No response to first-line tenofovir+lamivudine+efavirenz despite optimization according to baseline resistance testing: impact of resistant minority variants on efficacy of low genetic barrier drugs.
BACKGROUND
Resistance testing has been implemented into clinical guidelines as it has shown some beneficial effect on subsequent therapy response.


METHODS
Routine population-based genotypic resistance testing for a newly diagnosed HIV-1 patient revealed the presence of resistance mutations M41L, V179D and T215E within reverse transcriptase and no mutations within protease. Four weeks after initiation of the combination tenofovir+lamivudine+efavirenz, no response was observed despite good adherence to therapy and efavirenz drug levels in the therapeutic range. Retrospective single genome sequencing of the baseline sample revealed the presence of minority viral variants with additional mutations: a mutation conferring resistance to lamivudine (M184IV), a thymidine associated mutation (K219R) and mutations possibly associated with non-nucleoside reverse transcriptase resistance (F227S, M230IV).


CONCLUSIONS
This case illustrates that undetected drug-resistant minority variants can reduce the efficacy of a normally very potent first-line regimen tenofovir+lamivudine+efavirenz. The presence of drug-resistance mutations at diagnosis should be considered as a warning sign against the use of low genetic barrier drugs in first-line regimens, even when these drugs are considered to be active according to routine resistance testing.
Van Laethem
Kristel
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. kristel.vanlaethem@uz.kuleuven.ac.be
De Munter
Paul
P
Schrooten
Yoeri
Y
Verbesselt
Rene
R
Van Ranst
Marc
M
Van Wijngaerden
Eric
E
Vandamme
Anne-Mieke
AM
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D063065:Organophosphonates / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D000068698:Tenofovir
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000068698:Tenofovir; D000225:Adenine; C098320:efavirenz