. 2011

Detail Information

Publications18

  1. pmc Decay of K103N mutants in cellular DNA and plasma RNA after single-dose nevirapine to reduce mother-to-child HIV transmission
    Shayne Loubser
    AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
    AIDS 20:995-1002. 2006
    ..As this may influence subsequent treatment responses, a better understanding of the dynamics of decay and persistence of this variant is needed...
  2. pmc Impact of antiretroviral drugs in pregnant women and their children in Africa: HIV resistance and treatment outcomes
    Roger Paredes
    IrsiCaixa AIDS Research Institute, Badalona, Catalonia, Spain
    J Infect Dis 207:S93-100. 2013
    ....
  3. pmc Initiation of antiretroviral therapy before 6 months of age is associated with faster growth recovery in South African children perinatally infected with human immunodeficiency virus
    Stephanie Shiau
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
    J Pediatr 162:1138-45, 1145.e1-2. 2013
    ..To describe the effects of age at antiretroviral therapy (ART) initiation on growth outcomes among children infected with HIV followed for 48 months after treatment initiation...
  4. ncbi Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy
    Stephen Arpadi
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, Columbia University Medical Center, 630 W 168th Street, New York, NY 10032, USA
    Arch Dis Child 98:258-64. 2013
    ..We compared metabolic profiles and regional fat of children on ritonavir-boosted lopinavir (lopinavir/ritonavir), lamivudine and stavudine to those switched to nevirapine, lamivudine and stavudine...
  5. pmc Lipid profiles in young HIV-infected children initiating and changing antiretroviral therapy
    Renate Strehlau
    Empilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
    J Acquir Immune Defic Syndr 60:369-76. 2012
    ..Here we examined lipid profile changes in a cohort of young children before and after suppression on an initial ritonavir-boosted lopinavir (LPV/r)-based regimen and after switch to a nevirapine (NVP)-based regimen...
  6. pmc Adherence and viral suppression among infants and young children initiating protease inhibitor-based antiretroviral therapy
    Chloe A Teasdale
    ICAP Columbia University, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
    Pediatr Infect Dis J 32:489-94. 2013
    ....
  7. ncbi Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial
    Louise Kuhn
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Columbia University, New York, NY 10032, USA
    Lancet Infect Dis 12:521-30. 2012
    ..We present the long-term outcomes of switching nevirapine-exposed children to nevirapine-based treatment after effective suppression of virus replication with a protease-inhibitor-based regimen...
  8. ncbi HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine
    Gillian M Hunt
    AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
    AIDS 25:1461-9. 2011
    ..To describe the prevalence of HIV-1 drug resistance mutations at the time of treatment initiation in a large cohort of HIV-infected children previously exposed to single-dose nevirapine (sdNVP) for prevention of transmission...
  9. pmc Antiretroviral therapy responses among children attending a large public clinic in Soweto, South Africa
    Tammy M Meyers
    Department of Paediatrics, Harriet Shezi Children s Clinic, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
    Pediatr Infect Dis J 30:974-9. 2011
    ..The aim of this study was to determine treatment responses of children in a routine setting where first-line therapy with lopinavir/ritonavir is routinely included for young children...
  10. pmc Adherence and virologic suppression during the first 24 weeks on antiretroviral therapy among women in Johannesburg, South Africa - a prospective cohort study
    Ziad El-Khatib
    Nordic School of Public Health NHV, Gothenburg, Sweden
    BMC Public Health 11:88. 2011
    ..We assessed risk factors for incomplete adherence among a cohort of HIV-infected women initiating ART and examined associations between adherence and virologic response to ART...
  11. pmc Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children
    Anitha Moorthy
    Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    Clin Infect Dis 52:514-21. 2011
    ..Nevirapine resistance after failed prophylaxis to prevent mother-to-child human immunodeficiency virus (HIV) transmission can compromise subsequent nevirapine-based highly active antiretroviral therapy (HAART)...
  12. pmc Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment
    Cordula Frohoff
    Gertrude H Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America
    PLoS ONE 6:e17273. 2011
    ..We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir...
  13. pmc Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa
    Barbara S Taylor
    Division of Infectious Diseases, Department of Medicine, University of Texas Health Sciences Center at San Antonio, USA
    AIDS Res Hum Retroviruses 27:945-56. 2011
    ..Only children who received RTV-based ART developed major PI-related resistance mutations, and use of this regimen should be avoided...
  14. pmc Initial response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age in South Africa: effect of cotreatment for tuberculosis
    Cordula Reitz
    Gertrude H Sergievsky Center and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, New York 10032, USA
    J Infect Dis 201:1121-31. 2010
    ..We investigated factors associated with viral suppression and mortality among young children initiating ART...
  15. ncbi Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial
    Ashraf Coovadia
    Empilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa
    JAMA 304:1082-90. 2010
    ..However, there are limitations of continuing PI-based therapy indefinitely and reuse of nevirapine has many advantages...
  16. pmc Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy
    Kelly Smith
    Columbia University College of Physicians and Surgeons, New York, New York, USA
    AIDS 23:1097-107. 2009
    ..To determine the incidence, clinical manifestations and risk factors for immune reconstitution inflammatory syndrome (IRIS) in young children initiating highly active antiretroviral therapy (HAART)...
  17. pmc Persistent minority K103N mutations among women exposed to single-dose nevirapine and virologic response to nonnucleoside reverse-transcriptase inhibitor-based therapy
    Ashraf Coovadia
    Empilweni Clinic, Coronation Women and Children Hospital, Johannesburg, South Africa
    Clin Infect Dis 48:462-72. 2009
    ....
  18. pmc Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment
    Stephanie Shiau
    Gertrude H, Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY USA
    BMC Pediatr 14:39. 2014
    ..The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART...