The emergence of drug resistant HIV variants at virological failure of HAART combinations containing efavirenz, tenofovir and lamivudine or emtricitabine within the UK Collaborative HIV Cohort.
BACKGROUND
Lamivudine (3TC) and emtricitabine (FTC) are guideline choices for combination highly active antiretroviral therapy (HAART). 3TC has a shorter intracellular half life than FTC and may be more likely to lead to the development of drug resistant HIV variants.


METHODS
In this study we analysed linked data from the observational UK Collaborative HIV Cohort (CHIC) Study and UK HIV Drug Resistance Database (HDRD) to investigate the rate of development of K65R or M184V resistance mutations in patients failing on combinations containing tenofovir (TDF) and efavirenz (EFV) with either 3TC or FTC. Virological failure was defined as 1 viral load >400 copies/ml. Rates were stratified by demographic variables, baseline viral load, current CD4 count, current viral load and year of starting regimen. Significant associations were identified using Poisson regression models and multivariable analyses were performed adjusting for the variables above. Logistic regression was used to determine whether there were any significant associations between type of regimen and detection of resistance mutation.


RESULTS
5455 patients received either (or both) 3TC, TDF and EFV or FTC, TDF and EFV contributing 6465 treatment episodes over 9962 person-years follow up. 47 of these episodes were preceded by resistance tests showing development of K65R or M184V mutation and were hence excluded. The majority of treatment episodes consisted of FTC- (n = 5190) rather than 3TC- (n = 1228) based regimens. 21 cases of K65R were detected over the course of follow up, giving an overall event rate of 0.21 (95% CI: 0.12-0.31)/100 person years follow up (PYFU). The overall event rate for detection of M184V was 0.38 (95% CI: 0.26-0.5)/100 PYFU. 201 patients receiving either regimen for the first time experienced virological failure. Of those receiving 3TC (n = 53), 7 (13.2%), 12 (22.6%) and 15 (28.3%) developed K65R, M184V and either K65R or M184V respectively. Of those receiving FTC (n = 148), 13 (8.8%), 20 (13.5%) and 26 (17.6%) developed K65R, M184V and either K65R or M184V respectively. Although patients on 3TC were more likely to develop resistance, this was not statistically significant in univariable (OR 1.85 (95% CI: 0.89-3.85, p = 0.09)) or multivariable analyses (OR 1.89 (95% CI: 0.89-4.01, p = 0.1)).


CONCLUSIONS
We have not found evidence of an increased risk of development of M184V and K65R in patients exposed to 3TC.
Regional Infectious Diseases Unit, NHS Lothian, UK. Electronic address: naomi.bulteel@nhs.net.
Naomi
N
Bulteel
Loveleen
L
Bansi-Matharu
Duncan
D
Churchill
David
D
Dunn
David
D
Bibby
Teresa
T
Hill
Caroline
C
Sabin
Mark
M
Nelson
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / 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; D017211:Treatment Failure
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D003841:Deoxycytidine; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz
Drug resistance; Emtricitabine; HIV; Lamivudine; Virological failure