M184V is associated with decreased development of TAMs

The M184V mutation, which leads to high-grade lamivudine (3TC, Epivir) resistance and also leads to some decrease in activity of didanosine (ddI, Videx), zalcitabine (ddC, Hivid) and abacavir (ABC, Ziagen), does have some beneficial effects.

These include the potential to delay the development of thymidine associated mutations (TAMs), increased susceptibility of M184V virus to zidovudine (AZT, ZDV, Retrovir) and stavudine (d4T, Zerit) by decreasing their removal by pyrophosphorolysis, and decreased replication capacity of M184V virus.

In a recent study published in AIDS, investigators evaluated the association between M184V and the number of TAMs and phenotypic fold resistance to nucleoside reverse transcriptase inhibitors (NRTIs). In order to perform this evaluation, they obtained the baseline plasma samples from all patients enrolled in the CNAB3002 study and determined the patients’ treatment history and cumulative time on antiretroviral therapy. The patients were stratified for previous or current lamivudine use and genotypes and phenotypes of these patients were obtained.

Overall, 72% of patients had lamivudine included in their antiretroviral regimen. Many patients had also been exposed to zidovudine or stavudine, 74 and 26% of lamivudine -experienced and 80 and 20% of lamivudine -naïve patients, respectively. M184V was detected in 99% of lamivudine -experienced patients, but in none of the lamivudine -naive patients (P < 0.001). HIV isolates with three or more TAMS were more commonly found in lamivudine -naïve than in lamivudine -experienced patients, nine and 36%, respectively (P<0.001).

In particular, the lamivudine naïve patients had higher rates of D67N (33 versus 8%, P < 0.005), K70R (33 versus 16%, P < 0.005), L210W (26 versus 7%, P < 0.005) and T215Y/F (56 versus 27%, P < 0.005). Using a multivariate analysis, the incidence of TAMS in this population was associated with the plasma viral load, time on antiretroviral therapy, M184V, or a combination of these factors. Finally, the phenotypic data obtained for 64 lamivudine-experienced and 20 lamivudine-naive patients showed that M184V isolates had a significantly lower median fold resistance for zidovudine (1.8 versus 26) and stavudine (1.1 versus 2.1).

The authors conclude: “M184V is significantly associated with a lower incidence of TAMs and a lower incidence of resistance to zidovudine and stavudine. As the majority of patients in this study were on dual therapies, it would be premature to generalise these results to patients receiving first-line highly active antiretroviral therapy (HAART).

“However, the results suggest that patients on HAART, if maintained on a failing regimen, would have less resistance to thymidine analogues with lamivudine in the regimen than without. HAART should be changed soon after virological failure to avoid the accumulation of mutations, especially in regimens without lamivudine. Prospective studies to investigate the benefit of maintaining selective pressure on M184V after switching to a new regimen are warranted.”