Positive and negative drug selection pressures on the N348I connection domain mutation: new insights from in vivo data.
BACKGROUND
There is conflicting evidence on specific reverse transcriptase inhibitors to which the N348I mutation in the connection domain of HIV type-1 reverse transcriptase confers resistance. Here, we examined associations between the emergence of N348I and antiretroviral history in a large clinical database.


METHODS
We analysed 5,353 resistance tests (that were sequenced beyond codon 348) among 2,266 antiretroviral-experienced patients. Associations between N348I and individual antiretroviral drug exposure were estimated using a matched case-control approach. Cases were defined as the first resistance test where N348I was detected; for each case, the 10 closest (in calendar time) N348N tests were selected as controls. Odds ratios (ORs) adjusted for effects of all other drugs were estimated by conditional logistic regression.


RESULTS
N348I was detected in 198 (8.7%) cases. Drugs that were statistically significantly positively associated with N348I were efavirenz (OR 1.55, 95% confidence interval [CI] 1.08-2.23; P=0.017) and nevirapine (OR 2.06, 95% CI 1.49-2.85; P<0.001). Tenofovir disoproxil fumarate (TDF) was significantly negatively associated (OR 0.27, 95% CI 0.15-0.48; P<0.001) with N348I. Similar findings were observed when the analysis was repeated to include only those tests within 2 years of the resistance test. Effects for zidovudine and stavudine were evident only in an additional analysis, which considered exposure to both drugs jointly within 2 years prior to the resistance test: exposure to zidovudine alone (OR 4.61, 95% CI 1.83-11.61; P<0.001) and exposure to stavudine alone (OR 3.39, 95% CI 1.32-8.71; P=0.011).


CONCLUSIONS
This is the first clinical evidence to suggest that efavirenz might select for N348I in addition to nevirapine, that stavudine might select for N348I in addition to zidovudine and that TDF might protect against the mutation.
Price
Huw
H
Chelsea and Westminster NHS Foundation Trust, London, UK.
Asboe
David
D
Pozniak
Anton
A
Gazzard
Brian
B
Fearnhill
Esther
E
Pillay
Deenan
D
Dunn
David
D
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D003521:Cyclopropanes; D030541:Databases, Genetic; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D004359:Drug Therapy, Combination; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D009154:Mutation / Q000187:drug effects; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018119:Stavudine / Q000494:pharmacology / Q000627:therapeutic use; D000068698:Tenofovir; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019829:Nevirapine; D000068698:Tenofovir; D018119:Stavudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000225:Adenine; C098320:efavirenz