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Lopinavir select another drug
HIV-1 protease inhibitor

DRUG RESISTANCE SUMMARY
Prepared by David Katzenstein, M.D., and Jonathan Schapiro, M.D.


Name of drug:
spaceLopinavir (LPV), Kaletra™, ABT-378/r

Mechanism of action:
spacePeptidomimetic inhibitor of HIV-1 protease
 
Mutations associated with drug resistance: Mutations at positions 10, 20, 24, 32, 36, 46, 47, 48, 50, 53, 54, 63, 71, 73, 77, 82, 84, 90 and 93 may all contribute to some degree to lopinavir resistance. The degree to which each individual mutation impacts lopinavir is still not completely understood. Although it is clear that some mutations have a greater effect than others, this is still the subject of intense study.
Phenotypic resistance: Combinations of the common protease mutations show increasing degrees of phenotypic resistance to lopinavir as the number of mutations grows. In vitro studies have generated viruses showing up to a 340-fold increase in phenotypic resistance to lopinavir depending on the combination of mutations present. Although larger numbers of mutations may often be required to achieve higher levels of resistance, viruses containing four mutations including L10F, M46I, I47V and I50V showed a 31-fold increase. Clinical samples showing up to 99-fold increases have also been described.
Cross-resistance: Studies to date suggest that the genetic mechanisms of resistance to lopinavir are similar to the genetic mechanisms of resistance to most other PIs, and that most PI-resistant isolates (with the probable exception of nelfinavir-resistant isolates containing D30N) are likely to have some degree of reduced susceptibility to lopinavir. Data clearly suggest, however, that lopinavir/ritonavir can inhibit PI-resistant virus, resulting in clinical utility. This is not due to a unique mutational pattern, but rather to the very high plasma lopinavir concentrations that are obtained through ritonavir boosting. Not all degrees of resistance can be overcome by lopinavir, and the ability of lopinavir to clinically inhibit virus from patients failing other PIs is dependent on which mutations have developed and how many have accumulated. Studies are now evaluating which mutational patterns can be overcome by lopinavir/ritonavir and which cannot. In patients who are NNRTI naïve, using lopinavir/ritonavir in conjunction with an NNRTI obtained good clinical results even when up to 6 to 7 mutations were present. Similar data are needed for patients who do not have the option of using an NNRTI, as lower numbers of mutations may preclude lopinavir/ritonavir use in those patients.
Emergence of resistance in vivo: Few data are available from naïve patients receiving lopinavir/ritonavir to determine the characteristic pattern of mutations developing upon failure. Data from in vitro work and PI-experienced patients failing lopinavir/ritonavir suggests this may not be very different from those seen with other PIs such as indinavir and ritonavir, although the precise patterns remain to be determined.
Clinical correlates of resistance: Failure of PI therapy can be multifactorial. Not all patients failing therapy containing a PI demonstrate protease mutations. Still the presence of protease mutations is strongly correlated with therapeutic failure and changing therapy based on the mutations determined improves virological response.
Other comments: The ability of a PI to inhibit HIV is both a function of the intrinsic susceptibility of the specific virus to the drug (which mutations it might have) and the amount of drug the virus is exposed to. Since lopinavir obtains such high blood levels when boosted by ritonavir, even a virus with some degree of reduced susceptibility to lopinavir is inhibited with good clinical results. Therefore, although a virus may have developed intrinsic cross-resistance to lopinavir as a result of previous PI therapy, clinically it may remain very susceptible to lopinavir/ritonavir therapy.
Additional drug information:
Kaletra (lopinavir) prescribing information is available at: http://www.rxabbott.com/pdf/kaletrapi.pdf


Bibliography
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  2. Harrigan, P. R., I. Kinghorn, S. Bloor, S. D. Kemp, I. Najera, A. Kohli, and B. A. Larder 1996. Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility. J. Virol. 70:5930-5934.

  3. Harrigan, P. R., C. Stone, P. Griffin, I. Najera, S. Bloor, S. Kemp, M. Tisdale, and B. Larder 2000a. Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group. J. Infect. Dis. 181:912-920.

  4. Harrigan, P. R., C. Van Den Eynde, and B. A. Larder 2001. Quantitation of lopinavir resistance and cross-resistance and phenotypic contribution of mutations shared with other protease inhibitors. Antivir. Ther. 6:40.

  5. Hurst, M., and D. Faulds 2000. Lopinavir. Drugs. 60:1371-9; discussion 1380-1.

  6. Kempf, D. J., J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode 2001. 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. 75:7462-9.

  7. Molla, A., S. Brun, K. Garren, H. Mo, B. Richards, T. Marsh, J. Sylte, M. King, L. Han, E. Sun, and D. Kempf 2001. Patterns of resistance to lopinavir in protease inhibitor-experienced patients following viral rebound during lopinavir/ritonavir therapy. Antivir. Ther. 6:49.

  8. Prado, J. G., T. Wrin, J. Beauchaine, L. Ruiz, C. Petropoulos, B. Clotet, R. D'Aquila, and J. Martinez-Picado 2001. Lopinavir resistance of amprenavir-selected, replication-impaired mutants of HIV-1. Antivir. Ther. 6:51.

  9. Lopinavir susceptibility data and references (Stanford HIV RT and Protease Sequence Database)

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