GMHC Treatment Issues - Vol. 9, No. 12 - December 1995
Rick Loftus

Markers of this increased immune activity, such as elevated Ig's, can predict CD4 cell count declines and progression of disease.1 Some scientists believe these overactive immune responses contribute to HIV reproduction, illness, wasting or the loss of normal immune function. If so, suppressing such responses early on might slow progression.

T-Cell Activation Promotes Disease Progression

Activated CD4 cells are cells with high metabolic activity. They are dividing and producing large amounts of cytokines as part of the immune response to infection. These activated CD4 cells are more easily infected by HIV and produce more virus than resting CD4 cells.2

Activation of CD4 cells also may play a more direct role in their gradual disappearance from the bloodstream during HIV infection. Unlike resting cells, activated cells can undergo a form of cell suicide called apoptosis, which is a natural way for the body to rid itself of cells that are no longer needed.

Numerous investigators have observed a high level of apoptosis in CD4 cells taken from HIV-infected patients (who would seem to need more of such cells) in late stage and asymptomatic disease. The trigger for this apoptosis is unknown, but suspects include the HIV envelope protein gp120 or defective antigen-presenting cells. Apoptosis can be prevented in the test tube by immunosuppressive drugs, particularly cyclosporine3 and prednisolone.4

B-Cell Hyperactivation and Immune Complexes

One of the first abnormalities observed in HIV-positive people was hyperimmunoglobulinemia -- abnormally high levels of antibodies. Why B-cells of HIV positive people make abnormal amounts of antibodies is unknown. The cause may be an indirect signal from HIV, cytokines such as IL-6, or a co-factor such as Epstein-Barr Virus, which is known to infect B-cells and spark antibody production. Whatever the cause, many different B-cells (which recognize many different antigens) are producing antibodies, as well as TNF and IL-6.

Several lines of evidence suggest that abnormal antibody levels may contribute to disease in AIDS. Some of the antibodies may be targeted against the body's own tissues, resulting in autoimmune reactions that are a common finding in HIV-positive people. High levels of antibodies that link to antigens and circulate in the blood, called circulating immune complexes (CICs), also have been found in people with AIDS-related conditions, and these levels correlate with decreasing CD4 counts.5 CICs can collect in certain tissues, causing inflammation that may lead to fevers and joint pain. CICs may also cause tissue damage and may be the source of AIDS-related thrombocytopenia (low platelets), neuropathy or kidney damage.6

Several drugs that inhibit activated lymphocytes have been proposed for or have entered trials for HIV infection or AIDS. (Cytokine inhibitors and drugs such as aspirin, which may dampen certain harmful inflammatory immune responses, but whose effects on lymphocytes are complex, will not be covered in this review.) Given that the hyperactivation of the immune system is prevalent primarily early in HIV disease and that immune suppressive agents may exacerbate opportunistic infections when people become symptomatic, the effects of such treatment may depend upon the stage of disease.

Cyclosporine

Cyclosporine (also called Cyclosporin A, CsA for short) is used to prevent graft rejection in patients with organ transplants. The drug acts specifically against T-cells in the early stages of activation. Reports on the use of this drug in people with HIV are contradictory.

In 1985, French workers reported that six people with AIDS had increases in CD4 counts after one week's treatment with cyclosporine.7 There were dramatic rises in patients' CD4 cell counts (from baseline counts below 150 to final results above 300). These increases were not sustained, though.

Researchers in Canada treated eight men with AIDS using 7.5 mg/kg per day of CsA for an average of 54 days. The Canadians could not confirm the French results and concluded that CsA treatment actually might be harmful. In this study, CD4 and CD8 counts decreased significantly but returned approximately to their initial values after the treatment was stopped. The side effects were significant and included pain, fatigue, loss of appetite, weight loss and progression of KS.8

In 1993, a German meta-analysis of 53 people who were infected with HIV during transplant operations found a much slower course of HIV-related disease progression among those whose regimen included CsA.9 The researchers found that the cumulative incidence of AIDS five years after the transplants was 31 percent among 40 patients who received CsA, versus 90 percent for 13 who did not. (The fact that the percentages do not equal an even number of patients was not explained.) Progression for CsA-treated patients was comparable to the normal rate for other AIDS risk groups, versus the faster progression seen in transplant patients.

Bias may have entered into this analysis. Since the study was non-randomized, those treated with CsA simply may have been in better health before the transplant. Also, at the time of the reports, CsA was cutting-edge treatment, so simply being treated with CsA may indicate that those patients were getting better care overall.

The effect of CsA treatment during primary infection, after organ transplant or otherwise, is a unique circumstance that might not reflect CsA's effect later in disease. CsA treatment may have reduced the number of activated CD4 cells susceptible to infection, and therefore the viral load at a particularly critical period of infection (see article on primary infection, page 1.)

Meanwhile, the original French team conducted a pilot study using 7.5 mg/kg per day of CsA in 27 asymptomatic HIV positive patients with higher CD4 cell counts than in the previous study (median of 523).10 During the treatment (which lasted a median of 11 months) CD4 cell counts were stable, CD8 cell counts declined and lymphadenopathy disappeared in fourteen of eighteen patients.11

Despite researcher's contention that CsA stabilized CD4 cell counts, seven patients discontinued treatment due to CD4 declines. Most of the patients stopped drug due to severe side effects, including seven cases of kidney toxicity, three of low platelets, two of hepatitis and one each of anemia, hypertension and nerve tingling. Five others stopped for personal reasons.

There have been no randomized, controlled trials of CsA in HIV to confirm the results of the French or German studies, although the NIH ACTG immunology committee is considering one. Whatever the benefit of CsA therapy might be, it would be coupled with significant drawbacks, particularly the drug's high price and severe side effects.

Corticosteroids

Corticosteroid drugs are analogs of natural hormones, made by the adrenal glands, that have anti-inflammatory properties. These drugs are used as short-term treatments for a host of AIDS-related conditions, such as neuropathy, esophageal ulcers, various skin rashes and thrombocytopenia. They are combined with other drugs to treat AIDS-related KS, acute Pneumocystis carinii pneumonia and tuberculosis and to reduce the increased intracranial pressure due to toxoplasmosis or CNS lymphoma.

Despite their common use among people with HIV and AIDS, the effects of corticosteroids on primary HIV infection have been given little formal study. Researchers at the University of Virginia reported on their experience with the common corticosteroid prednisone in six HIV-positive hemophiliac boys. They noted clinical improvements, including increases in platelet counts (five of six patients) and decreased lymph node swelling (two of six patients). Four of the six boys gained weight, but this may have been mostly water retention. Serum concentrations of immunoglobulin G declined in all, but there were no changes in IgA or IgM. No significant changes were seen in HIV levels or in CD4 or CD8 counts.14

In 1992, the same French team that carried out the CsA trials began an uncontrolled, unblinded safety study of the corticosteroid prednisolone for HIV infection. Forty-four patients with CD4 cell counts between 200 and 799 (mean of 421) received oral prednisolone (PRD) at a dose of 0.5 mg/kg of body weight for six months, and 0.3 mg/kg for the remainder of a year.

CD4 cell counts increased significantly between days fifteen and 120 of the study, with a sustained mean increase of 119 after one year. Those who started the study with counts over 500 had higher mean increases (137). CD8 cell levels remained unchanged, as did HIV levels. Percentages of activated CD4 cells decreased significantly, and the percentage of cells undergoing apoptosis in lab tests also declined sharply. Researchers also noted a reduction in serum antibody levels. As in the Virginia report, lymphadenopathies decreased.

No major side effects were seen. After one year, systolic blood pressure slightly increased as did weight (from 146 to 150 pounds). Both of these effects were probably due to water retention. The team concluded that corticosteroid therapy in this group of asymptomatic or mildly symptomatic patients was safe and effective in reducing markers of T- and B-cell activation. They hypothesized that the immediate increase in plasma CD4 cell counts may have been due to decreased apoptotic cell death in the lymph nodes.

Of the 44 patients, eleven had been taking AZT at 500 mg/day for at least six months before the study, and they maintained this regimen. Results for AZT users were not significantly different from non-users. And while CD4 cell apoptosis appeared to decrease, there was no change in the abnormally low proliferation of patients' CD4 cells in response to foreign antigens during lab tests.

These results are more encouraging than those for CsA, but there are reasons for caution. Though corticosteroids are often used in the short-term treatment of inflammation associated with infections, long-term use has been associated with reactivation of herpes viruses, Pneumocystis carinii, tuberculosis and various fungal infections.15 Corticosteroids also have been associated with exacerbation of AIDS-KS.16 These drugs have rarely been associated with the development of KS in people with other diseases, and it remains unclear if their use increases the risk of developing KS for people with HIV. A search of the MACS cohort database showed no significant increase in the rate of KS development among corticosteroid users.17 Still, this theoretical risk cannot be discounted.

Cyclophosphamide

Cyclophosphamide (CY) at high doses has been used in cancer chemotherapy regimens. In low doses (up to about 120 mg/day), the drug has well-documented immunomodulatory properties18 and has been used to treat several immune disorders, including lupus and Wegener's granulomatosis. Early laboratory work demonstrated that B-cells were more suppressed by CY than were T-cells, and that CD8 cells were more sensitive to the drug than other T-cell subsets.19,20

Studies comparing CY at 1,000 mg/m2 of body surface and 300 mg/m2 in advanced melanoma patients showed that the lower-dose did not cause the marked reduction in lymphocyte levels effected by the higher dose. T-cell proliferation in response to mitogen stimulants in vitro was unaffected by either dose, as was the number of CD8 cells and CD4 to CD8 ratio.21,22 Other groups have seen decreases in CD8 counts with increases in CD4 levels and CD4 to CD8 ratio.23 Doses of CY at 25-50 mg/day caused reduction of serum antibody levels as well as in total lymphocyte counts.24,25

The Community Research Initiative on AIDS (CRIA) in New York is launching an independent pilot study of CY this fall. The study will look at very low doses of CY (3 to 18 mg/day), since doses above 50 mg/day can cause typical chemotherapy side effects such as nausea, vomiting, hair loss and drops in white blood cell counts. Another risk for patients using moderate doses of CY is a higher risk of developing certain cancers.

The CRIA study will be an open-label trial in ten individuals with CD4 counts from 300 to 600 who have abnormally elevated total antibody levels. Doses will start at 3 mg/day, with escalation every six weeks in 3 mg/day increments. The goal is to find a dose that reduces B-cell activity (as reflected in decreased levels of antibodies and CICs) without adversely affecting CD4, white blood cell or HIV levels. For information, call Bette Smith at 212/924-3934.

Methotrexate

Like CY, methotrexate (MTX) is used at high doses as a cancer chemotherapy, while at lower doses, from five to 20 mg/week, MTX suppresses inflammation in immune disorders such as Wegener's granulomatosis, rheumatoid arthritis and psoriasis.26,27 At these doses, MTX has anti-inflammatory effects, and can reduce levels of various markers of immune activity, particularly serum antibodies and rheumatoid factor, a component of immune complexes characteristic of rheumatoid arthritis.28

Numerous side effects are associated with MTX treatment. These vary according to dose. Bone marrow suppression has been seen with MTX but is infrequent at the lower doses used for arthritis. The most common side effects of lower doses of MTX are gastrointestinal (nausea, diarrhea, anorexia, oral ulcers). Such toxicities appear to be lessened by co-administration of folic acid.29 Even at the low doses used in autoimmune disease, though, MTX treatment for periods greater than three months is associated with development of opportunistic infections, especially Pneumocystis carinii pneumonia and varicella zoster.30

The DATRI network of the National Institute of Allergy and Infectious Disease's Division of AIDS is launching a pilot study (DATRI 013) of low-dose MTX for HIV-positive volunteers this winter. Twenty persons with CD4 counts over 350 will be randomly assigned to one of two doses, five or 10 mg/week, co-administered with folic acid supplements. Volunteers may not have been taking antiretroviral medications in the previous six months.

Due to concerns about inducing opportunistic infections, treatment will be limited to twelve weeks. If safety is demonstrated at these doses, a third cohort will be started at 10 mg/week and escalated to 15 mg/week through a twelve-week period.

The goal of the study is to find a safe dose that reduces levels of inflammatory immune markers (including TNF, interferons, beta-2 microglobulin, antibody levels, and activated T-cell subsets) without adversely affecting CD4 or white blood cell counts or HIV levels.

CRIA will be a site for DATRI 013. For information, call Dr. Connie Abelardo at 212/924-3934. Other sites are Wayne State University in Detorit, Cedar Sinai Hospital in Los Angeles, University of Kansas in Witchita, University of Texas Southwest Medical Center in Dallas.

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17 Jacobson, L. Personal communication, Jun 28, 1995.

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24 Fauci AS et al. New England Journal of Medicine. Dec 30, 1971; 285(27):1493-6.

25 Fauci AS et al. Arthritis & Rheumatism. Jul-Aug 1974; 17(4):355-61.

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27 Jeurissen ME et al. The Netherlands Journal of Medicine. Aug, 1989; 35(1-2):44-58.

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