Biomedical subjects

Chris Stone

Publications and source records attributed to Chris Stone.

4 recordsLinked to original sources

PubMed2004

Human immunodeficiency virus type 1 reverse transcriptase mutation selection during in vitro exposure to tenofovir alone or combined with abacavir or lamivudine.

Mutations selected or deselected during passage of human immunodeficiency virus strain HXB2 or resistant variants with tenofovir (TFV), abacavir (ABC), and lamivudine (3TC) differed depending on the drug combination and virus genotype. In the wild-type virus, TFV-ABC and TFV-3TC selected K65R (with reduced susceptibility to all three inhibitors) and then Y115F. TFV-containing regimens might increase K65R selection, which confers multiple nucleoside reverse transcriptase inhibitor resistance.

Adenine↗

PubMed2004

Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors.

OBJECTIVE: To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy. DESIGN: The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults. METHODS: Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed. RESULTS: Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1-2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with > or = 3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus (P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), > or = 4 mutations were required to diminish virological response significantly (P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense HIV assay and the Antivirogram assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/microl by weeks 12-28. CONCLUSIONS: Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.

Acquired Immunodeficiency Syndrome↗

PubMed2003

HIV-1 reverse transcriptase and protease resistance mutations selected during 16-72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study.

OBJECTIVE: To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen. METHODS: Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs + other ART. The median follow-up was 48 weeks (range week 16-72). RESULTS: Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had > or = 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): G to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) and V1081 (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the G190 mutations (OR=8.9, P<0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and 154V were de-selected, and mutations I50V, I or V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at position 10 were observed in 20/49 (41%) isolates. CONCLUSION: Prior NNRTI and NRTI therapy influences the pathway of resistance to efavirenz. In this study, the prevalence of mutations selected by efavirenz were different from those described in less ART-experienced patients. Baseline Y181C was associated with the development of mutations at position 190, but not L100I or K103N. In this patient population, abacavir with efavirenz preferentially selected for L74V but not for thymidine analogue mutations. M184V was rarely selected and was maintained in only 77% of patients who did not add lamivudine or didanosine. Finally, amprenavir-specific mutations were selected in the background of other primary protease inhibitor mutations, confirming the distinct resistance profile of amprenavir.

Alkynes↗

PubMed2002

M184V is associated with a low incidence of thymidine analogue mutations and low phenotypic resistance to zidovudine and stavudine.

The resistance of HIV clinical isolates with or without M184V was analysed in relation to plasma HIV-1-RNA level and time on therapy. The number of thymidine analogue mutations (TAMs) was lower in isolates with M184V, this was independent of plasma HIV-1-RNA level and time on therapy for T215F/Y, D67N and L210W. This suggests a direct effect of M184V on the reduced selection of TAMs. Lamivudine use was significantly associated with lower median fold resistance to zidovudine and stavudine.

Drug Resistance, Microbial↗