Treatment Issues, Vol 11, No 1; January 1997
Theo Smart

But if GM-CSF is too dangerous to use in people with HIV, why has Dr. David Ho proposed (last November at the Third International Conference on Drug Therapy in HIV Infection in Birmingham, England) conducting studies that would throw it in the mix with triple drug antiretroviral therapy? And why is Immunex, the Seattle company that markets GM-CSF in the U.S., now enrolling a very large study using this drug in people with late-stage AIDS who are not neutropenic? The reasons are somewhat unconventional and have little relation to each other. The results of these studies may determine whether GM-CSF is to have a supporting role in the treatment of HIV infection when combined with the new highly active antiretroviral therapies or a larger role as broad opportunistic infection preventive for advanced disease.

Fixing the Phagocytes

GM-CSF belongs to a family of cytokines called colony-stimulating factors that promote the production of various blood cells in the bone marrow. GM-CSF regulates the development of neutrophils, macrophages, monocytes and eosinophils. The other CSFs include granulocyte-CSF (G-CSF), which specifically induces neutrophil production, and macrophage-CSF (M-CSF), which stimulates macrophages and monocytes. The pharmaceutical versions of these natural immune cell hormones are produced by genetically altered yeast, E. coli or mammalian cells.

The use of CSFs to treat neutropenia in cancer patients has been long established. Since neutrophils play a major role in fighting microbes such as bacterial, fungi and parasites, patients with neutropenia are particularly susceptible to bacterial and disseminated fungal infections. In a study of GM-CSF in neutropenic cancer patients, the agent was shown to reduce mortality caused by fungal infections.1 Neutropenia is fairly common in people with AIDS. It may be caused by a number of factors including HIV infection itself, opportunistic infections, nutritional deficiencies (vitamin B12, folate) or treatments such as AZT, Bactrim/Septra, ganciclovir and cancer chemotherapy. Both G-CSF and GM- CSF have been shown to increase neutrophil count in people with HIV, but a number of laboratory studies suggest that both GM-CSF and G-CSF do more than encourage the proliferation of neutrophils. There is a substantial body of data showing that these cells are functionally impaired in people with HIV,2,3,4,5 although just how these deficits occur is not fully understood. The CSFs have shown the ability to restore the function of these damaged cells, enhancing their phagocytic activity, microbe killing ability and antigen presentation. Specifically, GM-CSF-treated neutrophils, monocytes and macrophages have exhibited increased activity against bacteria, HIV, fungi, MAC, TB, cryptosporidia and Pneumocystis carinii.

Thirty-five HIV-infected individuals treated with GM-CSF for a mean of 9.7 weeks had no major opportunistic infections while on treatment in one report.6 Another GM-CSF study involved 32 KS patients with chemotherapy-induced neutropenia. No bacterial infections occurred, and only 19% of the patients developed an opportunistic infection over the median seven-month duration of the study.7

A few small GM-CSF studies have been carried out in people with HIV who were not neutropenic. Two of four AIDS patients with resistant esophageal candidiasis experienced a complete response in a study of GM-CSF at 150 mg/kg of body weight per day in combination with itraconazole or amphotericin. One participant had a partial response, and the other, who had several other AIDS-related complications, died before receiving two weeks of treatment with GM-CSF.8 Improved anti-mycobacterial activity was seen with GM-CSF in one MAC study,9 and better clinical and radiologic responses were seen in pediatric AIDS patients randomized to receive GM-CSF or nothing in combination with standard TB therapy.10

Immunex's Gamble

All the laboratory data and the small pilot studies have encouraged Immunex to run a large opportunistic infection prevention study in over 500 people who are not neutropenic or only mildly so. The six-to-twelve month multi-center trial will enroll very advanced patients with a CD4 count less than 50, or less than 100 if they have had a prior AIDS-defining illness (other than KS). Study participants will receive 250 mg of GM-CSF or placebo three times a week. Given the possibility that GM-CSF may increase viral load, study subjects are expected to take antiretrovirals (the study will be discontinued if a ten-fold increase in viral load is observed after three months). Other immunomodulators are forbidden.

The study's primary endpoint will be the total number of opportunistic infections over time, including recurrent and bacterial infections. It will also evaluate the time to progression of disease, survival, incidence of specific opportunistic infections and quality of life. At the higher doses used to treat neutropenia, GM-CSF can cause adverse reactions such as fever, bone pain, joint and muscle pain, headache and other flu-like symptoms. Analgesic or anti-fever medication usually can control such side effects. (For more information on this study, which is open to enrollment, call (800) TRIALS-A.)

Immunex is taking a big chance. For one thing, a 500 patient study is an expensive proposition. Furthermore, although GM-CSF may improve microbe killing over the short term in a cell culture dish, what is going on in the body of a person with HIV is extremely complex. GM-CSF administration may very well increase the level of other cytokines known to have harmful effects, such as tumor necrosis factor alpha.

The company additionally is conducting two studies in HIV-positive volunteers with oral candidiasis unresponsive to fluconazole. The first study will compare continuing on fluconazole alone to the effect of adding daily GM-CSF to the fluconazole. In the second study volunteers will be switched to intravenous amphotericin B with or without GM-CSF. (The GM-CSF will be administered as a 250 mg/day subcutaneous injection in both studies.) These two trials are still on-going, but already, unofficial sources report that the fluconazole trial so far is not detecting any positive benefits to adding GM-CSF.

Purging the Reservoirs

Immunex is not convinced that GM-CSF substantially contributes to viral load. Even if it does, though, the company believes that this danger could be offset by the improvement in immune function elicited by GM-CSF. In contrast, Dr. Ho foresees using GM-CSF in conjunction with the potent new anti-HIV combination therapies precisely because of its HIV-stimulatory effect.

Current anti-HIV therapies only affect new virus particles produced in cells with active HIV. Administering agents known to excite cells latently infected by HIV might provoke them into viral production. Cytokines like IL-2 might shorten the time to clearance of HIV from the pool of quiescent CD4 cells, and factors like GM-CSF would increase the turnover in the reservoir of latently infected monocytes and macrophages.

The data on whether GM-CSF stimulates HIV is somewhat equivocal. Most studies show that it does promote HIV,11,12,13 but a number of cell culture studies suggest that it inhibits HIV replication in macrophages. An Australian study reported that GM-CSF blocked viral replication in macrophages sometime after reverse transcription in a dose-dependent fashion.14 A Japanese study published about a year ago found that certain steps of HIV-replication were inhibited in macrophages stimulated by GM- CSF, and that HIV did not replicate well in these cells. The authors concluded that "the suppression of HIV replication in GM-CSF-induced macrophages may provide a model of the latency of HIV infection in vivo."15

Some of GM-CSF's effect may be time-dependent, or, as Immunex has argued, moderated by the immune activation that GM-CSF incites. A study presented in Washington last year at the Third Conference on Retroviruses and Opportunistic Infections suggested that HIV-infected monocytes and macrophages produced 15-fold more virus particles when activated by GM- CSF, but there was no increase in the rate of new cell infection when compared to controls.16 A study using SIV also found that GM-CSF treated cultures produced more viral material, but after controlling for the increased number of cells, there was no increase in SIV production on a per cell basis.17

The few studies that report that GM-CSF upregulates HIV production used levels of HIV p24 antigen to evaluate HIV activity, a somewhat suspect measure.18,19 Other studies based on p24 report no consistent change or reductions in viral activity in persons on GM-CSF.20,21,22 The context in which GM-CSF is used, such as in patients on chemotherapy for secondary infections or cancer, is difficult to interpret. It should be remembered that chemotherapy suppresses lymphocyte proliferation and therefore may temporarily reduce viral activity by reducing the pool of infectable cells. In one of the studies that reported increases in p24 antigen while on GM-CSF, viral activity fell when AZT was reinstituted.23 In vitro studies suggest that GM-CSF increases the activity of AZT (and d4T) in macrophages, possibly by increasing the necessary cellular processing of the drug.24 The same study reported reduced activity for ddI and ddC, it should be added. Two recent investigations employing the new PCR assay to monitor viral load in patients on stable AZT report that use of GM-CSF has no consistent effect on viral load.25,26

The lack of effect on overall viral load should not come as a surprise in light of the small proportion of the viral reservoir constituted by infected macrophages. According to Dr. Ho's estimates, infected monocytes and macrophages contribute less than 1% of the total viral load. But that small trickle is important to clear out. Whether GM-CSF is the best agent for effecting this clearance remains to be seen. Cell culture studies suggest that M-CSF may promote HIV replication more efficiently. Dr. Ho also is considering that compound, which is licensed to Chiron but not yet marketed in this country.

References:

1 Rowe JM et al. Blood. July 15, 1995; 2(86):457-62.

2 Smith PD et al. Journal of Infectious Diseases. May, 1990; 161(5):999-1005.

3 Collins HL and Bancroft GI. European Journal of Immunology. June, 1992; 22(6):1447-54.

4 Robin G et al. Lymphokine Cytokine Research. August 1991; 10(4):257-63.

5 Fl° RW et al. AIDS. June 1994; 8(6):771-7.

6 Manfredi R et al. Journal of Chemotherapy. August, 1996; 8(4):214-20.

7 Nassar F. Antimicrobial Agents and Chemotherapy. September, 1994; 38(9):2162-4.

8 Baldwin GC et al. Blood. October, 1989.74(5):1673-7.

9 Kemper C et al. The Thirty-Fifth Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 1995; Abstract G109.

10 Gorbea MC et al. The Ninth International Conference of AIDS. June 6-11, 1993; Abstract PO-B07-1196.

11 Perno CF, et al. Blood. August 15, 1992; 80(4):995-1003.

12 Koyanagi Y et al. Science. September, 1988; 241:1673-5.

13 Kitano K et al Blood. April 15, 1991; 77(8):1699-1705.

14 Maerz A et al. Annual Conference of the Australia Society of HIV Medicine. November 3-6, 1994; 6:248.

15 Matsuda S et al. AIDS Research and Human Retroviruses. September, 1995; 11(9):1031-8.

16 Perno CF et al. Third Conference on Retroviruses and Opportunistic Infections. January 28-February 1, 1996; abstract 139.

17 Walsh DG et al. American Journal of Pathology. October 1991; 139(4):877-87.

18 Pluda JM et al. Blood. August 1, 1990; 76(3):463-72.

19 Kaplan LD et al. Journal of Clinical Oncology. June, 1991; 9(6):929-40.

20 Levine JD et al. Blood. December 15, 1991, 78(12):3148-54.

21 Scadden DT et al. Am J Clin Oncol. 1991; 14(suppl 1): S40-4.

22 Davey RT Jr et al: Journal of Infectious Diseases. July, 1991;164(1):43-52.

23 Pluda JM et al. Blood. August 1, 1990; 76(3):463-72.

24 Perno CF et al. AIDS Research and Human Retroviruses. August, 1990; 6(8):1051-5.

25 Scadden DT, et al. AIDS Research and Human Retroviruses. August 10, 1996; 12(12):1151-1159.

26 Davison FD et al. Journal of Clinical Pathology. September 1994, 47(9):855-7.

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