ABSTRACT: Objectives: to determine the correlation between resistance phenotype and genotype at the start of multidrug rescue therapy (MDRT) with as many as nine antivirals in heavily pretreated patients and to determine whether short-term virological outcome is predicted by the number of 'effective' drugs taken as determined by drug resistance assays
Methods: Genotypic and phenotypic data were available for 59 patients who had failed at least two regimens and were started on MDRT. The median plasma viral load (pVL) and CD4 counts were 63,000 copies/mL and 180 cell/mm3 when MDRT was initiated. Patients were highly exposed to prior therapy: lamivudine (98%), stavudine (93%), zidovudine (90%), didanosine (88%), indinavir (83%), saquinavir (76%), ritonavir (63%), zalcitabine (52%), nevirapine (36%), nelfinavir (17%), delavirdine (9%), efavirenz (2%) and abacavir (2%). A median of seven (range 2-12) antiretrovirals had been prescribed prior to the initiation of MDRT. Phenotypic susceptibility was defined as a <10-fold-increase of IC50 compared to wild-type (Virco Antivirogram). Susceptibility by genotype as determined after sequence comparison with the Virco database.
Results: There was a strong correlation (Spearman's p>0.5) between genotypic calls and phenotype for each antiretroviral except for abacavir and stavudine (moderate correlation) and zalcitabine and didanosine (low correlation), perhaps owing to the fact that >10-fold resistance to these agents was relatively rare in this study. Initial response to therapy appeared to be related to the number of 'effective' agents taken: decreases in pVL after starting MDRT were 0, -0.9, -1.6 and -1.3 log10 for MDRT regimens including zero, one, two and three 'effective' agents of the multidrug regimen (genotype) or -0.2, -0.05, -0.9 or -1.5 log10 for zero, one, two or three agents (phenotype). Interestingly, patients with five, six or seven 'effective' agents in their regimen generally had a poorer response than those with only one or two 'effective' drugs.
Conclusions: Genotype-phenotype correlations are strong for most antivirals. Patients responding well to MDRT tended to be sensitive to one to three agents of their complex treatment regimen.
