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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 transmitted drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT Inhibitor (NNRTI) drug-resistance mutation (DRM) in individuals with intermediate or high-level transmitted NRTI or NNRTI resistance from a meta-analysis of 287 studies published between 2000 and 2013 are shown. Low- and middle- income countries include 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. Major NRTI DRMs include those with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. Major NNRTI DRMs include those with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding major DRMs in the list / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance.
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pone.0145772.g001: Prevalence of major NRTI and NNRTI resistance mutations in individuals with transmitted drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT Inhibitor (NNRTI) drug-resistance mutation (DRM) in individuals with intermediate or high-level transmitted NRTI or NNRTI resistance from a meta-analysis of 287 studies published between 2000 and 2013 are shown. Low- and middle- income countries include 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. Major NRTI DRMs include those with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. Major NNRTI DRMs include those with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding major DRMs in the list / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance.

Mentions: Fig 1 shows the absolute and cumulative prevalence of the major NRTI and NNRTI DRMs in RT sequences from a recently published individual-level meta-analysis of more than 50,000 ARV-naïve individuals in 287 published studies [16]. M184V was the most common transmitted major NRTI-associated DRM, occurring in 54% of viruses from individuals with intermediate or high-level NRTI TDR in LMICs and 31% of viruses from individuals with intermediate or high-level NRTI TDR in upper-income countries. M184I, K65R, L74V/I, Y115F and the TAMs K70R and T215Y/F were the next most common transmitted major NRTI DRMs. The TAMs M41L, D67N/E/G and K219Q/E/N/R and the T215 revertant mutations (T215C/D/E/S/I/V) were the most common non-major transmitted NRTI DRMs. Subtype was not a major determinant of which NRTI DRMs occurred in TDR isolates in LMICs.


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 transmitted drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT Inhibitor (NNRTI) drug-resistance mutation (DRM) in individuals with intermediate or high-level transmitted NRTI or NNRTI resistance from a meta-analysis of 287 studies published between 2000 and 2013 are shown. Low- and middle- income countries include 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. Major NRTI DRMs include those with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. Major NNRTI DRMs include those with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding major DRMs in the list / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145772.g001: Prevalence of major NRTI and NNRTI resistance mutations in individuals with transmitted drug resistance.Absolute and cumulative prevalence of each major nucleoside (NRTI) and nonnucleoside RT Inhibitor (NNRTI) drug-resistance mutation (DRM) in individuals with intermediate or high-level transmitted NRTI or NNRTI resistance from a meta-analysis of 287 studies published between 2000 and 2013 are shown. Low- and middle- income countries include 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. Major NRTI DRMs include those with an HIVDB score ≥30. There were no insertions or deletions between codons 67 and 70. Major NNRTI DRMs include those with an HIVDB score ≥60. Absolute %: number of individuals with DRM / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance. Cumulative %: number of individuals with one or more of the preceding major DRMs in the list / number of individuals with intermediate or high-level transmitted NRTI or NNRTI resistance.
Mentions: Fig 1 shows the absolute and cumulative prevalence of the major NRTI and NNRTI DRMs in RT sequences from a recently published individual-level meta-analysis of more than 50,000 ARV-naïve individuals in 287 published studies [16]. M184V was the most common transmitted major NRTI-associated DRM, occurring in 54% of viruses from individuals with intermediate or high-level NRTI TDR in LMICs and 31% of viruses from individuals with intermediate or high-level NRTI TDR in upper-income countries. M184I, K65R, L74V/I, Y115F and the TAMs K70R and T215Y/F were the next most common transmitted major NRTI DRMs. The TAMs M41L, D67N/E/G and K219Q/E/N/R and the T215 revertant mutations (T215C/D/E/S/I/V) were the most common non-major transmitted NRTI DRMs. Subtype was not a major determinant of which NRTI DRMs occurred in TDR isolates in LMICs.

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