XIV International HIV Drug Resistance Workshop: Clinical response

Two studies of atazanavir (ATV, Reyataz) and ritonavir (RTV, Norvir) focused on cut-off values that would help determine response to treatment. Eoin Coakley from Virologic further assessed data from two Bristol Myers Squibb (BMS) studies 043: ATV plus 2 NRTIs and 045: ATV/r in combination with tenofovir (TDF) and NRTI. The biologic cut-off value for ATV has been established at 2.3 fold change using the Virologic PhenoSense assay. This current analysis attempted to define phenotypic clinical cut-offs for ATV and ATV/r correlating to changes in viral load from baseline and the number of patients achieving viral load below 400 copies/ml at week 24. The study defined phenotypic cut-off values at

Another study from Paris developed this concept further to define a clinically relevant genotype score for resistance to ATV/r. Anne-Genevieve Marcelin from Pitié-Salpetrière in Paris reported data from the Swiss Cohort Study where 62 PI experienced patients who had a VL of >1000 copies/ml at baseline and had been switched to ATV/r (300mg/100mg) in combination with other antiretrovirals. Patients had prior exposure to 7.5 antiretroviral drugs. Analysis was based upon selection of mutations most strongly associated with virological response. At month 3, 82% of patients had a virological response with 56% having a VL

The number of active drugs also had an impact on virologic response. In patients with a resistance score of 3 or more, virologic response was linked to:

The authors suggest that switching PI-experienced patients with detectable virus to an ATV/r containing regimen as well as monitoring the ATV/r resistance score can help to predict a better response in patients that have three or more mutations from the selected ATV mutation profile.

Impact of thymidine analogue mutations (TAMS)

With extensive use of NRTIs as the backbone to many treatment regimens, understanding the profile and mechanisms of resistance to nucleoside and nucleotide analogues remains critical. Several studies at the workshops focused on the emergence and kinetics of thymidine analogue mutations (TAMS) including resistance to tenofovir (TDF).

Urvi Parikh from Pittsburgh University explained the impact of the K65R mutation which confers decreased sensitivity to all nucleoside analogues except AZT. Their data support the argument that this may be the result of antagonism between K65R and TAMs that occur through a combination of excision, incorporation or discrimination kinetics within the reverse transcription process. When viruses with K65R and TAMs are cloned together they reduce sensitivity to AZT but also to TDF and abacavir when compared to the presence of K65R as a single mutation which does not produce resistance to AZT.

Experiments show that K65R diminishes the capacity of reverse transcriptase to excise AZT-monophosphate which in turn reverses AZT resistance. What is now better understood is that viruses with K65R and TAMs exhibit only low level AZT resistance and the impact of resistance is associated with the TAM pathway, in particular the pathway selected by the 41 mutation. TDF-DP is less incorporated by 65RT conferring 16-fold less resistance than WT but this effect can be partially restored 4-fold by the selection of TAM 67. K65R, the authors conclude causes resistance to TDF precisely because it slows down the catalytic rate of TDF-DP incorporation and that the 67 pathway is antagonistic to K65R as it partially restores this catalytic rate. TAMs can therefore help to reverse resistance to TDF. These data are important as most patients not only have significant AZT experience but more so with the routine use of TDF in clinical practice.

Can TAMs have an effect on NNRTIs? The effect of hypersusceptibility (HS) to NNRTIs has been previously reported. The team at Virologic further described how specific profile of nucleoside analogue mutations (nonTA NAMs) may be associated with NNRTI HS. Using site-directed mutagenesis they defined the susceptibility of NNRTI patterns and compared these against AZT:

The authors conclude that these mutations enhance susceptibility to EFV in an incremental manner (K65R>L74V>M184V) and to AZT (M184V>L74V>>K65R). Whilst these data are promising especially for patients constructing salvage strategies, it is nevertheless difficult to associate clinical significance with increased or hypersusceptibility. (26)