Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection

Background. Structured treatment interruption (STI) may allow viral replication in the presence of decreased plasma drug levels, with risk of selection of resistance mutations. Methods. For patients recruited for an STI study, genotypic resistance testing was performed at baseline (before receipt of any treatment), immediately before the STI, and 2 weeks after each interuption of therapy. Results. During 20 (18%) of 112 STI cycles (95% CI, 11% - 26%), resistance mutations were selected; 6% of the mutations were de novo (i.e., not detected before the start of STI), and 12% were archived mutations (i.e., mutations already detected before the STI). Overall, resistance mutations during STI were selected in 9 ( 26%) of 35 patients; 5 (14%) of the mutations were de novo, and 4 (12%) were archived mutations. Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were selected in 3 (23%) of 13 patients receiving NNRTI-based regimens (all mutations were de novo). Mutations conferring resistance to lamivudine were selected in 9 (50%) of 18 patients receiving lamivudine-containing regimens (4 [22%] were de novo, and 5 [28%] were archived mutations). Mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs), excluding the M184V mutation, were selected in 2 (6%) of 35 recipients of NRTIs (1 [3%] of these mutations was de novo, and 1 [3%] was an archived mutation. Finally, mutations conferring resistance to protease inhibitors were selected in none of the 22 patients receiving protease inhibitors. In most cases, de novo and archived mutations were selected during the first STI cycle, and their number did not increase during successive cycles. Plasma viral load decreased to undetectable levels in all the patients when the earlier drug regimen was reintroduced. Conclusions. Genotypic mutations are selected during STI in a high proportion of patients (especially in patients receiving NNRTIs or lamivudine). Approximately one-half of selected mutations were archived mutations. Patients who had archived mutations did not have a higher risk of accumulating new mutations than did patients who were infected with wild-type virus before the STI.