Resistance to Antiretroviral Agents
Resistance to Antiretroviral Agents
Objective: To assess temporal changes in prevalence of transmitted HIV-1 drug resistance in a homogeneous cohort of newly infected individuals.
Methods: Pretreatment genotypic and phenotypic drug resistance was tested in 154 subjects with primary HIV-1 infection identified between 1995 and 2001 (group A; n = 76) and 1999 and 2001 (group B; n = 78). Sequence analysis was assessed by population-based sequencing. Virus susceptibility to antiretroviral agents was determined by the PhenoSense assay (ViroLogic).
Results: The frequency of resistance-associated mutations in protease (PR) and reverse transcriptase (RT) genes increased from 13.2% (1995-1998) to 19.7% (1999-2001). Although the overall prevalence of viruses with phenotypic resistance did not vary (1995-1998, 10.0%; 1999-2001, 10.8%), the distribution of drug classes changed [nucleoside RT inhibitor (NRTI): 8.3% to 2.7%; non-NRTI: 5.0% to 8.1%; protease inhibitors (PI): 1.7% to 5.4%]. The decrease of phenotypic resistance to NRTI in 1999-2001 was caused by the absence of transmitted lamivudine-resistant variants. Phenotypically susceptible variants with aspartic acid or serine residues at position 215 of RT (5.3%; P = 0.04) instead emerged. Hypersusceptibility to PI decreased from 18.3% to 5.4% (P = 0.02) while the amino acid substitutions in PR increased over time: M36I (6.6% to 19.7%) and A71V/T (3.9% to 15.8%).
Conclusions: There was an increase in the number of HIV-1 variants with both genotypic and phenotypic resistance to non-NRTI and PI over time. Furthermore, viruses with altered genotypes compatible with thymidine analogue or PI exposure but susceptible phenotypes were seen in 1999-2001. The latter findings suggest transmission of viruses from subjects who have either changed or discontinued therapy.
Monitoring newly infected patients for HIV-1 resistance to antiretroviral agents is important for the assessment of optimal treatment for the individual as well as for the public health considerations. The presence of drug-resistant viral variants poses a significant challenge to effective pharmacological intervention at any stage of infection, including acute and early HIV-1 infection. Early initiation of appropriate treatment in the setting of acute HIV-1 infection provides the best opportunity for effective antiretroviral therapy and for restoration of the immune responses. Drug-resistant HIV-1 in acutely infected individuals considerably diminishes the likelihood of long-term viral suppression and, therefore, reduces the potential benefits of early treatment intervention.
Data from Europe and North America have suggested that the prevalence of transmitted drug-resistant HIV-1 variants in recently infected individuals ranges from 10 to 20%. However, there is no single consensus definition of 'drug resistance'. Frequencies of transmitted viral resistance reported are dependent on the detection method used (genotyping or phenotyping), the cohort studied, and the definition of resistance with respect to associated mutations and the 'fold' reduced susceptibility to specific antiretroviral drugs.
It has been suggested that the epidemic of drug-resistant HIV-1 is mainly generated by the selection of drug-resistant variants during therapy. The fact that an increase in frequency of drug resistance in newly infected individuals is observed in both the United Kingdom and North America implies that the transmission of resistant HIV-1 is likely because of the growing number of patients in whom current antiretroviral regimens are non-suppressive. In the British cohort, the risk of being infected with a viral variant containing resistance-associated mutations increased over time (adjusted relative risk per year: 1.74). Similarly, the frequency of isolates with phenotypic resistance increased in subjects with recent HIV-1 infection identified in North America (16.5% in 1999-2000 versus 4.6% in previous years). We can, therefore, speculate that changes in the accessibility and quality of pharmacological treatment have influenced and will continue to influence the patterns of transmitted drug-resistant HIV-1 viral variants.
Based on our previously reported findings that transmission of HIV-1 variants with resistance- associated mutations occurred in a sizeable proportion of acutely infected subjects (16%), the present study examines and characterizes further the evolving resistance patterns in newly HIV-1 infected individuals identified between 1995 and 2001.
Objective: To assess temporal changes in prevalence of transmitted HIV-1 drug resistance in a homogeneous cohort of newly infected individuals.
Methods: Pretreatment genotypic and phenotypic drug resistance was tested in 154 subjects with primary HIV-1 infection identified between 1995 and 2001 (group A; n = 76) and 1999 and 2001 (group B; n = 78). Sequence analysis was assessed by population-based sequencing. Virus susceptibility to antiretroviral agents was determined by the PhenoSense assay (ViroLogic).
Results: The frequency of resistance-associated mutations in protease (PR) and reverse transcriptase (RT) genes increased from 13.2% (1995-1998) to 19.7% (1999-2001). Although the overall prevalence of viruses with phenotypic resistance did not vary (1995-1998, 10.0%; 1999-2001, 10.8%), the distribution of drug classes changed [nucleoside RT inhibitor (NRTI): 8.3% to 2.7%; non-NRTI: 5.0% to 8.1%; protease inhibitors (PI): 1.7% to 5.4%]. The decrease of phenotypic resistance to NRTI in 1999-2001 was caused by the absence of transmitted lamivudine-resistant variants. Phenotypically susceptible variants with aspartic acid or serine residues at position 215 of RT (5.3%; P = 0.04) instead emerged. Hypersusceptibility to PI decreased from 18.3% to 5.4% (P = 0.02) while the amino acid substitutions in PR increased over time: M36I (6.6% to 19.7%) and A71V/T (3.9% to 15.8%).
Conclusions: There was an increase in the number of HIV-1 variants with both genotypic and phenotypic resistance to non-NRTI and PI over time. Furthermore, viruses with altered genotypes compatible with thymidine analogue or PI exposure but susceptible phenotypes were seen in 1999-2001. The latter findings suggest transmission of viruses from subjects who have either changed or discontinued therapy.
Monitoring newly infected patients for HIV-1 resistance to antiretroviral agents is important for the assessment of optimal treatment for the individual as well as for the public health considerations. The presence of drug-resistant viral variants poses a significant challenge to effective pharmacological intervention at any stage of infection, including acute and early HIV-1 infection. Early initiation of appropriate treatment in the setting of acute HIV-1 infection provides the best opportunity for effective antiretroviral therapy and for restoration of the immune responses. Drug-resistant HIV-1 in acutely infected individuals considerably diminishes the likelihood of long-term viral suppression and, therefore, reduces the potential benefits of early treatment intervention.
Data from Europe and North America have suggested that the prevalence of transmitted drug-resistant HIV-1 variants in recently infected individuals ranges from 10 to 20%. However, there is no single consensus definition of 'drug resistance'. Frequencies of transmitted viral resistance reported are dependent on the detection method used (genotyping or phenotyping), the cohort studied, and the definition of resistance with respect to associated mutations and the 'fold' reduced susceptibility to specific antiretroviral drugs.
It has been suggested that the epidemic of drug-resistant HIV-1 is mainly generated by the selection of drug-resistant variants during therapy. The fact that an increase in frequency of drug resistance in newly infected individuals is observed in both the United Kingdom and North America implies that the transmission of resistant HIV-1 is likely because of the growing number of patients in whom current antiretroviral regimens are non-suppressive. In the British cohort, the risk of being infected with a viral variant containing resistance-associated mutations increased over time (adjusted relative risk per year: 1.74). Similarly, the frequency of isolates with phenotypic resistance increased in subjects with recent HIV-1 infection identified in North America (16.5% in 1999-2000 versus 4.6% in previous years). We can, therefore, speculate that changes in the accessibility and quality of pharmacological treatment have influenced and will continue to influence the patterns of transmitted drug-resistant HIV-1 viral variants.
Based on our previously reported findings that transmission of HIV-1 variants with resistance- associated mutations occurred in a sizeable proportion of acutely infected subjects (16%), the present study examines and characterizes further the evolving resistance patterns in newly HIV-1 infected individuals identified between 1995 and 2001.