News Briefs
by BETA Editorial Staff
FDA Approves Roche Viral Load Test
On June 3, 1996, the Food and Drug Administration
(FDA) approved the viral load test manufactured and distributed by Roche
Diagnostic Systems Inc. (a subsidiary of Roche Molecular Systems Inc.).
The assay, known as the Amplicor HIV-1 Monitor Test, is a reverse transcriptase
polymerase chain re-action (RT-PCR) test that amplifies and measures the
amount of HIV RNA in the blood plasma; the test can measure viral load
levels as low as 400 HIV RNA copies/mL. The test was approved for HIV
disease prognosis, or predicting the risk of disease progression. Approval
was based in part on clinical studies that demonstrated that persons with
higher viral load levels experienced more rapid disease progression and
had a higher risk of death. In 2 studies of persons with advanced HIV
disease, a high pre-treatment viral load or a five-fold or greater increase
in viral load predicted accelerated disease progression.
The Roche test is the first viral load assay
using this technology to be FDA-approved; approval came less than 7 months
after Roche submitted their application. The test currently costs $150-200;
the price is expected to decline as the test becomes more widely available.
Roche has announced plans to offer 2 free Amplicor HIV-1 Monitor test
kits to all HIV positive persons in the U.S. for a 60-day period starting
June 17, 1996. For information on the free test kits, call 888-TEST-PCR.
For more on viral load, see page 9.
HIV Home Test Kit Approved
Confide is the first anonymous HIV home
test with counseling service to be approved by FDA. The new test was developed
and will be marketed by a company called Direct Access Diagnostics, a
subsidiary of Johnson and Johnson.
The new test has 3 components: an over-the-counter
home blood collection kit, HIV-1 antibody testing at a certified lab and
a test result center that provides the results and counseling. The procedure
allows for complete anonymity.
The testing process begins by reading a
pretest counsel-ing booklet. Using an enclosed retractable lancet, the
test-kit user takes a blood sample from the finger and places it on a
test card imprinted with a unique identification number. The test card
is then mailed in a prepaid, preaddressed pro-tective envelope to the
Confide laboratory. Results may be obtained 7 days later by calling a
toll-free number. Counseling and referrals are offered at the same time
that results are delivered.
The test will be available over-the-counter
on a limited basis in Texas and Florida in June 1996. Nationwide distribution
will not begin until early 1997. Confide will retail for about $40, part
of which will be donated to AIDS research; it will cost $50 if ordered
by calling 1-800-THE-TEST.
An FDA advisory committee recommended approval
of the home testing kit at a June 1994 meeting, after concluding that
the potential benefits outweighed the potential risks. The risks center
mainly around the counseling issue. Critics contend that, without face-to-face
counseling, some test-kit users may commit suicide.
HIV Dynamics
HIV
Variation and Disease Progression
A team of researchers including Steven Wolinsky,
MD, at Northwestern University Medical School and David Ho, MD, at the
Aaron Diamond AIDS Research Center, has evaluated the number of genetic
variants of HIV found in the blood of HIV-infected individuals and attempted
to correlate that information with rates of disease progression. Contrary
to a widely accepted model of HIV disease which contends that extremely
rapid rates of evolution give HIV an advantage in overcoming host immune
defenses, the team found that those whose disease progressed fastest were
the ones who exhibited the least genetic diversity in their HIV. Those
with many different genetic varieties of HIV progressed more slowly.
The study, reported in the April 26, 1996
issue of Science, was based on blood samples taken every 3-6 months from
6 volunteers, 2 of whom showed rapid declines in CD4 cell counts, 2 with
moderate declines and 2 with relatively stable CD4 cell counts. The sample
size was small and the study has not yet been replicated to validate the
findings. If the study is confirmed, some basic assumptions about how
HIV causes immune decline will need to be reevaluated.
Wolinsky SM and others. Adaptive
evolution of human immunodeficiency virus-type 1 during the natural course
of infection. Science 272:537-41. April 26, 1996.
HIV
Replication, Infected Cell Life Span
A team of researchers led by David Ho ,
MD, of the Aaron Diamond AIDS Research Center in New York, estimates that
10 to 30 billion new HIV viral particles are produced each day. In a study
reported in Science on March 15, 1996, blood samples were drawn
from 5 volunteers who were taking the newly approved protease inhibitor
drug ritonavir (Norvir, produced by Abbott Laboratories) at a dose of
600 mg twice daily. Polymerase chain reaction (PCR) measurements of HIV
RNA in the plasma were taken every 6 hours for the first 2 days, then
once daily for 6 more days.
The team assumed that ritonavir does not
affect the rate at which infected cells produce new HIV, and that after
about 1.25 days after beginning ritonavir, the HIV produced by infected
cells is noninfectious. Calculations based on these assumptions allowed
Ho and his team to estimate that the average life span of an HIV virion
(a single virus particle) in the blood is 0.2-0.4 days, while the average
life span of an infected cell is 1.4-3 days.
The report provides further evidence that
there is no latency period in HIV infection, and offers some theoretical
principles to guide treatment strategies. According to the Ho team, "an
effective antiviral agent should detectably lower the viral load in plasma
after only a few days of treatment." Because of the enormous daily
turnover of HIV, mutation rates are even higher than previously thought.
Hence, the development of resistance to the current generation of antiretroviral
drugs when used as monotherapy is inevitable, and "effective treatment
must instead force the virus to mutate simultaneously at multiple positions
in the viral genome by means of a combination of multiple, potent antiretroviral
agents."
Perelson A and others. HIV-1 dynamics
in vivo: virion clearance rate, infected cell life-span and viral generation
time. Science 271:1582-85. March 15, 1996.
Fusin:
HIV Cofactor
Since 1984, researchers have known that
the receptor protein for HIV is CD4, but CD4 alone is not enough to permit
passage of HIV into immune system cells. In the May 10, 1996 issue of
Science, the long-sought cofactor was identified by a team of researchers
at the National Institutes of Health (NIH). Fusin is a protein that helps
cells fuse with the surface of HIV. Without the presence of both the CD4
receptor and fusin on the cell surface, HIV cannot infect the cell.
The discovery of fusin, coupled with recent
research findings that suggest that certain inflammation-causing cytokines
can block HIV's ability to infect cells, raises some new possibilities.
It may be that these cytokines (which not everyone produces in abundance)
will block fusin, preventing HIV fusion with immune cells. If so, that
could explain why some people are able to resist HIV infection despite
multiple exposures to the virus, and why some people with HIV are long-term
nonprogressors. Furthermore, strategies could be developed to block fusins
and prevent new infections in people who are exposed but not infected,
or the spread of infection in people already infected with HIV.
A second important avenue of research will
probably open up as a result of the identification of fusin. It may now
be possible to genetically engineer rabbits or other animals to produce
fusins, and an animal model for AIDS could at last be developed. Current
models based on simian immunodeficiency virus (SIV) infection are inadequate
to answer the questions researchers most want answered about human AIDS.
One of the team of researchers, Edward Berg,
MD, cautions that there are very likely different kinds of fusin that
play different roles for different strains of HIV. This is the first,
but probably not the only, fusin or cofactor that will be discovered.
Blueprints for Research and Prevention
Office
of AIDS Research Advisory Committee Report
A report issued on March 13, 1996, by the
118-member AIDS Research Program Evaluation Working Group criticizes AIDS
research at NIH and recommends that the Office of AIDS Research (OAR)
retain control over research at the 24 institutes and centers that comprise
NIH. Another key recommendation is to strictly define AIDS and AIDS-related
research, in order to redirect funding for research that is unrelated
or indirectly related to AIDS into research which is clearly related to
AIDS and done by non-NIH scientists.
Other recommendations from the advisory
committee include:
- Bolster current vaccine research by creating
an NIH vaccine research unit within the National Institutes of Allergy
and Infectious Diseases (NIAID)
- Refocus funding away from areas of drug
discovery that are likely to be done by pharmaceutical companies
- Provide a blueprint for future HIV prevention
efforts
- Integrate all existing adult clinical
trials networks into one.
Recommendations
for Prophylaxis against HIV-Related Infections
The United States Public Health Service
and the Infectious Diseases Society of America published extensive consolidated
guidelines for the prevention of opportunistic infections (OI) associated
with HIV disease in July 1995. A condensed version of the guidelines appeared
in the February 1, 1996 issue of Annals of Internal Medicine. The original
report is available from the Centers for Disease Control and Prevention
National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849-6003;
telephone 800-458-5231.
The current recommendations for preventing
OI are ranked in order of importance. The designation "A" indicates
those that are strongly recommended (both strong evidence and substantial
clinical benefit support prophylaxis), "B" designates those
recommended for consideration (moderate evidence or strong evidence for
only limited benefit) and "C" indicates those that are considered
optional (poor evidence for prophylaxis). These recommendations differ
from previous ones in 3 areas: prophylaxis for Pneumocystis carinii
pneumonia (PCP), Mycobacterium avium complex disease (MAC) and
toxoplasmosis.
For preventing PCP as well as toxoplasmosis,
trimethoprim-sulfamethoxazole (TMP-SMX, brand name Bactrim or Septra)
is recommended, and guidelines for desensiti-zation are included (see
also the update on pneumonia on page 13.) After a reanalysis of the data
from rifabutin studies, the threshold for the initiation of prophylaxis
for MAC disease has been reduced from 100 to 75 cells/mm3 or
fewer. See summary
of guidelines, this issue.
Powderly W. Prophylaxis for HIV-related
infection: a work in progress. Annals of Internal Medicine 124(3):
342-4. February 1, 1996.
USPHS/IDSA guidelines for the prevention
of opportunistic infections in persons with human immunodeficiency virus:
a summary. Annals of Internal Medicine 124(3): 348-68. February
1, 1996.
Research
Agenda for HIV-Infected Children
Over the past few years, some exciting research
advances have offered hope for ways to reduce perinatal HIV transmission,
the mode responsible for nearly all new pediatric HIV infections today.
The FDA has approved a highly publicized AZT regimen, which requires both
mother and newborn to take AZT for a period of weeks, gives intravenous
AZT during childbirth, and was shown in AIDS Clinical Trials Group (ACTG)
076 to reduce transmission rates by nearly two-thirds. Another experimental
and promising strategy involves the non-nucleoside reverse transcriptase
inhibitor drug nevirapine (Viramune). Currently under study in clinical
trials, this promising regimen requires mother and newborn to take only
a single dose.
It is widely hoped that these and upcoming
strategies will drastically reduce the numbers of pediatric cases of HIV/AIDS.
In order for this hope to be realized, pregnant HIV positive women must
have the information and resources to act accordingly. The number of new
infections among women, especially minorities, and their children hints
at the staggering socioeconomic and political factors that must be addressed
in order to curtail new pediatric infections. According to the National
Center for Health Statistics, there are approximately 10,000 HIV-infected
children in the U.S. In order for these children to receive the care they
require, research into pediatric antiviral strategies and other strategies
related to managing HIV disease must continue. Particularly conspicuous
is the lack of pediatric trials of the new protease inhibitors, the latest
best antiviral hope for persons with HIV. To date, there are virtually
no pediatric data, and the protease inhibitors that are already FDA-approved
cannot be used by children.
See also HIV/AIDS
in Children, this isuue.
Nucleoside Analogs
3TC
Patient Assistance Program Expanded
In response to requests from community advocates,
Glaxo Wellcome has acted to increase patient access to the nucleoside
analog drug 3TC (Epivir). On May 20, 1996, the Patient Assistance Program
was broadened to include patients who are qualified to receive their HIV/AIDS
drugs from state drug-assistance programs, but who are unable to access
3TC due to either state funding shortages or the absence of 3TC on the
formulary of the state program for which they qualify. In addition, a
60-day extension of drug availability has been added for patients receiving
3TC through the expanded access program. For further information, contact
the Patient Assistance Program at 1-800-722-9294.
PMPA
Prevents Vaginal SIV Transmission
The nucleotide analog PMPA (Gilead Sciences),
in preclinical testing for possible use in the treatment of HIV infection,
was intravaginally administered in topical gel form to female primates
who were then challenged with simian immunodeficiency virus (SIV), a retrovirus
related to HIV. One hundred percent of the PMPA-treated primates (4 of
4) were protected from SIV infection, while both control animals who were
also challenged with SIV showed signs of SIV transmission and infection
within 2 weeks of exposure. Human studies of PMPA will begin this year;
the topical drug will undoubtedly be evaluated for its ability to prevent
HIV transmission from infected sexual partners.
Protease Inhibitors
Saquinavir
Prolongs Survival and Slows Disease Progression
The final analysis of the Hoffmann-La Roche
sponsored study NV14256, a randomized, double-blind comparison of saquinavir
(Invirase) versus ddC (HIVID) versus the combination in 1,086 HIV positive
volunteers showed that the combination reduced mortality more than two-thirds
and reduced disease progression by about one-half. The results showed
that there were 28 deaths among those who received only ddC, 34 a-mong
those who received only saquinavir and 9 among those on the combination.
There were 85 instances of disease pro-gression on ddC, 77 on saquinavir
and 46 on the combination.
Study participants had at least 16 weeks
of prior AZT therapy and CD4 cell counts at baseline were between 50 and
300 cells/mm3. All participants were followed for a median
of 73-74 weeks. More participants in the combination group completed the
protocol than in either monotherapy group; the main reason for discontinuing
participation among the ddC monotherapy group was toxicity, including
peripheral neuropathy.
A study of the new gel-cap formulation of
saquinavir has been initiated at 40 sites in the U.S. Participants must
be at least 13 years old and there are no CD4 cell count restrictions.
Most participants will not have used any protease inhibitor drug previously,
although 100 of the total 400 participants will have received prior treatment
with a protease inhibitor. For further information, call the AIDS Clinical
Trials Information Service at 1-800-TRIALS-A.
Non-nucleoside reverse transcriptase inhibitors
Nevirapine
Recommended for Approval
An antiviral drugs advisory committee unanimously
recommended on June 7, 1996 that the Food and Drug Administration grant
nevirapine (Viramune, produced by Boehringer Ingelheim Pharmaceuticals,
Inc) accelerated approval for use in combination with other anti-HIV drugs
for the treatment of HIV infection. The meeting was unusual, in that the
decision was made both quickly and unanimously. Nevirapine is the first
member of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class
of drugs to receive FDA approval.
Although committee members did not wish
to limit the use of nevirapine in combination with other antiretroviral
drugs to a specific CD4 cell range, it was noted that the best results
were seen when patients started the drug at the same time that they began
using a previously untried nucleoside analog. Triple combination regimens
demonstrated the greatest decreases in viral load and the most sustained
increases in CD4 cell count among study participants. The committee also
wanted assurance from Boehringer Ingelheim that clinical studies of drug
interactions will be performed quickly. A study of the interactions between
saquinavir and nevirapine is underway, and similar studies are planned
for ritonavir and indinavir.
The side effect profile for nevirapine is
favorable, with rash being the most common event experienced, usually
within the first few weeks of initiating therapy. The incidence of severe
rash and Stevens-Johnson syndrome, a potentially lethal inflammation of
the skin or mucous membranes, was limited to 0.5% of all study participants.
Boehringer Ingelheim has developed a rash management protocol. See Non-Nucleoside
Reverse Transcriptase Inhibitors,
this issue.
An expanded access program for Viramune
was launched in April to make the drug available to adult and pediatric
patients with progressive, symptomatic disease. To be eligible, participants'
CD4 cell counts must be below 200 cells/mm3. Children under
13 years of age must have a CD4 percentage of less than 14% or they must
have had a less than 50% decrease in CD4 percentage in the previous 6
months. Pregnant or breastfeeding women are excluded, as is anyone using
certain medications that interact with Viramune. Physicians may call 1-800-595-5494
to enroll their eligible patients.
Delavirdine
Expanded Access Program
Upjohn Pharmacia, makers of the experimental
non-nucleoside reverse transcriptase inhibitor drug delavirdine (Rescriptor),
instituted an expanded access program for the drug on April 1, 1996. The
program will make delavirdine available to men and women (who are not
pregnant or breast-feeding) over the age of 13 who have CD4 cell counts
from 0-300 cells/mm3, are failing other therapies and are receiving
at least one other antiretroviral drug. Physicians may register their
eligible patients by calling 1-800-779-0070.
Delavirdine has been studied in more than
2,600 study participants and has been found to be synergistic with other
antiretroviral drugs such as AZT and ddI. Clinical studies of combination
therapy with delavirdine plus AZT or ddI resulted in an average 68% decrease
in viral load and an average CD4 count increase of 25 cells/mm3.
See a review of non-nucleoside reverse transcriptase
inhibitor drugs in development, see Non-Nucleoside
Reverse Transcriptase Inhibitors,
this issue.
HIV Vaccines
VaxSyn
Testing Comes to an End
Further testing of the MicroGeneSys candidate
therapeutic vaccine VaxSyn, based on the HIV envelope protein gp160, has
been halted because the vaccine did not demonstrate statistically significant
clinical benefit. A pivotal 5-year study at the Walter Reed Army Institute
of Research in Washington, DC, and NIAID gave VaxSyn or placebo to 608
volunteers. The data suggest that VaxSyn had no impact on the course of
HIV disease. A similar study of VaxSyn conducted in Canada recruited 278
volunteers who were injected with gp160 or placebo. According to lead
investigator Chris Tsoukas, MD, of the Canadian HIV Trials Network, "analysis
of the data has revealed no clinical benefit from this product nor any
usefulness in maintaining immune competence."
VaxSyn has a history of controversy. In
1992, former Senator Russell Long (Democrat, Louisiana) successfully lobbied
Congress for $20 million in Department of Defense money to fund a large
trial of the candidate vaccine. Bernadine Healy, MD, then director of
NIH, took exception to the allocation and lobbied successfully for the
funds to be transferred to general vaccine research efforts at NIH.
New
Vaccine Strategy
NIAID is developing guidelines for HIV vaccine
development that will allow vaccine developers to proceed smoothly along
the pathway to licensing if they meet precise criteria at each step of
development. The criteria have not yet been established, but the promise
of clear guidelines should remove some of the obstacles to vaccine development
that have plagued vaccine developers in the past. Potential vaccine developers
in private industry have been hesitant to commit research funds to HIV
vaccine research when NIAID appears to change requirements and expectations
frequently.
Anthony Fauci, MD, Director of NIAID, also
called for a balance between basic and empirical vaccine research, for
better collaboration with drug industry and academic partners in vaccine
development, for better exploitation of opportunities to hasten vaccine
research and for better links with other organizations that are pursuing
development of vaccines, such as the Joint United Nations Programme on
HIV/AIDS, Great Britain's Medical Research Council and France's Agence
Nationale de Recherches sur le SIDA.
Opportunistic Infections
DaunoXome
Available for Advanced Kaposi's Sarcoma
DaunoXome, a chemotherapy agent for advanced
Kaposi's sarcoma (KS) that consists of daunorubicin encased in fat globules
called liposomes, won FDA approval for marketing in April 1996. DaunoXome
is the second liposomal drug product to be developed by Nexstar Pharmaceuticals,
following liposomal amphotericin B (AmBisome). Data from the randomized,
controlled trial that compared DaunoXome with the standard chemotherapy
combination of adriamycin, bleomycin and vincristine (ABV) showed no statistical
differences in survival rates, time to treatment failure, or time to disease
progression between the 2 regimens. However, the participants who received
DaunoXome experienced less neuropathy, hair loss and heart toxicity, and
were able to gain weight while on treatment.
DaunoXome has been available by prescription
since May 1, 1996. The standard dosage is 40 mg/m2 every 2 weeks. A patient
assistance program has been established to help people applying for federal
and private assistance, to answer questions and to assist with reimbursement.
Call 1-800-226-2056 for more information or to enroll.
Women and HIV
Do
Injectable Contraceptives Increase the Risk of HIV Infection?
An animal study at the Aaron Diamond AIDS
Research Center in New York City has raised concern that 2 popular birth
control methods -- the injectable Depo-Provera and Norplant, which is
implanted under the skin -- may elevate the risk of contracting HIV in
women who use them. The study found that female monkeys that were given
progesterone, a natural human hormone, were 7 times more likely than monkeys
receiving placebo to be infected with simian immunodeficiency virus (SIV)
after vaginal exposure.
Progesterone is associated with thinning
of the vaginal mucous membranes. Although earlier studies had raised the
possibility that use of exogenous (not produced by the body) progesterone
might make it easier for the virus to cross the vaginal membrane and enter
and infect circulating blood cells, the investigators in this study say
they did not expect to actually see such striking results.
Results of animal studies do not necessarily
translate to humans. Moreover, the monkey study used natural progesterone,
whereas Depo-Provera and Norplant use a synthetic version called progestin.
Nonetheless, the increasing popularity of these methods worldwide and
especially in developing nations with high rates of HIV infection have
triggered swift development of human studies. The same division of NIH
that sponsored the monkey study is funding a New York study involving
15 women, who will receive progestin or placebo. Monthly measurements
will be made of vaginal mucus layer thickness to determine if the synthetic
hormone actually causes thinning of human vaginal linings.
To date, the concern offers additional support
for the recommendation to use barrier methods such as condoms for protection
against sexually transmitted diseases, which neither Depo-Provera nor
Norplant claims to prevent. Whether or not they actually elevate risk
for HIV infection remains to be seen.
New Public Health Service Recommendations on HIV Postexposure Prophylaxis
by Ronald Baker, PhD
Individuals exposed to HIV in the workplace
should start anti-HIV treatment with a 3-drug regimen within 1-2 hours
after exposure to HIV, according to new recommendations from the Public
Health Service (PHS). The recommended triple drug therapy consists of
AZT (200 mg 3 times daily) plus 3TC (150 mg 2 times daily) plus indinavir
(800 mg 3 times daily). If indinavir is not available, saquinavir is recommended
at 600 mg 3 times daily. If the acquired HIV strain is resistant to AZT,
3TC and indinavir, the group advises seeking expert consultation on an
alternative regimen. Individuals identified for postexposure prophylaxis
(PEP) should receive expert medical care and appropriate counselling.
The provisional PHS recommendations appear in the June 7, 1996 issue of
the Morbidity and Mortality Weekly Report, published by the Centers for
Disease Control and Prevention (CDC).
Can
Drug Treatment Eradicate HIV from the Body?
The objective of PEP with AZT/3TC/indinavir
is to eradicate HIV before the virus establishes infection in the body.
The prophylactic 3-drug regimen should be taken for [at least] 4 weeks.
Even though animal studies suggest that PEP is not effective when initiated
later than 24-36 hours after infection with HIV, starting AZT/3TC/indinavir
therapy as late as 2 weeks after initial infection should be considered
for those at highest risk for infection, say the recommendations. In these
cases, even if the 3-drug regimen fails to eradicate the infection, very
early treatment of HIV infection may be beneficial.
Studies
on Prevention of HIV Infection through Sexual Contact
The preliminary PHS treatment
recommendations are intended only for use in trying to prevent infection
from workplace-associated exposure to HIV (e.g., a stick with a contaminated
needle). Several U.S. medical centers are studying the same treatment
regimen (AZT/3TC/indinavir) started within the first few days of acute
infection in individuals exposed to HIV through sexual conduct. The studies
will evaluate whether the 3-drug therapy can eradicate HIV in these individuals.
Page last updated 23 July 1996
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