Información del artículo
El tratamiento con lopinavir potenciado con ritonavir (LPV/r) en monoterapia ha demostrado ser una alternativa eficaz, sobre todo en el mantenimiento de pacientes con tratamiento de combinación y supresión virológica prolongada. La monoterapia con LPV/r se asocia con un número mayor de episodios de viremia de nivel bajo, en comparación con el tratamiento de combinación, sin que en la mayoría de los casos se hayan detectado mutaciones de resistencia. La incidencia de aparición de mutaciones mayores de resistencia en los estudios OK piloto y OK04 ha sido muy baja: 0,51 por 100 pacientes-año, y ha estado relacionada principalmente con las mutaciones en posiciones 46, 54 y 82, que no han afectado a otras opciones terapéuticas. La contribución de mutaciones de resistencia de nivel bajo a la pérdida de control virológico parece limitada y, en todo caso, no parece diferente de lo observado para el tratamiento de combinación, aunque este fenómeno deberá estudiarse en ensayos más amplios a largo plazo.
Palabras clave:
VIH
Lopinavir
Monoterapia
Mutaciones de resistencia
Treatment with lopinavir/ritonavir (LPV/r) monotherapy has been shown to be an effective alternative, especially in the maintenance of patients previously treated with combination therapy and prolonged virological suppression. LPV/r monotherapy is associated with a greater number of low-level viremia episodes than combination therapy, without resistance mutations being detected in the majority of patients. The incidence of the development of major resistance mutations in the OK pilot and OK04 studies was very low: 0.51 per 100 patients-year, and was mainly related to mutations in positions 46, 54 and 82, which have not compromised other therapeutic options. The contribution of low-level resistance mutations to loss of virological control seems small, and no different from that observed in combination therapy. However, this phenomenon should be studied in larger, long-term trials.
Key words:
HIV
Lopinavir
Monotherapy
Resistance mutations
El Texto completo está disponible en PDF
Bibliografía
[1.]
D.V. Havlir, I.C. Marschner, M.S. Hirsch, A.C. Collier, P. Tebas, R.L. Bassett, et al.
Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team.
N Engl J Med, 339 (1998), pp. 1261-1268
[2.]
G. Pialoux, F. Raffi, F. Brun-Vezinet, V. Meiffredy, P. Flandre, J.A. Gastaut, et al.
A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team.
N Engl J Med, 339 (1998), pp. 1269-1276
[3.]
M.H. Reijers, G.J. Weverling, S. Jurriaans, F.W. Wit, H.M. Weigel, R.W. Ten Kate, et al.
Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study.
Lancet, 352 (1998), pp. 185-190
[4.]
J.R. Arribas, F. Pulido, R. Delgado, A. Lorenzo, P. Miralles, A. Arranz, et al.
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).
J Acquir Immune Defic Syndr, 40 (2005), pp. 280-287
[5.]
F. Pulido, J.R. Arribas, R. Delgado, E. Cabrero, J. Gonzalez-Garcia, M.J. Perez-Elias, et al.
Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV.
AIDS, 22 (2008), pp. F1-F9
[6.]
D.J. Kempf.
Ritonavir and Lopinavir/ritonavir.
[7.]
A. Carrillo, K.D. Stewart, H.L. Sham, D.W. Norbeck, W.E. Kohlbrenner, J.M. Leonard, et al.
In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor.
J Virol, 72 (1998), pp. 7532-7541
[8.]
M.S. King, R. Rode, I. Cohen-Codar, V. Calvez, A.G. Marcelin, G.J. Hanna, et al.
Predictive genotypic algorithm for virologic response to lopinavir-ritonavir in protease inhibitor-experienced patients.
Antimicrob Agents Chemother, 51 (2007), pp. 3067-3074
[9.]
J. Friend, N. Parkin, T. Liegler, J.N. Martin, S.G. Deeks.
Isolated lopinavir resistance after virological rebound of a ritonavir/lopinavir-based regimen.
AIDS, 18 (2004), pp. 1965-1966
[10.]
F. Conradie, I. Sanne, W. Venter, J. Eron.
Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient.
AIDS, 18 (2004), pp. 1084-1085
[11.]
D.J. Kempf, J.D. Isaacson, M.S. King, S.C. Brun, Y. Xu, K. Real, et al.
Identification of Genotypic Changes in Human Immunodeficiency Virus Protease That Correlate with Reduced Susceptibility to the Protease Inhibitor Lopinavir among Viral Isolates from Protease Inhibitor-Experienced Patients.
J Virol, 75 (2001), pp. 7462-7469
[12.]
H.M. Mo, M.S. King, K. King, A. Molla, S. Brun, D.J. Kempf.
Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: Mutation patterns and baseline correlates.
J Virol, 79 (2005), pp. 3329-3338
[13.]
N.T. Parkin, C. Chappey, C.J. Petropoulos.
Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance.
AIDS, 17 (2003), pp. 955-961
[14.]
J.G. Prado, T. Wrin, J. Beauchaine, L. Ruiz, C.J. Petropoulos, S.D. Frost, et al.
Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity.
AIDS, 16 (2002), pp. 1009-1017
[15.]
S.Y. Rhee, J. Taylor, G. Wadhera, A. Ben Hur, D.L. Brutlag, R.W. Shafer.
Genotypic predictors of human immunodeficiency virus type 1 drug resistance.
Proc Natl Acad Sci USA, 103 (2006), pp. 17355-17360
[16.]
S.Y. Rhee, T. Liu, J. Ravela, M.J. Gonzales, R.W. Shafer.
Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4,183 persons undergoing genotypic resistance testing.
Antimicrob Agents Chemother, 48 (2004), pp. 3122-3126
[17.]
C. De Mendoza, C. Garrido, A. Corral, N. Zahonero, V. Soriano.
Prevalence and impact of HIV-1 protease mutation L76V on lopinavir resistance.
AIDS, 22 (2008), pp. 311-313
[18.]
M. Nijhuis, A.M.J. Wensing, W. Bierman, D. De Jong, W.J.M. Van Rooyen, R. Kagan, et al.
A novel genetic pathway involving L76V and M46I leading to lopinavir/r resistance.
Antiviral Therapy, 12 (2007), pp. S140
[19.]
G. Pierone Jr, J. Mieras, D. Bulgin-Coleman, C. Kantor, J. Shearer, L. Fontaine, et al.
A pilot study of switch to lopinavir/ritonavir (LPV/r) monotherapy from nonnucleoside reverse transcriptase inhibitor-based therapy.
HIV Clin Trials, 7 (2006), pp. 237-245
[20.]
G. Pierone, J. Mieras, C. Kantor, D. Bulgin-Coleman, J. Shearer, L. Fontaine, et al.
Genotypic and Phenotypic Resistance Observations among Patients with Viremia while on Lopinavir/Ritonavir Monotherapy.
47th ICAAC (Interscience Conference on Anticrobial and Chemotherapy),
[21.]
D.W. Cameron, B.A. Da Silva, J.R. Arribas, R.A. Myers, N.C. Bellos, N. Gilmore, et al.
A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy.
J Infect Dis, 198 (2008), pp. 234-240
[22.]
J.F. Delfraissy, P. Flandre, C. Delaugerre, J. Ghosn, A. Horban, P.M. Girard, et al.
Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients.
AIDS, 22 (2008), pp. 385-393
[23.]
J. Ghosn, C. Delaugerre, M.L. Chaix, P. Flandre, J. Galimand, I. Cohen-Codar, et al.
Week 96 final analysis of resistance mutations in protease gene and in cleavage site of Gag protein for patients failing on a first-line lopinavir/ritonavir single-drug regimen in the Monark Trial.
Antiviral Therapy, 13 (2008), pp. A139
[24.]
C. Delaugerre, P. Flandre, M.L. Chaix, P. Dellamonica, F. Raffi, H. Juger, et al.
Protease gene mutations in a trial comparing first-line lopinavir/ritonavir monotherapy to lopinavir/ritonavir plus zidovudine/lamivudine (MONARK Trial).
Antiviral Therapy, 12 (2007), pp. S84
[25.]
J. Gathe, R. Yeh, C. Mayberry.
Single-agent Therapy with Lopinavir/ritonavir Suppresses Plasma HIV-1 Viral Replication in HIV-1 Naive Subjects: IMANI-2 48-Week Results.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention Sydney,
[26.]
Nunes EP, Oliveira MS, Almeida MMTB, Pilotto J, Ribeiro J, Faulhaber J, et al. 96-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. 11th EACS, Madrid, Spain, October 2007 [Abstract P7.5/04].
[27.]
F. Pulido, R. Delgado, I. Perez-Valero, J. Gonzalez-Garcia, P. Miralles, A. Arranz, et al.
Long-term (4 years) efficacy of lopinavir/ritonavir monotherapy for maintenance of HIV suppression.
J Antimicrob Chemother, 61 (2008), pp. 1359-1361
[28.]
Pulido F, Arribas JR, Delgado R, Lorenzo A, Miralles P, Arranz A, et al. Lopinavir-ritonavir (LPV/r) monotherapy (MT) for maintenance of viral suppression: combined analysis of 3 different cohorts from 2 clinical trials. AIDS. 2008 [En prensa].
[29.]
Pulido F, Perez-Valero I, Delgado R, Arranz A, Pasquau J, Portilla J, et al. Risk Factors for Loss of Virological Suppression in Patients Receiving Lopinavir-Ritonavir Monotherapy for maintenance of HIV suppression. Antiviral therapy. 2008 [En prensa.].
[30.]
Pulido F, Delgado R, Arranz A, Rubio R, Pasquau J, Ocampo A, Portilla J, et al. Three year Efficacy of Lopinavir/ritonavir Monotherapy in the OK04 Trial. 48 th FCAAC, Washington DC, 2008 [Abstract H-1240]
[31.]
J.R. Arribas, F. Pulido, R. Delgado, E. Cabrero, J. Pasquau, J. Portilla, et al.
Drug Resistance Outcomes At 48 Weeks In The OK04 Trial: A Comparative Trial of Single-Drug Maintenance Therapy with Lopinavir/Ritonavir vs Triple Therapy with Lopinavir/Ritonavir.
14th CROI (Conference on Retroviruses and Opportunistic Infection),
[32.]
G. Jourdain, N. Ngo-Giang-Huong, S. Le Coeur, C. Bowonwatanuwong, P. Kantipong, P. Leechanachai, et al.
Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy.
N Engl J Med, 351 (2004), pp. 229-240
[33.]
E.K. Halvas, G.M. Aldrovandi, P. Balfe, I.A. Beck, V.F. Boltz, J.M. Coffin, et al.
Blinded, multicenter comparison of methods to detect a drug-resistant mutant of human immunodeficiency virus type 1 at low frequency.
J Clin Microbiol, 44 (2006), pp. 2612-2614
[34.]
S. Palmer, M. Kearney, F. Maldarelli, E.K. Halvas, C.J. Bixby, H. Bazmi, et al.
Multiple, linked human immunodeficiency virus type 1 drug resistance mutations in treatment-experienced patients are missed by standard genotype analysis.
J Clin Microbiol, 43 (2005), pp. 406-413
[35.]
J. Johnson.
Clinical Implications of Low-frequency HIV-1 Variants.
14th CROI (Conference on Retroviruses and Opportunistic Infection),
[36.]
J.A. Johnson, J.F. Li, X. Wei, J. Lipscomb, D. Bennett, A. Brant, et al.
Simple PCR assays improve the sensitivity of HIV-1 subtype B drug resistance testing and allow linking of resistance mutations.
PLoS ONE, 2 (2007), pp. e638
[37.]
McKinnon JE, Delgado R, Arribas JR, Pulido F, Mellors JW. More Frequent Detection of Lopinavir Resistance by Single Genome Sequencing at Virologic Failure of Lopinavir/Ritonavir Maintenance Therapy in the OK04 Study. XVII International HIV Drug Resistance Workshop, Sitges, Junio 2008.
Copyright © 2008. Elsevier España S.L.. Todos los derechos reservados
