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ANTIVIRALS
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The Delta study, together with the results of ACTG175 and CPCRA 007 help guide the
use of nucleoside analogues. AZT/ddI and AZT/ddc are useful as first line therapy. If treatment is preceded by AZT monotherapy,
then AZT/ddI is also useful but AZT/ddc has limited activity. Importantly, the BW3422502 study (Schooley RT et al. J Infect Dis
.1996) indicates that failure of combinations of ddc or ddI with AZT is generally
due to AZT resistance and not ddI/ddC resistance. It may be useful, therefore, to replace the AZT component in failing combinations
for second line therapy. A clinically proven combination without AZT is ddc + saquinavir, those that show significant viral
load reductions are d4T/ddI, d4T/3TC, d4T/nelfinavir, and other non-nucleoside/protease inhibitor combinations. Choice of first combination may influence benefit of future therapies and should therefore be considered carefully. |
Drugs such as AZT and the 'related' chemicals 3TC, d4T, ddC and ddI need to be converted
to their antiviral form inside cells if they are to work. If these drug are not converted they have no anti-HIV activity.
As treatment with combinations of anti-HIV drugs becomes the standard of care, some researchers are concerned that cells will not
be able to convert all of these drugs into their anti-HIV form.
Researchers in England have been conducting experiments with cells and several drugs
including AZT, 3TC and ddC. They found that when cells were given 3TC and ddC they were unable to convert ddC into its anti-HIV
form. 3TC did not affect the conversion of AZT. The researchers suggested that combination treatment with 3TC and ddC may not
be useful.
REFERENCES:
1. Veal GJ, Hoggard PG, Barry MG, Koo S and other nucleoside analogues for intracellular
phosphorylation. AIDS 1996;10(5):546-548.
Source: TreatmentUpdate 69, Volume 8, no 5 - July 1996; A publication of the Community
AIDS Treatment Information Exchange (CATIE).
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The clinical effects of phosphorylation competition are not known. In the Glaxo Wellcome
CAESAR study adding 3TC to AZT/ddC or AZT/ddI provided similar clinical benefit to adding 3TC to AZT alone. Protease inhibitors
and NNRTIs do not require activation so do not compete at this level. |
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OPPORTUNISTIC ILLNESS
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Three teams of researchers from the United States, Canada and Europe say they may
have found a better way to treat and prevent, at least temporarily, a bacterial infection that is one of the hallmarks of AIDS.
Mycobacterium avium, is the third most common infection in AIDS patients. One in five
people with AIDS will typically develop it.
The findings, from studies that looked at various drug regimens, "are welcome news,"
said Dr. Robert Horsburgh Jr. of Emory University in Atlanta. All the studies were published in The New England Journal of Medicine.
In the first study, a group led by Dr. Stephen Shafran of the University of Alberta
in Edmonton, Canada, found that a combination of three drugs cleared the infection in 78 percent of the patients, compared with
a cure rate of only 40 percent in patients who got a four-drug combination (at 6 months).
The three drugs were rifabutin produced by Pharmacia UpJohn under the brand name Mycobutin;
ethambutol, also known as Myambutol and produced by Lederle; and clarithromycin, produced by Abbott Laboratories Inc.
under various names, including Biaxin and Klaricid.
The four-drug regimen that was far less effective consisted of clofizimine, produced
by Ciba-Geigy as Lamprene; ciprofloxacin, produced under the brand name Ciproxin by Bayer; rifampicin, and ethambutol.
In the second study, Dr. Mark Pierce of Vanderbilt University in Nashville and his
colleagues in the United States and Europe found that regular use of clarithromycin tablets twice a day lowered the risk of infection
from 16 percent, which was the rate among placebo recipients, to 6 percent for volunteers who got the drug.
All of the 667 volunteers in the study, conducted by a team that included four Abbott
researchers, had substantial immunodeficiency.
The third study, led by Dr. Diane Havlir of the University of California at San Diego,
looked at a different drug, azithromycin, and found that only 7.6 percent of the patients who took it once a week developed
mycobacterium avium compared with 15.3 percent who took rifabutin, the previous standard therapy.
Combining the drugs worked even better, producing an infection rate of only 2.8 percent.
But the abdominal pain, diarrhoea and nausea produced by the combination made the two-drug treatment significantly more unpleasant
than the azithromycin therapy alone, the researchers said.
With the new findings, Horsburgh said, drug treatment designed to prevent Mycobacterium
avium "should be considered the standard of care."
Source: Reuters NewMedia, Inc. Reston Town Center, 1750 Presidents Street, Suite 250,
Reston, VA 22090
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It still remains unclear what the cost/benefits and risk/benefits of MAI prophylaxis
are, especially in the UK where the incidence rate appears to be lower than in the USA and Australia. Failure of prophylaxis
may also make the disease more difficult to treat in these patients. All of the drugs mentioned in these studies are available in Europe, but only one, rifabutin, is licensed for MAI prophylaxis. At the present time MAI prophylaxis is not widely used in Europe. |
This statement provides information on the results of a clinical trial that compared
the standard dose of clarithromycin (500 mg bid) with a higher dose (1000 mg bid) for treatment of HIV-infected patients with
disseminated infection by Mycobacterium avium Complex (MAC). Based on the study findings of poorer survival associated with the
high dose compared to the standard dose, NIAID recommends that treatment of these patients with clarithromycin should not exceed
the approved dose of 500 mg twice daily. The study was conducted by the Terry Beirn Community Programs for Clinical Research
on AIDS (CPCRA), a clinical research network sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). NIAID
is providing this preliminary information to you as a health care provider while the investigators are preparing a manuscript
for submission to a peer-reviewed medical journal.
Source: NATIONAL INSTITUTES OF HEALTH, National Institute of Allergy and Infectious
Diseases July 23, 1996
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Clarithromycin is currently licensed in the U.K. for the treatment of upper and lower respiratory tract, skin and soft tissue infections. This advice is included here if off-label usage for MAI is occurring. |
Sulfadiazine-associated nephrotoxicity occurs more frequently among HIV-positive patients
than HIV-negative patients, according to a German team of researchers.
Sulfadiazine is commonly used to treat Toxoplasma gondii infection, the most common
CNS-opportunistic infection affecting AIDS patients. Dr. Klaus Becker of Heinrich Heine University in Dusseldorf and colleagues
searched the literature for HIV-positive patients who experienced sulfadiazine-associated renal impairment and identified 35
cases. The incidence of symptomatic renal impairment among HIV-positive patients was twice that reported for HIV-negative patients.
The incidence for HIV-negative patients ranges between 1% and 4%.
There are no well-defined groups of HIV-positive individuals who are at particular
risk for sulfadiazine-associated nephrotoxicity, he reports. Therefore, evaluation of renal function should be performed before
commencing treatment, and patients should be closely monitored while on sulfadiazine. Daily fluid intake should be at least 2L,
and any potential nephrotoxic co-medication should be avoided, Dr. Becker adds. "An average daily dose of 4 g sulfadiazine should
not be exceeded in the norm-weighted patient," but if a dose increase is necessary, patient plasma levels should not exceed
15 mg/dL."
If nephrotoxicity develops, the aim "...is to (re)institute physicochemical urinary
solubility of sulfadiazine and its metabolites," Dr. Becker explains. Urine alkalinisation and forced rehydration often achieve
this end, without having to stop treatment. With proper compliance, the "...outcome of this drug-related side effect is usually
excellent, and rare relapses will similarly respond well."
Ref: Medicine 1996;75:185-194.
Source: Reuters Health Information Systems, 825 Eight Street, 31st Floor, New York,
NY 10019
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OBSTETRICS
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HIV-1 can infect the placenta as early as the first trimester of pregnancy, reported
Chiara De Andreis of Milan and colleagues in the June issue of the journal AIDS. The researchers said they found HIV in two-thirds
of cord blood samples analysed in their study of 30 HIV-positive women. They said, however, that more research was needed
to determine "the source of HIV in cord blood and the possible contribution of placental or maternal cells infected with HIV to
vertical transmission of the virus."
Source: Reuters (19/07/96)
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PATHOGENESIS
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Two separate teams of researchers have found evidence that a small fraction of the
white population may be genetically less capable of infection by the AIDS virus.
The findings confirm the real-world importance of recent laboratory discoveries about
how the virus enters cells. More significantly, it points the way toward a potentially useful target for future drugs.
Both teams focused on the CCR-5 receptor, a protein on the surface of the cells of
the human immune system that is one of two targets of infection by human immunodeficiency virus (HIV). The receptor functions as
a docking bay the virus must enter before injecting its genetic material into the cell -- the crucial act of infection.
Coming at the subject from different directions, the two research groups concluded
that about 1 percent of white people of European ancestry lack the gene their bodies need to make the CCR-5 receptor. This "mutant
state" appears to confer protection against infection by HIV.
One group, headed by Nathaniel R. Landau at the Rockefeller University in New York,
studied two men who had been frequently exposed to the AIDS virus but had never contracted it. Both were members of the 1 percent
mutant population. The other team, headed by Marc Parmentier at the Free University of Brussels, found no such people among
more than 700 HIV-infected European men.
The Belgian researchers did not find the mutation in blood samples from 124 uninfected
people from West or Central Africa, or in 248 uninfected Japanese. Similarly, the New York group sought, but could not find
it, among 46 Venezuelans. The mutation may be absent, or just rarer, in non-whites and non-Europeans.
The phenomenon of people who are exposed to HIV but do not acquire it is not limited
to whites. The first well-described examples were a group of prostitutes in Kenya. It is possible that non-white ethnic groups
have similar, but undiscovered, inborn genetic errors that confer resistance.
The New York study is published in the journal Cell. The Belgian work will be published
later this month in Nature.
In June, two research groups (one of them Landau's) reported that CCR-5 was a major
co-receptor required by "macrophage-tropic" AIDS viruses. Those are the types that almost always pass the infection from one person
to another. Later, after years of infection, many of the billions of viruses in an infected person undergo mutation and become
"T-tropic" strains. Those strains require that a cell have a different co-receptor, called fusin, in order to be infected.
Both CCR-5 and fusin are called co-receptors because HIV always needs another receptor -- called CD4 -- in order to enter immune
system cells.
The earlier studies involved laboratory experiments, whereas the new research points
to CCR-5's clinical importance.
"Often we find that what is significant in [laboratory] tissue culture may not be
important in the whole individual," said William E. Paul, head of the office of AIDS research at the National Institutes of Health.
"In this case, however, the two studies strongly suggest that these receptors are critical to the infectious process. They also
suggest that [pharmaceutical] agents targeting these receptors might form the basis of therapies."
Specifically, a drug that could block the CCR-5 receptor might keep the virus from
spreading throughout an infected person's immune system as widely as it otherwise might. A vaccine could possibly stimulate the
production of antibodies that block CCR-5 receptors, preventing initial infection.
Distribution of the mutant CCR-5 gene is actually more complicated than is suggested
by the existence of a protected 1 percent of the population. That is because, for almost all genes, a person gets two copies
or "doses" -- one from the mother and one from the father.
Often, having one defective copy of a gene makes little or no difference to a person's
health. But in the case of CCR-5, having one normal and one mutant copy appears to offer some protection.
The Belgian scientists found that 83 percent of healthy, uninfected people had two
normal copies of CCR-5; 16 percent had one normal and one mutant copy; and 1 percent had two mutant copies.
Among 723 HIV-infected people, however, the numbers were different. About 90 percent
had two normal CCR-5 genes; 10 percent had one normal and one mutant gene; and none had two mutant genes. This suggests that
having a mutant gene -- even just one in a pair -- gives some protection because such people are found less frequently in the HIV-infected
population sample than one would have predicted.
Source: The Washington Post, 1150 15th St. N.W., Washington, DC 20071 - Friday, August
9 1996; Page A02
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It is not yet known if lacking the CCR-5 receptor may confer some health disadvantages to persons carrying the mutant gene |