Tập trung vào các xét nghiệm gần đây được phát triển để phát hiện sự kháng thuốc/cảm thụ đối với các chất ức chế men sao chép ngược

Francesca Marino-Merlo1, Beatrice Macchi2, Daniele Armenia3, Maria Concetta Bellocchi3, Francesca Ceccherini-Silberstein3, Antonio Mastino4,5, Sandro Grelli3
1IRCCS Centro Neurolesi “Bonino-Pulejo,” Messina, Italy
2Department of Systems Medicine, “University of Rome Tor Vergata”, Rome, Italy
3Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
4Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
5The Institute of Translational Pharmacology, CNR, Rome, Italy

Tóm tắt

Sinh học của HIV khá phức tạp do tỷ lệ sao chép cao, tái tổ hợp thường xuyên và sự xuất hiện của đột biến. Điều này dẫn đến sự hình thành của một số biến thể khác nhau được gọi là quasispecies. Thêm vào đó, sự tiềm tàng trong các nguồn chứa cho phép sự tái kích hoạt định kỳ của quá trình sao chép virus. Sự sao chép nhanh chóng của HIV cho phép virus thoát khỏi phản ứng miễn dịch và thiết lập sự kháng thuốc có thể thu được thông qua việc lựa chọn thuốc và/hoặc được truyền từ người này sang người khác. Điều này đã thúc đẩy, trong suốt nhiều năm qua, việc phát triển một loạt các xét nghiệm nhằm xác định sự kháng thuốc và cảm thụ, được sử dụng cả trong thực hành lâm sàng và trong nghiên cứu kháng virus. Các chất ức chế men sao chép ngược (RT) có vị trí nổi bật trong số các thuốc chống HIV, luôn được sử dụng từ lúc bắt đầu cho đến nay trong các phác đồ kháng virus phổ biến nhất. Bài điểm qua ngắn này nhằm cung cấp cái nhìn tổng quan về những nỗ lực gần đây trong việc phát triển các phương pháp đáng tin cậy và đơn giản hơn, cả về loại hình genotypic và phenotypic, để phát hiện cụ thể sự kháng thuốc và cảm thụ đối với các chất ức chế men sao chép ngược.

Từ khóa

#HIV #kháng thuốc #cảm thụ #xét nghiệm #chất ức chế men sao chép ngược

Tài liệu tham khảo

Alexander HK, Bonhoeffer S (2012) Pre-existence and emergence of drug resistance in a generalized model of intra-host viral dynamics. Epidemics 4(4):187–202. https://doi.org/10.1016/j.epidem.2012.10.001

Al-Salama ZT (2017) Elsulfavirine: first global approval. Drugs 77(16):1811–1816. https://doi.org/10.1007/s40265-017-0820-3

Armenia D, Fabeni L, Alteri C, Di Pinto D, Di Carlo D, Bertoli A, Gori C, Carta S, Fedele V, Forbici F, D'Arrigo R, Svicher V, Berno G, Pizzi D, Nicastri E, Sarmati L, Pinnetti C, Ammassari A, D'Offizi G, Latini A, Andreoni M, Antinori A, Ceccherini-Silberstein F, Perno CF, Santoro MM (2015) HIV-1 integrase genotyping is reliable and reproducible for routine clinical detection of integrase resistance mutations even in patients with low-level viraemia. J Antimicrob Chemother 70(6):1865–1873. https://doi.org/10.1093/jac/dkv029

Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, Mgodi NM, Matovu Kiweewa F, Nair G, Mhlanga F, Siva S, Bekker LG, Jeenarain N, Gaffoor Z, Martinson F, Makanani B, Pather A, Naidoo L, Husnik M, Richardson BA, Parikh UM, Mellors JW, Marzinke MA, Hendrix CW, van der Straten A, Ramjee G, Chirenje ZM, Nakabiito C, Taha TE, Jones J, Mayo A, Scheckter R, Berthiaume J, Livant E, Jacobson C, Ndase P, White R, Patterson K, Germuga D, Galaska B, Bunge K, Singh D, Szydlo DW, Montgomery ET, Mensch BS, Torjesen K, Grossman CI, Chakhtoura N, Nel A, Rosenberg Z, McGowan I, Hillier S (2016) Use of a vaginal ring containing Dapivirine for HIV-1 prevention in women. N Engl J Med 375(22):2121–2132. https://doi.org/10.1056/NEJMoa1506110

Bellocchi MC, Forbici F, Palombi L, Gori C, Coelho E, Svicher V, D'Arrigo R, Emberti-Gialloreti L, Ceffa S, Erba F, Marazzi MC, Silberstein FC, Perno CF (2005) Subtype analysis and mutations to antiviral drugs in HIV-1-infected patients from Mozambique before initiation of antiretroviral therapy: results from the DREAM programme. J Med Virol 76(4):452–458. https://doi.org/10.1002/jmv.20382

Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, Heneine W, Kantor R, Jordan MR, Schapiro JM, Vandamme AM, Sandstrom P, Boucher CA, van de Vijver D, Rhee SY, Liu TF, Pillay D, Shafer RW (2009) Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PLoS One 4(3):e4724. https://doi.org/10.1371/journal.pone.0004724

Brorson K, Xu Y, Swann PG, Hamilton E, Mustafa M, de Wit C, Norling LA, Stein KE (2002) Evaluation of a quantitative product-enhanced reverse transcriptase assay to monitor retrovirus in mAb cell-culture. Biologicals 30(1):15–26. https://doi.org/10.1006/biol.2001.0290

Castor D, Low A, Evering T, Karmon S, Davis B, Figueroa A, LaMar M, Garmon D, Mehandru S, Markowitz M (2012) Transmitted drug resistance and phylogenetic relationships among acute and early HIV-1-infected individuals in New York City. J Acquir Immune Defic Syndr 61(1):1–8. https://doi.org/10.1097/QAI.0b013e31825a289b

Chabria SB, Gupta S, Kozal MJ (2014) Deep sequencing of HIV: clinical and research applications. Annu Rev Genomics Hum Genet 15:295–325. https://doi.org/10.1146/annurev-genom-091212-153406

Cihlar T, Laflamme G, Fisher R, Carey AC, Vela JE, Mackman R, Ray AS (2009) Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother 53(1):150–156. https://doi.org/10.1128/aac.01183-08

Cingolani A, Antinori A, Rizzo MG, Murri R, Ammassari A, Baldini F, Di Giambenedetto S, Cauda R, De Luca A (2002) Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA). Aids 16(3):369–379

De Clercq E (2016) Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF). Biochem Pharmacol 119:1–7. https://doi.org/10.1016/j.bcp.2016.04.015

Codoner FM, Pou C, Thielen A, Garcia F, Delgado R, Dalmau D, Alvarez-Tejado M, Ruiz L, Clotet B, Paredes R (2011) Added value of deep sequencing relative to population sequencing in heavily pre-treated HIV-1-infected subjects. PLoS One 6(5):e19461. https://doi.org/10.1371/journal.pone.0019461

Cohen CJ, Molina JM, Cahn P, Clotet B, Fourie J, Grinsztejn B, Wu H, Johnson MA, Saag M, Supparatpinyo K, Crauwels H, Lefebvre E, Rimsky LT, Vanveggel S, Williams P, Boven K (2012) Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE trials. J Acquir Immune Defic Syndr 60(1):33–42. https://doi.org/10.1097/QAI.0b013e31824d006e

Covens K, Dekeersmaeker N, Schrooten Y, Weber J, Schols D, Quinones-Mateu ME, Vandamme AM, Van Laethem K (2009) Novel recombinant virus assay for measuring susceptibility of human immunodeficiency virus type 1 group M subtypes to clinically approved drugs. J Clin Microbiol 47(7):2232–2242. https://doi.org/10.1128/jcm.01739-08

Cozzi-Lepri A, Noguera-Julian M, Di Giallonardo F, Schuurman R, Daumer M, Aitken S, Ceccherini-Silberstein F, D'Arminio Monforte A, Geretti AM, Booth CL, Kaiser R, Michalik C, Jansen K, Masquelier B, Bellecave P, Kouyos RD, Castro E, Furrer H, Schultze A, Gunthard HF, Brun-Vezinet F, Paredes R, Metzner KJ (2015) Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing. J Antimicrob Chemother 70(3):930–940. https://doi.org/10.1093/jac/dku426

DeStefano JJ, Alves Ferreira-Bravo I (2018) A highly sensitive aptamer-based HIV reverse transcriptase detection assay. J Virol Methods 257:22–28. https://doi.org/10.1016/j.jviromet.2018.04.005

Doyle T, Dunn DT, Ceccherini-Silberstein F, De Mendoza C, Garcia F, Smit E, Fearnhill E, Marcelin AG, Martinez-Picado J, Kaiser R, Geretti AM (2015) Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades. J Antimicrob Chemother 70(11):3080–3086. https://doi.org/10.1093/jac/dkv243

Eberle J, Seibl R (1992) A new method for measuring reverse transcriptase activity by ELISA. J Virol Methods 40(3):347–356

Eisenstein M (2015) Startups use short-read data to expand long-read sequencing market. Nat Biotechnol 33(5):433–435. https://doi.org/10.1038/nbt0515-433

Feng M, Wang D, Grobler JA, Hazuda DJ, Miller MD, Lai MT (2015) In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways. Antimicrob Agents Chemother 59(1):590–598. https://doi.org/10.1128/aac.04201-14

Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R (2009) Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother 53(2):487–495. https://doi.org/10.1128/aac.01156-08

Frezza C, Balestrieri E, Marino-Merlo F, Mastino A, Macchi B (2014) A novel, cell-free PCR-based assay for evaluating the inhibitory activity of antiretroviral compounds against HIV reverse transcriptase. J Med Virol 86(1):1–7. https://doi.org/10.1002/jmv.23748

Frezza C, Grelli S, Federico M, Marino-Merlo F, Mastino A, Macchi B (2016) Testing anti-HIV activity of antiretroviral agents in vitro using flow cytometry analysis of CEM-GFP cells infected with transfection-derived HIV-1 NL4-3. J Med Virol 88(6):979–986. https://doi.org/10.1002/jmv.24418

Gatell JM, Morales-Ramirez JO, Hagins DP, Thompson M, Keikawus A, Hoffmann C, Rugina S, Osiyemi O, Escoriu S, Dretler R, Harvey C, Xu X, Teppler H (2014) Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc 17(4 Suppl 3):19532. https://doi.org/10.7448/ias.17.4.19532

Geretti AM, Conibear T, Hill A, Johnson JA, Tambuyzer L, Thys K, Vingerhoets J, Van Delft Y (2014) Sensitive testing of plasma HIV-1 RNA and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resistance prior to starting first-line antiretroviral therapy with etravirine or efavirenz. J Antimicrob Chemother 69(4):1090–1097. https://doi.org/10.1093/jac/dkt474

Gianella S, Richman DD (2010) Minority variants of drug-resistant HIV. J Infect Dis 202(5):657–666. https://doi.org/10.1086/655397

Goodwin S, McPherson JD, McCombie WR (2016) Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet 17(6):333–351. https://doi.org/10.1038/nrg.2016.49

Gulick RM (2018) Investigational antiretroviral drugs: what is coming down the pipeline. Top Antivir Med 25(4):127–132

Heneine W, Yamamoto S, Switzer WM, Spira TJ, Folks TM (1995) Detection of reverse transcriptase by a highly sensitive assay in sera from persons infected with human immunodeficiency virus type 1. J Infect Dis 171(5):1210–1216

Hertogs K, de Bethune MP, Miller V, Ivens T, Schel P, Van Cauwenberge A, Van Den Eynde C, Van Gerwen V, Azijn H, Van Houtte M, Peeters F, Staszewski S, Conant M, Bloor S, Kemp S, Larder B, Pauwels R (1998) A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother 42(2):269–276

Hoffmann D, Garcia AD, Harrigan PR, Johnston IC, Nakasone T, Garcia-Lerma JG, Heneine W (2011) Measuring enzymatic HIV-1 susceptibility to two reverse transcriptase inhibitors as a rapid and simple approach to HIV-1 drug-resistance testing. PLoS One 6(7):e22019. https://doi.org/10.1371/journal.pone.0022019

Japour AJ, Mayers DL, Johnson VA, Kuritzkes DR, Beckett LA, Arduino JM, Lane J, Black RJ, Reichelderfer PS, D'Aquila RT, Crumpacker CS (1993) Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group. Antimicrob Agents Chemother 37(5):1095–1101

Johnson JA, Li JF, Wei X, Lipscomb J, Irlbeck D, Craig C, Smith A, Bennett DE, Monsour M, Sandstrom P, Lanier ER, Heneine W (2008) Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy. PLoS Med 5(7):e158. https://doi.org/10.1371/journal.pmed.0050158

Kawamoto A, Kodama E, Sarafianos SG, Sakagami Y, Kohgo S, Kitano K, Ashida N, Iwai Y, Hayakawa H, Nakata H, Mitsuya H, Arnold E, Matsuoka M (2008) 2'-Deoxy-4'-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants. Int J Biochem Cell Biol 40(11):2410–2420. https://doi.org/10.1016/j.biocel.2008.04.007

Kellam P, Larder BA (1994) Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates. Antimicrob Agents Chemother 38(1):23–30

Kokkayil P, Kurapati S, Negi N, Vajpayee M (2014) Comparative evaluation of a reverse transcriptase based assay for HIV-1 viral load quantitation in resource limited settings. J Virol Methods 203:1–4. https://doi.org/10.1016/j.jviromet.2014.02.021

Kokkula C, Palanisamy N, Ericstam M, Lennerstrand J (2016) SYBR green II dye-based real-time assay for measuring inhibitor activity against HIV-1 reverse transcriptase. Mol Biotechnol 58(10):619–625. https://doi.org/10.1007/s12033-016-9961-y

Laborde ND, Pleasants E, Reddy K, Atujuna M, Nakyanzi T, Chitukuta M, Naidoo S, Palanee-Phillips T, Baeten JM, Montgomery ET (2018) Impact of the dapivirine vaginal ring on sexual experiences and intimate partnerships of women in an HIV prevention clinical trial: managing ring detection and hot sex. AIDS Behav 22(2):437–446. https://doi.org/10.1007/s10461-017-1977-1

Lai MT, Feng M, Falgueyret JP, Tawa P, Witmer M, DiStefano D, Li Y, Burch J, Sachs N, Lu M, Cauchon E, Campeau LC, Grobler J, Yan Y, Ducharme Y, Cote B, Asante-Appiah E, Hazuda DJ, Miller MD (2014) In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother 58(3):1652–1663. https://doi.org/10.1128/aac.02403-13

Larder BA, Darby G, Richman DD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243(4899):1731–1734

Li JF, Linley L, Kline R, Ziebell R, Heneine W, Johnson JA (2016) Sensitive sentinel mutation screening reveals differential underestimation of transmitted HIV drug resistance among demographic groups. Aids 30(9):1439–1445. https://doi.org/10.1097/qad.0000000000001099

Llibre JM, Walmsley S, Gatell JM (2016) Backbones versus core agents in initial ART regimens: one game, two players. J Antimicrob Chemother 71(4):856–861. https://doi.org/10.1093/jac/dkv429

Lovatt A, Black J, Galbraith D, Doherty I, Moran MW, Shepherd AJ, Griffen A, Bailey A, Wilson N, Smith KT (1999) High throughput detection of retrovirus-associated reverse transcriptase using an improved fluorescent product enhanced reverse transcriptase assay and its comparison to conventional detection methods. J Virol Methods 82(2):185–200

Margolis DA, Brinson CC, Smith GHR, de Vente J, Hagins DP, Eron JJ, Griffith SK, Clair MHS, Stevens MC, Williams PE, Ford SL, Stancil BS, Bomar MM, Hudson KJ, Smith KY, Spreen WR (2015) Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis 15(10):1145–1155. https://doi.org/10.1016/s1473-3099(15)00152-8

Margot NA, Liu Y, Miller MD, Callebaut C (2016) High resistance barrier to tenofovir alafenamide is driven by higher loading of tenofovir diphosphate into target cells compared to tenofovir disoproxil fumarate. Antivir Res 132:50–58. https://doi.org/10.1016/j.antiviral.2016.05.012

Margot N, Cox S, Das M, McCallister S, Miller MD, Callebaut C (2018) Rare emergence of drug resistance in HIV-1 treatment-naive patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for 144 weeks. J Clin Virol 103:37–42. https://doi.org/10.1016/j.jcv.2018.03.012

Marino-Merlo F, Frezza C, Papaianni E, Valletta E, Mastino A, Macchi B (2017) Development and evaluation of a simple and effective RT-qPCR inhibitory assay for detection of the efficacy of compounds towards HIV reverse transcriptase. Appl Microbiol Biotechnol 101(22):8249–8258. https://doi.org/10.1007/s00253-017-8544-6

Markowitz M, Sarafianos SG (2018) 4′-Ethynyl-2-fluoro-2′-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor. Curr Opin HIV AIDS 13(4):294–299. https://doi.org/10.1097/coh.0000000000000467

McGowan I, Dezzutti CS, Siegel A, Engstrom J, Nikiforov A, Duffill K, Shetler C, Richardson-Harman N, Abebe K, Back D, Else L, Egan D, Khoo S, Egan JE, Stall R, Williams PE, Rehman KK, Adler A, Brand RM, Chen B, Achilles S, Cranston RD (2016) Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment. Lancet HIV 3(12):e569–e578. https://doi.org/10.1016/s2352-3018(16)30113-8

Metzker ML (2010) Sequencing technologies - the next generation. Nat Rev Genet 11(1):31–46. https://doi.org/10.1038/nrg2626

Metzner KJ, Giulieri SG, Knoepfel SA, Rauch P, Burgisser P, Yerly S, Gunthard HF, Cavassini M (2009) Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and -adherent patients. Clin Infect Dis 48(2):239–247. https://doi.org/10.1086/595703

Metzner KJ, Rauch P, Braun P, Knechten H, Ehret R, Korn K, Kaiser R, Sichtig N, Ranneberg B, van Lunzen J, Walter H (2011) Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naive patients. J Clin Virol 50(2):156–161. https://doi.org/10.1016/j.jcv.2010.10.001

Metzner KJ, Scherrer AU, Preiswerk B, Joos B, von Wyl V, Leemann C, Rieder P, Braun D, Grube C, Kuster H, Boni J, Yerly S, Klimkait T, Aubert V, Furrer H, Battegay M, Vernazza PL, Cavassini M, Calmy A, Bernasconi E, Weber R, Gunthard HF (2013) Origin of minority drug-resistant HIV-1 variants in primary HIV-1 infection. J Infect Dis 208(7):1102–1112. https://doi.org/10.1093/infdis/jit310

Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, Xu X, Rodgers A, Lupinacci L, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C (2018) Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV 5(5):e211–e220. https://doi.org/10.1016/s2352-3018(18)30021-3

Noguera-Julian M, Edgil D, Harrigan PR, Sandstrom P, Godfrey C, Paredes R (2017) Next-generation human immunodeficiency virus sequencing for patient management and drug resistance surveillance. J Infect Dis 216(suppl_9):S829–s833. https://doi.org/10.1093/infdis/jix397

Palella FJ Jr, Armon C, Buchacz K, Cole SR, Chmiel JS, Novak RM, Wood K, Moorman AC, Brooks JT (2009) The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: a cohort study. Ann Intern Med 151(2):73–84

Panel on Antiretroviral Guidelines for Adults and Adolescents (2018) Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of health and human services. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 20 June 2018

Paredes R, Lalama CM, Ribaudo HJ, Schackman BR, Shikuma C, Giguel F, Meyer WA III, Johnson VA, Fiscus SA, D'Aquila RT, Gulick RM, Kuritzkes DR (2010) Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis 201(5):662–671. https://doi.org/10.1086/650543

Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, Tian H, Smith D, Winslow GA, Capon DJ, Whitcomb JM (2000) A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 44(4):920–928

Peuchant O, Thiebaut R, Capdepont S, Lavignolle-Aurillac V, Neau D, Morlat P, Dabis F, Fleury H, Masquelier B (2008) Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy. Aids 22(12):1417–1423. https://doi.org/10.1097/QAD.0b013e3283034953

Pizzato M, Erlwein O, Bonsall D, Kaye S, Muir D, McClure MO (2009) A one-step SYBR Green I-based product-enhanced reverse transcriptase assay for the quantitation of retroviruses in cell culture supernatants. J Virol Methods 156(1–2):1–7. https://doi.org/10.1016/j.jviromet.2008.10.012

Pyra H, Boni J, Schupbach J (1994) Ultrasensitive retrovirus detection by a reverse transcriptase assay based on product enhancement. Proc Natl Acad Sci U S A 91(4):1544–1548

Rai MA, Pannek S, Fichtenbaum CJ (2018) Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs 23(2):149–157. https://doi.org/10.1080/14728214.2018.1474202

Rimsky L, Van Eygen V, Hoogstoel A, Stevens M, Boven K, Picchio G, Vingerhoets J (2013) 96-Week resistance analyses of rilpivirine in treatment-naive, HIV-1-infected adults from the ECHO and THRIVE phase III trials. Antivir Ther 18(8):967–977. https://doi.org/10.3851/imp2636

Saladini F, Giannini A, Boccuto A, Vicenti I, Zazzi M (2018) Agreement between an in-house replication competent and a reference replication defective recombinant virus assay for measuring phenotypic resistance to HIV-1 protease, reverse transcriptase, and integrase inhibitors. J Clin Lab Anal 32:e22206. https://doi.org/10.1002/jcla.22206

Santoro MM, Fabeni L, Armenia D, Alteri C, Di Pinto D, Forbici F, Bertoli A, Di Carlo D, Gori C, Carta S, Fedele V, D'Arrigo R, Berno G, Ammassari A, Pinnetti C, Nicastri E, Latini A, Tommasi C, Boumis E, Petrosillo N, D'Offizi G, Andreoni M, Ceccherini-Silberstein F, Antinori A, Perno CF (2014) Reliability and clinical relevance of the HIV-1 drug resistance test in patients with low viremia levels. Clin Infect Dis 58(8):1156–1164. https://doi.org/10.1093/cid/ciu020

Schader SM, Oliveira M, Ibanescu RI, Moisi D, Colby-Germinario SP, Wainberg MA (2012) In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine. Antimicrob Agents Chemother 56(2):751–756. https://doi.org/10.1128/aac.05821-11

Sears JF, Khan AS (2003) Single-tube fluorescent product-enhanced reverse transcriptase assay with Ampliwax (STF-PERT) for retrovirus quantitation. J Virol Methods 108(1):139–142

Shaw WH, Lin Q, Muhammad ZZ, Lee JJ, Khong WX, Ng OT, Tan EL, Li P (2016) Identification of HIV mutation as diagnostic biomarker through next generation sequencing. J Clin Diagn Res 10(7):Dc04–Dc08. https://doi.org/10.7860/jcdr/2016/19760.8140

Simen BB, Simons JF, Hullsiek KH, Novak RM, Macarthur RD, Baxter JD, Huang C, Lubeski C, Turenchalk GS, Braverman MS, Desany B, Rothberg JM, Egholm M, Kozal MJ (2009) Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. J Infect Dis 199(5):693–701. https://doi.org/10.1086/596736

Sluis-Cremer N, Wainberg MA, Schinazi RF (2015) Resistance to reverse transcriptase inhibitors used in the treatment and prevention of HIV-1 infection. Future Microbiol 10(11):1773–1782. https://doi.org/10.2217/fmb.15.106

Somogyi PA, Gyuris A, Foldes I (1990) A solid phase reverse transcriptase micro-assay for the detection of human immunodeficiency virus and other retroviruses in cell culture supernatants. J Virol Methods 27(3):269–276

Walter H, Schmidt B, Korn K, Vandamme AM, Harrer T, Uberla K (1999) Rapid, phenotypic HIV-1 drug sensitivity assay for protease and reverse transcriptase inhibitors. J Clin Virol 13(1–2):71–80

Weber J, Vazquez AC, Winner D, Rose JD, Wylie D, Rhea AM, Henry K, Pappas J, Wright A, Mohamed N, Gibson R, Rodriguez B, Soriano V, King K, Arts EJ, Olivo PD, Quinones-Mateu ME (2011) Novel method for simultaneous quantification of phenotypic resistance to maturation, protease, reverse transcriptase, and integrase HIV inhibitors based on 3'Gag(p2/p7/p1/p6)/PR/RT/INT-recombinant viruses: a useful tool in the multitarget era of antiretroviral therapy. Antimicrob Agents Chemother 55(8):3729–3742. https://doi.org/10.1128/aac.00396-11

Wegner SA, Wallace MR, Aronson NE, Tasker SA, Blazes DL, Tamminga C, Fraser S, Dolan MJ, Stephan KT, Michael NL, Jagodzinski LL, Vahey MT, Gilcrest JL, Tracy L, Milazzo MJ, Murphy DJ, McKenna P, Hertogs K, Rinehart A, Larder B, Birx DL (2004) Long-term efficacy of routine access to antiretroviral-resistance testing in HIV type 1-infected patients: results of the clinical efficacy of resistance testing trial. Clin Infect Dis 38(5):723–730. https://doi.org/10.1086/381266

Wensing AM, Calvez V, Gunthard HF, Johnson VA, Paredes R, Pillay D, Shafer RW, Richman DD (2017) 2017 update of the drug resistance mutations in HIV-1. Top Antivir Med 24(4):132–133

White KLMN, Stray K, Yu H, Stepan G, Boojamra C, Mackman R, Ray A, Miller MD, Cihlar T (2017) GS-9131 is a novel NRTI with activity against NRTI-resistant HIV-1. [CROI Abstract 2017] In Special Issue: Abstracts From the 2017 Conference on Retroviruses and Opportunistic Infections. Top Antivir Med 25(suppl 1):179s. https://www.iasusa.org/tam/april-2017-special-issue

Wu S, Yan P, Yan Y, Qiu L, Xie M (2015) A single-loop recombinant pseudotyped-virus-based assay to detect HIV-1 phenotypic resistance. Arch Virol 160(6):1385–1395. https://doi.org/10.1007/s00705-015-2386-2

Wu VH, Smith RA, Masoum S, Raugi DN, Ba S, Seydi M, Grobler JA, Gottlieb GS (2017) MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine) exhibits potent activity against HIV-2 isolates and drug-resistant HIV-2 mutants in culture. Antimicrob Agents Chemother 61:e00744-17. https://doi.org/10.1128/aac.00744-17

Xiaobai Z, Xi C, Tian H, Williams AB, Wang H, He J, Zhen J, Chiarella J, Blake LA, Turenchalk G, Kozal MJ (2014) Prevalence of WHO transmitted drug resistance mutations by deep sequencing in antiretroviral-naive subjects in Hunan Province, China. PLoS One 9(6):e98740. https://doi.org/10.1371/journal.pone.0098740