Dataset Information

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.

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.

SUBMITTER: Rhee SY

PROVIDER: S-EPMC4388826 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

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 Soo-Yon SY Blanco Jose Luis JL Jordan Michael R MR Taylor Jonathan J Lemey Philippe P Varghese Vici V Hamers Raph L RL Bertagnolio Silvia S Rinke de Wit Tobias F TF Aghokeng Avelin F AF Albert Jan J Avi Radko R Avila-Rios Santiago S Bessong Pascal O PO Brooks James I JI Boucher Charles A B CA Brumme Zabrina L ZL Busch Michael P MP Bussmann Hermann H Chaix Marie-Laure ML Chin Bum Sik BS D'Aquin Toni T TT De Gascun Cillian F CF Derache Anne A Descamps Diane D Deshpande Alaka K AK Djoko Cyrille F CF Eshleman Susan H SH Fleury Herve H Frange Pierre P Fujisaki Seiichiro S Harrigan P Richard PR Hattori Junko J Holguin Africa A Hunt Gillian M GM Ichimura Hiroshi H Kaleebu Pontiano P Katzenstein David D Kiertiburanakul Sasisopin S Kim Jerome H JH Kim Sung Soon SS Li Yanpeng Y Lutsar Irja I Morris Lynn L Ndembi Nicaise N Ng Kee Peng KP Paranjape Ramesh S RS Peeters Martine M Poljak Mario M Price Matt A MA Ragonnet-Cronin Manon L ML Reyes-Terán Gustavo G Rolland Morgane M Sirivichayakul Sunee S Smith Davey M DM Soares Marcelo A MA Soriano Vincent V VV Ssemwanga Deogratius D Stanojevic Maja M Stefani Mariane A MA Sugiura Wataru W Sungkanuparph Somnuek S Tanuri Amilcar A Tee Kok Keng KK Truong Hong-Ha M HM van de Vijver David A M C DA Vidal Nicole N Yang Chunfu C Yang Rongge R Yebra Gonzalo G Ioannidis John P A JP Vandamme Anne-Mieke AM Shafer Robert W RW

PLoS medicine 20150407 4

<h4>Background</h4>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.<h4>Methods and findings< ...[more]

PMID: 25849352

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Dataset Information

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.

Background

Methods and findings

Conclusions

Publications

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.

Similar Datasets

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