Safety and efficacy of two different triple drug combinations in which either lamivudine or didanosine were administered with stavudine plus indinavir.

Abstract

Triple drug combinations have become the leading therapeutic approach against HIV infection [1,2]. Usually, they produce rapid and profound drops in plasma HIV viral load, often below the detection limit of most assays. However, HIV replication is not fully suppressed and reappears later on in some patients, mainly in those previously pretreated or in those with poor compliance to drug regimens. In these circumstances the virus evades the drug pressure, and ongoing replication provides HIV with the opportunity to develop mutations that confer drug resistance. This failure is relevant for both current and future treatments, since cross-resistance can influence the efficacy of subsequent therapies. We therefore compared two triple drug combinations in zidovudine-pretreated patients, and analysed, on an intent-to-treat basis, their impact on short-term viral load and development of drug resistance mutations that might jeopardize subsequent therapy options [3]. A total of 54 HIV-infected patients with CD4 counts below 350 × 106 cells/l who were pretreated with zidovudine for longer than 6 weeks were randomly assigned to stavudine (40 mg b.i.d.) plus indinavir (800 mg t.i.d.) with either lamivudine (3TC; 150 mg b.i.d.) or didanosine (ddI; administered as a single dose, 400 mg once daily). Undetectable levels of plasma viraemia using the second generation branched DNA assay (Quantiplex HIV 2.0, Chiron, Emeryville, California, USA) were achieved in a substantial proportion of individuals receiving both drug regimens during the first 6 months of therapy (Table 1).Table 1: . Number of patients with undetectable levels of plasma viraemia.However, one-fifth of the patients in the 3TC arm and more than one-third of those in the ddI arm did not clear viraemia or a recurrence in viral load was recognised later in the first 6 months of therapy. The codon 151 mutation, which is a marker for resistance to multiple reverse transcriptase inhibitors [4], was recognised in two patients after 6 months triple drug therapy. This finding could explain the lack of full HIV suppression observed in one individual in the ddI arm as well as the early recurrence experienced by another in the 3TC arm. However, the codon 184 mutation, linked to high-level resistance to 3TC [5], was recognised in five (62.5%) out of eight patients who were exposed to the drug without achieving undetectable levels of viraemia after 3 months on therapy. In contrast, none of the subjects exposed to ddI without clearing viraemia developed the codon 74 mutation, which has been associated with ddI resistance. With respect to drug compliance, patients undergoing 3TC therapy tended to have better tolerance to the treatment than those receiving ddI, despite the last drug being administered as a single daily dose. In conclusion, more than 70% of zidovudine-pretreated patients achieved undetectable levels of plasma viraemia after 1 month of being treated with a triple combination of stavudine plus indinavir plus either 3TC or ddI. Although 3TC tended to be better tolerated than ddI, the emergence of high-level resistance to 3TC in those who did not achieve undetectable levels of viraemia or showed an early viral recurrence, needs to be kept in mind since failure and resistance to 3TC might jeopardize future therapeutic options, such as those including ddI or zalcitabine. Furthermore, the rapid development of the codon 184 mutation conferring resistance to 3TC might be used as a surrogate marker for lack of full HIV suppression in any regimen including this drug.