Clearly, there is an important need to develop a new class of antiretroviral compounds -- compounds that will not be prone to the same resistance mutations that reduce the effectiveness of the 3 major currently approved HIV medication classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors.

A major hope among researchers and clinicians is that a new type of drug called a CCR5 antagonist, which targets a part of HIV itself rather than a product the virus uses to replicate (like the protease enzyme), will be less likely to encounter problems of resistance. (At the same time, however, it cannot be ruled out that effective resistance to CCR5 antagonists may occur on the basis of alternate receptor usage involving the selection of viruses that display tropism for CXCR4 coreceptors instead of CCR5.)

In a 10-day monotherapy study, presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy in October 2004, a CCR5 antagonist termed GSK873140 (873140 for short) was shown to possess important antiviral activity.¹ That study demonstrated decreases in viral load of 1.66 log₁₀ copies/mL at the highest doses tested.

At this conference, James Demarest of GlaxoSmithKline presented the results of the latest study on 873140, in which the antiviral activity of 873140 was assessed against a broad array of viruses obtained from clinical plasma samples containing divergent HIV-1 envelopes.

Samples had been obtained from treatment-naive patients, as well as treatment-experienced patients who were on a failing regimen at the time samples were collected. Samples came from a mostly male (80%) cohort, of mostly white (62%) patients. The tissue culture susceptibility of these viral envelopes to 873140 was evaluated using the PhenoSense HIV entry assay, performed at Virologic, Inc., in California. This assay uses an engineered cell line that expresses CD4 and only CCR5. Analysis of both variance and linear regression methods were employed.

The results showed that the median IC₅₀ value for the R5-tropic virus samples studied (n = 338) was 6.81nM. At the same time, 95% of the total number of samples studied had IC₅₀ values of less than 16.5nM, while samples from treatment-experienced patients (5.83nM) were more susceptible to 873140 than were samples from treatment-naive patients (6.71nM). Importantly as well, the CCR5-relevant components of dual-tropic (R5 and X4) viruses were susceptible to 873140, possessing a median IC₅₀ value of 3.61nM.

In other words, 873140 displayed activity against R5-tropic envelopes derived from both treatment-naive and treatment-experienced patients. The plasma concentrations of 873140 that are generally achieved in clinical studies are higher than the IC₅₀ values that were determined in this study, suggesting that 873140 will be efficacious for the treatment of HIV-associated disease.

It is also interesting that dual-tropic samples may have lower IC₅₀ values than viruses displaying only R5 tropism, although further research will be necessary to determine the basis for this observation.

In general, 873140 appears to be an excellent compound that should be further developed for potential use in antiretroviral chemotherapy. The findings of this study add considerable new information to previous data presented at other conferences over the past year.^1-4

Footnotes

1. Lalezari J, Thompson M, Kumar P, et al. 873140, a novel CCR5 antagonist: antiviral activity and safety during short-term monotherapy in HIV-infected adults. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; Oct. 30 - Nov. 2, 2004; Washington, D.C. Abstract H-1137b.

2. Sparks S, Adkison K, Shachoy-Clark A, Piscitelli S, Demarest J. Prolonged duration of CCR5 occupancy by 873140 in HIV-negative and HIV-positive subjects. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; Feb. 22-25, 2005; Boston, Mass. Abstract 77.

3. Kitrinos K, LaBranche C, Stanhope M, Madsen H, Demarest J. Clonal analysis detects pre-existing R5X4-tropic virus in patient demonstrating population-level tropism shift on 873140 monotherapy. Antiviral Therapy. 2005;10:S68.

4. LaBranche CC, Davison D, Ferris RG, et al. Studies with 873140, a novel CCR5 antagonist, demonstrates synergy with enfuvirtide and potent inhibition of enfuvirtide resistant R-5 tropic HIV-1. Antiviral Therapy. 2005;10:S73.