AIDS Treatment News #165, December 18, 1992
Dave Gilden

AIDS TREATMENT NEWS recently obtained from independent sources an unreleased, detailed statistical analysis of the trial data, performed by members of the University of California Los Angeles Department of Biomathematics. That report raises questions about the completeness of HemaCare's summary description of the data collected so far. Conclusions about PHT's long-term therapeutic value must await the findings of planned two-year phase III studies.

PHT aims to restore people's ability to control their HIV infections after immune deficiency has set in. Patients receive monthly infusions of blood plasma pooled from asymptomatic HIV-positive individuals who are continuing to produce high levels of anti-HIV antibodies.

The data released by the company in October seemed promising. After a year on full dose PHT, volunteers who started with T- helper counts of 50 to 200 experienced an average T-helper cell loss of two per cent, compared to a 35 per cent reduction for those on placebo. The benefit from PHT appeared to be dose-related: Volunteers receiving half dose fell between the two values, with an average 25 percent T-helper cell loss. Five deaths occurred on the placebo arm, three on the half-strength arm and one on the full-strength arm. The company reported no significant adverse affects from the therapy, and no withdrawals because of toxicity.

While not questioning PHT's safety, the full statistical analysis presents a more confused picture than do the sketchy press releases. Most of the trial volunteers yielding usable data -- 93 out of 155 -- had T-helper cell counts of less than 50. No significant benefits to volunteers with such low counts were detected. This result conforms to a past study by Abraham Karpas, Sc.D., of the University of Cambridge. Dr. Karpas' small study observed that the benefits of passive immunotherapy for people with people with ARC were much more long-lasting than for people with AIDS. [See Proceedings of the National Academy of Sciences, USA, volume 67, October 1990, pages 7613-7617).

Joshua Levy, M.D., HemaCare's research director, told AIDS TREATMENT NEWS that the decision to focus on people with depleted T-helper populations was based on reasons of compassion as well as a desire to quickly obtain decisive data. The positive findings HemaCare reported are based on 62 individuals with T-helper counts of 50 to 200. This small sample size reduced the possibility of obtaining clear-cut, statistically significant findings. The full statistical analysis shows that average T-helper counts in the 50 to 200 segment of the trial did jump upward in the first six months. But the one-year data are not as good: T-helper counts on full dose in this group, up 33.7 percent above baseline at six months, had fallen back essentially to baseline by one year.

The trend in the second six months raises the question of how well PHT preserves T-helper cells in the long run. An analysis carried out by the statisticians that gave greater weight to later T-helper counts revealed little significant treatment effect compared to the simple endpoint analysis HemaCare publicized.

As for survival rates, only a trend considered largely lacking in statistical significance was found when other factors were taken into consideration along with T-helper count. These factors included AIDS or ARC diagnosis, weight loss and baseline p24 antigen level.

An unexpected problem is that original T-helper counts are missing for 29 of the 203 volunteers in the trial as a whole. In the full-dose PHT arm, the baseline T-helper counts are unknown for 5 of the 17 deaths. This gap might have seriously skewed the results; adding just one more death to the full- dose, 50-to-200 helper T-helper segment of the trial would alter the announced results considerably.

To get an independent view of PHT, we spoke with a staff member at one large AIDS clinic that is treating 30 patients with a passive immune technique similar in principle to PHT. According to this source, T-helper counts have not generally risen in treated patients, although skin conditions of all sorts have markedly improved. This benefit could be due to other antibodies in the plasma as well as to the anti-HIV ones, the source observed. He noted that enthusiasm for the therapy was waning at his clinic.

As was largely true in the HemaCare study, passive immunotherapy is being applied in this clinic as a rescue technique for people with T-helper counts under 50. It is unclear what kills T-helper cells at this stage of disease. Their further loss may not be due to current HIV activity at all, but to immune dysfunction springing from past infection. Also, HIV in advanced AIDS is reproducing rapidly and therefore can mutate to escape neutralization by particular antibodies. It would seem that passive immunotherapy's effectiveness would be limited under these conditions.

Michael Roth, M.D., is a Santa Monica immunologist who has had six years experience administering passive immunotherapy in his AIDS practice. He thinks that the critical factor determining passive immunotherapy's effectiveness is clinical health. Some patients who have near-zero T-helper counts but no history of opportunistic infections have remained stable and in good health for years on passive immunotherapy, he told AIDS TREATMENT NEWS.

Drs. Roth and Karpas both think that PHT and similar therapies would be most useful for extending the asymptomatic period by several years in persons with moderately affected immunity (T-helper counts of 200 to 400).

But it is difficult to test PHT's effectiveness in this group because of its members slow rate of decline. HemaCare is now seeking a "treatment IND" from California's Food and Drug Branch (a state equivalent of the FDA) to try PHT in people with T-helper counts in the 200 to 400 range. The two-year, open-label treatment IND will allow HemaCare to administer PHT and collect data at its four California infusion centers. HemaCare also will attempt to recover costs from patients' insurance companies. (The company does envision some free distribution to those unable to pay.) Meanwhile, a double- blind, two-year-long phase III trial involving volunteers with T-helper counts of 50 to 200 will begin this winter if the FDB approves.

Over 100 volunteers from the phase II trial will continue to receive PHT. This is important because one small French study indicated that discontinuing this therapy led to rapid deterioration in people with advanced immune deficiency. [D. Vittecoq et al., Journal of Infectious Diseases, Feb. 1992, 165(2):364-8]

HemaCare expects to be administering PHT to 900 people soon and is actively seeking donors with sufficient HIV- neutralizing antibodies. Donors receive $25 per donation plus free blood tests.

A beneficial rebound effect from the periodic plasma withdrawals may raise donors' antibody levels, indirectly making passive immunotherapy of benefit to them, too. In the completed HemaCare trial, about 90 per cent of regular donors maintained stable T-helper levels over the year. According to HemaCare, donor data revealed a statistically significant, overall slight T-helper increase when analyzed by a method that controlled for other factors. The meaning of such a result should be qualified, though, since there is no control group for purposes of comparison. It is possible that any carefully selected group of individuals with high anti-HIV antibody levels would spontaneously show stable or even increasing T-helper counts whether or not they donated plasma.

Comment

Tanya Youvan, M.S., HemaCare's PHT project manager, faxed us a five-page letter taking exception to some of the statements in a draft of this article. She wrote that HemaCare has hired a new statistician to redo the analysis. His report is due soon and, Ms. Youvan claimed, will provide most of the missing baseline T-helper counts. Ms. Youvan also argued that the just-completed PHT trial was only a phase I/II study that was not supposed to provide conclusive efficacy data.

We welcome re-examination of the PHT data and further testing of this therapy. But people with HIV are now making decisions about trying PHT and they need as much information as possible. HemaCare's overly optimistic announcements of its trial results were made two months ago. They claimed improved survival and statistically significant maintenance of T- helper cell levels on the basis of an analysis the company now feels it has to redo.

Ms. Youvan's objections did not touch two central points: (1) Average T-helper cell counts were not "maintained," but rose in the first six months and then starting falling. By the end of the 12 month period, they were about equal to baseline in the 50-200 T-helper group, suggesting that T-helper count increases may be temporary. (2) The missing baseline helper T-cell data make the survival findings uncertain.

Ms. Youvan conceded that firm conclusions about who PHT benefits, and for how long, must wait for the larger study now being planned. But we should not be too critical of the optimistic publicity HemaCare generated. The blood-products company has taken on a very complex, neglected project beyond its normal area of expertise. The need for prolonged testing has proved extremely costly to the company, which has had to cover the testing expenses through internal financing.

The focus on persons with low T-helper counts may have backfired, costing the company more in the long run. It nevertheless was a valiant move on moral grounds. It provided a plausible treatment alternative to people who had none, as most clinical trials exclude people with late-stage AIDS.

HemaCare in the past has been faulted for releasing its results through press conferences and other non-research forums (such as the National AIDS Update Conference). It now promises to submit its findings in a peer-reviewed medical journal for publication -- which would help to resolve the remaining questions.

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