Drug-drug interactions based on pharmacogenetic profile between highly active antiretroviral therapy and antiblastic chemotherapy in cancer patients with HIV infection

The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug-drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug-drug interaction, a useful list of pharmacogenomic markers is provided

Residual phenotypic susceptibility to doravirine in multidrug-resistant HIV-1 from subjects enrolled in the PRESTIGIO Registry

Objectives: Doravirine shows a rather distinct resistance profile within the nonnucleoside reverse tran-scriptase inhibitor (NNRTI) class. This study aimed to evaluate the phenotypic susceptibility to doravirine, rilpivirine and etravirine in a panel of multidrug-resistant (MDR) HIV-1 isolates collected from people living with HIV (PLWH) enrolled in the PRESTIGIO Registry.Methods: Recombinant viruses expressing PLWH-derived protease, reverse transcriptase coding regions were generated from plasma samples at virological failure with documented resistance to protease in-hibitors, nucleoside reverse transcriptase inhibitors, NNRTIs and integrase strand transfer inhibitors. In vitro susceptibility was assessed through a phenotypic assay measuring fold-change values with respect to the reference NL4-3 virus. Genotypic susceptibility was computed by the Stanford HIVdb algorithm 8.9-1.Results: Plasma samples were collected from 22 PLWH: 20 (91%) were male, median age 55 years (IQR 50-58), time since HIV-1 diagnosis 27 years (23-31) and time on antiretroviral treatment 23 years (22- 26). Median doravirine, etravirine and rilpivirine fold-change values were 9.8 (2.9-40.4), 42.9 (3.1-100.0) and 100.0 (17.9-100.0), respectively. According to the fold-change cut-offs, full susceptibility was observed in five (23%), four (18%) and one (5%) cases with doravirine, etravirine and rilpivirine, respectively. Ir-respective of the presence of specific doravirine mutations, higher numbers of NNRTI mutations corre-lated with higher fold-change values for doravirine. By comparing the distribution of fold-change values with the Stanford HIVdb predicted susceptibility, a significant correlation was detected for doravirine and rilpivirine but not etravirine.Conclusion: Despite extensive cross-resistance among NNRTIs, doravirine can be a valid option in a pro-portion of PLWH with MDR HIV-1. Doravirine activity appeared to be inferred with fair accuracy by the HIVdb algorithm.(c) 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved