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

• Published in: PLoS medicine 2015-04, Vol.12 (4), p.e1001810-e1001810
• Main Authors: Rhee, Soo-Yon, Blanco, Jose Luis, Jordan, Michael R, Taylor, Jonathan, Lemey, Philippe, Varghese, Vici, Hamers, Raph L, Bertagnolio, Silvia, Rinke de Wit, Tobias F, Aghokeng, Avelin F, Albert, Jan, Avi, Radko, Avila-Rios, Santiago, Bessong, Pascal O, Brooks, James I, Boucher, Charles A B, Brumme, Zabrina L, Busch, Michael P, Bussmann, Hermann, Chaix, Marie-Laure, Chin, Bum Sik, D'Aquin, Toni T, De Gascun, Cillian F, Derache, Anne, Descamps, Diane, Deshpande, Alaka K, Djoko, Cyrille F, Eshleman, Susan H, Fleury, Herve, Frange, Pierre, Fujisaki, Seiichiro, Harrigan, P Richard, Hattori, Junko, Holguin, Africa, Hunt, Gillian M, Ichimura, Hiroshi, Kaleebu, Pontiano, Katzenstein, David, Kiertiburanakul, Sasisopin, Kim, Jerome H, Kim, Sung Soon, Li, Yanpeng, Lutsar, Irja, Morris, Lynn, Ndembi, Nicaise, Ng, Kee Peng, Paranjape, Ramesh S, Peeters, Martine, Poljak, Mario, Price, Matt A, Ragonnet-Cronin, Manon L, Reyes-Terán, Gustavo, Rolland, Morgane, Sirivichayakul, Sunee, Smith, Davey M, Soares, Marcelo A, Soriano, Vincent V, Ssemwanga, Deogratius, Stanojevic, Maja, Stefani, Mariane A, Sugiura, Wataru, Sungkanuparph, Somnuek, Tanuri, Amilcar, Tee, Kok Keng, Truong, Hong-Ha M, van de Vijver, David A M C, Vidal, Nicole, Yang, Chunfu, Yang, Rongge, Yebra, Gonzalo, Ioannidis, John P A, Vandamme, Anne-Mieke, Shafer, Robert W
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Africa; AIDS; Americas; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antiretroviral drugs; Asia; Base Sequence; DNA sequencing; Drug resistance; Drug Resistance, Viral; Europe; Gene expression; Genetic aspects; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Identification and classification; Medicin och hälsovetenskap; Methods; Microbial drug resistance; Molecular Epidemiology; Mutation; Phylogeny; Studies
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1001810

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. 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 d