High Drug Resistance Prevalence among Vertically HIV-Infected Patients Transferred from Pediatric Care to Adult Units in Spain

Mulder, Miguel de; Yebra, Gonzalo; Navas, Adriana; José, María Isabel de; Gurbindo, María Dolores; González-Tomé, María Isabel; Mellado, María José; Saavedra-Lozano, Jesús; Muñoz‐Fernández, María Ángeles; Ory, Santiago Jiménez de; Ramos, José Tomás; Holguín, África

doi:10.1371/journal.pone.0052155

Cited by 35 publications

(39 citation statements)

References 38 publications

(54 reference statements)

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“…However, since none of them presented DRM to RT inhibitors, the high VL observed in the last available determination in three patients with known viremia would suggest bad adherence to treatment. The high rate of DRM to all drug classes among the 64 patients with available resistance data during LPV/r treatment is in agreement with the long history of therapy, frequent regimen switches and drug experience, and high off-labels ARV exposure, as previously reported [24, 28,37,38]. Some limitations to the study are the relatively late initiation of LPV/r in this cohort (9.5 years), the high rate of patients including LPV/r as at least third line treatment (with severe failure background), the high evolution of ARV options in children and adolescents during the study period and the late formal approval of LPV/r use in children.…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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BackgroundThe 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.MethodologyPatients 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.ResultsA 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.ConclusionsA 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.

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Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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“…This will always require expert virologist input. While virological failure with triple class exposure was reported in 12% of children in Europe 186, rates of triple class resistance are variable, ranging from 12 to 32% and increasing with age 187, 188. Construction of effective third‐line and subsequent regimens, ideally with at least two and preferably three fully active agents, requires expert advice.…”

Section: When To Switch Resistance Testing and Second And Subsequentmentioning

confidence: 99%

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

et al. 2015

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The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV‐1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short‐term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long‐term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first‐ and second‐line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART ‘pipeline’ of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

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“…Partial sequences of the pol gene from pediatric patients are described in [34], and sequences from adult patients were collected from different sources [33–35]. Sequences encompassed 334 amino acids: the 297 amino acids of the viral protease ( PR ), and a fragment coding for the first 37 amino acids of the reverse transcriptase ( RT ) (1,002 nucleotides, positions 2,255–3,256 of HXB2 subtype B reference strain, GenBank accession number K03455).…”

Section: Methodsmentioning

confidence: 99%

“…First, it includes patients with detailed follow up information of infection [30–32] and ART resistance [33–36]. This means that data on the above-mentioned clinical parameters, as well as virus sequences of the pol gene and frequency of drug resistance mutations, are available for a large number of individuals [34–36]. Second, the pediatric cohort includes patients of all ages, from new-borns to 21 years-old patients, many of which were infected perinatally [33].…”

Section: Introductionmentioning

confidence: 99%

Clinical Determinants of HIV-1B Between-Host Evolution and their Association with Drug Resistance in Pediatric Patients

et al. 2016

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Understanding the factors that modulate the evolution of virus populations is essential to design efficient control strategies. Mathematical models predict that factors affecting viral within-host evolution may also determine that at the between-host level. Although HIV-1 within-host evolution has been associated with clinical factors used to monitor AIDS progression, such as patient age, CD4 cells count, viral load, and antiretroviral experience, little is known about the role of these clinical factors in determining between-host HIV-1 evolution. Moreover, whether the relative importance of such factors in HIV-1 evolution vary in adult and children patients, in which the course of infection is different, has seldom been analysed. To address these questions, HIV-1 subtype B (HIV-1B) pol sequences of 163 infected children and 450 adults of Madrid, Spain, were used to estimate genetic diversity, rates of synonymous and non-synonymous mutations, selection pressures and frequency of drug-resistance mutations (DRMs). The role and relative importance of patient age, %CD4, CD4/mm3, viral load, and antiretroviral experience in HIV-1B evolution was analysed. In the pediatric HIV-1B population, three clinical factors were primary predictors of virus evolution: Higher HIV-1B genetic diversity was observed with increasing children age, decreasing CD4/mm3 and upon antiretroviral experience. This was mostly due to higher rates of non-synonymous mutations, which were associated with higher frequency of DRMs. Using this data, we have also constructed a simple multivariate model explaining between 55% and 66% of the variance in HIV-1B evolutionary parameters in pediatric populations. On the other hand, the analysed clinical factors had little effect in adult-infecting HIV-1B evolution. These findings highlight the different evolutionary dynamics of HIV-1B in children and adults, and contribute to understand the factors shaping HIV-1B evolution and the appearance of drug-resistance mutation in pediatric patients.

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High Drug Resistance Prevalence among Vertically HIV-Infected Patients Transferred from Pediatric Care to Adult Units in Spain

Cited by 35 publications

References 38 publications

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

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

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

Clinical Determinants of HIV-1B Between-Host Evolution and their Association with Drug Resistance in Pediatric Patients

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