Possible Causes of Early Treatment Failure With a Novel ARV Regimen

Introduction

High rates of early virologic failure have recently been reported among previously untreated, HIV-infected patients who received the triple-nucleoside/nucleotide regimen of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) as their initial therapy.^[1,2] At the Second International AIDS Society Conference on HIV Pathogenesis and Treatment in July 2003, Charles Farthing of the AIDS Healthcare Foundation in Los Angeles, California,^[1] presented data from a small prospective pilot study in which 19 antiretroviral-naive patients received a once-daily regimen of ABC 600 mg, 3TC 300 mg, and TDF 300 mg. At week 8, 11 patients (58%) failed to experience at least a 2-log₁₀ decline from baseline or had a viral rebound after initial viral suppression.

Preliminary results from GlaxoSmithKline's ESS30009 study were recently summarized in a letter to physicians.^[2] This trial was a randomized, prospective, open-label, multicenter trial in antiretroviral-naive patients that evaluated the investigational fixed-dose formulation of ABC 600 mg/3TC 300 mg in combination with efavirenz (EFV) 600 mg or TDF 300 mg administered once daily. An interim analysis conducted by week 8 showed that 50 of 102 (49%) patients randomized to receive ABC/3TC/TDF failed to achieve a 2-log₁₀ reduction in viral load from baseline or had a 1-log₁₀ or greater increase above the viral load nadir on any visit. In comparison, only 5 of 92 patients (5%) who received ABC/3TC/EFV met these criteria.

Several potential explanations for the early loss of antiviral potency by this drug regimen are presently being considered, including (1) a low genetic barrier to resistance posed by the regimen, (2) inadequate intracellular pharmacokinetic properties of 3TC and/or ABC when dosed once daily, and (3) potential negative drug-drug interactions between TDF and ABC. This article reviews available data and discusses these potential factors as they may relate to the early treatment failures observed in these 2 studies.

In both of the prospective studies of ABC/3TC/TDF described above, specimens obtained from patients with virologic failure demonstrated initial response followed by an early and vigorous viral rebound.^[1,2] These findings are consistent with the rapid selection of a preexisting viral population that is resistant to 1 or more component drugs of the therapeutic regimen. Indeed, the early time to viral rebound observed in these trials is similar to that observed in studies of dual-NRTI (nucleoside reverse transcriptase inhibitor) regimens containing 3TC, which pose an insufficient genetic barrier to the development of resistance.^[3]

In the study by Farthing and colleagues,^[1] isolates from 9 of 11 patients who experienced treatment failure had a M184V mutation, and 4 had the combination of M184V + K65R; no patient experienced a K65R mutation alone. In the ESS30009 trial, all of 14 patients with treatment failure for whom genotype results were available had the M184V mutation, and 8 of the 14 (57%) had both the M184V and K65R mutations.^[2]

The frequent and early selection of M184V with this regimen is surprising since it would be expected that both TDF and ABC should exhibit potent activity against these variants.^[4,5] The K65R mutation confers reduced antiviral activity to both ABC and TDF, as well as to 3TC.^[4,6,7,8] Thus, the sequence of viral rebound might be explained by the initial selection and outgrowth of the M184V population, followed by the additional selective pressure for an additional mutation, K65R, from within the replicating M184V subpopulation. Alternatively, in some patients, the regimen might select for a preexisting dual-M184V/K65R mutant, which would be more likely to preexist in patients with high baseline viral load measurements.

In this regard, the genotypes from patients with early virologic failure in these studies often report mixed populations of M184I/V or M184V/K65R.^[1,2] It is likely, therefore, that with longer duration of replication, the combination of M184V/K65R would be found consistently.

Phenotypes of K65R mutants from several studies have demonstrated varying degrees of moderate resistance to ABC and ddI (didanosine).^[9,10] Surprisingly, little or no phenotypic resistance to TDF has been detected, despite the corresponding genotypes.^[10,11] The reason for this remains unclear. One potential factor influencing the phenotypic results may be the effect of a coexisting M184V mutant, which is known to resensitize HIV to TDF. Another explanation might be the effect of shifting virus populations that occurs around the time of viral rebound, creating mixtures of M184V, M184V/K65R, and wild-type virus. It has been reported recently that minor populations of wild-type virus coexisting with resistant virus may lead to an underestimate of resistance in single-cycle phenotype assays.^[12]

Medscape HIV/AIDS. 2003;9(2) © 2003 Medscape

Cite this: Possible Causes of Early Treatment Failure With a Novel ARV Regimen - Medscape - Sep 11, 2003.