Drug resistance in the HIV-1-infected paediatric population worldwide: a systematic review.

BACKGROUND: Drug resistance monitoring of the paediatric HIV-1-infected population is required to optimize treatment success and preserve future treatment options. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Systematic and periodic studies among infected children are crucial to design a more suitable first- or second-line therapy.

Trends in Drug Resistance Prevalence, HIV-1 Variants and Clinical Status in HIV-1-infected Pediatric Population in Madrid: 1993 to 2015 Analysis.

BACKGROUND: The expanded use of long-term antiretroviral treatments in infected children may exacerbate the problem of drug resistance mutations selection, which can compromise treatment efficiency. OBJECTIVE: We describe the temporal trends of HIV drug resistance mutations and the HIV-1 variants during 23 years (1993 to March 2016) in the Madrid cohort of HIV-infected children and adolescents. METHODS: We selected patients with at least one available HIV-1 pol sequence/genotypic resistance profile, establishing different groups according to the sampling year of first resistance data. We determined the prevalence of transmitted drug resistance mutations or acquired drug resistance mutations (DRM), the drug susceptibility among resistant viruses and HIV-1 variants characterized by phylogeny across time. RESULTS: A total of 245 pediatric patients were selected, being mainly female, Spanish native, perinatally infected and carrying HIV-1 subtype B. At first sampling, most pediatric patients were on antiretroviral therapy and heavily pretreated. During 1993 to 2016, transmitted drug resistance mutations was found in 13 (26%) of 50 naive children [non-nucleoside reverse transcriptase inhibitors (NNRTI), 14.6%; nucleoside reverse transcriptase inhibitors (NRTI), 10.4%; protease inhibitors, 8.7%]. DRM appeared in 139 (73.2%) of 190 pretreated patients (NRTI, 64.5%; NNRTI, 36%; protease inhibitors, 35.1%). DRM to NNRTI was higher in last 5 years. Non-B variants infected 14.5% of children and adolescents of the Madrid Cohort, being mainly intersubtype recombinants (76.5%), including complex unique recombinant strains. They caused 3.4% infections before 2000, rising to 85.7% during 2011 to 2016. CONCLUSIONS: Periodic surveillance resistance and molecular epidemiology studies in long-term pretreated HIV-infected pediatric populations are required to optimize treatment regimens. Results will permit a better understanding of long-time dynamics of viral resistance and HIV-1 variants in Spain.

Impact of Clinical Parameters in the Intrahost Evolution of HIV-1 Subtype B in Pediatric Patients: A Machine Learning Approach.

Determining the factors modulating the genetic diversity of HIV-1 populations is essential to understand viral evolution. This study analyzes the relative importance of clinical factors in the intrahost HIV-1 subtype B (HIV-1B) evolution and in the fixation of drug resistance mutations (DRM) during longitudinal pediatric HIV-1 infection. We recovered 162 partial HIV-1B pol sequences (from 3 to 24 per patient) from 24 perinatally infected patients from the Madrid Cohort of HIV-1 infected children and adolescents in a time interval ranging from 2.2 to 20.3 years. We applied machine learning classification methods to analyze the relative importance of 28 clinical/epidemiological/virological factors in the HIV-1B evolution to predict HIV-1B genetic diversity (d), nonsynonymous and synonymous mutations (dN, dS) and DRM presence. Most of the 24 HIV-1B infected pediatric patients were Spanish (91.7%), diagnosed before 2000 (83.3%), and all were antiretroviral therapy experienced. They had from 0.3 to 18.8 years of HIV-1 exposure at sampling time. Most sequences presented DRM. The best-predictor variables for HIV-1B evolutionary parameters were the age of HIV-1 diagnosis for d, the age at first antiretroviral treatment for dN and the year of HIV-1 diagnosis for ds. The year of infection (birth year) and year of sampling seemed to be relevant for fixation of both DRM at large and, considering drug families, to protease inhibitors (PI). This study identifies, for the first time using machine learning, the factors affecting more HIV-1B pol evolution and those affecting DRM fixation in HIV-1B infected pediatric patients.

Impact of lopinavir-ritonavir exposure in HIV-1 infected children and adolescents in Madrid, Spain during 2000-2014.

BACKGROUND: The most-used protease-inhibitor in children is Lopinavir-ritonavir (LPV/r), which provides durable suppression of viral load and increases CD4+T-counts. This study describes the virological outcome of the HIV-1-infected paediatric population exposed to LPV/r during 15 years in Spain. METHODOLOGY: Patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different line therapy during 2000-2014 were selected. The baseline epidemiological-clinical features, viral suppression, changes in CD4+T-CD8+T cell counts and drug susceptibility were recorded before and during LPV/r exposure. Drug resistance mutations (DRM) were identified in viruses from samples collected until 2011. We predicted drug susceptibility to 19 antiretrovirals among those carrying DRM using the Stanford's HIVdb Algorithm. RESULTS: A total of 199 (37.3%) of the 534 patients from the cohort were exposed to LPV/r during 2000-2014 in first (group 1), second (group 2) or more line-therapies (group 3). Patients were mainly Spaniards (81.9%), perinatally infected (96.5%) with subtype-B (65.3%) and HIV-diagnosed before year 2000 (67.8%). The mean age at first LPV/r exposure was 9.7 years. After protease-inhibitor exposure, viral suppression was higher in groups 1 and 2 than in group 3. Viral suppression occurred in 87.5%, 68.6% and 64.8% patients from groups 1, 2 and 3, respectively. Among the 64 patients with available resistance data during LPV/r treatment, 27(42.3%) carried DRM to protease-inhibitor, 28 (58.3%) to reverse-transcriptase-inhibitors and 21 (43.7%) to non-reverse-transcriptase-inhibitors. Darunavir/ritonavir, atazanavir-ritonavir and tipranavir/ritonavir presented the highest susceptibility and nelfinavir the lowest. CONCLUSIONS: A better lymphocyte recovering occurred when protease-inhibitor was taken as part of a first-line regimen and a higher number of patients reached viral suppression. The least compromised antiretrovirals for rescue antiretroviral regimens, according to DRM in the LPV/r-exposed-paediatric cohort, were mainly the new protease inhibitors.

Genetic Variability of HIV-1 for Drug Resistance Assay Development.

A hybridization-based point-of-care (POC) assay for HIV-1 drug resistance would be useful in low- and middle-income countries (LMICs) where resistance testing is not routinely available. The major obstacle in developing such an assay is the extreme genetic variability of HIV-1. We analyzed 27,203 reverse transcriptase (RT) sequences from the Stanford HIV Drug Resistance Database originating from six LMIC regions. We characterized the variability in a 27-nucleotide window surrounding six clinically important drug resistance mutations (DRMs) at positions 65, 103, 106, 181, 184, and 190. The number of distinct codons at each DRM position ranged from four at position 184 to 11 at position 190. Depending on the mutation, between 11 and 15 of the 24 flanking nucleotide positions were variable. Nonetheless, most flanking sequences differed from a core set of 10 flanking sequences by just one or two nucleotides. Flanking sequence variability was also lower in each LMIC region compared with overall variability in all regions. We also describe an online program that we developed to perform similar analyses for mutations at any position in RT, protease, or integrase.