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Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

Rhee SY, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, Hamers RL, Bertagnolio S, Rinke de Wit TF, Aghokeng AF, Albert J, Avi R, Avila-Rios S, Bessong PO, Brooks JI, Boucher CA, Brumme ZL, Busch MP, Bussmann H, Chaix ML, Chin BS, D'Aquin TT, De Gascun CF, Derache A, Descamps D, Deshpande AK, Djoko CF, Eshleman SH, Fleury H, Frange P, Fujisaki S, Harrigan PR, Hattori J, Holguin A, Hunt GM, Ichimura H, Kaleebu P, Katzenstein D, Kiertiburanakul S, Kim JH, Kim SS, Li Y, Lutsar I, Morris L, Ndembi N, Ng KP, Paranjape RS, Peeters M, Poljak M, Price MA, Ragonnet-Cronin ML, Reyes-Terán G, Rolland M, Sirivichayakul S, Smith DM, Soares MA, Soriano VV, Ssemwanga D, Stanojevic M, Stefani MA, Sugiura W, Sungkanuparph S, Tanuri A, Tee KK, Truong HH, van de Vijver DA, Vidal N, Yang C, Yang R, Yebra G, Ioannidis JP, Vandamme AM, Shafer RW - PLoS Med. (2015)

Bottom Line: Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes.Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes.Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford University, Stanford, California, United States of America. Leuven—University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.

ABSTRACT

Background: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.

Methods and findings: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.

Conclusions: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

No MeSH data available.


Related in: MedlinePlus

A snapshot of an interactive map plotting the prevalence of transmitted drug resistance in 111 countries from 287 studies between 2000 and 2013 (http://hivdb.stanford.edu/surveillance/map/).Each study is represented by a circle. The size of the circle is proportional to the number of individuals in the study. The circle color indicates the prevalence of overall TDR in the study: white (<2.5%), pale yellow (2.5% to 4.9%), orange (5.0% to 9.9%), and red (≥10.0%). Each study can also be located on a sidebar, which lists each publication, percent overall TDR, number of individuals, and the country (or countries) where the study was conducted. Clicking on a sidebar row or a study circle in the interactive version of the map at http://hivdb.stanford.edu/surveillance/map/ generates a pop-up box with additional information including a link to the appropriate PubMed reference, the TDR prevalence by ARV class, the median year of virus sampling, the source of virus isolation, the mechanism of participant recruitment, and the virus subtype distribution (a pop-up box of the study Bila13 is shown as an example). The complete set of data associated with a study can be reviewed by clicking on the “Resistance (%)” link either on the sidebar or within the study circle pop-up menu.
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pmed.1001810.g002: A snapshot of an interactive map plotting the prevalence of transmitted drug resistance in 111 countries from 287 studies between 2000 and 2013 (http://hivdb.stanford.edu/surveillance/map/).Each study is represented by a circle. The size of the circle is proportional to the number of individuals in the study. The circle color indicates the prevalence of overall TDR in the study: white (<2.5%), pale yellow (2.5% to 4.9%), orange (5.0% to 9.9%), and red (≥10.0%). Each study can also be located on a sidebar, which lists each publication, percent overall TDR, number of individuals, and the country (or countries) where the study was conducted. Clicking on a sidebar row or a study circle in the interactive version of the map at http://hivdb.stanford.edu/surveillance/map/ generates a pop-up box with additional information including a link to the appropriate PubMed reference, the TDR prevalence by ARV class, the median year of virus sampling, the source of virus isolation, the mechanism of participant recruitment, and the virus subtype distribution (a pop-up box of the study Bila13 is shown as an example). The complete set of data associated with a study can be reviewed by clicking on the “Resistance (%)” link either on the sidebar or within the study circle pop-up menu.

Mentions: There was a median of 91 individuals per study (interquartile range [IQR]: 49–174). Ninety-five (33%) of 287 studies were conducted in SSA (11,536 individuals; 32 countries), 56 (20%) in SSEA (6,522 individuals; seven countries), 42 (15%) in Europe (11,802 individuals; 30 countries), 38 (13%) in Latin America/Caribbean (5,628 individuals; 20 countries), 27 (9%) in North America (9,283 individuals; four countries), 12 (4%) in the upper-income countries of Asia (4,950 individuals; five countries), 12 (4%) in FSU countries (1,365 individuals; nine countries), three (1%) in North Africa (157 individuals; three countries), and two (1%) in Australia (627 individuals). Table 1 summarizes the epidemiologic characteristics and virus subtypes, and Table 2 summarizes the median TDR prevalence by ARV class in the seven most commonly studied regions. The epidemiologic characteristics, TDR prevalence, CPR analysis, and link to each study publication can be accessed using an interactive map on the HIVDB website (http://hivdb.stanford.edu/surveillance/map/; Fig 2).


Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

Rhee SY, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, Hamers RL, Bertagnolio S, Rinke de Wit TF, Aghokeng AF, Albert J, Avi R, Avila-Rios S, Bessong PO, Brooks JI, Boucher CA, Brumme ZL, Busch MP, Bussmann H, Chaix ML, Chin BS, D'Aquin TT, De Gascun CF, Derache A, Descamps D, Deshpande AK, Djoko CF, Eshleman SH, Fleury H, Frange P, Fujisaki S, Harrigan PR, Hattori J, Holguin A, Hunt GM, Ichimura H, Kaleebu P, Katzenstein D, Kiertiburanakul S, Kim JH, Kim SS, Li Y, Lutsar I, Morris L, Ndembi N, Ng KP, Paranjape RS, Peeters M, Poljak M, Price MA, Ragonnet-Cronin ML, Reyes-Terán G, Rolland M, Sirivichayakul S, Smith DM, Soares MA, Soriano VV, Ssemwanga D, Stanojevic M, Stefani MA, Sugiura W, Sungkanuparph S, Tanuri A, Tee KK, Truong HH, van de Vijver DA, Vidal N, Yang C, Yang R, Yebra G, Ioannidis JP, Vandamme AM, Shafer RW - PLoS Med. (2015)

A snapshot of an interactive map plotting the prevalence of transmitted drug resistance in 111 countries from 287 studies between 2000 and 2013 (http://hivdb.stanford.edu/surveillance/map/).Each study is represented by a circle. The size of the circle is proportional to the number of individuals in the study. The circle color indicates the prevalence of overall TDR in the study: white (<2.5%), pale yellow (2.5% to 4.9%), orange (5.0% to 9.9%), and red (≥10.0%). Each study can also be located on a sidebar, which lists each publication, percent overall TDR, number of individuals, and the country (or countries) where the study was conducted. Clicking on a sidebar row or a study circle in the interactive version of the map at http://hivdb.stanford.edu/surveillance/map/ generates a pop-up box with additional information including a link to the appropriate PubMed reference, the TDR prevalence by ARV class, the median year of virus sampling, the source of virus isolation, the mechanism of participant recruitment, and the virus subtype distribution (a pop-up box of the study Bila13 is shown as an example). The complete set of data associated with a study can be reviewed by clicking on the “Resistance (%)” link either on the sidebar or within the study circle pop-up menu.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388826&req=5

pmed.1001810.g002: A snapshot of an interactive map plotting the prevalence of transmitted drug resistance in 111 countries from 287 studies between 2000 and 2013 (http://hivdb.stanford.edu/surveillance/map/).Each study is represented by a circle. The size of the circle is proportional to the number of individuals in the study. The circle color indicates the prevalence of overall TDR in the study: white (<2.5%), pale yellow (2.5% to 4.9%), orange (5.0% to 9.9%), and red (≥10.0%). Each study can also be located on a sidebar, which lists each publication, percent overall TDR, number of individuals, and the country (or countries) where the study was conducted. Clicking on a sidebar row or a study circle in the interactive version of the map at http://hivdb.stanford.edu/surveillance/map/ generates a pop-up box with additional information including a link to the appropriate PubMed reference, the TDR prevalence by ARV class, the median year of virus sampling, the source of virus isolation, the mechanism of participant recruitment, and the virus subtype distribution (a pop-up box of the study Bila13 is shown as an example). The complete set of data associated with a study can be reviewed by clicking on the “Resistance (%)” link either on the sidebar or within the study circle pop-up menu.
Mentions: There was a median of 91 individuals per study (interquartile range [IQR]: 49–174). Ninety-five (33%) of 287 studies were conducted in SSA (11,536 individuals; 32 countries), 56 (20%) in SSEA (6,522 individuals; seven countries), 42 (15%) in Europe (11,802 individuals; 30 countries), 38 (13%) in Latin America/Caribbean (5,628 individuals; 20 countries), 27 (9%) in North America (9,283 individuals; four countries), 12 (4%) in the upper-income countries of Asia (4,950 individuals; five countries), 12 (4%) in FSU countries (1,365 individuals; nine countries), three (1%) in North Africa (157 individuals; three countries), and two (1%) in Australia (627 individuals). Table 1 summarizes the epidemiologic characteristics and virus subtypes, and Table 2 summarizes the median TDR prevalence by ARV class in the seven most commonly studied regions. The epidemiologic characteristics, TDR prevalence, CPR analysis, and link to each study publication can be accessed using an interactive map on the HIVDB website (http://hivdb.stanford.edu/surveillance/map/; Fig 2).

Bottom Line: Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes.Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes.Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford University, Stanford, California, United States of America. Leuven—University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.

ABSTRACT

Background: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.

Methods and findings: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.

Conclusions: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

No MeSH data available.


Related in: MedlinePlus