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ICAAC 2005; Washington, D.C.; December 16-19, 2005

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The Body PRO Covers: The 45th Interscience Conference on Antimicrobial Agents and Chemotherapy

Researchers Uncover Possible Alternative Pathway to Tenofovir Resistance

December 17, 2005

HIV has a remarkable ability to adapt to its surroundings. Thanks to its error-prone replication, the virus can develop mutations that confer a growth advantage in certain situations, such as in the presence of antiretroviral therapy. Although the fitness of the virus may be reduced in the presence of such mutations in comparison with wild-type virus, these mutations enable the virus to proliferate despite the presence of antiretrovirals. For some drugs, a single mutation can confer high-level resistance. Yet for other drugs, high-level resistance requires the serial accumulation of multiple mutations and thus emerges more slowly.

The current study follows up on the ESS30009 clinical trial in which previously drug-naive patients were treated with the combination of abacavir (ABC, Ziagen) + lamivudine (3TC, Epivir) + tenofovir (TDF, Viread). As previously reported, a high proportion of these individuals failed the therapeutic regimen, as evidenced by high viral loads. Many possessed the M184V/I mutation, and a high proportion also developed the K65R substitution. Interestingly, the K70E mutation was also selected in a number of individuals in the ESS30009 study.

Until recently, the K70E substitution was mostly seen in association with resistance to adefovir (Hepsera) both in vivo and in vitro, although it has been detected in some individuals treated with tenofovir as well.

In the context of the ESS30009 study, viral mixtures that were either wild type or mutated at position K70 were occasionally associated with mixtures of the K65R substitution. Robert Lloyd and colleagues hence undertook a clonal analysis to determine whether the K70E and K65R substitutions might be simultaneously present within the same viral genome or whether the selection of these mutations occurred individually in distinct viral populations.

The study investigators included Lloyd, who is a scientist at Research Think Tank, a contract organization working in collaboration with GlaxoSmithKline (Glaxo) scientists, and several of the lead clinicians who participated in the ESS30009 clinical trial. It should be noted that Glaxo was the commercial sponsor of the ESS30009 study.

Data were obtained for 81 individuals for whom plasma samples were available 20 to 30 weeks after the initiation of abacavir + lamivudine + tenofovir therapy. In all cases in which K70E was observed, this mutation was seen as a mixture consisting of both wild-type K70K and mutated K70E populations. In addition, K65K/R mixtures were also observed in individuals in whom the K70E substitution could be identified. Accordingly, clones of the pol gene were prepared from viral samples consisting of such mixtures. A total of 305 clones were analyzed from the isolates of six patients. The results showed that the K65R and K70E substitutions were never present together within the same viral genome, thus suggesting that the selection of these substitutions occurred independently within different viral populations.

These results are consistent with the findings of site-directed mutagenesis assays in which both the K65R and K70E mutations were simultaneously introduced into a common viral backbone. This mutant combination diminished the viral replication capacity to less than 2.4% of that of wild type. The replication capacity was further reduced to less than 0.01% of that of wild type when the M184V substitution was also present.

These findings demonstrate that the K70E mutation continues to be rare but is more extensively associated with therapeutic failure in the context of the ESS30009 study than has been seen with other regimens.

Because both tenofovir and adefovir are similar molecules with regard to structure and function, the K70E mutation may have been selected more frequently in the ESS30009 study than would otherwise be expected for regimens that do not contain either tenofovir or adefovir.

It is interesting that site-directed mutagenesis data indicate that the presence of K70E in addition to K65R and M184V may result in further resistance to tenofovir, abacavir and lamivudine over and above that associated with the K65R-M184V mutant combination. The reason that all of the mutations have yet to be identified in a single viral backbone in the clinic is doubtless related to viral fitness.

The clinical significance of the findings reported here are not readily apparent, especially in view of the fact that future clinical studies are unlikely to include the combination of abacavir + lamivudine + tenofovir due to its poor antiviral efficacy.

Reference

Abstract: HIV-1 RT mutations K70E and K65R are not present on the same viral genome when both mutations are detected in plasma (Poster H-1066)
Authored by: R Lloyd, J Huong, E Rouse, P Gerondelis, M Lim, M Shaefer, A Rodriguez, J Gallant, R Lanier, LL Ross

Affiliations: Res. Think Tank, Alpharetta, GA, GlaxoSmithKline, Research Triangle Park, NC, Univ. of Miami, Miami, FL, Johns Hopkins Univ., Baltimore, MD
View poster: Download PDF


It is a part of the publication The 45th Interscience Conference on Antimicrobial Agents and Chemotherapy.
 



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