HIV-1 drug resistance genotypic profiles in children with undetectable plasma viremia during antiretroviral therapy

Laboratório de Virologia, Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, São Paulo, Brazil.
The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases (Impact Factor: 1.3). 02/2011; 15(1):60-5. DOI: 10.1016/S1413-8670(11)70141-6
Source: PubMed


Treatment of HIV-1 infection with highly active antiretroviral therapy has led to sustained viral suppression in the plasma in a large number of children. However, studies have suggested that the integrated provirus in resting CD4+ T lymphocytes could be a source of reactivatable virus and maintain drug-resistant virus. We evaluated the resistance-related mutations in children receiving antiretroviral therapy with prolonged viral suppression. Thirty-two peripheral blood mononuclear cell samples from 16 children with viral loads that had been below detection limits for at least 12 months were obtained at two different time points and the DNAs sequenced. The median CD4 cell count was 1,016 cells/mm³ (347-2,588) and 938 cells/mm³ (440-3,038) at the first and second time points, respectively. The median follow-up time was 15 months (9-27). Six (37.5%) and seven (43.75%) of the 16 patients showed at least one NRTI-associated mutation in the first and second samples, respectively. Two out of 16 (12.5%) had an NNRTI-associated mutation at the first time point and three out of 16 (18.75%) at the second. In addition, 14 out of 16 (87.5%) had at least one PI-associated mutation at both time points. Despite plasma HIV-1 RNA suppression for at least 12 months, resistance-related mutations from previous antiretroviral failures could still be detected in archival virus. Furthermore, viral evolution occurred at the reverse transcriptase region in spite of viral suppression to levels below 400 copies/mL. Persistence of archival resistant virus may be relevant when considering future treatment options.

Download full-text


Available from: Ricardo Diaz, Jun 19, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review: Current antiretroviral treatment regimens represent significant improvements in the management of HIV-1 infection; however, these regimens have not achieved a functional or sterilizing cure. One barrier to achieving a cure may be suboptimal antiretroviral concentrations in sanctuary sites throughout the body, including the central nervous system, gut-associated lymphoid tissue, lymph nodes, and tissue macrophages. This review will focus on the problems associated with achieving effective concentrations in these restricted sanctuary sites, and potential strategies to overcome these barriers. Recent findings: Sufficient data exist to conclude that antiretroviral drug distribution is not uniform throughout the body. Low tissue/reservoir concentrations may be associated with viral replication. Multiple means to increase drug concentrations in sanctuary sites are being investigated, including modification of currently utilized drugs, blockade of transporters and enzymes that affect drug metabolism and pharmacokinetics, and local drug administration. Accumulating data suggest these methods increase antiretroviral concentrations in reservoirs of viral replication. No method has yet resulted in the complete clearance of HIV. Summary: New strategies for increasing antiretroviral concentrations in predominant sites of viral replication may provide more effective means for elimination of viral sanctuaries. Additional research is necessary to optimize antiretroviral tissue distribution in order to inhibit virus replication fully, and avoid resistance and replenishment of viral reservoirs that may persist in the face of antiretroviral therapy.
    No preview · Article · Feb 2013 · Current opinion in HIV and AIDS
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug resistance monitoring of the paediatric HIV-1-infected population is required to optimize treatment success and preserve future treatment options. To explore the current knowledge of HIV drug resistance (HIVDR) in naive and pretreated HIV-1-infected paediatric populations across diverse settings and sampling time periods. PubMed database screened until May 2013. We selected publications including data on transmitted (TDR) and acquired drug resistance mutation (DRM) rates and/or pol sequences for HIVDR testing in paediatric patients. We recorded the children's country, age, study period, number of children with pol sequences, presence or absence of antiretroviral treatment (ART) at sampling time, viral region sequenced, HIVDR rate to the three main drug classes (single, double or triple), the considered resistance mutation list and performed assay, specimen type, HIV-1 variants and subtyping methodology when available. Forty-one selected studies showed HIVDR data from 2538 paediatric HIV-1-infected patients (558 naive and 1980 pretreated) from 30 countries in Africa (11), Asia (6), America (10) and Europe (3). Both TDR and DRM prevalence were reported in 9 studies, only TDR in 6 and only DRM in 26. HIVDR prevalence varied across countries and periods. Most studies used in-house resistance assays using plasma or infected cells. HIV-1 non-B variants were prevalent in 18 paediatric cohorts of the 24 countries with reported subtypes. Only five countries (Uganda, Spain, the UK, Brazil and Thailand) presented resistance data in ≥200 patients. Systematic and periodic studies among infected children are crucial to design a more suitable first- or second-line therapy.
    Preview · Article · Apr 2014 · Journal of Antimicrobial Chemotherapy