The Body PRO Covers: The 10th Conference on Retroviruses and Opportunistic Infections

Predicting NRTI Options by Linking Reverse Transcriptase Genotype to Phenotypic Breakpoints

February 11, 2003

  • Prediction of NRTI Options by Linking Reverse Transcriptase Genotype to Phenotypic Breakpoints (Poster 586)
    Authored by E.R. Lanier, D. Irlbeck, L. Ross, P. Gerondelis, M. Underwood, N. Parkin, C. Chappey, M. St. Clair
    View the original abstract

Lanier and colleagues presented data on the significance of certain HIV-1 reverse transcriptase (RT) gene codon changes and their capacity to produce resistance (or reduced susceptibility) to antiretroviral (ARV) nucleoside reverse transcriptase inhibitors (NRTIs). There is currently some uncertainty as to which NRTI concentration or fold-change increase causes a virus resistant to one drug to become resistant to multiple NRTIs, compared to wild-type viruses that do not have evidence of resistance. The concentration at which a drug loses activity and the virus is less susceptible to the drug is referred to as the phenotypic breakpoint. This fold change is slightly different for each NRTI. Although it is known, with some degree of certainty, which mutations are associated with resistance to a particular NRTI (and hence the defined phenotypic breakpoint for that NRTI), less is known about combination mutational patterns and the relationship of resistance to multiple NRTIs. Mutations are usually referred to by their position number, followed by a letter, which indicates the amino acid change that confers resistance for a particular drug (i.e., 184V is the RT gene mutation which confers resistance to 3TC [lamivudine, Epivir]).

The investigators studied over 10,000 patient samples sent to Virologic, Inc., which had been evaluated for NRTI resistance by both genotyping (sequencing the virus) and by phenotyping (growing a virus in the presence of NRTIs using the PhenoSense assay). The authors presented their findings in ten tables showing different combinations of RT gene mutations and the resulting phenotype (susceptible or not susceptible) for each of the NRTI drugs and a summary table showing the impact of 30 different combinations of mutations on all NRTI drugs. The combination of 67N, 70R and 184V, for example, only demonstrates resistance to 3TC and ddC (zalcitabine, Hivid), whereas the combination of 41L, 184V, 210W and 215Y/F demonstrates resistance to all NRTIs. Although 41L, 67N, 70R, 210W, and 215Y/F are all thymidine analogue mutations (TAMs, drugs like AZT [zidovudine, Retrovir] and d4T [stavudine, Zerit]), we don't know how many of these mutations and which specific ones determine which NRTIs the virus truly becomes resistant to.

The authors presented some discussion and calculations indicating that because of the high replication rate in drug-naive patients, some of these NRTI-associated mutations probably already exist in viruses as a single-mutation mutant. However, viruses with multiple mutations probably do not, and appear only under pressure of ARV exposure. Drugs like AZT require several mutations for high-level resistance to be present. Other drugs like 3TC only require one mutation for high-level resistance to develop.

Certain mutations like 65R (tenofovir [TDF, Viread]), 74V (ddI [didanosine Videx]), and 184V (3TC) when present together, can have profound implications for other NRTIs, particularly as additional mutations arise. It is likely that the initial choice of an NRTI combination determines the specific mutations that would develop after a failing regimen. In other words, particular combinations of NRTIs force the virus down different pathways of resistance mutation development. The mutation set that develops will have profound effects on the choice of the next regimen because certain mutation sets confer broad class resistance to all NRTIs, whereas other NRTI mutation sets only confer resistance to that specific drug. The current data presented is not associated with any patient clinical history and outcome or what NRTIs these patients were taking or may have been exposed to in the past. Although this study better defines the mutations that are associated with decreased activity among NRTIs, how these mutations arise (under what NRTI combination) will require further study.

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