Ritonavir (RTV), Norvir (liquid formulation and soft-gel cap)
Peptidomimetic inhibitor of HIV-1 protease
Mutations associated with drug resistance:
Mutations at positions 10, 20, 32, 36, 46, 47, 48, 50, 53, 54, 63, 71, 73, 77, 82, 84, 90 and 93 may all contribute to some degree to ritonavir resistance. The degree to which each individual mutation impacts ritonavir varies greatly. Although V82A is often considered the key signature mutation developing with ritonavir 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 ritonavir is seen.
Cross-resistance:
Ritonavir and indinavir show a very similar resistance pattern and cross-resistance between these agents is very tight. Lopinavir shares many mutations with ritonavir but the clinical impact is less due to the very high exposures obtained when these agents are given together as the lopinavir/ritonavir combination pill. Patients failing nelfinavir often retain susceptibility to ritonavir since the mutation D30N pathway has developed. Other pathways to nelfinavir resistance may produce varying degrees of cross-resistance. Patients failing ritonavir are often resistant to nelfinavir. Cross-resistance between ritonavir 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 ritonavir monotherapy, or failing ritonavir in combination with NRTIs, often develop V82, I84V or L90M mutations in addition to multiple other minor mutations or polymorphisms. Position 82 is often the first to mutate although in some it is position 84. Other mutations accumulate in an orderly fashion if selective pressure is continued, increasing the degree of resistance.
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:
Due to the toxicity associated with higher doses, ritonavir is most commonly used today at doses lower than the originally approved 600 mg X 2 with the intent of increasing the levels of a second co-administered PI (ritonavir boosting). Various doses ranging from 100 - 400 mg X 2 are often used. Although few data are available, it appears that ritonavir is usually not driving the development of resistance in these dual PI regimens. Although this is the current wisdom, it may be that in certain situations, ritonavir does at least partially drive resistances depending on the co-administered PI, its dose and the dose of ritonavir used for boosting.
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40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada.
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Ritonavir (RTV), Norvir (liquid formulation and soft-gel cap) 
