Transmitted Drug Resistance and HIV Diversity Among Adolescents Newly Diagnosed With HIV in Spain.

BACKGROUND: Virologic characterization of newly HIV-diagnosed adolescents could help to improve their specific needs. The objective was to describe the transmitted drug resistance mutations (TDR) and its transmission by clusters in this population in Spain. METHODS: TDR to retrotranscriptase and protease inhibitors included in the WHO TDR list 2009 implemented in the Calibrated Population Resistance tool v8.0 (Stanford) were studied in HIV pol sequences from all HIV-diagnosed adolescents (12-19-year-old) enrolled during 2004-2019 period in the Spanish pediatric and adult (CoRISpe-CoRIS) cohorts. The found TDR were compared with the provided by the Stanford algorithm v9.0 2021. HIV-1 variants and transmission clusters were also studied. RESULTS: Among 410 HIV-1 adolescents diagnosed, 141 (34.4%) had available ART-naive sequences. They were mostly male (81.6%), Spanish (55.3%) and with behavioral risk (92.2%), mainly male-to-male sexual contact (63.1%). TDR prevalence was significantly higher by Stanford versus WHO list (18.4% vs. 7.1%; P = 0.004). The most prevalent TDR by the WHO list was K103N (3.6%) and by Stanford E138A (6.6%), both at retrotranscriptase. E138A, related to rilpivirine/etravirine resistance, was absent in the WHO list. One in 4 adolescents carried HIV-1 non-B variants. We described 5 transmission clusters, and 2 carried TDR mutations. CONCLUSIONS: Our data suggest a high TDR prevalence in adolescents with a new HIV diagnosis in Spain, similar to adults, 2 active TDR transmission clusters, and the need for the WHO TDR list update. These findings could have implications for the options of the recently available rilpivirine-related long-acting treatment and in first-line regimen election.

HIV Transmembrane Glycoprotein Conserved Domains and Genetic Markers Across HIV-1 and HIV-2 Variants.

HIV envelope transmembrane glycoproteins gp41 (HIV-1) and gp36 (HIV-2) present high variability and play a key role in the HIV-host cell membrane's fusion, as a target for human broadly neutralizing antibodies (bnAbs) and drugs. Thus, a better knowledge of amino acid (aa) conservation across structural domains and HIV variants can help to identify conserved targets to direct new therapeutic and diagnostic strategies. All available gp41/gp36 nucleotide sequences were downloaded from Los Alamos National Laboratory (LANL) HIV Sequence Database, selecting 17,078 sequences ascribed to HIV-1 and HIV-2 variants with ≥3 sequences. After aligning and translating into aa with MEGAv6.0, an in-house bioinformatics program (EpiMolBio) was used to identify the most conserved aa and the aa changes that were specific for each variant (V-markers) vs. HXB2/BEN (HIV-1/HIV-2) reference sequence. We analyzed the presence of specific aa changes among V-markers affecting infectivity, gp41 structure, function, or resistance to the enfuvirtide viral fusion inhibitor (T-20). We also inferred the consensus sequences per HIV variant, describing in each HIV-1 group (M, N, O, P) the conservation level along the complete gp41 per structural domain and locating in each binding site the anti-gp41 human Abs (bnAbs and non bnAbs) described in LANL. We found 38.3/59.7% highly conserved aa present in ≥90% of the 16,803/275 gp41/gp36 sequences ascribed to 105/3 HIV-1/HIV-2 variants, with 9/12.6% of them showing complete conservation across LANL sequences. The fusion peptide, its proximal region, the N-heptad repeat, and the membrane-proximal external region were the gp41 domains with ≥84% of conserved aa in the HIV-1 consensus sequence, the target of most Abs. No natural major resistance mutations to T-20 were observed. Our results show, for the first time, a complete conservation study of gp41/gp36 per variant in the largest panel of HIV variants analyzed to date, providing useful information for a more rational design of drugs, vaccines, and molecular detection tests targeting the HIV transmembrane glycoprotein.

High drug resistance levels could compromise the control of HIV infection in paediatric and adolescent population in Kinshasa, the Democratic Republic of Congo.

BACKGROUND: The inadequacy of HIV viraemia and resistance monitoring in Africa leads to uncontrolled circulation of HIV strains with drug resistance mutations (DRM), compromising antiretroviral therapy (ART) effectiveness. This study describes the DRM prevalence and its therapeutic impact in HIV-infected pediatric patients from Kinshasa (Democratic Republic of Congo, DRC). METHODS: From 2016-2018, dried blood were collected from 71 HIV-infected children and adolescents under ART in two hospitals in Kinshasa for HIV-1 DRM pol analysis, predicted ARV-susceptibility by Stanford and phylogenetic characterization. RESULTS: HIV-1 sequences were recovered from 55 children/adolescents with 14 years of median-age. All had received nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI, NNRTI), 9.1% protease inhibitors (PI) and only one integrase inhibitor (INI). Despite the use of ART, 89.1% showed virological failure and 67.3% carried viruses with major-DRM to one (12.7%), two (47.3%), or three (5.5%) ARV-families. Most children/adolescents harbored DRM to NNRTI (73.5%) or NRTI (61.2%). Major-DRM to PI was present in 8.3% and minor-DRM to INI in 15%. Dual-class-NRTI+NNRTI resistance appeared in 53.1% of patients. Viruses presented high/intermediate resistance to nevirapine (72.9% patients), efavirenz (70.9%), emtricitabine/lamivudine (47.9%), rilpivirine (41.7%), etravirine (39.6%), doravidine (33.3%), zidovudine (22.9%), among others. Most participants were susceptible to INI and PI. Great diversity of variants was found, with a high rate (40%) of unique recombinants. CONCLUSION: The high DRM prevalence observed among HIV-infected children and adolescents in Kinshasa could compromise the 95-95-95-UNAIDS targets in the DRC. It also reinforces the need for routine resistance monitoring for optimal rescue therapy election in this vulnerable population to control the spread of resistant HIV in the country.

Virological outcome among HIV infected patients transferred from pediatric care to adult units in Madrid, Spain (1997-2017).

The aim of this transversal study was to describe the virological and immunological features of HIV-infected youths transferred from pediatric to adult care units since 1997 vs. the non-transferred patients from the Madrid Cohort of HIV-infected children and adolescents in Spain. We included 106 non-transferred and 184 transferred patients under clinical follow-up in 17 public hospitals in Madrid by the end of December 2017. Virological and immunological outcomes were compared in transferred vs. non-transferred patients. ART drug resistance mutations and HIV-variants were analyzed in all subjects with available resistance pol genotypes and/or genotypic resistance profiles. Among the study cohort, 133 (72.3%) of 184 transferred and 75 (70.7%) of 106 non-transferred patients had available resistance genotypes. Most (88.9%) of transferred had ART experience at sampling. A third (33.3%) had had a triple-class experience. Acquired drug resistance (ADR) prevalence was significantly higher in pretreated transferred than non-transferred patients (71.8% vs. 44%; p = 0.0009), mainly to NRTI (72.8% vs. 31.1%; p < 0.0001) and PI (29.1% vs. 12%; p = 0.0262). HIV-1 non-B variants were less frequent in transferred vs. non-transferred (6.9% vs. 32%; p < 0.0001). In conclusion, the frequent resistant genotypes found in transferred youths justifies the reinforcement of HIV resistance monitoring after the transition to avoid future therapeutic failures.