Divergent distribution of HIV-1 drug-resistant variants on and off antiretroviral therapy

OBJECTIVE: To investigate the distribution of drug-resistant HIV-1 variants in plasma RNA and peripheral blood monuclear cell (PBMC) DNA at treatment failure while on therapy and after stopping therapy. DESIGN: Fifty-eight patients failing their first highly active antiretroviral treatment while on therapy and 50 patients after a median of 18.6 weeks after treatment interruption following multiple treatment failures were analysed. METHODS: Paired plasma HIV-1 RNA and PBMC HIV-1 DNA were used for genotypic antiretroviral resistance testing. Drug resistance was computed by using the Stanford on-line genotype interpretation system. RESULTS: The extent of drug resistance was larger in plasma RNA than in PBMC DNA in the on-therapy group (P=0.004) and in PBMC DNA than in plasma RNA in the off-therapy group (P=0.04). Interpretation of genotype based on PBMC DNA and plasma RNA in the on-therapy and in the off-therapy group would have missed detection of resistance to one or more drugs in 21 and 22% of the patients, respectively, compared to interpretation based on the other blood compartment. In a subset of 27 patients for whom a sample before stopping therapy was available, there was a significant decrease in the number of RNA (mean 8.1 to 5.3, P=0.004), but not DNA (mean 6.8 to 5.7, P=0.143), resistance mutations following treatment interruption. CONCLUSION: While plasma RNA is the material of choice for early detection of drug resistance while on therapy, analysis of PBMC DNA may additionally support and possibly improve sensitivity of resistance testing in the absence of therapy.