A Rational Approach to the Selection and Sequencing of Nucleoside/Nucleotide Analogues: A New Paradigm

While the value of highly active antiretroviral therapy (HAART) is unquestionable, its use as a life-long therapy will require a more structured and strategic approach to the sequential use of antiretroviral agents than has previously been the case. A complex cocktail of factors influences the durability of a given regimen, but the durability of HAART requires a carefully planned approach to the selection of agents across multiple regimens from first-line onwards, based on considerations of drug cross-resistance and sequenceability at regimen failure. Despite considerable ongoing interest in sequencing protease inhibitors and even non-nucleoside reverse transcriptase inhibitors, there has been little study into the optimal sequence of nucleoside reverse transcriptase inhibitor (NRTI) drugs in consecutive regimens. Historical practice, clinical experience and force of habit have all emphasized the use of thymidine analogue-based first-line combinations and the frequent retention of a thymdine analogue at all subsequent stages until a salvage situation is reached. Emerging data clearly associates thymidine analogue-derived reverse transcriptase mutations with loss of drug susceptibility and clinical response to other members of the NRTI class, particularly when present alongside other NRTI-associated mutations. Any approach to strategic therapy across multiple treatment lines will require, as a basic tenet, that agents with the greatest potential for cross-resistance be used later in therapy rather than earlier. To this end, a move away from the universal use of the thymidine analogues in first-line therapy is likely as strategic thinking becomes more integrated into clinical management in HIV disease. However, more clinical investigation is required into both the performance of alternative first-line NRTI combinations and the individual sequenceability of NRTI drugs, in the absence of the class reductions in susceptibility conferred by accumulations of thymidine analogue mutations that are the corollary to most current definitions of ‘treatment-experienced’. Another basic tenet of strategic therapy is that while drugs with high potency in treatment-experienced individuals, and favourable cross-resistance profiles, are urgently required for the salvage of patients with limited options, constraining such agents to this niche merely cements the bad habits which led to an early salvage situation in the first place. Potent drugs with low cross-resistance should be investigated at all stages of therapy, including first-line, for their potential to provide not only individual regimen durability but also to extend the number of effective, successive treatment lines. Just as highly cross-resistant agents are best used later in therapy, poorly cross-resistant agents may provide an even greater strategic advantage in first- or second-line regimens than they do when used where little else is likely to work.