This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2023 Apr 5:2023.04.05.23288183.

doi: 10.1101/2023.04.05.23288183.

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

Tom Loosli^{1

2}, Stefanie Hossmann³, Suzanne M Ingle⁴, Hajra Okhai⁵, Katharina Kusejko^{1

2}, Johannes Mouton⁶, Pantxika Bellecave⁷, Ard van Sighem⁸, Melanie Stecher^{9

10}, Antonella d'Arminio Monforte¹¹, M John Gill^{12

13}, Caroline A Sabin⁵, Gary Maartens⁶, Huldrych F Günthard^{1

2}, Jonathan A C Sterne⁴, Richard Lessells^{14

15}, Matthias Egger^{3

4

15}, Roger Kouyos^{1

2}

Affiliations

¹ Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
² Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
³ Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland.
⁴ Population Health Sciences, Bristol Medical School, University of Bristol, UK.
⁵ Institute for Global Health, University College London, UK.
⁶ Department of Medicine, University of Cape Town, Cape Town, South Africa.
⁷ Virology laboratory, University Hospital Bordeaux, Bordeaux, France.
⁸ Stichting hiv monitoring, Amsterdam, the Netherlands.
⁹ German Center for Infection Research (DZIF), Partner-Site Cologne-Bonn, Cologne, Germany.
¹⁰ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf.
¹¹ Italian Cohort Naive Antiretrovirals, (ICONA) L'Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Milano, Italy.
¹² Southern Alberta Clinic, Calgary, AB, Canada.
¹³ Department of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁴ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
¹⁵ Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

PMID: 37066200
PMCID: PMC10104228
DOI: 10.1101/2023.04.05.23288183

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

Tom Loosli et al. medRxiv. 2023.

[Preprint]. 2023 Apr 5:2023.04.05.23288183.

doi: 10.1101/2023.04.05.23288183.

Authors

Affiliations

¹ Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
² Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
³ Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland.
⁴ Population Health Sciences, Bristol Medical School, University of Bristol, UK.
⁵ Institute for Global Health, University College London, UK.
⁶ Department of Medicine, University of Cape Town, Cape Town, South Africa.
⁷ Virology laboratory, University Hospital Bordeaux, Bordeaux, France.
⁸ Stichting hiv monitoring, Amsterdam, the Netherlands.
⁹ German Center for Infection Research (DZIF), Partner-Site Cologne-Bonn, Cologne, Germany.
¹⁰ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf.
¹¹ Italian Cohort Naive Antiretrovirals, (ICONA) L'Azienda Socio Sanitaria Territoriale (ASST) Santi Paolo e Carlo, Milano, Italy.
¹² Southern Alberta Clinic, Calgary, AB, Canada.
¹³ Department of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁴ Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
¹⁵ Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

PMID: 37066200
PMCID: PMC10104228
DOI: 10.1101/2023.04.05.23288183

Update in

HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis.
Loosli T, Hossmann S, Ingle SM, Okhai H, Kusejko K, Mouton J, Bellecave P, van Sighem A, Stecher M, d'Arminio Monforte A, Gill MJ, Sabin CA, Maartens G, Günthard HF, Sterne JAC, Lessells R, Egger M, Kouyos RD. Loosli T, et al. Lancet HIV. 2023 Nov;10(11):e733-e741. doi: 10.1016/S2352-3018(23)00228-X. Epub 2023 Oct 10. Lancet HIV. 2023. PMID: 37832567 Free PMC article.

Abstract

Background: The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) in first- and second-line antiretroviral therapy (ART) may facilitate emerging resistance. We combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for DTG resistance.

Methods: Eight cohorts from Canada, Europe, and South Africa contributed data on individuals with genotypic resistance testing on DTG-based ART. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models.

Results: We included 750 people with genotypic resistance testing on DTG-based ART between 2013 and 2022. Most had HIV subtype B (N=444, 59·2%) and were treatment-experienced; 134 (17.9%) were on DTG dual and 19 (2.5%) on DTG monotherapy. INSTI DRMs were detected in 100 (13·3%) individuals; 21 (2·8%) had more than one mutation. Most (N=713, 95·1%) were susceptible to DTG, 8 (1·1%) had potential-low, 5 (0·7%) low, 18 (2·4%) intermediate and 6 (0·8%) high-level DTG resistance. The risk of DTG resistance was higher on DTG monotherapy (adjusted odds ratio (aOR) 37·25, 95% CI 11·17 to 124·2) and DTG lamivudine dual therapy (aOR 6·59, 95% CI 1·70 to 25·55) compared to combination ART, and higher in the presence of potential-low/low (aOR 4.62, 95% CI 1.24 to 17.2) or intermediate/high-level (aOR 7·01, 95% CI 2·52 to 19·48) nucleoside reverse transcriptase inhibitors (NRTI) resistance. Viral load on DTG showed a trend towards increased DTG resistance (aOR 1·42, 95% CI 0·92 to 2·19 per standard deviation of log₁₀ area under the viral load curve).

Interpretation: Among people experiencing virological failure on DTG-based ART, INSTI DRMs were uncommon, and DTG resistance was rare. DTG monotherapy and NRTI resistance substantially increased the risk for DTG resistance, which is of concern, notably in resource-limited settings.

PubMed Disclaimer

Conflict of interest statement

SMI reports grant funding from NIH NIAAA for the work of ART-CC (payment to institution). AvS reports funding from the Dutch Ministry of Health, Welfare and Sport for the maintenance of the ATHENA database, and grant funding from the European Centre for Disease Prevention and Control (ECDC) (payment to institution). MJG reports honoraria as Ad Hoc member of HIV National Advisory Board from Merck, Gilead Sciences, and ViiV, and a leadership position as Medical Director S Alberta HIV clinic. CAS has received funding from Gilead Sciences, ViiV Healthcare and Janssen-Cilag for membership of Data Safety and Monitoring Committees, Advisory Committees and for preparation of educational material. HFG has received personal fees from Merck, Gilead Sciences, ViiV, GSK, Janssen, Johnson and Johnson and Novartis, as an advisor/consultant or for DSMB membership and has received a travel grant from Gilead. JACS reports funding for research in this publication from NIH NIAAA (payment to institution), UK NIHR (payment to institution), and the University of Bern (payment to institution). RL reports support for research in this publication by the National Institute of Allergy & Infectious Diseases of the National Institutes of Health under award number R01AI152772, and support from the National Institute of Allergy & Infectious Diseases of the National Institutes of Health under award number R01AI167699 for a separate project pertaining to HIV treatment strategies. ME reports funding for research in this publication from the Swiss National Science Foundation (32FP30-18949) and the National Institutes of Health (Cooperative Agreement AI069924 and R01 AI152772-01). RK reports funding for research in this publication from the Swiss National Science Foundation and the National Institute of Allergy & Infectious Diseases of the National Institutes of Health, and reports grant funding from Gilead Sciences. All other authors declare no competing interest.

Figures

**Figure 1:. Prevalence of DTG resistance and INSTI DRMs.**
Genotypic resistance tests of 750 people with genotypic resistance testing on DTG-based ART were analysed using the Stanford resistance algorithm to determine INSTI DRMs and resistance level to DTG. Both major and accessory INSTI DRMs were considered for the number of INSTI DRMs. People with no INSTI DRMs (N = 650, 86·7%), and who are susceptible to DTG (N = 713, 95·1%) are not displayed.

**Figure 2:. INSTI drug resistance mutations found in 750 people experiencing virologic failure on a DTG-based regimen.**
Drug resistance mutations were classified as major and accessory according to the Stanford resistance database. Bars are coloured by previous history of first generation INSTIs (raltegravir, elvitegravir).

**Figure 3:. Rate ratio for the number of INSTI DRMs.**
A negative binomial generalised linear model was fit to the number of major and accessory INSTI DRMs in 750 people with virological failure on DTG-based ART. The plot shows uni- and multivariable point estimates and 95% confidence intervals of rate ratios.

**Figure 4:. Odds ratios for DTG resistance levels with 95% confidence intervals from uni- and multivariable ordinal logistic models for genotypic DTG resistance.**
Cohorts were included as random effect. DTG resistance levels in people with virological failure on DTG-based ART were assessed using the Stanford resistance algorithm.

See this image and copyright information in PMC

References

1. WHO. Update of recommendations on first- and second-line antiretroviral regimens. Geneva, Switzerland:World Health Organization; WHO. 2019. p. 3.
1. The Lancet HIV. End resistance to dolutegravir roll-out. Lancet HIV. 2020. Sep 1;7(9):e593. - PubMed
1. Llibre JM, Pulido F, García F, García Deltoro M, Blanco JL, Delgado R. Genetic barrier to resistance for dolutegravir. AIDS Rev. 2015;17(1):56–64. - PubMed
1. Cottrell ML, Hadzic T, Kashuba ADM. Clinical pharmacokinetic, pharmacodynamic and druginteraction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013;52(11):981–94. - PMC - PubMed
1. Cevik M, Orkin C, Sax PE. Emergent resistance to dolutegravir among instinaive patients on first-line or second-line antiretroviral therapy: A review of published cases. Open Forum Infect Dis. 2020;7(6). - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

This is a preprint.

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

Affiliations

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

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources