Análisis de la variabilidad genética y de resistencias a antirretrovirales en la cohorte de niños y adolescentes infectados por VHI-1 de la Comunidad de Madrid

Abstract

A total of 561 patients were registered from the beginning of the epidemic until December 2015, in the Madrid Cohort of HIV-infected children and adolescents ascribed to the National Pediatric Cohort with HIV (CoRISpe). Two hundred and eighty-nine of them where under current clinical follow-up in pediatric (43.9%) or adult units (56.1%). The Madrid Cohort includes almost all HIV-1-infected children and adolescents under clinical follow-up in 9 public hospitals in Madrid, and represents 57.3% of the infected pediatric population in Spain to date. Despite having a good clinical and immunological situation at sampling time, nearly all had a history of HIV‐related symptoms, were heavily pretreated and had a long history of treatment combinations. We observed that the fixation of drug resistance mutation (DRM) is a major obstacle for an effective treatment. In 2011, twenty-four patients (9%) were infected by viruses harboring resistance to the main three drug families (TC-DRM) (protease inhibitor (PI), nucleoside retrotranscripatase inhibitors (NRTI) and non-NRTI (NNRTI)). This rose to 24.4% among those 197 patients with resistance data. Despite the presence of HIV-1 TC-DRM in our pediatric Cohort, some drugs maintained their susceptibility, mainly the new PI (tipranavir and darunavir (DRV)) and NNRTI (etravirine and rilpivirine). Additionally, we summarize data from the 199 patients exposed to lopinavir-ritonavir (LPV/r) as first or rescue therapy during 2000 to 2014 with data recorded before and during LPV/r treatment. We also present data from DRM and predicted susceptibility to PI among virus carrying DRM. Despite the selection of DRM, good clinical status at the last clinic visit during LPV/r treatment was observed in these patients. DRV/ritonavir presented the highest susceptibility and NFV the lowest. Considering the period 1993 to March 2016, we recorded the temporal trends of drug resistance and observed that more than half of the non-B variants infecting the pediatric Madrid Cohort were intersubtype recombinants. This reflects the increasing heterogeneity of the HIV epidemic in our country. Lastly, and applying multivariate models, we explored how 28 clinical parameters used to monitor disease progression were associated with within-host HIV-1 subtype B genetic diversity. The best-predictor variables for HIV-1B evolutionary parameters were: 1) for d: age of HIV-1 diagnosis; 2) for dN: age at first antiretroviral therapy; and 3) for ds: year of HIV-1 diagnosis. The Thesis highlights the importance of an active and periodic surveillance of drug resistance prevalence among HIV‐1 infected children who require lifelong treatment and of the HIV‐1 diversity to study their impact on HIV infection outcome. The presented data will be useful not only for pediatricians, but also for clinicians attending adults, since a large number of perinatally infected children in Spain are reaching adulthood and being transferred to adult hospital units.