HIV-1 chemoprophylaxis and archived drug resistance in infants

Summary

Principal Investigator: Deborah Persaud
Abstract: Nearly three million children worldwide have human immunodeficiency virus type 1 (HIV-1)/AIDS, and most live in sub-Saharan Africa where access to antiretroviral drugs is limited. Highly active antiretroviral therapy (HAART) reduces disease progression and mortality, but in low-income countries often the only HAART option is combination therapy with nevirapine (NVP). Single-dose NVP (SD-NVP) is also commonly used to prevent peripartum HIV-1 transmission, but it causes rapid selection of NVP-resistant (NVP-R) HIV-1 in up to 80% of subtype C infected women and infants. Within a year this chemoprophylaxis- induced NVP-R HIV-1 decays from the plasma and replicating cellular pools and is replaced with drug-sensitive wild-type HIV-1, providing a rationale for reusing NVP in HAART. We have shown in children that drug-resistant HIV-1 arising during non-suppressive antiretroviral therapy is archived in replication competent forms in resting CD4+T cells and is continuously activated to produce low level viremia even when viral loads are <50 copies/ml on HAART, precluding reuse of drugs from failed regimens. We will test the hypothesis that NVP reuse in subtype C infected infants with SD-NVP exposure causes selection of NVP-R variants and subsequent rebound viremia despite decay of NVP-R from plasma and even when virus replication had been controlled. In the context of two ongoing clinical trials using different approaches to reusing NVP to treat HIV-1 infected African infants (Neverest and PACTG P1060), we will use sensitive molecular and genotyping assays to analyze plasma and cellular samples to: 1. Quantify the extent of NVP-R HIV-1 cellular reservoirs in subtype C infected infants exposed to prophylactic SD-NVP. 2. Determine persistence of NVP-R HIV-1 variants in plasma of SD-NVP exposed infants whose first suppressive HAART regimen lacks an NNRTI, and emergence of lamivudine-resistance in these infants after re-exposure to NVP. 3. Characterize the kinetics and prevalence of NVP and lamivudine-resistant HIV-1 variants in subtype C infected infants during the first month of therapy with NVP-based HAART that includes lamivudine. Because so many women and infants live with HIV-1 infection worldwide, understanding the long-term effects on cellular reservoirs and treatment success caused by nevirapine resistance arising during chemoprophylaxis is critical for assessing prevention and treatment strategies for these vulnerable populations. Because so many women and infants live with HIV-1 infection worldwide, understanding the long-term effects on cellular reservoirs and treatment success caused by nevirapine resistance arising during chemoprophylaxis is critical for assessing prevention and treatment strategies for these vulnerable populations.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants
    Anitha Moorthy
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    PLoS ONE 4:e4096. 2009
  2. pmc Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age
    Deborah Persaud
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    AIDS 26:1483-90. 2012
  3. pmc Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission
    Deborah Persaud
    Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
    AIDS Res Hum Retroviruses 27:823-9. 2011
  4. 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
  5. pmc Analysis of the optimal cut-point for HIV-p24 antigen testing to diagnose HIV infection in HIV-exposed children from resource-constrained settings
    M Tamhane
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    J Clin Virol 50:338-41. 2011
  6. pmc Use of dried-blood-spot samples and in-house assays to identify antiretroviral drug resistance in HIV-infected children in resource-constrained settings
    Carrie Ziemniak
    Department of Pediatrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building, Baltimore, Maryland 21205, USA
    J Clin Microbiol 49:4077-82. 2011
  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

Scientific Experts

  • Louise Kuhn
  • Deborah Persaud
  • Anitha Moorthy
  • Carrie Ziemniak
  • Ya Hui Chen
  • M Tamhane
  • Andrea Ruff
  • Abubaker Bedri
  • Elaine J Abrams
  • Tammy Meyers
  • Yohannes Mengistu
  • N Segaren
  • Wei Yann Tsai
  • Ashraf Coovadia
  • G K Siberry
  • Y Simeon-Fadois
  • Paul Palumbo
  • Gayle Sherman
  • Y H Chen
  • C Shiu
  • Leila Khaki
  • C B Thompson
  • S Irivinti
  • Renate Strehlau
  • D De
  • B Gautney
  • L Jeannis
  • Susan H Eshleman
  • C Eustache
  • P Tamma
  • Birgitte B Simen
  • S Khamadi
  • Usha Balasubramaniam
  • Smita Kulkarni
  • Arvind V Bhore
  • Amita Gupta
  • Anju Kagal
  • Sandesh Patil
  • Renu Bharadwaj
  • Jayagowri Sastry
  • Robert Bollinger
  • Nikhil Gupte
  • Varadharajan Venkataramani
  • Nishi Suryavanshi
  • Vandana Kulkarni
  • Srikanth Tripathy
  • Ramesh Bhosale
  • Madhuri Thakar

Detail Information

Publications7

  1. pmc Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants
    Anitha Moorthy
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    PLoS ONE 4:e4096. 2009
    ....
  2. pmc Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age
    Deborah Persaud
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    AIDS 26:1483-90. 2012
    ..Identification of HIV infection in exposed infants facilitates early therapy, which may limit viral reservoirs that maintain HIV infection under HAART...
  3. pmc Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission
    Deborah Persaud
    Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
    AIDS Res Hum Retroviruses 27:823-9. 2011
    ....
  4. 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)...
  5. pmc Analysis of the optimal cut-point for HIV-p24 antigen testing to diagnose HIV infection in HIV-exposed children from resource-constrained settings
    M Tamhane
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    J Clin Virol 50:338-41. 2011
    ..The cut-point optical density (OD) selected for discriminating between positive and negative samples may need assessment due to regional differences in mother-to-child HIV-transmission rates...
  6. pmc Use of dried-blood-spot samples and in-house assays to identify antiretroviral drug resistance in HIV-infected children in resource-constrained settings
    Carrie Ziemniak
    Department of Pediatrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building, Baltimore, Maryland 21205, USA
    J Clin Microbiol 49:4077-82. 2011
    ..DBS genotyping using in-house assays provides an alternative for antiretroviral drug resistance testing in children in resource-constrained regions but may require region-specific optimization before widespread use...
  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...