Lalezari and colleagues presented data from a Phase I study looking at the safety and antiviral activity of the CCR5 antagonist 837140 currently in development by GlaxoSmithKline.

In addition to the CD4 receptor, CCR5 and CXCR4 are additional molecules that reside on the surface of CD4+ cells, which HIV must use to gain entry into the cell. In most patients with early or less-advanced disease, the predominant form of HIV that is seen in the blood is CCR5 receptor (or R5) positive.

In more advanced disease, the predominant virus type is CXCR4 (or X4) positive. CCR5 antagonists are a new class of antiretroviral agents that bind to the HIV-1 co-receptor CCR5 and block one of the routes by which the virus enters into cells.

The study was a randomized, double-blinded, placebo-controlled, dose escalation trial, in which 40 patients were given 837140 treatment with a moderate moderate-fat meal for 10 days. The dosing strategies included: 200 mg once daily, 200 mg twice daily, 400 mg once daily and 600 mg twice daily.

The study was performed in both treatment-naive and treatment-experienced adults, although no patient who was treatment experienced had received any antiretroviral treatment in the preceding 12 weeks. Plasma viral load had to be greater than 5,000 copies/mL and CD4+ nadir had to be greater than 200 cells/mm³. In addition, the patient had to have R5 virus as demonstrated by a modified PhenoSense phenotypic assay.

Most of the patients were male, about half were treatment naive. Twenty percent of the patients also had hepatitis C virus infection. The CD4+ cell count and viral load means in the treatment groups ranged from 297 to 404 cells/mm³ and 4.2 to 4.7 log₁₀ copies/mL, respectively. Viral load changes demonstrated a dose response (meaning greater reductions in viral load with increasing doses), with the highest dose demonstrating a 1.66 log₁₀ copies/mL reduction (maximum reduction 2.75 log₁₀ copies/mL) at 10 days.

After treatment discontinuation, viral load returned to pretreatment levels. No CD4+ cell count change information was presented.

The medication was well tolerated, with no serious or significant adverse events reported. Common side effects included gastrointestinal symptoms, which generally resolved in most patients after about 3 to 4 days on the drug. Phenotypic assays were performed to see if the patient's virus required increased drug concentrations, which would be a marker of reduced susceptibility or drug resistance. No significant difference was noted.

The study also looked at the efficiency of R5 receptor blocking on CD4+ cells and found that more than 95% of the R5 receptors were blocked by the drug. The researchers also noted that the R5 receptors tended to stay blocked for several days after the patients had stopped the drug.

This short-term study showed that 873140 blocks the R5 receptor very well, is well tolerated and, as a single agent, has impressive potency in terms of viral load reduction.

This compound is now going into Phase II trials, where patients will receive it for a longer period of time. It remains to be seen whether the viral load reduction is sustained, whether new or significant side effects emerge, and whether resistance or loss of potency develops because of R5 receptor changes (and therefore poor 873140 binding). Based on the preliminary data reported here, this medication and class may become a welcome addition to currently available regimens.