Low-abundance HIV species and their impact on mutational profiles in patients with virological failure on once-daily abacavir/lamivudine/zidovudine and tenofovir
| Autor: | Joseph Horton, Belinda Ha, Lisa L. Ross, Richard Elion, E. R. Lanier, C. Cohen, Peter Gerondelis, E. Rouse, Edwin DeJesus |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
Microbiology (medical) Adolescent Anti-HIV Agents Mutation Missense Organophosphonates HIV Infections Microbial Sensitivity Tests Biology medicine.disease_cause resistance Young Adult Zidovudine Abacavir Antiretroviral Therapy Highly Active Drug Resistance Viral medicine Humans Pharmacology (medical) Treatment Failure Viremia Tenofovir Original Research thymidine analogue mutations Aged Pharmacology clonal analysis Mutation Reverse-transcriptase inhibitor Abacavir/Lamivudine/Zidovudine K65R Adenine virus diseases Lamivudine biochemical phenomena metabolism and nutrition Middle Aged biology.organism_classification Virology Dideoxynucleosides Drug Combinations Infectious Diseases Lentivirus HIV-1 RNA Viral Viral load medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | Background HIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir. Methods HIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA ≥ 400 copies/mL at 24–48 weeks). Results Fourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log10 copies/mL, and 4.0 log10 copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) ± M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample. Conclusions The majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|