Passive Immune Therapy in Acquired Immunodeficiency Syndrome

We read with concern the article on passive hyperimmune therapy in the treatment of acquired immunodeficiency syndrome (AIDS).’ In this report, the investigators attempted to show the efficacy of plasma taken from asymptomatic human immunodeficiency virus (H1V)-positive donors with antibody to HIV on the clinical course of AIDS patients. The investigators set up four requirements to establish efficacy: decreased mortality, improved length of survival, decreased number of opportunistic infections, and positive changes in CD4 count. Overall, there was no efficacy, ie, no statistically significant changes during the study period! The concept of passive immune modulation of HIV infection is attractive: however, in general, with viral diseases antibody is useful in preventing primary infection, but it usually requires cell-mediated immunity and/or other antiviral responses for eradication. Levy et all misstate the findings of the reference they cite when they note that “Hyperimmune plasma . . . [is] useful in the treatment . . .”; in their references, hyperimmune plasma or immunoglobulin preparations provided effective prophylaxis (prevention, not modification of ongoing infection). In the Levy et al study,’ only a minority of patients (72 of the original 220) were reported to have some “benefit”; in these, three of the stated criteria for efficacy (mortality, survival, and infections) were not significantly different from controls. The fourth, a change in the level of CD4 cells, was “statistically significant” only in a subpopulation of 32 patients among the 72, and then with a wide standard deviation. Considering that the majority of the patients studied did not meet even this criterion, the data must be viewed with caution. A previous study of such therapy indicated that the level of neutralizing antibody in the passively transfused plasma was important in producing a reduction in cultured virus in recipients.* Neutralizing antibody was determined in two separate laboratories in the Levy et all study, but no data are given about the infused material other than it was active against a broad strain of isolates. In the baseline data of Table 2, the full-dose group antibody to p24 data excludes 5 “outliers” with antibody titers of greater than 1:5,000. What was the fate of such individuals? Did their elevated titers contribute to the alleged improvement in this group? The Levy et al report’ is littered with such phrases as “near statistical significance,” “suggested benefit,” or “favorable trend,” which are only useful in obfuscating the lack of rigor of the data. They found that the number of opportunistic infections was not different for the three groups as well as the number of deaths in each group. No data were provided about the nature of any of the deaths. Were they infectious or due to other AIDS complications? Two deaths were not AIDS related; how was that determined? It is stated that there were no instances of viral transmission from donor plasma but there are no studies to prove this finding, nor appropriate techniques detailed in the Materials and Methods. Such statements and omissions are troubling. In experimental systems in primates, passive immunization is only successful using material from animals shown to be immune when administered to prevent retroviral infection. Studies in animals already infected and using plasma from animals also infected but asymptomatic (as is done in this study) were unsuccessful and may have accelerated the disease.’ Finally, it appears the study by Levy et al’ was completed in 1992. Are there follow-up data on the fate of the three groups? Specifically, is there any evidence of rebound or accelerated disease in the treated groups over the controls in the years after the study and the submission of this report in June of 1994? In the Vittecoq et al study: stopping the anti-HIV infusions resulted in a “rebound” effect with 7 of 9 in the treatment group dying, versus only 1 of 9 in the control group. In a larger study by this same French group, they also found no survival benefit with hyperimmune plasma but have continued to give it for fear of this “rebound” e f f e ~ t . ~ We believe that the results of the Levy et al report’ do not support a move to a phase 3 study.