Passive transfer of anti-HIV antibodies has been tested for the treatment of HIV since the late 1980s, when investigators attempted to suppress viral replication with infusions of inactivated hyperimmune plasma pooled from HIV-infected donors [
7‐
12]. Jackson et al. (1988) demonstrated in six subjects that infusions of plasma from donors with high titers of anti-p24 (HIV core antigen) led to clearance of p24 antigen in the blood for up to 11 weeks [
9]. Karpas et al. (1988) showed similar results in 10 subjects following infusion of hyperimmune plasma [
10,
11]. However, follow-up studies that were randomized and placebo-controlled were less clear in their findings. Jacobson et al. (1993) showed in 65 subjects that monthly infusions of anti-HIV hyperimmune plasma as compared with placebo had no impact on quantitative HIV cultures, CD4 counts, incidence of opportunistic infections, or death [
7]. Still, a trend towards longer survival and delayed opportunistic infections was observed. Levy et al. (1994) also showed that in a randomized, placebo-controlled trial of 220 subjects, infusions of hyperimmune plasma led to improved clinical outcomes only in subjects with CD4 counts 50–200 cells/mm
3 who received the highest dose [
13]. In this subset of subjects, a significant increase in CD4 count was observed, but overall, differences in mortality did not reach statistically significance. On the other hand, Vittecoq et al. (1995) observed that passive immunotherapy did lead to a significant delay in the appearance of the first AIDS-defining event in 86 subjects as compared to placebo when given more frequently (every 2 weeks), as well as a mortality benefit [
8]. A retrospective analysis of changes in plasma HIV RNA confirmed that after the third dose, there was a significant difference in viral load between the passive immunotherapy and placebo groups [
14]. These early studies provided the key observation that infusion of HIV-specific antibodies can lead to reductions in plasma virus that may lead to clinical benefits.