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Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen.
Antivir Ther. 2007; 12(1):25-30.AT

Abstract

OBJECTIVE

Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options.

DESIGN

Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV.

METHODS

Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV).

RESULTS

Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A (n=4) characterized by M184V without further regimen-associated mutations, group B (n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C (n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options.

CONCLUSIONS

Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline.

Authors+Show Affiliations

J.W. Goethe University Hospital, Institute for Medical Virology, Frankfurt, Germany. M.Stuermer@em.uni-frankfurt.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17503744

Citation

Stürmer, Martin, et al. "Evolution of Resistance Mutations During Low-level Viral Replication in HIV-1-infected Patients Treated With Zidovudine/lamivudine/abacavir as a First-line Regimen." Antiviral Therapy, vol. 12, no. 1, 2007, pp. 25-30.
Stürmer M, Dauer B, Moesch M, et al. Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen. Antivir Ther (Lond). 2007;12(1):25-30.
Stürmer, M., Dauer, B., Moesch, M., Haberl, A., Mueller, A., Locher, L., Knecht, G., Hanke, N., Doerr, H. W., & Staszewski, S. (2007). Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen. Antiviral Therapy, 12(1), 25-30.
Stürmer M, et al. Evolution of Resistance Mutations During Low-level Viral Replication in HIV-1-infected Patients Treated With Zidovudine/lamivudine/abacavir as a First-line Regimen. Antivir Ther (Lond). 2007;12(1):25-30. PubMed PMID: 17503744.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen. AU - Stürmer,Martin, AU - Dauer,Brenda, AU - Moesch,Manfred, AU - Haberl,Annette, AU - Mueller,Axel, AU - Locher,Leo, AU - Knecht,Gaby, AU - Hanke,Nora, AU - Doerr,Hans W, AU - Staszewski,Schlomo, PY - 2007/5/17/pubmed PY - 2007/6/8/medline PY - 2007/5/17/entrez SP - 25 EP - 30 JF - Antiviral therapy JO - Antivir. Ther. (Lond.) VL - 12 IS - 1 N2 - OBJECTIVE: Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options. DESIGN: Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV. METHODS: Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV). RESULTS: Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A (n=4) characterized by M184V without further regimen-associated mutations, group B (n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C (n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options. CONCLUSIONS: Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline. SN - 1359-6535 UR - https://www.unboundmedicine.com/medline/citation/17503744/Evolution_of_resistance_mutations_during_low_level_viral_replication_in_HIV_1_infected_patients_treated_with_zidovudine/lamivudine/abacavir_as_a_first_line_regimen_ L2 - http://www.diseaseinfosearch.org/result/9735 DB - PRIME DP - Unbound Medicine ER -