Potential for easier selection of K65R mutation with tenofovir pressure in subtype C HIV-1 isolates

HIV Treat Bull - Vol. 7, No. 7/8, July/August 2006

In second poster, authored by Mark Wainberg and coworkers, the same group presented findings from a study using a tissue culture based strategy to evaluate differences related to subtype and circulating recombinant forms (CRF) in the development of resistance in to TDF. [1]

Representative subtype B (n=4), C (n=6), A/CRF1 (n=3), CRF2 (n=3), G (n=1), and HIV-2 (n=3) isolates were selected for resistance to TDF, 3TC and ddI in cell culture. The investigators determined sequence diversity among subtypes and time to development of TDF resistance by genotype. Cell-based phenotypic and reverse transcriptase assays were used to determine the effects of the K65R substitution on drug susceptibility and viral replicative capacity.

The investigators reported that the K65R mutation confers resistance to TDF. They reported that subtype C viruses possess unique polymorphisms in RT codons 64 (AAG_AAA), 65 (AAA_AAG), and 66 (AAA_AAG), and that these are absent in other viral subtypes.

The K65R mutation (AAG_AGG) was found at 12 weeks in four subtype C viruses with TDF pressure. No mutations conferring resistance to TDF were found in four subtype B (>52–74 weeks), one of each of A, AG and G (>30–33 weeks) and three HIV-2 (>27–29 weeks) selections. K65R appeared by weeks 55 and 73 weeks in two subtype AE (CRF1) selections.

In contrast, there was no variation in time to emergence of M184V with 3TC pressure (weeks 8–14) among subtypes. The time to emergence of K65R was attenuated in M184V-containing subtype C isolates.

The K65R transitions in subtype C, B and AE conferred similar 4–10 fold resistance to TDF and 5–40 fold cross-resistance to each of abacavir, 3TC, and ddI, while not affecting AZT susceptibility.

There were no significant differences in the relative replicative capacities of subtype C, B and AE viruses containing K65R as compared to wild type.

The investigators wrote: “TDF-based regimens will need to be carefully monitored in subtype C infections for possible facilitated selection of K65R. In addition, these data establish concern in regard to the use of TFV in HIV prevention studies in areas of the world in which subtype C viruses are predominant.”

comment

While unique characteristics (ie enhanced pathogenicity) have been erroneously ascribed to subtype C by some of the scientists on these studies, the potential clinical ramifications of these findings need to be reproduced in larger numbers by additional research groups.

We know from larger studies that most of the protease and RT positions associated with drug resistance in subtype B viruses are selected by antiretroviral therapy in one or more non-B subtypes as well and there is no evidence that non-B viruses develop resistance by mutations at positions that are not associated with resistance in subtype B viruses [2], although the pathway to the development of mutations in non-B subtypes is not well-established.

What is well established is that adherence to antiretroviral therapy is the key to preventing the emergence of drug resistance. The latest reports from Botswana are that adherence rates are high and that at the Infectious Diseases Care Clinic (IDCC) at Princess Marina Hospital in Gaborone, which monitors and manages patients with treatment failure, only 4% of the clinic’s 14,000 patients have had to be switched to second or third line regimens. As the African continents first national ART programme, Botswana’s efforts will be closely watched by its neighbours and by the world.

References

1. Brenner BG, Oliveira M, Weinberg M et al. Facilitated selection of K65R resistance with tenofovir pressure in subtype C HIV-1 isolates. XV International HIV Drug Resistance Workshop, Sitges, Spain, July 2006. Abstract 150.
2. Kantor R et al, Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration. PLoS Med. 2005 Apr;2(4):e112. Epub 2005 Apr 26.

2008-03-10
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