Passive immunotherapy is a process in which plasma is donated by healthy HIV-positive people who have a high CD4 count and whose plasma has been found to have high levels of neutralising antibodies (those which prevent the growth of HIV in laboratory tests). The plasma from several donors is then pooled so that it is likely to contain antibodies effective against many strains of HIV and treated to kill HIV and any other disease-causing organisms. It is then infused, usually at monthly intervals, into people with ARC or AIDS who have lost their own ability to make the antibodies.

The therapy stems from the observation in some studies that healthy HIV-infected individuals have a high level of neutralising antibodies against HIV whilst people with AIDS have at best low levels of such antibodies but a high level of virus in the blood.

Passive immunotherapy is called passive because it involves giving someone else's antibodies to the recipients, as opposed to therapies like vaccines which encourage the body to make its own antibodies.

Passive immunotherapy is also known as passive immunisation or passive hyperimmune therapy (sometimes abbreviated to PHIT).

Current use

Passive immunotherapy is an unlicensed, experimental therapy. Several studies have tried to measure its effectiveness by looking for reductions in p24 antigen levels; however this marker may be meaningless since the infusions are likely to contain anti-p24 antibodies which may simply `mop up' free p24 antigen without making any difference to the underlying disease process.

Other studies have not been properly controlled e.g. they have compared plasma infusions to a placebo rather than with plasma from HIV-negative people, which would allow a better comparison of the significance of the anti-HIV antibodies contained in the treatment.

Nevertheless, some studies have suggested that passive immunotherapy can improve or delay the development of new symptoms, especially when used at relatively high CD4 counts. It has also been suggested that the treatment can reduce levels of detectable HIV (which is more significant than a reduction in p24 antigen) in the bloodstream. Despite some reports in the press, studies of passive immunotherapy have not shown any statistically significant improvement in survival.

Side-effects of the treatment can include headaches, nausea, fevers, coldness in the hands and feet and transient rashes. There have been reports that two plasma recipients may have become infected with hepatitis C, possibly as a result of inadequate sterilisation of the donated plasma.

Donating the plasma does not appear to be at all harmful; in fact, it appears to be beneficial, perhaps because it stimulates the body to produce more antibodies, raising levels to be higher than before donation of plasma. There have also been intriguing reports that donors CD4 counts may stabilise. Only blood plasma is donated; blood cells are separated off by plasmapheresis and returned to the donor.

Taking it

One study found that when regular treatment with passive immunotherapy was stopped, p24 levels rebounded to levels higher than before treatment and were accompanied by severe clinical deterioration. This suggests that severely immunosuppressed people should not stop passive immunotherapy without starting an alternative treatment.

Getting it

Passive immunotherapy is no longer being studied in the UK.

Key research

Although naturally developing anti-HIV antibodies may be inadequate to control disease progression, it is hypothesized that methods to boost or elicit high titre antibodies in AIDS patients may be beneficial in limiting viral spread or preventing new infection. Fultz found that, in macaques and mangabeys, the presence of neutralizing antibodies or antibodies that inhibit SIV reverse-transcriptase activity did not correlate with protection from clinical disease.

Jackson treated 6 people with advanced ARC or AIDS for at least 1.5 years with plasma from donors with high titres of p24 antibodies. In the period immediately following each infusion, there was a loss of HIV antigenaemia, a reduction in the fraction of participants with positive plasma and lymphocyte HIV cultures, fewer opportunistic infections and improvements in symptom score, weight and Karnofsky performance score.

Karpas (1988) enrolled 10 people in an open trial of passive immunotherapy. All showed clearance of HIV antigenaemia after monthly infusions of immune plasma. In addition, Karpas (1990) reported dramatic loss of detectable viraemia, as measured by polymerase chain reaction assays for both plasma HIV DNA and RNA, after the second infusion in all 8 participants tested.

Vittecoq conducted a phase I study of the safety and efficacy of passive immunotherapy in 18 people diagnosed with AIDS for longer than 6 months and with CD4 counts below 100. Participants were randomised to receive transfusions (every 2 weeks for 14 weeks) of either heat-inactivated anti-HIV antibody-rich plasma from 9 asymptomatic HIV-positive donors with CD4 counts above 400 and no detectable p24 antigen (Group 1), or seronegative fresh-frozen plasma from 56 HIV-negative healthy donors (Group 2). All participants were receiving AZT (500 mg/day) and aerosolised pentamidine as PCP prophylaxis. The number of OIs was significantly reduced in Group 1 (2 vs 8). One death occurred in each group, due to recurrent CMV disease. p24 antigen levels dramatically declined in Group 1 and 6/9 became p24 antibody positive by day 2 after the first transfusion; p24 levels remained unchanged in Group 2. In the post-transfusion period, after week 20, severe clinical deterioration occurred in Group 1: 8/9 developed poorly-tolerated fever; 4/9 had diarrhoea; 3/9 developed CMV viraemia; 1 had pancytopenia. Antigenaemia returned to positive, at a level higher than before treatment in most cases. Reintroduction of treatment for Group 1 at week 34 was associated with clear regression of symptoms in 4/9; between weeks 34 and 42 three participants died.

LeFrè²¥ (1993) enrolled 86 individuals with symptomatic HIV infection and a CD4 count below 200 in a placebo-controlled phase II study of passive immunotherapy (300 ml of plasma rich in p24 antibodies every 14 days over a 1 year period) versus infusions of standard seronegative plasma. Placebo recipients had a 3-fold greater probability of developing new AIDS-defining events than immunotherapy recipients. 26 people receiving passive immunotherapy had no new events compared to 13 of the controls. No significant difference in the number of deaths was observed (7 in the treated group and 11 in the control group).

LeFrè²¥ (1995) reported that participants in the above trial who received passive immunotherapy experienced a significant increase in viral load when compared with the control group, and also had significantly higher viral load at the end of the study period. There was no difference between the CD4 count of treated people and the untreated control group. It has been suggested that the increase in viral load seen in this study reflects the killed HIV present in the passive immunotherapy plasma, rather than an increase in infectious virus levels within the individual. This view is supported by Karpas 1990 study, reported above.

Jacobson conducted a randomized, double-blind, controlled trial of human anti-HIV hyperimmune plasma. 63 people with AIDS received 250 ml of either HIV-immune plasma or HIV antibody-negative plasma every 4 weeks. Although nonsignificant trends toward improved survival and delayed occurrence of a new opportunistic infection were noted, no significant effects on absolute CD4 lymphocyte counts or quantitative HIV viraemia were seen. The only notable toxicity was the allergenicity to be expected from infusing plasma products, usually manifesting as urticaria (nettle-rash). These results do not rule out the potential usefulness of passive immunization with different preparations, but did fail to demonstrate clinical benefit of the product studied.

Levy randomised 220 people with AIDS or severe ARC and CD4 counts below 200 receive anti-HIV plasma or placebo (500 or 250 cc intravenously each month). The anti-HIV plasma was derived from healthy HIV-positive donors, pooled, and sterilized with beta-propiolactone. At 12 months no overall differences in survival or CD4 counts were observed. In a subgroup analysis of 72 patients with CD4 counts between 50 - 200, treated patients had significantly increased CD4 counts compared with placebo recipients (32.7 cell increase vs. 2.5 cell decrease). However, significantly better survival was not observed among these treated patients.

Stricker assessed the clinical and immunological effects of repeated plasma donation among 487 asymptomatic HIV-positive donors with initial CD4 counts above 400 and anti-p24 antibody titres above 1.3125. Only 6.7% of donors followed for at least one year experienced a CD4 decline below 400. Based on matched historical controls, about 21% of this cohort would have been expected to experience a drop in CD4 count below 400 over the study period. Similar apparently beneficial effects of donating plasma have been reported by Bainbridge.

Osther treated 14 HIV-positive individuals for 5-7 days with intravenous infusions of highly purified anti-HIV antibodies derived from pigs which had been inoculated with killed HIV particles (a substance known as PASSHIV-1). 2/14 participants were retreated 3 months later with PASSHIV-1 for an additional 5 days to evaluate side-effects from retreatment with porcine immunoglobulins. 10 had no side-effects from PASSHIV-1 therapy, 3 experienced transient urticarial eruptions which responded to antihistamine administration and one participant who received concomitant administration of human gammaglobulin experienced serum sickness. All patients demonstrated a significant improvement in fatigue, weight, fever, polyneuropathy, bronchitis, candidiasis, diarrhoea and dermatitis. 1/5 with KS demonstrated a greater than 50% improvement. Mean CD4 cell counts in the group rose from 143 to 234 4-6 months following completion of therapy. 4 p24 antigenaemic participants became antigen-negative after treatment.

Skinhoj treated 55 HIV-positive people with either PASSHIV-1 (5 or 15 gms) or a matching maltose solution, given intravenously over 5 days. No significant differences in CD4 count or clinical outcome were observed between the groups.

References

Bainbridge DR et al. Can repeated plasma donation by asymtpomatic HIV-infected individuals delay the onset of AIDS?. Philos Trans R Soc Lond B Biol Sci 352(1355):763-770, 1997.

Fultz PN et al. Humoral response to SIV/SMM infection in macaque and mangabey monkeys. J AIDS 3:319-323, 1990.

Jackson G et al. Passive immunoneutralization of human immunodeficiency virus in patients with advanced AIDS. Lancet 647-651, 1988.

Jacobson JM et al. Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection. JID 168(8):298-305, 1993.

Karpas A et al. Effects of passive immunisation in patients with ARC and AIDS. PNAS USA 85(23):9234-9237, 1988.

Karpas A et al. Polymerase chain reaction evidence for human immunodeficiency virus 1 neutralization by passive immunization in patients with AIDS and AIDS-related complex. PNAS USA 87:761-767, 1990.

LeFrè²¥ JJ et al. Passive immunotherapy in AIDS: results of a double blind randomised phase II study. 1st Natl Conf on Human Retroviruses, Washington, abstract L12, 1993.

LeFrè²¥ JJ et al. Passive immunotherapy in AIDS: Biological results of a double blind randomised study. 2nd Natl Conf on Human Retroviruses, Washington, abstract LB10, 1995.

Levy J et al. Efficacy and safety of passive hyperimmune therapy (PHT) in HIV disease: results of a 12-month study. 9th Intl Conf AIDS, Berlin, abstract B28-2149, 1993.

Osther K et al. PASSHIV-1 treatment of patients with HIV-1 infection. A preliminary report of a Phase I trial of hyperimmune porcine immunoglobulin to HIV-1. AIDS 6:1457-1464, 1992.

Skinhoj P et al. Safety and efficacy of PASSHIV-1 treatment in patients with advanced HIV-infection. Fifth European Conference on Clinical Aspects and Treatment of HIV Infection, Copenhagan, abstract 837, 1995.

Stricker RB et al. Potential benefit of repeated plasma donation in asymptomatic HIV-infected individuals. 16th Annual Mtg of Amer Soc for Apheresis, abstract, March 1995.

Vittecoq D et al. Passive immunotherapy in AIDS: a randomised trial of serial HIV-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. JID 166(2):364-368, 1992.

Zolla-Pazner S et al. Editorial review: Passive immunization for the prevention and treatment of HIV infection. AIDS 6:1235-1247, 1992.