Stavudine in the face of cross-resistance between HIV-1 nucleoside reverse transcriptase inhibitors: a review

Despite the current availability of over 15 antiretroviral drugs, diminishing antiretroviral options due to drug cross-resistance constitute a real challenge beyond first-line therapy. Although stavudine (d4T) shares several resistance mutations with other drugs in its class -i.e. nucleoside analogue mutations (NAMs)- literature regarding the actual impact of NAMs on HIV-1 resistance to d4T is conflicting. Several studies conducted over the past few years have, however, shown that the frequency with which d4T selects NAMs is much lower than using zidovudine (AZT), particularly when combined with lamivudine (3TC). In the latter case, NAMs have been found in less than 5% of cases after more than 12 weeks of therapy. In vitro studies have also shown that the impact of d4T on phenotypic drug susceptibility is much lower than that of AZT, with similar genotypic profiles. Few clinical trials have attempted to define a clinically relevant cut-off for phenotypic resistance to d4T. The results of these trials differ considerably and are highly dependent on the studied population. Nonetheless, these data help to clarify the strategic use of d4T in antiretroviral therapy, and to determine the best sequencing options for nucleoside reverse transcriptase inhibitors.