AIDSWEEKLY Plus, 20 May 1996 issue; Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588
Daniel J. DeNoon, Senior Editor

Long-term follow-up of the first patients to receive a therapeutic HIV vaccine shows that those who responded to the vaccine have had a relatively favorable clinical course.

The results raise two important questions:

* Did the vaccine change the course of HIV disease in those who received it while they were still well enough to respond?

* Or did response to the vaccine merely identify patients who would have done relatively well without it?

These questions may soon be answered. The Salk HIV Immunogen, now called Remune, in March 1996 became the first therapeutic HIV vaccine to reach U.S. Phase III clinical efficacy trials. An additional Phase III clinical trial has just begun in Thailand.

A Phase I trial of the vaccine treatment began in 1987. It enrolled 25 HIV seropositive patients, 23 with persistent generalized lymphadenopathy (PGL) and two with asymptomatic HIV infection.

Now University of Southern California researcher Alexandra M. Levine and colleagues report on the long-term clinical follow-up of these first patients to receive the vaccine ("Initial Studies on Active Immunization of HIV Infected Subjects Using a gp120-Depleted HIV-1 Immunogen: Long-Term Follow-Up," Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 1996;11:351-364).

Levine et al. noted that the Phase I trial was not designed to test for clinical efficacy.

"HIV-1 Immunogen in IFA appears to be safe and immunogenic," Levine et al. wrote.

Since this study was designed and executed as a Phase I safety and immunogenicity study, without a control population, no conclusions can be made regarding clinical efficacy, which will require long-term, placebo-controlled clinical studies."

Indeed, the trial offered no conclusive evidence of efficacy. But one factor seemed to differentiate those who did well from those who did poorly: delayed-type hypersensitivity (DTH) skin-test responses to the vaccine. These HIV/DTH tests were performed separately from vaccine inoculations.

Of the 12 patients who developed a DTH response to the immunogen, one developed an opportunistic infection some five years after beginning the study and later died. Another of these patients developed Kaposi's sarcoma (KS).

Of the 13 patients who did not develop a DTH response to the immunogen, nine developed AIDS. Seven of these patients died.

"Differences were also observed in terms of HIV-DNA copy number, CD4 percentages, and anti-p24 antibody patterns between the HIV/DTH responsive and nonresponsive groups, suggesting a more favorable clinical course in the former," Levine et al. wrote.

HIV DNA copy numbers decreased or remained stable in six of nine HIV/DTH responders and in five of nine HIV/DTH nonresponders.

The HIV/DTH responders entered the study with a mean CD4(+) T-cell count of 448 cells/(micro)L; they had a median decline in this count of 9.4 percent per year. The HIV/DTH nonresponders entered the study with a median CD4(+) T-cell count of 318 cells/(micro)L; they had an average decline in this count of 29.6 percent per year.

"HIV/DTH responders took longer than nonresponders to become HIV culture positive," Levine et al. reported. "Thus, of 106 HIV viral cultures performed in the 12 HIV/DTH responders, 47 (44 percent) required greater than seven days to demonstrate culture positivity, while only three of 68 cultures (4 percent) in the HIV/DTH nonresponsive group required longer than seven days to become positive."

There were no significant adverse effects of immunization with the HIV-1 Immunogen, and long-term follow-up revealed no evidence that the treatment accelerated progression to AIDS.

If the patients who developed a DTH response to Remune truly tended to benefit from the treatment, "it would be useful to determine whether there are other immunologic factors which correlate with the capacity to develop such responsiveness," Levine et al. suggested.

Prior to his death in June 1995, co-author Jonas Salk endorsed the hypothesis that a shift from T-helper type 1 (Th1)-mediated immunity (characterized primarily by cellular immune responses) to Th2-mediated immunity (characterized primarily by humoral immune responses) occurs during progression to AIDS (see Clerici et al., J Inf Dis 1992;165:1012-9 and Shearer et al., Chem Immunol 1992;54:21- 43).

This shift is paralleled by a loss of in-vitro responsiveness to recall antigens.

"If a correlation exists between Th1 predominance and the ability to develop HIV/DTH reactivity following immunization, then Th subset status might serve as a basis for prognosis and stratification in future trials," Levine et al. suggested.

The Salk HIV-1 Immunogen, or Remune, is an envelope- depleted HIV particle created by Jonas Salk and colleagues at the Salk Institute, San Diego, California. It is now owned by the Immune Response Corp., Carlsbad, California.

Salk suggested that a suitable immunogen could - at least in those who have not yet developed profound immune deficiency - elicit and maintain the factors responsible for the initial, protective immune response to HIV.

In order to create an HIV immunogen Salk and colleagues used gamma radiation and beta propiolactone to inactivate HIV. After depletion of the viral envelope, the inactivated virus was purified, concentrated to 1,000 (micro)g/ml, and either emulsified in mineral oil for intramuscular injection or emulsified in saline solution for intradermal inoculation. Incomplete Freund's adjuvant (IFA) is used with the immunogen to maximize immunogenicity.

In early 1995 an advisory committee to the U.S. Food and Drug Administration (FDA) said it didn't believe the vaccine would do a lot of good - but it recommended that the FDA approve Phase III clinical trials (see AIDS Weekly, February 6, 1995).

"I am not at all excited about the data I've seen," said the committee's chairman, Dr. Stanley Lemon of the University of North Carolina. "But I would be thrilled to be proven wrong."

The panel told the FDA there were some indications that the HIV-1 Immunogen might inhibit HIV from increasing in patients' blood but no evidence that it did any more for patients in the long run than a placebo.

However, that small indication was enough for the panel to recommend that Immunogen become the first therapeutic vaccine to advance to Phase III clinical trials, in as many as 5,000 people.

The committee warned that patients should not expect a miracle from the vaccine, whose effects it said had been exaggerated by its maker, Immune Response Corporation.

The FDA has sent the company a warning letter questioning whether early studies were performed properly. The letter alleged that some inappropriate patients may have been included and that data analysis was skewed to show the product in a better light.

In March 1996, the FDA followed the panel's recommendation and gave the manufacturer permission to begin efficacy trials (See AIDS Weekly Plus, March 4, 1996). These trials are currently underway.

In a separate action, the FDA also gave permission for Immune Response Corp. to export Remune for clinical trials in Thailand (See AIDS Weekly Plus, April 8 & 15, 1996).

The Ministry of Public Health in Thailand recently approved a one year double-blind, placebo-controlled clinical trial. The trial will be conducted in Thailand by Mahidol University in collaboration with Trinity Medical Group.

The initial trial involves 300 HIV infected individuals with CD4 counts from 300 to 550 cells/(micro)L and evaluates the safety, immunogenicity and effect on CD4 levels of treatment with Remune.

Future clinical trials of HIV infected individuals in Thailand may include a 2,000-person clinical endpoint trial to determine the effectiveness of Remune in delaying the progression of HIV infection to AIDS, and an open-label safety trial involving up to 7,700 individuals.

Clinical trials conducted in Thailand are monitored by an independent clinical research organization, and conducted under the guidelines of the Thailand Ministry of Public Health and the World Health Organization (WHO).

In September 1995, Immune Response and Trinity Medical Group entered into an agreement for the development and commercialization of Remune in Thailand and certain other Southeast Asian countries. Trinity is responsible for the costs of conducting and monitoring these clinical trials while Immune Response provides Remune for these trials.

A footnote to the Levine et al. study reads:

"The authors sadly acknowledge the death of Dr. Jonas Salk on June 23, 1995; Dr. Salk was thoroughly involved in the preparation of this manuscript, and was entirely responsible for the concept of this therapeutic approach."

The corresponding author for this study is Alexandra M. Levine, Department of Medicine, Division of Hematology, University of Southern California School of Medicine, Kenneth Norris Jr. Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, California 90033-0804.

Copyright (c) 1995 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.

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Copyright © 1996 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.