This year's HIV Drug Resistance Workshop included several interesting presentations of new data on resistance to existing and experimental nucleoside analog drugs. Here, we review data relevant to novel and/or new-generation compounds, including MIV-310 (alovudine), boranophosphates, and D-FDOC, as well as to currently available agents, most notably tenofovir (TDF) and the thymidine analogs.

MIV-310 (alovudine)
Calvez et al reported on the antiviral profile of a previously studied compound termed 3‚-deoxy-3‚-fluorothymidine (MIV-310, alovudine), and demonstrated in a phase 2 pilot study that this compound had profound antiviral activity and resulted in significant reductions in viral load [1]. Moreover, these results were demonstrated in individuals whose virus had significant mutational patterns due to extensive pre-treatment histories. Indeed, MIV-310 was active against HIV that had as many as three thymidine analog mutations (TAM), although the number of individuals studied (n = 15) is too low for truly meaningful conclusions to be drawn. Nonetheless, these data speak to the need to pursue further clinical studies in regard to this compound that had once been thought to be lacking in antiviral potential.

In a poster presentation on MIV-310, Vrang et al further demonstrated the activity of this nucleoside against a wide array of resistant HIV isolates [2]. In addition, this group demonstrated that tissue culture selection for resistance to MIV-310 was apparently difficult to demonstrate in studies performed with MT-4 cells and the 3B isolate of HIV. Of course, further analysis should be conducted using clinical isolates of HIV that may be more prone to resistance development than laboratory, clonal varieties. Nonetheless, a clear consensus from the conference is that MIV-310 is deserving of further extensive study and that it may play a useful role in salvage regimens in heavily nucleoside pre-treated patients.

Boranophosphate nucleosides and D-FDOC
Other compounds that were discussed at the Workshop include a series of -boranophosphate nucleoside analogs with the ability to suppress replication of viruses resistant to AZT, 3TC, and other nucleosides [3]. The compounds studied apparently have the ability to act in concert with other NRTI so as to render the latter compounds resensitized in chain termination assays. Although the mechanism of this activity remains to be fully elucidated, these results argue for further study of this series of compounds.

Another novel compound, discussed by Schinazi et al, was D-FDOC, a dioxolane pyrimidine nucleoside compound that also possesses activity against viruses with common nucleoside resistance-conferring mutations [4]. In tissue culture studies, this agent was found to be active against viruses containing a variety of TAMs, as well as M184V. Some degree of resistance was observed in regard to the K65R substitution in both tissue culture and biochemical assays performed with the active triphosphate derivative of this substance. These results suggest that further study of this compound is warranted.

Thymidine analog cross-resistance
Garcia-Lerma et al presented further evidence of cross-resistance between AZT and d4T by documenting that the latter compound can select for both the T215Y and K65R mutations in tissue culture [5]. The finding in regard to the K65R substitution is novel and suggests that this substitution may play a more important role in resistance to d4T than previously thought.

Kuritzkes et al also reported that resistance to d4T and AZT can emerge in a similar fashion in patients who were treated with either of these compounds [6]. In a study in which treatment regimens included either AZT/3TC or d4T/3TC, plus other drugs, this group reported that the emergence of TAMs occurred at comparable rates in association with both nucleoside backbones. However, the AZT/3TC arm showed a greater tendency toward development of two or more TAMs; this group also had a propensity toward more frequent development of the M41L mutation. The scientists hypothesized that the earlier emergence of M41L in individuals receiving AZT/3TC as opposed to d4T/3TC may have led to a greater tendency toward development of multiple TAMs.

Lennerstrand et al discussed the concept of AZT resensitization in viral isolates containing the M184V mutation [7]. This group demonstrated that the substitution was able to reduce levels of resistance to each of AZT, ABC, d4T, and TDF, among isolates that contained the 69S-SG complex. Further study will be necessary to clarify the mechanisms involved.

Marcelin et al reported that the emergence of TAMs in heavily treated patients occurs in stepwise fashion, and that this process can occur through either of two different pathways [8]. One of these, as previously reported, seems to be initiated with M41L, while the other seems to follow the emergence of the T215Y substitution. Depending on which one of these mutations occurs first, major differences may subsequently emerge with regard to the likelihood of development of specific additional TAMs in NRTI-treated.

Tenofovir
Finally, several presentations dealt with the use of TDF in treatment-experienced patients. Miller et al reported that TAMs at positions 41, 210 and 215 frequently co-emerged in multiply-experienced patients and that the emergence of these mutations was associated with diminished responsiveness to tenofovir [9]. In other instances, the K65R mutation was associated with diminished treatment responsiveness. The highest levels of TDF failure were associated with a prior accumulation of five or more TAMs prior to TDF usage. This group speculated that the continued usage of thymidine analogs in treatment may hasten the accumulation of multiple TAMs, even in the context of concomitant TDF therapy.

A different group reported that in the presence of the Q151M mutation, insertions at position 67-70 of RT, and also K65R, were associated with resistance to TDF [10]. Although the M184V substitution may have had an effect with respect to TDF resensitization, the mutations at positions 44 and 118 did not affect levels of TDF sensitivity. Both K65R and L210W seem to be predictive of TDF resistance, and the reporting investigators concluded that the M184V resensitization effect may mandate the co-administration of 3TC with TDF in AZT-experienced patients.

References
(NOTE: hotlinks to abstracts may require registration for Abstracts Online)

V Calvez, R Tubiana, J Ghosn, M Wirden, AG Marcelin, C Westling, H Shoen, J Harmenberg, G Mårdh, B Öberg, C Katlama. MIV-310 reduces markedly viral load in patients with virological failure despite multiple-drug therapy: results from a 4-week Phase II study. Antiviral Ther 2002; 7:S4.
L Vrang, H Zhang, S Palmer, E-Y Kim, T Merigan, B Öberg. In vitro effects of MIV-310 (alovudine, 3°-fluorodeoxythymidine, FLT) against HIV mutants. Antiviral Ther 2002; 7:S18.
J Deval, B Selmi, B Schneider, P Meyer, J Boretto, S Sarfati, D Deville-Bonne, C Guerreiro, J Janin, M Véron, B Canard. The use of alpha-boranophosphate nucleoside analogues to suppress HIV-mediated multidrug resistance to lamivudine, dideoxynucleosides, and zidovudine. Antiviral Ther 2002; 7:S8.
RF Schinazi, J Mellors, S Erickson-Viitanen, J Mathew, U Parikh, P Sharma, M Otto, Z Yang, CK Chu, DC Liotta. D-FDOC: a dioxolane pyrimidine nucleoside with activity against common nucleoside-resistant HIV-1. Antiviral Ther 2002; 7:S15.
G García-Lerma, H MacInnes, S Nidtha, D Bennett, H Weinstock, W Heneine. In vitro selection of the T215Y and K65R mutations by stavudine and demonstration of high-level resistance to stavudine. Antiviral Ther 2002; 7:S28.
DR Kuritzkes, RL Bassett, RK Young, H Barrett, JL Koel, JD Hazelwood, VA Johnson for ACTG 306 and 370 Protocol Teams. Rate of emergence of thymidine analogue resistance mutations in HIV-1 reverse transcriptase selected by stavudine or zidovudine-based regimens in treatment-naïve patients. Antiviral Ther 2002; 7:S31.
J Lennerstrand, T Bergroth, X-W Shao, A Van Cauwenberge, P Mc Kenna, A Sönnerborg. Cross-resistance patterns for HIV-1 multi-nucleoside resistant mutants with mutations associated with re-sensitization to zidovudine. Antiviral Ther 2002; 7:S33.
AG Marcelin, M Wirden, C Delaugerre, P Viegas, A Simon, C Katlama, V Calvez. Selection of thymidine analogue mutations by nucleoside reverse transcriptase inhibitors occurs step by step and through two different pathways. Antiviral Ther 2002; 7:S34.
MD Miller, L Zhong, S Chen, NA Margot, M Wulfsohn. Multivariate analyses of antiviral response to tenofovir DF therapy in antiretroviral-experienced patients. Antiviral Ther 2002; 7:S12.
K Wolf, H Walter, T Schnell, W Keulen, N Beerenwinkel, J Selbig, A-M Vandamm5, K Korn, B Schmidt. The drug resistance profile of tenofovir: a story of resistance and resensitization. Antiviral Ther 2002; 7:S16.