Thymidine analogue mutations rare in first-line HAART failure

Further evidence that the failure of first-line regimens containing 3TC, efavirenz or nevirapine is unlikely to result in thymidine analogue resistance mutations was presented by Italian researchers at this week’s Sixth International Congress on Drug Therapy in HIV Infection in Glasgow.

Cross-resistance between the thymidine analogues (AZT and d4T) is of considerable concern when planning the sequencing of nucleoside analogue backbones for first, second and third line treatment, and when recycling nucleoside analogues such as d4T and ddI in salvage regimens.

Franco Maggiolo and colleagues from the Ospedale Riuniti in Bergamo reported on genotypic and virtual phenotype patterns in 30 male patients experiencing failure of their first triple antiretroviral regimen.

Patients had been on therapy for an average of 21 months, and had had viral load above the limits of detection for an average of 13.6 months, with a median RNA at the time of genotyping of 6,175 copies/ml.

All were receiving 3TC, 19 were receiving AZT, ten were receiving d4T and 1 was receiving ddI. In addition, 22 received a protease inhibitor, 8 received a non-nucleoside reverse transcriptase inhibitor and one received a protease inhibitor and an NNRTI. Sixteen of the 22 protease inhibitor recipients were receiving treatment with nelfinavir.

Twenty-eight out of 30 patients developed the M184V mutation associated with 3TC resistance, and eight out of nine patients developed the K103N mutation associated with NNRTI resistance. Thirteen out of 22 developed primary protease mutations.

However, only three patients developed mutations associated with resistance to AZT or d4T, despite the prolonged period of viral rebound on thymidine analogue treatment. One patient developed a 41L mutation and two patients developed the 67N, 70R and 219Q mutations. None developed the 215Y mutation associated with high level AZT resistance.

None of these patients developed significant reductions in phenotypic sensitivity to AZT or d4T as measured by virtual phenotype. Reductions in sensitivity to protease inhibitors were also infrequent.

See Resistance to NRTIs in the Anti-HIV therapy: Resistance section on this website for further details of thymidine analogue resistance mutations and cross-resistance between AZT and d4T.