Tenofovir, resistance and K65R and concomitant nucleosides

1 September 2003. Related: Conference reports, Antiretrovirals, Drug resistance.

Simon Collins, HIV i-Base

Further information about tenofovir resistance and approaches to using this new drug were provided in several abstracts. Much of this information, and the discussions it generates involve the development of the tenofovir-associated K65R mutation and this has an overlapping cross-resistance profile with abacavir and ddI.

Parikh and colleagues from the University of Pittsburgh looked at the frequency of K65R and its association with other nucleoside mutations in the Virco and Stanford databases. Susceptibility was determined using a single/multiple cycle assay. [1]

Among more than 60,000 samples in the Virco database containing nucleoside mutations, K65R increased in frequency from 0.8% in 1998 to 2.1% in 2002 and 3.8% in 2003. A mononuclear clone containing K65R showed reduced susceptibility of 2.5 to >10-fold to all D- and L-acyclic nucleoside but not to AZT. A strong negative correlation was found between presence of K65R and AZT-associated mutations. Addition of K65R to AZT-resistant clones (41L, 210W, 215Y and 67N, 70R, 215F, 219Q) increased AZT susceptibility 10-fold (reducing resistance from 30-fold to 3-fold).

In a second abstract, Winston and colleagues from the Chelsea and Westminster Hospital in London reported a similar increase in the incidence of K65R from 1.7% prior to October 2000 to 4% over the following two years to October 2002. Although abacavir, ddI and tenofovir were not associated alone with development of K65R, certain combinations were. Fourteen percent of isolates were from patients using tenofovir with ddI and 32% were using tenofovir, ddI and abacavir. Forty-one percent of resistance tests from people using tenofovir/abacavir/ddI showed K65R. Concurrent thymidine analogues reduced the risk of K65R by 76% (OR 0.24, 95% CI 0.1-0.5). [2]

Miller presented Gilead’s resistance analysis from the 903 study that compared tenofovir to d4T, both against a backbone of 3TC and efavirenz. By week 96 approximately 12% of patients had failed virologically in each arm (n=36 tenofovir, n=38 d4T). [3]

K65R developed in almost one quarter of failures in the tenofovir arm (8/36), compared to around 5% of failures in the d4T arm (2/38). Development of K65R only showed low level changes in tenofovir susceptibility (mean 1.2-fold, range 0.9-2.2) increased susceptibility to AZT (0.5 fold) and low level changes for ddI and abacavir. The majority of patients in each arm showed resistance to efavirenz and/or 3TC and efavirenz resistance always preceded or accompanied K65R. A study by Deval and colleagues suggested that M184V with K65R increased tenofovir sensitivity and reduced viral fitness at a molecular level by reducing binding of natural nucleotides, although aiming principally for maximal suppression with no development of resistance must still be preferable to strategies based on driving a virus with low replicative capacity. [4]

Data on the clinical responses following failure of tenofovir-based treatment has been previously presented on a handful of patients but included successful responses to subsequent therapy, including several patients with K65R who chose to continue tenofovir therapy.

Van Rompay and colleagues suggested that continued tenofovir therapy is needed to maintain a CD8-mediated response that actually mediates K65R suppression, following a study of four SIV-infected rhesus macaques. [5]

Comment

Tenofovir was already being included in first-line therapy in the UK prior to change in the EMEA recommendations in June 2003, especially as it was approved for first-line therapy in the US, largely driven by the convenience of a one-pill, once-daily formulation.

Although incidence of K65R is low compared to exposure to tenofovir (2.7%) it is high (almost 25%) in those people whose treatment fails – and the implication for cross-resistance to both existing and pipeline nucleosides means that further research and information in this area will be highly significant.

There may be a reason not to experiment with adherence using once daily regimens based on the tenofovir/ddI combination or to use this combination only once adherence and viral suppression has been obtained. The role of a thymidine-including combination with tenofovir, may be less protective than these studies suggest as some patients using Trizivir+tenofovir in the ESS40013 study reported at the IAS meeting (abstract 42) failed with K65R.

References:

Unless stated otherwise, references are to the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, 10-14 June 2003; published as part of Antiviral Therapy Volume 8 Issue 3.

1. Parikh U, Koonz D, Hammond J et al – K65R: a multi-nucleoside resistance mutation of low but increasing frequency. Abstract 136.
2. Winston A, Pozniak A, Gazzard B et al – Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase? Abstract 137.
3. Miller MD, Margot NA, McColl DJ et al – Characterisation of resistance mutation patterns emerging over two years during first-line antiretroviral treatment with tenofovir DF or stavudine in combination with lamivudine and efavirenz. Abstract 135.
4. Deval J, White KL, Miller MD et al – Drug resistance and viral fitness at a molecular level: the case for viral fitness. Abstract 34.
5. Van Romay KKA, Singh R, Wingfild C et al – Immune-mediated suppression of virulent simian immunodeficiency virus induced by tenofovir treatment. Abstract 70.