Resistance against integrase strand transfer inhibitors and relevance to HIV persistence

Viruses

Volumn 7, Issue 7, 2015, Pages 3703-3718

  Mesplède, Thibault ^a   Wainberg, Mark A ^a,b  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

Author keywords

Dolutegravir; Elvitegravir; HIV; HIV eradication; Integrase strand transfer inhibitors; R263K; Raltegravir; Resistance; Viral fitness; Viral reservoirs

Indexed keywords

ATAZANAVIR; DOLUTEGRAVIR; ELVITEGRAVIR; EMTRICITABINE; INTEGRASE; RALTEGRAVIR; RNA DIRECTED DNA POLYMERASE; TENOFOVIR; INTEGRASE INHIBITOR;

CLINICAL TRIAL (TOPIC); GENE MUTATION; GENETIC VARIABILITY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; PERSISTENT VIRUS INFECTION; REVIEW; TREATMENT FAILURE; VIRAL CLEARANCE; VIRUS REPLICATION; VIRUS TRANSMISSION; ANIMAL; ANTIVIRAL RESISTANCE; DRUG EFFECTS; ENZYMOLOGY; GENETICS; HIV INFECTIONS; HUMAN IMMUNODEFICIENCY VIRUS 1; METABOLISM; VIROLOGY;

ANIMALS; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS;

EID: 84936939943     PISSN: None     EISSN: 19994915     Source Type: Journal    
DOI: 10.3390/v7072790     Document Type: Review

References (71)

1. Cohen, J. Can combination therapy overcome drug resistance? Science 1993, 260, 1258–1258.
2. Wainberg, M.A.; Zaharatos, G.J.; Brenner, B.G. Development of antiretroviral drug resistance. N. Engl. J. Med. 2011, 365, 637–646.
3. Land, S.; McGavin, K.; Birch, C.; Lucas, R. Reversion from zidovudine resistance to sensitivity on cessation of treatment. Lancet 1991, 338, 830–831.
4. Delaugerre, C.; Valantin, M.A.; Mouroux, M.; Bonmarchand, M.; Carcelain, G.; Duvivier, C.; Tubiana, R.; Simon, A.; Bricaire, F.; Agut, H.; et al. Re-occurrence of HIV-1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure. AIDS 2001, 15, 2189–2191.
5. Waters, L.J.; Barber, T.J. Dolutegravir for treatment of HIV: Spring forwards? Lancet 2013, 381, 705–706.
6. Wills, T.; Vega, V. Elvitegravir: A once-daily inhibitor of HIV-1 integrase. Expert Opin. Investig. Drugs 2012, 21, 395–401.
7. Katlama, C.; Murphy, R. Dolutegravir for the treatment of HIV. Expert Opin. Investig. Drugs 2012, 21, 523–530.
8. Wainberg, M.A.; Quashie, P.K.; Mesplede, T. Dolutegravir HIV integrase inhibitor treatment of HIV infection. Drug Future 2012, 37, 697–707.
9. Rockstroh, J.K.; DeJesus, E.; Lennox, J.L.; Yazdanpanah, Y.; Saag, M.S.; Wan, H.; Rodgers, A.J.; Walker, M.L.; Miller, M.; DiNubile, M.J.; et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: Final 5-year results from startmrk. J. Acquir. Immune Defic. Syndr. 2013, 63, 77–85.
10. Blanco, J.L.; Varghese, V.; Rhee, S.Y.; Gatell, J.M.; Shafer, R.W. HIV-1 integrase inhibitor resistance and its clinical implications. J. Infect. Dis. 2011, 203, 1204–1214.
11. Mesplede, T.; Quashie, P.K.; Wainberg, M.A. Resistance to HIV integrase inhibitors. Curr. Opin. HIV AIDS 2012, 7, 401–408.
12. Wainberg, M.A.; Mesplede, T.; Quashie, P.K. The development of novel HIV integrase inhibitors and the problem of drug resistance. Curr. Opin. Virol. 2012, 2, 656–662.
13. Quashie, P.K.; Mesplede, T.; Wainberg, M.A. HIV drug resistance and the advent of integrase inhibitors. Curr. Infect. Dis. Rep. 2012, 15, 85–100.
14. Mesplede, T.; Quashie, P.K.; Zanichelli, V.; Wainberg, M.A. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann. Med. 2014, 46, 123–129.
15. Mesplede, T.; Wainberg, M. Integrase strand transfer inhibitors in hiv therapy. Infect. Dis. Ther. 2013, 2, 83–93.
16. Lennox, J.L.; Dejesus, E.; Berger, D.S.; Lazzarin, A.; Pollard, R.B.; Ramalho Madruga, J.V.; Zhao, J.; Wan, H.; Gilbert, C.L.; Teppler, H.; et al. Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-Week efficacy, durability, subgroup, safety, and metabolic analyses. J. Acquir. Immune Defic. Syndr. 2010, 55, 39–48.
17. Lennox, J.L.; DeJesus, E.; Lazzarin, A.; Pollard, R.B.; Madruga, J.V.; Berger, D.S.; Zhao, J.; Xu, X.; Williams-Diaz, A.; Rodgers, A.J.; et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with hiv-1 infection: A multicentre, double-blind randomised controlled trial. Lancet 2009, 374, 796–806.
18. Markowitz, M.; Nguyen, B.Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J.O.; Crumpacker, C.S.; Isaacs, R.D.; et al. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J. Acquir. Immune Defic. Syndr. 2009, 52, 350–356.
19. Markowitz, M.; Nguyen, B.Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J.O.; Crumpacker, C.S.; Isaacs, R.D.; et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: Results of a 48-week controlled study. J. Acquir. Immune Defic. Syndr. 2007, 46, 125–133.
20. Eron, J.J., Jr.; Rockstroh, J.K.; Reynes, J.; Andrade-Villanueva, J.; Ramalho-Madruga, J.V.; Bekker, L.G.; Young, B.; Katlama, C.; Gatell-Artigas, J.M.; Arribas, J.R.; et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: A randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect. Dis. 2011, 11, 907–915.
21. Raffi, F.; Babiker, A.G.; Richert, L.; Molina, J.M.; George, E.C.; Antinori, A.; Arribas, J.R.; Grarup, J.; Hudson, F.; Schwimmer, C.; et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 Week results from the neat001/anrs143 randomised non-inferiority trial. Lancet 2014, 384, 1942–1951.
22. Ghosn, J.; Mazet, A.A.; Avettand-Fenoel, V.; Peytavin, G.; Wirden, M.; Delfraissy, J.F.; Chaix, M.L. Rapid selection and archiving of mutation e157q in HIV-1 DNA during short-term low-level replication on a raltegravir-containing regimen. J. Antimicrob. Chemother. 2009, 64, 433–434.
23. Sax, P.E.; DeJesus, E.; Mills, A.; Zolopa, A.; Cohen, C.; Wohl, D.; Gallant, J.E.; Liu, H.C.; Zhong, L.; Yale, K.; et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012, 379, 2439–2448.
24. Cohen, C.; Elion, R.; Ruane, P.; Shamblaw, D.; DeJesus, E.; Rashbaum, B.; Chuck, S.L.; Yale, K.; Liu, H.C.; Warren, D.R.; et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of hiv infection. Aids 2011, 25, F7–F12.
25. Kulkarni, R.; Abram, M.E.; McColl, D.J.; Barnes, T.; Fordyce, M.W.; Szwarcberg, J.; Cheng, A.K.; Miller, M.D.; White, K.L. Week 144 resistance analysis of elvitegravir/cobicistat/emtricitabine/ tenofovir DF versus atazanavir+ritonavir+emtricitabine/tenofovir DF in antiretroviral-naive patients. HIV Clin. Trials 2014, 15, 218–230.
26. Wohl, D.A.; Cohen, C.; Gallant, J.E.; Mills, A.; Sax, P.E.; Dejesus, E.; Zolopa, A.; Liu, H.C.; Plummer, A.; White, K.L.; et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir df for initial treatment of HIV-1 infection: Analysis of week 144 results. J. Acquir. Immune Defic. Syndr. 2014, 65, e118–e120.
27. DeJesus, E.; Rockstroh, J.K.; Henry, K.; Molina, J.M.; Gathe, J.; Ramanathan, S.; Wei, X.; Yale, K.; Szwarcberg, J.; White, K.; et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of hiv-1 infection: A randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012, 379, 2429–2438.
28. Elion, R.; Molina, J.M.; Ramon Arribas Lopez, J.; Cooper, D.; Maggiolo, F.; Wilkins, E.; Conway, B.; Liu, Y.P.; Margot, N.; Rhee, M.; et al. A randomized phase 3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results. J. Acquir. Immune Defic. Syndr. 2013, 63, 494–497.
29. Molina, J.M.; Lamarca, A.; Andrade-Villanueva, J.; Clotet, B.; Clumeck, N.; Liu, Y.P.; Zhong, L.; Margot, N.; Cheng, A.K.; Chuck, S.L. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: Randomised, double-blind, phase 3, non-inferiority study. Lancet Infect. Dis. 2012, 12, 27–35.
30. Zolopa, A.; Sax, P.E.; DeJesus, E.; Mills, A.; Cohen, C.; Wohl, D.; Gallant, J.E.; Liu, H.C.; Plummer, A.; White, K.L.; et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/ tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: Analysis of week 96 results. J. Acquir. Immune Defic. Syndr. 2013, 63, 96–100.
31. Clumeck, N.; Molina, J.M.; Henry, K.; Gathe, J.; Rockstroh, J.K.; DeJesus, E.; Wei, X.; White, K.; Fordyce, M.W.; Rhee, M.S.; et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs. ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: Analysis of week 144 results. J. Acquir. Immune Defic. Syndr. 2014, 65, e121–e124.
32. Rockstroh, J.K.; DeJesus, E.; Henry, K.; Molina, J.M.; Gathe, J.; Ramanathan, S.; Plummer, A.; Wei, X.; Abram, M.; Cheng, A.K.; et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs. ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir df for initial treatment of HIV-1 infection: Analysis of week 96 results. J. Acquir. Immune Defic. Syndr. 2013, 62, 483–486. [PubMed]
33. Kulkarni, R.; Abram, M.; Rhee, E.G.; Fordyce, M.W.; Szwarcberg, J.; Miller, C.D.; White, K. Week 144 resistance analyses of the phase 3 evg/cobi/ftc/tdf studies. In Proceedings of the 21st Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 3–6 March 2014; Poster number 587.
34. Walmsley, S.L.; Antela, A.; Clumeck, N.; Duiculescu, D.; Eberhard, A.; Gutierrez, F.; Hocqueloux, L.; Maggiolo, F.; Sandkovsky, U.; Granier, C.; et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N. Engl. J. Med. 2013, 369, 1807–1818.
35. Van Lunzen, J.; Maggiolo, F.; Arribas, J.R.; Rakhmanova, A.; Yeni, P.; Young, B.; Rockstroh, J.K.; Almond, S.; Song, I.; Brothers, C.; et al. Once daily dolutegravir (s/gsk1349572) in combination therapy in antiretroviral-naive adults with HIV: Planned interim 48 week results from spring-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect. Dis. 2012, 12, 111–118.
36. Clotet, B.; Feinberg, J.; van Lunzen, J.; Khuong-Josses, M.A.; Antinori, A.; Pokrovskiy, V.; Dumitru, I.; Fehr, J.; Ortiz, R.; Saag, M.; et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (flamingo): 48 Week results from the randomised open-label phase 3b study. Lancet 2014, 383, 2222–2231.
37. Raffi, F.; Jaeger, H.; Quiros-Roldan, E.; Albrecht, H.; Belonosova, E.; Gatell, J.M.; Baril, J.G.; Domingo, P.; Brennan, C.; Almond, S.; et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (spring-2 study): 96 Week results from a randomised, double-blind, non-inferiority trial. Lancet Infect. Dis. 2013, 13, 927–935.
38. Raffi, F.; Rachlis, A.; Stellbrink, H.J.; Hardy, W.D.; Torti, C.; Orkin, C.; Bloch, M.; Podzamczer, D.; Pokrovsky, V.; Pulido, F.; et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with hiv-1 infection: 48 Week results from the randomised, double-blind, non-inferiority spring-2 study. Lancet 2013, 381, 735–743.
39. Eron, J.J.; Clotet, B.; Durant, J.; Katlama, C.; Kumar, P.; Lazzarin, A.; Poizot-Martin, I.; Richmond, G.; Soriano, V.; Ait-Khaled, M.; et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant hiv type 1 infection: 24-Week results of the viking study. J. Infect. Dis. 2013, 207, 740–748.
40. Akil, B.; Blick, G.; Hagins, D.P.; Ramgopal, M.N.; Richmond, G.J.; Samuel, R.M.; Givens, N.; Vavro, C.; Song, I.H.; Wynne, B.; et al. Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-Week results from viking-4, a randomized study. Antivir. Ther. 2014, 20.
41. Castagna, A.; Maggiolo, F.; Penco, G.; Wright, D.; Mills, A.; Grossberg, R.; Molina, J.M.; Chas, J.; Durant, J.; Moreno, S.; et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-Week results of the phase III viking-3 study. J. Infect. Dis. 2014, 210, 354–362.
42. Cahn, P.; Pozniak, A.L.; Mingrone, H.; Shuldyakov, A.; Brites, C.; Andrade-Villanueva, J.F.; Richmond, G.; Buendia, C.B.; Fourie, J.; Ramgopal, M.; et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: Week 48 results from the randomised, double-blind, non-inferiority sailing study. Lancet 2013, 382, 700–708.
43. Quashie, P.K.; Mesplede, T.; Han, Y.S.; Oliveira, M.; Singhroy, D.N.; Fujiwara, T.; Underwood, M.R.; Wainberg, M.A. Characterization of the r263k mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J. Virol. 2012, 86, 2696–2705.
44. Mesplede, T.; Quashie, P.K.; Osman, N.; Han, Y.; Singhroy, D.N.; Lie, Y.; Petropoulos, C.J.; Huang, W.; Wainberg, M.A. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology 2013, 10, 22–28.
45. Wares, M.; Mesplede, T.; Quashie, P.K.; Osman, N.; Han, Y.; Wainberg, M.A. The m50i polymorphic substitution in association with the r263k mutation in HIV-1 subtype b integrase increases drug resistance but does not restore viral replicative fitness. Retrovirology 2014, 11, 7–14.
46. Mesplede, T.; Osman, N.; Wares, M.; Quashie, P.K.; Hassounah, S.; Anstett, K.; Singhroy, D.N.; Han, Y.; Wainberg, M.A. Addition of e138k to r263k in hiv integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity. J. Antimicrob. Chemother. 2014, 69, 2733–2740.
47. Wainberg, M.A.; Mesplede, T.; Raffi, F. What if HIV were unable to develop resistance against a new therapeutic agent? BMC Med. 2013, 11, 249–254.
48. Oliveira, M.; Mesplede, T.; Quashie, P.K.; Moisi, D.; Wainberg, M.A. Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. AIDS 2014, 28, 813–819.
49. Singhroy, D.N.; Wainberg, M.A.; Mesplede, T. Combination of the r263k and m184i/v resistance substitutions against dolutegravir and lamivudine decreases hiv replicative capacity. Antimicrob. Agents Chemother. 2015, 59, 2882–2885.
50. Mesplede, T.; Moisi, D.; Oliveira, M.; Ibanescu, I.; Ohnona, F.; Brenner, B.; Wainberg, M.A. Dolutegravir inhibits HIV-1 env evolution in primary human cells. AIDS 2015, 29, 659–665.
51. Letendre, S.L.; Mills, A.M.; Tashima, K.T.; Thomas, D.A.; Min, S.S.; Chen, S.; Piscitelli, S.C.; Song, I.H.; Extended ING116070 study team. Ing116070: A study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. Clin. Infect. Dis. 2014, 59, 1032–1037.
52. Min, S.; Song, I.; Borland, J.; Chen, S.; Lou, Y.; Fujiwara, T.; Piscitelli, S.C. Pharmacokinetics and safety of s/gsk1349572, a next-generation hiv integrase inhibitor, in healthy volunteers. Antimicrob. Agents Chemother. 2010, 54, 254–258.
53. Min, S.; Sloan, L.; Dejesus, E.; Hawkins, T.; McCurdy, L.; Song, I.; Stroder, R.; Underwood, M.; Chen, S.; Fujiwara, T.; et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS 2011, 25, 1737–1745.
54. Castellino, S.; Moss, L.; Wagner, D.; Borland, J.; Song, I.; Chen, S.; Lou, Y.; Min, S.S.; Goljer, I.; Culp, A.; et al. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob. Agents Chemother. 2013, 57, 3536–3546.
55. Adams, J.L.; Patterson, K.B.; Prince, H.M.; Sykes, C.; Greener, B.N.; Dumond, J.B.; Kashuba, A.D. Single and multiple dose pharmacokinetics of dolutegravir in the genital tract of HIV-negative women. Antivir. Ther. 2013, 18, 1005–1013.
56. Kobayashi, M.; Yoshinaga, T.; Seki, T.; Wakasa-Morimoto, C.; Brown, K.W.; Ferris, R.; Foster, S.A.; Hazen, R.J.; Miki, S.; Suyama-Kagitani, A.; et al. In vitro antiretroviral properties of s/gsk1349572, a next-generation hiv integrase inhibitor. Antimicrob. Agents Chemother. 2011, 55, 813–821.
57. Greener, B.N.; Patterson, K.B.; Prince, H.M.; Sykes, C.S.; Adams, J.L.; Dumond, J.B.; Shaheen, N.J.; Madanick, R.D.; Dellon, E.S.; Cohen, M.S.; et al. Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing. J. Acquir. Immune Defic. Syndr. 2013, 64, 39–44.
58. Croteau, D.; Letendre, S.; Best, B.M.; Ellis, R.J.; Breidinger, S.; Clifford, D.; Collier, A.; Gelman, B.; Marra, C.; Mbeo, G.; et al. Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1. Antimicrob. Agents Chemother. 2010, 54, 5156–5160.
59. Blanco, J.L.; Whitlock, G.; Milinkovic, A.; Moyle, G. HIV integrase inhibitors: A new era in the treatment of HIV. Expert Opin. Pharmacother. 2015, 16, 1313–1324.
60. Osman, N.; Mesplède, T.; Quashie, P.K.; Oliveira, M.; Zanichelli, V.; Wainberg, M.A. Dolutegravir maintains a durable effect against HIV replication in tissue culture even after drug washout. J. Antimicrob. Chemother. 2015, in press.
61. Gandhi, R.T.; Zheng, L.; Bosch, R.J.; Chan, E.S.; Margolis, D.M.; Read, S.; Kallungal, B.; Palmer, S.; Medvik, K.; Lederman, M.M.; et al. The effect of raltegravir intensification on low-level residual viremia in hiv-infected patients on antiretroviral therapy: A randomized controlled trial. PLoS Med. 2010, 7.
62. Gandhi, R.T.; Coombs, R.W.; Chan, E.S.; Bosch, R.J.; Zheng, L.; Margolis, D.M.; Read, S.; Kallungal, B.; Chang, M.; Goecker, E.A.; et al. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J. Acquir. Immune Defic. Syndr. 2012, 59, 229–235.
63. Hatano, H.; Strain, M.C.; Scherzer, R.; Bacchetti, P.; Wentworth, D.; Hoh, R.; Martin, J.N.; McCune, J.M.; Neaton, J.D.; Tracy, R.P.; et al. Increase in 2-ltr circles and decrease in d-dimer after raltegravir intensification in treated HIV-infected patients: A randomized, placebo-controlled trial. J. Infect. Dis. 2013, 208, 1436–1442.
64. Negredo, E.; Massanella, M.; Puertas, M.C.; Buzon, M.J.; Puig, J.; Perez-Alvarez, N.; Molto, J.; Perez-Santiago, J.; Bonjoch, A.; Jou, A.; et al. Early but limited effects of raltegravir intensification on CD4 t cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy. J. Antimicrob. Chemother. 2013, 68, 2358–2362.
65. Llibre, J.M.; Buzon, M.J.; Massanella, M.; Esteve, A.; Dahl, V.; Puertas, M.C.; Domingo, P.; Gatell, J.M.; Larrouse, M.; Gutierrez, M.; et al. Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: A randomized 48-week study. Antivir. Ther. 2012, 17, 355–364.
66. Chege, D.; Kovacs, C.; la Porte, C.; Ostrowski, M.; Raboud, J.; Su, D.; Kandel, G.; Brunetta, J.; Kim, C.J.; Sheth, P.M.; et al. Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: A randomized controlled trial. AIDS 2012, 26, 167–174.
67. Hatano, H.; Hayes, T.L.; Dahl, V.; Sinclair, E.; Lee, T.H.; Hoh, R.; Lampiris, H.; Hunt, P.W.; Palmer, S.; McCune, J.M.; et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J. Infect. Dis. 2011, 203, 960–968.
68. Chéret, A.; Nembot, G.; Mélard, A.; Lascoux, C.; Slama, L.; Miailhes, P.; Yeni, P.; Abel, S.; Avettand-Fenoel, V.; Venet, A.; et al. Intensive five-drug antiretroviral therapy regimen versus standard tripe-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS147): A randomised, open-label, phase 3 trial. Lancet Infect. Dis. 2015, 15, 387–396.
69. Markowitz, M.; Evering, T.; Garmon, D.; Caskey, M.; la Mar, M.; Rodriguez, K.; Sahl, V.; Palmer, S.; Prada, N.; Mohri, H. A randomized open-label study of 3- versus 5-drug combination antiretroviral therapy in newly HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. 2014, 66, 140–147.
70. Ananworanich, J.; Chomont, N.; Fletcher, J.L.K.; Pinyakorn, S.; Schuetz, A.; Sereti, I.; Rerknimitr, R.; Dewar, R.; Kroon, E.; Vandergeeten, C.; et al. Markers of HIV reservoir size and immune activation after treatment in acute HIV infection with and without raltegravir and maraviroc intensification. J. Virus Erad. 2015, 1, 116–122.
71. Buzon, M.; Codoner, F.M.; Frost, S.D.W.; Pou, C.; Puertas, M.C.; Massanella, M.; Dalmau, J.; Llibre, J.M.; Stevenson, M.; Blanco, J.; et al. Deep molecular characterization of HIV-1 dynamics under suppressive HAART. PLoS Pathog. 2011, 7, e1002314.