Further development of resistance infrequent in patients taking tenofovir despite low-level viremia and K65R mutation

Maintaining tenofovir treatment after viral rebound and the emergence of the K65R tenofovir resistance mutation does not appear to result in the accumulation of further high-level, cross-class resistance, according to research published in the March edition of AIDS.

Continuation of antiretroviral therapy in the presence of HIV-1 replication and anti-retroviral drug resistance can result in continued clinical benefit. The further development of resistance mutations is, however a risk for patients electing to continue antiretroviral therapy under these conditions.

The K65R mutation is the preferred pathway to tenofovir resistance. This mutation also confers decreased sensitivity to all NRTIs except AZT and d4T. In tenofovir clinical trials the development of K65R was observed in less than 3% of patients.

K65R associates with a subset of NRTI mutations, including the multinucleoside drug resistance mutation Q151M. It rarely associates with the thymidine analogue-associated mutations (TAMs) or the L74V mutation.

In a Gilead-sponsored analysis of study 910, American researchers assessed the development of additional resistance mutations in patients with K65R and incomplete viral load suppression over prolonged therapy with tenofovir and other antiretroviral drugs.

Study 910 was an open-label, roll-over study of tenofovir 300mg with other antiretroviral drugs for patients who had completed either of two other specific tenofovir clinical studies. Genotypic analysis were performed on plasma samples at baseline and the end of the study.

Of 536 patients who entered study 910, ten patients had detectable K65R at baseline. Three patients had K65R upon entering their original study and seven patients had developed K65R while in their original study. All ten had received tenofovir in their original study. Antiretroviral regimens in study 910 were maintained at the discretion of the investigator, but all included tenofovir.

Upon completion of study 910 (a median of 18 months), genotypic resistance testing was carried out on HIV-1 isolates from ten patients with baseline K65R.

Two out of the 10 patients lost detectable K65R and gained a similar pattern of TAMs (D67N, K70R and K219Q or K29E). Both patients were taking stavudine in their regimen in addition to tenofovir and other antiretroviral drugs at study 910 initiation. Two patients maintained K65R but lost detectable M184V mutations associated with 3TC (lamivudine) treatment. Three other patients gained a K219E or K219R mutation in addition to their K65R mutation. Finally one patient each gained an A62V, L74V, Y115F, V118I or H221Y mutation.

No cases of detectable multinucleoside drug resistance development either with the Q151M pattern or a T69 insertion were observed in the study. Given the known compatibility of the Q151M complex with K65R, the authors suggest that these results indicate that there is a low potential for the development of Q151M after the development of K65R.

The investigators conclude that the results of the study suggest that further resistance development beyond K65R is not rapid or frequent in patients maintained on tenofovir containing antiretroviral therapy after viral rebound and the development of the K65R mutation.