Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542

Abstract

Viral entry inhibitors represent an emerging mode of therapy for human immunodeficiency virus type 1 (HIV-1) infection. PRO 542 (CD4-immunoglobulin G2) is a tetravalent CD4-immunoglobulin fusion protein that broadly neutralizes primary HIV-1 isolates. PRO 542 binds to the viral surface glycoprotein gp120 and blocks attachment and entry of virus into CD4(+) cells. Previously, PRO 542 demonstrated antiviral activity without significant toxicity when tested at single doses ranging to 10 mg/kg. In this study, 12 HIV-infected individuals were treated with 25-mg/kg single-dose PRO 542 and then monitored for safety, antiviral effects, and PRO 542 pharmacokinetics for 6 weeks. The study examined two treatment cohorts that differed in the extent of HIV-1 disease progression. PRO 542 at 25 mg/kg was well tolerated and demonstrated a serum half-life of 3 days. Statistically significant acute reductions in HIV-1 RNA levels were observed across all study patients, and greater antiviral effects were observed in the cohort of patients with more advanced HIV-1 disease. In advanced disease (HIV-1 RNA > 100,000 copies/ml; CD4 lymphocytes < 200 cells/mm(3)), PRO 542 mediated an 80% response rate and statistically significant approximately 0.5 log(10) mean reductions in viral load for 4 to 6 weeks posttreatment. Similar findings were obtained in an analysis of all (n = 11) advanced disease patients treated to date with single doses of PRO 542 ranging from 1 to 25 mg/kg. In addition, a significant correlation was observed between antiviral effects observed in vivo and viral susceptibility to PRO 542 in vitro. The findings support continued development of PRO 542 for salvage therapy of advanced HIV-1 disease.

FIG. 1.

Effects of PRO 542 on HIV-1 RNA. (A) Mean change in HIV-1 RNA levels for cohort 1 patients (Pts, n = 7) (B to F) HIV-1 RNA levels of individual cohort 2 patients (patients 8 to 12). Viral load data for cohort 2 patients are plotted on an identical scale to facilitate interpatient comparisons. PRO 542 was administered at time zero, as indicated by an arrow. The dotted line indicates the predose viral load.

FIG. 2.

Correlations between antiviral response in vivo and viral susceptibility to PRO 542 in vitro. Linear regression analysis of the correlation between clinical antiviral effects (4-week viral AUC) and baseline in vitro viral susceptibility to PRO 542 (relative IC₅₀) as measured in the PhenoSense Entry assay (Table 1). (A) Cohort 2 patients (n = 5). (B) All 12 study patients. r is the Pearson correlation coefficient of the best-fit line, and P reflects the significance that the slope of the line differs from zero. Viral AUC represents the area under the viral load-time curve. For this analysis, viral load was log-transformed and normalized to the pretreatment value, and time was expressed in days (e.g., as in Fig. 3). By way of example, a constant 0.5 log₁₀ reduction in HIV-1 RNA for 28 days would translate into a 4-week viral AUC of −14 days, whereas a constant 1 log₁₀ reduction would give a 4-week viral AUC of −28 days.

FIG. 3.

Antiviral effects of PRO 542 in advanced disease. Mean log₁₀ change in viral load is plotted for cohort 2 patients with PRO 542-susceptible virus (R5 and X4 relative IC₅₀ values < 5; patients 8 to 11). PRO 542 was administered at time zero, as indicated by an arrow. Asterisks indicate reductions that were significantly different from zero in two-sided t tests. In addition, the day 3, day 14, and day 21 reductions were significant (P < 0.05) in one-sided tests.