Impact of V106I on Resistance to Doravirine (V106IFC)
Phenotypic and Site Directed Mutagenesis Analysis on the Impact of V106I in HIV-1 Reverse Transcriptase on Resistance to Doravirine
Objective. To study the impact of V106I mutation in the reverse transcriptase of HIV-1 on the activity of Doravirine.
Clinical hypotheses.
Doravirine shows a unique resistance pattern with a higher genetic barrier to resistance than other NNRTIs. In contrast to K103N or E138A, the prevalence of single mutations and/or combination of mutations against Doravirine is low. However, in a recent survey conducted in Spain the study investigators have found a V106Iprevalence similar to K103N and E138A. There is a clear need to understand the real impact of this mutation on Doravirine resistance.
調査の概要
詳細な説明
Testing for transmitted drug resistance (TDR) in the reverse transcriptase and protease in newly diagnosed patients with HIV is recommended by treatment guidelines. Currently clinical practice for first line treatment is moving to a test and treat approach. In this setting, Spanish GESIDA guidelines indicate that a first line protease (PI) or integrase (INI) inhibitor-based regimen may be started even if results from baseline resistance are yet not available. This indication is based on the very low prevalence of INI or PI TDR.
In Europe, TDR to NNRTIs has stabilized between 4-5%. Doravirine has a unique mutational pattern and its activity is affected by mutations that are usually not found at baseline as TDR (V106A/M, V108I, Y188L, G190S, F227 C/L/V, M230I/L, L234I, P236L Y318F and K103N/Y181C), as a recent European survey has already shown. In addition, these findings have been confirmed in a survey the study investigators have conducted in Spain. However, in this study the Stanford algorithm was used to evaluate clinical resistance to NNRTIs and, surprisingly found an unexpected high prevalence of resistance to Doravirine (as high as for first generation NNRTIs). Study investigators detected that resistance to Doravirine was mainly driven by V106I mutation, which Stanford scores as "low-level resistance".
MeditRes is a consortium of HIV clinical virologists from France (leader Anne-Genevieve Marcellin, Paris), Italy (leader Francesca Ceccerini-Silbesrtein, Rome, Spain (leader Federico García, Granada), Greece (leader Dimitrios Paraskevis, Athens) and Portugal (leader Perpetua Gomes, Lisbon). Each of these team leaders has access/coordinate local or national cohorts in their countries.
This study aims to investigate the prevalence of V106I TDR in patients joining the MEDITRES consortium during years 2018 and 2019. In patients carrying V106I in the background of a wild-type virus phenotypic resistance to Doravirine will be evaluated the Fold-Change (FC) will be calculated. In addition, Site Directed Mutagenesis (SDM) will be used to evaluate FC to Doravirine in the background of B and CRF02-AG subtypes. Patient recruitment will follow general recruitment procedures to be incorporated into each running cohorts currently contributing to MEDITRES (multicentre, prospective cohort of HIV-positive, antiretroviral-naïve subjects over 18 years of age, including both seroprevalent and seroconverter patients).
研究の種類
入学 (予想される)
連絡先と場所
研究連絡先
- 名前：Federico Garcia, PhD
- 電話番号：+34649894291
- メール：fegarcia@ugr.es
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
サンプリング方法
調査対象母集団
説明
Inclusion Criteria:
Antiretroviral-naïve subjects over 13 years of age, including both seroprevalent and seroconverter patients
Exclusion Criteria:
Patients with prior antiretroviral exposure
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研究計画
研究はどのように設計されていますか？
デザインの詳細
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Fold Change in resistance to Doravirine
時間枠：Day 0
|
Change in EC50 for resistance to Doravirine in the presence of V106I
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Day 0
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協力者と研究者
出版物と役立つリンク
一般刊行物
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