High prevalence of the K65R mutation in Botswana patients treated with ddI/d4T-based regimens

Although the K65R substitution can cause extensive cross-resistance among currently prescribed NRTIs, this mutation has been found relatively rarely among HIV positive people with subtype B using antiretroviral drugs. An increase in the frequency of K65R mutations among people treated in industrialised countries, is associated with extensive use of tenofovir (TDF) over the past few years.

Investigators from Botswana-Harvard School of Public Health AIDS Initiative, Botswana; McGill University AIDS Centre, Canada; Princess Marina Hospital, Botswana and Harvard School of Public Health, USA had previously found, using cell culture TDF selections, that the time to emergence of K65N varies among subtypes with the most rapid development found for HIV-1 subtype C virus. Additionally they had found emergence of the K65R in 3/8 Botswana patients treated with ddI-containing regimens.

Following these observations, Florence Doualla-Bell and coworkers from the group, performed a study evaluating the incidence of K65R in patients who received antiretroviral therapy, both in first and second line regimens, through the Botswana National Antiretroviral Treatment Programme.

They analysed the reverse transcriptase (RT) genotypes of subtype C isolates from 23 patients from Botswana who had treatment failure, while on combination regimens that included ddI and d4T.

Ten of these patients had initiated treatment with ddI/d4T-based regimens while 13 had started therapy with AZT/3TC/NVP or AZT/3TC/EFV before switching to ddI and/or d4T containing regimens.

The investigators found that 7/23 patients with virological failure had the K65R substitution, after a median exposure to combination ddI/d4T of only 8 months (range 418 months). Four of these individuals developed K65R while still receiving ddI/d4T at the time of genotyping; 3/7 patients developed only K65R, while 4 others also developed Q151M, F116Y, and S68G.

The association of K65R/M184V was seen in 2 patients who had received both ddI/d4T and AZT/3TC-based regimens. In contrast, 8/13 patients who received 3TC/AZT in their initial regimen mostly developed thymidine-associated mutations (TAMs) eg M41L, D67N, K70R, T215Y/F and 219E/Q, while 5/13 had no NRTI resistance.

The investigators suggested that the presence of TAMs in patients who first received AZT/3TC may explain the non-emergence of K65R while subsequently receiving ddI/d4T,due to presumed antagonism among these mutations.

They concluded that the K65R substitution may emerge at a higher frequency in people with subtype C viruses who receive treatment with ddI/d4T. This high rate was strongly associated with the absence of TAMs at baseline.

The investigators wrote: In view of widespread ARV access in sub-Saharan countries, these findings establish a degree of concern in regard to the possibility that certain mutations, such as K65R, may emerge more rapidly in viruses of subtype C. They also noted that the first line regimen currently recommended by the Botswana guidelines is AZT/3TC/EFV or NVP which may explain why the incidence of the K65R mutation is not elevated in currently treated individuals.

Doualla-Bell F, Avalos A, Brenner B et al. Ref: High prevalence of the K65R mutation in human immunodeficiency virus-infected Botswana patients treated with ddI/d4T-based regimens. XV International HIV Drug Resistance Workshop, Sitges, Spain, July 2006. Abstract 46.