Detalle de: Prevalence of drug-resistant HIV-1 genotypes in heavily pre-treated patients on current virological failure

The availability of new and more potent antiretroviral drugs has dramatically improved the life expectancy of HIV-infected patients. However, this benefit seems to decline over time as a consequence of the unfavourable impact of side-effects or the emergence of drug-resistant viruses [1,2]. Salvage regimens including as many new compounds as possible often provide the better outcome in individuals experiencing treatment failure [3]. However, in those who have already been exposed to almost all available drugs, the chances for virological response are quite low [3]. In this situation, recent reports have suggested that information on the drug resistance profile can help to design the best salvage intervention [4–6]. Laboratory data derived from analyses of a large number of specimens from heavily pre-treated individuals might provide the opportunity to recognize different genotypic behaviours for distinct drugs [7], and whether some compounds show more robustness facing resistance than others, and can therefore be chosen as preferred candidates for rescue interventions. Automatic sequencing was performed using ABI Prism 377 in HIV RNA extracted from the plasma of samples referred to our institution during 1999 from many Spanish cities. Data selected for this analysis belonged to 115 specimens from individuals fulfilling the following three criteria: (i) past exposure for longer than 6 months to one or more drugs belonging to all three different families (nucleosides, non-nucleosides, and protease inhibitors); (ii) evidence of acceptable compliance with current and past therapies; and (iii) current plasma viral load of over 500 HIV RNA copies/ml. Samples from individuals on drug holidays for longer than 2 weeks before the time of the study were excluded from the analysis, because the reversion of circulating mutant genotypes can occur thereafter [8,9]. Table 1 summarizes the rate of drug-resistant mutations found at key positions [1] for each of the three families of antiretroviral drugs in our study population. In agreement with other studies [10,11], mutations associated with zidovudine resistance were the most frequently found: T215Y/F in 65% and M41L in 56% of individuals. Likewise, lamivudine-resistant mutants (M184V) were common (30%), whereas mutations linked to didanosine (L74I) or stavudine (V75L) were rarely recognized (7 and 5%, respectively). Multi-nucleoside-resistant genotypes (Q151M and T69 inserts) were also uncommon (5 and 3%, respectively).Table 1: Prevalence of key drug-resistant mutations in 115 heavily pre-treated HIV-infected patients on virological failure. Considering the loss of sensitivity provided by each mutation to different drugs, and interpreting their presence according to the most recent drug resistance database [12], the estimated minimum rate of resistance was as follows. For nucleoside analogues, resistance occurred at the following rates: zidovudine (66%), lamivudine (33%), zalcitabine (28%), didanosine (9%), and stavudine (8%). With respect to non-nucleosides, because there is extensive cross-resistance among them, resistance was recorded in up to 48% of individuals, either for nevirapine or efavirenz. Finally, the rate of resistance to protease inhibitors was as follows: indinavir (49%), ritonavir (36%), nelfinavir (20%), and saquinavir (19%). Overall, resistant genotypes affected the different antiretroviral drug families at the following rates: all three drug classes (multi-drug resistance), 26%; two classes, 39%; one class, 21%; and no classes, 14%. In conclusion, most individuals (99/115; 86%) with significant past exposure to all antiretroviral drug classes and current virological failure carry drug-resistant genotypes. Resistance to zidovudine, lamivudine, non-nucleosides, indinavir, or ritonavir appeared in more than one third of samples, which is in agreement with results recently reported in a similar study conducted in France [7]. On the other hand, the recognition of the lack of known mutant genotypes in 16 individuals (14%) was an unexpected finding, and should prompt the investigation of alternative mechanisms of failure, such as the ‘occult’ lack of compliance, intestinal malabsorption, or cellular resistance pathways. Carlos Briones Vincent Soriano Juan González-Lahoz