Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Soo Yon Rhee; Vici Varghese; Susan P. Holmes; Gert U. Van Zyl; Kim Steegen; Mark A. Boyd; David A. Cooper; Sabin Nsanzimana; Shanmugam Saravanan; Charlotte Charpentier; Tulio de Oliveira; Mary Ann A. Etiebet; Federico Garcia; Dominique Goedhals; Perpetua Gomes; Huldrych F. Günthard; Raph L. Hamers; Christopher J. Hoffmann; Gillian Hunt; Awachana Jiamsakul; Pontiano Kaleebu; Phyllis Kanki; Rami Kantor; Bernhard Kerschberger; Vincent C. Marconi; Jean D'amour Ndahimana; Nicaise Ndembi; Nicole Ngo-Giang-Huong; Casper Rokx; Maria M. Santoro; Jonathan M. Schapiro; Daniel Schmidt; Lillian Seu; Kim C.E. Sigaloff; Sunee Sirivichayakul; Lindiwe Skhosana; Henry Sunpath; Michele Tang; Chunfu Yang; Sergio Carmona; Ravindra K. Gupta; Robert W. Shafer

doi:10.1016/j.ebiom.2017.03.024

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Soo Yon Rhee, Vici Varghese, Susan P. Holmes, Gert U. Van Zyl, Kim Steegen, Mark A. Boyd, David A. Cooper, Sabin Nsanzimana, Shanmugam Saravanan, Charlotte Charpentier, Tulio de Oliveira, Mary Ann A. Etiebet, Federico Garcia, Dominique Goedhals, Perpetua Gomes, Huldrych F. Günthard, Raph L. Hamers, Christopher J. Hoffmann, Gillian Hunt, Awachana JiamsakulPontiano Kaleebu, Phyllis Kanki, Rami Kantor, Bernhard Kerschberger, Vincent C. Marconi, Jean D'amour Ndahimana, Nicaise Ndembi, Nicole Ngo-Giang-Huong, Casper Rokx, Maria M. Santoro, Jonathan M. Schapiro, Daniel Schmidt, Lillian Seu, Kim C.E. Sigaloff, Sunee Sirivichayakul, Lindiwe Skhosana, Henry Sunpath, Michele Tang, Chunfu Yang, Sergio Carmona, Ravindra K. Gupta, Robert W. Shafer

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Original language	English
Pages (from-to)	225-235
Number of pages	11
Journal	eBioMedicine
Volume	18
DOIs	https://doi.org/10.1016/j.ebiom.2017.03.024
Publication status	Published - Apr 2017
Externally published	Yes

Keywords

Antiretroviral therapy
Drug resistance
HIV-1
Reverse transcriptase
Tenofovir
WHO-recommended first-line

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2017.03.024

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Rhee, S. Y., Varghese, V., Holmes, S. P., Van Zyl, G. U., Steegen, K., Boyd, M. A., Cooper, D. A., Nsanzimana, S., Saravanan, S., Charpentier, C., de Oliveira, T., Etiebet, M. A. A., Garcia, F., Goedhals, D., Gomes, P., Günthard, H. F., Hamers, R. L., Hoffmann, C. J., Hunt, G., ... Shafer, R. W. (2017). Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration. eBioMedicine, 18, 225-235. https://doi.org/10.1016/j.ebiom.2017.03.024

@article{c5a9a74016d44c1ea5aeb6af1ee0c35e,

title = "Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration",

abstract = "Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-na{\"i}ve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.",

keywords = "Antiretroviral therapy, Drug resistance, HIV-1, Reverse transcriptase, Tenofovir, WHO-recommended first-line",

author = "Rhee, {Soo Yon} and Vici Varghese and Holmes, {Susan P.} and {Van Zyl}, {Gert U.} and Kim Steegen and Boyd, {Mark A.} and Cooper, {David A.} and Sabin Nsanzimana and Shanmugam Saravanan and Charlotte Charpentier and {de Oliveira}, Tulio and Etiebet, {Mary Ann A.} and Federico Garcia and Dominique Goedhals and Perpetua Gomes and G{\"u}nthard, {Huldrych F.} and Hamers, {Raph L.} and Hoffmann, {Christopher J.} and Gillian Hunt and Awachana Jiamsakul and Pontiano Kaleebu and Phyllis Kanki and Rami Kantor and Bernhard Kerschberger and Marconi, {Vincent C.} and {D'amour Ndahimana}, Jean and Nicaise Ndembi and Nicole Ngo-Giang-Huong and Casper Rokx and Santoro, {Maria M.} and Schapiro, {Jonathan M.} and Daniel Schmidt and Lillian Seu and Sigaloff, {Kim C.E.} and Sunee Sirivichayakul and Lindiwe Skhosana and Henry Sunpath and Michele Tang and Chunfu Yang and Sergio Carmona and Gupta, {Ravindra K.} and Shafer, {Robert W.}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = apr,

doi = "10.1016/j.ebiom.2017.03.024",

language = "English",

volume = "18",

pages = "225--235",

journal = "eBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

Rhee, SY, Varghese, V, Holmes, SP, Van Zyl, GU, Steegen, K, Boyd, MA, Cooper, DA, Nsanzimana, S, Saravanan, S, Charpentier, C, de Oliveira, T, Etiebet, MAA, Garcia, F, Goedhals, D, Gomes, P, Günthard, HF, Hamers, RL, Hoffmann, CJ, Hunt, G, Jiamsakul, A, Kaleebu, P, Kanki, P, Kantor, R, Kerschberger, B, Marconi, VC, D'amour Ndahimana, J, Ndembi, N, Ngo-Giang-Huong, N, Rokx, C, Santoro, MM, Schapiro, JM, Schmidt, D, Seu, L, Sigaloff, KCE, Sirivichayakul, S, Skhosana, L, Sunpath, H, Tang, M, Yang, C, Carmona, S, Gupta, RK & Shafer, RW 2017, 'Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration', eBioMedicine, vol. 18, pp. 225-235. https://doi.org/10.1016/j.ebiom.2017.03.024

TY - JOUR

T1 - Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen

T2 - An International Collaboration

AU - Rhee, Soo Yon

AU - Varghese, Vici

AU - Holmes, Susan P.

AU - Van Zyl, Gert U.

AU - Steegen, Kim

AU - Boyd, Mark A.

AU - Cooper, David A.

AU - Nsanzimana, Sabin

AU - Saravanan, Shanmugam

AU - Charpentier, Charlotte

AU - de Oliveira, Tulio

AU - Etiebet, Mary Ann A.

AU - Garcia, Federico

AU - Goedhals, Dominique

AU - Gomes, Perpetua

AU - Günthard, Huldrych F.

AU - Hamers, Raph L.

AU - Hoffmann, Christopher J.

AU - Hunt, Gillian

AU - Jiamsakul, Awachana

AU - Kaleebu, Pontiano

AU - Kanki, Phyllis

AU - Kantor, Rami

AU - Kerschberger, Bernhard

AU - Marconi, Vincent C.

AU - D'amour Ndahimana, Jean

AU - Ndembi, Nicaise

AU - Ngo-Giang-Huong, Nicole

AU - Rokx, Casper

AU - Santoro, Maria M.

AU - Schapiro, Jonathan M.

AU - Schmidt, Daniel

AU - Seu, Lillian

AU - Sigaloff, Kim C.E.

AU - Sirivichayakul, Sunee

AU - Skhosana, Lindiwe

AU - Sunpath, Henry

AU - Tang, Michele

AU - Yang, Chunfu

AU - Carmona, Sergio

AU - Gupta, Ravindra K.

AU - Shafer, Robert W.

PY - 2017/4

Y1 - 2017/4

N2 - Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

AB - Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

KW - Antiretroviral therapy

KW - Drug resistance

KW - HIV-1

KW - Reverse transcriptase

KW - Tenofovir

KW - WHO-recommended first-line

UR - http://www.scopus.com/inward/record.url?scp=85016506361&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2017.03.024

DO - 10.1016/j.ebiom.2017.03.024

M3 - Article

C2 - 28365230

AN - SCOPUS:85016506361

SN - 2352-3964

VL - 18

SP - 225

EP - 235

JO - eBioMedicine

JF - eBioMedicine

ER -

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Abstract

Keywords

UN SDGs

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