Chapter 11 : Antiretroviral Agents

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Antiretroviral Agents, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819439/9781555819422.ch11-1.gif /docserver/preview/fulltext/10.1128/9781555819439/9781555819422.ch11-2.gif


In 1987, zidovudine became the first approved agent in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Almost 30 years later, more than 26 additional agents in six drug classes have been approved. These include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (entry inhibitor), a chemokine coreceptor antagonist (entry inhibitor), integrase strand transfer inhibitors (Table 1), and pharmacokinetic enhancers. This success is the result of a prodigious effort to dissect the virus’ replication cycle and the virion's interaction with its CD4 target cells to identify promising drug targets. It also illustrates the interdependency of the drug development process, knowledge of disease pathogenesis, and use of sensitive therapeutic monitoring tools like plasma HIV-1 RNA levels and drug resistance testing.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1.

Replication cycle of HIV-1 with current targets for antiretroviral therapy.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2.

Chemical structures of HIV entry inhibitors.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3.

Chemical structures of HIV nucleoside/nucleotide reverse transcriptase inhibitors.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4.

Chemical structures of HIV nonnucleoside reverse transcriptase inhibitors.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5.

Chemical structures of HIV integrase inhibitors.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6.

Chemical structures of HIV protease inhibitors.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 7.

Chemical structures of pharmacoenhancers.

Citation: Kubin C, Taylor B, Hammer S. 2017. Antiretroviral Agents, p 169-214. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Günthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, Hoy JF, Mugavero MJ, Sax PE, Thompson MA, Gandhi RT, Landovitz RJ, Smith DM, Jacobsen DM, Volberding PA . 2016. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA 316 : 191 210.[PubMed]
2. Coghlan ME, Sommadossi JP, Jhala NC, Many WJ, Saag MS, Johnson VA . 2001. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases. Clin Infect Dis 33 : 1914 1921.[PubMed]
3. Matthews T, Salgo M, Greenberg M, Chung J, DeMasi R, Bolognesi D . 2004. Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nat Rev Drug Discov 3 : 215 225.[PubMed]
4. Westby M, van der Ryst E . 2005. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother 16 : 339 354.[PubMed]
5. Lu L, Yu F, Cai L, Debnath AK, Jiang S . 2016. Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41. Curr Top Med Chem 16 : 1074 1090.[PubMed]
6. Lalezari JP, Latiff GH, Brinson C, Echevarría J, Treviño-Pérez S, Bogner JR, Thompson M, Fourie J, Sussmann Pena OA, Mendo Urbina FC, Martins M, Diaconescu IG, Stock DA, Joshi SR, Hanna GJ, Lataillade M ; AI438011 study team . 2015. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lancet HIV 2 : e427 e437.[PubMed]
7. Thompson M, Lalezari J, Kaplan R . 2015. Attachment inhibitor prodrug BMS–663068 in ARV-experienced subjects: Week 48 Analysis, abstr 2015 Conference on Retroviruses and Opportunistic Infections, Seattle, February 23–24, 2015.
8. Gathe J, Cade J, DeJesus E . 2013. Week-24 Primary analysis of cenicriviroc vs efavirenz, in combination with emtricitabine/tenofovir, in treatment-naïve HIV-1+ adults with CCR5-tropic virus, abstr 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, March 3–6, 2013.
9. TaiMed-Biologics-Inc . 2016. TMB-355 (Ibalizumab), on TaiMed Biologics Inc. http://www.taimedbiologics.com/en/info/TMB355.aspx. Accessed September 6, 2016.
10. Lalezari J, Kush D, Kowalczyk U, Kazempour K, Pourhassan N, Maddon PJ . 2016. PRO140 SC monotherapy (MT) provides long-term, full virologic suppression in HIV patients, abstr ASM Microbe, Boston, June 16–20, 2016.
11. He Y, Xiao Y, Song H, Liang Q, Ju D, Chen X, Lu H, Jing W, Jiang S, Zhang L . 2008. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 283 : 11126 11134.[PubMed]
12. Latinovic O, Reitz M, Le NM, Foulke JS, Fätkenheuer G, Lehmann C, Redfield RR, Heredia A . 2011. CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells. Virology 411 : 32 40.[PubMed]
13. Gatell J . 2014. 48-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naïve HIV-infected patients, abstr 12th International Congress on HIV Drug Therapy, Glasgow, United Kingdom, November 2–6, 2014.
14. 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 L-G, 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 for the MTN-020–ASPIRE Study Team . 2016. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med NEJMoa1506110.[PubMed]
15. Smith RA, Raugi DN, Wu VH, Leong SS, Parker KM, Oakes MK, Sow PS, Ba S, Seydi M, Gottlieb GS ; University of Washington-Dakar HIV-2 Study Group . 2015. The nucleoside analog BMS-986001 shows greater in vitro activity against HIV-2 than against HIV-1. Antimicrob Agents Chemother 59 : 7437 7446.[PubMed]
16. Friedman E, Schuermann D, Rudd DJ, Fox-Bosetti S, Zhang S, Robberechts M, Hueser A, Hazuda DJ, Iwamoto M, Grobler J . 2016. A single monotherapy dose of MK-8591, a novel NRTI, suppresses HIV for 10 days, abstr Conference on Retroviruses and Opportunistic Infections, Boston, 2016.
17. Cha YJ, Lim KS, Park MK, Schneider S, Bray B, Kang MC, Chung JY, Yoon SH, Cho JY, Yu KS . 2014. Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects. Drug Des Devel Ther 8 : 1613 1619.[PubMed]
18. Margolis DA, Brinson CC, Smith GH, de Vente J, Hagins DP, Eron JJ, Griffith SK, St Clair MH, Stevens MC, Williams PE, Ford SL, Stancil BS, Bomar MM, Hudson KJ, Smith KY, Spreen WR LAI116482 Study Team . 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 : 1145 1155.[PubMed]
19. Margolis DA, González-García J, Stellbrink H, Eron JJ, Yazdanpanah Y, Griffith S, Dorey D, Smith KY, Williams P, Spreen W . 2016. Cabotegravir+Rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results, abstr Conference on Retroviruses and Opportunistic Infections, Boston, 2016.
20. Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Sun Y, Samanta H, Terry B, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Healy M, Meanwell NA, Cockett M, Hanumegowda U, Regueiro-Ren A, Krystal M, Dicker IB . 2016. Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage. Antimicrob Agents Chemother 60 : 3956 3969.[PubMed]
21. Hwang C, Schürmann D, Sobotha C, Sevinsky H, Ravindran P, Xiao H, Ray N, Krystal M, Dicker IB, Lataillade M . 2015. Antiviral activity/safety of a second-generation HIV-1 maturation inhibitor, abstr CROI 2015, Seattle, WA.
22. Whitney JB, Lim SY, Osuna CE, Sanisetty S, Barnes TL, Cihlar T, Miller M, Geleziunas R, Hesselgesser J . 2016. Repeated TLR7 agonist treatment of SIV+ monkeys on ART can lead to viral remission, abstr Conference on Retroviruses and Opportunistic Infections, Boston, 2016.
23. Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O'Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E . 2000. Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74 : 8358 8367.[PubMed]
24. Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pohlmann S, Sfakianos JN, Derdeyn CA, Blumenthal R, Hunter E, Doms RW . 2002. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 99 : 16249 16254.[PubMed]
25. Melby T, Despirito M, Demasi R, Heilek-Snyder G, Greenberg ML, Graham N . 2006. HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis 194 : 238 246.[PubMed]
26. Hartt JK, Liang T, Sahagun-Ruiz A, Wang J-M, Gao J-L, Murphy PM . 2000. The HIV-1 cell entry inhibitor T-20 potently chemoattracts neutrophils by specifically activating the N-formylpeptide receptor. Biochem Biophys Res Commun 272 : 699 704.[PubMed]
27. Trottier B, Walmsley S, Reynes J, Piliero P, O'Hearn M, Nelson M, Montaner J, Lazzarin A, Lalezari J, Katlama C, Henry K, Cooper D, Clotet B, Arastéh K, Delfraissy JF, Stellbrink HJ, Lange J, Kuritzkes D, Eron JJ Jr, Cohen C, Kinchelow T, Bertasso A, Labriola-Tompkins E, Shikhman A, Atkins B, Bourdeau L, Natale C, Hughes F, Chung J, Guimaraes D, Drobnes C, Bader-Weder S, Demasi R, Smiley L, Salgo MP . 2005. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. J Acquir Immune Defic Syndr 40 : 413 421.[PubMed]
28. Wensing AM, Calvez V, Günthard HF, Johnson VA, Paredes R, Pillay D, Shafer RW, Richman DD . 2015. 2015 Update of the Drug Resistance Mutations in HIV-1. Top Antivir Med 23 : 132 141.[PubMed]
29. Su C, Melby T, DeMasi R, Ravindran P, Heilek-Snyder G . 2006. Genotypic changes in human immunodeficiency virus type 1 envelope glycoproteins on treatment with the fusion inhibitor enfuvirtide and their influence on changes in drug susceptibility in vitro. J Clin Virol 36 : 249 257.[PubMed]
30. Lu J, Deeks SG, Hoh R, Beatty G, Kuritzkes BA, Martin JN, Kuritzkes DR . 2006. Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis. J Acquir Immune Defic Syndr 43 : 60 64.[PubMed]
31. Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC . 2002. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46 : 1896 1905.[PubMed]
32. Charpentier C, Jenabian MA, Piketty C, Karmochkine M, Tisserand P, Laureillard D, Bélec L, Si-Mohamed A, Weiss L . 2011. Dynamics of enfuvirtide resistance mutations in enfuvirtide-experienced patients remaining in virological failure under salvage therapy. Scand J Infect Dis 43 : 373 379.[PubMed]
33. Lu J, Sista P, Giguel F, Greenberg M, Kuritzkes DR . 2004. Relative replicative fitness of human immunodeficiency virus type 1 mutants resistant to enfuvirtide (T-20). J Virol 78 : 4628 4637.[PubMed]
34. Ray N, Harrison JE, Blackburn LA, Martin JN, Deeks SG, Doms RW . 2007. Clinical resistance to enfuvirtide does not affect susceptibility of human immunodeficiency virus type 1 to other classes of entry inhibitors. J Virol 81 : 3240 3250.[PubMed]
35. Xu L, Pozniak A, Wildfire A, Stanfield-Oakley SA, Mosier SM, Ratcliffe D, Workman J, Joall A, Myers R, Smit E, Cane PA, Greenberg ML, Pillay D . 2005. Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41. Antimicrob Agents Chemother 49 : 1113 1119.[PubMed]
36. Reeves JD, Miamidian JL, Biscone MJ, Lee FH, Ahmad N, Pierson TC, Doms RW . 2004. Impact of mutations in the coreceptor binding site on human immunodeficiency virus type 1 fusion, infection, and entry inhibitor sensitivity. J Virol 78 : 5476 5485.[PubMed]
37. Joly V, Fagard C, Grondin C, Descamps D, Yazdanpanah Y, Charpentier C, Colin de Verdiere N, Tabuteau S, Raffi F, Cabie A, Chene G, Yeni P the ANRS 130 Apollo Trial Group . 2013. Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo). Antimicrob Agents Chemother 57 : 758 765.[PubMed]
38. Gandhi RT, Bosch RJ, Aga E, Albrecht M, Demeter LM, Dykes C, Bastow B, Para M, Lai J, Siliciano RF, Siliciano JD, Eron JJ for the AIDS Clinical Trials Group A5173 Team . 2010. No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy. J Infect Dis 201 : 293 296.[PubMed]
39. Lalezari JP, Henry K, O'Hearn M, Montaner JSG, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M TORO 1 Study Group . 2003. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348 : 2175 2185.[PubMed]
40. Nelson M, Arastéh K, Clotet B, Cooper DA, Henry K, Katlama C, Lalezari JP, Lazzarin A, Montaner JSG, O'Hearn M, Piliero PJ, Reynes J, Trottier B, Walmsley SL, Cohen C, Eron JJ Jr, Kuritzkes DR, Lange J, Stellbrink HJ, Delfraissy JF, Buss NE, Donatacci L, Wat C, Smiley L, Wilkinson M, Valentine A, Guimaraes D, Demasi R, Chung J, Salgo MP . 2005. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr 40 : 404 412.[PubMed]
41. Clotet B, Bellos N, Molina J-M, Cooper D, Goffard J-C, Lazzarin A, Wöhrmann A, Katlama C, Wilkin T, Haubrich R, Cohen C, Farthing C, Jayaweera D, Markowitz M, Ruane P, Spinosa-Guzman S, Lefebvre E ; POWER 1 and 2 study groups . 2007. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 369 : 1169 1178.[PubMed]
42. Hicks CB, Cahn P, Cooper DA, Walmsley SL, Katlama C, Clotet B, Lazzarin A, Johnson MA, Neubacher D, Mayers D, Valdez H ; RESIST investigator group . 2006. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 368 : 466 475.[PubMed]
43. Reynes J, Arastéh K, Clotet B, Cohen C, Cooper DA, Delfraissy JF, Eron JJ, Henry K, Katlama C, Kuritzkes DR, Lalezari JP, Lange J, Lazzarin A, Montaner JS, Nelson M, O’ Hearn M, Stellbrink HJ, Trottier B, Walmsley SL, Buss NE, Demasi R, Chung J, Donatacci L, Guimaraes D, Rowell L, Valentine A, Wilkinson M, Salgo MP . 2007. TORO: ninety-six-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals. AIDS Patient Care STDS 21 : 533 543.[PubMed]
44. Raffi F, Katlama C, Saag M, Wilkinson M, Chung J, Smiley L, Salgo M . 2006. Week-12 response to therapy as a predictor of week 24, 48, and 96 outcome in patients receiving the HIV fusion inhibitor enfuvirtide in the T-20 versus Optimized Regimen Only (TORO) trials. Clin Infect Dis 42 : 870 877.[PubMed]
45. Arenzana-Seisdedos F, Virelizier J-L, Rousset D, Clark-Lewis I, Loetscher P, Moser B, Baggiolini M . 1996. HIV blocked by chemokine antagonist. Nature 383 : 400.[PubMed]
46. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA . 1996. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381 : 667 673.[PubMed]
47. Lederman MM, Penn-Nicholson A, Cho M, Mosier D . 2006. Biology of CCR5 and its role in HIV infection and treatment. JAMA 296 : 815 826.[PubMed]
48. Moore JP, Kitchen SG, Pugach P, Zack JA . 2004. The CCR5 and CXCR4 coreceptors—central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 20 : 111 126.[PubMed]
49. Wolinsky SM, Veazey RS, Kunstman KJ, Klasse PJ, Dufour J, Marozsan AJ, Springer MS, Moore JP . 2004. Effect of a CCR5 inhibitor on viral loads in macaques dual-infected with R5 and X4 primate immunodeficiency viruses. Virology 328 : 19 29.[PubMed]
50. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M . 2005. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49 : 4721 4732.[PubMed]
51. Vourvahis M, Fang J, Checchio T, Milton A, Weatherley B, McFadyen L, Heera J . 2013. Pharmacokinetics, safety, and tolerability of maraviroc in HIV-negative subjects with impaired renal function. HIV Clin Trials 14 : 99 109.[PubMed]
52. Gulick RM, Fatkenheuer G, Burnside R, Hardy WD, Nelson MR, Goodrich J, Mukwaya G, Portsmouth S, Heera JR . 2014. Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients. J Acquir Immune Defic Syndr 65 : 78 81.[PubMed]
53. Kindberg E, Mickienė A, Ax C, Åkerlind B, Vene S, Lindquist L, Lundkvist A, Svensson L . 2008. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis. J Infect Dis 197 : 266 269.[PubMed]
54. Lim JK, Louie CY, Glaser C, Jean C, Johnson B, Johnson H, McDermott DH, Murphy PM . 2008. Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic. J Infect Dis 197 : 262 265.[PubMed]
55. Sierra-Madero J, Di Perri G, Wood R, Saag M, Frank I, Craig C, Burnside R, McCracken J, Pontani D, Goodrich J, Heera J, Mayer H . 2010. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. HIV Clin Trials 11 : 125 132.[PubMed]
56. Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, Jenkins TM, Perros M, van der Ryst E . 2006. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 80 : 4909 4920.[PubMed]
57. Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, Stockdale M, Dorr P, Ciaramella G, Perros M . 2007. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 81 : 2359 2371.[PubMed]
58. Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, Clumeck N, Walmsley S, Ting N, Coakley E, Reeves JD, Reyes-Teran G, Westby M, Van Der Ryst E, Ive P, Mohapi L, Mingrone H, Horban A, Hackman F, Sullivan J, Mayer H . 2010. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis 201 : 803 813.[PubMed]
59. Wilkin TJ, Goetz MB, Leduc R, Skowron G, Su Z, Chan ES, Heera J, Chapman D, Spritzler J, Reeves JD, Gulick RM, Coakley E . 2011. Reanalysis of coreceptor tropism in HIV-1-infected adults using a phenotypic assay with enhanced sensitivity. Clin Infect Dis 52 : 925 928.[PubMed]
60. Cooper DA, Heera J, Ive P, Botes M, Dejesus E, Burnside R, Clumeck N, Walmsley S, Lazzarin A, Mukwaya G, Saag M, van Der Ryst E . 2014. Efficacy and safety of maraviroc vs. efavirenz in treatment-naive patients with HIV-1: 5-year findings. AIDS 28 : 717 725.[PubMed]
61. Hunt PW, Harrigan PR, Huang W, Bates M, Williamson DW, McCune JM, Price RW, Spudich SS, Lampiris H, Hoh R, Leigler T, Martin JN, Deeks SG . 2006. Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia. J Infect Dis 194 : 926 930.[PubMed]
62. Wilkin TJ, Su Z, Kuritzkes DR, Hughes M, Flexner C, Gross R, Coakley E, Greaves W, Godfrey C, Skolnik PR, Timpone J, Rodriguez B, Gulick RM . 2007. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin Infect Dis 44 : 591 595.[PubMed]
63. Gulick R, Wilkin T, Chen Y, Landovitz R, Amico K, Young A, Richardson P, Marzinke M, McCauley M, Mayer K . HPTN 069/ACTG 5305: Phase II Study of Maraviroc-Based Regimens for PrEP in MSM, Abs #103 CROI 2015, Seattle, WA.
64. Trkola A, Ketas TJ, Nagashima KA, Zhao L, Cilliers T, Morris L, Moore JP, Maddon PJ, Olson WC . 2001. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 75 : 579 588.[PubMed]
65. Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC . 2006. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother 50 : 3289 3296.[PubMed]
66. Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Larson JA, Weinheimer SP, Lewis ST . 2009. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 53 : 450 457.[PubMed]
67. Arribas JR, Horban A, Gerstoft J, Fätkenheuer G, Nelson M, Clumeck N, Pulido F, Hill A, van Delft Y, Stark T, Moecklinghoff C . 2010. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS 24 : 223 230.[PubMed]
68. Bruno CJ, Jacobson JM . 2010. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection. J Antimicrob Chemother 65 : 1839 1841.[PubMed]
69. Tenorio AR . 2011. The monoclonal CCR5 antibody PRO-140: the promise of once-weekly HIV therapy. Curr HIV/AIDS Rep 8 : 1 3.[PubMed]
70. Andrews CD, Spreen WR, Mohri H, Moss L, Ford S, Gettie A, Russell-Lodrigue K, Bohm RP, Cheng-Mayer C, Hong Z, Markowitz M, Ho DD . 2014. Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science 343 : 1151 1154.[PubMed]
71. Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, Marshall DJ, Crump JA, Kapiga SH, Sam NE, Sinangil F, Pancera M, Yongping Y, Zhang B, Zhu J, Kwong PD, O'Dell S, Mascola JR, Wu L, Nabel GJ, Phogat S, Seaman MS, Whitesides JF, Moody MA, Kelsoe G, Yang X, Sodroski J, Shaw GM, Montefiori DC, Kepler TB, Tomaras GD, Alam SM, Liao HX, Haynes BF . 2011. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol 85 : 9998 10009.[PubMed]
72. Bornholdt ZA, Turner HL, Murin CD, Li W, Sok D, Souders CA, Piper AE, Goff A, Shamblin JD, Wollen SE, Sprague TR, Fusco ML, Pommert KB, Cavacini LA, Smith HL, Klempner M, Reimann KA, Krauland E, Gerngross TU, Wittrup KD, Saphire EO, Burton DR, Glass PJ, Ward AB, Walker LM . 2016. Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak. Science 351 : 1078 1083.[PubMed]
73. Li L, Sun T, Yang K, Zhang P, Jia WQ . 2010. Monoclonal CCR5 antibody for treatment of people with HIV infection. Cochrane Database Syst Rev ( 12) : CD008439.[PubMed]
74. Gray GE, Laher F, Lazarus E, Ensoli B, Corey L . 2016. Approaches to preventative and therapeutic HIV vaccines. Curr Opin Virol 17 : 104 109.[PubMed]
75. Bournazos S, Gazumyan A, Seaman MS, Nussenzweig MC, Ravetch JV . 2016. Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency. Cell 165 : 1609 1620.[PubMed]
76. Burton DR, Hangartner L . 2016. Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu Rev Immunol 34 : 635 659.[PubMed]
77. Halper-Stromberg A, Nussenzweig MC . 2016. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest 126 : 415 423.[PubMed]
78. Lu CL, Murakowski DK, Bournazos S, Schoofs T, Sarkar D, Halper-Stromberg A, Horwitz JA, Nogueira L, Golijanin J, Gazumyan A, Ravetch JV, Caskey M, Chakraborty AK, Nussenzweig MC . 2016. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352 : 1001 1004.[PubMed]
79. Scheid JF, Horwitz JA, Bar-On Y, Kreider EF, Lu CL, Lorenzi JC, Feldmann A, Braunschweig M, Nogueira L, Oliveira T, Shimeliovich I, Patel R, Burke L, Cohen YZ, Hadrigan S, Settler A, Witmer-Pack M, West AP Jr, Juelg B, Keler T, Hawthorne T, Zingman B, Gulick RM, Pfeifer N, Learn GH, Seaman MS, Bjorkman PJ, Klein F, Schlesinger SJ, Walker BD, Hahn BH, Nussenzweig MC . 2016. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535 : 556 560.[PubMed]
80. Stephenson KE, Barouch DH . 2016. Broadly Neutralizing Antibodies for HIV Eradication. Curr HIV/AIDS Rep 13 : 31 37.[PubMed]
81. Wagh K, Bhattacharya T, Williamson C, Robles A, Bayne M, Garrity J, Rist M, Rademeyer C, Yoon H, Lapedes A, Gao H, Greene K, Louder MK, Kong R, Karim SA, Burton DR, Barouch DH, Nussenzweig MC, Mascola JR, Morris L, Montefiori DC, Korber B, Seaman MS . 2016. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection. PLoS Pathog 12 : e1005520.[PubMed]
82. Aussedat B, Vohra Y, Park PK, Fernández-Tejada A, Alam SM, Dennison SM, Jaeger FH, Anasti K, Stewart S, Blinn JH, Liao HX, Sodroski JG, Haynes BF, Danishefsky SJ . 2013. Chemical synthesis of highly congested gp120 V1V2 N-glycopeptide antigens for potential HIV-1-directed vaccines. J Am Chem Soc 135 : 13113 13120.[PubMed]
83. Abram ME, Hluhanich RM, Goodman DD, Andreatta KN, Margot NA, Ye L, Niedziela-Majka A, Barnes TL, Novikov N, Chen X, Svarovskaia ES, McColl DJ, White KL, Miller MD . 2013. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother 57 : 2654 2663.[PubMed]
84. Gautam R, Nishimura Y, Pegu A, Nason MC, Klein F, Gazumyan A, Golijanin J, Buckler-White A, Sadjadpour R, Wang K, Mankoff Z, Schmidt SD, Lifson JD, Mascola JR, Nussenzweig MC, Martin MA . 2016. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533 : 105 109.[PubMed]
85. Ledgerwood JE, Coates EE, Yamshchikov G, Saunders JG, Holman L, Enama ME, DeZure A, Lynch RM, Gordon I, Plummer S, Hendel CS, Pegu A, Conan-Cibotti M, Sitar S, Bailer RT, Narpala S, McDermott A, Louder M, O'Dell S, Mohan S, Pandey JP, Schwartz RM, Hu Z, Koup RA, Capparelli E, Mascola JR, Graham BS; VRC 602 Study Team . 2015. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol 182 : 289 301.[PubMed]
86. Pereira AS, Smeaton LM, Gerber JG, Acosta EP, Snyder S, Fiscus SA, Tidwell RR, Gulick RM, Murphy RL, Eron JJ Jr . 2002. The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS Clinical Trials Group Study 850). J Infect Dis 186 : 198 204.[PubMed]
87. Dudley MN . 1995. Clinical pharmacokinetics of nucleoside antiretroviral agents. J Infect Dis 171( Suppl 2) : S99 S112.[PubMed]
88. Moyle G . 2000. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 22 : 911 936, discussion 898.[PubMed]
89. Hanna GJ, Johnson VA, Kuritzkes DR, Richman DD, Brown AJ, Savara AV, Hazelwood JD, D'Aquila RT . 2000. Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine, and nevirapine. J Infect Dis 181 : 904 911.[PubMed]
90. Hu Z, Giguel F, Hatano H, Reid P, Lu J, Kuritzkes DR . 2006. Fitness comparison of thymidine analog resistance pathways in human immunodeficiency virus type 1. J Virol 80 : 7020 7027.[PubMed]
91. Larder BA, Darby G, Richman DD . 1989. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243 : 1731 1734.[PubMed]
92. Clavel F, Hance AJ . 2004. HIV drug resistance. N Engl J Med 350 : 1023 1035.[PubMed]
93. Kuritzkes DR, Bassett RL, Hazelwood JD, Barrett H, Rhodes RA, Young RK, Johnson VA ; Adult ACTG Protocol 306 370 Teams . 2004. Rate of thymidine analogue resistance mutation accumulation with zidovudine- or stavudine-based regimens. J Acquir Immune Defic Syndr 36 : 600 603.[PubMed]
94. Chamberlain PP, Ren J, Nichols CE, Douglas L, Lennerstrand J, Larder BA, Stuart DI, Stammers DK . 2002. Crystal structures of Zidovudine- or Lamivudine-resistant human immunodeficiency virus type 1 reverse transcriptases containing mutations at codons 41, 184, and 215. J Virol 76 : 10015 10019.[PubMed]
95. Götte M, Arion D, Parniak MA, Wainberg MA . 2000. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. J Virol 74 : 3579 3585.[PubMed]
96. Nikolenko GN, Palmer S, Maldarelli F, Mellors JW, Coffin JM, Pathak VK . 2005. Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: balance between RNase H activity and nucleotide excision. Proc Natl Acad Sci USA 102 : 2093 2098.[PubMed]
97. Muniz CP, Soares MA, Santos AF . 2014. Early selection of resistance-associated mutations in HIV-1 RT C-terminal domains across different subtypes: role of the genetic barrier to resistance. J Antimicrob Chemother 69 : 2741 2745.[PubMed]
98. Lengruber RB, Delviks-Frankenberry KA, Nikolenko GN, Baumann J, Santos AF, Pathak VK, Soares MA . 2011. Phenotypic characterization of drug resistance-associated mutations in HIV-1 RT connection and RNase H domains and their correlation with thymidine analogue mutations. J Antimicrob Chemother 66 : 702 708.[PubMed]
99. von Wyl V, Ehteshami M, Demeter LM, Bürgisser P, Nijhuis M, Symons J, Yerly S, Böni J, Klimkait T, Schuurman R, Ledergerber B, Götte M, Günthard HF; Swiss HIV Cohort Study . 2010. HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy. Clin Infect Dis 51 : 620 628.[PubMed]
100. Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS AIDS Clinical Trials Group 384 Team . 2003. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 349 : 2293 2303.[PubMed]
101. Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, Delfraissy JF, Jemsek J, Rivero A, Rozenbaum W, Schrader S, Sension M, Vibhagool A, Thiry A, Giordano M . 2004. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 36 : 1011 1019.[PubMed]
102. Vibhagool A, Cahn P, Schechter M, Smaill F, Soto-Ramirez L, Carosi G, Montroni M, Pharo CE, Jordan JC, Thomas NE, Pearce G . 2004. Triple nucleoside treatment with abacavir plus the lamivudine/zidovudine combination tablet (COM) compared to indinavir/COM in antiretroviral therapy-naïve adults: results of a 48-week open-label, equivalence trial (CNA3014). Curr Med Res Opin 20 : 1103 1114.[PubMed]
103. DeJesus E, Herrera G, Teofilo E, Gerstoft J, Buendia CB, Brand JD, Brothers CH, Hernandez J, Castillo SA, Bonny T, Lanier ER, Scott TR ; CNA30024 Study Team . 2004. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 39 : 1038 1046.[PubMed]
104. Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK ; Study 934 Group . 2006. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354 : 251 260.[PubMed]
105. Services DoHaH . 2016. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. AIDSinfo, http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
106. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O'Neill E, Bazin B, Delfraissy J-F, Culnane M, Coombs R, Elkins M, Moye J, Stratton P, Balsley J ., 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 331 : 1173 1180.[PubMed]
107. Cardo DM, Culver DH, Ciesielski CA, Srivastava PU, Marcus R, Abiteboul D, Heptonstall J, Ippolito G, Lot F, McKibben PS, Bell DM Centers for Disease Control and Prevention Needlestick Surveillance Group . 1997. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med 337 : 1485 1490.[PubMed]