HIV-1 drug resistance in people on dolutegravir-based ART: Collaborative analysis of cohort studies

Loosli, Tom; Hossmann, Stefanie; Ingle, Suzanne M; Kusejko, Katharina; Mouton, Johannes P.; Bellecave, Pantxika; Sighem, Ard van; Stecher, Melanie; Monforte, Antonella d′Arminio; Gill, M John; Sabin, Caroline; Maartens, Gary; Guenthard, Huldrych F; Lessells, Richard; Egger, Matthias; Kouyos, Roger D.

doi:10.1101/2023.04.05.23288183

Cited by 3 publications

(1 citation statement)

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“…15,34 Additionally, the presence of NRTI DRMs and the use of DTG monotherapy were each associated with an increased risk of resistance to DTG compared with no NRTI DRMs and the use of at least a three-drug regimen, respectively, in a pooled cohort study. 61 CAB has a higher barrier to resistance than EVG or RAL in vitro; however, its barrier to resistance is lower than that of BIC or DTG. 14 In rare cases of virologic failure in clinical trials using CAB and rilpivirine, the failure was usually associated with emergent integrase and NNRTI resistance mutations.…”

Section: Introductionmentioning

confidence: 91%

HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective

Carr,

Mackie,

Paredes

et al. 2023

Antiviral Therapy

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Contemporary antiretroviral therapy (ART) regimens have high barriers to the development of drug resistance. However, resistance to earlier antiretrovirals and uncommon cases of resistance to contemporary ART illustrate the continued need for good clinical management of HIV drug resistance. Here, we describe HIV drug-resistance mechanisms, the interaction of HIV drug-resistant mutations and the patterns of drug resistance to contemporary ART. We then provide guidance on the management of HIV drug resistance, including how to limit the development of resistance and manage virologic failure that is complicated by resistance. To complement this, links to resources and treatment guidelines are provided that can assist with the interpretation of HIV drug resistance test results and optimal ART selection in the clinic.

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Section: Introductionmentioning

confidence: 91%

HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective

Carr,

Mackie,

Paredes

et al. 2023

Antiviral Therapy

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Predicting emergent Dolutegravir resistance in South Africa: A modelling study

Loosli,

Hauser,

Josi

et al. 2024

Preprint

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Summary Background: In response to the rising prevalence of non-nucleoside reverse transcriptase inhibitors (NNRTIs) resistance, millions of people living with HIV (PWH) have switched to dolutegravir-based antiretroviral therapy (ART). Understanding the possible emergence of dolutegravir resistance is essential for health policy and planning. We developed a mathematical model to predict the trends of dolutegravir resistance in PWH in South Africa. Methods: MARISA (Modelling Antiretroviral drug Resistance In South Africa) is a deterministic compartmental model consisting of four layers: (i) the cascade of care, (ii) disease progression, (iii) gender, and (iv) drug resistance. MARISA was calibrated to reproduce the HIV epidemic in South Africa. We assumed dolutegravir was introduced in 2020. We extended the model by including key resistance mutations observed in PWH experiencing virologic failure on dolutegravir-based ART (G118K, E138AKT, G140ACS, Q148HKNR, N155H, and R263K). Model outcomes were acquired (ADR) and transmitted drug resistance (TDR) to dolutegravir and NNRTIs stratified by duration on failing dolutegravir-based ART and under different counterfactual scenarios of switching to protease-inhibitor (PI)-based ART. Finding: The model predicts that ADR will increase rapidly, from 18.5% (uncertainty range 12.5% to 25.4%) in 2023 to 46.2% (32.9% to 58.9%) in 2040. The prevalence of ADR in 2040 increased with the duration of virologic failure on dolutegravir-based ART: 18.0% (12.2% to 23.7%) for 6 months of failing ART compared to 54.8% (41.1% to 63.9%) for over 1.5 years. For TDR, the model predicts a slow but steady increase from 0.1% (0.1% to 0.2%) in 2023 to 8.8% (4.4% to 17.3%) in 2040. Transmitted NNRTI resistance will cease to increase but remain prevalent at 7.7% in 2040. Rapid resistance testing-informed switching to PI-based ART would substantially reduce both ADR and TDR. Interpretation: The prevalence of dolutegravir ADR and TDR will likely increase, with the 10% threshold of TDR possibly reached by 2035, depending on monitoring and switching strategies. The increase will likely be greater in settings where resources for HIV-1 RNA monitoring and resistance testing or options for switching to alternative ART regimens are limited. Funding: Swiss National Science Foundation, National Institutes of Health, UZH URPP Evolution in Action

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Optimising HIV drug resistance testing laboratory networks in Kenya: insights from systems engineering modelling

Wang,

Kingwara,

Wagner

et al. 2024

BMJ Open

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BackgroundHIV drug resistance (DR) is a growing threat to the durability of current and future HIV treatment success. DR testing (DRT) technologies are very expensive and specialised, relying on centralised laboratories in most low and middle-income countries. Modelling for laboratory network with point-of-care (POC) DRT assays to minimise turnaround time (TAT), is urgently needed to meet the growing demand.MethodsWe developed a model with user-friendly interface using integer programming and queueing theory to improve the DRT system in Kisumu County, Kenya. We estimated DRT demand based on both current and idealised scenarios and evaluated a centralised laboratory-only network and an optimised POC DRT network. A one-way sensitivity analysis of key user inputs was conducted.ResultsIn a centralised laboratory-only network, the mean TAT ranged from 8.52 to 8.55 working days, and the system could not handle a demand proportion exceeding 1.6%. In contrast, the mean TAT for POC DRT network ranged from 1.13 to 2.11 working days, with demand proportion up to 4.8%. Sensitivity analyses showed that expanding DRT hubs reduces mean TAT substantially while increasing the processing rate at national labs had minimal effect. For instance, doubling the current service rate at national labs reduced the mean TAT by only 0.0%–1.9% in various tested scenarios, whereas doubling the current service rate at DRT hubs reduced the mean TAT by 37.5%–49.8%. In addition, faster batching modes and transportation were important factors influencing the mean TAT.ConclusionsOur model offers decision-makers an informed framework for improving the DRT system using POC in Kenya. POC DRT networks substantially reduce mean TAT and can handle a higher demand proportion than a centralised laboratory-only network, especially for children and pregnant women living with HIV, where there is an immediate push to use DRT results for patient case management.

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HIV-1 drug resistance in people on dolutegravir-based ART: Collaborative analysis of cohort studies

Cited by 3 publications

References 36 publications

HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective

HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective

Predicting emergent Dolutegravir resistance in South Africa: A modelling study

Optimising HIV drug resistance testing laboratory networks in Kenya: insights from systems engineering modelling

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