Background:  The K65R mutation is seldom selected with current treatment strategies. It has been selected with sub-optimal therapies such as tenofovir/didanosine/abacavir (TDF/ddI/ABC) regimens. The K65R limits the number of nucleoside reverse transcriptase inhibitor (NRTI) options. However, it has the potential to decrease phenotypic zidovudine (AZT)-resistance and rarely occurs concurrently with thymidine analogue mutations (TAM). Thus, patients with the K65R mutation usually maintain AZT as options.   

Methods:  We studied 3 patients who experienced virologic failure associated with the K65R and other resistance mutations. Their drug regimens were then intensified with AZT without changing any other drugs despite genotypic resistance.

Results:  Patient 1 was experiencing therapy failure with ABC/ddI/lamivudine (3TC); Patient 2, who never attained undetectable viremia in 4 years of treatment, failed while taking ABC/ddI/TDF. Genotype testing at virologic failure showed K65R, L74V, M184V, and the Y115F mutations to be present in both patients. Patient 3, who failed on TDF/3TC+nevirapine (NVP), demonstrated the K65R, G190S, and Y181C mutations. Their failing regimens were intensified with AZT while the other drugs were continued, despite resistance mutations to all the drugs in their regimens. All 3 patients had an immediate viral load reduction to undetectable levels within 4 weeks:  Patient 1 dropped more than 2 logs from 5300 copies/mL to <50 copies, patient 2 dropped > 3 logs from 48,000 to <20 copies, and patient 3 had a 1.4 log reduction from 1130 to <50 copies/mL. Follow-up time ranged from 15 months to 2 years. All 3 patients have maintained <50 copies/mL and all 3 remain on their regimens.

Conclusions:  In these patients with the K65R mutation and no TAM, AZT was added to regimens in which genotypic testing showed resistance to all their drugs. AZT was the only active drug, but this addition was enough to achieve sustained viral load reductions to >50 copies/mL.