       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 Los, 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
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