title: Drug-resistance development differs between HIV-1-infected patients failing first-line antiretroviral therapy containing nonnucleoside reverse transcriptase inhibitors with and without thymidine analogues.
abstract: OBJECTIVE
  We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group).
  
  
  METHODS
  Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA.
  
  
  RESULTS
  A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log₁₀ copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P < 0.001).
  
  
  CONCLUSIONS
  At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure.
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: M M
authors.initials: MM
authors.lastname: Santoro
authors.forename: C
authors.initials: C
authors.lastname: Sabin
authors.forename: F
authors.initials: F
authors.lastname: Forbici
authors.forename: L
authors.initials: L
authors.lastname: Bansi
authors.forename: D
authors.initials: D
authors.lastname: Dunn
authors.forename: E
authors.initials: E
authors.lastname: Fearnhill
authors.forename: E
authors.initials: E
authors.lastname: Boumis
authors.forename: E
authors.initials: E
authors.lastname: Nicastri
authors.forename: A
authors.initials: A
authors.lastname: Antinori
authors.forename: G
authors.initials: G
authors.lastname: Palamara
authors.forename: A
authors.initials: A
authors.lastname: Callegaro
authors.forename: D
authors.initials: D
authors.lastname: Francisci
authors.forename: A
authors.initials: A
authors.lastname: Zoncada
authors.forename: F
authors.initials: F
authors.lastname: Maggiolo
authors.forename: M
authors.initials: M
authors.lastname: Zazzi
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: F
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: C
authors.initials: C
authors.lastname: Mussini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000494:pharmacology / Q000627:therapeutic use; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000009:adverse effects* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D017211:Treatment Failure; D019562:Viral Load; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use; D000099227:Abacavir
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D003841:Deoxycytidine; D015224:Dideoxynucleosides; D004338:Drug Combinations; D000068679:Emtricitabine; D054303:HIV Reverse Transcriptase; D019259:Lamivudine; D063065:Organophosphonates; D000068698:Tenofovir; D013936:Thymidine; D015215:Zidovudine; D000099227:Abacavir; C109078:lamivudine, zidovudine drug combination; C514824:reverse transcriptase, Human immunodeficiency virus 1
keywords: first-line regimen; genotypic resistance test; resistance to reverse transcriptase inhibitors; virological failure