Changes in human immunodeficiency virus type 1 populations after treatmentinterruption in patients failing antiretroviral therapy

Mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcript ase and protease that confer resistance to antiretroviral agents are usuall y accompanied by a reduction in the viral replicative capacity under drug-f ree conditions. Consequently, when antiretroviral treatment is interrupted in HIV-l-infected patients harboring drug-resistant virus, resistant quasi- species appear to be most often replaced within several weeks by wild-type virus. Using a real-time PCR-based technique for the selective quantificati on of resistant viral sequences in plasma, we have studied the kinetics of the switch from mutant to wild-type virus and evaluated the extent to which minority populations of resistant viruses not detected by genotyping persi st in these individuals. Among 12 patients with viruses expressing the V82A or L90M resistance mutation who had undergone a 3-month interruption of th erapy and for whom conventional genotyping had revealed an apparent total r econversion to wild-type virus, minority populations expressing these mutat ions, representing 0.1 to 21% of total virus, were still detectable in 9 ca ses. Kinetic studies demonstrated that viruses expressing resistance mutati ons could be detected for >5 months after the discontinuation of treatment in some patients. Most of the minority resistant genomes detected more than 3 months after the interruption of therapy carried only part of the mutati ons present in the resistant viruses prior to treatment interruption and ap peared to result from the emergence of existing strains selected at earlier stages in the development of drug resistance, Thus, following the interrup tion of treatment, viral populations containing resistance mutations can pe rsist for several months after the time when conventional genotyping techni ques detect only wild-type virus. These populations include viral strains w ith only some of the resistance mutations initially present, strains that p resumably express better fitness under drug-free conditions.