Skip Navigation LinksHome > June 15, 2001 - Volume 15 - Issue 9 > Accumulation of lopinavir resistance-associated mutations ov...
AIDS:
Research Letters

Accumulation of lopinavir resistance-associated mutations over 3 years follow-up of patients on highly active antiretroviral therapy: implication in salvage therapy

Tsuchiya, Kiyoto; Matsuoka, Saori; Hachiya, Atsuko; Yasuoka, Akira; Tachikawa, Natsuo; Kikuchi, Yoshimi; Genka, Ikumi; Teruya, Katsuji; Kimura, Satoshi; Oka, Shinichi

Free Access
Article Outline
Collapse Box

Author Information

AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan.

Sponsorship: This work was partly supported by a grant-in-aid for AIDS research from the Ministry of Health and Welfare of Japan (H12-AIDS-001), and the Organization of Pharmaceutical Safety and Research (96-1).

Received: 26 January 2001; accepted 14 February 2001.

More than half the patients with HIV-1 infection are likely to experience virological failure with current combination therapeutic regimens including protease inhibitors (PI) [1]. The main reason of this failure is attributed to the accumulation of PI resistance-associated mutations, with primary or secondary mutations to respective drugs. Viruses with only three mutations as a result of previous therapy show cross-resistance to most currently available PI even though primary mutations were spared [2], which makes effective salvage therapy difficult. Lopinavir, co-formulated with a low dose of ritonavir, is a potent new PI because of its very high in-vivo drug concentrations and small phenotypic change per mutation, namely high genetic barriers. On the basis of genotypic breakpoints as a clinically relevant interpretation determined in multiple PI-experienced patients, viruses with up to five lopinavir resistance-associated mutations are sensitive, with six or seven mutations they are still intermediate, whereas those with over eight mutations are resistant to lopinavir [3,4]. Therefore, lopinavir is expected to be used as an effective salvage therapy in heavily treated patients.

We retrospectively analysed the accumulation of mutations in our patients who were PI-naive at entry to the study, and had been treated with PI-containing regimens for more than 3 years. A total of 141 patients had commenced PI-containing therapies at the AIDS Clinical Center, International Medical Center of Japan by December 1997. All patients were included in this study, even though regimens had been modified for various reasons such as treatment failure, side-effects, or tolerability/adherence issues in some patients. In most patients, the plasma viral load decreased to less than 400/ml after therapy. If the viral load reappeared at greater than 103/ml or did not decrease to less than 103/ml after 3 months of therapy, a genotypic resistance assay [5] using plasma samples was performed every 3 months thereafter. The number of lopinavir resistance-associated mutations [3] in the protease region at codons 10, 20, 24, 46, 54, 63, 71, 82, 84, and 90 were counted. Once therapy failed and viruses with four or more mutations were identified, the patient was regarded as harbouring resistant virus latently if the next therapy successfully decreased the virus to undetectable levels. The cumulative percentages of patients with four to five mutations and six to seven mutations are presented in Fig. 1. None of the patients harboured viruses with eight or more mutations as of December 2000. At 42 months after the commencement of therapy, 30 patients (21.3%) had viruses with four to five mutations, and 11 (7.8%) had viruses with six to seven mutations. Frequent sites of mutations of the virus with four to five mutations were L63P/T (86.67%), L10I/V (66.67%), A71I/T/V (60.0%), and L90M (60.0%), and for those with six to seven mutations they were L63P (100%), A71I/T/V (90.9%), L90M (90.9%), L10F/I (81.82%), M46I/L (72.73%), and I84V (63.64%).

Fig. 1
Fig. 1
Image Tools

On the basis of these results, lopinavir can be used in salvage therapy, and is expected to be effective in the majority of cases. However, viruses with six to seven mutations may easily progress towards resistance to lopinavir. In our study, viruses with six to seven mutations started to appear at 9 months after the commencement of therapy. To avoid lopinavir resistance, we recommend testing for drug resistance within 6 months after the commencement of therapy if the patient shows virological failure.

Kiyoto Tsuchiya

Saori Matsuoka

Atsuko Hachiya

Akira Yasuoka

Natsuo Tachikawa

Yoshimi Kikuchi

Ikumi Genka

Katsuji Teruya

Satoshi Kimura

Shinichi Oka

Back to Top | Article Outline

References

1. Lucas G, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med 1999, 131: 81 –87.

2. Hachiya A, Aizawa-Matsuoka S, Tanaka M. et al. Rapid and simple phenotypic assay for drug susceptibility of human immunodeficiency virus type-1 by using CCR5 expressing HeLa/CD4+cell clone 1-10 (MAGIC-5). Antimicrob Agents Chemother 2001, 45: 495 –501.

3. Kempf DJ, Isaacson J, King M, et al. Definition of genotypic breakpoints for ABT-378/ritonavir (ABT-378/r) for use in the interpretation of HIV resistance testing. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, September 2000 [Abstract 1264].

4. Brun S, Kempf DJ, Molla A, et al. Analysis of viral isolates following viral load rebound on therapy with ABT-378/ritonavir (ABT-378/r). 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, September 2000 [Abstract 2112].

5. Gatanaga H, Aizawa S, Kikuchi Y. et al. Anti-HIV effect of saquinavir combined with ritonavir is limited by previous long-term therapy with protease inhibitors. AIDS Res Hum Retroviruses 1999, 15: 1493 –1498.

Cited By:

This article has been cited 15 time(s).

Antiviral Therapy
Virological success of lopinavir/ritonavir salvage regimen is affected by an lopinavir/ritonavir-related increasing number of mutations
Bongiovanni, M; Bini, T; Adorni, F; Meraviglia, P; Capetti, A; Tordato, F; Cicconi, P; Chiesa, E; Cordier, L; Cargnel, A; Landonio, S; Rusconi, S; Monforte, AD
Antiviral Therapy, 8(3): 209-214.

AIDS Patient Care and Stds
Successful treatment with atazanavir and lopinavir/ritonavir combination therapy in protease inhibitor-susceptible and protease inhibitor-resistant HIV-infected patients
Gilliam, BL; Chan-Tack, KM; Qaqish, RB; Rode, RA; Fantry, LE; Redfield, RR
AIDS Patient Care and Stds, 20(): 745-759.

Infection
Safety, efficacy and development of resistance under the new protease inhibitor lopinavir/ritonavir: 48-week results
Voigt, E; Wasmuth, JC; Vogel, M; Mauss, S; Schmutz, G; Kaiser, R; Rockstroh, JK
Infection, 32(2): 82-88.
10.1007/s15010-004-3059-3
CrossRef
Journal of Antimicrobial Chemotherapy
Mutations at codons 54 and 82 of HIV protease predict virological response of HIV-infected children on salvage lopinavir/ritonavir therapy
Jimenez, JL; Resino, S; Martinez-Colom, A; Bellon, JM; Munoz-Fernandez, MA
Journal of Antimicrobial Chemotherapy, 56(6): 1081-1086.
10.1093/jac/dki356
CrossRef
Pediatric Infectious Disease Journal
Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children
Resino, S; Bellon, JM; Ramos, JT; Navarro, ML; Martin-Fontelos, P; Cabrero, E; Munoz-Fernandez, MA
Pediatric Infectious Disease Journal, 23(): 923-930.
10.1097/01.inf.0000142170.52155.7f
CrossRef
Clinical Infectious Diseases
Serious bradyarrhythmia that was possibly induced by lopinavir-ritonavir in 2 patients with acquired immunodeficiency syndrome
Kikuchi, Y; Genka, I; Ishizaki, A; Sunagawa, K; Yasuoka, A; Oka, S
Clinical Infectious Diseases, 35(4): 488-490.

Journal of Clinical Virology
Primary nelfinavir (NFV)-associated resistance mutations during a follow-up period of 108 weeks in protease inhibitor naive patients treated with NFV-containing regimens in an HIV clinic cohort
Tsuchiya, K; Matsuoka-Aizawa, S; Yasuoka, A; Kikuchi, Y; Tachikawa, N; Genka, I; Teruya, K; Kimura, S; Oka, S
Journal of Clinical Virology, 27(3): 252-262.
PII S1386-6532(02)00179-8
CrossRef
Infections in Medicine
Controversial approaches in HIV infection: Is there a role for lopinavir/ritonavir monotherapy?
Chan-Tack, KM; Edozien, A
Infections in Medicine, 23(8): 342-+.

Medicina Clinica
HIV infection. Irreversible mistakes not to be repeated
Artigas, JMG
Medicina Clinica, 134(9): 399-401.
10.1016/j.medcli.2009.02.020
CrossRef
Journal of Antimicrobial Chemotherapy
Immunovirological outcomes in 70 HIV-1-infected patients who switched to lopinavir/ritonavir after failing at least one protease inhibitor-containing regimen: a retrospective cohort study
Bongiovanni, M; Bini, T; Tordato, F; Cicconi, P; Melzi, S; Repetto, D; Sollima, S; Rusconi, S; Monforte, AD
Journal of Antimicrobial Chemotherapy, 51(1): 171-174.
10.1093/jac/dkg045
CrossRef
Antiviral Therapy
Long-term virological response to multiple sequential regimens of highly active antiretroviral therapy for HIV infection
Kaufmann, IR; Khanna, N; Weber, R; Perrin, L; Furrer, H; Cavassini, M; Ledergerber, B; Vernazza, P; Bernasconi, E; Rickenbach, M; Hirschel, B; Battegay, M
Antiviral Therapy, 9(2): 263-274.

Internal Medicine
Current status of HIV infection in the AIDS Clinical Center (ACC)
Oka, S; Yasuoka, A
Internal Medicine, 41(1): 58-59.

Journal of Antimicrobial Chemotherapy
Use of lopinavir/ritonavir in HIV-infected patients failing a first-line protease-inhibitor-containing HAART
Bongiovanni, M; Chiesa, E; Di Biagio, A; Meraviglia, P; Capetti, A; Tordato, F; Cicconi, P; Biasi, P; Bini, T; Monforte, AD
Journal of Antimicrobial Chemotherapy, 55(6): 1003-1007.
10.1093/jac/dki113
CrossRef
Journal of Antimicrobial Chemotherapy
Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study
Resino, S; Bellon, JM; Ramos, JT; Gonzalez-Rivera, M; de Jose, MI; Gonzalez, MI; Gurbindo, D; Mellado, MJ; Cabrero, E; Munoz-Fernandez, MA
Journal of Antimicrobial Chemotherapy, 54(5): 921-931.
10.1093/jac/dkh431
CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
The Efficacy of Lopinavir in Individuals Experiencing Protease Inhibitor Failure
Gilleece, YC; Qazi, NA; Morlese, JF; Mandalia, S; Gazzard, BG; Pozniak, AL; Nelson, MR
JAIDS Journal of Acquired Immune Deficiency Syndromes, 32(2): 238-240.

Back to Top | Article Outline

© 2001 Lippincott Williams & Wilkins, Inc.

Login