Emergence of Minor Populations of Human Immunodeficiency Virus Type 1 Carrying the M184V and L90M Mutations in Subjects Undergoing Structured Treatment Interruptions

Abstract

The use of structured treatment interruption (STI) in human immunodeficiency virus (HIV)-infected subjects is currently being studied as an alternative therapeutic strategy for HIV-1. The potential risk for selection of drug-resistant HIV-1 variants during STI is unknown and remains a concern. Therefore, the emergence of drug resistance in sequential plasma samples obtained from 28 subjects with chronic HIV infection was studied. They underwent 4 cycles of 2-week STI, followed by 8-week retreatment with highly active antiretroviral therapy identical to that used before STI, and they had never failed treatment before undergoing STI. At week 40, treatment was stopped for a longer period. Minor populations of drug-resistant variants were detected by quantitative real-time polymerase chain reaction, by use of allele-discriminating oligonucleotides for 2 key resistance mutations: L90M (protease) and M184V (reverse transcriptase). The approximate discriminative power was 0.1%. In 14 of 25 and in 3 of 25 subjects, the M184V and the L90M mutations, respectively, were detected as minor populations, at different times during STI. Overall, these results indicate that, in subjects undergoing multiple STIs, HIV-1 variants carrying drug-resistance mutations can emerge during periods of increased HIV-1 replication.

Selection of drug‐resistant HIV‐1 during the early phase of viral decay is uncommon in treatment‐naïve patients initiated on a three‐ or four‐drug antiretroviral regimen including lamivudine

“…It has been reported that the M184I/V mutation may be selected after cessation of lamivudine-containing therapy because of its relative long half-life [Metzner et al, 2003;Yerly et al, 2003]. In this study, it was seen that selection of lamivudine-resistant virus may also occur after cessation of therapy.…”

“…However, it is still not clear to which extent infection of new cells occurs during the phase of viral decay after initiation of suppressive ART, and whether viral replication can lead to the early selection of drugresistant viruses. When treatment failure occurs after a period of undetectable viremia, minority drug-resistant quasispecies can emerge as the major viral population [Metzner et al, 2003;Charpentier et al, 2004;Roquebert et al, 2006;Svedhem et al, 2007]. These variants can either be pre-existing or evolve in the setting of incomplete viral suppression.…”

Inefficient Vaginal Transmission of Tenofovir-Resistant HIV-1

“…For this reason, current ART therapies consist of a cocktail of multiple drugs with different classes of action to prevent or at least postpone the development of drugresistant HIV within the patient's life span. Drug-resistant viruses can be transmitted (11)(12)(13)(14). During new infections, certain mutations like M184V are rarely detected by routine genotyping, but significantly higher proportions can be detected using more-specific methodology (11,13,14).…”

“…Drug-resistant viruses can be transmitted (11)(12)(13)(14). During new infections, certain mutations like M184V are rarely detected by routine genotyping, but significantly higher proportions can be detected using more-specific methodology (11,13,14). The inherent ability of replicating HIV to revert to a drug-sensitive genotype in the absence of drug pressure makes it difficult to study in patients, especially if (i) the time, duration, and route of infection are unknown, (ii) there is no way to prove ART-naïve status, and (iii) the HIV sequence in the infecting partner is unknown.…”

Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors

“…It is now recognized that plasma virus is composed of a mixture of numerous quasispecies (8). In patients undergoing treatment and harboring resistant viral strains, the dominant quasispecies is accompanied by minority populations expressing distinct resistance genotypes (8,14,21,34,46). Because these viral species can evolve independently, an initially minority population, having followed a distinct evolutionary pathway, could emerge as the dominant population, either because it had evolved higher resistance or because a change in drug pressure gave that population a growth advantage over the prior majority population.…”