Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy.
BACKGROUND
We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome.


METHODS
We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured.


RESULTS
M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns.


CONCLUSIONS
Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.
Averbuch
Diana
D
Hadassah University Medical Center, Jerusalem, Israel.
Schapiro
Jonathan M
JM
Lanier
E Randall
ER
Gradstein
Serge
S
Gottesman
Giora
G
Kedem
Eynat
E
Einhorn
Menachem
M
Grisaru-Soen
Galia
G
Ofir
Michal
M
Engelhard
Dan
D
Grossman
Zehava
Z
D019380:Anti-HIV Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D012641:Selection, Genetic; D013936:Thymidine / Q000031:analogs & derivatives*; D014779:Virus Replication; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D013936:Thymidine