Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen.
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.


METHODS
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.
Stürmer
Martin
M
J.W. Goethe University Hospital, Institute for Medical Virology, Frankfurt, Germany. M.Stuermer@em.uni-frankfurt.de
Dauer
Brenda
B
Moesch
Manfred
M
Haberl
Annette
A
Mueller
Axel
A
Locher
Leo
L
Knecht
Gaby
G
Hanke
Nora
N
Doerr
Hans W
HW
Staszewski
Schlomo
S
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D004279:DNA, Viral / Q000097:blood*; D015224:Dideoxynucleosides / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D016903:Drug Monitoring; D024882:Drug Resistance, Viral / Q000235:genetics*; D005500:Follow-Up Studies; D005838:Genotype; D005858:Germany; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D008715:Methionine; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013936:Thymidine; D013997:Time Factors; D017211:Treatment Failure; D014633:Valine; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use*; D000099227:Abacavir
D019380:Anti-HIV Agents; D004279:DNA, Viral; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; D008715:Methionine; D018894:Reverse Transcriptase Inhibitors; D013936:Thymidine; D014633:Valine; D015215:Zidovudine; C418262:abacavir, lamivudine, and zidovudine drug combination; D000099227:Abacavir