Potent and Sustained Antiviral Response of Raltegravir-based Highly Active Antiretroviral Therapy in HIV Type 1-infected Children and Adolescents
ABSTRACT There are pediatric patients receiving many highly active antiretroviral therapy (HAART) regimens entailing drug resistance mutations that complicate HAART effective therapies.
This was a multicenter retrospective study of 19 multidrug-resistant children and adolescents enrolled from July 2007 to October 2009. Patients were nonresponders because no reduction in HIV type 1 (HIV-1) RNA to undetectable levels was observed during their previous antiretroviral treatment history. The long-term effectiveness of raltegravir (RAL)-based salvage therapy was assessed through a longitudinal analysis of immunologic, virologic, and clinical status of the patients.
Median age was 16.0 (15.0-18.0) years. At baseline, median HIV-1 RNA was 10,000 (4.0 log10 copies/mL) (interquartile range [IQR]: 4300-83,000), and median CD4T-cell count was 329 (18.2% cells/μL) (IQR: 175-452). The backbone regimen included at least 1 fully active drug in 17/19 (89%) patients. Median follow-up with HAART including RAL was 80.1 weeks (IQR: 49.4-96.4): 16/19 (84%) exposed for >120 weeks and 6/19 (32%) >100 weeks. After RAL-based therapy, 4/19 (21%) patients achieved HIV-1 RNA <400 copies and 13/17 (68%) reached HIV-1 RNA <50 copies: 6 (32%) within the first month and 7 (37%) within the first 4 months. CD4+ T-cell recovery (70% to 90% of the baseline values) was observed in 17/19 (89%) patients. No deaths, AIDS-defining illnesses, or symptoms of severe intolerance were recorded. Only 2 patients experienced mild-moderate short-term skin rash. Two (11%) patients had sustained and optimum adherence to HAART. No patients showed resistance mutations to RAL after follow-up.
We observed a sustained antiviral response and improved immunologic indices in multidrug-resistant pediatric patients, most of whom had received RAL as part of salvage regimens with at least 1 fully active drugs.
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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.Journal of Antimicrobial Chemotherapy 04/2014; 69(8). DOI:10.1093/jac/dku104 · 5.44 Impact Factor
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ABSTRACT: Raltegravir was the first HIV integrase strand-transfer inhibitor to be approved by the US FDA, in October 2007, for the treatment of HIV-1 infection in combination with other antiretroviral agents. Raltegravir can be used in treatment-naïve and -experienced patients, as well as for the treatment of multidrug-resistant infection. Raltegravir exists in two formulations: a film-coated tablet administered orally at 400 mg twice daily, and a chewable tablet administered orally at 300 mg twice daily. In 2011, raltegravir was also approved for the treatment of children and adolescents, ages 2-18 years. For adolescents (ages 12-18 years), the recommended dose is 400 mg twice daily (film-coated tablet). If children (ages 6-12 years) weigh at least 25 kg, the film-coated tablet is recommended at 400 mg twice daily. Otherwise, patients receive the chewable tablet according to weight-based dosing at approximately 6 mg/kg/dose. Studies are ongoing for children ages 4 weeks to 2 years, and preliminary efficacy and safety data are promising. This article reviews current studies on the efficacy, safety, and pharmacokinetics of raltegravir in the pediatric population and the challenges of treating HIV in children and adolescents.Adolescent Health, Medicine and Therapeutics 01/2013; 4:79-87. DOI:10.2147/AHMT.S29462
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ABSTRACT: Abstract HIV-1 entry begins with viral envelope glycoprotein gp120 interacting with host-cell CD4 and an entry coreceptor (mainly chemokine receptors CCR5 or CXCR4). Inhibitors of particular coreceptors are being developed in order to exploit this step of cellular infection. However, effectiveness of these drugs requires matching of the administered therapeutic to coreceptor use by the viral variants infecting each patient. Patient viruses may use only CCR5 (R5), only CXCR4 (X4) or both (D/M). Most patients in early disease have R5 variants, with the presence of X4 variants increasing as disease progresses; the infecting subtype also affects the prevalence of X4 variants. Phenotypic, genotypic and clinical trial tests are in use to determine coreceptor utilization by HIV-1 variants, termed tropism, and to predict the response to entry inhibitors. Maraviroc is the only approved entry-coreceptor inhibitor and inhibits CCR5-gp120 interaction. Clinical trials of maraviroc in specific patient subgroups are elucidating the drug's role in contemporary clinical practice. Treatment failure to this and other CCR5 inhibitors has been shown to result from either outgrowth of X4 variants or through resistance mutations leading to R5 variants that are able to enter cells using drug-bound CCR5; thus, new entry inhibitors seek to circumvent this mechanism of resistance.Critical Reviews in Microbiology 03/2014; DOI:10.3109/1040841X.2013.867829 · 6.09 Impact Factor