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Past Issues
Volume 15, number 10
October 2001
Contents
All My Trials
A research coordinator and her subjects tell why they do it
The Talk of Silver Spring
Q&A about tenofovir's approval
The Meeting that Wasn't
ICAAC sidetracked, but tenofovir abstracts tell the tale
Opinion
Rethinking priorities in this brave new world
Both Sides Now
Many Paths Bring People to Research
By Sue Gibson
Why I Work in Research
In U.S. hospitals, nurses keep medical records in fairly understandable
English — well, maybe more Latin than English — but despite
the jargon, a patient's story is told with words. Research nursing
is different. Research medicine has its own system of numerical
codes to account for almost every conceivable medical event that
a patient might experience while on a study. Every ache, pain and
rash, every drug consumed, every lab test blip, whether related
to HIV or not, has to be carefully coded and recorded for as long
as a participant is enrolled. It's the perfect job for the hopelessly
anal-retentive. That's why I love it.
A good research coordinator has to be incredibly conscientous about
details when preparing for a patient's visit, while meeting with
the patient, then just as painstakingly thorough about doing the
paperwork afterward. Everything recorded goes into the computer
at the data center, where it is checked for consistency. For example,
if someone in an HIV trial has a motorcycle accident, the date of
the patient's back injury and lacerations must coincide with the
dates that antibiotics and pain medication were given. If it doesn't,
the computer spits it out and a trial monitor asks for clarification
at her next scheduled visit. That's why everything must be put into
the file while it's still fresh in the mind.
It took me many years to discover research. When I graduated from
nursing school in 1980 there was a shortage of nurses and we had
our pick of jobs. I decided to keep working on the internal medicine
ward of the big-city public hospital where I'd received most of
my training. We dealt with organ failure, autoimmune diseases and
a wide range of non-contagious infections; the variety made the
work interesting and challenging. But I especially liked being able
to give care to people who couldn't afford to be treated by the
other hospitals in town. Our hospital rejected no one.
After a couple of years, I moved to the renal transplant unit.
Transplanting kidneys involves artificially inducing immune deficiency
with drugs in order to prevent tissue rejection. On this ward I
became familiar with several unusual infections such as pneumocystis
carinii pneumonia (PCP) and cytomegalovirus (CMV) that transplant
patients often came down with when their immune systems were suppressed.
Oddly, we started to hear that on the East and West coasts, certain
non-transplant patients were also developing these rare infections.
At first, the "gay plague" that was terrorizing San Francisco and
New York seemed remote. But soon, doctors began talking about the
"4H"s that seemed to be susceptible: homosexuals, heroin users,
hemophiliacs, and Haitians.
Since I had several gay male friends, I paid close attention. One
friend in particular started to develop certain suspicious symptoms
such as enlarged lymph nodes, shingles, and weight loss. Despite
my alarm, common sense told me if this syndrome was only showing
up in these specific populations, then it was probably not spread
by casual contact. So when I heard that nurses had left meal trays
outside the door of a patient with Kaposi's sarcoma, I transferred
back to internal medicine. I welcomed the opportunity to dispense
care where it was so clearly needed and I wanted to learn more about
the syndrome that was still being called GRID (gay-related immune
deficiency). Within a few years the syndrome had a new name, a causative
virus had been identified and many of my friends and acquaintances
had tested positive. Sometime during that period, I too seroconverted.
I worked on the internal medicine ward until 1993, compulsively
keeping a list of the names of my patients who had died. When I
finally decided to make a change, I took a job at a small outpatient
infusion company run by two women, one of whom had lost her brother
to AIDS. But when HAART came along bringing the miraculous "Lazarus
effect" in 1996, that business began to fail and I cut back to working
just a few part-time hours per week.
One day the director of a community-based organization where I
volunteered asked me if I could come over and "help out" in their
small research clinic. I agreed, though with some hesitation, since
I knew nothing about research nursing. The clinic had been contracting
with pharmaceutical companies to conduct Phase III drug trials,
but after a period of downsizing, only one research nurse remained.
I jumped right in, learning the ropes from him and from the site
monitors sent by the drug companies. Before long I realized I'd
found heaven. I loved everything about research! Not just because
I'm naturally obsessive about details, but also because I rediscovered
the joy of providing people with cutting-edge treatments, lab tests,
and medical visits — at no cost to them! Plus, the new drugs
were working. People looked and felt better. It seemed research
was finally paying off.
Entering the world of research during the advent of protease inhibitors
also meant that my contact with the dying diminished. Fewer people
with HIV were getting desperately sick, and the volunteers in the
trials I was coordinating tended to be at earlier stages of their
HIV disease. I was thankful and excited to be a part of something
that had the potential to slow or possibly stop the devastation
that I'd seen so often in the past.
It was only later, after I learned that resistance develops when
inadequate doses and drugs are given, that I realized with horror
I had been complicit in decreasing some people's options by doling
out each new drug, one at a time, as it came on the market. I still
have a lot of anxiety when I imagine that something we learn in
the future might tell us that something we're doing now is wrong.
After about three and a half years in the little community-based
clinic, I moved to the infectious diseases clinic at a larger, busier
university medical center, which is where I work today. Though I
ended up in research by accident, it feels like a more honest place
for me to be. Instead of saying, "Take your medicine; it's good
for you," I can comfortably tell people that, "this is a new product
or a new combination and we don't yet fully understand what the
risks and benefits might be. Thank you for helping to find out."
Why They Volunteer
Over the years I've learned that people choose to participate in
research studies for many kinds of reasons. I recently got in touch
with some former and current "lab rats" to ask them about their
experiences. No research study can benefit everyone, but in general
I've found that when people are well treated and they understand
the risks, they have had positive experiences. Even so, not everyone
had an easy time of it.
Mike
Not a volunteer in the strictest sense, Mike was barely a teenager
when he began taking walloping doses of the only AIDS drug available
at the time, AZT. He didn't tolerate its toxicities very well and
had to have repeated blood transfusions. A few years later, he enrolled
in a trial and started taking ddI. This was when it came in a packet
like Carnation Instant Breakfast.
"I remember the ddI was extremely disgusting," he recalls. "Almost
so bad that I'd rather die of AIDS than take it! I remember throwing
up the ddI most of the time, but NOTHING was as bad as those high
AZT doses.
"I don't really remember much from around that time. From the age
of 15 to 21, everything is really jumbled — I guess it was
a period of stress or something," he laughs.
"It's never comforting knowing you're a guinea pig but it would
be nice to be informed why certain drugs smell like gasoline and
make your mouth numb. I understand the contribution of drug trials,
but I don't like taking these drugs. Of course, nobody does."
Mike can't forget the role the pharmaceutical companies played
in distributing blood products to treat his hemophilia during the
years when HIV was clearly in the blood supply. He also recalls
how the distributors and the FDA remained silent. "I feel completely
helpless relying on drug companies that seem like they have had
more experience trying to kill me than trying to help me. It's like
my health just doesn't compare to the value of their stock."
Mark
Another experienced research participant I spoke with has a long
track record of helping others in the HIV community. For Mark, joining
a research study seems to have been a natural extension of his volunteer
instinct.
The first clinical trial Mark participated in investigated treatments
for staphylococcus infection. "I was just recovering from a surgically
caused staph infection. [The principal investigators of the study]
came to me and said, 'We don't want to pressure you, but...' They
asked me to please consider their study. [Ultimately] the study
was discontinued. I still don't know if I was getting the real drug
or the placebo."
Even so, when asked if he felt the experience benefited him, Mark
replied, "Yes, I think so. If nothing else, I was contributing to
the gaining of knowledge. Participating in studies is one small
way I can [pay back] the privilege of being taken care of by the
medical community. And it takes studies to find answers. Information
is power."
While altruism is a remarkably common, yet undervalued, motivation
for participating in research, the best match between subject and
study comes when the research addresses an unanswered question that
will not only help society, but can help the volunteer's situation
as well.
Currently Mark is in a trial to study the usefulness of phenotypic
resistance testing in constructing treatment regimens. He needed
to switch drugs because of virologic failure and because of toxicity.
"One of my drugs was destroying my liver. They ran a phenotype and
found out [my virus] was resistant to every [antiretroviral drug]
out there. [They found the least resistance] to two drugs and they
put me on those. And I'm on open-label tenofovir. But this study
[continues] whether I'm on meds or not."
Mark feels that he is benefiting from this trial as well. "They
found a combination that hopefully will be working. I don't go in
for my first labs [for a couple of weeks yet]. I'm assuming they'll
be working! I believe in the theory of positive thinking."
Participation in research doesn't take the place of comprehensive
medical care. Although the principal investigator of a trial is,
on occasion, required to examine research volunteers, that physician
is not directly responsible for medical issues not related to the
study. Study participants need to keep seeing their primary care
providers on a regular basis. A big part of the research coordinator's
job is to ensure that there is a flow of information between providers
and the investigators. For instance, lab results collected for the
study can be shared with a patient's provider at no expense to the
patient, his insurance company, or to federal Ryan White Care Act
funds. When the protease inhibitors first appeared, the reimbursement
issue was a big incentive for many people to join trials, especially
those who lacked insurance or were afraid to use the insurance they
had. With the various AIDS drug assistance programs (ADAP) in place,
that's become less of a motivator.
Then as now, a major incentive for joining a study is the hope
of gaining access to an experimental drug before it's approved.
But this is never a certainty. Since research studies need to create
a difference between how groups of participants are treated, no
one in a randomized trial can be guaranteed access to a particular
regimen. For people with limited choices, expanded access safety
studies may offer a better shot at getting a desired experimental
drug. Unfortunately, expanded access programs are rarely large enough
or started early enough to fully meet everyone's need for new treatment
options.
Time and again though, research volunteers often say that the most
important health benefit they receive from being in a clinical trial
— over and above the value of an experimental drug — is
the close and careful attention they get from the research staff.
As Mark pointed out, "The sheer fact that I'm on a study, I feel
I get closer medical attention, and for that I'm very grateful.
To be on a study is actually easier for me than going to my regular
doctor — it's less stressful. I'm not in the same waiting room
with the mass of people going to see the clinic doctors. It's almost
like you're getting VIP treatment."
As is evident in the next case, joining a research study can open
doors to a quality of care unimaginable at a local clinic.
Gerri and Jason
Gerri was first alerted to her own HIV status when her son, Jason,
was diagnosed at three months of age in 1989. At diagnosis, Jason's
physician referred the family to several larger cities in a quest
for care, since AZT was not available for babies at that time. Jason
was unsuccessfully screened for three studies before being enrolled
in a trial at the National Institutes of Health (NIH), in Bethesda,
MD. He finally received AZT oral suspension, his prognosis improved
and he lived for two and a half more years. He participated in a
second trial that, as Gerri recalls, involved an IV pump, but this
did not help him. "It's the luck of the draw," postulates Gerri,
"Some things work and some things don't." With pride, she says,
"Jason was a pioneer. At least we had hope; at least he had a chance.
We learned a lot about what [medicinal therapy] can do and what
it can't."
In 1990, while staying with Jason at Children's Inn, a home-away-from-home
for children being treated at NIH, some of the other mothers suggested
that Gerri look into NIH trials being conducted for adults. "At
the time, I was just on AZT and was getting anemic and tired. I
had no energy, wasn't looking good, and was losing weight. I checked
into a ddI trial and was accepted."
The ddI product was the same stuff Mike took — a powder she
had to mix with four ounces of water. "I mixed it with warm water
because it seemed to dissolve better and I took it on an empty stomach.
Carrying it back on the plane, I had two huge boxes of ddI. I didn't
want to check it; I wanted to have it with me."
Gerri believes the research benefited her: "Most definitely. My
blood work [improved]." She feels that the extra medical attention
she got by flying to NIH every six weeks worked to her advantage
although it was tough. "The travel was draining me. It was exhausting,
but I would say it helped me because they would collaborate with
my physician.
"There's the social part of it, too. Most of the people I met were
men, and they were gay. It was a lot of fun. I enjoyed seeing the
same people who were on the same schedule. We learned from each
other. I got to realize that I wasn't alone. It was very important
for me to know that I wasn't going through this by myself. Some
of their stories were actually worse than mine, [with] the discrimination
they had seen. We looked each other up when one of us was sick,
or one of our kids was sick or had died."
But when ddI was finally approved, her support system ended. "The
ddI trial was discontinued due to lack of government funding. They
decided not to do any long-term trials; they were only going to
do short-term studies. Videx was approved by then, so I could go
back home and be seen by my doctor and receive the same thing. But
I missed the adventure; being tied down at home as the caregiver,
it was my one chance to escape and have fun. I was working as a
peer educator at the local AIDS foundation and my brother was dying
[of complications of AIDS], so I lost most of my contacts. I was
very upset, knowing that I wouldn't see my [NIH] friends anymore
— the health care workers in addition to the patients. I felt
I was losing family members."
Gerri later joined another trial in her community. "I had oral
hairy leukoplakia and I became a participant [in a trial] to treat
that. I liked it because it was herbal, and it worked."
She also entered a major pharmaceutical study: "I tried all the
approved drugs. The last trial I participated in was Kaletra. I'm
still on it and my viral load is undetectable and my T-cells are
on the rise. Although the virus is not progressing, I am seeing
some side effects from being on a triple combo — Ôprotease
paunch' and my veins are prominent."
Yet she still has reservations about the kind of studies she would
feel comfortable with. "I would only participate in Phase III trials;
I wouldn't have the guts [to volunteer for earlier phase trials]
unless I was desperate. Right now my viral load is undetectable
for the first time in my life so I wouldn't want to risk that ...
and I have more of a reason [to be careful] since my daughter has
been born."
Gerri's two-year-old daughter, Alaina, has been a trial participant,
too. "When she was born, she was given a one time dose of nevirapine,
but she continued taking oral AZT [until they knew she wasn't infected]."
Gerri is open to joining other research studies in the future if
they'll have her. "There is a Serostim trial going on, but they
don't provide transportation and they say I don't have enough wasting.
It's very frustrating when trying to enroll in studies because they
only want people who aren't too healthy or too sick. Mainly they
want more healthy people in the trials because if you have healthy
people, you're probably going to have more promising results than
if you have sick people.
"The other frustrating thing that I've seen related to clinical
trials is that there are far more men participating than women and
someone needs to take a look at why. I suspect that women are more
in the caregiver kind of role. They make sacrifices every day, taking
care of their husbands, their family, their children, and they always
put others first."
I asked Gerri if she had ever been in a study that didn't benefit
her. "No, trials work to a degree. After a while the drugs lose
their efficacy. I envision them as lily pads, and when one starts
sinking, you hop on another one before it starts sinking, hoping
one day that you reach dry land. I think subjects know that they
are human lab rats and that [no one can] guarantee that the trial
is going to help. Hopefully people won't look at it as a guarantee,
because nothing's guaranteed in life except death."
I asked Gerri where she thinks she would be today without research.
"I wouldn't say there's no doubt, but I probably would have been
dead. Research hasn't cured me, but it has given me my life back."
Why We Keep Showing Up
These stories illustrate a few of the ways that research has affected
and has been affected by real people living with HIV in the United
States. Mike, Jason, Gerri and Mark represent only a snapshot of
those who have extended themselves — sometimes in desperation,
sometimes when there were less risky choices — to help discover
what a new therapy has to offer. They have taken risks, and as with
all things uncertain, sometimes they have benefited and other times
they haven't. But, like volunteers in most trials, they made a contribution
to the body of knowledge that has brought HIV treatment to its current
state and will hopefully continue to provide better options.
As for me, I'm continually impressed with the dedication people
demonstrate when they volunteer for clinical trials. They show up
for research clinic visits in addition to keeping appointments with
their regular health care provider. They sit patiently while I ask
an endless number of tedious questions and, in most cases, collect
multiple tubes of blood. Together, we wait anxiously for lab results
and have an ongoing dialog about whether this study is helping.
Though we rarely say so, I think we understand each in our own way
that helping to move research forward is the best chance we have
to make sure no one else has to go through what Mike and Gerri and
Jason did.
On Approval
By Bob Huff
On October 3rd, in Silver Spring, Maryland, the Federal Food and
Drug Administration convened a meeting of its antiviral advisory
committee to discuss issues pertaining to the approval of a new
HIV drug, tenofovir disoproxil fumarate (TDF), branded "Viread"
by its sponsor, Gilead Sciences. Although the opinions of advisory
committees are not binding upon the actions of the FDA, and in this
case, the regulators did not even ask for a formal vote on tenofovir,
historically, the agency has paid careful attention to the views
of its expert advisors.
The group's deliberations provide a great deal of insight into
the drug approval process, the ways different doctors and scientists
view drug safety and efficacy, and the issues raised by this drug
in particular.
What follows is an interpreted but faithful report of some of the
participants' questions and opinions. For more comprehensive reviews
of the data supporting Gilead's application for TDF and detailed
descriptions of the clinical trials that supplied the data, you
may wish to consult reports prepared by various online information
resources (see Web addresses at the end of this article).
After a brief presentation of safety and efficacy data by the sponsor
and a summary presentation by the FDA, committee members began asking
questions to clarify their understanding of the data.
Q: One person died while on study 902. Do you know why?
A: The patient had a history of depression and committed
suicide.
Q: In study 901, why were average CD4 cell count increases
greater at the 300mg doses than at the 600mg doses?
A: The CD4 variability in study 901 is probably due to the
small number of patients involved. From the study of high-dose,
intravenous tenofovir (study 701), it appeared that the maximum
anti-HIV activity was reached at the 300mg dose. So there is no
further data on the 600mg dose after the 902 study.
Q: At 24 weeks, 3 percent of patients had the K65R mutation
in the viral reverse transcriptase. Has that proportion remained
consistent in subsequent weeks and in larger trials?
A: Yes, the rate remains low even after expanded dosing.
Q: How many patients in study 902 had a viral load higher
than 50,000 copies/mL?
A: I don't know, but looking at the quartile baseline viral
load, in the highest quartile the mean baseline viral load was about
70,000 copies/mL.
Q: Is continuation of 3TC necessary to get the increased
activity of TDF against 3TC resistant virus?
A: We don't know.
Q: How durable was viral suppression over time; how often
did blips in viral load occur during the year?
A: I don't know.
Q: Do you have any information on the number of previous
drugs that the patients had used?
A: No.
Q: Did you collect adherence data during the trials?
A: No.
Osteomalacia Interlude
At several points in the meeting the committee turned its attention
to specific concerns about an unusual bone formation abnormality
associated with lack of phosphorus availability that was seen at
high doses of tenofovir in animal studies. Parts of those discussions
are collected here.
Q: Were continuous 24-hour urine tests done to look for
abnormal phosphorus levels?
A: No, only spot urine collections were performed and these
tests showed no statistically significant differences in the median
change from baseline phosphorus fractional excretion between people
on TDF and those on placebo.
Q: The differences may not have been statistically significant;
nevertheless it appears that fractional phosphorus levels were higher
for TDF at every time point on the slide.
A: They were not significant differences.
Q: Do you have any information about alcohol abuse or chronic
diarrhea in regards to phosphate wasting in the study patients?
A: This was not analyzed.
Gilead hired a bone disease expert to put the toxicity issue
into context. Dr. Teitelbaum made his presentation by telephone:
"Some bone basics: This problem is not the decreased mass of mineralized
bone known as osteoporosis. In osteomalacia, bone is normally made,
but unmineralized bone matrix accumulates because it cannot be mineralized
in its environment.
"Bone doctors love to see osteomalacia because they can cure it.
Hypophosphatemia (low blood phosphate level) is the most common
cause — the bone is not seeing enough phosphate. If circulating
levels of phosphate are normal, osteomalacia will not develop.
For example, patients on excessive antacid therapy can bind phosphate
in the gut and develop osteomalacia; however, they recover when
antacids are stopped.
"From the TDF data, this is not about hyperphosphaturia (due to
excess renal excretion of phosphorus) because urine phosphate elevations
were not seen. Therefore this is not serious in this case.
"The serious osteomalacia seen in the monkeys was reversible. The
worst possible scenario for humans is that a patient develops osteomalacia
as severe as was seen in the monkeys. They then stop the drug, get
supplementation and they are cured."
Back to the Questions
The FDA invited two bone disease experts as independent evaluators
of the toxicity data. Dr. Leukert attended by telephone; Dr. Bone
(his real name) was present in person:
Q: (Dr. Bone) I would like to see a rate of decline for
phosphate. Is there histology from the no-effect dose on monkeys?
A: No, histology is only available from the monkeys with
osteomalacia.
Q: On the dog study, vitamin D levels were reduced. Was
this seen on any other studies?
A: No other vitamin D levels were taken.
Q: (Dr. Leukert) When did phosphorus supplementation begin
for patients in the studies?
A: It was mixed. Some began supplements at their first low
phosphorus reading and 51 patients did not receive supplements.
Most had low phosphate levels on no more than two consecutive visits.
Q: Were any specific questions asked to elicit the incidence
of bone pain?
A: No.
Q: (Dr. Bone) Regarding the necropsy studies on dogs and
monkeys: Did you find a no-effect dose in that histology?
A: In dogs, the doses were 10-fold higher than in human
doses; in rats, doses were 20-fold that of the human dose. The no-effect
dose was 100mg/kg (similar to a daily dose of 6,000mg for a person;
the recommended adult dose of TDF is 300mg/day). It was only after
toxicity showed up in the efficacy studies that bone toxicity studies
were designed.
Q: Did you measure magnesium status in humans or animals?
A: No, we only measured total serum magnesium levels.
Q: Your bone mass density (BMD) studies are mostly from
lumbar spine and femurs. Were any BMD done on the forearm —
non-load bearing, cortical BMD measurements?
A: No cortical measurements were made.
Q: What is your long-term safety study commitment for TDF?
A: Most safety data will come from study 910 in which patients
will be followed until December 2002. The safety data gained from
expanded access patients will be reported separately.
Which Side Are You On?
At this point, the FDA representative presented the big question
that the agency wanted the committee to consider and a round-table
discussion commenced.
In what population has efficacy been shown?
Dr. Yogev: Efficacy has not been proved in a population with high
viral loads or in those naïve to antiretroviral therapy. I
wonder if the mean reduction of viral load by -0.6 log over placebo
will also hold for those with higher viral loads? In other words,
should TDF be among the first line of drug choices?
Dr. Hamilton: Whether or not naïve patients have been shown
to respond is not as important as the issue of treating experienced
patients with higher viral loads. Frankly, most of the people treated
in these two studies may not have needed treatment at all, given
the new guidelines. (Mean CD4 counts were about 375 and the mean
viral load was under 10,000 copies.) I don't feel compelled to drive
the virus low when it is futile and unnecessary.
Dr. Pomerantz: Some data is missing but we think we know what that
is. We don't have data for naïve patients or for those with
high viral loads — so there are two missing data sets.
Dr. Shapiro: We haven't seen a lot of data. This experienced population
may be exposed to certain risks, but we also think that there are
benefits that outweigh the risks. However, the risk is greater than
the benefit for those who have many other options. So the risk/benefit
equation is mixed.
Dr. Tebas: Before using this drug in naïve people, I want
them to show me some more data.
Dr. Munk: I have a question for the FDA: In the past, have broad
approvals been given to drugs based on data from naïve populations
but little data from experienced patients? (Yes.) Then I think it
would be a departure from past practices to limit the indication.
Dr. Kumar: There seems to be no significant safety concerns with
using this drug in the population where we would be most likely
to see side effects. However, if state AIDS drug assistance programs
(ADAP) won't pay for it due to a limited indication, that's a problem.
Dr. Stanley: First let me say that in Texas, once a drug is approved,
we don't second-guess the physician; our state programs would pay.
However, I continue to have concerns about making this broadly recommended
at this time. There are unanswered questions: Does TDF need to be
used along with a protease inhibitor in a regimen for naïve
patients? The study in progress for naïve patients only looks
at it combined with a non-nucleoside RT inhibitor (NNRTI). But it
is clearly efficacious in salvage therapy and we should go ahead
with it.
Dr. Wood: Obviously there is a need for this drug. If it is approved,
it will be used. The people who need it and will use it right away
will likely have high viral loads. So the sooner we can get efficacy
information for them, the better.
Dr. Pomerantz: It's a tough call. HIV treatment is a dynamic field.
It's not like it was five years ago. I don't think we need to have
two data sets missing and still put it out there.
Dr. Wong: I want to put another face on what we're talking about.
We shouldn't ask sponsors to prove that their drugs are the best
in all situations. We are considering an approval that is substantially
more restrictive than for any other antiretroviral drug. What they've
shown is that their drug is safe and effective for adults with HIV
infection. And we shouldn't try to split that any further.
Query to the FDA: How long will it take to get data from the
trials in naïve patients?
FDA: When the new data is submitted, we will decide if it gets
a 6- or a 10-month review. It may take about a year to receive the
data, review it and make a decision.
Dr. Johnson: There is excellent data on the treatment-experienced.
I think we're splitting hairs. There is no upper limit to salvage
use, no matter what the viral load. With regard to the treatment-naïve
population, we have no precedent for half a label.
Dr. Sun: On safety, this drug seems to be safe. On efficacy, it's
a lot easier to extrapolate from experienced to naïve patients.
There is biological plausibility. naïve patients will be getting
a greater number of active drugs than the patients on these studies
did. History may not be helpful here; five years ago we didn't have
protease inhibitor-experienced patients. We typically extrapolate
data to multiple uses without specifying them on the label.
Dr. Hamilton: We have two potentially competing responsibilities:
First, evaluate the data in a cut and dried way. A second responsibility,
by implication, is what we recommend to the public. We should separate
in our minds what we say. We probably agree about what the data
says but should compromise with a cooperative sponsor about what
the details of the approval will be.
Dr. Yogev: I have concerns about patients coinfected with hepatitis
B virus using this drug if it results in HBV resistance. The label
should warn about the risk of using only one active anti-HBV drug.
I would also prefer to restrict the indication to people with lower
viral loads.
Dr. Stanley: Our recommendations have weight, as Dr. Hamilton said.
The drug is important for salvage, but people will use it as they
wish. But what I'm comfortable with is to say what we saw in the
data.
Dr. Gulick: Let me summarize: We're unanimous about its value for
the experienced salvage population. But there are concerns about
using it in patients with high baseline viral load and in treatment-naïve
patients. This is a tough call. How much extrapolation are we comfortable
with? In the guidelines for accelerated approval, a meaningful benefit
over existing treatments must be shown, yet we don't have comparative
data.
The members who would support a broad indication are more comfortable
extrapolating from this data. They also cite precedence as a guideline.
Dr. Gulick then asked for an informal and nonbinding vote.
Wang: Full approval.
Shapiro: Want to see more PK data.
Kumar: Given everything we've seen it should not be restricted.
Yogev: I'm uncomfortable with full approval.
Stanley: This is a whole new kind of drug. We need to know more
about the interactions.
Pomerantz: For naïve patients, I'd like to make the sponsor
show us that the drug is effective one more time. There's no hurry
to jump the gun with full approval. I would recommend TDF for use
in those with prior experience.
Wood: naïve patients usually have high viral load so I don't
think it is reasonable to extrapolate.
Tebas: The biggest impact of our decision will be on marketing.
If FDA approves the broader indication, then we will see the drug
marketed to naïve patients.
Munk: I'd vote for full approval based on prior practices. I'm
also concerned that a partial indication may deter some ADAP programs
from adding the drug to their formularies.
Sun: Can we get full approval with caveats about the data that
is lacking?
Gulick: I'm concerned about the risk/benefit ratio. I'd vote to
restrict its indication while waiting for the pending data.
Drs. Leukert and Bone abstained.
On October 26, the FDA approved tenofovir without restrictions
for use in adults with HIV.
For more information on the Web
National AIDS Treatment Advocacy Project:www.natap.org
Treatment Action Group: www.treatmentactiongroup.org
British National AIDS Manual (aidsmap): www.aidsmap.com
amfAR HIV Treatment Directory: www.amfar.org/t
U.S. Food and Drug Administration: www.fda.gov
Gilead Sciences: www.gilead.com
Gilead's Trials for tenofovir disoproxil fumarate
(Viread) Study 701: This was a Phase I, dose ranging
trial of intravenous infusion of tenofovir to show safety and activity.
Study 901: This was a Phase I placebo-controlled study of
tenofovir monotherapy in 49 individuals for four weeks. Both treatment
experienced and naïve patients participated. Oral doses of
75mg, 150mg, 300mg, and 600mg were evaluated. Based on this study
the adult dose of 300mg/day was selected. These results were present
to the FDA.
Study 902: This was a Phase II trial in 189 treatment-experienced
individuals. Three doses of TDF were compared to each other and
to placebo by intensifying stable HAART regimens. Viral load differences
were evaluated after 48 weeks. Individuals who added a daily 300mg
dose of tenofovir had a mean viral load that was -0.62 logs lower
than those who received placebo. These results were presented to
the FDA.
Study 903: This is an ongoing 48 week Phase III trial in
600 treatment-naïve patients. The trial is comparing a regimen
of efavirenz plus lamivudine (3TC) with either tenofovir or stavudine
(d4T). Results will be available near the middle of 2002.
Study 907: This is an ongoing 48 week Phase III trial in
552 treatment-experienced patients. It is a treatment intensification
study similar in design to Study 902. By week 24, the mean reduction
of viral load for those receiving tenofovir was about -0.6 logs
lower than for those who received placebo. These results were presented
to the FDA.
Study 910: Patients who were in studies 902 and 907 may
continue in this longer-term follow up study of safety and durability.
Expanded Access Program: Individuals who have failed prior
antiretroviral therapy, regardless of their CD4 cell count or viral
load, may be eligible to receive tenofovir under this program. Enrollment
is through a physicians' hotline. Call 1-800-GILEAD-5.
Tenacious Tenofovir Struts its
Stuff in a Virtual ICAAC
By Bob Huff
The annual medical meeting called the Interscience Conference on
Antimicrobial Agents and Chemotherapy, or ICAAC, is one of the research
community's most important venues for reporting on the progress
of new anti-infective drugs, including those for HIV. This year's
event, originally scheduled for late September in Chicago, was postponed
for three months due to travel uncertainty following the terror
attack on New York. But the book containing abstracts of the meeting's
presentations and posters was already in the mail. Rather than let
this information sit unread until the New Year, we present a two-part
look at some of what ICAAC might have offered. In this issue we
review a number of studies concerning a new antiretroviral drug,
tenofovir disoproxil fumarate (TDF). Next month we'll look at some
research on salvage therapy and drug interactions.
Keep in mind that abstracts are submitted many months in advance
of the conference and often report preliminary or partial data compared
to the final poster presentation.
Tenofovir
A new drug likely to be appearing in the regimens of people with
diminished susceptibility to most anti-HIV agents is tenofovir,
a soon-to-be approved nucleotide HIV reverse transcriptase (RT)
inhibitor with activity against a number of drug-resistant viral
mutations. Tenofovir is sponsored by Gilead Sciences. (See the discussion
of the tenofovir FDA advisory committee reported elsewhere in this
issue.)
A notable innovation in Gilead's development plan for tenofovir
was the decision to first evaluate the drug's benefit in a treatment-experienced
population. This is significant to the HIV community because data
from so-called "salvage" studies will be particularly relevant to
those most likely to be among the first wave of tenofovir users.
The decision to study the drug in a trial of treatment intensification
among a population with advanced disease also probably helped accelerate
tenofovir towards approval. Finally, Gilead's decision to develop
trials for a population with advanced disease and extensive treatment
experience gave many people an opportunity to gain early access
to one of the few new drugs likely to help them.
However, this strategy came with risks. No HIV drug has been fully
approved without data showing efficacy in previously untreated individuals.
While there is no scientific rationale why a drug that lowers viral
load in treatment experienced people with drug-resistant virus would
not also lower viral load in those who are treatment naïve,
there have been concerns that the FDA will not grant full approval
to tenofovir for use in both naïve and experienced adults.
Despite this concern, it's not clear that the abstract status of
partial approval (which will not prevent doctors from prescribing
the drug for any patient) would outweigh the convenience of an easy-to-take,
once-a-day pill with much-needed activity against drug-resistant
strains of virus. On October 26, the FDA approved tenofovir without
restrictions for use in adults with HIV.
Interactions and Pharmacokinetics
One common frustration of people who take and prescribe HIV drugs
is the lack of data about possible differences in absorption and
clearance of drugs due to an individual's weight, age or gender.
A new drug's key pharmacokinetic (PK) investigations are most often
performed using HIV-negative individuals — usually males. Studies
to evaluate demographic factors on dosing and blood levels of HIV
drugs are rare, especially after a drug has been approved for sale.
A-504 (Abstract references are listed at the end of this
article)
Gilead analyzed results from PK studies among 17 people with HIV
and 36 without, to evaluate PK characteristics of the drug by gender,
serostatus, weight and age. Although not a prospective study, the
analysis found no significant associations between these demographic
factors and the pharmacokinetics of tenofovir. For a drug about
to enter widespread usage in combination with any of fifteen other
approved HIV drugs, even this slim amount of data is helpful. Hopefully,
this sort of research will become a part of all drug development
plans. Physicians and community members should impress upon drug
company representatives at every opportunity the crucial need for
this kind of data to be made available whenever a new drug comes
to market. Gilead also has studies planned or in progress to investigate
the PK performance of tenofovir for patients with renal or liver
disease.
I-1729
Gilead investigators also conducted a study of tenofovir to address
concerns about potential PK interactions with ddI due to a shared
route of elimination through the kidneys. Fourteen HIV-negative
individuals were randomized into two groups, each group to receive
either tenofovir or ddI individually for one week. Then, after another
week off drugs as a washout period, all participants took the combination
of tenofovir and ddI for one final week. The pharmacokinetics of
tenofovir were not affected by ddI, although mean blood levels of
ddI over time (AUC) increased by about 40 percent. A retrospective
examination of safety data from two 24-week studies in which ddI
was given with or without tenofovir did not find a significant difference
between the groups in the incidence of pancreatitis or neuropathy,
the two most important toxicities of ddI.
Safety
I-1930
Gilead investigators also reported on a 291-person open-label safety
study in highly treatment-experienced patients with CD4 cell counts
below fifty. Tenofovir was part of a regimen that, in 91 percent
of patients, included lopinavir/ritonavir (Kaletra). With a mean
duration on tenofovir of 25 weeks, 15 percent experienced a serious
adverse event (SAE), 8 percent dropped out due to adverse events,
and 3 percent died of AIDS-related causes. Severe (Grade 3) adverse
events included pneumonia and diarrhea (4 percent each). About a
quarter of these patients had Grade 3 elevation of triglycerides.
An earlier, similar drug developed by Gilead called adefovir was
abandoned as an AIDS drug after kidney damage developed in some
people at doses necessary for activity against HIV (at lower doses,
adefovir remains promising as an anti-hepatitis B drug.) There has
been a great deal of concern that tenofovir might also cause or
exacerbate existing renal damage. This study included both people
who had previously taken adefovir and those who hadn't; no significant
changes in serum creatinine or phosphorus were observed in either
group.
Efficacy
I-1929
One of the highlights of ICAAC this year was to have been a presentation
of data from an extension of Gilead's 48-week trial of tenofovir
in 189 patients who were, again, treatment experienced. Individuals
on stable antiretroviral therapy were initially randomized to add
tenofovir at daily doses of 75, 150, or 300mg or placebo. Those
on the 300mg dose experienced a mean -0.62 log reduction of viral
load from baseline. The ICAAC paper was to present data on 135 patients
who continued therapy with 300mg open label tenofovir beyond 48
weeks. Their mean reduction in viral load from baseline remained
at -0.6 log by week 72. The safety profile at two years also remained
consistent with earlier reports.
Resistance
I-1928
A report from a 253-patient virology substudy of Gilead's large
Phase III trial in treatment-experienced individuals with unsuppressed
viral load explains why tenofovir is likely to be embraced by people
with drug-resistant virus. At baseline, nearly all had a nucleoside
RT resistant mutation; 69 percent with viral mutations associated
with loss of susceptibility to AZT and the other thymidine analogs;
68 percent with the 3TC-resistance mutation; and 45 percent with
both. Despite this broad cross-resistance to nucleoside RT inhibitors,
at 24 weeks, those receiving tenofovir had a mean viral load -0.59
log below that of the placebo group. Of 171 who had a genotypic
test performed at the end of 24 weeks, only 68/171 had a sufficiently
high viral load to allow sequencing. Of these, only 5/68 patients
had the characteristic K65R RT mutation associated with resistance
to tenofovir. In addition, significantly fewer people on tenofovir
subsequently developed mutations that confer resistance to protease
inhibitors, most likely because the rate of viral replication was
held to a lower level by improved suppression.
Loss of susceptibility to DNA chain terminating RT inhibitors occurs
generally via two mechanisms. One collection of RT mutations known
as thymidine analog mutations, or TAMS (D67N, K70R, T215Y, and others),
tends to allow more frequent dislodging of chain terminating drug
molecules, which unblocks the DNA chain and lets reverse transcription
continue. AZT is particularly prone to this kind of resistance.
A different RT mutation (M184V) reduces the activity of 3TC by impeding
the drug molecule's fit into the enzyme's active site. Two posters
reported on the effects of these mechanisms on the activity of tenofovir.
I-1754
A three-dimensional "snapshot" of tenofovir caught in the act of
terminating a DNA chain in the clutches of RT was obtained by X-ray
crystallography. Although these kinds of pictures are somewhat fuzzy,
the investigators report observing a void in an area of the tenofovir/RT
complex where the M184V RT mutation typically blocks 3TC from binding.
The authors propose that the lack of a bulky structure in this region
of the tenofovir molecule allows its activity against 3TC-resistant
HIV.
I-1755
As an extension of this research, Gilead offered a poster ranking
the ease with which mutated RT can remove nucleoside chain terminators.
As expected, AZT led the list, followed by D4T, ddC and to a lesser
extent, abacavir. Least affected were 3TC, ddI and tenofovir, in
that order. The report concludes by restating the observation that
the activity of tenofovir appears to be little affected by either
of these two mechanisms for NRTI resistance.
I-1756
Finally, another Gilead sponsored study examined phenotypic resistance
(Virco method) to tenofovir in HIV isolates derived from 1000 treatment-naïve
and 5000 treatment-experienced individuals. Since nearly 98 percent
of treatment-naïve isolates were susceptible to tenofovir at
levels less than 3-fold greater than that for a wild-type control
virus, the dividing line, or cutoff between tenofovir resistance
and susceptibility was set at 3-fold. With this level established,
the 5000 clinical isolates from treatment-experienced patients were
tested. Only 5 percent of the samples had greater than 5-fold losses
in susceptibility to tenofovir and 88 percent were within the "normal"
3-fold range. Eighty-five percent of samples resistant to 3TC were
susceptible to tenofovir; for AZT-resistant isolates, the proportion
was 71 percent. Results with isolates resistant to other NRTI drugs
were similar.
I-1759
Interestingly, the M184 mutation associated with 3TC resistance,
in the presence of TAMS, may actually increase the susceptibility
of RT to tenofovir. It's not known if 3TC therapy must be continued
for this hypersusceptability effect to be useful as part of a treatment
strategy.
Way to Go
These abstracts represent only a sample of the research that will
contribute to our knowledge base about tenofovir. Additional studies
and fresher data will emerge during the coming months and results
from the large confirmatory trials should be known in about a year.
Gilead is to be commended for taking a risky path in collecting
data for tenofovir's approval; we know more about this drug in the
populations in which it is most likely to be used than any previously
approved HIV treatment. But even after approval for tenofovir is
granted — for whatever the indication — studies must be
continued that address open questions about possible toxicity, interactions,
and the drug's effectiveness over extended periods of time.
Abstracts from 41st ICAAC:
A-504
B. P. KEARNEY, Effect of Demographic Variables on the Pharmacokinetics
of Tenofovir DF in HIV-Infected Patients and Healthy Subjects
I-1729
J. FLAHERTY, Coadministration of Tenofovir DF (TDF) and Didanosine
(ddI): a Pharmacokinetic (PK) and Safety Evaluation
I-1930
S. BECKER, Safety Profile of Tenofovir Disoproxil Fumarate (TDF)
in Patients with Advanced HIV Disease
I-1929
R. SCHOOLEY, Tenofovir DF: an Interim Analysis of the Open Label
Extension Phase from a 48 Week, Randomized, Double Blind, Placebo
Controlled Study in Antiretroviral Experienced Patients
I-1928
M. D. MILLER, Anti-HIV Responses and Development of RT Mutations
in Antiretroviral-Experienced Patients Adding Tenofovir DF (TDF)
Therapy: Baseline and Week 24 Genotypic Analyses of Study 907
I-1754
S. TUSKE, Structure of a Complex of HIV-1 RT with dsDNA Template-Primer
Terminated with Tenofovir
I-1755
L. K. NAEGER, Nucleoside RT Inhibitor Removal and Nucleoside RT
Resistance
I-1756
P. R. HARRIGAN, Phenotypic Analysis of Tenofovir Susceptibility
among 5000 Clinical HIV-1 Isolates
I-1759
N. SHULMAN, Impact of M184V/I Mutation on HIV Phenotypic Resistance
to Nucleoside Analogs (NRTIs) in NRTI-Experienced Patients
Opinion
Change and Rumors of Change
By Gregg Gonsalves
Congress has wisely chosen to not allow the advent of a recession
and the unexpected billions of dollars needed to respond to the
events of September 11th to imperil current levels of funding for
biomedical research. Yet in this time of upheaval and adjustment
it has become critical that we evaluate our priorities for basic
and applied AIDS research and start planning for a new era.
Help Basic Research Get Out of the Box
- Tomorrow's AIDS researchers: where are they? There is no certainty
that once the first generation of researchers on AIDS heads into
retirement that we are going to have new recruits to follow them
into the battle on HIV. We need to train more clinician-scientists,
those MD/PhDs who have a foot in both care and basic research,
and make it worthwhile for plain-old MDs and PhDs to head into
the AIDS research field.
- New targets for antiretroviral therapy: the drug companies won't
do it and the NIH doesn't know how. Drug companies usually wait
for new therapeutic developments from academic molecular biology
to be well established before embarking on novel drug discovery
and development programs for AIDS (e.g. T-20). NIH-funded academics
studying previously untargeted HIV proteins don't have an incentive
to apply their basic insights to the development of new drug screens.
So we have a no-man's land where drug discovery on approaches
other than RT and protease inhibition are languishing. We need
a mechanism to link the best molecular biologists on HIV's other
enzymes with the best industry minds in drug screening, discovery
and development.
- Man can't live by antivirals alone: AIDS is a disease of the
immune system and there should be a way to harness the body's
own disease fighting know-how to fight HIV. This will take a substantial
new investment in HIV immunology and basic human immunology as
well. The best basic immunologists are happy working on mice,
and the HIV immunologists are often simply shackled to doing specialty
assays for vaccine studies.
- We need to ask for the resignation of Judith Vaitukaitas, the
Director of the National Center for Research Resources, who has
presided over an acute and growing shortage of rhesus macaques
for vaccine studies for almost a decade and done nothing to respond
to it. She has been raked over the coals in Science magazine,
by Harold Varmus, the former NIH director, and by Neal Nathanson,
the former director of the NIH's Office of AIDS Research, but
no one seems to be able to get rid of her. Large, comparative
studies of vaccines in monkeys would be a boon to our vaccine
effort, but Dr. Judy doesn't seem to care.
Protect the Public Health with Longer-Term Research
AIDS activists worked successfully to expedite drug approvals to
get new agents to market at speeds unheard of twenty years ago.
Now the industry should give back something to the community by
endowing a fund to conduct rigorous post-marketing surveillance
studies of their drugs by independent researchers or clinical trials
networks.
Industry has no incentive to study its drugs after FDA approval
and the NIH clinical trials networks have been timid about conducting
meaningful studies that industry won't support. Someone has to invest
in studying the long-term effects of these drugs and public funding
should pay for these public health studies. Alternatively, industry
can work hand in hand with the community to get Congress to authorize
and fund the Agency for Health Care Policy and Research (AHCPR)
and its Centers for Education and Research on Therapeutics to conduct
such studies.
This is a short list, but it's a start. Let's take advantage of
this time of change to make changes that matter.
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