Clinical Implications of HIV-1 Minority Variants

Abstract

Technologic advances in human immunodeficiency virus type 1 (HIV-1) sequencing have revolutionized the study of antiretroviral drug resistance and are increasingly moving from the laboratory to clinical practice. These techniques are able to detect HIV-1 drug resistance mutations present at low frequencies not detectable by current HIV-1 genotyping assays. For a number of commonly used antiretroviral medications, such as nonnucleoside reverse transcriptase inhibitors, the detection of these drug-resistant minority variants significantly increases the risk of treatment failure. The level of evidence, however, is insufficient to determine the impact of HIV-1 minority variants for several other classes of antiretroviral medications. Clinicians should be aware of the novel technologies that are moving into routine clinical use and the clinical implications of HIV-1 minority variants. Additional studies are needed to determine the optimal platform for clinical application of these new technologies and to provide guidance to clinicians on the type and frequency of clinically important HIV-1 minority variants.

Sensitive Deep-Sequencing-Based HIV-1 Genotyping Assay To Simultaneously Determine Susceptibility to Protease, Reverse Transcriptase, Integrase, and Maturation Inhibitors, as Well as HIV-1 Coreceptor Tropism

“…As described above, DeepGen HIV detected additional (minority) HIV-1 drug resistance mutations and non-R5 variants compared to population sequencing; however, the clinical relevance of these minority members of the viral population is still under debate (33,51,55,57,(127)(128)(129). It is reasonable to assume that under appropriate selection (i.e., drug pressure), minority variants carrying drug resistance mutations will eventually outcompete other members of the viral population, and the earlier these mutations are detected, the sooner the proper strategy can be defined to control the growth of these viruses.…”

“…It is reasonable to assume that under appropriate selection (i.e., drug pressure), minority variants carrying drug resistance mutations will eventually outcompete other members of the viral population, and the earlier these mutations are detected, the sooner the proper strategy can be defined to control the growth of these viruses. However, the threshold for the identification of significant low-level variants may be mutation and/or antiretroviral drug dependent (32); therefore, early detection of drug-resistant HIV-1 minority variants, or non-R5 variants in the case of CCR5 antagonists, may contribute to the prediction of clinical or treatment outcome (32,36,57,63,127). Additional effort, most likely in the form of longitudinal studies, is needed to better understand the clinical relevance of these minority HIV-1 variants.…”

“…However, and although this is still uncertain, drug-resistant HIV-1 minority variants (i.e., those present in as low as 1% of the viral population) have been suggested to be clinically relevant, as they have a high chance of selection under antiretroviral drug pressure conditions (49)(50)(51)(52)(53)(54)(55)(56)(57). For that reason, a series of ultrasensitive assays have been developed to detect drug-resistant HIV-1 minority variants, e.g., allele-specific PCR (49,58), oligonucleotide ligation assays (33,59), and deep (next-generation) sequencing (60)(61)(62).…”

HIV Drug Resistance Testing by High-Multiplex “Wide” Sequencing on the MiSeq Instrument

“…The depth of coverage obtained (typically several thousands to tens of thousands of reads per sample [20,21]) can be used to detect lowfrequency variants and to study within-host HIV evolution (22). Several studies have clearly demonstrated that the presence of low-frequency drug-resistant variants, particularly those with NNRTI resistance, can negatively affect treatment outcomes (20,(23)(24)(25)(26)(27).…”

The emergence of drug resistant HIV variants and novel anti–retroviral therapy

“…It is noteworthy that the replicative as well as transmission properties of mutant and wild type variants are highly different. For example, certain data suggest that some drug resistant variants possess reduced replicative capacity in comparison with wild-type virus and therefore, drug resistant infection might be of some virological benefit to the hosts' immune system [39][40][41] .…”