Viral resistance burden and APOBEC editing correlate with virological response in heavily treatment-experienced people living with multi-drug resistant HIV

Background: The impact of drug resistance mutational load and APOBEC editing in heavily treatment-experienced (HTE) people living with multidrug-resistant HIV has not been investigated. Material and methods: We explored the HIV-DNA and HIV-RNA mutational load of drug resistance and APOBEC-related mutations through next-generation sequencing (NGS, Illumina MiSeq) in 20 failing HTE persons enrolled in the PRESTIGIO registry. Results: Patients showed high levels of both HIV-DNA (4.5 [4.0-5.2] log10 copies/106 T-CD4+ cell) and HIV-RNA (4.5 [4.1-5.0] log10 copies/mL) with complex resistance patterns in both compartments. Among the 255 drug resistance mutations found, 66.3% were concordantly detected in both HIV-DNA and HIV-RNA; 71.3% of mutations were already present in historical Sanger genotypes. At intra-patient frequency >5%, a considerable proportion of mutations detected through DNA-NGS were found in historical genotypes but not through RNA-NGS, and few patients had APOBEC-related mutations. Of 14 individuals who switched therapy, those five who failed treatment had DNA resistance with higher intra-patient frequency, higher DNA/RNA mutational load in a context of tendentially less pronounced APOBEC editing compared to those who responded. Conclusions: Using NGS in HIV-DNA and HIV-RNA together with APOBEC editing evaluation might help to identify HTE individuals with MDR who are more prone to experience virological failure.