Rare resistance mutation, K65N, means that multiple NRTIs don't work well

A rare resistance mutation is associated with a poor response to anti-HIV therapy and the emergence of further resistance to antiretroviral drugs, according to a case report published in the March 21^st edition of AIDS. Phenotypic resistance testing may be necessary to detect the mutation, as it would not be detected using genotypic resistance testing alone.

It is well known that a single resistance mutation can reduce the effectiveness of antiretroviral drugs, and the K65R mutation is known to confer resistance to many drugs in the nucleoside/nucleotide (NRT/NtRTI) reverse transcriptase inhibitor class of drugs. The impact of other mutations at codon 65 is not well understood.

Now, however, doctors from the US have observed a poor response to HIV treatment and the development of multiple other resistance mutations in a patient with the rare K65N mutation. This mutation reduces the effectiveness of NRTI drugs.

The patient was a 30-year-old African American gay man. With a CD4 cell count of 19 cells/mm³ and a viral load of approximately 175,000 copies/ml he enrolled on a clinical trial in April 2003 and started antiretroviral therapy consisting of the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva), abacavir (Ziagen) and 3TC (lamivudine, Epivir).

No NNRTI or NRTI resistance mutations were seen in blood samples obtained at baseline. Although the patient’s viral load declined to approximately 75 copies/ml after eight weeks of treatment, it rebounded to 2,000 copies/ml by week twelve. Genotypic and phenotypic resistance tests revealed the presence of the K65N mutation as well as the L1001 and K103N mutations that confer resistance to NNRTIs.

By week 30, the Y115F mutation had also developed and the patient had reduced susceptibility to efavirenz, nevirapine and the NRTIs abacavir, 3TC and ddI, as well as the nucleotide analogue tenofovir. After 32 weeks of treatment, the man’s viral load was 100,000 copies/ml and his CD4 cell count was only 26 cells/mm³.

Poor adherence was reported by the patient for the entire duration of his treatment, and he was lost to follow-up after week 32 after he moved to another US state.

The investigators conducted a search of the Stanford database of HIV-1 genotypes and identified only five other individuals with K65N or K65N/K mixture. In all but one case the patients had been heavily pre-treated with NRTIs and no single NRTI was particularly associated with K65N.

“The K65N is an example of a rare amino acid variant conferring NRTI resistance in the absence of other known NRTI resistance mutations”, write the investigators. They add, “this finding highlights the utility of phenotypic resistance testing, as the presence of this mutation can impact on drug susceptibility and this impact would not be detected using current drug susceptibility algorithms in combination with genotyping alone.”