Compositions and methods for determining the susceptibility of a pathogenic virus to protease inhibitors
View Patent ↗The present invention provides an approach for developing an algorithm for determining the effectiveness of anti-viral drugs based on a comprehensive analysis of paired phenotypic and genotypic data guided by phenotypic clinical cut-offs. In one aspect, the algorithm allows one to provide a patient with effective treatment. It helps predict whether an infected individual will respond to treatment with an anti-viral compound, thereby allowing an effective treatment regimen to be designed without subjecting the patient to unnecessary side effects. Also, by avoiding the administration of ineffective drugs, considerable time and money is saved.
1. A method for determining whether a human immunodeficiency virus (HIV) has an increased likelihood of having reduced susceptibility to treatment with lopinavir, comprising:
(a) detecting, in said HIV, the presence or absence of one or more of the HIV protease mutations listed in Table 7;
(b) assigning a weighting factor to each mutation as provided in Table 7; and
(c) adding said weighting factors to get a total score for said HIV,
wherein said HIV has an increased likelihood of being resistant to treatment with lopinavir if said total score is equal to or greater than 6.
2. The method of claim 1 , wherein said HIV has an increased likelihood of being resistant to treatment with lopinavir if said total score is equal to or greater than 7.
3. The method of claim 1 , wherein said HIV has an increased likelihood of being resistant to treatment with lopinavir if said total score is equal to or greater than 8.
4. The method of claim 1 , wherein the mutation is detected in a nucleic acid of said HIV that encodes the protease.
5. The method of claim 4 , wherein said presence or absence of said mutation in said protease is detected by hybridization with a sequence-specific oligonucleotide probe to a nucleic acid sequence of said human immunodeficiency virus encoding said mutation, wherein the occurrence of hybridization indicates said presence or absence of said mutation.
6. The method of claim 5 wherein said sequence-specific oligonucleotide probe hybridizes to a nucleic acid encoding said mutation and the presence of hybridization indicates the presence of said mutation.
7. The method of claim 4 , wherein said presence or absence of said mutation in said protease is detected by nucleic acid sequencing.
8. The method of claim 1 , wherein said human immunodeficiency virus is human immunodeficiency virus type 1 (HIV-1).
9. The method of claim 1 wherein the method comprises detecting the presence or absence of a mutation associated with reduced susceptibility to treatment with lopinavir at 2 or more of the amino acid positions.
10. A method for determining whether an individual infected with a human immunodeficiency virus (HIV) has an increased likelihood of having reduced susceptibility to treatment with lopinavir, comprising:
(a) detecting, in a sample from said individual, the presence or absence of one or more of the HIV protease mutations listed in Table 7;
(b) assigning a weighting factor to each mutation as provided in Table 7; and
(c) adding said weighting factors to get a total score for said individual wherein said individual has an increased likelihood of being resistant to treatment with lopinavir if said total score is equal to or greater than 6.
11. The method of claim 10 , wherein said individual has an increased likelihood of being resistant to treatment with lopinavir if said total score is equal to or greater than 7.
12. The method of claim 10 , wherein said individual has an increased likelihood of being resistant to treatment with lopinavir if said total score is equal to or greater than 8.
13. The method of claim 10 , wherein the mutation is detected in a nucleic acid of said HIV that encodes the protease.
14. The method of claim 13 , wherein said presence or absence of said mutation in said protease is detected by hybridization with a sequence-specific oligonucleotide probe to a nucleic acid sequence of said human immunodeficiency virus encoding said mutation, wherein the occurrence of hybridization indicates said presence or absence of said mutation.
15. The method of claim 14 wherein said sequence-specific oligonucleotide probe hybridizes to a nucleic acid encoding said mutation and the presence of hybridization indicates the presence of said mutation.
16. The method of claim 13 , wherein said presence or absence of said mutation in said protease is detected by nucleic acid sequencing.
17. The method of claim 10 , wherein said human immunodeficiency virus is human immunodeficiency virus type 1 (HIV-1).
18. The method of claim 10 wherein the method comprises detecting the presence or absence of a mutation associated with reduced susceptibility to treatment with lopinavir at 2 or more of the amino acid positions.
19. The method of claim 10 , wherein the individual is undergoing or has undergone prior treatment with lopinavir or a different protease inhibitor.