Introduction

One of the most challenging limitations of antiretroviral therapy is the emergence of drug-resistant mutants of HIV, which occurs in 30–40% of treated patients. This chapter outlines the virologic, pharmacologic, and host factors involved in the development of HIV drug resistance, the clinical rationale for resistance testing, the various commercially available testing modalities, and the role of testing algorithms in clinical management. Several excellent reviews on HIV drug resistance testing have recently been published [1–8].

Virologic factors contributing to development of drug resistance

Several points regarding HIV replication (see also Chapters 2,4, and 5) are essential for understanding the development of HIV drug resistance and are reviewed here. Retrovirus replication (Figure 21.1) is rapid [9–12], and error prone [13, 14]. During reverse transcription, error rates have been estimated at 1 error per 1–300 000 incorporated bases [15, 16]. As a result, it is likely that drug-resistance mutants are present prior to initiation of drug therapy [18]. Retrovirus replication proceeds with frequent recombination between different viruses, sometimes with potentially significant genetic differences [23], and recent epidemiologic studies provide strong evidence of frequent recombination within patients [19–22]. HIV recombination was described in a premature infant multiply transfused with blood from two different HIV-infected donors [23], and other in vitro and animal in vivo experiments [18, 24, 25] support this observation. Under conditions of drug selection pressure, recombination may represent a potent mechanism responsible for facilitating the spread of drug-resistance mutations [21, 22].