Contents
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AIDS Watch:
Downward trends in AIDS deaths and hospitalizations, but not for all,
and for a variety of reasons
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Stop Them before They Kill More:
Data reviews halt three trials earlier than planned
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Get the NAC?:
New trial results heighten interest in this familiar antioxidant
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Treatment Briefs:
FDA approves nelfinavir for adults and children and ritonavir for children,
Merck will broaden Crixivan availability as of May 1, patient assistance programs
for viral load tests
Some Relief from the Epidemic
by Jill A. Cadman
Authorities from a wide variety of sources, international, national and local,
are reporting that death and hospitalization rates for persons with AIDS dropped
sharply in 1996. Medication to treat or prevent opportunistic infections,
increased utilization of medical care and combining nucleoside analogs are the
reasons posited for these decreases. While some experts state that it is too soon
to attribute the downward trends to combination therapy that incorporates
protease inhibitors, all agree that these potent new treatment options should
further increase survival.
CDC Reports on National Trends
In February, the U.S. Centers for Disease Control and Prevention (CDC)
announced that AIDS surveillance data for 1996 mark the first decline in AIDS
deaths nationwide since the beginning of the epidemic. The estimated number of
deaths among people with AIDS, which had increased steadily though 1994, rose
only slightly in 1995 and headed downward for the first time in 1996. From last
January through June, the estimated number of AIDS deaths was 13% less than for
the same period in 1995. The breakdown by racial/ethnic group is as follows:
non-Hispanic whites had a 21% decrease, non-Hispanic blacks a 2% decrease,
Hispanics a 10% decrease, Asian/Pacific Islanders a 6% decrease, and American
Indians/Alaskan Natives a 32% decrease. Deaths due to AIDS did not decline among
women and those infected through heterosexual contact but increased in both these
groups by 3%.
AdvertisementAccording to CDC spokesperson Tammy Nunnally, the agency attributes the
decline in
deaths to prevention efforts that have slowed the overall epidemic and to
improved
treatments, especially prophylactic drugs to prevent opportunistic infections
(OIs).
Ms. Nunnally stated that the current downward trend in AIDS-associated deaths was
not being attributed to the widespread use of new combination regimens
incorporating
protease inhibitors. The CDC update reads, "While it is too soon to
determine the
impact
protease inhibitors will have on these trends, these drugs promise to
further
lengthen the lifespan of individuals with AIDS." Still greater reductions in
AIDS
mortality rates are expected for the future, provided the drugs are well
tolerated
and stand up to long-term use.
As the number of AIDS deaths declines, the number of people living with AIDS
(AIDS
prevalence) has increased substantially, up 10% since 1995. The growth in the
total
number of people diagnosed with AIDS each year continues to slow, according to
the
consistent case definition of AIDS the CDC now uses to monitor trends. There was
an
increase of about 3% per year from 1992 through 1994 and a 2% increase in 1995.
Meanwhile the demographics of the epidemic are changing with those people
infected through heterosexual contact having the greatest proportionate increase
within the total AIDS population. The numbers of minorities and women with HIV
are also increasing significantly. The CDC notes that as the rate of new HIV
infections remains stable or increases, and AIDS deaths continue to decrease,
additional resources will be needed for services, treatment and care.
New York City Confirms the Trend
Mary Ann Chiasson, Dr.P.H., the Assistant Commissioner for Disease
Intervention Research of the New York City Department of Health, presented
additional findings at this winter's Fourth Conference on Retroviruses and
Opportunistic Infections (abstract 376). She described the downward trend in the
city's HIV/AIDS mortality. New York City has only 3% of the US population but 16%
of US AIDS cases. It has had more than 60,000 deaths from AIDS, which became the
third leading cause of death in 1988. AIDS mortality increased six-fold from 1983
to 1986, then by about 11% per year to 19.4 deaths per day in 1994. In 1995, for
the first time since the beginning of the epidemic, the death rate did not
increase. It reached a plateau of 19.3 deaths per day in 1995 and began a steady
decline in 1996 from 19.5 per day in January to 11.5 per day in July.
This is a drop of 41% for the first seven months of 1996. Dr. Chiasson
indicated that the decline in deaths was not preceded by a dramatic decline in
newly diagnosed AIDS cases in New York City and did not attribute this as a
factor. She noted that the rate of new infections (measured by proxy using the
number of new AIDS cases reported each year) appeared to have leveled off for
several years leading up to 1995. Dr.
Chiasson stated, "We would expect the number of deaths to plateau following
a
plateauing in AIDS cases." This was the case in 1994 and 1995 when the
number of
deaths remained essentially flat throughout the year. The Department of Health
had
expected the same in 1996, but while the rate of new infections remained stable,
the rate of deaths decreased sharply in all demographic groups beginning in April
of 1996. Dr. Chiasson said this trend was surprising and felt that further study
was
warranted to determine the cause.
The New York City Department of Health study concluded that the reasons for
the decline in AIDS deaths have yet to be determined, but suggests that early
diagnosis, prophylaxis for OIs and new antiviral therapies may be slowing
mortality. Further increases in funding enabled the State AIDS Drug Assistance
Program (ADAP) to add protease inhibitors to the formulary in July of 1996 (see
Treatment Issues, May 1996, page 8), but this new coverage postdated the onset of
the death rate decline.
Dr. Chiasson said that the drop in the death rate preceded the widespread use
of triple combination therapy with protease inhibitors but may reflect changes in
treatment guidelines starting in 1994 which moved away from monotherapy and
recommended combining nucleoside analogs. Dr. Chiasson also acknowledged the
availability of Epivir (3TC) prior to the general use of protease inhibitors. She
is hoping to conduct a study in conjunction with the CDC looking at treatment in
people who died in comparison with treatment in people who did not.
Treatment and services became more widely available in New York when federal
Ryan White CARE Act funding more than doubled in fiscal year 1994 (see graph).
Dr. Chiasson further observed, "Deaths began to decline as funding
increased. I think that the set up of these very comprehensive medical care
services through Ryan White had to have had some impact on mortality by making
treatments accessible to everyone. But I can't prove it. It is certainly
appealing as a partial explanation."
Also in New York City, the St. Vincent's Hospital AIDS Center, located in the
heart of the hard-hit Greenwich Village/Chelsea neighborhoods, conducted a study
to look specifically at the impact of new antiviral therapies on inpatient and
outpatient hospital utilization. From the beginning of the epidemic until 1994,
St. Vincent's has experienced annual increases in patient admissions and total
hospital stays for HIV-related illnesses. These figures leveled off in 1994 and
then began decreasing significantly by the end of 1995. At the same time, the
number of individuals served on an outpatient basis steadily increased.
In 1994, St. Vincent's began implementing certain changes in the delivery of
care including increased utilization of homecare and outpatient infusion services
for the management of opportunistic infections (OIs). Besides advances in
antiviral therapy, the advent of prophylaxis for OIs such as MAC, fungal
infections, toxoplasmosis and CMV is among the possible factors behind the drop
in patient admissions
Gabriel Torres, M.D., the director of the AIDS Center, also presented study
results at the Fourth Conference on Retroviruses (abstract 264). Dr. Torres
reported that in 1994, prior to the availability of protease inhibitor therapy,
the average number of inpatients (average inpatient daily census) peaked at 136
for HIV-related conditions. During 1995, protease inhibitors and Epivir (3TC)
were available to patients only through clinical trials or expanded access
programs. The average inpatient census during this year dropped 5%. In late 1995
3TC and the first protease inhibitor, saquinavir, were approved by the FDA. ADAP
was not yet covering protease inhibitors, but 3TC was immediately added to the
formulary. There was a significant drop in the average inpatient census beginning
at the end of 1995, with a concomitant rise in outpatient visits. In the first
quarter of 1996, ritonavir and indinavir also received FDA approval. From 1995 to
1996, the inpatient census dropped by 24% to an average of 79 patients in 1996,
inpatient admissions dropped by 10.5%, total inpatient days fell by 23.6%, and
the average length of stay was shortened by 15.9%
During this same period, the medical center experienced a 33% increase in
ambulatory visits. These included visits for HIV testing and counseling, primary
medical care and early intervention services.
According to Dr. Torres, "The introduction of protease inhibitors into
anti-HIV treatment regimens has had a dramatic effect on treatment patterns in
our clinic and on our patients' daily lives. We are seeing fewer infections and
fewer hospitalizations. In addition, greater public awareness of the existence of
new, potent treatment options clearly has led more people to seek care before
they become seriously ill."
Across the Country and Overseas
The St. Vincent's figures are consistent with New York statewide aggregate
data from 30 designated AIDS Centers, which show average length of stay dropping
by one day for each of the years from 1993 to 1996. Total admissions for HIV/AIDS
declined from 60,157 to 54,448 from 1994 to 1995.
In Philadelphia, lower AIDS death rates were reported, but activists there
expressed concern at disparities between blacks and whites. From 1995 to 1996,
deaths dropped by 41% for whites and only 13% for blacks.
Peter Ruane, M.D., of Tower Infectious Disease Medical Associates in Los
Angeles, reported results at the Fourth Conference on Retroviruses (abstract 262)
of a two-year study conducted at Tower. Tower provides primary care to
approximately 480 HIV-infected patients, 50% of whom meet the CDC definition of
AIDS. The study was designed to examine the effects of adding additional
antivirals on medical services provided and on the actual cost of care.
Tower began recommending dual combination therapy in early 1995 and in 1996
added
treatment guidelines that called for triple combination therapy with protease
inhibitors. By October, 1996 approximately 62% of patients had been prescribed a
protease inhibitor (up from 9% in 1995). Dr. Ruane stated that "hospital
days began to drop when we started prescribing double combination therapy with
AZT and 3TC, but they dropped farther -- and faster -- when we added protease
inhibitors."
Utilization of medical care dropped by every measure, including hospital stays
and
referrals to specialists. For example, the mean number of patients receiving home
care
fell 93%, from 67.6 to 5. Dr. Ruane attributed this to the reduced incidence of
opportunistic infections. He stated that "among compliant patients, we have
not seen
a new case of CMV in a year."
There was an equally dramatic increase in medication cost between 1994 and
1996, 116% for patients with CD4 counts above 50 and 301% for patients with CD4
counts under 50. However, Dr. Ruane concluded that for each dollar of increased
spending on drug therapies, $2 was saved on overall treatment costs, especially
for the patients with under 50 CD4 cells.
The French experience apparently mirrors the decreasing mortality rates in the
U.S. The number of AIDS deaths fell in 1996 for the first time since the start of
the epidemic. The Ministry of Health released a statement that 2,285 people had
died of AIDS in France last year, a decrease of 25% from 1995. The number of new
cases also fell, in contrast to the U.S.. French officials attributed the
declines to improved drugs and preventive programs.
Looking Ahead
Clearly the efforts to control the AIDS epidemic through research, prevention
and treatment are finally beginning to pay off. Whether the benefits of
combination therapy with protease inhibitors are already evident in the downward
trends in AIDS deaths and hospitalization, or whether we are just beginning to
see their true impact remains to be clarified. Either way, the trend should
continue as long, and only as long, as new drugs are developed and added to the
antiviral armamentarium before HIV develops widespread resistance to existing
agents.
It is distressing that certain sectors of the population have not reaped the
same benefits from advances in health care. AIDS is threatening to become a
disease in which patients' outcome is determined more by socio-economic standing
than by the state of medical science.
As Simple as Better Access to Medical Care?
New York City Department of Health graph comparing deaths from HIV/AIDS in New
York
City and Ryan White funding: Sharp increases in Ryan White CARE Act money made
medical services widely available just as the AIDS death rate declined for the
first time.
[See graph in printed version.]
Spring Cleaning in Trial Land
by Dave Gilden
In the past month, investigators shut down three major indinavir trials earlier
than
planned. The implications of these trials' striking results, so clear-cut that
they
made further follow-up superfluous, go beyond the use of indinavir-containing
regimens.
Ending trials early says that the answers to questions the trials tested were
more
obvious than investigators had thought. We can say, with the benefit of
hindsight,
that such studies need not have been organized in the manner that they were.
When prematurely terminating trials becomes a pattern rather than an exception,
then hindsight should become foresight. The three trials' closure illuminates the
new trial design issues that have arisen in this era of highly active antiviral
therapy (HAART).
ACTG 320: The Skeletons in the Closet
In stopping ACTG 320 at the end of February, the AIDS Clinical Trials Group
ended the
group's largest ongoing effort. ACTG 320 was supposed to enroll 1,750 volunteers
over
nine months and follow them for a year. The volunteers had to be HIV-positive
persons
with CD4 counts under 200 and more than three months previous AZT therapy. They
would
be randomly assigned to receive either AZT/3TC or AZT/3TC/indinavir and monitored
for
the occurrence of AIDS-defining illness or death. (ACTG 320 was a clinical
endpoint
trial meant to confirm indinavir's FDA approval under the accelerated approval
rules.)
When ACTG 320 was announced in 1995, it received widespread community
criticism because
it was felt to be a waste of resources. AZT/3TC plus indinavir surely would prove
better
than AZT/3TC by itself, so that the point under study was not terribly
interesting from
a scientific perspective. Further, potential participants would be hesitant to
enroll in
the trial because they did not want to be assigned to the AZT/3TC combination
without
indinavir. People who did enroll would check their viral loads and rapidly drop
out if
they were not receiving a treatment with acceptable potency. Finally, indinavir's
manufacturer, Merck & Co., should be paying for indinavir's confirmatory trial,
not
the government-sponsored ACTG.
Enrollment began in January, 1996 and did indeed fall short. After more than a
year, only 1,156 participants (17% women) had signed up. They were followed for a
median of 39 weeks. About 20% of participants dropped out of the study, though
most of these continued to be followed for disease progression. Another 9%
changed nucleoside analogs within the context of the study. (To reduce the
drop-out rate, study participants were allowed to modify the AZT/3TC part of the
combination, substituting d4T for AZT in the event of drug intolerance or
perceived disease progression short of one of the study endpoints.) In both
cases, the alterations involved twice as many people on the double combination as
on the triple.
The mounting differences in disease progression obviated any need to continue
the trial as planned. Eighteen people died in the AZT/3TC arm and only eight in
the AZT/3TC/indinavir arm. There were 45 other AIDS-defining events in those
receiving only AZT/3TC versus 25 in those who also got indinavir. Overall, the
risk of disease progression was calculated to have been cut in half by adding
indinavir to AZT/3TC. An analysis of CD4 count and viral load trends has yet to
be completed.
A simple-minded inference to draw from this trial is that three drugs are
better than two -- period. Making such a broad statement is quite a stretch. The
results were dominated by events in trial participants starting with CD4 counts
less than 50. In the trial stratum having CD4 counts from 50 to 200, disease
progression was low with both regimens, and the difference was not statistically
significant. We also cannot draw any conclusions from this trial about long-term
differences in outcome. If ACTG 320 had been extended to two or three years, the
difference between the two treatment arms might vanish, depending on such issues
as the emergence of drug resistant HIV and the limits to an HIV-damaged immune
system's ability to defend the body for opportunistic infections. Long-term
effectiveness is particularly important for people with higher CD4 counts who
face a decision on what medications to take even though it may be some time
before serious illness threatens them.
ACTG 320 cannot tell what is the best strategy for people with prior AZT
exposure, just that adding 3TC and indinavir is better than adding 3TC alone. It
could even be that the combination of 3TC/indinavir is just as good as
AZT/3TC/indinavir in these people, at least over nine months. The trial also has
nothing to say for the many people who already have an extensive history with
both AZT and 3TC together. Probably just adding indinavir will do them little
good.
One interesting point is that the ACTG 320 cohort on AZT/3TC is now eligible
for a rollover trial, ACTG 368, in which participants will receive indinavir plus
DMP 266 and/or 1592U89. These are two experimental reverse transcriptase
inhibitors of unprecedented potency that require HIV to make several mutations
before it can become resistant. It may well turn out in this trial that the right
two drugs are every bit as good as the three-drug combination of
AZT/3TC/indinavir. Indinavir plus either 266 or 1592 might even be active enough
that it is not necessary to take the three together.
An enormous number of questions remain unanswered. The lessons of ACTG 320 are
very limited. They merely confirm the results of Merck protocol 035, which looked
at CD4 count and viral load trends in about 90 AZT-experienced volunteers taking
AZT/3TC, indinavir or the three drugs together. ACTG 320 also repeats the results
of a number of previous disease progression trials that added an additional agent
onto simpler regimens and found disease progression significantly reduced.
To achieve this modest end, ten people had their lives cut short.
Merck Protocol 028: A Dirty, but not Quick, Trial in Brazil
The most meaningful part of ACTG 320 may turn out to be the viral load data it
eventually yields. This data probably will show such a strong parallel between
reduction of HIV levels and reduction of disease events that one-year clinical
endpoints trials like ACTG 320 will be deemed unnecessary in the future. But even
if that holds true, the ACTG 320 viral load information was anticipated a year
ago by data from Merck protocols 035 and the much larger 028. Protocol 028, which
was terminated in March for reasons similar to ACTG 320, also was a disease
progression trial. Its initial viral load and CD4 count data were released along
with those of 035 at the FDA advisory committee hearing that led to indinavir's
approval (see Treatment Issues, March, 1996, pages 2-3).
Protocol 028 was designed for people with CD4 counts under 250 without any
prior anti-HIV therapy. The 996 trial participants (28% female) received either
AZT alone, indinavir alone or the AZT/indinavir combination. Last summer, people
taking the AZT-containing regimens were offered 3TC in addition, based on the
data from 035. Participants' short period on 3TC is not considered to have
affected the results.
The purpose of looking at this treatment-naive population with advanced HIV
was to obtain rapid disease progression data uncontaminated by issues of
resistance to AZT. Even without AZT resistance, it would have been highly
surprising if the AZT monotherapy arm had done as well as either of the arms that
included indinavir. The trial took place in Brazil because that is where a large
number of untreated people with low CD4 counts could be found.
Many Brazilians were not impressed by Merck's largess. Since the trial's
inception in April, 1995, community groups have protested it as unethical. The
monotherapy arms are considered substandard therapy likely to trigger HIV drug
resistance that would limit patients' future options, especially in regards to
protease inhibitors. Furthermore, Brazilians were unhappy that no changes in
therapy were allowed until a defined clinical endpoint occurred. Trial
participants would have to suffer through a series of minor ailments and falling
CD4 counts until a major AIDS-defining ailment transpired. Individual viral load
test results were not given to participants, and such tests were not available in
Brazil outside the trial.
Coincidentally or not, 028 was halted a day after a major article on the
subject appeared in the Miami Herald. The viral load and CD4 count data at a
median of 58 weeks reflected the pattern of a year ago: For the AZT monotherapy
cohort, viral load was down an average of .25 log (44%) and CD4 count was up an
average of 21 cells/mm3. For indinavir alone, the corresponding figures were
viral load down .76 log (83%) and CD4 count up 103, and for the AZT/indinavir
combination, viral load decreased 1.03 log (91%) and CD4 count climbed 112. As in
past comparative trials, AZT did little, either alone or as part of the double
combination, and this insignificant role was reflected in the clinical data -- 6%
on the double combination experienced an AIDS-defining condition compared to 7.8%
on indinavir alone and 18% on AZT alone. The difference between the first two
arms is not considered statistically significant.
There were about 40 extra deaths or serious illnesses on the AZT monotherapy
arm to prove a point that had become obvious. All survivors in the trial will now
receive indinavir for life, compliments of Merck. The company hopes the state
health system will supply the AZT/3TC or other drugs that patients should take in
combination with its protease inhibitor, but the public health plan has supplied
AZT/3TC irregularly so far. If the Brazilians in the trial now obtain all three
drugs, many will face the problem that first they received AZT then AZT/3TC and
then finally had indinavir added on. In the U.S., such an incremental sequence is
considered highly undesirable because it allows HIV to become resistant to each
medication, one at a time.
ACTG 333: Moving on, Quickly
A major issue in the controversy surrounding the Brazilian trial was the
threat of drug resistance arising from incomplete HIV suppression. Even the best
viral load reduction in that trial (1.03 logs from indinavir plus AZT, with only
42% below 500 copies/ml, the limit of detection) was not enough to shut down
HIV's evolution. The magnitude of this threat was underscored by data from ACTG
333, which was "interrupted" in March.
ACTG 333 was a test of the consequences of long-term use of the current "hard
capsule" formulation of saquinavir (brand name: Invirase). In this form,
saquinavir is very poorly absorbed by the digestive system, and the effect on HIV
is extremely modest (see Treatment Issues, May, 1996, pages 3-4). Participants in
ACTG 333 had been on the saquinavir hard capsule for at least 48 weeks, and the
median time on saquinavir was 112 weeks. They were assigned to receive their
current nucleoside analogs plus either indinavir or the new saquinavir
formulation in a soft gelatin capsule. This new formulation is much more
absorbable. At the recommended dose (1,200 mg three times a day), it attains
blood levels of saquinavir that are six to eight times greater than the previous
saquinavir regimen (the hard capsule at 600 mg thrice daily). A third, comparison
group was supposed to take the old hard capsule version of saquinavir for another
eight weeks and then were to switch to open-label indinavir.
An analysis of the week eight viral loads of the first 72 volunteers (the plan
was to enroll 144) registered results still more paltry than Merck's 028 trial.
Those who stayed on hard capsule saquinavir were unchanged, as expected. Those
who were switched to the soft gelatin capsule saw their viral loads drop by a
mere .23 log (42%) on average, accompanied by an average CD4 count rise of 37.
For the volunteers who were switched to indinavir, viral loads dropped by .58 log
(74%) while CD4 counts increased by 23 cells/mm3. These responses were not good
enough for the investigators. ACTG 333's design required termination of any
regimen that did not achieve at least a 0.7 log (80%) reduction in HIV. Trial
enrollment is now halted, and those on the hard capsule will be shifted to
indinavir while those on the soft gelatin saquinavir capsule will be offered the
choice of taking indinavir instead. When switching, trial participants should
consider changing their other anti-HIV medications at the same time as a further
guarantee against inadequate viral suppression and the rise of drug resistance.
Monitoring of CD4 counts and viral load will continue until July 14.
What happened? Nobody knows yet, but the widespread presumption is that the
problem is one of evolving drug resistance. Certainly exposing HIV to a low level
of a given drug and then later upping the virus' exposure is the classic way to
encourage the evolution of resistance to that agent. Lab studies of drug
resistance are based on this technique. It would not be surprising if saquinavir
resistance developed. And if indinavir's activity was diminished, too, then that
could well be because the mutations that cause reduced sensitivity to saquinavir
also lead to reduced sensitivity to indinavir. To achieve sufficient HIV
suppression, volunteers should have been advised to change their concomitant HIV
drugs in the first place. The ACTG 333 investigators are now checking trial
participants' HIV for drug resistance, using both test tube culture tests and
probes for genetic mutations.
Comment: New Ways to Answer the Basic Questions
ACTG 333 could represent the future as far as testing anti-HIV drugs is
concerned. Agents that do not show immediate and continuous viral suppression of
sufficient magnitude would be quickly discarded. The Food and Drug Administration
is planning a meeting this summer of its Antiviral Drugs Advisory Committee to
enshrine this approach. Anti-HIV drugs would receive accelerated approval based
on short-term, 16-week viral load data, and drugs would receive permanent, full
approval when a longer term viral load response, out to a year, say, was
documented. (This proposal reportedly comes from Glaxo Wellcome, which now has
two HIV drugs under development, the nucleoside analog 1592U89 and the protease
inhibitor 141W94.)
Trial participants would then be taken off study drugs if they failed to show
a viral load reduction or their HIV levels started to rebound. There would be no
need to prove what turns out to be a very limited point by letting them get sick,
as happened in ACTG 320 or Merck 028. The problem is that you cannot optimize
drug regimens just by looking at viral load response, even at one year. Viral
load responses do not necessarily reveal the total duration of response or
suggest drugs that could replace the current regimen should it start to fail. For
this you need an analysis of the "genetic barrier" surrounding the
virus, i.e., the number and position of gene mutations necessary to cause
significant losses in sensitivity to a given combination.
Two drugs might be as good as three only for a short period if HIV needs just
a couple of mutations to evade them. Cross-resistance is the other issue that
analyzing the genetic basis of resistance helps resolve. Mutations at certain
positions can negate the activity of several drugs at once, making certain drugs
unworkable as second line replacements for certain other ones.
But even having a resistance analysis in hand does not provide complete power
to predict a therapy's effect. Some mutations may hamper HIV replication while
others may lead to increased virulence. Multiple resistance mutations may have a
range of interactions, from disabling the virus to resensitizing it to certain
drugs or even reinvigorating it. The drugs themselves may have positive or
negative interactions, both in relation to the virus and the body's metabolism.
AZT and d4T seem to compete with each other for activation (phosphorylation)
within cells, for example, whereas ritonavir increases saquinavir levels by
blocking its metabolism in the liver.
The situation is far too complex to individually evaluate each combination
regimen. One way around this dilemma is to run large post-marketing strategy
trials. Participants and their doctors would be given wide latitude about which
particular regimens to start with or switch to, so long as they followed the
stated strategies, such as attempting to reach specific viral load goals or
interpreting mutation tests in a particular way. At planned timepoints, the
status of participants' HIV infection would be assessed and correlations between
healthy outcomes and treatment history would be used to create guidelines for
optimum care.
A NAC for Controversy
by Dave Gilden and Jill Cadman
The role of nutrition and vitamin supplementation in treating diseases has
always been controversial. This month and next, we will examine the class of
compounds known as antioxidants and the role they may play in slowing HIV disease
progression. While some reports have come to negative conclusions, many others
have suggested varying degrees of benefit. The most recent positive report
appeared in the March Proceedings of the National Academy of Sciences, USA.1 Its
results linked deficiency of glutathione, a major cellular antioxidant, with
shortened survival in HIV-infected individuals who have CD4 counts below 200.
NAC, or N-acetylcysteine, is essential for the synthesis of glutathione, and the
PNAS study indicates that oral administration of NAC can replenish glutathione
stores in people with HIV.
The paper's lead author, Leonore Herzenberg, Ph.D., of Stanford University,
summarizes her research conclusions in this manner: "We are not saying that
people should take NAC, just that the data are consistent with NAC being useful
[in prolonging survival] and that people with HIV should avoid behaviors that
deplete glutathione" such as chronic intake of alcohol or acetaminophen
(Tylenol). Given limitations in the study's organization, the inferences drawn
from it must remain tentative.
Glutathione is a key antioxidant compound required for the smooth functioning
of all cells. It is composed of three amino acids: cysteine, glutamine and
glycine. Besides acting as an antioxidant, glutathione is involved in protein
synthesis, amino acid transport, and in the recycling of other antioxidants, such
as vitamin C. Test tube studies2 have noted that lowering intracellular
glutathione levels decreases cell survival and limits T-cell response to foreign
antigens. At the same time, the cells become more easily activated and more
liable to improper programmed cell death ("apoptosis") in response to
inflammatory cytokines such as tumor necrosis factor alpha (TNFa). HIV
replication also increases in these cell cultures. Other studies, though, have
found no glutathione deficiency in people with HIV, hence belittling the
compound's role in disease progression.3
The Stanford Study -- Glutathione and Survival
Just this month, Leonore and Leonard Herzenberg and colleagues at Stanford
University published the findings from two analyses -- one an investigation of
the correlation of glutathione level in CD4 cells with CD4 count and the other a
trial designed to determine whether orally administered NAC replenishes low
glutathione levels.1 Researchers then went on to retrospectively analyze the
survival rate of the populations in both studies. The HIV-positive volunteers had
to have CD4 counts under 500 (no lower limit) and to be free of active
opportunistic infections or malignancies. Nearly all the 204 participants were
men.
In the initial survey, glutathione levels in CD4 cells closely correlated with
CD4 count. The average glutathione level in 79 uninfected controls was 28% above
those of 107 people with HIV and CD4 counts above 200. Glutathione levels in the
controls averaged 41% higher than the 97 HIV-positive volunteers with CD4 counts
below 200. Two to three years later, the researchers found that these glutathione
levels were highly predictive of survival in the stratum with CD4 counts below
200: Eighty-five percent of the 28 persons who started out with glutathione
levels within the normal range were still alive 900 days out, compared to only
about 18% of the 69 with below normal glutathione levels. (The small number of
deaths in the 107 volunteers with initial CD4 counts above 200 made it impossible
to find any correlation between glutathione and survival in that stratum).
Reviewing the findings, Dr. Herzenberg maintains that glutathione levels are a
more important predictor of survival than CD4 count. She commented, "If you
simply look at people with T-cells under 200, then T-cell count is the risk
factor. However, if you take into account glutathione levels, that steals the
significance of T-cells."
The Stanford Study -- Glutathione Replenishment
Dr. Herzenberg went on to state that she does not know if restoring
glutathione levels will necessarily increase survival. Low levels of glutathione
are associated with other illnesses and may be merely an incidental effect of HIV
infection rather than the cause of poor survival. Although the Stanford
researchers warn against taking substances such as alcohol or acetaminophen that
deplete glutathione stores, the long-term effect of these substances on disease
progression remains undetermined.
The second part of the Stanford study took the first steps in determining the
benefits of administering NAC in an effort to restore glutathione levels. Dr.
Herzenberg maintains that the trial can be viewed as a Phase I safety study and
showed that there were no harmful effects to the participants at the highest
dosages. Really, though, the trial was so loosely organized that it could be
better characterized as a pilot or feasibility study that would serve as a
preface for more rigorous investigation.
Participants started at 8,000 mg of NAC per day but had the option of reducing
this amount. Final daily doses ranged from 3,200 mg to 8,000 mg, with a median of
4,400 mg. Dr. Herzenberg now thinks that these extremely high doses, prompted by
previous studies showing low absorption of oral NAC,4 probably are not necessary.
The common dosages of one to two grams a day should be sufficient.
The 53 trial participants came from the survey participants with subnormal
glutathione. They all took part in the initial eight-week randomized,
placebo-controlled phase of the study. By the end of this first phase, those who
received NAC had largely restored their blood glutathione concentrations, with
the average level increasing to 113% of baseline. In contrast, the placebo
group's average glutathione level remained virtually unchanged. All subjects
completing the eight-week phase were offered open-label NAC for an additional six
months.
Although the researchers considered NAC safe, there was nonetheless a
substantial number of dropouts. Among the 37 participants with CD4 counts below
200 taking either placebo or NAC, nine left the trial, mainly in the first week,
because of nausea, digestive upset or rash, and three decided against entering
the open-label continuation phase after being on placebo for eight weeks.
Twenty-five others, 13 from the NAC arm and 12 from the placebo arm, did
continue, but most of those did not complete the extra 240 day follow-up period.
By day 200, half the remaining participants had dropped out. (For the trial group
as a whole, median follow-up was similar, 24 weeks.)
Dr. Herzenberg claims that the high drop-out rate was not because of side
effects or disease progression. She says that some participants simply did not
like the taste of NAC, which was administered as 800 mg effervescent tablets. She
also contends that since adverse events were evenly divided between the NAC and
placebo groups, the filler present in both the real NAC and placebo tablets was
probably to blame.
When checking up on survival two to three years after the baseline readings,
the investigators found that among those in the lower CD4 stratum, the 25
participants who received NAC had a statistically significant better survival
rate than 19 similar individuals who either did not enter the continuation phase
or never entered the trial in the fist place although eligible to do so. Dr.
Herzenberg argues that "the survival curve for subjects who took NAC is
displaced towards higher survival for about the same length of time as the
subject took NAC." To be more precise, no one died in the NAC group in the
first year whereas four people did in a "no-NAC" comparison group.
After that, the survival curves for the two groups descended at roughly the same
rate through the second year.
But this comparison is dubious. It is based on measuring the experience of the
25 who continued in the trial to 19 persons, dubbed the "no-NAC" group,
who either dropped out in the first weeks or refused to start once they were
admitted. One would suspect that this "no-NAC" group had some distinguishing
characteristics, probably related to greater illness in the first place. After
extensive investigation, the Stanford investigators have not identified any such
characteristic, however.
The PNAS paper only gives a sketchy account of the NAC trial. There are no
analyses of CD4 count trends (which apparently were flat for the NAC takers in at
least the first eight week randomized portion of the trial, but this has little
significance), opportunistic infections or adverse events, as is usually the case
in reporting the results of clinical trials. A formal, full trial report is only
now in preparation for publication. Also, viral load assays are currently being
run on stored plasma samples. A third planned paper will describe the relation
between glutathione levels, NAC treatment and viral load.
Dr. Herzenberg affirms that the trial data indicate that improved survival is
linked with restoring glutathione levels, but she acknowledges the need for
prospective long-term trials of NAC. A formal trial would monitor differences in
CD4 counts, viral loads or opportunistic infection occurrence in a single
population, some of whom were randomly assigned to receive NAC while others took
a placebo. Sophisticated testing is not likely to occur in the foreseeable future
for this inexpensive over-the-counter product. "We would like very much to
continue, but we can't find a sponsor," she says.
NAC obviously is not the equal of the protease inhibitors, but it could well
provide some extra benefit. While waiting for further information, Dr. Herzenberg
recommends using NAC as adjunctive therapy. There are no tests commercially
available to determine glutathione levels in a given individual. Since NAC is a
low cost, readily available and non-toxic compound, Dr. Herzenberg nonetheless
reasoned, "Why not take it?"
Other Studies are Conflicting
As noted above, many researchers in addition to the Herzenbergs have
postulated the use of glutathione replacement therapy in the treatment of HIV
infection to enhance the immune system. A continuous slow stream of papers come
out on the subject, and the Stanford study is not the only recent report.
Wulf Dršge of the German Cancer Research Center in Heidelberg was the first
investigator of glutathione deficiency in people with HIV5 and the original
proponent of NAC for restoring glutathione levels. But Dr. Dršge soon became
concerned that NAC might promote HIV replication. On the one hand, even a
moderate deficiency might be harmful to the immune system and contribute to the
pathology of HIV infection. On the other, superoptimal levels of the antioxidant
might suppress vital immune cell activity.
Dr. Dršge undertook two studies to determine whether this was the case. Both
studies revealed that NAC does not increase viral replication and at high dosages
may have an inhibitory effect. But he warned that the high level of NAC required
for such inhibition could be disruptive to immune cell metabolism, which requires
a certain level of oxidation, and cautioned against taking the 3,000 to 8,000 mg
doses used in the Stanford study. He advised against attempting to conduct trials
that looked at short-term effects on HIV replication rather than long-term
improvements in immune functioning.
Last May at a conference in Paris, Dr. Dršge presented a review of his work on
glutathione and NAC.6 He argued that abnormally low cysteine and glutathione
levels coincide with a decline in CD4 counts and were both a consequence and
cause of HIV infection, tipping the balance in favor of the virus. He also
described his institute's experience with administering NAC to patients for up to
four years. Doses of NAC were adjusted in each patient to maintain normal plasma
cysteine levels and ended up ranging from 600 to 3,000 mg/day. The possible
influence of NAC on the progression of disease in the German patients was not
described in this presentation.
A second warning7 was published recently by a group from Johns Hopkins
University looking at the effects of NAC and OTC. (OTC is another source of
cysteine for glutathione. It had no effect on CD4 count or viral load in a six
week dose-ranging trial in 24 HIV-positive volunteers with CD4 counts over 400 --
although it may have raised glutathione levels at the highest dose.8)
The Johns Hopkins study found that NAC enhanced HIV replication in cell
cultures consisting of resting peripheral blood mononuclear cells (PBMCs)
pretreated with NAC or OTC before infection. The source of HIV was a latently
infected lab cell line added to the PBMCs. The enhanced HIV activity seemed to
arise from an increase in cell-to-cell transmission from the infected cells to
the PBMCs via cell clumping. Similarly, HIV could be more frequently detected in
a mouse model of HIV infection when the mice were pretreated with OTC and then
inoculated with HIV. These models differ in a number of ways from giving NAC to
people with highly active HIV infections. The viral load data from the Stanford
study will help clarify their relevance.
The Johns Hopkins group concluded by recommending that HIV-infected people
receiving NAC should also receive appropriate antiviral therapy since adding AZT
to the cell cultures abrogated NAC's apparent HIV-promoting effect. In the
Stanford test of NAC, everyone was receiving a stable nucleoside analog regimen
(protease inhibitors were still unavailable at that time).
Finally, a Swedish group last August published the results of a true
randomized, placebo-controlled trial of NAC in HIV infection.9 Forty-five
volunteers with CD4 counts above 200 were assigned to receive either 800 mg of
NAC per day or placebo for a period of 16 weeks. Also included was a comparison
group of 16 HIV-negative volunteers. The HIV-negative group had higher cysteine
but not significantly higher glutathione concentrations than the HIV-positive
trial participants. Conversely half of the volunteers with HIV had elevated TNFa
levels. The group as a whole also evinced increased oxidative stress (as measured
by the investigators' assays of free radical production by neutrophils.)
Plasma cysteine levels did return to normal in the NAC group while remaining
low in the placebo group. Tumor necrosis factor levels also declined in the NAC
group. Otherwise there was no appreciable benefit: CD4 counts declined slightly
in the placebo group while remaining stable in the NAC group, but this difference
was not statistically significant. Also, glutathione levels remained unchanged,
as did the investigators' measure of oxidative stress.
The Swedish authors ended by calling for further controlled studies at higher
dosages and longer periods of time. As indicated by even the recent reports, NAC
and glutathione have a controversial history in HIV, and it may turn out that
higher doses, though perhaps not as high as those used at Stanford, may have a
role in preserving immune system function. That remains an open question, though.
So does the niche NAC could fill in the era of highly active antiviral therapies
-- reducing HIV levels by more than 99% could go a long way to relieving
oxidative stress all by itself.
It is probably not practical or ethical at this point to run simple active
compound versus placebo trials of long duration with an eye toward collecting
information on clinical endpoints or disease progression (see pages 4-7 of this
issue). For NAC, there is no financial incentive to do so, either. Still, it
would be enlightening to track viral load and immune function in people taking
NAC plus antivirals compared to others with similar anti-HIV regimens without
NAC. Such an observational study need not be inordinately expensive and would
yield important further information on the benefits of altering the cellular
environment while treating HIV.
1 Herzenberg L et al. Proceedings of the National Academy Of Sciences, USA. March
4, 1997; 94(5):1967-72.
2 Roederer M. Novel HIV Therapeutic Strategies (symposium). Cambridge Healthtech
Institute. Nov. 20-21, 1996.
3 Pirmohamed M et al. AIDS. May, 1996; 10(5):501-7.
4 Kalebic T et al. Proceedings of the National Academy of Sciences, USA. Feb.,
1991; 88(3):986-90.
5 Eck HP et al. Biochemistry Hope-Seyler. Feb., 1989; 370(2):101-8.
6 Droge W et al. Oxidative Stress and Redox Regulation (symposium). Paris,
France, May 21-24, 1996.
7 Chen P et al. AIDS. Jan., 1997: 11(1):39-41.
8 Kalayjian RC et al. Journal of Acquired Immune Deficiency Syndromes. Apr.,
1994; 7(4):369-74.
9 Akerlund B et al. European Journal of Clinical Pharmacology. August, 1996;
50(6):457-61.
Treatment Briefs
FDA Approves Nelfinavir
On March 14, the U.S. Food and Drug Administration granted Agouron's protease
inhibitor nelfinavir (brand name: Viracept) clearance for distribution through
the agency's accelerated approval procedure. Nelfinavir is the fourth protease
inhibitor to be approved for adults and the first to be approved for children.
The FDA-approved indication gives broad guidelines for usage, simply stating,
"for the treatment of HIV infection when antiretroviral therapy is
warranted." The adult dosage is 750 mg three times a day. The pediatric
formulation is available in an oral powder and doses are determined by weight for
children two to 13 years old. For optimal absorption, it is best to take
nelfinavir with a meal or a light snack.
Nelfinavir has considerable stability in the body, which allows patients some
leeway in scheduling their doses. Agouron spokeswoman Joy Schmitt commented,
"In all of our clinical trials as well as our expanded access programs,
we've always simply stated TID dosing [three times daily]. It's been as loosely
structured as that. There hasn't been a need to put a timing on it, though
obviously there needs to be common sense on how an individual would take the
drug."
The most common reported side effect is mild to moderate diarrhea, which
according to the package insert can usually be controlled with non-prescription
drugs. Although the FDA did not require that nelfinavir be used along with other
antiviral therapy, the package insert recommends combining it with nucleoside
analogs.
There has been much speculation on the utility of using nelfinavir as
first-line treatment. This is because HIV that develops nelfinavir resistance may
not be cross-resistant to the other current protease inhibitors, which could be
used as follow-up drugs. But such a conclusion is based on HIV isolates taken
from just five patients during nelfinavir therapy, according to the official
package insert. The isolates demonstrated emerging resistance to nelfinavir but
did not exhibit decreased susceptibility to the other protease inhibitors in lab
cultures.
For those people who have become resistant to other protease inhibitors and
need to switch treatments, nelfinavir could be an option. However, the package
insert notes that six of seven HIV isolates that had developed reduced
sensitivity to ritonavir during therapy with that protease inhibitor also showed
decreased sensitivity to nelfinavir. For more information on the nelfinavir
resistance question, see Treatment Issues, February, 1997, pages 6-8.
Nelfinavir is 29% more expensive than Merck's indinavir (Crixivan), with a
wholesale cost of $5650 for a year's supply. Although the New York State AIDS
Drug Assistance Program included nelfinavir on its list of covered drugs even
before FDA approval, widespread inclusion of nelfinavir in Medicaid and ADAP
formularies will further stretch scarce public health resources. There is a
nelfinavir patient assistance program reachable at 888/777-6637. The program will
first attempt to find outside means of reimbursement but can provide the drug
free of charge if necessary. Agouron will also provide nelfinavir free of charge
to uninsured children in the U.S..
Ritonavir Approved for Children
The FDA also granted approval for a pediatric ritonavir formulation on March
14. In so doing, the agency increased the number of protease inhibitors available
for children from zero to two in one day (see above for nelfinavir). Dosing
recommendations are based on safety data collected from ongoing studies of
children aged two to 16. The safety of ritonavir in children under two has not
been established. When taking ritonavir, children unfortunately suffer from the
same long list of side effects and drug-drug interactions as adults do. The
evaluation of ritonavir's antiviral effect in children is still in progress. An
interim report at this winter's Fourth Conference on Retroviruses and
Opportunistic Infections (abstract 722) indicated that ritonavir's antiviral
activity in children was similar to that in adults.
Since indinavir (Crixivan) entered the market in March, 1996, its
manufacturer, Merck & Co., has given the mail-order Stadtlander's Pharmacy
exclusive distribution rights in order to manage the limited supplies available.
This was to be a temporary situation until Merck was able to bring new production
facilities on line later that year. After many delays, Merck will finally expand
the distribution program to include other pharmacies as of May 1, 1997. But sales
will still be limited to participating pharmacies, and people must still enroll
in a cumbersome distribution program. We are not yet at the point when a person
can walk into a pharmacy with a script for this protease inhibitor and expect to
have it filled immediately.
Any pharmacy or provider interested in dispensing indinavir can register with
Merck. Participating pharmacies will report certain identifying patient
information so Merck can continue to monitor and control distribution. This is
referred to as "enrolling" patients and is being handled through a subsidiary of
Merck called PAID Prescriptions. The participating pharmacy will only receive a
month's supply of indinavir for each enrolled patient after transmitting the
pertinent information to PAID (via fax, phone or computer network). Pharmacies
must also confirm with PAID each month that the patient needs to refill an order
before the medication will be shipped (PAID will fax a reminder to the
pharmacist).
It is therefore very important to make sure the pharmacist requests the refill
in advance so that it will be ready to be picked up when needed.
According to a Merck spokesperson, indinavir will not be going into normal
distribution in the foreseeable future. Merck states that special measures are
still necessary in order to insure all patients have uninterrupted access to the
drug. Although production has increased, supplies must still be closely monitored
due to demand in nations where indinavir is newly approved. (Indinavir has been
approved in 49 countries to date, the most recent being Albania).
Those patients already enrolled and receiving indinavir through Stadtlander's
may continue to do so by simply filling out the monthly refill cards as usual. No
one is under any obligation to continue using Stadtlander's, and those who wish
to switch will be able to mark a box on the April refill card to that effect.
These people should then enroll with another pharmacy and make sure there will be
no problems with insurance coverage. A new paper prescription will be required in
most cases by the new pharmacy, but doctors will not have to call to enroll
patients, as was the case in the past. New patients just beginning indinavir can
sign up with their participating pharmacy of choice. Note that there may be a two
or three day delay between enrolling and receiving indinavir for the first time.
Anyone who needs help enrolling in the distribution program, locating a
participating pharmacy, or obtaining financial assistance should call
888/CRIXIVAN.
Both Chiron and Roche have set up patient assistance programs (PAP) to ensure
there is access to viral load tests for those who have no current means of
payment.
The number to call for information (in English or Spanish) for the Roche
program for PCR tests is 888/TEST-PCR. The PAP representative will first
determine whether the caller is eligible for coverage through an insurance
company and will assist in negotiating with that carrier. If third-party
reimbursement cannot be arranged and the applicant is qualified, Roche will send
the applicant's doctor a voucher for a free test, along with the address of the
laboratory designated to perform the test. There is supposed to be a two week
turnaround time from initial call to approval for those who qualify. Eligible
patients are entitled to a maximum of five free tests per calendar year and must
go through a simplified recertification process for each additional test.
The number to call for information on Chiron's bDNA PAP is 800/775-7533. This
is the reimbursement hotline, which assists people in finding payment methods and
working out problems with claims (prior to April 15, 1997 inquiries about the PAP
can be directed to 888/HIV-LOAD) The bDNA test is still not FDA-approved, but,
according to a survey done by Chiron, most claims are being paid for by private
insurers, Medicaid or ADAP. For those who have no means of payment, Chiron is
working with certain local hospitals and clinics that serve indigent or uninsured
patients to provide free tests on site. This means that a person must register
with a participating medical facility in order to have access to the program.
Facilities are being targeted in large urban areas with several sites already on
line in San Francisco, Los Angeles, Boston and Chicago and others planned in
cities with large populations of people living with AIDS. The program is not
available to those outside the immediate geographic area.
One final note for those who had PCR tests performed last summer under Roche's
free introductory program and never received the results due to a massive logjam
at the labs involved: Roche is still offering two complimentary replacement tests
(see Treatment Issues, November, 1996, page 12). Physicians can request coupons
for patients in this situation until the end of June. The coupons are valid for
six months from date of issue and can be unofficially transferred to any patient.
Doctors can also call the PAP number, 888/TEST-PCR, to obtain the coupons.
Editor: Dave Gilden
Associate Editor: Jill Cadman
Medical Consultant: Gabriel Torres, M.D.
Art Director: Adam Zachary Fredericks
Technical & Marketing Coordinator: Chuck Sock
Proofreaders: Carole Lemens, Susan McCreight, Carol Vizzier
Volunteer Support Staff: Edward Friedel, Helen Kane, Lenore Rey, Eva Zysman
Treatment Issues is published twelve times yearly by GMHC, Inc. All rights
reserved. Noncommercial reproduction is encouraged. Subscription lists are kept
confidential.
GMHC Treatment Education and Advocacy 129 West 20th Street, New York, NY 10011
Fax: 212/337-3656 e-mail: DAVE_G@gmhc.org © 1997 Gay Men's Health Crisis, Inc.
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