15th HIV Resistance Workshop: new NRTIs

This article is more than 18 years old. Click here for more recent articles on this topic

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).

Glossary

strain

A variant characterised by a specific genotype.

 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

nucleotide

A building block of DNA or RNA, chemical structures that store genetic information. 

referral

A healthcare professional’s recommendation that a person sees another medical specialist or service.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

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:

Impact with TAM containing strains

FC 3.0 for NcRTI-1

AZT

FC 63

A62V+P133H

FC 26 for NcRTI-1

AZT

FC 2.0

TAMs + A62V

FC 2.7

TAMs + P133H

FC 2.3

Reversal of AZT resistance with A62V

FC 3.6

Reversal of AZT resistance with P133H

FC 0.6

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.

References

D Jochmans et al. The in vitro resistance profile of NcRTI-1 is complementary with the resistance profile of tenofovir and zidovudine. Fifteenth HIV Drug Resistance Workshop, Sitges, Spain, abstract 16, 2006.