GMHC Treatment Issues - Vol. 9, No. 12 - December 1995 ------------------------------------------------------------- Published by the Gay Men's Health Crisis, Treatment Education Department, 129 West 20th Street, New York, NY 10011 ------------------------------------------------------------- Treatment for Primary Infection by Theo Smart Despite its theoretical appeal, there has long been little attempt to diagnose or treat HIV during primary HIV infection -- the acute stage of disease just after transmission. The weakness of available anti-HIV drugs and the lack of sensitivity of diagnostic assays led most researchers to abandon the field. Recent developments, though, have prompted prominent virologist David Ho, M.D., Ph.D., to argue that a more aggressive approach to treatment during primary infection may now offer significant clinical advantages. "Recent scientific findings and therapeutic developments converge to favor an aggressive interventional strategy early in the course of HIV-1 infection," Dr. Ho wrote in a recent commentary.1 These developments include a better understanding of viral replication and viral variance during primary infection as well as late stage disease. The rate of replication during these periods may drive (or at least reflect) disease progression. The viral population in persons recently infected with HIV also turns out to be relatively homogeneous and less likely to quickly become resistant to therapy. Given the rate of viral replication and variation later in disease, drug resistance is almost unavoidable. Another significant development is the availability of much more potent antiretroviral drug regimens (including PMPA -- see page 3). Dr. Ho, who directs the Aaron Diamond AIDS Research Center in New York, is currently working with his colleague Martin Markowitz, M.D., on two studies evaluating combination antiviral therapy with AZT, 3TC and a protease inhibitor (either indinavir or ritonavir) in people recently infected with HIV. Primary Infection and HIV Setpoint Primary HIV infection usually passes unnoticed in most individuals. Symptoms, such as fevers, swollen glands, rashes and diarrhea, are frequently mistaken for the flu or the common cold. If a person undergoing primary infection does seek medical attention, HIV is rarely diagnosed unless there is good reason to suspect it (such as a known recent exposure). During primary infection, viral load levels are extremely high, but this initial burst of viral replication is brought under control within several weeks by cytotoxic T-lymphocytes (CTLs). The CTLs can reduce virus levels by a thousand-fold or more, a greater reduction than any currently available treatment can accomplish. Two recent studies suggest that the level at which an individual's viral load eventually plateaus (the HIV "setpoint") predicts the rate at which that person will progress to AIDS. If antiviral therapy can help to lower the viral load setpoint so that there is a more stable equilibrium with the immune system, it might slow disease progression. The first study followed 62 men from the Multicenter AIDS Cohort Study (MACS) for at least four years, measuring their HIV RNA levels at seroconversion to HIV-positive on the standard ELISA test.2 Researchers reported that those developing AIDS within the course of the study had higher viral loads at seroconversion than those who did not progress to AIDS. A viral load measured at greater than 100,000 copies of HIV RNA (the HIV gene set) per milliliter of plasma at seroconversion was associated with more than a ten-fold increase in risk of progression to AIDS. A second study of stored blood samples from 42 seroconverters found that the people who advanced to AIDS within four years had the highest setpoints as measured after seroconversion, those who progressed within four to nine years had lower setpoints, and those who did not develop AIDS within six to eleven years had the lowest setpoints.3 AZT Primary Infection Study Dr. Ho cites one study that indicates early AZT therapy does indeed offer limited clinical benefit. This European Australian Cooperative Study evaluated six months of AZT treatment (250 mg twice daily) versus placebo in 77 persons with primary HIV infection.4 During the mean follow-up of fifteen months, seven opportunistic infections occurred in patients on placebo, and only one in the group on AZT. These opportunistic infections were not AIDS-defining events, but conditions like thrush and herpes zoster that may predict future progression. The rest of the data is hard to interpret because the two groups of patients were not perfectly matched at entry -- CD4 cells were higher and viral load was significantly lower in those on placebo. The patients on AZT nevertheless had a CD4 count at six months that was 130 points higher than those on placebo. This difference was not quite statistically significant, though, and the difference in CD4 cell count dwindled after treatment discontinuation. But at two years of follow-up, the AZT group still appeared to have at least a 50 point higher CD4 count on average. As usual, HIV levels dropped in both groups after primary infection, when the anti-HIV immune response commenced. Because of the small size of the study and the fact that everyone had a fairly substantial drop in viral load, the difference between those on AZT and placebo was not statistically significant. However, AZT-treated people had a viral load reduction that was about 70 percent greater than those on placebo -- which is identical to the reduction that AZT can achieve later in disease. There was no rebound in viral load after treatment discontinuation. Although the researchers found the 215 codon mutation that helps confer high-level resistance to AZT in six out of 58 patients at baseline (four in the AZT group and two in the placebo group), they could find no evidence of additional resistance emerging in response to the six months of AZT treatment, which lends support to Dr. Ho's contention that resistance may be slow to develop in response to treatment during primary infection. AZT resistance often occurs within less than four months in more advanced patients.5 AZT monotherapy has not fared so well in a number of other studies. An earlier Australian study noted a decrease in CD8 cells in seven people treated with AZT (one gram a day) for 56 days as compared to fifteen untreated historic controls, although there was no difference in post-treatment absolute CD4 cell counts.6 This was not a randomized study, and the doses of AZT used were higher and more toxic than the current recommended dose. DATRI 002, a National Institute of Allergy and Infectious Diseases study of AZT monotherapy in primary infection, has had trouble finding acceptable volunteers. New Studies Dr. Ho's final argument in favor of aggressive treatment during primary infection is that much more benefit can be expected from the more potent combination regimens becoming available. Accordingly, Dr. Markowitz's studies evaluate one year of treatment with AZT/3TC/protease inhibitor in people infected with HIV within the last three months. Participants can test positive for antibodies to HIV or can have a positive test for p24 antigen (HIV core protein). The main endpoint will be the change in viral load. Screening has already begun for the first trial, an open label study of AZT, 3TC and ritonavir in twelve patients. The second study will begin within a month and randomizes 18 patients to receive either AZT/3TC/indinavir, AZT/3TC or indinavir monotherapy (in a 2:1:1 ratio). What happens in either study after the first year depends upon the responses seen in the volunteers. If viral load becomes undetectable, trial participants may elect to have lymph node biopsies to see whether the virus has been cleared from the germinal centers which can serve as a reservoir for the virus. For more information, call 212/725-0018. Since neither study is placebo-controlled, it may be difficult to ascertain the extent to which treatment can supplement the anti-HIV immune response unless the treatment's effects are dramatic. Another potential pitfall is that treatment before seroconversion (while viral replication is extremely high) may have a different effect than treatment following seroconversion. Reducing replication before seroconversion (when the rates of replication are at the highest) may have a greater clinical effect. Three drugs at once may represent a formidable challenge for the single strain of virus attacking a person during primary infection. There remains the possibility that HIV will acquire resistance to the therapy being administered. This may limit a patient's options for treatment in the future, when disease progression accelerates. One last consideration: as virologists, Drs. Ho and Markowitz may naturally look to targeting HIV. But since it is the cell-mediated immune response that is primarily responsible for the initial massive reduction in viral load, it would make as much sense to evaluate therapies that can sustain or enhance this response. Appropriate immune modulators or cytokines such as IL-12 clearly should be tested in primary infection. 1 Ho, D. The New England Journal of Medicine. August 17, 1995; 333(7):450-1. 2 Mellors, JW et al. Annals of Internal Medicine. Apr 15 1995; 122(8):573-9. 3 Henrard, DR. Journal of the American Medical Association. Aug 16 1995; 274(7):554-8. 4 Kinloch De Lo‘s, S et al. The New England Journal of Medicine. Aug 17 1995; 333(7):408-13. 5 Nelson R et al. Tenth International Conference on AIDS. Aug 7-12 1994; 10(1):104 (abstract no PA0033). 6 Tindall B et al. AIDS. Jan 1993; 7(1):128-9. ******************************************** A Kinder, Gentler ddC. . . For $7,200 a Year Following its advisory committee recommendation (see last month's Treatment Issues), the Food and Drug Administration in December granted the first formal approval for a protease inhibitor to Hoffmann-La Roche's saquinavir (brand name: Invirase). The drug now can be marketed for use in individuals with "advanced HIV disease" in combination with approved nucleoside analogs such as AZT and ddC. Side effects from saquinavir are relatively minor, but as the accompanying graph shows, the improvement in CD4 counts from Invirase by itself is very small and short-lived. Invirase performs no better than ddC, which itself has a minor effect. (The graph is from the preliminary analysis of 451 evaluable volunteers in a large ongoing trial of saquinavir and ddC in people with long prior AZT treatment.) By the sixteenth week, CD4 counts for both drugs used as monotherapy are below their pretreatment values. As for antiviral impact, ddC has a greater effect (based on the same trial). ddC yields a stable 50 percent decline in plasma HIV compared to a stable nine percent decline for saquinavir. Saquinavir's main advantage is that it is a relatively benign way of slightly boosting the mediocre performance of nucleoside analogs, as the graph's top curve shows. But the retail price is $7,200 per year! ********************************* 3TC/AZT: Just Another Combination The Food and Drug Administration in November followed up its advisory committee's recommendation and granted formal approval to 3TC (brand name: Epivir) for use in combination with AZT to any stage of HIV infection. No other combination has this sort of approval. 3TC/AZT is widely considered the best of all available nucleoside analog combinations. It is certainly the newest combination, but, as the accompanying graph illustrates, the boost in CD4 cell counts from AZT/3TC is not significantly different than from ddI/AZT. (The graph gives a tentative comparison by superimposing the data reported from Glaxo's NUCA 3001 trial of 3TC plus AZT with data from the ACTG 175 trial. Patients in both studies had similar CD4 cell counts at baseline (about 350) and no prior anti-HIV treatment.) One reason why 3TC/AZT is considered superior is the laboratory finding that the genetic mutation in HIV giving rise to 3TC resistance also counteracts the mutations that confer resistance to AZT. It is thought that HIV cannot be resistant simultaneously to both drugs. An analysis by Victoria Johnson, M.D., of drug resistance in the North American AZT-experienced 3TC study (NUCA 3002) found that dual resistance to AZT and 3TC does indeed take place. Of seven HIV trial participants showing evidence of high-level resistance to 3TC at week twelve, five were strongly resistant to both drugs at week twelve and four were resensitized to AZT by week twelve. Another eighteen trial participants were not resistant to AZT in the first place, and so could receive none of the presumed benefits of 3TC resistance. Six people checked by the investigators were still not resistant to 3TC at week twelve. Probably most continued to have virus sensitive to both drugs. The moral of our story is: Observe what is happening in the human body rather than relying on simple laboratory findings. ******************************* A Shot a Day Keeps the SIV Away A drug that could prevent or reverse primary HIV infection would be dramatically better than drugs that only delay disease progression. Hence the excitement over a paper in the November 17 Science reporting that Gilead Sciences' new antiviral compound PMPA can prevent the closely related simian immunodeficiency virus (SIV) infection in macaque monkeys. PMPA functions like a partially activated nucleoside analog that does not need as much phosphorylation by cells. It was found to prevent SIV even when begun one day after inoculation with the virus. The study was conducted by researchers at the University of Washington who injected 25 macaques with PMPA (20 or 30 mg/kg of body weight) daily for four weeks, beginning either 48 hours before, four hours after or 24 hours after inoculation with SIV. Ten untreated monkeys were inoculated with SIV as a control. During the course of the study and through the 56 weeks of follow-up, the team could find no evidence of SIV infection in the blood or lymph nodes of any of the macaques that received PMPA. Nor could they find any trace of SIV in two monkeys killed at forty weeks for extensive testing of organs and tissue. All of the untreated monkeys, in contrast, developed SIV. According to Norbert Bischofberger of Gilead Sciences, there also are indications that the PMPA-treated monkeys have developed cytotoxic T-lymphocytes capable of killing SIV-infected cells. The treated monkeys may have, in effect, been vaccinated against SIV by exposure to a limited amount of live virus. The researchers are now studying this immune response in lab cultures. They plan to rechallenge the macaques soon with a new dose of SIV in the absence of treatment. A group at the California Regional Primate Research Center in Davis is now studying PMPA in baby rhesus macaques. The monkeys are infected with SIV at birth and therapy begun three weeks later. Preliminary data at six months show that this regimen preserves health while reducing viral load one thousand-fold. Further studies are underway in adult monkeys exposed to SIV via their mucosal membranes rather than intravenously. PMPA may yet prove to be unprotective in HIV or in mucosal infections (the most common kind of initial exposure to HIV) because different, more long-lived cells (such as macrophages) are predominantly the target of sexually transmitted virus. If such a cell is infected, it may serve as a reservoir for the virus for a much longer time than infected T-cells, which usually die within two days. PMPA has proved relatively nontoxic in cell culture and animal studies, so comparatively high doses may be safely administered. Gilead plans to quickly evaluate the activity of PMPA in both perinatal transmission and primary HIV infection. Before the end of this year, the company will start with a pharmacokinetic study comparing intravenous and oral administration. -- TS ************************************************************* Immunosuppressive Drugs and Corticosteroids for HIV Infection by Rick Loftus The idea of using immunosuppressive drugs for HIV infection may seem bizarre, since the end point of HIV infection is called Acquired Immune Deficiency Syndrome. Particularly in its earlier stages, though, HIV infection is associated with chronic stimulation of the immune system. The hyperactive immune responses in people with HIV include overproduction by B-cells of antibodies (also called immunoglobulins or Ig's); abnormal levels of messenger molecules called cytokines, such as tumor necrosis factor (TNF) -alpha and interferon-alpha; and increased activation of T-cells. 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. 1 Fahey JL et al. New England Journal of Medicine. Jun 28 1990; 322(26):166-72. 2 Zagury D et al. Science. Feb 21, 1986; 231(4740):850-3. 3 Amendola A et al. FEBS Letters. Feb 21, 1994; 339(3):258-64. 4 Andrieu JM and Lu W. AIDS Research and Human Retroviruses. Aug 1, 1995; 11(Supplement 1, abstract108):S91. 5 McDougal JS et al. Journal of Clininical Immunology. Mar 1985; 5(2):130-8. 6 Walsh CM et al. New England Journal of Medicine. Sept 6, 1984; 311(10):635-9. 7 Walgate R. Nature. November 7-13, 1985; 318(6041):3. 8 Phillips A et al. Canadian Medical Association Journal. Jun 15, 1989; 140(12):1456-60. 9 Schwarz A et al. Transplantation. Jan 1993; 55(1):95-103. 10 Levy R et al. Tenth International Conference on AIDS. Aug 7-12, 1994; 10(1):217, Abst. PB0298. 11 Andrieu JM. Clinical Immunology and Immunopathology. May 1988; 47(2):181-98. 12 Karpas A et al. Proceeding of the National Academy of Sciences USA. Sept 1, 1992; 89(17):8351-5. 13 Thali M et al. Nature. Nov 24, 1994; 372(6504):363-5. 14 Saulsbury FT et al. The Southern Medical Journal. Apr, 1991; 84(4):431-5. 15 Corey L. Journal of Infectious Diseases. Apr 1995; 171(4):521-2. 16 Gill P et al. Annals of Internal Medicine. Dec 1, 1989; 110(11):937-40. 17 Jacobson, L. Personal communication, Jun 28, 1995. 18 Hengst JCD, Kempf RA. Clinical Immunology of Allergy. 1984; 4:199-216. 19 Shand FL, Liew FY. European Journal of Immunology. 1980; 10:480-3 20 Diamanstein T, et al. Journal of Immunology. 1981; 126:1717-9. 21 Berd D et al. Cancer Research. Mar 1984; 44(3):1275-80. 22 Berd D et al. Cancer Research. Jun 15, 1987; 47(12):3317-21. 23 Sahasrabudhe DM et al. Journal of Biological Response Modifiers. Dec 1986; 5(6):581-94. 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. 26 Hoffman GS et al. Arthritis & Rheumatism. Nov, 1992; 35(11):1322-9. 27 Jeurissen ME et al. The Netherlands Journal of Medicine. Aug, 1989; 35(1-2):44-58. 28 Van de Putte LBA et al. Clinical & Experimental Rheumatology. Mar-Apr, 1993; 11 Supplement 8:S97-9. 29 Weinblatt ME. New England Journal of Medicine. Feb 2, 1995; 332(5):330-1. 30 LeMense GP Sahn SA. American Journal of Respiratory Critical Care Medicine. Jul, 1994; 150(1):258-60. ********************************* Sandoz Axes Cyclosporine Research When researchers at Sandoz, the Swiss pharmaceutical giant that manufactures cyclosporine, checked the anti-HIV activity of over 200 of the compound's derivatives, they made a surprising discovery. These chemicals' ability to inhibit HIV in the test-tube did not correlate with their ability to suppress lymphocyte activation. In particular, "NIM 811" stopped HIV three times more potently than cyclosporine but was a 1,700-fold weaker immunosuppressant. Sandoz researchers and their associates reported their findings in a remarkably detailed series of articles published over the last fourteen months.1-4 They found that the cyclosporine family binds to the cellular enzyme cyclophilin A. Cyclophilin probably is involved in folding proteins into their proper shape as well as transporting proteins into cells' nuclei. Cyclophilin binds to one area of HIV gag (core) protein that is little affected by genetic mutation. It is packaged into the core of HIV particles as they bud off from cells. When NIM 811 or other active members of its family are present, two things happen: 1) the HIV particles budding off of cells are not infectious; and 2) uninfected cells are protected from functional HIV, which never reaches their nuclei. NIM 811 as well as cyclosporine produced these effects in cultures of CD4 lymphocytes and monocytes, the two main cell reservoirs of HIV, and against a wide variety of HIV strains. NIM 811 seemed preferable to cyclosporine overall on the basis of safety and efficacy. Animal toxicology and oral bioavailability studies all were positive for NIM 811. In mice, rats, dogs and monkeys, concentrations of NIM 811 were safely reached that far exceeded effective levels in the test tube. And then. . . Sandoz canceled the project just when human trials of NIM 811 were within sight. The company claims it did so because it could not make sufficient quantities of the molecule. Sandoz attempted unsuccessfully to breed the fungi that produce cyclosporine and NIM 811 to increase their output of the latter. The cell cultures died, reportedly because high levels of NIM 811 is poisonous to them. But there are those who believe that Sandoz gave up too readily. Oswald Weber of Projekt Information in Munich, Germany notes, "[Production difficulties are] an argument we've already heard a number of times whenever pharmaceutical companies start looking for excuses. . . " Indeed, Sandoz has not pursued possible alternative production methods. There is an underlying reason that could explain the company's lack of motivation: Sandoz's main interest is bone marrow and organ transplants (hence, cyclosporine), which may also involve gene therapy applications. Except for such gene therapy, the company is not interested in infectious disease research. This stance arises from business strategy. It does not represent a particular bias against AIDS: Sandoz recently bought a small, highly regarded American biotech company, one of whose activities is in fact anti-HIV gene therapy research. This same reasoning was at play in 1991, when Sandoz abandoned its line of monoclonal antibodies. Rights to the antibodies were eventually bought up by Protein Design Labs, another small biotech company, but in the process, development of the products was set back four years. (See Treatment Issues, July/August 1995, pages 7-8.) Sandoz supposedly is continuing to make available small quantities of the NIM 811 to outside researchers, who could at least prove the principle that a cyclophilin inhibitor like NIM 811 is a practical way to attack HIV. But what company is going to license NIM 811 if it is labeled impossible to mass produce for the market? Right now, the sort of delay encountered by the monoclonal antibodies is the best fate NIM 811 can hope for. --DG 1 Rosenwirth B et al. Antimicrobial Agents & Chemotherapy. Aug 1994; 38(8):1763-72. 2 Thali M et al. Nature. Nov 24 1994; 372(6504):363-5. 3 Steinkasserer A et al. Journal of Virology. Feb 1995; 69(2):814-24. 4 Rosenwirth B et al. Journal of Virology. Apr 1995; 69(4):2451-61. **************************** Cytolin: Hype-Driven Therapy by Dennis Sawyer Recently there has been considerable interest among the public and the media concerning an unapproved immune-based therapy called Cytolin. Following an article about Cytolin in last September's edition of Out magazine, AIDS organizations around the country, and especially in Los Angeles where Cytolin use is centered, received many queries about this substance, whose distribution is taking place outside FDA-sanctioned channels. Products arising in such an unregulated environment frequently are rushed into human use without the proper lab and animal studies to gather preliminary safety and efficacy information. Cytolin is no exception. The Rationale for Cytolin Cytolin is the trade name for an experimental therapy under development by CytoDyn of New Mexico, Inc., a start-up biotech firm led by a physicist named Al Allen. It reportedly consists of a specific antibody derived from mice that is infused over twenty minutes, with repeat administration every four weeks. The mouse antibodies that make up Cytolin do not recognize or bind to HIV at all. They only recognize and bind to a specific protein, known as S6F1, found on the surface of a subgroup of CD8 cells that help control viral infections. In theory, Cytolin should not interfere with the critical functions provided by other immune cells that lack the S6F1 surface proteins. According to a paper published in 19901 by Joyce Zarling and research conducted by Al Allen,2 HIV over-stimulates circulating S6F1-marked CD8 cells, causing them to "behave inappropriately." The CD8 cells destroy essential CD4 cells whether those cells are infected with HIV or not, "eventually facilitating immune system collapse." CytoDyn also has stated that "various" (uncited) studies have pointed out the detrimental effects of S6F1-marked cells on immune function according to two additional scenarios: 1) The S6F1 cells might themselves be providing a pathway needed by HIV to replicate, or 2) the S6F1 cells might be interfering with the body's mechanism (the monocyte-macrophages) to clear infected cells. Risks and Benefits Thus far, a few hundred individuals have received Cytolin with their ongoing treatment regimens under the supervision of their primary care providers. As expected with the introduction into the body of a non-human protein-based substance like mouse antibodies, administration of Cytolin causes serum and protein sickness. Some patients experienced mild flu-like serum sickness reactions, such as low-grade fever, swollen lymph nodes, and body aches within hours of Cytolin injection. Temporary mood changes, such as depression, irritability and anxiety lasting for several days were also reported. The occurrence of these side effects, largely attributable to cytokine release, can be minimized by administering ibuprofen such as Advil or Motrin to the patients just prior to infusion and for twelve hours thereafter. Several patients have also developed much more serious allergic or anaphylactic reactions. Taking Benadryl prior to Cytolin may reduce these possibly fatal reactions, but this has not been established. Critics also have warned that Cytolin can neutralize the critical role that CD8 cells possessing S6F1 play in killing cancerous or virus-infected cells. Cytolin may promote the spread of lymphomas or Epstein-Barr virus, for example. Proponents of Cytolin have claimed that both increases in CD4 counts and improvements of immune responses, as measured by delayed-type hypersensitivity skin tests, have occurred in treated patients with early HIV disease. Apparent resolutions of molluscum contagiosum, a skin condition associated with HIV infection, were seen in some Cytolin recipients. But one doctor reports that of 19 patients on Cytolin, 13 experienced a "clinically significant" event. It is hard to judge the importance of such anecdotal evidence. The medical experience of individuals on Cytolin is not recorded in a precise or uniform manner. Those who drop therapy because they are doing poorly tend to get lost from the record entirely. Also, Cytolin's proponents do not weigh the effects of concomitant therapies taken for HIV and opportunistic infections. Now, Victor Beer, M.D., of Los Angeles will conduct an initial dose-ranging trial to gauge the pharmacodynamics and safety of Cytolin in 16 healthy HIV-positive people with CD4 counts between 200 and 500 and no prior or stable (at least two months) antiretroviral therapy. Endpoints include viral load and CD4 counts. Participants will receive either placebo, "the current dose of Cytolin," two times the current dose or five times the current dose. Larger trials are envisioned for next summer. While awaiting some reliable data, those eager to try this agent should remember Cytolin's risks as well as its promise. 1 Zarling, JM et al. Journal of Immunology. Apr 15 1990; 144(8):2992-8. 2 Company literature. A report on the science study of A.D. Allen at al. Lay Language Summary. **************** Treatment Briefs Ritonavir Expanded Access Abbott Laboratories has announced details of the expanded access program for its protease inhibitor, ritonavir. Any person with HIV who is over twelve years old and has a CD4 cell count below 50 is eligible. The drug, in capsule or liquid form, will be provided by lottery to around 2,000 people worldwide (U.S. total: 1,200) in January, 1996. Participants in the lottery must register by December 30, 1995. Doctors and people who want to enroll can call 800/414-AIDS or fax 800/336-2879 for additional information and the (relatively simple) application forms. You can e-mail Abbott Laboratories at ritonavir@pond.com. The program also has a site on the Internet's World Wide Web (http://www.pond.com/ritonavir). Abbott is conducting a lottery because it says that the present available supply of ritonavir is highly limited. The company expects to file for FDA by the end of March, 1996, which could get ritonavir into pharmacies this summer. In response to AIDS activists' suggestions, Abbott will be collecting survival data to compare the experience of those applicants who receive drug through the lottery with those who do not. Note that Abbott has a long list of drugs incompatible with ritonavir due to ritonavir's impairment of liver metabolism. These drugs include the analgesics codeine, Demerol and Darvon; rifabutin; the antifungals ketoconazole and fluconazole; Roche's protease inhibitor Invirase (saquinavir); the anti-ulcer medication Tagamet; and various psychotropic agents such as Paxil, Xanax, Valium and Halcion. Peptide T Peptide T offers no benefit for people with HIV-related cognitive impairment, according to results from a National Institute of Mental Health (NIMH) sponsored study. The 215-person trial found no significant differences between the drug and placebo in overall neuropsychological function or in any of seven separately measured outcomes. In response to these findings, Peptide Technologies of Australia, parent company to Peptech, has decided to discontinue all further studies of peptide T in the U.S., including the recently opened trial reported in September's Treatment Issues. Representatives of Peptech, the American subsidiary, claim to still believe in the drug. They are looking for alternative financing while independently analyzing the NIMH's data. Pregnancy, HIV and Immune Status A prospective British study of 145 women monitored immunologically during and after pregnancy revealed no evidence that pregnancy itself negatively affected their immunological markers. Although the women's CD4 lymphocyte counts fell during pregnancy, the CD4 and CD8 percent of total lymphocytes remained stable. The change in the CD4 count is related to a decline in the absolute lymphocyte count that occurs as a result of pregnancy and not to the redistribution of CD4 and CD8 cells observed in HIV disease progression. After pregnancy, CD4 counts rose, and the CD4 percentage was 2.5 points higher on average than would have been expected had there been no pregnancy. Another prospective study of 416 Kenyan pregnant women who were matched and compared to a group of 407 HIV-negative controls also did not find any major differences in CD4 and CD8 counts during and after pregnancy. Both groups had lower CD4 percent but not CD4 counts after giving birth compared to prenatally. Most studies of HIV-positive pregnant women have been done among asymptomatic populations. It is still unclear if pregnancy would have a deleterious effect on women with AIDS or symptomatic HIV disease. In addition, further studies are needed that evaluate the effect of pregnancy on viral load. (RP Brettle. AIDS. Sept. 1995; 9(9):1177-84 and M Temmerman. AIDS. Sept. 1995; 9(9):1057-60.) Treating CMV GI Disease A randomized study of 48 patients with CMV gastrointestinal disease who received open-label ganciclovir or foscarnet found similar response rates to the two drugs. Patients were assessed using a visual analog score of symptoms, appearance of lesions on endoscopy and the presence of CMV inclusion bodies on repeat biopsy specimens after treatment. Eighty-three percent of those receiving foscarnet and 85 percent of those receiving ganciclovir showed a response by endoscopy and the CMV inclusion bodies disappeared in 73 percent of these. Seventy-three percent of patients relapsed during follow-up. The time to progression was not significantly different among the two groups (sixteen vs. thirteen weeks). Survival in both groups was less than 40 weeks and did not seem to be affected by continuing maintenance therapy. Patients were not randomized to maintenance or no maintenance. Only ten patients received maintenance therapy compared to 39 who did not. A much larger, randomized clinical trial is required to determine whether patients with CMV GI disease benefit from maintenance therapy. (C Blanshard et al. Journal of Infectious Diseases Sept 1995; 172(3):622-8). Adenovirus Infections in HIV-Positive Patients A prospective surveillance study of 63 HIV-positive patients and nine HIV-negative partners found evidence of adenovirus infection in 18 of the HIV-positive patients The analysis was done using restriction enzyme analysis. The most frequent site of infection was the gastrointestinal system in 17 of 18 patients with subgenus D, while urinary tract infection was caused by subgenus B or D. Diarrhea was present in 41 percent of those in whom adenovirus was found in the stool. Patients with low CD4 counts (under 150) had prolonged fecal excretion of adenovirus. How much adenovirus infection contributes to morbidity in AIDS patients is unclear, although one review of the literature showed that 45 percent of AIDS patients infected with adenovirus die within two months of virus detection. (SH Khoo. Journal of Infectious Diseases. Sept 1995; 172(3):629-37). Steroids for PCP Do Not Increase OI Risk A Spanish study compared the risk of TB in 72 patients with PCP who received steroids during their bout of pneumonia to the risk in 57 patients who did not. The mean total dose of steroid (methylprednisolone) was 420 mg and mean total days of use was twelve. The twelve and 24 months rates of both TB and atypical mycobacteria infections were similar for both groups. Rates of other AIDS-related conditions such as CMV and KS were also similar, although other authors have found higher rates of these infections after a short course of steroids in AIDS patients. (A Martos. AIDS. Sept 1995; 9(9):1037-41) Chinese Herb Trial St. Luke's-Roosevelt Hospital in New York has opened a phase I/II clinical trial of the combination of AZT and TJ-9, a preparation of a traditional oriental medicine known as Sho-Saiko-To (SSKT), or Xiao Chai Hu Tang. SSKT is a blend of seven medicinal herbs including bupleurum, scutelaria radix, pinellia, fresh ginger, ginseng, jujube and glycyrrhizin. It has been used for thousands of years to treat what the Chinese call lesser yang disorders, which include fevers, influenza, bronchitis, respiratory ailments, malaria, jaundice and hepatitis. SSKT appears to be fairly safe, although it has been reported to induce pneumonitis in a few elderly patients. In vitro data suggest that the blend may have anti-HIV activity by directly inhibiting reverse transcriptase, and by decreasing TNF-alpha and free radical promotion of viral replication.1,2 The data also suggest that the herbal formula is strongly synergistic with AZT.3 Additionally, SSKT may have some immune modulatory effects. The St. Luke's-Roosevelt study will compare AZT plus SSKT (fifteen grams a day, divided into two packets drunk as a tea, three times a day) to AZT in 40 HIV-positive people with CD4 cell counts between 150 and 400, and a viral load greater than 20,000 RNA copies per ml. The study will last at least six months and will monitor patients for changes in viral load and other surrogate markers. For more information call Alison Spencer at 212/523-7238. The doses chosen are those used traditionally in Chinese medicine. The study will not gather data on how well people's bodies absorb and distribute the herbal blend. This is unfortunate as there are no such data available, and therefore no way of knowing whether the concentrations found active in the laboratory can be achieved in human beings. This lapse will make the study results harder to interpret. For example, if an antiviral effect is seen, would it be greater at higher doses? Also, SSKT is available from a number of sources, including the PWA Health Group in New York, and the cost of treatment can add up over time. It would be nice to know if SSKT does indeed reach its target cells. 1 Buimovici-Klein E. Antiviral Research. Oct-Nov 1990; 14(4-5):279-86. 2 Miyamoto K et al. Eighth International Conference on AIDS. Jul 19-24 1992; 2(abstract PoA 2345):A60. 3 Maitra U et al. Tenth International Conference on AIDS. Aug 7-12 1994; 1(abstract PB0491):265. Copyright (c) 1995 - GMHC Treatment Issues. Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+