Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 7 July/August, 1993
David Gold

Salk Vaccine

The Salk HIV-1 Vaccine Immunotherapy ( also known as the Salk Immunogen) received the most attention of any HIV immune therapy at the conference. Produced by a joint venture of Immune Response and Rhone-Poulenc Rorer, the vaccine is made from inactivated HIV- 1 (minus the gp120 envelope) with Incomplete Freund's Adjuvant (IFA), a mineral and oil emulsion used to increase the antigenicity of the vaccine. Jonas Salk, the polio vaccine pioneer, first proposed the idea of therapeutic vaccination for HIV-infected people in 1987 and has been involved in the development of this product.

Dr. Alexandra Levine of the University of Southern California School of Medicine presented information on three trials of the Salk Immunogen. The first trial enrolled 23 gay men who were given eight 100ug doses of the Immunogen over three years. Participants were followed for a period of 4.3 years for clinical observation and 3.3 years for laboratory observations. No serious side effects were reported; 48 percent reported pain at the administration site and 22 percent reported fever or rash. Twelve of the 23 (52 percent) developed a delayed-type hypersensitivity (DTH) response to vaccine antigens. DTH is a skin test which measures certain aspects of the cellular immune system. (For a broader discussion of therapeutic vaccines, and the limitations of DTH responses, see Treatment Issues, June 1993). The investigators claim that those with a DTH response maintained greater CD4 cell levels (that is, the vaccine group did not lose as many cells as the placebo group) and had fewer opportunistic infections and deaths. Levine concluded from this study that there was a "correlation between DTH response and CD4 stability."

The second study randomized 40 patients to receive 50, 100, 200, 400ug of the Salk Immunogen or placebo (in this case, IFA alone). Patients in the study entered with over 600 CD4 cells. The researchers claim that a dose of 100ug or more produced significantly greater humoral immune responses, as measured by anti-p24 antibodies, and cellular immune responses, as measured by DTH skin reactions.

The third study was the most significant part of the presentation. This phase II/III randomized, double-blind study enrolled 103 asymptomatic HIV-positive patients with CD4 counts ranging from 233 to 1211, with a mean of 656. Participants were randomized to receive 100ug of Immunogen or IFA placebo at baseline, three, and six months. After the third dose, the study investigators report a significant increase in anti-p24 antibodies and DTH responses in those receiving the Immunogen. The vaccine group also showed a significant increase in body weight (2.3 kilograms for the vaccine group versus .5kg for the placebo group). Side effects were limited to injection site reactions.

The greatest stir was created by Levine's report that the treatment arm had a significantly lower increase in the amount of HIV viral burden, as measured by DNA PCR. Using this measurement, viral burden increased 10 percent in vaccine group and 48 percent in placebo group over the course of one year. According to the researchers, this difference is statistically significant. However, there was no difference in the amount of HIV found by viral culture or by p24 antigen levels. In addition, no difference in CD4 levels was found, although this may have been expected in a short trial of relatively high CD4 cell individuals. Furthermore, researchers conclude that there was a "significant increase or stabilization" in cell-mediated immune responses as measured by DTH reactions. No data on cytotoxic lymphoproliferative responses, another measure of cellular immune response, were presented.

Immediately after Levine's presentation, debate began over whether the reported effect on viral load was meaningful. In a press conference, Salk acknowledged that "these (results) are simply trends." Dr. David Ho of the Aaron Diamond AIDS Research Center in New York commented that the "very minor change in viral burden is within the variability of the assay." Dr. Anthony Fauci of the National Institute of Allergies and Infectious Diseases (NIAID) described the results as "statistically significant but not overly impressive."

The high profile of financial analysts in the Salk Immunogen presentations must also be noted. Of course, the pharmaceutical industry is profit driven. However, the role of investors in this case appeared disproportionate. At the presentation, the first several rows of the auditorium were filled with investment analysts providing a slide-by-slide report of the data by cellular phone back to their headquarters. A strange and disconcerting sight, indeed. In any event, Wall Street seemed to concur with Salk's scientific critics; Immune Responses' stock dropped 26 percent after the presentation.

New, More Powerful Adjuvants

Dani Bolognesi of Duke University reported that antibody levels induced in seronegative volunteers by several new HIV preventive vaccines are approaching levels seen in HIV-infected individuals. In a plenary session devoted primarily to preventive vaccines, Bolognesi reported QS-21, a new adjuvant developed by Cambridge Biotech which is derived from Quillafa saponaria, a type of soapbark tree.[1] QS-21 produces "far higher neutralizing antibodies, and reasonably impressive CTL responses." QS-21 is in a Phase I trial with Genentech's gp120 vaccine in 80 seronegative volunteers which began in May 1993. Bolognesi did not indicate if QS-21 will be used in therapeutic vaccine preparations.

Genentech gp120

J.D. Allan of Harvard Medical School reported an ongoing trial of Genentech's two gp120 vaccines (MN and IIIB strains). In the trial, 122 HIV-positive individuals are randomized to one of six arms (either MN vaccine, IIIB vaccine, combination of both MN and IIIB vaccines, alternating regimens of both vaccines, or a placebo). Both humoral and cellular immune responses were produced.[2]

Immuno AG gp160

In a study of 21 HIV-positive individuals randomized to receive Immuno AG's gp160 vaccine, Hepatitis B vaccine, or placebo, gp160 vaccine was well tolerated and induced new lymphoproliferative responses.[3] Immuno AG announced that it will start a Phase I trial of gp160 with an MN strain in 20 asymptomatic HIV-positive adults with over 500 CD4 cells. In a trial of 55 HIV-negative individuals, gp160 (IIIB strain) induced new antibodies and a "vigorous lymphoproliferative response."[4]

Chiron/Biocine gp120

James Kahn of the University of California at San Francisco reported a study of Biocine's gp120 vaccine (SF2 strain). Thirty HIV-negative volunteers received four injections of gp120 vaccine with MF-59 or MTP-PE (two adjuvants produced by Chiron) and twelve received either placebo or the just adjuvants. According to Kahn, antibodies in those who received gp120 vaccine with the new adjuvants persisted up to six months after the third injection. Interestingly, Kahn suggested that antibodies from the study volunteers might be collected and infused into HIV-infected people as an experiment in passive immunization.[5]

Canary Pox Vectors

In a French study, twenty HIV-negative adults were given gp160 vaccine in a live canary pox virus vector at baseline and one month, followed by gp160 boosters at three and six months. Immunizations were safe and well tolerated. Neutralizing antibodies and lymphoproliferative responses were reported.[6]

MicroGeneSys gp160

In a Canadian study of MicroGeneSys' gp160 vaccine (also known as VaxSyn), 21 HIV-positive individuals with over 500 CD4 cells were given 160ug or 320ug of the vaccine six times the first year, three per year thereafter. After an average of three years follow-up, VaxSyn was safe and well-tolerated. A statistically significant increase in CD4 cells over baseline was observed during the first year, but by week 68 these increases were non-significant, and by week 84 a statistically non-significant decline was observed.[7]

Viral Technologies HGP-30

Prem Sarin of Viral Technologies presented information on HGP-30, a vaccine based on the p17 core protein of HIV (most of the other vaccines currently in clinical trials are based on the envelope proteins, such as gp120 or gp160). In a study of 39 HIV-negative individuals, antibody responses and cytotoxic T-cell responses were found after administration of HGP-30.[8] Sarin also disclosed that the company has tested other adjuvants which may increase the immune reactions to the vaccine. A trial in HIV-positive volunteers will begin shortly.

Pentoxifylline

There were three reports on the use of pentoxifylline (PTX, and also known by its brand name Trental.) Two studies were reported by Dr. Bruce Dezube of the Beth Israel Hospital in Boston.[9] These studies indicate that PTX three times per day for eight to sixteen weeks decreases triglycerides (TG) and Tumor Necrosis Factor (TNF) levels. In a cohort of patients with advanced AIDS (median CD4 cells were 32) given PTX 400mg TID (three times daily), triglycerides dropped an average of 67mg/di and TNF levels dropped in ten of sixteen patients. HIV load dropped in four, remained even in ten, and increased in one. In the cohort given PTX 800mg TID, TNF fell in half the patients. HIV levels dropped in four, stayed the same in six and increased in one. The drug was well-tolerated. One patient in each cohort developed fevers probably from the drug.

Dr. Joe Sonnabend of the Community Research Initiative on AIDS in New York City presented preliminary data on their community based PTX trial.[10, 11] Forty five patients were enrolled; 32 completed twelve weeks of therapy. The data presented are based on patients who completed eight weeks of therapy. Twelve patients discontinued study medication, four due to adverse experiences. Only one of these four were randomized to receive PTX. Sonnabend concludes "Ex vivo production of TNF by peripheral blood monocytes from HIV infected individuals with under 300 CD4 cells was significantly lower in patients after receiving PTX for eight weeks compared to patients receiving placebo."

Cyclosporin

In a wide-ranging plenary session devoted to the pathogenesis of HIV disease, Dr. Anthony Fauci asked whether some form of immune suppressive therapy may actually slow HIV disease progression. Some theories of HIV pathogenesis suggest that parts of the immune system in HIV-infected people appear hyperstimulated, even though AIDS is usually considered a syndrome of immune suppression. Fauci cites a German study which examined four patients who contracted HIV from kidney transplants in 1984.[12] All of these patients were given cyclosporin, an immune suppressive drug widely used in organ transplant surgery. Two died 66 and 74 months later, but not from HIV-related causes. The other two have not developed symptoms or infections typical of AIDS. Moreover, the authors claim that a review of case reports of 53 patients who developed HIV from transplants or transfusions found that the 40 patients who received an immune suppressive regimen, like cyclosporin, had a lower incidence of AIDS than the 13 who did not receive immunosuppressive therapy (five- year cumulative risk of AIDS 31 percent versus 90 percent). It should be noted that these are only retrospective case reports from a small number of patients and that cyclosporin can be a very toxic drug. Furthermore, several studies have examined the use of cyclosporin in HIV infected patients. While most are inconclusive, one study from Canada reported rapid clinical deterioration after cyclosporin use in patients with AIDS.[13] For this reason, cyclosporin is not recommended in HIV-infected patients at this time. Interestingly, Sandoz, the Swiss drugs giant which manufacturers cyclosporin, is reportedly working on cyclosporin analogs which inhibit specific T cell functions, without causing general immune suppression.

Thymic Peptides

Two abstracts reported studies about so-called "thymic hormone products." In an Italian study in which 147 HIV-positive individuals (less than 500 CD4) were randomized to either AZT or AZT and thymostimulin (TP1), the TP-1 arm had less toxic effects from AZT, including fewer blood transfusions and lower hepatic toxicities (SGPT).[14] A multi-site trial of 352 HIV-positive individuals (200 to 500 CD4) compared AZT to AZT plus Thymopentin (TP-5). The authors report that TP-5 with AZT reduces disease progression in asymptomatic HIV positive patients.[15] These two studies were both reported as posters so it was more difficult to discuss the details of these trials with the investigators. Alpha Interferon

Alpha interferon (IFN-A) is a natural protein secreted by immune cells in response to viral infection. A manufactured version of IFN-A is approved to treatment Kaposi Sarcoma (KS), hepatitis B virus, and hepatitis C virus. Test tube studies have shown that IFN-A reacts synergistically with AZT against HIV. Therefore, some suggest that IFN-A be used in combination with AZT as an anti-HIV treatment. Clinical trials of this combination are ongoing and several abstracts were presented in Berlin. In a German study, asymptomatic or mildly symptomatic patients with rapidly declining CD4 levels were randomized to receive AZT and IFN-A 3 million international units (MIU) three times weekly or AZT alone. Ten patients on the IFN-A containing regimen and seven on the AZT control arm completed 24 weeks of treatment. No difference in CD4 counts was observed between the two arms.[16]

Another German study raised concerns about IFN-A treatment for HIV.[17] In a two year double blind study, 36 patients (less than 350 CD4) were randomized to AZT, AZT plus IFN-A .75 MIU daily, or AZT plus Beta Interferon (IFN-B) .75 MIU daily. After 12 months, there was a marked CD4 cell decrease and five opportunistic infections in the IFN-A containing group compared to two opportunistic infections in the other groups. Furthermore, after 24 months, four patients in the IFN-A containing regimen developed pronounced neurological disorders. No patients in the other arms developed neurological disorders. Eight of twelve patients died in the IFN-A group compared with four and three deaths in other two treatment groups. "In this study," the investigators conclude, "we were unable to find an additional benefit in a ZDV therapy combined with IFN alpha or beta. It has to be discussed whether low dose IFN alpha may cause progression and neurologic complications in HIV disease." A Spanish study randomized 112 HIV-positive patients with less than 300 CD4 cells to receive either AZT 500mg/day or AZT 300mg plus IFN-A 5 MIU daily for the first month, reduced to three times per week thereafter.[18] A preliminary analysis of 62 patients who have completed six months of therapy "has not demonstrated significant differences in the groups."

Finally, two other studies presented at the conference failed to demonstrate significant increases in CD4 cells from the use of IFN- A with AZT.[19, 20] One study showed a decrease in p24 antigen levels but no difference in CD4 counts.[21] A Belgian study reported a significant increase in the percent of CD4 cells among those given IFN-A plus AZT.[22]

On the brighter side, a new form of IFN-A called N3-Alferon is being tested at the Walter Reed Army Hospital. Investigators report it to be ten to 1000 times more effective in vitro against HIV and to have dramatically lower symptoms.[23]

Low Dose Oral Alpha Interferon: "Kemron"

Kemron, an oral form of alpha interferon given in doses over 100,000 times lower than conventional subcutaneous doses, created an international stir a few years ago when Kenyan researchers reported dramatic improvements, including "HIV-seroreversions" (that is, HIV-positive to HIV-negative), with the drug. Since the original report, at least twelve different studies failed to replicate these results. At this year's conference, another study which failed to find any benefit to Kemron was reported. This Ugandan study, funded by the World Health Organization, followed 560 HIV-positive patients who were randomized and double blinded to either oral alpha interferon (Kemron, 150 international units per day) or placebo over 60 weeks. The researchers found no difference in mortality, progression of disease, body weight, and CD4 counts. None of the patients reverted to HIV-negative status.

Despite the volume of data which now prove no benefit to Kemron, the National Institutes of Health has planned its own study and scurrilous individuals, including some physicians, have continued to sell Kemron (or other versions of oral interferon) at incredible mark-ups to people with HIV. Some reports indicate that Kemron may be selling for as much as $1000 per month.

Interleukin-2

Fauci discussed a trial of Interleukin-2 conducted at the National Institutes of Health.[24] Interleukin-2 is a naturally occurring protein secreted by immune cells to stimulate other immune cells, particularly T cells. Like alpha interferon, IL-2 has been manufactured and is approved for kidney cancer in several countries. In addition, it is under development for other diseases, including AIDS. In the study, eight patients with less than 200 CD4 cells were given IL-2 18 MIU daily for five days every two months with AZT or ddI. Four of the eight patients had an average 100 percent increase in CD4 cells by six to ten months. However, five of the eight patients had to reduce IL-2 doses due to fever and "subjective toxicities." In addition, these were very small numbers of patients and there is no indication that these CD4 cell increases have clinical significance.

IVIG

Intravenous immune globulin (IVIG) is an approved treatment for immune deficiencies characterized by impaired antibody production. In a study at the Houston Immunological Institute, eighteen HIV- positive patients with less than 500 CD4 cells were randomized to receive IVIG six grams once a week or placebo for six weeks.[25] No difference was found in CD4 counts, p24 antigen levels, or DTH skin tests. In a German study, 35 patients (30 AIDS, five ARC) were treated with high dose IVIG (4g/kg twice a week every three weeks) and compared to a control group of 31 patients (24 AIDS, seven ARC).[26] After 26 weeks, there were fewer hospitalizations in the IVIG group. A National Institutes of Health (NIH) trial of 313 HIV- positive children suggests that IVIG may slow the decline of CD8 cells in children with AIDS.[27]

Conclusion

This year's conference saw a far greater discussion about basic science and immunology. There was a particular focus on the importance of cell-mediated responses and the different cytokines that are released during the course of HIV disease. A greater understanding of these two phenomenon will undoubtedly increase the likelihood of developing effective immune therapies for HIV.

1 Bolognesi DP. Abstract PS-05-1. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

2 Allan JD, et al. Abstract PO-B27-2137. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

3 Schwartz D, et al. Abstract PO-A28-0668. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

4 Gorse G, et al. Abstract WS-B27-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

5 Kahn J, et al. Abstract WS-B27-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

6 Pialoux G, et al. Abstract WS-B27-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

7 Tsoukas CM, et al. Abstract PO-B27-2134. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

8 Goldstein AL, et al. Abstract PO-B27-2139. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

9 Dezube BJ, et al. Abstract PO-B28-2142. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

10 Sonnabend JA, et al. Abstract PO-A28-0664. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

11 Sonnabend JA. Personal Communication. Data on file at GMHC.

12 Schwarz A, et al. Abstract PO-B28-2145. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

13 Phillips A, et al. Canadian Medical Association Journal. 1989; 140: 1456.

14 Palmisano L, et al. Abstract PO-B28-2147. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

15 Goldstein G, et al. Abstract PO-B28-2144. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

16 Jablonowski H, et al. Abstract PO-B28-2148. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

17 Brockmeyer NH, et al. Abstract PO-B26-1987. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

18 Clotet B, et al. Abstract PO-B26-1988. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

19 Carosi G, et al. Abstract PO-B26-2000. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

20 Villarreal RM, et al. Abstract PO-B26-2077. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

21 Barbarini G, et al. Abstract PO-B26-2027. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

22 Henrivaux PH, et al. Abstract PO-B26-2080. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

23 Skillman DR, et al. Abstract PO-B26-1998. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

24 Kovacs JA, et al. Abstract PO-B28-2155. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

25 Stroud S, et al. Abstract PO-B28-2157. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

26 Kiehl M, et al. Abstract PO-A28-0658. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

27 Mofensen L, et al. Abstract PO-B01-0877. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

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