Clinical Implications of HIV Drug Resistance to Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

This review focuses on issues pertinent to the epidemiology and clinical interpretation of resistance tonucleos(t)ide reverse transcriptase inhibitors. Nucleoside reverse transcriptase inhibitor resistance mutations,and especially thymidine analog mutations, remain the most common form of resistance detectedin drug-naive patients. At the same time, improved treatment strategies, changes in prescribingpolicies, and prompt management of treatment failure are changing the prevalence and patterns ofnucleoside reverse transcriptase inhibitor resistance in treatment-experienced patients. The clinicalinterpretation of nucleoside reverse transcriptase inhibitor resistance is being increasingly refined,helped by improved understanding of resistance pathways, development of sophisticated methodsof analysis of genotypic resistance patterns, and introduction of clinically relevant cutoffs. Correlation ofgenotypic and phenotypic resistance data to clinical outcomes is essential to allow appropriate interpretation.In some cases, phenotypic data, either obtained directly by phenotypic tests or extrapolatedfrom genotypic results, provide the most immediate predictors of virologic response. In other cases,genotypic analyses identify mutations that impact on responses without showing a marked effect onthe phenotype, by either acting as “sentinelâ€? markers for the presence of resistance undetectable bystandard methods, or by lowering the genetic barrier to the evolution of resistance. The potential benefitsof nucleoside reverse transcriptase inhibitor resistance, through hypersusceptibility and fitnesseffects, are also increasingly understood and exploited in clinical practice. Although progress has beensignificant, there remain many challenges. It is often questioned whether genotypic scores and clinicalcutoffs obtained by various methods and from frequently small datasets can be reliably extrapolatedto the general population of treated patients. At the same time, there is a need to define the role ofreverse transcriptase mutations that are identified by statistical analyses as being associated withnucleoside reverse transcriptase inhibitor exposure, but have unknown effects on virus phenotype andclinical outcome. Novel mechanisms have also been proposed to play a role in nucleoside reversetranscriptase inhibitor resistance, including changes in RNaseH that are not targeted by routine testingat present. One additional, currently unresolved issue is the clinical relevance of minority resistantspecies and the feasibility of introducing ultra-sensitive resistance tests in routine diagnostic settings.The most appropriate viral-load cutoff for performing resistance tests and the reliability of resultsobtained at low copy numbers are similarly controversial. In spite of these limitations, resistance testingwith appropriate interpretation provides an important guide to successful treatment outcomes andnecessary support to the introduction of new treatment strategies.