Single Genome Sequencing of HIV-1 Gag and Protease Resistance Mutations at Virologic Failure during the Ok04 Trial of Simplified versus Standard Maintenance Therapy

Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372: 293–299.

Amico K.R. , Harman J.J. , Johnson B.T. Efficacy of antiretroviral therapy adherence interventions: a research synthesis of trials, 1996 to 2004. JAIDS 2006; 41: 285–297.

Bangsberg D.R. , Moss A.R. , Deeks S.G. Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. J Antimicrob Chemother 2004; 53: 696–699.

Badia X. , Lizan L. , Magaz S. Cost-effectiveness analysis of enfuvirtide (ENF) added to an optimized therapy compared with an optimized therapy in patients with HIV/ AIDS. HIV Clin Trials 2007; 8: 235–245.

Schackman B.R. , Scott C.A. , Sax P.E. Potential risks and benefits of HIV treatment simplification: a simulation model of a proposed clinical trial. Clin Infect Dis 2007; 45: 1062–1070.

Kantor R. , Shafer R.W. , Follansbee S. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS 2004; 18: 1503–1511.

Arribas J.R. , Pulido F. Early virologic rebound in a pilot trial of ritonavir-boosted atanazavir as maintenance monotherapy. J Acquir Immune Defic Syndr 2007; 46: 118.

Arribas J.R. , Pulido F. , Delgado R. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). JAIDS 2005; 40: 280–287.

Danel C. , Moh R. , Chaix M.L. Two-months-off, four-months-on antiretroviral regimen increases the risk of resistance, compared with continuous therapy: a randomized trial involving West African adults. J Infect Dis 2009; 199: 66–76.

Clumeck N. , Goebel F. , Rozenbaum W. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS 2001; 15: 1517–1526.

Swindells S. , DiRienzo A.G. , Wilkin T. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA 2006; 296: 806–814.

Moltó J. , Santos J.R. , Negredo E. Lopinavir/ritonavir monotherapy as a simplification strategy in routine clinical practice. J Antimicrob Chemother 2007; 60: 436–439.

Negredo E. , Bonjoch A. , Clotet B. Benefits and concerns of simplification strategies in HIV-infected patients. J Antimicrob Chemother 2006; 58: 235–242.

Ananworanich J. , Gayet-Ageron A. , Le Braz M. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomized trial. Lancet 2006; 368: 459–465.

Benson C.A. , Vaida F. , Havlir D.V. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis 2006; 194: 1309–1318.

Cohen C.J. , Colson A.E. , Sheble-Hall A.G. , McLaughlin K.A. , Morse G.D. Pilot study of a novel short-cycle antiretroviral treatment interruption strategy: 48-week results of the five-days-on, two-days-off (FOTO) study. HIV Clin Trials 2007; 8: 19–23.

Strategies for Management of Antiretroviral Therapy Study Group. CD4⁺ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355: 2283–2296.

Gathe J.C.Y.R. Jr. , Mayberry C. , Nemeck J. Single-agent therapy with lopinavir/ritonavir suppresses plasma HIV-1 viral replication in HIV-1 naive subjects: IMANI-2 48-week results. 4th International Aids Society Conference on HIV Pathogenesis, Treatment and Prevention. 22–25 July 2007, Sydney, Australia. Abstract WEPEB034.

McKinnon J.E. , Mellors J.W. , Swindells S. Simplification strategies to reduce antiretroviral drug exposure: progress and prospects. Antivir Ther 2009; 14: 1–12.

Wilkin T.J. , McKinnon J.E. , DiRienzo A.G. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy: final 48-week clinical and virologic outcomes. J Infect Dis 2009; 199: 866–871.

Bierman W.F. , van Agtmael M.A. , Nijhuis M. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS 2009; 23: 279–291.

Pulido F. , Arribas J.R. , Delgado R. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. AIDS 2008; 22: F1–F9.

Arribas J.R. , Delgado R. , Arranz A. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. JAIDS 2009; 51: 147–152.

Palmer S. , Kearney M. , Maldarelli F. Multiple, linked human immunodeficiency virus type 1 drug resistance mutations in treatment-experienced patients are missed by standard genotype analysis. J Clin Microbiol 2005; 43: 406–413.

Dam E. , Quercia R. , Glass B. Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog 2009; 5: e1000345.

Aoki M. , Venzon D.J. , Koh Y. Non-cleavage site gag mutations in amprenavir-resistant human immunodeficiency virus type 1 (HIV-1) predispose HIV-1 to rapid acquisition of amprenavir resistance but delay development of resistance to other protease inhibitors. J Virol 2009; 83: 3059–3068.

Kim R. , Baxter J.D. , Kim R. , Baxter J.D. Protease inhibitor resistance update: where are we now? AIDS Patient Care STDS 2008; 22: 267–277.

Malet I. , Roquebert B. , Dalban C. Association of gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients. J Infect 2007; 54: 367–374.

Verheyen J. , Litau E. , Sing T. Compensatory mutations at the HIV cleavage sites p7/p1 and p1/p6-gag in therapy-naive and therapy-experienced patients. Antivir Ther 2006; 11: 879–887.

Resch W. , Parkin N. , Watkins T. Evolution of human immunodeficiency virus type 1 protease genotypes and phenotypes in vivo under selective pressure of the protease inhibitor ritonavir. J Virol 2005; 79: 10638–10649.

Myint L. , Matsuda M. , Matsuda Z. Gag non-cleavage site mutations contribute to full recovery of viral fitness in protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48: 444–452.

Whitehurst N. , Chappey C. , Petropoulos C. , Parkin N. , Gamarnik A. Polymorphisms in p1-p6/p6* of HIV type 1 can delay protease autoprocessing and increase drug susceptibility. AIDS Res Hum Retroviruses 2003; 19: 779–784.

Maguire M.F. , Guinea R. , Griffin P. Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro. J Virol 2002; 76: 7398–7406.

Gatanaga H. , Suzuki Y. , Tsang H. Amino acid substitutions in gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors. J Biol Chem 2002; 277: 5952–5961.

Fehér A. , Weber I.T. , Bagossi P. Effect of sequence polymorphism and drug resistance on two HIV-1 gag processing sites. Eur J Biochem 2002; 269: 4114–4120.

Côté H.C. , Brumme Z.L. , Harrigan P.R. Human immunodeficiency virus type 1 protease cleavage site mutations associated with protease inhibitor cross-resistance selected by indinavir, ritonavir, and/or saquinavir. J Virol 2001; 75: 589–594.

Zennou V. , Mammano F. , Paulous S. , Mathez D. , Clavel F. Loss of viral fitness associated with multiple gag and gag-pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo. J Virol 1998; 72: 3300–3306.

Mammano F. , Petit C. , Clavel F. Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol 1998; 72: 7632–7637.

Huang Y. , Zhang L. , Ho D.D. Characterization of gag and pol sequences from long-term survivors of human immunodeficiency virus type 1 infection. Virology 1998; 240: 36–49.

Carrillo A. , Stewart K.D. , Sham H.L. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol 1998; 72: 7532–7541.

Zhang Y.M. , Imamichi H. , Imamichi T. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its gag substrate cleavage sites. J Virol 1997; 71: 6662–6670.

Doyon L. , Croteau G. , Thibeault D. Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J Virol 1996; 70: 3763–3769.

Mervis R.J. , Ahmad N. , Lillehoj E.P. The gag gene products of human immunodeficiency virus type 1: alignment within the gag open reading frame, identification of posttranslational modifications, and evidence for alternative gag precursors. J Virol 1988; 62: 3993–4002.

Katlama C. , Valantin M.A. , Algarte-Genin M. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS 2010; 24: 2365–2374.

Nunes E.P. , Oliveira M.S. , Almeida M. 48-Week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/ml on HAART – the KalMO Study. XVI International AIDS Conference. 13–18 August 2006, Toronto, ON, Canada. Abstract TUAB0103.

Singh K.T.A. , Jackson A. , Mguni S. , Higgs C. , Mandalia S. Single agent lopinavir/ritonavir (LPV/r) is as effective at maintaining viral suppression as continuation of standard ART at 24 weeks in patients who already have HIV RNA<50 copies/ ml. 11th European AIDS conference (EACS). 24–27 October 2007, Madrid, Spain. Abstract P7.5/06.

Cameron D.W. , da Silva B.A. , Arribas J.R. A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis 2008; 198: 234–240.

Gutmann C. , Cusini A. , Gunthard H.F. Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir. AIDS 2010; 24: 2347–2354.

Nunes E.P. , Santini de Oliveira M. , Mercon M. Monotherapy with lopinavir/ritonavir as maintenance after HIV-1 viral suppression: results of a 96-week randomized, controlled, open-label, pilot trial (KalMo study). HIV Clin Trials 2009; 10: 368–374.