TRATTO DALLA CONFERENZA : AIDS/ARC di SINTEL/SINTAGMA

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Titolo:BETA, #7 of 14

injected uninfected subjects with a p24-based vaccine involving a

yeast gene that generates a hybrid version of the protein.

British Biotechnology, which holds the patent, claims this

approach could yield an entirely new and inexpensive method of

producing antiviral vaccines.

Such claims are made for another process in clinical studies

in London. This type of immune therapy involves no portion of

the virus at all. Instead, CD4, the receptor on immune cells

that enables HIV to enter, is injected into mice, who generate

CD4 antibodies. These antibodies are then injected into humans,

generating "anti-idiotypes," or antibodies to antibodies, which

act as decoys, sopping up free virus.

Dr. Daniel Zagury has inoculated infected people in Paris and

in Zaire with gp160 encased in smallpox virus. This vaccine

therapy, the first ill humans, has been used in some patients

since early 1987. Of 6 Paris volunteers who have received the

full regimen-including several boosters and a separate therapy in

which T-cells are removed, stimulated and reinjected-all have

stabilized without signs of toxicity, according to Dr. Zagury.

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).

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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.

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ACTG 106

ARM AGENT ROUTE DOSE/FREQUENCY

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AZT oral 200 mg q8h (every 8 hours)

1 ddC oral 0.750 mg q8h

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AZT oral 200 mg q8h

2ddC oral 0.375 mg q8h

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AZT oral 100 mg q8h

3 ddC oral 0.750 mg q8h

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AZT oral 100 mg q8h

4 ddC oral 0.375 mg q8h

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AZT oral 50 mg q8h

5 ddC oral 0.750 mg q8h

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AZT oral 50 mg q8h

6 ddC --- NONE

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AZT and ddC

Combination Therapy

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

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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-PE Plus AZT or ddI

CD4-Pseudomonas exotoxin (CD4-PE) in combination with ddI or

AZT killed HIV in infected human blood cells, according to

results of a recent laboratory study at the NIAID. CD4-PE is a

hybrid compound that binds to HIV through its CD4 molecule, then

kills HIV infected cells expressing the HIV gp 120 protein. BETA

has reported on earlier studies of CD4-PE's action when used as a

single agent (June 1989 and April 1990 issues).

The NIAID researchers report strong synergistic action against

HIV in all the combinations of CD4-PE with AZT or ddI evaluated.

Untreated blood cells infected with HIV died within 16 days. When

used alone, CD4-PE delayed cell death, but most of the infected

cells eventually died. AZT, when used alone, prevented cell

death until treatment stopped. Then the blood cells died

quickly.

The combination of CD4-PE with AZT prevented cell death, and

when analyzed by PCR 2 weeks after stopping the combination

treatment, the researchers detected no HIV DNA in the blood

cells.

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

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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

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