| 
Past Issues
Volume 15, number 7/8
July/August 2001
Contents
Here's a Couple Billion. Buy Yourself
Something Nice.
The high cost of drug development: fact or propaganda?
A Peek at PK
Drug levels in the human body, explained
The Malaria/HIV Dynamic
Two epidemics intertwined
A Report from Arlington
Notes from AACTG Meetings
@#%$*!!!!!
A Treatment Issues editorial
What Does R&D Really Cost?
By Bob Huff
The pharmaceutical industry's trade group, Pharmaceutical Research
and Manufacturers of America (PhRMA), has long maintained that developing
a single new drug and bringing it to market takes on average 12
– 15 years and costs $500 million. A new report by Public Citizen,
a consumer group founded by Ralph Nader, estimates the pre-tax cost
of bringing a new drug to market during the nineties was only about
$107M. After taxes, they say, the outlay on research and development
(R&D) for each successful drug (which must also cover expenses for
unsuccessful candidates) could be as low as $71M. PhRMA immediately
responded by quoting new estimates upping their figure to $700M.
The wide gap between these estimates indicates the agendas of their
respective sources. PhRMA's mission is to defend the drug industry's
image and profits, which they do by portraying drug development
as a noble and arduous undertaking akin to scaling Mt. Everest.
Public Citizen, fighting unchecked profiteering to reduce the burden
of high drug prices on the poor and elderly, challenges the industry's
profits and ethics with press releases and lobbying. To counter
PhRMA's justification of high profits, Public Citizen and other
consumer organizations routinely underplay the amount and significance
of R&D performed by the pharmaceutical industry.
Estimating drug development costs isn't easy. Corporations jealously
guard research expenses, trade secrets and technology to mask their
activity from competitors. The earlier a product can be brought
to market, the longer the company may sell the product without competition.
In the past, two basic approaches have been used to gauge the outlay
needed to bring a drug from laboratory to pharmacy. An estimate
can be derived by analyzing several companies' drug development
projects individually. A drawback to this method is the reliance
on company-supplied figures for research that may not reflect actual
expenses. The price of research may also be estimated by using industry-wide
aggregate figures for R&D, then apportioning costs among the number
of drugs actually approved during the study period.
In 1991, Joseph DiMasi and colleagues from the Tufts Center for
the Study of Drug Development published a widely quoted, comprehensive
study of drug development costs. Using project data from confidential
surveys, the study estimated cash outlays of around $169M to successfully
bring a drug to market during a period beginning in the 1970s. PhRMA
relies on this research as the foundation for their statements about
the cost of drug development. However, PhRMA uses different assumptions
about a 'hidden' expense called opportunity cost that boosts this
estimate to the $500 million mark.
Opportunity costs are lost profits that could have been realized
if the money tied up in an enterprise had been invested elsewhere.
For example, if an investor put up $1 million in 1993 and has received
no return on that investment after 10 years, the opportunity cost
would be the interest that could have been realized if, say, T-bills
had been purchased instead. If T-bills consistently pay 8% per year,
and the interest is compounded, the opportunity to make $1.2M on
the original $1M has been lost. Investors, of course, put their
money into risky ventures such as biotech startups precisely because
they hope to far exceed the return on investment that T-bills guarantee.
Because of compounding, opportunity costs multiply over time and
particularly impact industries with long lead periods before revenues
can be generated, as is the case with pharmaceuticals. For these
industries, the amount of revenue ultimately needed to recoup an
initial cash outlay, recover the opportunity cost, and earn a profit
is magnified.
PhRMA's assumptions begin with DiMasi's original estimate of R&D
outlays with opportunity cost set at 9% and a 12-year development
period. A review of the Tufts study performed by the US Office of
Technology Assessment (OTA) subsequently calculated opportunity
cost at a higher rate, which pushed the estimate towards $360 million.
According to Public Citizen, this figure, when adjusted for inflation
and rounded up, became PhRMA's $500 million.
But Public Citizen says the OTA report also offers an alternative
analysis of development costs. R&D expenses are tax deductible,
but DiMasi's 1991 figures didn't consider the discount this offers.
If the original Tufts estimate is reduced by 34% in tax savings
and opportunity cost is subtracted, Public Citizen says the actual
cash outlay for bringing a new drug to market during the seventies
and eighties was actually closer to $65 million. Public Citizen
also stresses that, during the nineties, accelerated approval times
and special tax credits further reduced the cost — and the
risk — of researching and developing new drugs.
Phases and Stages
In general there are three stages to drug development:
- Basic research and preclinical development
- Human trials
- Regulatory review and approval
Because preclinical research rarely focuses on a single drug, studies
by DiMasi and others usually apportion total early phase expenses
among the few projects that actually enter clinical testing. Research-based
pharmaceutical companies may have large in-house science centers
dedicated to drug discovery. For a startup company, basic or preclinical
research may be dependent on only a few key individuals, post-docs
and students, with financial support coming from academia, government,
industry or private sources. Traditionally, government funding has
generously supported basic science research — partly for the
public good and partly in expectation that new commercial opportunities
will emerge. Industry investment in the uncharted waters of pure
research may not be small, but it is highly risky. Many profitable
drug products, Public Citizen says, owe their discovery and development
to research funded by US government grants, particularly by the
National Institutes of Health (NIH). Yet as the layers of dependencies
that enable scientific progress are peeled back, it's not so simple
to point to paternity.
After several years in preclinical development, there may be only
in vitro efficacy and animal safety data available for a new compound.
This is generally backed by collateral knowledge about similar chemical
compounds from which the new drug evolved. Given the many uncertainties,
the initiation of clinical research is a big step. In the US, human
trials can only begin after the results from a battery of toxicology,
mutagenicity and pharmacokinetic studies in animals have been submitted
to the FDA and a research plan has been approved. Increasingly,
the first use of a drug substance in humans is performed outside
of the US, so that human safety data can be submitted to the FDA
along with preclinical results when seeking permission to study
an investigational new drug (IND) in the States.
If a compound is determined safe during Phase I studies, larger
trials to prove its efficacy are performed. Phase II trials may
enroll several hundred people to demonstrate that the drug is active,
that there are benefits to using it, and that there is an optimum
dose. Phase III trials may enroll hundreds or thousands of people
and are designed to show the overall effectiveness of the drug compared
to standard treatments. Competition has intensified the need to
contain costs and this has resulted in shorter trial times and an
increasing number of trials conducted outside of the US. There is
also a trend to contract the work of conducting clinical trials
to third-party firms that specialize in human research. For new
HIV drugs in particular, offshore trials also provide access to
larger numbers of previously untreated people than can be found
in the US.
The investment required to develop a drug continues to ramp up
as each new phase is initiated. Every milestone in the process calls
for a business decision about whether to continue to invest money
or not. Based on a drug's progress and prospects, new capital must
be committed to continue development or else the drug is sidelined.
For startup biotech companies, new capital may be raised through
private or public stock offerings, loans, or sales of commercial
rights and licenses.
Failures or "dry holes" as they are known in the industry have
been frequent in recent HIV drug development history. For example,
adefovir, a nucleotide analog developed by Gilead Sciences, made
it to Phase III trials before being stopped by the FDA due to kidney
toxicity. Lodenosine and Remune have also hit crippling barriers
on the road to approval. In the rush for market share during the
mid-nineties, some drugs were apparently launched into clinical
trials without a full understanding of their limitations, toxicities,
and doses. Yet in the pharmaceutical business model, the cost of
bad decisions, bad drugs and bad luck must be recovered by income
derived from future products that successfully make it to market.
The Example of Protease Inhibitors
PhRMA's 12 to 15 year development time estimate was also based
on DiMasi's analysis of drugs discovered in the seventies and clinically
developed during the eighties. But in the past decade, several changes
have facilitated much shorter drug development and approval times.
First, the regulatory climate altered dramatically during the early
nineties for drugs in general, but especially for HIV drugs. New
FDA rules that accelerated the consideration of HIV drugs allowed
shorter periods of study, sped review in general and have significantly
reduced the time to market. The acceptance of viral load assay results
as surrogates for drug effectiveness trimmed trial durations and
helped reduce the number of enrollees needed. Recently the Tufts
group analyzed drugs approved during 1996 – 1998, finding the
average time in clinical development for 108 new drugs had dropped
from 8.5 years to 5.9 years. PhRMA, however, continues to use the
outdated figures. It's important to recognize how profoundly any
decrease in the time to approval will result in substantial reductions
in development costs, not only due to savings in cash outlays, but
more significantly in the reduced opportunity cost of investment.
It's also important to recognize that an economic incentive to cut
corners and compromise safety is in play. That's why we have the
FDA...and Public Citizen.
An analysis of the time needed to approve HIV drugs in the nineties
suggests that the clinical development of AIDS drugs was a bargain
compared to PhRMA's estimates for average drug development costs.
One easy-to-obtain measure of the time required to prove safety
and efficacy to the satisfaction of the FDA is the period between
when the first patent application for a new drug is filed and when
the drug is approved. By this measure, drug development times for
the protease inhibitors were brisk. (see Table 1) Fortunately,
due to the regulatory reforms, activist pressure and intense competition,
the system responded to the opportunity that protease inhibitors
offered and moved quickly, developing useful drugs that stemmed
the crisis.
Information about the details and timing of HIV drug research are
relatively easy to obtain because community and activist publications
have tracked the HIV/AIDS drug development process so closely. Typically,
the times required for each phase of clinical study of the HIV drugs
were less than those estimated by PhRMA for drugs in general (see
Table 2). Yet the financial investment in the development of
protease inhibitors remains opaque. Since the cost of drug development
is so strongly dependent on the time in development, the accelerated
approval of AIDS drugs likely helped to make the business risk manageable;
no company that successfully brought a protease inhibitor through
Phase I trials failed to have their drug approved.
| Table
1: Time to Develop Five Protease Inhibitors |
|
| Drug |
1st Patent Filed |
FDQ Approval |
Years |
| Saquinavir |
Nov. 1990 |
Dec. 1995 |
5 |
| Ritonavir |
Mar. 1995 |
Mar. 1996 |
1 |
| Indinavir |
May 1993 |
Mar. 1996 |
3 |
| Nelfinavir |
Feb. 1994 |
Mar. 1997 |
3 |
| Amprenavir |
Sept. 1993 |
Apr. 1999 |
6 |
| Table
2 |
|
| Drug |
Phase I
(yrs) |
Phase II
(yrs) |
Phase III
(yrs) |
NDA
Filed/
Review |
FDA
Approved |
Time in
Trials |
PhRMA
Report |
(1.5 yrs) |
(2 yrs) |
(3.5 yrs) |
(1.5 yrs) |
- |
(8.5 yrs) |
| Saquinivir |
Early
1991
(2) |
Mar.
1993
(.75) |
Jan.
1994
(1.7) |
Sept.
1995
(.3) |
Dec.
1995 |
6 |
| Indinavir |
Feb.
1993
(.75) |
Oct.
1993
(1.4) |
Feb.
1996
(1) |
Jan.
1996
(.2) |
Mar.
1996 |
3 |
| Nelfinavir |
Apr.
1994
(1.1) |
Jun.
1995
(.75) |
Feb.
1996
(.8) |
Dec.
1996
(3) |
Mar.
1997 |
3 |
Drugs Out of Bodies
The time needed for preclinical discovery and development are far
more difficult to gauge. It was breathtakingly fortuitous that the
similarity of HIV-protease to other aspartyl proteases already being
studied was so quickly recognized; that drug development was underway
with chemical entities known to inhibit these other enzymes; that
new tools in molecular biology made a simple HIV-specific activity
assay available for testing potential drugs. The first reports identifying
renin inhibitors as possible HIV protease inhibitors appeared in
1987. Precursor patents for protease inhibition of other viruses
date from 1984 and the first HIV-related patents were applied for
in 1990. Scientists at Merck and the National Cancer Institute (NCI)
published their crystal structures of HIV-protease in 1989, which
helped chemists tweak the fit of the inhibitor molecules they were
engineering. Reports of in vitro activity by several HIV-protease
inhibitor compounds were published in 1990 by researchers from Upjohn,
Roche, Abbott, Lilly, Smith Kline, and the NCI. Saquinavir, the
Roche HIV-protease inhibitor, entered human trials in 1991, as did
a few candidates from other firms that were ultimately abandoned
due to toxicity or poor bioavailability.
A case could be made that HIV-specific preclinical research on
protease inhibitors took anywhere from two to six years before first
human use. Adding on the duration of clinical development results
in a range of 8 to 12 years to bring these drugs to market —
which is in line with DiMasi's revised estimates. But it's difficult
to find the starting blocks in basic research since discoveries
in one field often enable breakthroughs in other, unrelated fields.
If the earlier research on peptidic renin inhibitors is considered
crucial, then the time for the preclinical development of HIV protease
inhibitors could be plausibly extended by ten years or more.
Two Companies. Two Plans.
The actual cash outlays expended for developing any single HIV
drug are not transparent in the financial records of the large pharmaceutical
makers. Costs for individual drugs are grouped together with multiple
product lines, many other drugs at several stages of development,
drugs already on the market, research performed in-house and research
acquired by license. Sales revenues from top-selling products are
often disclosed and it may be possible to see when sales of a new
drug impact revenues or when marketing expenses and prices go up.
But without inside information, it is difficult to distill the time
and money invested in a single drug.
A different approach to estimating the cost of developing a single
pharmaceutical product in isolation is to analyze the research expenses
of a small, publicly-held, start-up drug developer. A case study
of a company with one or two lead compounds can be made by accessing
publicly disclosed information in SEC filings that present statements
about the firm's financial status, business progress and risks.
It becomes relatively simple to chart the company's research and
development expenses over time as they change relative to milestones
in the drug's development.
Two HIV drug development companies lend themselves to this kind
of analysis and are presented here. Trimeris, Inc. and Triangle
Pharmaceuticals, Inc. are each similar in size and capitalization;
both were founded in 1993; and both are located in the same labor
market in North Carolina. However, the companies were organized
under very different business models. Trimeris is developing a novel
class of compounds based upon original work performed by its founder
as a virologist at Duke University. Triangle, in contrast, was organized
as a clinical phase development company to purchase or license promising
drugs from third parties and then guide them to regulatory approval.
As case studies, these observations may not be generalizable to
large pharmaceutical manufacturers for a number of reasons: Overhead
may be lower for a small company, economies of scale may benefit
a large company and the cost of capital for a biotech startup may
be considerably higher than for a large corporation. In addition,
tax considerations that may influence a large company's spending
do not impact a small startup with no revenue.
These two cases suggest that pharmaceutical development expenses
are not trivial, although they do not quite hit PhRMA's new estimate
of $700M per drug. Yet clearly, drug development depends on much
more than appropriating government-sponsored research and mounting
a few clinical trials to gain FDA approval.
Trimeris, Inc.
Trimeris, Inc. is a development-phase company involved with the
discovery and development of peptide-based fusion inhibitors. Trimeris
performs original research and actively seeks patents to protect
its discoveries and processes. Trimeris has a royalty-free patent
from Duke University for the underlying concept of fusion inhibition
with peptides. The company depends on collaboration with partners
for manufacturing and marketing.
Trimeris was founded in 1993 and commenced expenses for development
that year. The company has never made a profit and does not anticipate
any sales until early 2003. Trimeris' research and development expenses
include drug discovery research, drug synthesis and manufacturing
costs, patent-associated costs, pre-clinical toxicology tests, clinical
research, and employee compensation. From inception to March 2001,
Trimeris has spent about $130 million on administration and R&D.
In July 1999, Trimeris announced an agreement with Roche to develop
and market their HIV drug candidates, T-20 and T-1249, worldwide.
Beginning in mid-1999, Roche and Trimeris have shared US development
expenses for T-20 and T-1249 equally. Under the agreement the two
companies will split revenues on sales within the US and Canada.
In the rest of the world, Roche will bear all development costs
and pay Trimeris royalties on sales. The agreement with Roche to
share development costs was made at a point when Trimeris had invested
approximately $45M on research. R&D expenses increased rapidly after
the Roche agreement was signed and expensive Phase III trials were
started. By the end of March 2001, cumulative R&D expenses had reached
$170M. Some of Roche's investment has been delivered as milestone
payments to Trimeris, but most will be carried on Roche's books.
Any international expenses are Roche's exclusively. This results
in some uncertainty about predicting the ultimate investment in
launching T-20.
During the first three months of 2001, Trimeris reported spending
almost $14M on R&D. Since this amount is matched by Roche, total
R&D for the quarter ran $28M. At this rate, with no increases, over
$360M will have been invested in T-20 by the end of 2002 when approval
is anticipated. T-1249 is said to be about two years behind in the
pipeline.
If opportunity cost, calculated at a rate of 10% compounded quarterly
is considered, the investment figure could rise to $460M. That said,
Trimeris expects worldwide sales of T20 to reach $500M per year.
An unusual amount of R&D expense for T-20 may be due to extraordinary
investment in the manufacturing process. Because T-20 is not a "me-too"
drug, its synthesis on a commercial scale has required a significant
amount of research and capital investment that are not part of a
more conventional compound's development.
Trimeris, Inc. Cumulative R&D Expenses
Triangle Pharmaceuticals, Inc.
Triangle Pharmaceuticals, Inc. is a development-phase company that
is grooming several antiviral drug candidates for market approval.
Triangle's strategy is to focus on drug development rather than
drug discovery. The company purchases or licenses drugs that have
shown favorable pre-clinical or early phase clinical data. Triangle
concentrates on designing clinical trials and optimizing drug synthesis
for production, while the actual manufacturing and conduct of the
trials are out-sourced to third parties. The firm has relied on
clinical trials in countries other than the US for much of its later
phase research. The company says that out-sourcing offers flexibility
to shift emphasis among projects and respond to changes in opportunities
and funding. Developing a patent portfolio is not a significant
part of Triangle's strategy.
Triangle was founded in 1993 and commenced development expenses
in January 1994. No products have been approved and the company
has not yet made money. Currently, six drugs are in clinical development.
Triangle's development expenses include drug synthesis and manufacturing
costs, patent-associated costs, pre-clinical toxicology tests, clinical
research, and employee compensation. Payments of license fees secure
the company's right to develop and market its drug candidates. If
the fees are not met, these rights can be lost. The HIV drug DMP-450
was acquired in an outright purchase.
This strategy has risks. Trials for two of Triangle's candidate
drugs, FTC and DMP-450, were temporarily put on hold by the FDA
due to safety concerns. The FDA has also asked for additional clinical
trials for emiverine. Certain third parties — not the licensors
— have made patent claims involving FTC and DAPD, placing Triangle's
rights in jeopardy.
Since inception, Triangle has spent about $312 million on development,
license fees and purchased research. Approximately 2100 patients
have been enrolled in all phases of clinical trials for all of their
drug candidates. During 2000, drug synthesis and manufacturing comprised
the largest part of Triangle's development expenses. Expenses for
clinical trials, employee compensation, pre-clinical testing, and
consulting followed as the next largest categories.
Both Trimeris and Triangle have raised money from stock sales.
They both entered marketing and development deals with large pharmaceutical
corporations as the burdens of starting Phase III trials and developing
production capacity loomed. In exchange for exclusive or shared
marketing rights, links to large pharmaceutical companies to supply
capital and expertise for manufacturing, registration and sales
seem inevitable. But when investors understand the risks and commit
their time and money, it doesn't matter if they are loved or reviled.
The founder of Merck is famous for having said something to the
effect that, "When pharmaceutical companies do what is good for
people, the profits will follow" ... or not.
Triangle Pharmaceuticals
Cumulative Drug Development Expenses
Research versus Marketing
It's often claimed that pharmaceutical companies spend more money
on marketing than on researching and developing new drugs. The Pharmaceutical
Research and Manufacturers of America (PhRMA) recently countered
this charge with figures that showed the industry's marketing expenses
reaching only 61% of research and development (R&D) expenses during
2000. These are aggregates of expenses self-reported by members
of PhRMA in an annual survey. PhRMA points out that a considerable
portion of money spent on marketing goes for free physicians' samples
that ultimately helps poor people. The price basis for the samples
was not disclosed.
Figures from the audited financial statements of several large
pharmaceutical manufacturers involved with HIV medicine are hard
to reconcile with PhRMA's estimates. For example, BristolMyersSquibb
reported marketing and administration (M&A) expenses of $5.6B during
2000 and $1.9B spent on R&D during the same period. R&D amounted
to 10% of revenue while marketing and administration consumed 31%
— nearly three times as much. The reports of other companies
show similar patterns of expenditure (See Table). It should be noted
that financial statements usually report marketing and administration
(M&A) expenses as a single category, whereas PhRMA excluded administration
expenses from their figures. For two startup companies, Trimeris
and Triangle, with no products on the market and no significant
expenditures for marketing, R&D costs easily dominated each company's
cash expenses during 2000.
BristolMyersSquibb, alone among the large corporations, reported
advertising expenses separately from M&A. Even so, during 2000,
Bristol's advertising dollars ($1.7B) roughly equaled their R&D
dollars ($1.9B). After direct-to-consumer (DTC) advertising of prescription
drugs was allowed in 1997, advertising budgets, drug sales and prices
soared. As an example of the DTC marketing frenzy, Pfizer sponsors
Mark Martin's Viagra NASCAR race team at a reported $15 million
dollars a year — roughly the cost of a medium-sized Phase III
clinical trial.
Oddly, PhRMA's numbers don't seem to jibe with a simple reality
check. During 2000, they estimate, PhRMA's fifty-five members spent
$25.7B on R&D. But R&D expenses for just the four companies listed
below total $10B, which suggests that the industry-wide estimate
may be low. PhRMA also reports $1.8B spent on direct-to-consumer
marketing by their members in 1999. Yet, Bristol alone spent $2.4B
on advertising and product promotion during that year. Not so incidentally,
thirty-eight associate members of PhRMA are firms dedicated to pharmaceutical
advertising and communications.
Finally, PhRMA says that pharmaceutical makers spend a larger proportion
of revenue on research than either the aerospace or computer software
sectors. If we look at Boeing, with only 4% of its revenue going
to R&D, this is clearly true. In the case of Microsoft, both M&A
and R&D expenses are in line with those of the big drug companies
— although at 40%, its profits were at least two times greater.
As consolidation proceeds within the pharmaceutical industry, perhaps
PhRMA's members are dreaming of the day when they can enjoy monopoly
profits to rival Microsoft's.
| Marketing
versus R&D Expenses — 2000e |
|
| Corp. |
Rev.
(2000) |
Marketing &
Admin. |
% of
Revenue |
R&D |
% of Rev. |
Earnings
|
% of Rev. |
| Merck |
40.4B |
6.2B |
15% |
2.3B |
6% |
6.8B |
16.8% |
| Pfizer |
29.5B |
11.4B |
39% |
4.4B |
15% |
3.7B |
12.5% |
| Bristol |
18.2B |
5.6B* |
31% |
1.9B |
10% |
4.1B |
22.5% |
| Abbott |
13.7B |
2.9B |
21% |
1.4B |
10% |
2.8B |
20.4% |
| Triangle |
7.2M |
12.9M |
na |
107M |
na |
<110M> |
na |
| Trimeris |
1.0M |
15M** |
na |
38M |
na |
<51M> |
na |
| Boeing |
51B |
2.3B |
5% |
2.0B |
4% |
2,1B |
4% |
| Microsoft |
23B |
5.1B |
22% |
3.8B |
16% |
9.4B |
41% |
Source: SEC Edgar, 10K filings
* BMS: advertising only = 1.7B
** Trimeris = 100% Admin. |
The Ups and Downs of Drug
Levels: A PK Primer
By Bob Munk
Antiviral medications have a much harder time getting to work than
you do. Sure, you have to deal with the bus or subway, or traffic
on the streets. But look at what your meds go through! First they
get swallowed and dumped into a pool of acid in your stomach. Then
they dissolve, leave the stomach and start getting absorbed —
mostly through the lining of the small intestine. Then, the blood
from around the intestine carries them to the liver. Now, the liver
is an organ that's designed to break down (metabolize) and remove
foreign stuff from the blood, so most drugs have a tough time getting
past it. With many HIV drugs, only a tiny fraction of the medicine
actually gets past the liver and into the bloodstream. So far, this
journey is called "first-pass metabolism."
The amount of drug that makes it into your bloodstream, compared
to the amount that you put into your mouth, is called its "bioavailability."
If a drug has low bioavailability, then much of the drug is destroyed
by stomach acid, or is not absorbed in the small intestine, or is
removed by first-pass metabolism in the liver. The amount of drug
you take in a pill is calculated to correct for this so that the
amount you need actually ends up in the blood.
Once drugs are past the liver, the bloodstream carries them throughout
the rest of the body in about one minute. But they're still not
ready to go to work. Now they have to move from the bloodstream
and into the infected cells. But before this happens there are more
barriers.
The next problem is called protein binding. Proteins in the blood
(albumin and alpha-1 acid glycoprotein) stick to most of the drug
in the bloodstream and hold it hostage. This is a normal way to
distribute some messengers in the body. For example, adrenalin is
produced in the kidneys. Without protein binding, it might get absorbed
too soon. But blood proteins capture the adrenalin and carry it
all around the body so that some gets to the heart and brain where
it is needed.
Protein binding works like a fleet of trucks that load up most
of the available drug supply and drive it to locations all over
the body. The drug that's not loaded in the trucks is called the
"free fraction." This is the only amount that is free to leave the
bloodstream and go to work. As the free fraction is used up, the
blood proteins gradually unload more of the drug. Some drugs are
"highly protein bound" and can't get free. With certain drugs, less
than 1% ever gets to leave the bloodstream and go to work in the
cells.
Some areas of the body are "high security" zones. For example,
the "blood brain barrier," a tightly woven network of blood vessels,
protects our brain and spinal cord from toxins but also keeps most
antiviral drugs out. Other areas the body protects from outsiders
are the testicles and ovaries.
To get inside infected cells where they're needed, drugs have to
pass through the cell's membrane. The membrane is protected by chemical
"guards" that make sure only the right stuff gets in. For example,
the nukes (nucleoside analog reverse transcriptase inhibitors, NRTIs)
have an easy time getting past the membrane because they are so
similar to natural building materials the cell uses when it divides.
Chemical "hands" actually pull them into the cell. But once inside,
the nukes still have to go through three more steps of chemical
processing (called phosphorylization) before they are ready to work.
The other types of antiviral drugs—the NNRTIs and PIs—have
a harder time getting inside cells because they don't resemble anything
that the cell normally needs. Still, they can push their way inside
— even though a chemical "bouncer"called P-Glycoprotein might
push some of the drug back out again.
Do We Have Enough?
With all of these barriers, less than .01% of the medication you
swallow might ever make it inside your cells to fight the virus.
That's why it's critical to be sure that enough drug gets into the
bloodstream to start with. The study of the way drugs are absorbed
and move through the body is called pharmacokinetics (far' muh ko
kih NEH' tix), or PK, for short.
PK measures the ups and downs of drug levels in your body. For
example, when you take a dose of a medication, the drug level in
the blood goes up quickly. In a little while, it reaches its peak.
This is called Cmax — the maximum concentration.
As the drug is removed (metabolized) from your body by the liver
or kidneys, blood levels of the drug drop. Just before the next
dose enters your bloodstream, blood levels of the drug are at their
lowest. This is called the "trough," or Cmin — the
minimum concentration.
Another PK value measures how long a drug stays in the bloodstream.
It is calculated as the amount of time it takes for drug levels
to fall by 50%. This is called the "half-life" of the drug.
If you draw a graph of drug levels in the blood, you will see that
they rise quickly to the Cmax after a dose is taken,
then fall off over time until the next dose.
The same graph can also be used to measure the total exposure to
a drug. The "area under the curve," or AUC, is calculated by adding
up the area under the curved line that charts the peak and trough
levels of a drug.
Drug levels are different in different people. We all know some
people who can eat constantly and stay thin, and others who seem
to just look at food and gain weight. It's similar with drug levels.
Some people "process" drugs quickly and so have lower blood levels
— while others have higher levels with the same dosing. Drug
doses are based on PK averages for the people who were studied by
the drug company. It's possible that a person should use a lower
dose if they don't weigh very much, or if they have a slow metabolism.
If you have a large body or a quick metabolism, you might need a
higher dose. Your doctor might want to check your blood's drug level
if a medicine doesn't seem to work the way it should.
Pharmacokinetics:
Therapeutic Window — Peak and Trough
How is PK used?
PK studies help drug companies select a dose for a new drug. The
ideal dose should be strong enough to be effective without causing
too many side effects. We can start by setting upper and lower limits
on drug levels in the blood. This can be shown by the two horizontal
lines on our PK graph. The upper line represents the blood level
where people start to develop serious side effects. The lower line
represents the minimum drug levels that provide good control of
the virus. This is usually the drug concentration that cuts down
viral replication by 50%. This is called the "inhibitory concentration
(50)" or IC50. We want to keep drug concentrations above
the IC50, but below the level that will cause serious
side effects. The zone between these two lines is called the "therapeutic
window" — the range of drug concentrations where it's doing
more good than harm.
Each PK measurement puts some limits on the dosing:
- The Cmax is related to short-term side effects like
nausea or headache that hit after each dose. The Cmax
has to stay low enough to keep these at a safe and tolerable level.
- The Cmin relates to control of the virus. If the
Cmin drops too low, HIV can multiply and maybe develop
resistance to the drug. The higher the Cmin, the better
the viral control. Most manufacturers want to see the Cmin
stay several times higher than the IC50.
- The half-life of the drug determines how often you have to take
it. Drugs with a long half-life stay in the blood longer, and
might only have to be taken once or twice a day. If a drug has
a short half-life, it might have to be taken three or more times
a day.
- The AUC, which measures total exposure to the drug, is also
often related to control of the virus. The higher the AUC, the
better the control. It can also be related to the amount of long-term
side effects.
Let's say that a drug was approved based on three doses a day.
Then the manufacturer wants to make it easier for patients to take,
so they try to design a twice-daily dose. To do this, they will
rely on PK data.
- They start by putting more medication in each dose. Then they
try it out on a few people. Is the Cmax too high? Does
it cause too much nausea and headache when each dose is taken?
- Instead of 8 hours between doses, can the stronger dose be taken
every 12 hours? If the drug has a long half-life, maybe there
won't be a big difference in the minimum blood levels (Cmin).
How does the new Cmin after 12 hours compare to the
amount of drug needed to control the virus?
- What's the AUC (area under the curve) using the new twice-daily
dosing? If it's equal to or higher than the old AUC, then the
new dosing will probably be just as powerful against the virus.
With a wide therapeutic window, it's easier to make some of these
changes. There's more room to increase the dose without causing
bad side effects, and more room (time) to let the blood level drop
before it gets too low. With a narrow therapeutic window, there
may be just one choice for dosing.
Area Under the Curve (AUC)
measures Total Drug Exposure
The Best Curve is a Straight Line
The ideal situation is a constant level of drug in the body —
enough to control the virus, but not enough to cause a lot of side
effects. Instead of a graph showing peaks and troughs, we'd have
a flat line. This will never happen by swallowing pills, because
we get a large peak of drug with each dose. The only way to get
constant drug levels is with an intravenous (IV) infusion, or with
a pump like some diabetics use to take insulin. These methods of
taking medication are more expensive and complicated than taking
pills. Because they break the skin, there is also a risk of infection.
There is another way, however, to "smooth out" drug levels in the
blood. Blood levels drop when the drug is metabolized by the liver
and removed from the body. If we slow down this process, less of
the drug is removed from the blood. The concentrations stay higher
and the drug's half-life is extended.
The protease inhibitor ritonavir (Norvir) has this effect. For
example, if the protease inhibitor indinavir (Crixivan) is used
by itself, it has to be taken on an empty stomach, three times a
day, once every eight hours. The "trough" levels are not much higher
than the levels needed to stop the virus. But if indinavir is combined
with a small amount of ritonavir, the trough levels of indinavir
stay much higher, and you can take it just twice a day, with food.
Ritonavir has a similar effect when it's combined with other protease
inhibitors. These "ritonavir-boosted" regimens haven't been approved
by the FDA yet, but are getting a lot of attention from researchers.
Even though ritonavir is a protease inhibitor itself, its ability
to slow metabolism of other drugs in the liver is a special use
for the drug.
Pharmacokinetics can be very technical, but it's important to study
drug levels to help let people control their virus without suffering
too many side effects.
Glossary
AUC: Area under the curve, a measure of total exposure to
a drug over a 24-hour period.
Bioavailability: A measure of how much drug makes it into
the bloodstream, compared to how much we swallow.
Cmax: The maximum concentration of drug in the
blood. It occurs shortly after taking a dose.
Cmin: The minimum concentration of drug in the
blood. It occurs close to the time before the next dose is taken.
Half-life: A measure of how long a drug stays in the blood.
The length of time it takes for the blood concentration to drop
to 50% of Cmax.
IC50: Inhibitory concentration (50), the concentration
of drug that cuts viral replication by 50%.
NNRTI: Non-nucleoside reverse transcriptase inhibitor, a
type of antiviral drug. Examples are nevirapine (Viramune) and efavirenz
(Sustiva).
Nuke: Nucleoside analog reverse transcriptase inhibitor,
a type of antiviral drug. Examples are AZT (Retrovir) or d4T (Zerit).
Pharmacokinetics: The study of how drug levels change over
time in the body.
PI: Protease inhibitor, a type of antiviral drug. Examples:
indinavir (Crixivan), nelfinavir (Viracept).
Protein binding: A process that inactivates some of the
drug in the bloodstream and carries it throughout the body.
Therapeutic window: The difference or gap between the lowest
drug concentration that is helpful (controls the virus), and the
drug concentration that is harmful (causes too many side effects.)
Malaria and HIV
By Bob Huff
Reprinted from amfAR HIV/AIDS Treatment Directory Online, www.amfar.org
Depending on how you look at it, malaria has either a lot or very
little in common with HIV.
Both diseases kill millions of people each year, and both diseases
are scourges of developing nations in Africa, India, Southeast Asia
and South America. But HIV is pandemic, spread from person to person
by sexual contact in an increasingly mobile world. Malaria is endemic,
dependent on a local symbiosis between infected anopheline mosquitoes
and humans. The severe symptoms of malaria caused by the tiny parasite
Plasmodium falciparum appear within days and bring death to about
15 to 25% of those stricken when great quantities of infected red
blood cells are destroyed in a single burst. HIV infection is a
slow, insidious process that can take years to deplete immunologically
crucial white blood cells. AIDS results in death for nearly all
untreated patients.
Both diseases can be transmitted by contaminated blood. In the
eighties, some partially blamed the initial spread of HIV in Africa
on the transfusion of infected blood to treat malaria-associated
anemia. And a study in Brazil has tracked an outbreak of blood-borne
malaria among urban HIV-infected intravenous drug users. (Bastos)
The infection rates of both diseases can be reduced by behavior
changes, barrier protection (condoms or bed nets) and medical prophylaxis.
Vaccine development for both diseases has been slow. But malaria
can often be treated and cured with an inexpensive weeklong course
of drugs whereas current HIV treatment is a lifelong prospect of
daily medication at costs that have so far limited their use in
developing countries. Most people who contract HIV or malaria are
poor.
With shared geography and demographics, coinfection is common,
yet surprisingly few obvious clinical associations between HIV and
malaria are reported. Studies are contradictory about the frequency
and severity of malaria in HIV-infected people. Malaria does not
appear to act as a classic opportunist in immune-compromised hosts.
People who have grown up in endemic regions often retain partial
immunity to malaria, and there is no solid evidence that this immunity
is lost as HIV disease progresses.
HIV, Malaria and Pregnancy
One thing is clear: The two diseases critically intersect in the
bodies of pregnant women.
In parts of Africa, severe anemia during pregnancy can be caused
by nutritional deficits, hookworm, malaria or HIV disease. Asymptomatic
malaria can exacerbate the common mild anemia of pregnancy, and
recrudescence of malaria may be more frequent because of the immune
suppression normally experienced by pregnant women. Falciparum malaria
episodes are associated with low birth weight, fetal distress, premature
labor, and an increased number of stillbirths, miscarriages and
neonatal deaths. Placental malaria may be associated with an increased
frequency of mother-to-child HIV transmission. Acute falciparum
malaria during pregnancy is a particularly dangerous condition,
since any underlying anemia can be dramatically amplified by red
blood cell destruction. (Shulman)
More commonly, however, malaria is asymptomatic during pregnancy
and not always easily diagnosed. Research has shown that even such
subacute malaria can contribute to anemia and placental infection.
A clinical trial in Kenya reported that presumptive treatment of
all pregnant women in endemic malarial areas with only two doses
of sulfadoxine-pyrimethamine (SP) reduced the incidence of anemia
among first-time mothers by 39%. Another study observed a reduction
in the incidence of low birth-weight babies from 14% when only symptomatic
mothers were treated (fever case management) to 8% when all mothers
were treated presumptively. Treatment of all mothers with SP at
risk for malaria is now the standard of care in clinical settings
in Kenya and elsewhere. (Steketee; Shulman)
The role of HIV in this complex is illuminated by results from
a 1994 study conducted in rural hospitals in Malawi. Researchers
diagnosed malaria in 56% of first-time mothers with HIV compared
to 36% in first-time mothers who were HIV-negative. Among mothers
who had previously given birth, the incidence of malaria was 24%
for those with HIV and 11% for those without. All mothers had received
SP malaria prophylaxis in accordance with Malawi government guidelines.
(Verhoeff)
A Kenyan clinical trial compared two-dose SP with monthly dose
SP as presumptive malaria treatment during pregnancy. Investigators
reported that placental malaria was found in 25% of HIV-positive
women who received two-dose SP and in 7% of HIV-negative women on
the same regimen. Findings of placental malaria in HIV-positive
women dropped to 7% for women who received monthly presumptive SP
dosing during the second and third trimesters of pregnancy. (Parise)
A retrospective analysis of children born in a Malawi trial of
prenatal malaria chemoprophylaxis reported a sharply increased risk
of postnatal mortality when mothers had placental malaria, HIV or
both. A normal birth weight baby born to an HIV-infected woman with
placental malaria was 2.7 times more likely to die than the child
of an HIV-infected woman without placental malaria. This same child
was 4.5 times more likely to die than one born to an HIV-negative
woman who had placental malaria. The risk of postnatal death increased
to nearly 8 times if the infant had a low birth weight. (Bloland)
A heightened risk of HIV transmission with placental malaria could
be the result of one or more factors. There may be a disruption
of the placental cellular architecture that allows an intermingling
of maternal and fetal blood. Another mechanism might be that placental
malaria stimulates a local increase of HIV-infected macrophages
and other lymphocytes, and these increase the risk of viral transmission.
Or placental malaria may simply be a consequence of advanced HIV
infection and higher viral load, itself associated with mother-to-child
transmission. (Bloland)
To summarize, these findings suggest that women with HIV are at
greater risk of having malaria during pregnancy — a condition
that increases the risk of having a sick baby or of passing HIV
to the child. Prophylactic treatment lowers the incidence of subacute
and placental malaria. It can improve the health of the mother and
child and reduce the risk of placental transmission of both malaria
and HIV.
Do Malaria Treatments Affect HIV?
Possible answers to this question are raised by a study in Malawi
that reported a lowering of plasma HIV levels during SP treatment
of acute falciparum malaria. At baseline, 47 HIV-positive men and
women with confirmed symptomatic falciparum malaria had a median
viral load of 151,000 copies/mL. The baseline median viral load
of the control group, consisting of 42 asymptomatic, aparasitic
HIV-positive men and women, was 22,000 copies/mL. Twenty-seven malaria
subjects and 22 non-malaria subjects completed four weeks of follow-up.
After four weeks on treatment, the median viral load of the 27 malaria
patients had declined from 191,000 to 120,000 copies/mL. The median
viral load of the control group increased slightly. (Hoffman)
A different anti-malarial agent is chloroquine, a drug with immune
modulatory qualities that has also been reported to have an inhibitory
effect on HIV in vitro. (Pardridge; Savarino) Although conducted
before the availability of sensitive viral load assays, a clinical
trial that compared chloroquine to AZT in asymptomatic patients
reported equivalent reductions in recoverable HIV after 16 weeks.
(Sperber) A study in Uganda reported no difference between the incidence
(but not the severity) of malarial episodes in children with or
without HIV. The authors wondered whether the anti-HIV properties
of the chloroquine administered to both groups had confounded their
observations. (Kalyesubula) Compounds related to chloroquine are
currently being investigated as HIV integrase inhibitors. (Mathe)
Drug-resistant strains of malaria are threatening to cripple efforts
to arrest the epidemic. Chloroquine-resistant Plasmodium is widespread
in many parts of Southeast Asia and increasingly common in Africa.
Resistance to SP has been noted in Tanzania and elsewhere. Chloroquine
and SP, as first- and second-line treatments, once offered a cure
for about twenty cents per person. The drugs needed to treat resistant
strains of malaria cost many times that amount and will not be widely
available in poor countries. As with tuberculosis and HIV, the solution
to effective treatment of this resistance-prone pathogen may lie
in adopting combination therapy with agents that block the Plasmodium
life cycle at two crucial points instead of one, thereby multiplying
protection against resistance. (White)
Although expensive HIV drugs are not likely to become available
soon for everyday treatment in malarial regions, the efficacy of
low-cost, short-course antiretroviral therapy to prevent mother-to-child
transmission during birth has been established. The use of AZT and
nevirapine in pregnancy is growing and could soon become standard
of care throughout most of the world. Although pregnant women in
endemic malarial regions are routinely prescribed prophylaxis for
malaria, no studies have been made of the potential for pharmacologic,
toxic and teratologic interactions between these various classes
of drugs. (Okereke)
The Immunological Connection
The mechanisms used by the immune system to fight malaria are not
fully understood, although it is clear that both humoral and cell-mediated
immunity are involved and that various T-cell subsets are important
for regulating the immune response. (Troye-Blomberg) HIV too has
an intricate relationship with the immune system, and it appears
that there may be several points of intersection between the pathogenesis
and response to each disease.
Some have suggested that the malarial antigens and pigments released
during the burst of red blood cells stimulate cytokines that can
activate HIV replication. The investigators in Malawi who noted
lower HIV levels in people treated with SP also measured levels
of tumor necrosis factor (TNF alpha), a cellular signaling protein
or cytokine that has been associated with increased rates of HIV
replication. TNF alpha is released in response to anti-malarial
immune activation. But during SP malaria treatment, blood levels
of TNF alpha decreased. This adds weight to the suggestion that
suppressing malarial infection may result in a lowered HIV viral
burden. (Hoffman)
Different clinical manifestations of malaria are associated with
different states of immune dysregulation. In Ghana, children with
cerebral malaria had significantly higher levels of TNF, TNF receptors,
and IL-10 (another cellular signaling cytokine) than did those with
severe malarial anemia or uncomplicated malaria. (Akanmori)
This picture is further complicated by reports that various common
malaria treatments such as quinine and artesunate directly affect
TNF levels in vitro. (Ittarat)
Another cytokine that increases during acute malaria is granulocyte
colony stimulating factor (G-CSF). (Stoiser) G-CSF stimulates the
production of neutrophils (white blood cells that help fight bacterial
and fungal infections). A clinical trial of G-CSF versus placebo
in AIDS patients reported a significantly lower incidence of bacterial
infections for those receiving G-CSF but no difference in HIV viral
load. (Kuritzkes)
A connection between HIV and malaria may exist in the way the immune
system responds to certain similar molecular features on their structural
proteins. An analysis using Western blot antibody diagnostics found
overlapping immune reactivity in blood containing HIV antigens and
that with P. falciparum antigens. HIV-negative subjects from Papua,
New Guinea, an endemic malarial region, reacted positively to certain
HIV antigens. Similarly, blood from HIV-positive persons from non-malarious
regions reacted positively in immunoblot tests for antibodies to
P. falciparum antigen. (Elm)
If HIV infection stimulates an immune response to P. falciparum,
it may help explain unexpected findings of decreased malaria mortality
in a group of HIV-positive children. Of 121 children with HIV entering
a clinic in Kinshasa, Zaire, 41 had malaria. Half of the malaria
cases were moderate to severe, and all cases were treated with quinine.
None of the 41 children with HIV and malaria died compared to 25
of the 71 children with just HIV. While no one died in the coinfected
pediatric population, there was a 14% death rate among HIV-negative
children with malaria. The prevalence of malaria at this hospital
was the same for children with or without HIV. (Dayachi) These results
seem to be contradicted by a later Ugandan study finding that pediatric
malaria patients with HIV had more hospitalizations and required
more transfusions than those without HIV. (Kalyesubula)
Others have proposed that the immune response to malaria can increase
the pool of lymphocytes available for HIV infection, resulting in
accelerated progression to AIDS. Whether this actually occurs is
not known. Much research still needs to be done to understand the
interactions between the immune system and these all-too-common
pathogens.
References
Akanmori B, et al. Distinct patterns of cytokine regulation in
discrete clinical forms of Plasmodium falciparum malaria. Eur Cytokine
Netw 2000 Mar;11(1):113–8.
Bastos F, et al. Co-infection with malaria and HIV in injecting
drug users in Brazil: a new challenge to public health? Addiction
1999 Aug;94(8):1165–74.
Bloland P, et al. Maternal HIV infection and infant mortality in
Malawi: evidence for increased mortality due to placental malaria
infection. AIDS 1995, 9:721–6.
Dayachi F, et al. Decreased mortality from malaria in children
with symptomatic HIV infection. Int Conf AIDS. 1991 Jun 16–21;7(2):164
(abstract no. W.A.1291).
Elm J, et al. Serological cross-reactivities between the retroviruses
HIV and HTLV-1 and the malaria parasite Plasmodium falciparum. P
N G Med J 1998 Mar;41(1):15–22.
Hoffman I, et al. The effect of Plasmodium falciparum malaria on
HIV-1 RNA blood plasma concentration. AIDS 1999, 13:487–94.
Ittarat W, et al. The effects of quinine and artesunate treatment
on plasma tumor necrosis factor levels in malaria-infected patients.
Southeast Asian J Trop Med Public Health 1999 Mar;30(1):7-10.
Kalyesubula I, et al. Effects of malaria infection in human immunodeficiency
virus type 1-infected Ugandan children. Pediatr Infect Dis J. 1997
Sep;16(9):876–81.
Kuritzkes D, et al. Filgrastim prevents severe neutropenia and
reduces infective morbidity in patients with advanced HIV infection:
results of a randomized, multicenter, controlled trial. AIDS 12(1):65–74,
1998.
Mathe C, et al. Potential inhibitors of HIV integrase. Nucleosides
Nucleotides. 1999 Apr-May;18(4-5):681–2.
Okereke C. Management of HIV-infected pregnant patients in malaria-endemic
areas: therapeutic and safety considerations in concomitant use
of antiretroviral and antimalarial agents. Clin Ther 1999 Sep;21(9):1456–96;
discussion 1427–8.
Pardridge W, et al. Chloroquine inhibits HIV-1 replication in human
peripheral blood lymphocytes. Immunol Lett 1998 Nov;64(1):45–7.
Parise M, et al. Efficacy of sulfadoxine-pyrimethamine for prevention
of placental malaria in an area of Kenya with a high prevalence
of malaria and human immunodeficiency virus infection. Am J Trop
Med Hyg 1998 Nov;59(5):813–22.
Savarino A, et al. The anti-HIV-1 activity of chloroquine. J Clin
Virol 2001 Feb;20(3):131–5.
Shulman C, et al. Malaria in pregnancy: its relevance to safe-motherhood
programmes. Ann Trop Med Parasitol 1999 Dec;93 Suppl 1:S59–66.
Sperber K, et al. Comparison of hydroxychloroquine with zidovudine
in asymptomatic patients infected with human immunodeficiency virus
type 1. Clin Ther. 1997 Sep-Oct;19(5):913–23.
Steketee R, et al. Impairment of a pregnant woman's acquired ability
to limit Plasmodium falciparum by infection with human immunodeficiency
virus type-1. Am J Trop Med Hyg 1996;55(1 Suppl):42–9.
Stoiser B, et al. Serum concentrations of granulocyte-colony stimulating
factor in complicated Plasmodium falciparum malaria. Eur Cytokine
Netw 2000 Mar;11(1):75–80.
Troye-Blomberg M, et al. Immune regulation of protection and pathogenesis
in Plasmodium falciparum malaria. Parassitologia 1999 Sep;41(1-3):131–8.
Verhoeff F, et al. Increased prevalence of malaria in HIV-infected
pregnant women and its implications for malaria control. Trop Med
Int Health 1999 Jan;4(1):5–12.
White N, et al. Averting a malaria disaster. Lancet 1999; 353:
1965–7.
Report from the Adult AIDS
Clinical Trials Group (AACTG) Meeting
Arlington, VA, July 12–15, 2001
By Sue Gibson
Reprinted from amfAR HIV/AIDS Treatment Directory Online, www.amfar.org
Depression
The meetings opened with an interactive session on the study of
depression. We know that depression is a significant factor in nonadherence
[failure to take every dose of anti-retroviral therapy (ART)]. Dr.
Glenn Treisman, Director of AIDS Psychiatry Services at Johns Hopkins
University School of Medicine, said that depression could result
from diseases of the brain or from adverse situations. People living
with HIV (PLWH), he said, are often depressed due to disease, such
as neurochemical defects, limbic system impairments, post-partum
depression, or schizophrenia. Depression is associated with insomnia,
chronic pain, prior episodes of depression, and a family history
of depression. Depression responds well to medication. Dr. Treisman
also said that 20% of PLWH are demoralized — often due to grief,
and respond well with time, support, and socialization. Symptoms
of depression include sadness, loss of pleasure, suicidal thoughts,
and pessimism.
Judith Neidig, RN, PhD of Ohio State University, reported that
depression also carries with it, in addition to the risk of non-adherence,
risk of withdrawal from clinical trials, poorer health outcomes,
and high-risk sexual behaviors.
Women's Health Committee Meetings
The moderators of this session were Drs. Susan Cohn of the University
of Rochester Medical Center Infectious Diseases Unit and Jane Hitti,
Assistant Professor of Obstetrics and Gynecology at the University
of Washington Medical Center.
About 30% of the U.S. HIV+ population are women — 54% identify
as Caucasian, 23% as African American, 20% as Hispanic/Latina, 1%
as Asian, 1% as Native American, and <1% as "other".
It was reported in the Women's Health Committee/Pharmacology Committee
Interactive Session, that menstrual cycle does not appear to affect
drug absorption. However, menstrual cycle may affect the metabolism
of drugs, although probably by no more than 15%.
No pharmacokinetic differences between women and men have been
observed with the nucleoside analogs, although abacavir, the newest
drug in this class, has not been thoroughly studied yet.
Women may also be receiving larger doses of non-nucleoside reverse
transcriptase inhibitors (NNRTIs) than men — possibly due to
weight differences.
Finally, no significant gender differences have been seen with
the pharmacokinetics of protease inhibitors (PIs).
Later That Same Day...
In the Women's Health Committee business meeting, Alan Landay,
Ph.D. of the Department of Immunology/Microbiology at Rush-Presbyterian-St.
Luke's Medical Center proposed to study factors that modify the
female genital tract environment and influence its role as a portal
of entry for HIV. He thinks a couple of these factors may include
bacterial vaginosis, and an entity he calls "HIV Inducing Factor,"
which seems to be sensitive to PIs and may be associated with Epstein-Barr
virus.
Dr. Robert Coombs, Associate Professor, Division of Virology at
University of Washington, Seattle, hypothesized that female genital
tract inflammation increases HIV activation and replication. The
genital tract, he said, is a sanctuary separate from the bloodstream
with possibly different viral populations and varying degrees of
drug penetration.
Remarkably, human papilloma virus (HPV) and the associated changes
in cervical and anal cytology — including cancer, were not
mentioned at this meeting.
Dr. Anthony Fauci of NIAID finally said out loud what I've been
wanting acknowledged for a long time: We are aiming for long-term
control of HIV rather than eradication.
Dr. David Katzenstein, of Stanford University Medical Center (having
recently witnessed a solar eclipse) closed by drawing a beautiful
analogy of our hopes for research: "...to experience darkness at
noon and have it go away."
A Treatment Issues
Editorial
The Real Cost of Development
The pharmaceutical industry just doesn't get it. Here we are on
the cusp of a revolution in medicine, with genomic insights likely
to yield a generation of medicinal products safer and more effective
than any before; with burgeoning markets, record profits and a consumer
culture increasingly comfortable with drugs as a part of everyday
life — and humanity is facing an epoch of disease beyond historical
precedents. HIV, tuberculosis, malaria: these problems and more
are crying for medical, industrial and economic innovations —
but the corporate directors behind the pharmaceutical industry can't
get past their greedy obsession to own, control and milk the life
out of every cash cow they can corral.
Before the African AIDS crisis finally erupted onto international
TV screens last year, the world's corporate brain was busily wiring
up a global legal system to assure, among other things, universally
enforceable patent protections for corporate intellectual property.
Big Pharma was especially anxious to finally nail down the right
to market their drugs on a universal, and to every extent possible,
perpetual basis. The crucial issue for them was extending patent
protections to countries that had traditionally allowed generic
drug makers to run free. And despite the violent scene at the Seattle
meeting of the World Trade Organization in 1999, the future looked
rosy. Then AIDS got in the way. Activists from countries overrun
by the HIV plague started demanding that the new trade rules be
nullified because they kept lifesaving HIV drugs from reaching their
dying friends and families. It was an easy-to-understand issue,
and the media and the public paid attention, ultimately pressuring
the industry to drop an ugly lawsuit against South Africa.
But Big Pharma cooked its own goose. In the propaganda war over
reasonable and unreasonable profits, industry mouthpieces invariably
pander to ignorance. They spin teary tales of the onerous effort
Pharma expends to bring just one new health-giving drug to the poor
children and grandmothers who stoically await succor. (A spokeswoman
for PhRMA actually recently implored consumers to "Pray the companies
will always be successful.") But it only takes one story on the
nightly news about seniors bussing north to seek affordable medicine
in Canada, for these silly PR efforts to lose all credibility.
The truth is, if a cure, or a vaccine, or even a drug that doesn't
give you nightmares or gas ever comes along, it will undoubtedly
come from the for-profit sector. The drug companies make drugs.
They're quite good at it and they have a lot of money to spend on
developing new drugs — money that comes from selling the drugs
they've already developed. It's depressingly naive to think otherwise.
But because of the industry's obdurate greed and inept PR, it's
now commonly held lore that the drug industry is simply a usurper
and exploiter of other people's research, driven to drain unconscionable
monopoly profits from desperate and gullible people. That last bit,
of course, is largely true. And that's the problem.
For an industry that celebrates innovation, the pharmaceuticals
have been remarkably slow-witted about rethinking their devotion
to trade rules that suffocate humane commerce in the goods and ideas
they claim to own. Ownership at all costs — when the cost is
measured in millions of lives — is not defensible or acceptable.
The fall of communism didn't give the winners a license to act like
19th Century robber barons again. We need open discussion about
reasonable and unreasonable profits — not propaganda. We need
creative economic proposals, like Jean Lanjouw's idea to stimulate
tiered zones of patent protection. We need political leaders who
defend the aspirations of people around the world to lead healthy
and productive lives; who proclaim the right of people, through
government, to protect themselves from economic and cultural abuse.
And we need to hold out for a "new world order" that's able to reward
innovators without punishing the rest of us.
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