Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- an... - PubMed - NCBI
PLoS Med. 2015 Apr 7;12(4):e1001810. doi: 10.1371/journal.pmed.1001810. eCollection 2015.
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 SY1,
Blanco JL2,
Jordan MR3,
Taylor J4,
Lemey P5,
Varghese V1,
Hamers RL6,
Bertagnolio S7,
de Wit TF6,
Aghokeng AF8,
Albert J9,
Avi R10,
Avila-Rios S11,
Bessong PO12,
Brooks JI13,
Boucher CA14,
Brumme ZL15,
Busch MP16,
Bussmann H17,
Chaix ML18,
Chin BS19,
D'Aquin TT20,
De Gascun CF21,
Derache A22,
Descamps D23,
Deshpande AK24,
Djoko CF25,
Eshleman SH26,
Fleury H27,
Frange P28,
Fujisaki S29,
Harrigan PR30,
Hattori J31,
Holguin A32,
Hunt GM33,
Ichimura H34,
Kaleebu P35,
Katzenstein D1,
Kiertiburanakul S36,
Kim JH37,
Kim SS38,
Li Y39,
Lutsar I10,
Morris L33,
Ndembi N40,
Ng KP41,
Paranjape RS42,
Peeters M43,
Poljak M44,
Price MA45,
Ragonnet-Cronin ML46,
Reyes-Terán G11,
Rolland M37,
Sirivichayakul S47,
Smith DM48,
Soares MA49,
Soriano VV50,
Ssemwanga D35,
Stanojevic M51,
Stefani MA52,
Sugiura W31,
Sungkanuparph S36,
Tanuri A49,
Tee KK41,
Truong HH53,
van de Vijver DA14,
Vidal N54,
Yang C55,
Yang R39,
Yebra G32,
Ioannidis JP56,
Vandamme AM57,
Shafer RW1.
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.
- PMID:
- 25849352
- [PubMed - in process]
Free full text
No hay comentarios:
Publicar un comentario