Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who almost invariably harbor viral quasispecies with resistance-associated mutations (RAMs). The reference method for HIV genotypic resistance testing (GRT) has long been Sanger sequencing (SS), but next-generation sequencing (NGS), following recent progress in workflow and cost-effectiveness, is replacing SS because of higher sensitivity. From the PRESTIGIO Registry, we present a case of a 59-year-old HTE woman who failed darunavir/ritonavir plus raltegravir at low-viremia levels due mainly to high pill burden and poor adherence. NGS-GRT was performed on HIV-RNA at failure and the results were compared to all past SS-GRT data available (historical genotype). In this case, NGS-GRT did not detect any minority drug-resistant variants. After discussing several therapeutic options, the treatment was changed to dolutegravir 50 mg twice daily plus doravirine 100 mg once a day, based on clinical history, adherence issues, and pill burden, as well as the historical SS-GRT and the latest NGS-GRT results. At six months follow-up visit, the patient had HIV-RNA below 30 copies/ml and CD4+ T cell count increased from 673 cells/ mm3 to 688 cells/ mm3. Close follow-up of this patient is ongoing.

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