Mutations at positions 10, 20, 24, 32, 33, 36, 46, 47, 48, 53, 54, 63, 71, 73, 77, 82, 84, 90 and 93 may all contribute to some degree to indinavir resistance. The degree to which each individual mutation impacts indinavir varies greatly. Although V82A is often considered the key signature mutation developing with indinavir therapy, mutations M46I, I84V and L90M are also often seen.
Phenotypic resistance:
Substantial phenotypic resistance can be seen with various major mutations. V82A and I84V have a great impact even in isolation, but combinations of other mutations such as M46I, I54V and L90M also show a sizable effect. As major and minor mutations accumulate, growing phenotypic resistance to indinavir is seen.
Cross-resistance:
Indinavir and ritonavir show a very similar resistance pattern and cross-resistance between these agents is very tight. Lopinavir shares many mutations with indinavir but this may be overcome by the very high exposures obtained as it is administered with ritonavir boosting. Patients failing nelfinavir often retain susceptibility to indinavir since the mutation D30N pathway has developed. Other pathways to nelfinavir resistance may produce varying degrees of cross-resistance. Patients failing indinavir are often resistant to nelfinavir. Cross resistance between indinavir and saquinavir or amprenavir will depend on which and how many mutations have developed as a result of the first PI.
Emergence of resistance in vivo:
Subjects receiving indinavir monotherapy, or failing indinavir in combination with NRTIs, often initially develop mutations at positions 82, 84 or 90 in addition to multiple other minor mutations or polymorphisms.
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 virologic response.
Other comments:
Higher exposure to indinavir may be obtained by ritonavir boosting. This may overcome some degree of resistance and produce a virologic response in patients with modest resistance patterns. As multiple combinations of indinavir/ritonavir are often used, this response is currently difficult to predict and requires further study.
Condra, J., D. Holder, W. A. Schleif, K. K. Bakshi, R. M. Danovich, D. Graham, M. Shivaprakash, K. Holmes, A. Saah, R. Leavitt, J. Chodakewitz, and E. Emini 2000.
Genetic correlates of virological response to an indinavir-containing salvage regimen in patients with nelfinavir failure.
Antivir. Ther. 4, Supplement 1:44.
Condra, J. H., D. J. Holder, W. A. Schleif, O. M. Blahy, R. M. Danovich, L. J. Gabryelski, D. J. Graham, D. Laird, J. C. Quintero, A. Rhodes, H. L. Robbins, E. Roth, M. Shivaprakash, T. Yang, J. A. Chodakewitz, P. J. Deutsch, R. Y. Leavitt, F. E. Massari, J. W. Mellors, K. E. Squires, R. T. Steigbigel, H. Teppler, and E. A. Emini 1996.
Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor.
J. Virol. 70:8270-8276.
Indinavir (IDV), Crixivan
