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

Saladini, Francesco; Giammarino, Federica; Maggiolo, Franco; Ferrara, Micol; Cenderello, Giovanni; Celesia, Benedetto Maurizio; Martellotta, Ferdinando; Spagnuolo, Vincenzo; Corbelli, Giulio Maria; Gianotti, Nicola; Santoro, Maria Mercedes; Rusconi, Stefano; Zazzi, Maurizio; Castagna, Antonella

doi:10.1016/j.ijantimicag.2023.106737

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…Particularly, Santoro et al analysed 22 samples from 17 4DR-PLWH who previously failed twice-daily raltegravir-based or twice-daily dolutegravir-based regimens, obtaining genotypic and phenotypic data that confirmed that bictegravir and dolutegravir retain activity against most isolates derived from this fragile HTE population 34. Similarly, Saladini et al evaluated the phenotypic susceptibility to NNRTIs from 22 viremic 4DR-PLWH from the PRESTIGIO Registry: doravirine appeared to be a valid option for some 4DR-PLWH, and its activity seemed to be inferred with fair accuracy by the Stanford HIVdb algorithm 35. As what concerns molecules with new mechanisms of action, Saladini et al investigated the genotypic and phenotypic susceptibility to temsavir in a panel of samples collected from 24 individuals with 4DR (79% previously exposed to maraviroc or enfuvirtide): temsavir resistance-associated mutations were detected only in three cases, and there was no impact of viral tropism and/or exposure to other entry inhibitors on fostemsavir susceptibility 36.…”

Section: Cohort Descriptionmentioning

confidence: 99%

“… 34 Similarly, Saladini et al evaluated the phenotypic susceptibility to NNRTIs from 22 viremic 4DR-PLWH from the PRESTIGIO Registry: doravirine appeared to be a valid option for some 4DR-PLWH, and its activity seemed to be inferred with fair accuracy by the Stanford HIVdb algorithm. 35 As what concerns molecules with new mechanisms of action, Saladini et al investigated the genotypic and phenotypic susceptibility to temsavir in a panel of samples collected from 24 individuals with 4DR (79% previously exposed to maraviroc or enfuvirtide): temsavir resistance-associated mutations were detected only in three cases, and there was no impact of viral tropism and/or exposure to other entry inhibitors on fostemsavir susceptibility. 36 Analogously, Rusconi et al analysed samples from 24 4DR-PLWH, showing that only 33% harboured a phenotypically CCR5-tropic virus, but in these cases, leronlimab maintained full activity despite the presence of extensive drug resistance and heavy treatment experience.…”

Section: Cohort Descriptionmentioning

confidence: 99%

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Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors

Clemente,

Galli,

Lolatto

et al. 2024

BMJ Open

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PurposeThe PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population.ParticipantsThe PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry.Findings to dateThe open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples.Future plansThe registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole.Trial registration numberNCT04098315.

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Section: Cohort Descriptionmentioning

confidence: 99%

Section: Cohort Descriptionmentioning

confidence: 99%

Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors

Clemente,

Galli,

Lolatto

et al. 2024

BMJ Open

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Prevalence and Phenotypic Susceptibility to Doravirine of the HIV-1 Reverse Transcriptase V106I Polymorphism in B and Non-B Subtypes

Giammarino,

de Salazar,

Malet

et al. 2024

The Journal of Infectious Diseases

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Aim To evaluate the prevalence and in vitro susceptibility to doravirine of RT-V106I polymorphism detected in samples collected from drug-naïve subjects. Methods Doravirine susceptibility was measured in site-directed mutants (SDMs) containing V106I, V106A, V106 M and Y188L mutations in subtype B (NL4-3, HXB2) and CRF02_AG background and in recombinant viruses with RT harboring V106I alone derived from 50 PLWH. Results HIV-1 B subtype was detected in 1523/2705 cases. Prevalence of V106I was 3.2% in B and 2.5% in non-B subtypes, and was higher in subtype F (8.1%), and D (14.3%). Fold-changes (FC) in susceptibility for SDMs were below doravirine biological cutoff (3.0) for V106I, but not for V106A, V106 M, and Y188L. Clinically-derived viruses tested included 22 B (median FC 1.2 [IQR 0.9-1.6]) and 28 non-B subtypes (median FC 1.8 [IQR 0.9-3.0]). Nine (18%) viruses showed FC values equal or higher than the doravirine biological FC cutoff. Conclusions The prevalence of the HIV-1 RT-V106I polymorphism in MeditRes HIV consortium remains low, but significantly more prevalent in subtypes D and F. V106I minimally decreased the susceptibility to doravirine in SDMs and most clinical isolates. Reduced susceptibility seems to occur at increased frequency in subtype F1, however the clinical impact remains to be investigated.

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Doravirine responses to HIV-1 viruses bearing mutations to NRTIs and NNRTIs under in vitro selective drug pressure

Brenner

Oliveira

Ibanescu

et al. 2023

Journal of Antimicrobial Chemotherapy

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Objectives The NNRTI doravirine has been recently approved for the first-line treatment of HIV-infected patients, eliciting favourable responses against viruses bearing the K103N, Y181C and G190A mutations. This study used in vitro drug selections to elaborate the breadth of doravirine responses against viruses bearing NNRTI and NRTI resistance-associated mutations (RAMs). Methods WT clinical isolates (n = 6) and viruses harbouring common NRTI and NNRTI RAMs (n = 6) were serially passaged in escalating concentrations of doravirine, doravirine/islatravir, doravirine/lamivudine and rilpivirine over 24 weeks. Genotypic analysis ascertained the appearance and accumulation of NNRTI RAMs. Phenotypic drug susceptibility assays assessed resistance conferred by acquired NNRTI RAMs. Results For WT viruses, doravirine pressure led to the appearance of V108I or V106A/I/M RAMs after 8 weeks, conferring low-level (∼2-fold) resistance. After 24 weeks, the accumulation of three to six secondary RAMs, including F227L, M230L, L234I and/or Y318, resulted in high-level (>100-fold) resistance to doravirine. Notably, viruses with these doravirine RAMs remained susceptible to rilpivirine and efavirenz. This contrasted with rilpivirine where acquisition of E138K, L100I and/or K101E resulted in >50-fold cross-resistance to all NNRTIs. Doravirine selection of viruses bearing common NRTI and NNRTI RAMs showed delayed acquisition of RAMs compared with WT virus. Pairing doravirine with islatravir or lamivudine attenuated the development of NNRTI RAMs. Conclusions Doravirine showed favourable resistance profiles against viruses harbouring NRTI and NNRTI RAMs. The high barrier to resistance to doravirine coupled with the long intracellular half-life of islatravir may provide the opportunity for long-acting treatment options.

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

Cited by 3 publications

References 25 publications

Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors

Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors

Prevalence and Phenotypic Susceptibility to Doravirine of the HIV-1 Reverse Transcriptase V106I Polymorphism in B and Non-B Subtypes

Doravirine responses to HIV-1 viruses bearing mutations to NRTIs and NNRTIs under in vitro selective drug pressure

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