15th HIV Resistance Workshop: new NRTIs

The nucleoside reverse transcriptase inhibitors (NRTI) still provides the basic backbone to NNRTI or protease-inhibitor (PI) containing regimens. The historical introduction of NRTIs with sequential mono and dual-therapies has left many treatment-experienced patients harbouring persistent NRTI resistant strains. The introduction of a new sub-class within this group is certainly cause for interest especially with such little industry attention committed to developing new agents in this class.

Tibotec’s newest kid-on-the-NRTI-block is the nucleotide-competing reverse transcriptase inhibitor (NcRTI-1) a prototype that binds to the reverse transcriptase (RT) site in competition with the next incoming nucleotide. Tibotec assert that this ‘novel mechanism of action translates into a unique resistance profile’ active on resistant NNRTI and NRTI strains including insertion at position 69, thymidine-associated mutations (TAMs) and Q151M complex, all mutations conferring multi-drug resistance (MDR).

Interestingly, the two mutations that resulted in resistance to NcRTI-1 were M184V (associated with 3TC resistance) together with Y115F, most likely a polymorphic variant (FC in EC50 75 compared to wild-type). Additionally, they found that K65R (associated with tenofovir) could be reversed back to baseline and in fact most strongly correlated with a hyper-susceptibility (HS) response ((FC in EC50 0.5 compared to wild-type). The purpose of the analyses presented at the meeting was to investigate what Tibotec referred to as the ‘complementarity’ between NcRTI-1 and zidovudine (AZT).

Increasing concentrations of NcRTI-1 was examined against an AZT-associated thymidine analogue mutation (TAM) profile (M41L,D67N,K70R,T215Y). The researchers found that M184V was not selected in this experiment and in addition to the TAM mutations a novel profile was observed: A62V plus P133H. This genotype led to a reversal of the TAM resistance to AZT and resistance to NcRTI-1 with a FC >10.

Further breakdown of the analysis showed:

Interestingly, when the A62V and P133H mutations were added to wild-type virus there was little effect on AZT susceptibility (FC 0.8 on AZT) but a reduced response was observed to NcRTI-1 (FC 9.1).

Dan Kuritzkes from Harvard commented that this profile of activity was not unique and in fact a similar profile consisting of 184V plus other mutations leading to HS had been reported for a previous NRTI in development, namely dOTC.

An increasing scrutiny has emerged at these scientific workshops of assertions made by drug developers about cut-off values for reporting resistance or susceptibility. Discussions of technical cut-offs (related to assay limitations) or biological cut-off (related to viral activity) is no longer acceptable in the final analysis. What is required are clinical cut-off values that relate to clinical response in patients. As such the intrepid Charles Boucher from Utrecht University Medical School questioned why a four-fold reduction in susceptibility had been selected as the cut-off value. He asked for the biological variation and suggested that wild-type be measured as the reference for the cut-off value.