Subject: BETA (text)

Date: Feb 1 1991 (1794 lines)

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Bulletin of Experimental Treatments

for AIDS

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B-E-T-A (Bulletin of Experimental Treatments for AIDS)

*****

OPINION

COMBINATION THERAPY:

A NEW ERA

IN HIV THERAPEUTICS

Ronald A. Baker, PhD

Dr. David Kessler, the new Commissioner of the U. S. Food and

Drug Administration (FDA), has publicly endorsed a plan that

would allow "conditional" approval of certain drugs for AIDS and

cancer, once they have met safety standards. The FDA now appears

ready to approve ddI and ddC as prescription drugs for HIV

infection some time in the next few months.

Approval of 1 or both of these antivirals will mark the

beginning of a promising new era in the treatment of HIV

infection, characterized by the wide spread use of combination

antiviral therapy. Preliminary data from studies of people using

combined doses of AZT plus ddC or ddI suggest that combination

therapy is more effective, longer-lasting and less toxic than

treatment with AZT alone.

The only serious adverse effect from ddC is a dose-related

peripheral neuropathy, which clears when the drug is stopped.

ddI can also cause a mild, but reversible peripheral neuropathy.

The most serious potential side effect of ddI is pancreatitis, a

condition that can be life-threatening, but which usually

resolves after stopping the drug. The incidence of acute

pancreatitis among ddI clinical trial participants is low, less

than 3%.

In short, the potentially harmful side effects of both ddI and

ddC are well recognized, and several studies have shown that

these drugs are relatively safe when administered and monitored

carefully. In addition, combination treatment with AZT plus ddC

or ddI allows use of low doses of each drug, thus minimizing

toxic side effects and delaying the development of rug-resistant

HIV strains.

Approval of ddI and ddC will most immediately benefit the

thousands of people who are intolerant to or have failed on AZT,

the only drug licensed by the FDA to treat HIV infection. Recent

studies have shown clear benefits to many PWA and PWARC using ddI

or ddC: sustained T-helper cell increases, significant decreases

in p24 antigen levels and improved quality of life (e.g. weight

gain and improved functioning).

The greatest beneficiaries of FDA approval of ddI and ddC may

be people in early stages of HIV disease. Individuals who start

combination antiviral therapy with their immune systems in-tact

may stay healthy longer than is now possible with AZT

monotherapy. The early use of combination antiviral therapy

could slow disease progression for an extended time, possibly

long enough for scientists to develop more effective and less

toxic drugs.

In the future, new classes of antiviral compounds (non-

nucleoside analogs) will become important in the treatment of HIV

infection. This new generation of anti-HIV compounds is already

under study, and the FDA appears ready to establish more flexible

approval criteria, including laboratory markers such as T-helper

count and beta-2 microglobulin level, as well as clinical signs

such as improved quality of life. Until these new agents are

tested and approved, however, combination therapy using ddI, ddC

and AZT offers the current best chance to exert major effects

against HIV.

Petitions urging a speedy decision on approval of ddI and ddC

have been sent to the FDA by Project Inform, ACT/UP Golden Gate,

the Community Consortium of Physicians in San Francisco and B. A.

P. H. R. (Bay Area Physicians for Human Rights). These medical

and treatment activist organizations, supported by dozens of AIDS

agencies and individual researchers and physicians, petitioned

the FDA in December 1990 to direct the drug companies to submit

licensing applications for ddI and ddC by February I, 1991.

Furthermore, they petitioned the FDA to reach a decision on

approval of ddI and ddC by March 1,1991.

These urgent requests for a greatly accelerated review of ddI

and ddC have not been granted. We can only hope that the FDA and

the drug manufacturers were unable to meet these time lines

because of legitimate constraints. As the new chief of an

understaffed, underfunded and scandal-ridden agency, Dr. Kessler

may need more time to get his house in order. Because the

proposed reforms will radically change the FDA drug approval

process, powerful interest groups, both within and without the

agency, may stridently oppose many key reform recommendations.

This situation may contribute to delays in decision making and

implementation of the reforms.

Unfortunately, time is running out for people with HIV

disease, especially for those who require an immediate

alternative to AZT and cannot meet the rigid restrictions of the

expanded access programs. Timely approval of ddI and ddC is in

the best interests of a/I people taking AZT, regardless of their

stage of infection, since AZT monotherapy at best offers only a

transient slowing of disease progression.

It is an historic moment. Let us hope that the HIV positive

community and its supporters can soon celebrate FDA approval of

ddI and ddC and the beginning of a promising new era in the

treatment of HIV disease. Without access to these drugs,

patients and caregivers remain mired in a dark age filled with

the gloomy expectation of inevitable decline.

*****

Vaccines for HIV

Bill Hayes

1990 marked a fundamental change in opinion among researchers

from "if" an HIV vaccine could be developed to "when." With 7

possible vaccines now in human testing, skepticism about

producing vaccines for both the uninfected and those infected

with HIV has given way to cautious optimism. Many obstacles

remain, yet there are encouraging signs: none of the clinical

trials of HIV vaccines under way have yet reported toxic side

effects; there are indications in animal studies and in

preliminary data from human testing that several vaccines may

boost antibodies and, more significantly, may enhance T cells.

Some scientists estimate that a meaningful vaccine breakthrough

could occur within the next two years.

Vaccines: Immunization

or Immunogen

Vaccines work by mimicking a disease-causing organism, thus

stimulating the body's immune system against it. This immune

response could be a humoral response-production of antibodies to

control or neutralize the organism-or a cellular response, which

would mobilize white blood cells such as macrophages and natural

killer T-cells to attack it.

The term vaccine is broadly used to describe three different

approaches being used against HIV: immunization of those

uninfected; protection of perinatal transmission from infected

mother to fetus; and prevention of disease progression in people

a1ready infected with the virus. The premise of the latter, a

"therapeutic" or "immunogen" vaccine, is not to eliminate the

virus from the body entirely, but to render it dormant

permanently, effectively making the latency period of the virus a

lifelong state.

At present, there is more success, and activity, with

therapeutic vaccines than those to prevent primary infection, for

several reasons. The first is rather practical: a vaccine to

prevent primary infection will take much longer to test due to

the difficulties in establishing efficacy and the long latency

period of HIV. I other words, a vaccine's success or failure is

more immediately evident in those already infected.

Further, some feel the virus is s complex that a single

vaccine to immunize against HIV infection may be impossible-a

"cocktail" of treatments for the various strains of the virus may

be necessary. By first learning how to stop the activity of

these various strains in infected subjects, researchers will then

know how to immunize the uninfected population against them.

Most studies have found diminished benefits from therapeutic

vaccines in people who already have ARC or AIDS. But it is hoped

that therapeutic vaccines in combination with antivirals like

AZT, ddI, ddC or alpha interferon might help people at all stages

of disease progression.

Animal Research

FDA regulations stipulate that animal research must precede

testing of potential HIV vaccines in humans. Only chimpanzees

can be infected with HIV, yet they never develop full-blown AIDS,

making leaps from chimp data to humans problematic. Further,

because chimps are an endangered species, few are available, and

they are expensive. Rhesus monkeys, on the other hand, are

plentiful, relatively inexpensive, and easier to handle. Though

they do not react to HIV, they can be infected with simian

immunodeficiency virus (SIV), a retrovirus similar to HIV that,

to a degree, can be used as a model for human HIV infection.

A more recent development in animal models is the creation

through genetic engineering of an immunodeficient mouse, called

the SCID-hu (Severe Combined Immune Deficient) mouse, that will

not reject human white blood cells, and can therefore be infected

with HIV. The development of these altered mice, which are

neither as scarce nor as expensive as chimpanzees, has vastly

improved the pace of vaccine research.

Different Vaccine

Approaches

Thirty possible approaches for developing a safe and effective

vaccine against HIV are now under scrutiny. Some use a whole HIV

virus, which is "killed" by chemicals or radiation (the technique

used to create the polio vaccine). Others use a "recombinant"

approach, which isolates a portion or "subunit" of HIV from the

outer surface (the envelope) or the core of the virus by genetic

engineering. A related approach uses "virus-like particles" that

are created synthetically in the laboratory.

Certain recombinant vaccines incorporate an adjuvant, a

compound that improves the body's response to the vaccine.

Adjuvants are needed because proteins of HIV, which constitute

the majority of experimental vaccines developed so far, may not

elicit an immune response that is strong enough to confer

protection

Along with advances, scientists are encountering drawbacks in

their vaccine approaches. There is some concern that vaccines

using a whole virus could infect the uninfected, should a single

virus slip through the purification process. In those whose

immune systems are already compromised, boosting immunity might

boost HIV replication rather than suppress it. Finally, because

HIV mutates so rapidly, a vaccine must target a wide range of HIV

strains.

The 7 possible vaccines described below are listed

alphabetically by the company that holds the patent.

Bristol-Myers Squibb

Bristol-Myers Squibb of New York City is developing a

recombinant vaccine made by inserting fragments of gp160, a

protein on the envelope of the virus, into live but weakened

smallpox virus, which itself may provide an additional boost to

the immune system. (A similar vaccine has been developed by Dr.

Daniel Zagury -- see "Vaccine Research Abroad" below.) The

vaccine is being evaluated in uninfected people in Phase I safety

trials conducted by the National Institute of Allergy and

Infectious Diseases (NIAID). The company also has conducted a

toxicity study of its vaccine in combination with a booster shot

of the MicroGeneSys formula, and reports no side effects.

Chiron Corporation

Chiron Corporation of Emeryville, California, has begun Phase

I safety trials involving uninfected people of a recombinant

vaccine that also uses the gp160 protein. It is described as a

"pi 20" vaccine because the "g" or sugar molecule has been

removed. In addition, Chiron uses what it describes as a highly

potent synthetic adjuvant called MTP.

An earlier version of this vaccine was used in a small Swiss

study on uninfected men, with no side effects observed. Four men

involved in the study showed an immune response against the

virus. Chiron hopes to begin Phase I safety trials of a new

formulation for HIV negative subjects sometime this year.

Genentech, Inc.

Genentech's recombinant vaccine is based on an exact synthetic

copy of a portion of the HIV virus' envelope called gp120.

Researchers theorize that the immune system will spot the

injected bit of copied virus and battle the infection anew,

ultimately arresting disease progression in people who are

infected with HIV. Shots for rabies work in a similar fashion.

The South San Francisco company announced in November 1990

that it had begun Phase I safety studies of the vaccine at Walter

Reed Army Institute of Research in Washington, D. C. The 10-month

study involves 55 HIV positive military volunteers, both men and

women.

Genentech is enthusiastic about the potential vaccine because

it produced a powerful immune response in chimpanzees. The two

vaccinated animals reportedly remain uninfected more than a year

after exposure to the virus. The company is currently evaluating

the possibility of a separate human pilot study to test

recombinant gp120 as a potential vaccine to immunize uninfected

individuals.

Immune Response

Corporation

Perhaps the most highly publicized vaccine research has been

conducted by Immune Response Corporation of San Diego, which is

headed by Jonas Salk, who developed the first widely used polio

vaccine. Alone among potential vaccines, the "Salk Immunogen"

consists of killed HIV -- a whole virus with its genes scrambled

and the envelope protein gp120 removed. Salk hopes this killed

virus will act as a harmless decoy, tricking the body into

mounting a more aggressive response to HIV.

While Salk's critics contend that a killed-virus vaccine is

too blunt an instrument against so sophisticated an invader, Salk

adheres to his belief that a vaccine will have a greater chance

if it contains a wide spectrum of viral proteins, not just a

single fragment.

Research has been underway in HIV positive human volunteers

since November 1987. Early safety trials indicated that the

vaccine may have bolstered the volunteers' immune systems, but

results were not conclusive. Its efficacy will be clearer after

a current trial involving 100 people in early stages of HIV

infection is completed late this year. This trial will be

followed by a 3-year study involving 650 people who are infected

with HIV. Salk is hoping eventually to try the vaccine on

uninfected people.

IMMUN0-Ag

IMMUNO-Ag, a potential vaccine developed by scientists from

NIAID, the National Cancer Institute and IMMUNO-Ag of Vienna,

Austria, consists of gp160, a genetically engineered combination

of a protein carbohydrate termed a glycoprotein. Its composition

and structure precisely mimic the 3-dimensional shape of one of

the glycoproteins that forms part of the HIV envelope. Research

with other diseases in developing vaccines based on viral protein

has shown that matching the exact molecular shape of the protein

seems to be important. Recognizing the unique shape of the

harmless protein, it is theorized, the body will produce a strong

immune response against HIV.

Phase I safety trials involving 60 uninfected volunteers over

approximately 5 years, was announced by the NIAID in November

1990.

In earlier tests using IMMUNO-Ag, 2 versions of the potential

vaccine have been injected into 4 chimpanzees and "challenged"

with doses of pure HIV virus 100 times more than the amount

needed to cause infection. The vaccine prompted an immune

response in all the animals, and one of the chimpanzees has now

been free of HIV infection for nearly 3 years, according to the

company.

MicroGeneSys, Inc.

MicroGeneSys, of West Haven, Connecticut, is developing a

vaccine for both the uninfected and those who already have HIV.

The recombinant vaccine, produced by genetic engineering,

contains HIV envelope protein, gp160. The company says that its

formula seems to attack a wide range of strains, combats both

free virus and infected cells, and doesn't damage healthy cells

that have picked up harmless stray viral proteins. Like all

vaccines composed of viral particles, this one can't cause

infection.

In the first completed clinical trial of a potential HIV

vaccine, the MicroGeneSys formula was found to be safe after 2

years of study in 72 uninfected volunteers. No unusual reactions

were found, according to a January 1991 report in the Annals of

Internal Medicine. Researchers said that in general, the immune

response among trial volunteers were considerably weaker than

those seen after naturally occurring infection with HIV.

MicroGeneSys has begun a new round of tests, injecting higher

doses of the vaccine in 72 people. Hopes are that this dosage

will stimulate a stronger immune response.

MicroGeneSys is now finalizing plans for an efficacy trial.

Further studies are being planned to test the vaccine on HIV

positive pregnant women and on patients taking AZT. The FDA

recently granted approval for Phase I safety testing of a second

MicroGeneSys vaccine based on the core protein p24. If it

passes, the company hopes to run a study combining the 2

vaccines.

Viral Technologies, Inc. (CEL-SCI Corporation and Alpha-I

Biomedicals, Inc.)

San Francisco General Hospital announced in December 1990 that

would begin Phase I safety testing of a vaccine developed by

Viral Technologies, Inc., a joint venture of Cel-Sci Corporation

of Alexandria, Virginia, and Alpha-I Biomedicals, Inc.,

Washington, D. C.

The vaccine, which is intended to protect uninfected people,

is made from a synthetic form of the pI 7 protein found in the

core of the HIV virus. This protein is common to all strains of

the virus and would not be vulnerable to the usual genetic

mutation that affects the usefulness of other vaccines.

The company is encouraged about the vaccine's prospects. In

earlier human studies, the vaccine stimulate production of CD8+

cells, which re able to attack HIV-infected cells a~~~~0~g~0~~

the body, not just in the immune system. This is significant,

because infected cells are factories for the production of new

viruses. In order to stabilize the disease, infected cells need

to be destroyed before the virus overcomes the immune system.

Furthermore, the presence of CD8+ killer T-cells has been found

to be associated with a greater longevity of HIV-infected people.

Ethical and Scientific

Questions

The development of 1 or more successful vaccines against HIV

appears to be only a matter of time. Many critical scientific

and ethical questions related to vaccine development, however,

remain unanswered. Can a single vaccine protect against the many

varied strains of HIV? Will uninfected volunteers who test HIV

positive following vaccination encounter discrimination? Will

"world rights" be guaranteed for all HIV-infected persons to

access a successful vaccine?

Sources

AIDS vaccine outlook brighter, Koff reports. Dateline: NIAID.

September 1990. pp. 7-8.

Altman L. AIDS Vaccine found safe in human testing. The New York

Times, January 15, 1991. p. C-19.

Cohen J. AIDS vaccine conference: is more better? Science

250:19-20. October 19,1990.

Glass M et al. Second annual meeting of the National Cooperative

Vaccine Development Group for AIDS. Vaccine 8:413-414. August,

1990.

Johnson G. Man with a mission. The New York Times Magazine.

November 25, 1990. pp. 57-61.

Lehrman S. AIDS research turns optimistic. San Francisco

Examiner, November 28, 1990. p. B-1.

Massa R. So many theories, so little time. The Village Voice.

October 23,1990. p. 28.

New AIDS vaccine enters clinical testing. NIAID AIDS Agenda.

November 1990. p. 5.

Nobile P. A shot in the dark. Tire Village Voice, October

23,1990. pp. 24-36.

Perlman D. First human tests of a new AIDS vaccine. Sari

Francisco Chronicle, November 21,1990. p. A-2.

Report documents key immune response to AIDS vaccine. CDC AIDS

Weekly, September 24, 1990. p. 3.

Thorn M. Vaccine development. Treatment Issues 4(6):5-7. August

30, 1990.

*****

RESEARCH NOTES

Ronald A. Baker, PhD

0-75875: A Promising

New Antiviral

In order to replicate, HIV must produce an enzyme called

protease. Researchers from Upjohn Pharmaceuticals have prepared

a new compound, U-75875, that inhibits the processing of the HIV

protease in an essentially irreversible manner. This unique

accomplishment has generated intense interest in U-75875, even

though the drug is still in preclinical testing. AZT and other

drugs can also block HIV replication, but when these drugs are

removed from cell cultures with HIV, the virus again starts to

replicate.

Researchers working at NIAID laboratories produced U-75875 by

modifying the structure of another protease inhibitor, U-81749.

The resulting new compound is a much-improved version of its

predecessor. U-75875 completely blocked HIV replication in

cultures of human blood cells. Virus particles produced in the

presence of the drug were immature and non-infectious and

contained little or no p24 antigen and a greatly reduced amount

of the reverse transcriptase enzyme (RT).

U-75875 appears to be as potent as AZT in blocking HIV-1

replication in human blood cells and also inhibits HIV-2 and

simian immunodeficiency virus (SIV) proteases. The ability of U-

75875 to block replication of 2 strains of HIV and SIV adds

significantly to its therapeutic potential as a treatment for HIV

disease.

The strong anti-HIV activity of U-75875 was demonstrated in

spreading infection experiments. In cell cultures,

concentrations of the drug significantly lower than those

required for toxicity to human blood cells completely blocked the

spread of HIV for at least 1 month.

Animal studies suggest that concentrations of U-75875 higher

than those necessary for anti-HIV activity ill vitro can be

maintained for several hours without any signs of toxicity.

The NIAID and the FDA recognize the potential of this new

compound and are moving rapidly, in cooperation with Upjohn, to

begin Phase I human trials of U-75875. In addition to Upjohn,

other companies, including Hoffman-La Roche, Merck Sharp and

Dohme, Abbott and SmithKline, are testing other protease

inhibitors as anti-HIV agents. This new class of antivirals

(protease inhibitors) works differently against HIV than

nucleoside analogs like AZT, ddC and ddI, and may be a

significant advance in the search for compounds that inhibit HIV

replication without causing toxic side effects.

The Early Promise of

BI-RG-587

This new compound from Boehringer Ingelheim Pharmaceuticals

disables HIV in laboratory studies by blocking reverse

transcriptase (RT), an enzyme whose production is necessary for

HIV to replicate. AZT also blocks the RT enzyme but causes

unwanted side effects when the drug is absorbed by healthy cells.

BI-RG-587, however, acts only on HIV-infected cells, without

disrupting healthy, uninfected cells.

In animal studies, the new antiviral did not suppress the bone

marrow, and it crosses the blood-brain barrier even more

effectively than AZT. BI-RG-587 also shows activity against HIV

in lab cultures of blood cells taken from people using AZT.

Some researchers believe this compound could be important

because of its ability to inhibit several strains of HIV-1 at low

doses. The compound is also relatively simple to synthesize and

manufacture. A NIAID committee has already given BI-RG-587 a

high priority rating, which means that Phase I human trials of

the drug will probably begin soon. Only human trials can

determine if the new compound is as promising as the early

laboratory and animal studies suggest.

MAP 30: Momordica

Anti-H[V Protein

Researchers at New York University Medical Center have

produced a new protein compound in the laboratory that inhibits

HIV replication and direct cell-to-cell infection (syncytia).

The protein compound, MAP 30, has been isolated and purified from

the seeds and fruits of Momordica charantia, a medicinal plant

commonly used in China for its antiviral and anti-tumor activity

(see photographs). Momordica charantia is not native to the U.

S.

Proteins isolated from the seed extracts of the plant also

inhibit replication of the herpes simplex virus (HSV-1) and the

poliovirus I. Fruit extracts of Momordica charantia have been

shown to inhibit cancer in rats and lymphoma in mice.

Significantly1 the compound does not appear toxic to uninfected

cells. Investigator Sylvia Lee-Huang told BETA that the NIH will

soon announce results of preclinical testing of MAP 30 and hopes

to find a sponsor to further investigate the anti-HIV potential

of the compound.

-----------------------------------------------------------

ACTG 106

ARM AGENT ROUTE DOSE/FREQUENCY

---------------------------------------------------

AZT oral 200 mg q8h (every 8 hours)

1 ddC oral 0.750 mg q8h

---------------------------------------------------

AZT oral 200 mg q8h

2 ddC oral 0.375 mg q8h

---------------------------------------------------

AZT oral 100 mg q8h

3 ddC oral 0.750 mg q8h

---------------------------------------------------

AZT oral 100 mg q8h

4 ddC oral 0.375 mg q8h

---------------------------------------------------

AZT oral 50 mg q8h

5 ddC oral 0.750 mg q8h

---------------------------------------------------

AZT oral 50 mg q8h

6 ddC --- NONE

===================================================

AZT and ddC

Combination Therapy

Preliminary results of a Phase I/II study of 56 people taking

low doses of AZT and ddC for 52 weeks suggest the combination is

more beneficial than either drug used alone. Researchers are

comparing the effect of 6 different treatment regimens, 5 of

which combine ddC and AZT. In the sixth arm, participants take a

low dose (50 mg) of AZT alone every 8 hours. Principal

Investigator Dr. Margaret Fischl told BETA that, used alone, this

dose of AZT (150 mg/day) appears to be too low to produce

effective anti-HIV activity.

The volunteers all had AIDS and less than 200 T-helper cells

on study entry. The average T-helper count was 70. The dose

regimens in each study arm are outlined below. This is an

ongoing study (ACTG 106) and no firm conclusions can be drawn

from the existing data, but the preliminary findings look

promising. Among people in the combination arms, T-helper counts

rose significantly (average gain of 164) during one year of

treatment, then began to decline, but not below their starting

value. Only 1 patient died and only 4 developed opportunistic

infections during a year of combination therapy1 and these

occurred early, within the first few weeks of treatment,

suggesting that the combination treatment regimen is effective.

Principal Investigators Margaret Fischl and Douglas Richman

have begun an analysis and verification of the study data,

including a report on p24 antigen levels and the issue of drug

resistance. The NIAID is expected to release a full report on

the study sometime in February 1991.

ddI in Children

A study of symptomatic, HIV infected children taking ddI shows

promising results. Forty-three children took ddI at daily doses

of 60, 120,180,360 or 540 mg/m2 of body surface for 24 weeks.

The mean T-helper cell count in 38 of the children increased

from 218 to 327 after 20-24 weeks on ddI therapy. The T-helper

cell improvement was not dose dependent, but the marked

reductions in p24 antigen levels clearly were dose related.

The researchers report that the T helper cell rise with ddI

appears to be more sustained than with AZT. Most of the children

who experienced T helper cell increases after 12 weeks maintained

the increased levels for at least 24 weeks, with a few

maintaining the increases for more than a year. These responses

occurred in children who had never taken an antiretroviral drug

before as well as among those who had previously taken AZT. Two

of the children in the study developed pancreatitis, which

resolved promptly when the ddI was withdrawn.

The researchers emphasized that bioavailability is an

important factor in ddI treatment and that individualized

monitoring and dose adjustments may be important to achieve

optimal anti-HIV activity from ddI therapy.

ddC versus ddI

The first U. S. clinical trials to compare the effectiveness

and safety of ddI and ddC are about to begin. The 2-year study

is planned for 18 sites in 14 cities. Participants must be

either intolerant to or have failed treatment with AZT, have T-

helper counts of 300 of less, or have an AIDS diagnosis.

Exclusion criteria include previous treatment with ddI or ddC

and a history of pancreatitis, peripheral neuropathy,

uncontrolled seizures, excessive alcohol use or heart disease. In

San Francisco physicians may get more information about the trial

by calling the Community Consortium (415-426-9554). For other

trial locations call toll-free 1-800-874-2572.

CD4-IgG Disappoints

Genentech

Genentech recently announced that it is stopping studies of

CD4-IgG in adults with AIDS, while continuing research into the

drug's potential for blocking transmission of HIV from infected

mother to fetus. Although CD4-IgG appears safe, it has shown no

effectiveness in early human studies.

Researchers produced the drug by combining CD4 with

immunoglobulin-G (IgG), an artificial human antibody which they

hoped would stimulate an immune response in people with HIV

disease. It didn't.

Imuthiol (DTC): Antiviral or Immunomodulator?

Imuthiol may have both anti-HIV and immunomodulating

properties. The mechanism of the compound's action is not

clearly understood, although several studies in the United States

and Europe suggest that Imuthiol may reduce the number of

opportunistic infections in PWAs and delay HIV disease

progression.

The FDA, however, disputed the manufacturer's data and denied

its application to make the drug available in an expanded access

program. The drug patent belongs to a French company, Pasteur

Merieux.

DTC is one of the by-products of the breakdown of the drug

Antabuse, an anti-alcohol treatment available by prescription in

the United States. Side effects from Antabuse (and DTC) include

metallic taste, abdominal discomfort, fatigue, nausea, and

reduced mental alertness. If alcohol is ingested while on the

drug, severe nausea, vomiting and low blood pressure may result.

The November 1990 issue of Treatment Issues features a lengthy

article on the history of DTC, its prospects for new U. S. trials

and its recent approval as an AIDS/HIV treatment in New Zealand.

TLC-G-65: A New Drug

for MAI

The Liposome Company has begun Phase II trials of a new drug,

TLC-G-65, for the treatment of MAI, a life-threatening

opportunistic infection found in 30 - 50% of all PWA. Currently

there is no approved treatment for MAI, a disease that produces a

wasting syndrome accompanied by high fever, night sweats,

abdominal pain, diarrhea and weight loss. MAI also frequently

causes a severe anemia that may require frequent blood

transfusions.

MAI is difficult to treat, in part because it is an infection

inside affected cells. Conventional antibiotics usually don't

work well against MAI because they cannot penetrate into the

infected cells in concentrations high enough to kill the

infection.

TLC-G-65 is a new compound composed of an antibiotic enclosed

in liposomes, microscopic spheres surrounded by a fatty (lipid)

membrane. The cells in which MAI reside recognize liposomes as

foreign particles and "swallow" them. Once inside the infected

cell, the membranes of the liposomes breakdown, releasing the

antibiotic, which then kills the infected cell.

In laboratory studies, TLC-G-65 is highly effective against

MAI. In Phase I human trials the drug showed l no significant

toxicity. Phase II dose ranging and efficacy studies are now

under way at Parkland Memorial Hospital in Dallas, Texas.

Physicians interested in enrolling patients in upcoming Phase

II/III clinical trials may call the Liposome Company at 1-609-

452-7060.

The company has published a free informational booklet on MAI

in a question and answer format for interested patients.

Physicians or clinics who want single or multiple copies of the

booklet may also call the company at the number above.

Amphotericin B and

Fluconazole for

Cryptococcal Meningitis

Since the FDA approved fluconazole (Diflucan~) to treat

cryptococcal meningitis (CM) in January 1990, there has been

considerable controversy about its effectiveness compares to

amphotericin B, the traditional treatment of choice for the

disease. Amphotericin B, unfortunately, causes significant

toxicity, whether used alone or in combination with 5-

flucytosine. The search for a less toxic, but effective

alternative led to the development and eventual approval of

fluconazole. An article in AIDS Clinical Care (January 1991) by

Dr. John Stansell of San Francisco General Hospital reviews the

latest data on these 2 drugs and makes recommendations about how

to best use both treatments in PWA with cryptococcal meningitis.

A large study (ACTG 059) by the NIAID comparing the efficacy

of the 2 drugs has yielded important findings. The survival rate

among the 99 evaluable patients on either drug was approximately

the same (23%). Fluconazole appears to offer no more benefit

than amphotericin B (with or without 5-flucytosine) to people

with CM who are at high risk for early deterioration and death.

Dr. Stansell defines patients at high risk as those with altered

mental status and a CSF cryptococcal antigen level greater than

1:256.

For this patient group, the recommendation is to begin

treatment with amphotericin B (0.5 to 0.8 mg/kg/ day) and 5-

flucytosine (100 mg/kg/ ay) until the patient is stable or

improves, followed by treatment with fluconazole (400 mg/day),

for a total of 12 weeks of primary therapy. Physicians will need

to use their best judgement about the total dose and length of

treatment with amphotericin B and 5-flucytosine, based on the

individual's response to the therapy.

For people with CM who are at low risk (normal mental status

and CSF cryptococcal antigen less than 1:256) for early

deterioration and death, Dr. Stansell says physicians can

consider treatment with fluconazole (400 mg/day), without an

initial course of amphotericin B. In the NIAID study, the

patients at low risk did well on either drug as initial therapy.

Regardless of the primary treatment, all PWA with CM must take

lifelong suppressive therapy to prevent relapse of the disease.

Another NIAID study (ACTG 026) has shown that fluconazole (200

mg/day) is superior to amphotericin B as suppressive therapy and

is considerably less toxic. Dr. Stansell therefore recommends

that all patients who complete initial treatment with either drug

use fluconazole (200 mg/day) as maintenance therapy.

Amphotericin B Lipid Complex (ABLC) for Cryptococcal Meningitis

ABLC is a new drug formulated with amphotericin B enclosed in

a lipid complex in much the same manner as the drug design for

TLC-G-65 (see above). Bristol-Myers Squibb is conducting Phase

II trials of ABLC in 120 people with cryptococcal meningitis at

15 U. S. medical centers. Interested physicians and patients may

call the NIAID clinical trial Hotline for trial location sites

and entry criteria (1-800-874-2572).

ABLC could eventually become an important drug for people with

cancer or AIDS. In laboratory and animal studies, ABLC has 8 -

20 times less toxicity than the standard form of amphotericin B.

This "safety margin" may allow use of higher doses of ABLC than

are possible with amphotericin B alone.

Bristol-Myers Squibb is also planning trials of ABLC in people

with disseminated candidiasis, invasive pulmonary aspergillosis

and other fungal infections common in cancer and organ transplant

patients. For more information, call Bristol-Myers Squibb at 1-

609-921-5615.

566C80 for PCP

As reported in earlier issues of BETA (April 1990, August

1990), 566C80 is a promising new treatment for Pneumocystis

carinii pneumonia (PCP). In animal studies, the drug shows

potent activity against the Pneumocystis organism and may be able

to completely eradicate it. 566C80 also has an extremely low

toxicity profile. In Phase I safety and dose ranging studies,

only 1 person experienced adverse side effects that included

nausea, vomiting, headache and rash. The drug is taken orally,

which makes it convenient and easy to administer.

A Phase I/II study by the NIAID has enrolled 22 people to test

the safety and efficacy of 566C80 in people with mild to moderate

PCP. Burroughs Wellcome is conducting a Phase III trial comparing

the drug's effectiveness to one of the standard PCP treatments,

TMP-SMX (Septra).

Because of the drug's promise in early studies, trials of

566C80 as a prophylactic treatment for PCP are also under way.

The drug's effectiveness as a prophylactic will be tested in

comparison to both aerosolized pentamidine and Septra. For more

information about open trials of 566C80, call 1-800-874-2572.

566C80 for Toxoplasmosis

In addition to its potential as a potent anti-PCP agent,

566C80 also has shown strong activity against toxoplasmic

encephalitis in mice. An oral dose of 100 mg/kg/day for 10 days

protected 100% of mice against death from infection with 6

different strains of Toxoplasma gondii, the microorganism that

causes toxoplasmosis, including the most virulent strain (RH).

The NIAID is now recruiting for a safety and efficacy trial of

the drug for PWA with toxoplasmic encephalitis who cannot

tolerate or who have failed 011 standard therapy for the disease.

Conventional treatment for toxoplasmosis is pyrimethamine in

combination with sulfadiazine, a regimen that can cause adverse

side effects, including bone marrow suppression and a severe skin

rash. If left untreated, infection with Toxoplasma gondii may

lead to seizures, coma and death.

Researchers have developed a new laboratory method for

evaluating treatments for the cyst form of Toxoplasma gondii and

have used it to examine 6 drugs: pyrimethamine, sulphadiazine,

5-fluorouracil, clindamycin, azithromycin and 566C80. Cysts were

treated with all 6 drugs separately for 1 - 3 days, then injected

into mice.

Only those mice treated with 566C80 survived. No cysts were

found in the brains of these mice and their blood tested negative

for Toxoplasma gondii. These laboratory data suggest that 566C80

may work as a prophylactic treatment for toxoplasmosis, as well

as a therapy for the acute form of the disease.

Trimetrexate for PCP

and Toxoplasmosis

Trimetrexate was originally developed as an anti-cancer agent.

More recently, the drug has been available in combination with

leucoverin as a salvage treatment for PCP in people who fail on

standard treatments: TMP-SMX (Septra, Bactrim), pentamidine or

Dapsone. Physicians may call 1-800-537-9978 for information

about enrolling patients in a Treatment Investigational New Drug

Protocol (Treatment IND).

The U. S. government recently ; awarded exclusive patent

rights for trimetrexate to U. S. Bioscience, Inc., which plans to

apply for a New Drug Application (NDA) early this year for the

treatment of PCP. In laboratory studies, trimetrexate has also

shown activity against Toxoplasma gondii, the organism that

causes toxoplasmosis.

GM-CSF Near

FDA Approval

An FDA advisory committee has recommended approval for

granulocyte macrophage-colony stimulating factors (GM-CSF)

produced by 3 different companies. These immunomodulating drugs,

developed by Amgen, Immunex and Hoechst-Roussel Pharmaceuticals,

increase the number of white blood cells that the body uses to

fight off infections. The availability of GM-CSF following FDA

approval will be extremely helpful to cancer patients undergoing

chemotherapy, surgery or bone marrow transplants and to PWA with

depleted white blood cell counts resulting from AZT use.

These immunomodulating drugs are expensive: U. S. sales are

expected to reach $400 million a year within 3 years. Sales

worldwide may reach $1 billion annually, according to some

analysts. FDA approval means that many insurance carriers will

pay for at least part of the drugs' cost.

The FDA has also approved Ortho Biotech's Procrit~'

(erythropoietin), a genetically engineered form of a natural

hormone that helps to reverse anemia in some PWA. The cost of the

drug for a person with AZT-related anemia is high, perhaps $6,000

$8,500 a year for many patients.

Autologous CD8+

Infusion

This therapy consists of isolating CD8+ T-lymphocytes (T-

suppressor cells) from an HIV infected person, then stimulating

these cells to replicate outside the body by using cell-

activating proteins. The increased number of CD8+ cells are then

reinfused into the patient. The rationale for this treatment

rests on laboratory studies that show CD8+ cells can suppress HIv

in the blood cells of PWA.

Four people have enrolled in a 6-month ACTG Phase I dose-

ranging study of autologous CD8+ infusion plus interleukin-2

(IL-2) infusion at the University of Pittsburgh. IL-2 is an

immuno-modulating drug that produces a proliferation and

expansion of activated T-lymphocytes (white blood cells). The

first person to complete the protocol gained weight and reported

increased energy and sense of well-being. No toxicities have

been reported, except for flu-like symptoms during the IL-2

infusion.

Sandostatin for HIV-Related Diarrhea

Twenty U. S. trial sites will evaluate the effectiveness of

Sandostatin (octreotide acetate) in managing HIV-related

diarrhea. The drug is already used to control diarrhea in cancer

patients with intestinal tumors. Treatment with Sandostatin in

these patients has resulted in weight gain and restoration of

electrolyte balance. The drug's effect on HIV-related diarrhea

is unknown.

Two different clinical trials will test the effectiveness of

the drug in 200 PWA whose diarrhea has not been controlled by

other treatments. The first trial (4 weeks) is a dose ranging

study that also will determine how many PWA with significant

diarrhea respond to Sandostatin. Patients will self-administer

the drug by subcutaneous injection.

The second trial will determine the relapse rate, if any,

among people enrolled in the earlier trial who responded to

treatment with Sandostatin. For information about trial sites

and entry criteria, call Sandoz Pharmaceuticals' toll-free

hotline at 1-800-732-8096, Monday - Friday, 9 AM - 5PM Eastern

Standard Time.

Sandostatin is a synthetic form of somatostatin, a naturally

occurring hormone found in the brain, gastrointestinal tract and

other organs. Like somatostatin, Sandostatin inhibits bowel

secretions that can cause diarrhea. However, the drug is more

potent and longer acting than the natural hormone, according to

Sandoz officials.

HIV-related diarrhea can be caused by a variety of organisms,

including parasites, bacteria and viruses. Cytomegalovirus

(CMV), Mycobacterium avium intercellulare (MAI or MAC) and

cryptosporidium can cause severe diarrhea and wasting. These

infections are also often unresponsive to conventional

treatments. HIV specialists are anxious to find effective

therapies to prevent diarrhea that produces significant weight

loss and weakened nutritional status in people with HIV disease.

Bleomycin for Kaposi's Sarcoma

Bleomycin, a chemicotherapeutic drug, appears to be a safe and

reasonably effective treatment for HIV-related Kaposi's sarcoma

(KS). In a recent study, 60 people with KS associated with

systemic symptoms and/or T-helper cell counts below 400 received

either intramuscular bleomycin (5 mg/day for 3 days every 2 or 3

weeks) or intravenous infusion of the drug (6 mg/m3/day for4 days

every 4 weeks). There were 30 people in each treatment group.

Twenty-nine patients (48.3%) showed a partial response to

treatment as early as the first course of treatment and 20 of

them had responses that lasted 8 to 56 weeks. The mean duration

of therapy was 5 months. Thirteen patients showed no benefit

from the bleomycin treatment. Before developing KS, 8 of these

13 people were diagnosed with toxoplasmosis and treated with

pyoplasmosis rimethamine and sulfadiazine, a regimen that may

have adversely affected their response to bleomycin.

The researchers conclude that bleomycin causes minimal side

effects at the doses studied and produces a greater response rate

for KS than alpha interferon used alone or in combination. Based

on their experience in this study, the investigators recommend

intramuscular injection over I. V. infusion of bleomycin, since

the former is more convenient and less costly than the latter and

produces the same response rate.

Condylox for External

Genital Warts

The FDA has approved Condylox, a topical solution of .5%

podofilox, for treatment of genital warts. The new drug is the

only patient-applied therapy available for this sexually

transmitted disease. Human papilloma virus (HPV), the virus that

causes genital warts, may also play a role in the development of

cervical cancer in women.

Patients apply Condylox 2 times a day for 3 days, then stop

treatment for 4 days. Genital warts often recur, despite

treatment with Condylox or other agents, necessitating repeated

treatment regimens.

There are no data comparing the effectiveness of Condylox to

other therapies for genital warts, such as laser surgery,

cryosurgery (freezing) or injection with alpha interferon. All

these treatments must be performed by trained personnel in a

physician's office or clinic.

Doxycycline for Chlamydial Infections

Monodox, a new oral form of the antibiotic doxycycline, has

been approved for treatment of chlamydia, the most common

sexually transmitted disease (STD) in the U. S. Left untreated,

chlamydia may cause infertility in women with the infection.

Studies of Monodox by its manufacturer, Oclassen Pharmaceuticals,

suggest the drug produces fewer side effects than other currently

available treatments for chlamydial infections.

Clotrimazole for Vaginal Candidiasis

Gyne-Lotrimin (clotrimazole) has been approved as an over-the-

counter drug for the treatment of vaginal candidiasis, an

infection that can occur in women who are HIV positive or HIV

negative. In women who are HIV negative, vaginal candidiasis may

result from a variety of causes, including pregnancy, the use of

antibiotics or oral contraceptives. Among women who are HIV

positive, this fungal infection may occur as a result of the

immunosuppression caused by HIV infection.

Gyne-Lotrimin is the first over-the-counter medication

approved by the FDA to treat vaginal candidiasis. It became

available as a prescription drug in 1978.

Peridex as Prophylaxis for

Oral Candidiasis

Researchers are actively recruiting patients for a multicenter

trial to evaluate the effectiveness of Peridex rinse in

preventing or delaying oral candidiasis (thrush) in people with

HIV disease. To be eligible, patients must have had clinically

diagnosed oral candidiasis within the last 3 months. This is a

6-month, Phase III trial. In San Francisco, call Dr. Caroline

Dodd at UCSF (415-476-1690). For other trial locations,

telephone 1-800-874-2574, the toll-free hotline for clinical

trials information.

The active ingredient in Peridex is chlorhexidene gluconate,

an antimicrobial agent that has been studied for over 20 years by

its manufacturer, Procter and Gamble. Peridex is currently an

approved drug, available by prescription, for the treatment of

gingivitis and periodontitis. In laboratory studies,

chlorhexidine shows strong activity against Candida albicans, the

fungus that causes oral candidiasis. If left untreated, the

disease frequently prevents patients from eating, drinking or

taking oral drugs easily. This, in turn, may lead to other

problems for the patient.

Oral Alpha Interferon

A 4-month observational study of low-dose oral alpha

interferon shows no statistically significant changes in T-

helper cell counts among 167 people. SEARCH Alliance, a

community based research group in Los Angeles, conducted the

study. The group did not use Kemron, the form of the drug used

in the African study that generated so much attention last year

(BETA, April 1990).

About 25% of the volunteers in the Los Angeles study had a 10%

increase in their baseline T-helper counts, but this increase is

not considered statistically significant. There were also no

significant changes in the participants' p24 antigen levels. No

toxic side effects were reported by any study subjects.

This was not a controlled trial with standardized dosing or a

placebo arm. Although the study results cannot be relied upon as

proof that low-dose oral alpha interferon is ineffective against

HIV, it does offer valuable, practical information about the

drug's action in 167 people over a 16-week period. For more

information about the SEARCH study, send a self-addressed

envelope and a request to SEARCH Alliance, 7461 Beverly Blvd,

Suite 304, Los Angeles, CA 90036.

There are 2 ongoing studies of low-dose oral alpha interferon

at Mt. Sinai Medical Center in New York.

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End of display

[Copyright Ben Gardiner, 1993, for AIDS Info BBS, San Francisco,

California, U.S.A., 1-415-626-1246, source of this file. Only

non-commercial reproduction is permitted.]

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