GlaxoSmithKline yesterday unveiled the first findings on the effect of its chemokine antagonist in HIV-positive people at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington DC.
Three companies are developing chemokine receptor antagonists targeting the CCR5 receptor on human CD4 lymphocytes and macrophages, which is used as a coreceptor to facilitate entry by HIV during earlier stages of infection.
For reasons that are still poorly understood, the HIV population in an infected person begins to change as the CD4 cell count declines. HIV variants begin to emerge that can use another receptor, CXCR4, or both receptors. The appearance of these strains is closely associated with CD4 cell decline and viral load increases, leading some scientists to argue that this switch is what drives the disease process.
Once the CXCR4 virus begins to predominate, researchers fear that CCR5 antagonists will be of limited use for patients, and might even drive the virus population further in the direction of CXCR4 usage.
With this in mind two research groups set out to examine when CCR5 antagonists might have their maximum effect by looking at virus populations in large numbers of patients with varying CD4 cell counts and viral load levels.
Dr Graeme Moyle of the Chelsea and Westminster Hospital, London, reported on an analysis of coreceptor usage in 865 patients receiving treatment at the clinic. The analysis found that whilst CCR5 usage was influenced by CD4 cell count, CD4 percentage and viral load, even patients with low CD4 cell counts might still have CCR5-tropic virus populations, suggesting that baseline testing will be essential for identification of patients who can benefit from a CCR5 antagonist.
James Demarest of GlaxoSmithKline reported on a similar analysis in 325 treatment-naïve patients and 117 treatment-experienced patients, which found that decreasing CD4 / CD8 ratio was predictive of CXCR4 usage in treatment-naïve patients, whilst prior protease inhibitor treatment (odds ratio [OR] 4.17, p = 0.009) and increased age (OR 1.06 per one year increment) were predictive of CXCR4 usage in treatment-experienced patients. It is unclear at present if these predictors are surrogates for duration of infection or low CD4 nadir, and further analyses will be carried out by GlaxoSmithKline. Non-Caucasian ethnicity was also predictive of CXCR4 usage (OR 5.13).
Glaxo’s CCR5 antagonist
Steve Piscitelli of GlaxoSmithKline presented phase I / II results of a ten day monotherapy study of the company’s new CCR5 antagonist, a product codenamed 873140.
The study recruited 40 patients who were randomised to one of four doses of 873140 in the ratio 8:2 between the active agent and the placebo. 873140 was dosed at 200mg once daily, 200mg twice daily, 400mg once daily and 600mg twice daily.
Participants could have experienced failure of no more than two previous regimens, and had received no treatment for at least 12 weeks prior to beginning treatment in the study. Participants were required to have CD4 cell counts above 200 cells/mm3 and viral load above 5000 copies/ml, and were screened for CCR5-tropic virus in order to prevent selection of CXCR4-tropic virus by treatment in patients with mixed virus populations.
The study recruited 19 treatment-naïve patients and 21 treatment-experienced patients. Half of all participants were African-Americans and eight participants had hepatitis C infection. CD4 cell counts ranged from 297 to 404 cells/mm3.
Participants received ten days of treatment followed by a washout period to observe the rate of viral rebound. The largest viral load reduction was seen in the 600mg twice daily group (mean decrease 1.6 log10). Reductions of 1.03, 1.23, 0.46 and 0.12 log10 were seen in the 400mg once daily, 200mg twice daily, 200mg once daily and placebo groups respectively.
The lowest viral load achieved occurred between 24 and 36 hours after the discontinuation of treatment, suggesting that CCR5 receptors remain occupied for a considerable time after treatment is discontinued. This phenomenon may translate into treatment regimens that are more forgiving of the occasional missed dose, particularly when a CCR5 inhibitor is paired with drugs that have long half-lives.
Side effects were transient and concentrated during the first few days of treatment in almost all patients. Loose stools, abdominal pain and nausea were common in the first one to three days of treatment.
GlaxoSmithKline is planning to launch phase IIb studies to define a dose for development in early 2005. Two other companies – Pfizer and Schering-Plough – are also advancing with CCR5 antagonists.
Demarest J et al. HIV-1 co-receptor in treatment naïve and experienced subjects. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1136, 2004.
Lalezari J et al. 873140, a novel CCR5 antagonist: antiviral activity and safety during short-term monotherapy in HIV-infected adults. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1137b, 2004.
Moyle G et al. Prevalence and predictive factors for CCR5 and CXCR4 co-receptor usage in a large cohort of HIV positive individuals. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1135, 2004.