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HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

Rhee SY, Jordan MR, Raizes E, Chua A, Parkin N, Kantor R, Van Zyl GU, Mukui I, Hosseinipour MC, Frenkel LM, Ndembi N, Hamers RL, Rinke de Wit TF, Wallis CL, Gupta RK, Fokam J, Zeh C, Schapiro JM, Carmona S, Katzenstein D, Tang M, Aghokeng AF, De Oliveira T, Wensing AM, Gallant JE, Wainberg MA, Richman DD, Fitzgibbon JE, Schito M, Bertagnolio S, Yang C, Shafer RW - PLoS ONE (2015)

Bottom Line: This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings.One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance.The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford University, Stanford, CA, United States of America.

ABSTRACT
The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

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Prevalence of major NRTI and NNRTI resistance mutations in individuals with acquired drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT inhibitor (NNRTI) drug-resistance mutation (DRM) in 4,926 individuals with virological failure and intermediate or high-level acquired NRTI or NNRTI resistance while receiving a first-line NRTI/NNRTI-containing regimen are shown. Regimens include four AZT/d4T-containing regimens—AZT/d4T+3TC+EFV/NVP (n = 4,020), four TDF-containing regimens—TDF+3TC/FTC+EFV/NVP (n = 772), and two ABC-containing regimens—ABC+3TC+NVP/EFV (n = 134). Low- and Middle-Income Countries: Countries of Sub-Saharan Africa, South / Southeast Asia, and Latin America and Caribbean; Upper-Income Countries: Countries of North America and Europe, and upper-income countries in Southeast Asia. NRTI DRM with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. NNRTI DRMs with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding DRMs in the list / number of individuals with intermediate or high-level NRTI or NNRTI resistance.
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pone.0145772.g002: Prevalence of major NRTI and NNRTI resistance mutations in individuals with acquired drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT inhibitor (NNRTI) drug-resistance mutation (DRM) in 4,926 individuals with virological failure and intermediate or high-level acquired NRTI or NNRTI resistance while receiving a first-line NRTI/NNRTI-containing regimen are shown. Regimens include four AZT/d4T-containing regimens—AZT/d4T+3TC+EFV/NVP (n = 4,020), four TDF-containing regimens—TDF+3TC/FTC+EFV/NVP (n = 772), and two ABC-containing regimens—ABC+3TC+NVP/EFV (n = 134). Low- and Middle-Income Countries: Countries of Sub-Saharan Africa, South / Southeast Asia, and Latin America and Caribbean; Upper-Income Countries: Countries of North America and Europe, and upper-income countries in Southeast Asia. NRTI DRM with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. NNRTI DRMs with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding DRMs in the list / number of individuals with intermediate or high-level NRTI or NNRTI resistance.

Mentions: Fig 2 shows that in viruses from individuals in LMICs with intermediate or high-level NRTI resistance following VF on a first-line NRTI/NNRTI-containing regimen, the most common major DRMs were M184V (91.5%) and M184I (3.7%), K65R (9.8%), and the TAMs K70R (14.6%), T215Y (11.0%) and T215F (9.3%). About one-half of the viruses with K65R did not have M184V, making K65R the second largest contributor to the cumulative proportion of viruses with a major NRTI DRM. K65R also occurred in 48% of 467 individuals with VF on a first-line TDF-containing regimen (S5 Table). The TAMs nearly always occurred in combination with M184V and contributed less to the cumulative proportion of viruses with a major NRTI DRM than did K65R.


HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

Rhee SY, Jordan MR, Raizes E, Chua A, Parkin N, Kantor R, Van Zyl GU, Mukui I, Hosseinipour MC, Frenkel LM, Ndembi N, Hamers RL, Rinke de Wit TF, Wallis CL, Gupta RK, Fokam J, Zeh C, Schapiro JM, Carmona S, Katzenstein D, Tang M, Aghokeng AF, De Oliveira T, Wensing AM, Gallant JE, Wainberg MA, Richman DD, Fitzgibbon JE, Schito M, Bertagnolio S, Yang C, Shafer RW - PLoS ONE (2015)

Prevalence of major NRTI and NNRTI resistance mutations in individuals with acquired drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT inhibitor (NNRTI) drug-resistance mutation (DRM) in 4,926 individuals with virological failure and intermediate or high-level acquired NRTI or NNRTI resistance while receiving a first-line NRTI/NNRTI-containing regimen are shown. Regimens include four AZT/d4T-containing regimens—AZT/d4T+3TC+EFV/NVP (n = 4,020), four TDF-containing regimens—TDF+3TC/FTC+EFV/NVP (n = 772), and two ABC-containing regimens—ABC+3TC+NVP/EFV (n = 134). Low- and Middle-Income Countries: Countries of Sub-Saharan Africa, South / Southeast Asia, and Latin America and Caribbean; Upper-Income Countries: Countries of North America and Europe, and upper-income countries in Southeast Asia. NRTI DRM with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. NNRTI DRMs with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding DRMs in the list / number of individuals with intermediate or high-level NRTI or NNRTI resistance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696791&req=5

pone.0145772.g002: Prevalence of major NRTI and NNRTI resistance mutations in individuals with acquired drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT inhibitor (NNRTI) drug-resistance mutation (DRM) in 4,926 individuals with virological failure and intermediate or high-level acquired NRTI or NNRTI resistance while receiving a first-line NRTI/NNRTI-containing regimen are shown. Regimens include four AZT/d4T-containing regimens—AZT/d4T+3TC+EFV/NVP (n = 4,020), four TDF-containing regimens—TDF+3TC/FTC+EFV/NVP (n = 772), and two ABC-containing regimens—ABC+3TC+NVP/EFV (n = 134). Low- and Middle-Income Countries: Countries of Sub-Saharan Africa, South / Southeast Asia, and Latin America and Caribbean; Upper-Income Countries: Countries of North America and Europe, and upper-income countries in Southeast Asia. NRTI DRM with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. NNRTI DRMs with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding DRMs in the list / number of individuals with intermediate or high-level NRTI or NNRTI resistance.
Mentions: Fig 2 shows that in viruses from individuals in LMICs with intermediate or high-level NRTI resistance following VF on a first-line NRTI/NNRTI-containing regimen, the most common major DRMs were M184V (91.5%) and M184I (3.7%), K65R (9.8%), and the TAMs K70R (14.6%), T215Y (11.0%) and T215F (9.3%). About one-half of the viruses with K65R did not have M184V, making K65R the second largest contributor to the cumulative proportion of viruses with a major NRTI DRM. K65R also occurred in 48% of 467 individuals with VF on a first-line TDF-containing regimen (S5 Table). The TAMs nearly always occurred in combination with M184V and contributed less to the cumulative proportion of viruses with a major NRTI DRM than did K65R.

Bottom Line: This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings.One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance.The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford University, Stanford, CA, United States of America.

ABSTRACT
The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

Show MeSH
Related in: MedlinePlus