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Past Issues
Volume 18, number 1 & 2 (Double Issue)
January/February 2004
A Host of Characters
Human genetic factors on stage at Retrovirus
CYP Trip
Evidence of higher Sustiva levels in African-Americans
Retrovirus Retrospective
Webcasts from CROI bring major conference to wider audience
Call Me a CAB
Treatment advocates from around the world face Pharma
Out of the Lab
Resistence to RNAi seen
Docs Say "No" to Abbott
Boycott over Norvir price hike
Boosted Reyataz Reports
Comparable to Kaletra
AIDS Boondoggle at NIH
Gregg Gonsalves uncovers entrenched power in government clinical trials networks
HIV and Host Genetics
Complexity and Contradiction
By Bob Huff
I vividly remember the moment I understood how complex the life cycle of HIV
must be and how difficult it could become to find a cure. During a press briefing
at the 1989 International Conference on AIDS in Montreal, Professor Jay Levy, of
the University of California, San Francisco, was asked about the prospects for
halting the devastation of AIDS. He said the course of the disease in any one
person was due to interactions between the virus, the host and the environment.
Host genetics were stable, viral genetics evolved, but the environment within
the body could be manipulated with medicine. Science needed only to find some
process necessary to HIV's survival and block it — without upsetting
anything the host requires to remain healthy.
The first generation of HIV drugs targeted the virus itself. If they also
affected some of the body's systems, that was a side effect. Now, as we learn
more about HIV's dependency on the body's own cellular functions, a new generation
of therapies that act on host factors may be on the horizon. One potential advantage
to using drugs directed to host proteins is that viral resistance might become less
problematic. While HIV's genetics are wildly error-prone and produce an abundance
of mutations every day (and it only takes one successful mutant to launch a resistant
strain), the genetics of the human cell are stable. If you can block a host target
once, you should be able to block it again and again. Of course HIV may still find
a way to mutate around the impediment. A new class drugs called CCR5 blockers are
designed to keep HIV from interacting with a protein on T-cells that the virus
must bind to before it can infect a cell. The drugs stick to CCR5 and interfere
with HIV binding thereby restricting infection. But laboratory studies have
demonstrated that, as with every other treatment tried to date, HIV can eventually
produce a mutation that evades the obstacle.
So far, all evidence suggests that CCR5 can be blocked without causing harm
to the host, which is great news. But the big challenge to using drugs that disrupt
natural mechanisms is to make sure they only inhibit HIV's interactions with the
system and leave the normal activities alone.
Everyone into the Pool
To complicate matters, while any one person's genes are stable, there may be
important genetic variations between individuals in a population that influence
how well a medicine will work. One drug may not behave the same in every body.
This is because human genes evolve in a population the way viral genes do in a
body, albeit over a much longer period of time. This means there is diversity
in our gene pool. Furthermore, each set of genes has a twin; with one coming
from each parent. (This, as Bill Clinton knew, is the real meaning of sex.)
The gene pairs are called alleles, but not every pair is identical. For example,
most people have two working copies of the gene that makes the CCR5 protein that
HIV uses to infect new cells. But some people have only one working copy, and
a few have none. Because people without a working copy of the CCR5 gene can't
make the protein, very few of them become infected. And those who have
contracted HIV typically experience minimal disease progression; a CCR5 blocker
would be wasted on them.
Host genetics are increasingly recognized to play a role in everything
from one's initial susceptibility to HIV infection, to the strength and durability
of the immune defense the body can mount, the pace of viral replication and the
seriousness of damage done over time, to the likelihood that drug therapy will
be successful. A picture is emerging that shows the virus hijacking natural
mechanisms at nearly every stage of its life cycle to do the work of transporting,
reproducing and distributing itself. Yet we are only at the threshold of grasping
the design and shadings of the system's complexity.
At the 11th Annual Retrovirus Conference, HIV's dependence on its host was
the subject of a number of important presentations. Speaking at one of the final
sessions of the conference, Amalio Telenti, an HIV researcher from the Institute
of Microbiology at the University of Lausanne, Switzerland, offered a qualified
vision of how knowledge about host genetics might increasingly affect care and
treatment for people with HIV.
Biology used to be simple, said Telenti, describing a time when genetic
researchers were content to look for the role of single genes that produced
phenotypic traits such as blue eyes or fluffy coats. But the field has rapidly
evolved as we increasingly understand that phenotype is the net result of many
small contributions from multiple genes that shape the complex traits we see
in life.
Many host determinants and environmental factors at many points of interaction
cumulatively help determine the clinical course of HIV disease. Although many of
these factors are still unnamed, acting in concert they are responsible for the
wide variability in disease progression rates seen in populations. The time from
infection to a serious state of AIDS can average ten years in an untreated individual,
but can range from one year to possibly never for a few people. Telenti has modeled
the contribution of alleles of various markers of disease progression on the rate
of CD4 decline from 500 to 200 in members of the Swiss HIV Cohort. People with
the common alleles progressed on average in 5.1 years; those with bad alleles
progressed in 3.1 years and those with protective alleles in 7.7 years.
Since a newly diagnosed person may not need or want to begin antiretroviral
therapy right away, Telenti proposes that it would be useful to be able to predict
when treatment should be started. By analyzing certain host genetic determinants
associated with the course of HIV disease, it may one day be possible to predict
the slope of T-cell decline and estimate a date when treatment will become
advisable. Some of these determinants of faster or slower progression include
genes that affect co-receptor availability, such as CCR5, but there are many
others with less dramatic impact, such as various HLA types and genes for immune
system messengers such as IL10.
A whole host of other host factors come into play when antiretroviral therapy
is thrown into the mix. With multiple, variant transport molecules at the gut,
the liver and cell, each person will process and eliminate different drugs at
slightly different rates and may have different susceptibilities to toxicity.
Genetics can help explain the wide variability in drug concentrations that are
observed in population studies, and may explain why, for some people, drugs can
never quite control their virus.
Telenti says that at least 40 percent of the variance in infectivity and
diversity between individuals with HIV may be due to host factors. But, he
cautions, the data on most genetic associations represent modest effects with
wide confidence intervals. No single polymorphism likely controls the master
switch for progression. Yet some human proteins have the potential to grant
virtual immunity to HIV.
So Close...Yet So Far Away
APOBEC3G is a recently identified host protein with the potential to offer
innate protection from HIV by scrambling its genetic code. Unfortunately, a
viral protein called Vif readily binds to APOBEC3G and defeats its anti-HIV
properties. Immediately upon its discovery scientists began asking, could a
drug be designed that blocks Vif or binds to APOBEC3G and stops Vif from
shutting it down? Amazingly, there is only one amino acid standing between
runaway HIV infection and nearly complete immunity to the virus. Nathaniel
Landau, of the Salk Institute for Biological Studies in La Jolla, discovered
that if the negatively charged amino acid at position 128 of APOBEC3G changes
to a positively charged amino acid, then Vif no longer binds and HIV is
rendered harmless. Landau's team now plans to look for that mutation in
long-term non-progressors to see if perhaps their natural defenses are
impervious to Vif. Others will be looking for variant APOBEC3G in different
racial and ethnic groups.
APOBEC3G would normally have a tremendous impact on viral replication rates
but it is silent in the presence of HIV. Telenti says there are likely dozens
of genes that influence the pace of progression, with the net outcome due to a
balance between the influence of rapid and slow factors. Landau agrees. He
suspects there may be many factors present in cells in low quantities that, if
they were strongly expressed, could protect against the virus. One of these
may be a host protein called TRIM5; a potential contributor to innate immunity
that may explain why monkeys don't get AIDS. Matthew Stremlau, from the Dana-Farber
Cancer Institute in Boston, has discovered a protective factor that prevents human
HIV from establishing an infection in the simian host. HIV can attach to and enter
a monkey's cells, but gets stuck before it has a chance to replicate its RNA. TRIM5
apparently stops the viral capsid from uncoating and exposing its genetic payload.
Humans have a variant of TRIM5, but it is not able to block the virus nearly as
efficiently as monkey TRIM5. This new point of interference suggests the possibility
of administering a block with a drug or possibly gene therapy. More discoveries
like this are almost certainly waiting in the wings.
Budding Genius
Although much recent attention has been given to explaining how HIV binds to and
gets into a cell, far less is known about how a newly formed virus leaves a cell.
This phase of the viral life cycle is called budding. At the Sunday night plenary
that opened the conference, Wesley Sundquist, a virologist at the University of
Utah, gave a detailed tour of the mechanism HIV uses to export new virions from
an infected cell. First, all of the proteins and RNA that make up a new viral
particle must be guided through a briar patch of actin molecules that cluster
just below the lipid membrane and give shape and mobility to the cell. Then the
premature viral core has to be directed to a site on the membrane that is
permissive for virus release. Since HIV is clad in an envelope made up of its
host cell's lipid membrane, a new virion has to wrap some of the membrane around
itself like a tiny bubble then finally pinch off the last tethering bit before
it can go free. Cellular factors are at work in every step of the budding and
release process, another example of the body inadvertently helping to send new
viruses out into the world.
Sundquist's group identified a host protein associated with HIV budding
called TSG101. Fortunately, this protein had already been studied for its role
in a cellular housekeeping process that sends unwanted cell-surface proteins
to their destruction in the lysosome, a membrane-enclosed bubble inside the
cell filled with digestive enzymes. The obsolete proteins are marked for
destruction then conveyed from the cell's surface and inserted into the lipid
membrane of the lysosome. But before they can be destroyed they need to be
brought inside the bubble. This is done by pinching off bits of the membrane
holding the doomed proteins and forming tiny vesicles, which are released to
the interior of the lysosome. In this regard, vesicles are very similar to
HIV particles, and the mechanism that forms these vesicles is probably the
same process that HIV hijacks to engineer its release from the cell. TSG101
is kind of routing ticket that directs a protein to the vesicle formation
machinery. HIV seems to use TSG101 to send itself to the outside world
instead. The details of how this happens are complex and not fully understood,
although, Sundquist said, so far we know of at least 20 host proteins involved,
with more likely to be found. (Sundquist's fascinating lecture can be viewed
as a webcast at: www.retroconference.org) If HIV inserts itself
into this chain of events in some unique way, then a possible treatment might
be designed to stop or slow budding without causing havoc to any natural process.
All Over the Map
Variability is not only for genes; it occurs in the scientific literature
as well. Telenti took an aside to note the many published discrepancies
on the significance of certain host proteins for HIV pathogenesis.
P-glycoprotein (P-gp) is a membrane-bound drug transport molecule
that protects cells from toxic intruders such as cancer chemotherapies
and HIV antiretrovirals by pumping them out of cells. But by lowering
the concentrations of protease inhibitors within cells, P-gp can
hinder antiviral efficacy. Just as some people produce different
amounts of CCR5, some people have different alleles of the MDR1
(for multi-drug resistance) gene that produces P-gp, with different
sets of alleles producing greater or lesser amounts of P-gp. A study
by Telenti's group published two years ago found an association
between different MDR1 alleles and greater rises in CD4 counts within
six months of starting an antiretroviral regimen containing nelfinavir
or efavirenz. The theory is that people who express less MDR1 have
less P-gp, which means that less drug is pumped from their cells
and antiviral activity remains higher, longer. (See "The Genetic
Edge," GMHC Treatment Issues, January 2002.)
But other reports have suggested that P-gp, even in the absence of therapy,
might play a role in how permissive cells are to becoming infected with HIV.
A few laboratory-based experiments have shown a dramatic decrease in viral
replication in cells that produced P-gp abundantly; protection that was lost
when P-gp blockers were added. One theory holds that P-gp may be interfering
with various lipid molecules on the cell's surface that are needed to assist
with HIV fusion and entry. But these reports have been controversial, partly
because some of the cells studied expressed over 1,000 times as much P-gp as
T-cells do. A new report from Telenti's lab casts doubt on these previous
findings with results from an experiment using T-cells with normal levels
of P-gp.
T-cells were collected from 128 HIV-negative persons (representing the
variety of MDR1 alleles in that population). The cells were infected with
a laboratory strain of HIV and then characterized for permissiveness to
infection. When the MDR1 alleles of the donors were correlated with the
results of the permissiveness assay, no association was evident between
P-gp levels and a cell's susceptibility to HIV infection. But given that
such contributory associations are typically small, will these negative
results settle the matter? Or does the fact that multiple reports have
come up with multiple conclusions signal that something about the field
is not ready for prime time? The stakes are likely to be high.
Genes, Drugs and Money
One day, perhaps, before a person steps across the threshold to initiating
antiretroviral therapy, the pharmacogenetic likelihood of their response to
various medications may be evaluated. The genes for factors that influence
exposure to drugs, such as the cytochrome metabolic proteins, P-gp and other
transporters will no doubt be analyzed. Next, the toxicogenetic markers for
trouble will be examined to prevent toxic catastrophes. An HLA type associated
with abacavir hypersensitivity has been located and soon a simple screening
test might simplify the use of this drug. And recently an allele in the cystic
fibrosis gene has been associated with susceptibility to pancreatitis, a
well-known serious side effect of ddI toxicity.
But even mild toxicity can impact efficacy if intolerability leads to
discontinuation or missed doses. It would be helpful to know before a drug
is prescribed, who is at risk for having unpleasant reactions and who can
be predicted to have only benign side effects. One talk at the conference
showed that African-Americans may have higher blood levels of efavirenz
than European-Americans. But does that translate into better virologic
response or does it mean more dropouts due to CNS toxicity? Additional
study is required. Ritonavir-boosted protease inhibitors have become
standard-of-care, yet ritonavir elevates triglycerides and cholesterol for
too many who take it. Individuals with the apoE gene, found in 27 percent
of the population, are likely to have elevated lipids at baseline or a higher
risk for developing them. It may become useful to screen for that underlying
propensity before initiating treatment.
All of this has caught the attention of the U.S. Food and Drug Administration
(FDA), the body responsible for ensuring the safety of drugs in the U.S. In
attempting to understand the potential for genetic screenings to make medicines
safer, the FDA has asked the pharmaceutical industry to voluntarily provide
information on the pharmacogenetics of their drugs and has promised not to be
prejudiced by what they learn when it comes to regulatory decisions affecting
the companies. Many in the industry are skeptical and worry that this new body
of knowledge will slow drug approvals. Yet others see opportunity. By selecting
out individuals likely to have adverse events or fail to benefit, clinical trials
could become more focused and produce results sooner and with more information
on the safe use of the drugs.
Before this can happen, Telenti says, more — and better quality —
research must be done. In reviewing published reports of genetic associations,
Telenti found that contradictions and equivocal findings are the rule; only 30
percent of them can be considered true. Since the strength of association of
individual genes with complex traits tend to be weak, larger study samples,
stronger statistical methods and more rigorous study designs are needed. He
recommends building larger cohorts and research consortiums, including cohorts
in the developing world, with appropriate ethical safeguards. Finally, laboratory
scientists need to continue to uncover the biological secrets of genetic determinants
so that clinical medicine can make the most of them.
References:
Telenti A. Host genetics and pharmacogenetics: implications for clinical
practice. Program and abstracts of the 11th Conference on Retroviruses and
Opportunistic Infections (CROI); February 8–11, 2004; San Francisco,
California, Abstract 161.
Landau N. HIV Vif: Deactivation of a deadly deaminase. 11th CROI, 2004,
Abstract 103.
Stremlau M, et al. The cytoplasmic body component TRIM5 restricts HIV-1
infection in Old World Monkeys. Nature 427, 848–853.
Sundquist W. Cellular factors and HIV budding. 11th CROI, 2004, Abstract 6.
Bleiber G, May M, Suarez C, et al. MDR1 genetic polymorphism does not
modify either cell permissiveness or disease progression before treatment. JID,
15 February, 2004:189;583–586.
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Higher Sustiva Levels Seen in Some
African-Americans
Drug metabolism is highly complex and may be modulated by interactions between
multiple enzymes and environmental factors. Although the CYP3A4 enzyme responsible
for clearing many protease inhibitors from the system is best known, new enzymes
and new interactions continue to come to light. And for every new metabolic player
discovered there is the potential for genetic variability between individuals and
populations to complicate treatment decisions.
In a slide session at the 11th Annual Retrovirus Conference, Heather Ribaudo,
of the Harvard School of Public Health, reported on a study of the pharmacokinetics
of efavirenz conducted by the AIDS Clinical Trials Group (ACTG). The study, ACTG 5097s,
found that clearance of efavirenz from the body was increased by 32% in non-Hispanic
whites compared to blacks or Hispanics. She found a slight association between higher
blood levels of efavirenz and study discontinuations, although these did not seem to
relate to the incidence of CNS toxicity or to virologic response. An analysis of
discontinuations by race/ethnicity was not performed. No association with gender
was observed.
David Haas, of Vanderbilt University in Nashville, presented a genetic analysis
of a subset of 89 individuals from the A5097s study. Haas found that a single
nucleotide polymorphism (SNP) that changed the DNA code from a "G" to a "T" at
position 516 of the gene for the CYP2B6 metabolic enzyme was associated with slower
clearance of efavirenz, higher blood levels of the drug and more CNS-related side
effects.
Median AUC (a measure of total drug exposure) of efavirenz levels was about 3
times higher with the CYP2B6 position 516 TT allele than with GG. But after
controlling for these alleles, there was no association between race/ethnicity and
efavirenz levels. The TT and GT alleles were also significantly associated with a
greater number of CNS-related adverse events at the initiation of therapy, which
gradually disappeared by 24 weeks, even though higher efavirenz levels persisted.
However, there was no association with viral load response.
Overall, in the study and in a separate representative population sample of DNA,
at least one G516T allele appeared in 21% of European-Americans and in 38% of African
Americans. The double-dose TT allele occurred in about 20% of African-Americans but
in only 3% of European Americans. The study also detected a number of SNPs in other
metabolic enzymes, but none were as strongly associated with the blood levels of
efavirenz. While having the TT allele might be expected to predict better efficacy
of efavirenz, it may also contribute to higher discontinuation rates if side effects
are more pronounced. Both of these require further analysis.
The CYP2B6 G516T SNP had not previously been recognized as a factor in efavirenz
metabolism. This enzyme also metabolizes nevirapine, nicotine, tamoxifen, bupropion,
diazepam and Ecstasy, so more study of its impact on individual dosing and the
potential for drug-drug interactions should be followed-up. The effect of this
polymorphism on nevirapine is most critical, since it is poised to become the most
widely used antiretroviral drug in the world. Surveys of the frequency of the G516T
allele in worldwide populations should be conducted right away, and analysis of
Boehringer's extensive safety database should be done to look for correlations
of toxicity with the SNP. Studies should also continue to evaluate if genetic
testing for every known SNP affecting drug metabolism can help individualize
therapy to avoid toxicity and maximize efficacy.
Ribaudo H, et al. Relationships between efavirenz pharmacokinetics, side
effects, drug discontinuation, virologic response, and race: results from ACTG
A5095/A5097s. 11th CROI, 2004, Abstract 132.
Haas D, et al. A common CYP2B6 variant is associated with efavirenz
pharmacokinetics and central nervous system side effects: AACTG Study NWCS214.
11th CROI, 2004, Abstract 133.
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Best of the Retrovirus Webcasts
By Bob Huff
Some of the most important talks at the 11th Annual Retrovirus Conference
this year are now available as free webcasts. If you did not attend the conference
or were unable to catch every session, you can access over 20 hours of plenary
talks, mini-lectures and symposiums offered as video and audio accompanied by
synchronized slides. A low-speed connection offers voice and slides without the
video. As you work your way through these talks you will be exposed to the
latest issues in the science and social reality of HIV and AIDS.
Many of the talks delve deeply into scientific details of their subject and may
be incomprehensible to those without some background in the topic. Other talks
discuss the science in a clear manner and are worth tackling even if one's scientific
literacy is low. A few talks cover issues that everyone should become familiar with,
such as the crisis of HIV in the developing world, the state of the epidemic in U.S.
prisons and jails, and the potential for developing an effective microbicide. Here
is an annotated guide to Retrovirus on the web: www.retrovirus.org
General Interest
Stephen Lewis
(Sunday, 5:30 pm; Opening Plenary; Click the index button and skip to Lewis' talk)
If you have not heard of Stephen Lewis, or have only read his speeches on the plague
in Africa, start here. Listening to him is like witnessing a great orator from the
19th Century. Lewis sounds a clarion call for treatment and action in Africa. He
convinces in the language of necessity, compunction and love. This was truly the
keynote message for the conference.
Men on the DL
(Tuesday, 12:00 pm; Men on the "Down Low": More Questions than Answers.)
Greg Millet of the CDC discusses the situation of heterosexually-identified black
men in the U.S. who have sex with men. He reviews common assumptions about DL men,
the history of the term, outlines gaps in the research and makes recommendations
for filling those gaps.
HIV Care in Jail
(Tuesday, 12:00 pm; HIV in Jails and Prisons)
Jim McAuley of Chicago's Cook County Jail demonstrates that for many people, jail
is the only opportunity they have to access health care services. But the short
time spent in jail and the high turnover rate poses limitations to the amount of
care that can be delivered.
Psychiatric Issues in Youth
(Monday, 4:00 pm; Symposium on Emerging Long-term Complications)
Sharon Nachman of Stony Brook University in New York discusses what is known and
not known about psychiatric disorders in children and adolescents growing up with
HIV.
Global HIV / AIDS Issues
(Sunday, 3:00 pm; Symposium: Development in the Global Response to AIDS)
Scaling Up from the Top Down
David Miller of WHO presents a comprehensive, if dry, overview of the challenges
of scaling-up treatment, prevention and care efforts to reach millions of people
who urgently need them. Many of the issues he discusses are also applicable to
the need in the U.S. to reach and treat the large numbers of people with HIV who
remain unaware of their status or have not entered care.
Planning Treatment in Uganda
Alex Coutinho of TASO in Uganda discusses the scale-up effort in his country
where one million people have already died of AIDS, one million have been orphaned
and 25 million need treatment. The goal in Uganda is allow parents to live long
enough to raise their children. Coutinho focuses on plans for family-based
treatment programs aimed at rural areas. Don't miss the gallery of photos from
rural TASO treatment centers at the end of his talk.
Treatment in the Private Sector
Gavin Churchyard gives an interesting and detailed report about the first year
of the Anglo American Mining company's program for offering therapy to all
HIV-positive employees in their South African operations.
Clinical Science
These presentations start with a general overview of the issue and why it is
important before veering into deep waters. But stick with it; the presenters all
do a great job of making their points clearly with minimal jargon.
Herpes and HIV
(Wednesday, 10:00 am; Mini-lecture on Global AIDS)
Connie Celum, of the University of Washington, Seattle, describes the symptoms
of HSV-2 infection, its interactions with HIV disease, then reviews what is known
about the increased risk for HIV acquisition and transmission. Studies of acyclovir
therapy in discordant couples are proposed. Graphic content!
Tuberculosis and HIV
(Wednesday, 8:30 am; Plenary; Tuberculosis and HIV: Is there a Scientific Basis
for Hope?)
Peter Small, of the Bill and Melinda Gates Foundation, gives an overview of TB
infection and the history of efforts to vaccinate. He also notes increased interest
in the "subtle, ongoing dialog" between the host and the pathogen with a goal of
tipping the balance towards the host. His conclusions are worth wading through
some dense slides, particularly his recommendation that more cooperation is
needed between the TB and HIV research establishments.
Malaria and HIV
(Wednesday, 10:30 am; Interaction of HIV and Malaria)
Richard Steketee, of the CDC, offers viewers a "Malaria 101" talk, then describes
what is known about the interaction between these diseases in the developing world.
Women and HIV:
Microbicides
(Monday, 9:00 am; Plenary; How close are we to a microbicide?)
Robin Shattuck, of St. George's Hospital in London, details the considerable
challenges to developing an effective microbicide. One daunting example is
the large quantity of product required for current candidates to be effective
in animal models. Yet in the end, with the number of candidates and the
emerging commitment of resources, the longer-term outlook is promising.
Mother to Child Transmission
(Monday, 11:45 am; Mini-lecture: Treatment strategies for preventing MTCT)
Ten years after the first historic report that mother-to-child transmission of
HIV could be prevented with AZT, Elaine Abrams, of Harlem Hospital, reviews
the progress and the potential for continued roll-out of effective approaches.
Particular attention is paid to the emerging challenge of resistance in women
and children previously exposed to nevirapine.
Treatment Complications in Women
(Monday, 4:00 pm; Symposium on Long-term Complications of HIV)
Bone loss, lipid changes, and body shape changes associated with antiretroviral
drug therapy in women. Multiple speakers.
Deep Science (but worth the effort)
Budding and Release
(Sunday, 5:30 pm; Opening Plenary. Cellular Factors and HIV Budding)
Wesley Sundquist, of the University of Utah, Salt Lake. The details are boggling,
but the fact of how HIV subverts normal processes to engineer its escape from
cells is stunning.
APOBEC3G
(Tuesday, 9:00 am; Plenary, DNA Editing and Host Restriction Factors)
Michael Neuberger, of the Medical Research Council, Cambridge, UK, tells the
story of the discovery of APOBEC3G, a potent, innate anti-HIV defense.
For more on APOBEC3G, see:
(Tuesday, 4:00 pm; Symposium, Host Restriction Factors)
Multiple speakers
Future Therapy
(Wednesday, 4:00 pm; Symposium, Antiretroviral Therapy)
Warner Greene, of the Gladstone Institute in San Francisco, reviews potential
new drug targets emerging from basic research.
Amalio Telenti, of the University of Lausanne, discusses the challenges and
potential of using genetics to guide therapeutic choices.
Lisa Demeter, of the University of Rochester, gives a fascinating and
important talk on emerging evidence about NRTI drug resistance.
World CAB
Focus on International Drug Pricing
Over the past year and a half, HIV community members from around the globe
have begun meeting to discuss how they can advance treatment literacy and increase
PLWHA input into decisions by the research, education and care programs that
affect them. Community advisory boards (CABs) have long been an important
vehicle for representing the needs of people living with HIV to researchers
and drug companies in the developed world. In February of 2004, for the first
time, a World CAB was convened to allow PLWHAs from the developing world to
voice their concerns about drug pricing in their regions to senior-level
representatives of the multinational pharmaceutical industry. Twenty-eight
individuals from 21 countries met with officials responsible for global
pricing policy at Roche, Glaxo-Smith Kline, and Boehringer Ingelheim. The
following is a digest of two of those meetings.
Hoffman-LaRoche
Christopher Murray, Director of International Pharmaceuticals, Roche, Basel
MURRAY: All of our policies regarding access to our drugs come from
Roche headquarters in Basel. I have responsibility for these international
issues within the company. The Roche pricing policy for protease inhibitors
is that Least Developed Countries (LDC) receive a no-profit price from Roche
Basel. Currently, the Roche no-profit price is better than that of generic
versions of nelfinavir. Roche also offers a clear pricing policy for direct
supplies of Invirase and Viracept on ex-factory sales to low-income and
lower-middle-income countries as classified by the World Bank.
SUBHA: What does no-profit mean?
MURRAY: No-profit means no marketing or R&D costs are covered. It only
covers what it costs to get the drug into a finished pack; no financing or
inventory costs. There are no royalties paid to Pfizer, who owns the patents
on nelfinavir. Effectively, the no-profit price includes a contribution from
Roche. These prices are for direct sales from Basel. We only quote a price
in Swiss francs due to exchange rate fluctuations and zero margin. We don't
differentiate between public and private sectors. We don't differentiate
between any NGO (non-governmental organization). We will only re-price based
on changes in economy of scale or reduction of demand.
GREGG: But many of these lower- and middle-income countries still can't
afford your drugs.
MURRAY: You may not like the classifications, but this gives us transparency
in how we set our prices. I must be rigid because otherwise we will have to
negotiate with every country separately.
STERN: The price jumps from $880 in LDC to nearly $2,900 in lower-middle-income
countries. This says a lot about the profit to be gained in those countries.
MURRAY: Our transparency policy is not to negotiate country to country. The
prices we have today are derived from people in your countries saying exactly
how much they need.
GREGG: How did you make the decision on who gets the no-profit price?
MURRAY: Kofi Anan asked the pharmaceutical companies to offer the lowest
possible price in the Least Developed Countries, and we did.
LOBNA: Can't you offer the no-profit price in countries not on the LDC list
where there is a great need but no resources?
MURRAY: No. We are not going to have the no-profit price for regions other
than the LDC countries. The lower and middle income countries still receive a
reduced price from the European price. We offer an equitable pricing structure.
MARK: You can't say your prices are equitable even though they are uniform,
because people can't afford them. We're saying they are not fair, period.
MURRAY: There are huge variations in income levels within and among developing
countries. The classification includes oil-rich states and states with a strong
industrial base. High-income, non-OECD countries are classed as developing. They
pay the middle price of $2900. Upper-middle-income countries pay the regular
price. And all of these countries have different prices in-country depending
on distribution costs.
There are additional costs for freight, import duty taxes and distribution
to be added. For example, the no-profit price ex-Basel is 90.90 Swiss francs,
which becomes 125 Swiss francs in South Africa. That's 38% higher:
Clearing, freight and insurance adds 2.5%
Local packaging and quality control adds 6%
Local warehousing adds 4.5%
Distribution adds 8%
So the local cash price is net plus 21%. Then the government adds a 14%
VAT (value added tax), which equals a 38% increase.
LEI: We are puzzled by the huge differential between your prices and generic
prices.
MURRAY: The nelfinavir sold in Botswana is the same as sold anywhere else.
Our suppliers optimize their existing resources. But there is not a huge difference
in price between ours and generic nelfinavir.
GREEN: Would increased volume lower the cost?
MURRAY: You would need substantial volume increases to get small reductions
in price.
LEI: Are you looking at options to manufacture in countries where costs are
lower?
MURRAY: The manufacturing model is to have the machines running 24-hours a day
making the same product. Moving the site of production doesn't change the cost.
GREEN: We've heard multinational pharmaceutical companies say that this is our
rock bottom price. Then generics come in at 1% of that and the companies say:
"Now we can reduce the price."
MURRY: If Ranbaxy can make nelfinavir for $600, then you should buy it from
them.
OLIVE: Can those of you here from Africa afford nelfinavir?
MURRY: It is not our job to arrange funding. It's not our role to buy our
own products. It's the government's role. In South Africa the problem is political
apathy. When the government is only spending $5 to $10 a year per capita on
health, the situation is their responsibility, not Roche's.
HANNA: But most of the people who need your drugs are poor, so even if
they live in a middle income country, they have no access.
MURRAY: We don't have differential pricing within a country. There are
people in rich countries who can not afford the drugs. We will not reduce
the price any further.
GERMAN: If you know that the Global Fund will be providing the money for
a lower or middle income country, will this change your policy on who can
get the no-profit price?
MURRAY: No. We will work within the 3 by 5 plan to increase the volume,
but that won't change the no-profit status of the price. It is not possible
to negotiate for a better price in the middle income countries. We are
willing to be priced out of the market in those countries when generics
come in.
SUBHA: Can we discuss lowering the $880 price in least developed countries?
MURRAY: No.
MAURO: The most promising untapped market is in the developing world. Why
are you giving up on this market?
MURRAY: There is no profit for us.
SUBHA: I want you to leave us with a different message. You have to give
us something to help us get going with your drug.
MURRAY: I can't give you anything more. The fact that our drugs are not
affordable in some parts of the world is not Roche's responsibility. I can't
give you a warm glow when I leave the room.
World Bank Classification
of Economies
The World Bank divides economies on the basis of gross national
income (GNI) per capita. Pharmaceutical companies use these
classifications to set prices outside of the High Income countries. |
The 2002 divisions are: |
| Low-Income |
Average income under $735 per person per
year |
64 countries |
| Lower-Middle-Income |
Between $736 and $2,935 per person per year |
54 countries |
| Upper-Middle-Income |
Between $2,936 and $9,075 per person per year |
34 countries |
| High-Income |
Over $9,075 per person per year |
56 countries |
Boehringer Ingelheim
Larry Phillips, Director of Marketing, Virology and Infectious Diseases,
Boehringer Ingelheim.
PHILLIPS: There's quite a learning curve going on in our company about
providing access to our drugs in the developing world. For us, in terms
of price reductions, there are two ways to go about it. One way is you can
donate drugs, which we don't think is a solution. The other way is to grant
voluntary licenses to generic drug makers and create competition in the
market. We think the best idea is to have as many people producing nevirapine
as possible at the local level. True price reduction will never come from
one company; it has to come from competition.
Of course, we have to make sure a company we license has the obligation
and the capacity to actually produce the drug. We will then grant a voluntary
license, but they have to produce the drug and produce a quality drug.
ANASTASIA: Is the generic nevirapine the same as your Viracept?
PHILLIPS: There are some differences between the generics and drugs
from the developed world, but those mostly have to do with registration
issues and not necessarily with potency.
GREGG: Would you also grant voluntary licenses to middle income
countries?
PHILLIPS: Eligibility for our donation program is based on lower and
middle income status as classified by the World Bank. But in a country
where it is obvious that the people can't afford to pay for their
therapy, then we are willing to consider voluntary licenses.
Within the industry, everyone is worried about the diversion of generic
drugs back into the markets where they make their money. Everyone is
concerned with diversion and re-importation, and if it is handled irresponsibly,
it damages the process. We don't think it is an insurmountable problem, though.
But I think a lot of local legislation is needed. These people are crooks.
Voluntary licensing can't be done without some guarantees in the market.
There are also tricky issues with the FDA about voluntary licenses. One
has to do with safety. We have a safety reporting obligation, but we can't
make the generic companies report their safety.
GERMAN: Your company is interested in granting voluntary licenses. Which
countries have you done that with? Are you also interested in doing technology
transfer to those countries so they can learn to make the drugs?
PHILLIPS: Technology transfer varies from company to company. When we deal
with Ranbaxy, they already have a version of the drug, so it's no problem. We
are in active negotiations in South Africa; we are looking in Eastern Europe;
we have licensed the Indian companies; and there is a possibility to find one
in Asia and one in South America.
ANASTASIA: In Eastern Europe, I don't believe you can't find a producer in
our region.
PHILLIPS: Eastern Europe has not gotten the attention it deserves because
the immediate concern was Sub-Saharan Africa. You have to sell the idea of
making HIV drugs to generic makers. Some don't want to get into HIV because
it is such a hassle.
BEN: If BI's HCV protease inhibitor makes it to market, will you have
voluntary licenses in countries with large HCV prevalence like Egypt?
PHILLIPS: People like the voluntary license with nevirapine because it
is such an easy drug to make. With other drugs it won't be so easy.
GREEN: What royalties do you expect?
PHILLIPS: MSF calls for 3%, which is what we ask for. We ask the company
to put it into local HIV programs as part of the contract. But we can't
enforce it. If they don't do it we can't pull the license.
DELME: The 3% donation can't be enforced?
PHILLIPS: You could try to enforce it, but I don't know how you could.
What if you give a voluntary license and the company doesn't produce the
drug — do you take it back?
OLIVE: I'm a suspicious person. What's in it for you? I like what you're
saying but how does it translate into something we need?
PHILLIPS: Nothing is in it for us. It's philosophical in a sense: There
is both a business and an ethical component to pharma. We have a high
standard of health care in the North; but our industry doesn't sell cookies.
We want to make a profit and we know health is a human right. You can think
of all the reasons for why you can't deal with these problems, or you can
try to deal with them. It's the belief of the people on my team that the
industry must take responsibility for what is going on. But the governments
have to take responsibility too.
We found you can't just give drug away; you have to go out and market
it to governments. Within your ability as a company you have to approach
governments, WHO and NGOs. Then you need to get the people in your company
behind you and try to make it work.
STERN: In Jamaica, there is no patent on nevirapine and a company called
Lasco is distributing Cipla's Triomune at an inflated price.
PHILLIPS: The problem in Jamaica can best be addressed by competition.
Where people are poor, there is no way to make it perfect. The pharmacist
adds a markup because he wants to eat too.
ANASTASIA: In Ukraine the price of one package of your drug is 100 Euros,
in Belarus it is 280 Euros. What is the difference?
PHILLIPS: It's probably due to the local pharmacies. Whatever the ex-factory
price is, you can't be sure what the pharmacy sells it for. All we can do is
recommend a price.
SVILEN: In Bulgaria we have registered nevirapine, we have the money to buy
it, you have local reps there, but still we have no drug.
PHILLIPS: I don't have an answer for you.
LOBNA: In Egypt, the free nevirapine program works through UNICEF but only
two women have used it.
PHILLIPS: You have to market the program and tell them it is available, but
I can't force governments to use it. We say, use the MTCT donation sites to
build your treatment programs upon, since there is at least minimal infrastructure.
We lobby where we can, but the NGOs need to get going too.
AUGUSTINE: You've spoken of a strong presence in South Africa, but we don't
seem to see the effect in price reductions in Zambia.
PHILLIPS: We are working in Zambia with the nurses association on education.
The problem with the granting of voluntary licenses is to get the companies
started. With the tenders, you say, I've got a million dollars, how much drug
can you give me for that? Supply and demand regulates prices. Then, some
countries don't want you to import; they raises taxes at the border, etc. If
they can tell us how much drug they want and when, then I can do more.
AUGUSTINE: What are you doing in very rural areas where the need is great?
PHILLIPS: We've approached WHO to have them make these sites part of 3
by 5. We will give help and assistance to qualified groups but we don't want
to tell people what to do.
JAMES: Can you do extended stability studies so we can have extended
expiry dates, especially in the African climate?
PHILLIPS: We can look into that.
GREGG: What's the pricing policy in middle income places without generic
production?
PHILLIPS: We look at our own processes and try to make it cheaper. We
produce our drugs in a different regulatory environment and it costs more.
Maybe we can farm out production, but we still have to produce to FDA standards,
so it still costs more. Producing to WHO standards produces equivalent
therapeutic quality, but it costs less. Viramune is produced in Ohio, which
is probably not the cheapest place to make it.
GREGG: So, what is the price in those middle income countries?
PHILLIPS: Sixty cents per day, the same as in the AAI (Accelerating
Access Initiative) countries.
LOBNA: What are the criteria?
PHILLIPS: It is the World Bank criteria, but lower-middle-income
countries also get the AAI price.
LOBNA: In Egypt the problem is availability. There's no market so the
companies don't register the drugs. The big distributors don't order them.
There's no market for generic makers. We simply need cheaper prices.
PHILLIPS: I don't know about the situation there. Where we've had local
BI business units for a long time, they have become very independent. Like
a lot of companies, we let the local guys run the local businesses. Getting
them to approach HIV from a different standpoint has not been all that easy.
In the middle income countries prices are often negotiated on a case-by-case
basis.
SUBHA: Can you cite a good example of case-by-case negotiations?
PHILLIPS: The CARICOM (Caribbean Community and Common Market) countries
approached us as a group and asked for our lowest price, which is what they
got. When you apply for registration in Africa, sometimes you can do it in
a block for several countries. It would be good if that process were
streamlined for HIV.
STERN: I have your prices from the CARICOM negotiations and from your
Central American AAI negotiations. I see big disparities between countries
in the daily price of nevirapine. The CARICOM price is 60 cents per day,
but in very lower-middle-income countries like Nicaragua and El Salvador,
your price is $1.66 a day. These are countries where no generics are
registered so they must buy from BI.
PHILLIPS: Those countries are controlled by our business unit in
Mexico. The Caribbean is controlled by the Canadian BI office. It is
a big internal battle within the company. Any company has a lot of
politics; and we have a lot of people who came up through the pharmaceutical
industry.
STERN: So, here's my headline: "Mexican BI Executives Triple the Price
of Nevirapine for Central American People with AIDS." Is that correct?
PHILLIPS: I don't think that headline reflects the intention.
STERN: The AAI, UNAIDS and Peter Piot asked the companies to negotiate
in good faith with the regions, yet I know that Central America is paying
2.7 times as much as the Caribbean countries, even though they have lower
socio-economic status. So if Canadian BI and Mexican BI are not controlled
by German BI, we need to know about it.
SUBHA: Could we hear some solutions on how we could follow up on this?
PHILLIPS: Are these countries eligible for the lowest price, which
is 60 cents a day? Yes they are. Can I make that happen? Yes I can. And
I will. You can help me make this happen by working locally with the
representatives. Just please be certain that the prices you quote are BI
ex-factory prices and not distributor or pharmacy prices.
But, yes. I can go to the countries that meet the requirements for 60
cents per day and make that happen.
GREGG: Any country?
PHILLIPS: If any country fits the criteria we can do it.
World CAB Participants Represent!
AUGUSTINE CHELLA, ZAMBIA
Speaking as an African, I think treatment is life. Without treatment
there is no life. I'm coming from a society where the impact of HIV
is visible. In Zambia, where I'm from, we see 39 years of independence
and development eroded because of HIV and AIDS. We see its impact on
our economy, its impact on our industry, its impact on our educational
sector, where since 1999, my country lost 1,600 teachers and we have
only been able to train 1,000 teachers. This is a disaster and the
government accepts that we have a crisis before us, but the question is
treatment. Is treatment readily available in Zambia? No, it's not. We
have set a target to treat 10,000 Zambians by 2006, but up to now only
900 Zambians are on treatment. We have a population of two million people
living with HIV and about 600,000 of those need treatment immediately.
SUBHA RAGHAVAN, INDIA
In India we are very proud of our generic drug manufacturers for manufacturing
all of the potential regimens — but they don't make them accessible
to our own people. We export to the developing world, through the Clinton
Foundation, at a much cheaper price than we give our own. We pay one dollar
a day or more whereas we are giving it to the Clinton Foundation for 140
dollars per year. So we have this distinction of manufacturing every drug
under this umbrella, yet they are not available at affordable prices to our
own.
ROLAKE NWAGWU, NIGERIA
Two years ago we had no ARV access whatsoever. The very few drugs we had
were from the big pharmaceutical companies, from Glaxo and Roche, and it
was just too expensive. In 1998 I paid about 500 dollars a month for my
drugs. And that was unacceptable. Two years ago our government announced
the roll out of the ARV program and they said they had drugs for 10,000
adults and 5,000 children in 25 centers. The government is paying. These
are generic drugs, mainly from Cipla and Ranbaxy: lamivudine, stavudine
and nevirapine as individual drugs. The government buys the drugs for
about 30 dollars a month and gives them out for about seven dollars a
month. There is a waiting list to get in. When this program started, if
you went to the HIV clinic it was like death row. The HIV clinic was next
to antenatal, which was noisy because you have pregnant women and women
with babies; there's festivity there. Next door was the HIV clinic and
it was still, because people had no hope. A year later it became much
better because all those who came in sick could see people who used to
be like them who now had so much hope. So people wanted to get on this
program. After the quota was filled people were still desperate to get
on.
ANASTASIA KAMLYK, BELARUS
Most of the people in my country who need it do not have access to treatment.
Most of the countries in my region do not have many of the drugs registered.
In most countries in my region, AIDS is not a priority for government. Only
in Russia and Ukraine have we seen the Global Fund money. Some other countries
don't have that many official cases of AIDS so the pharmaceutical companies
aren't interested in them. It is not a huge market.
JAMES KAMAU, KENYA
MSF (Médicins Sans Frontières) are doing treatment and right
now they are reaching nearly 1,000 people. They are a fantastic example
of how to roll out ARV (antiretrovirals) in a resource-poor setting. They
are using the triple therapy combination in a single pill, Triomune. It's
working out to be much cheaper but the demand is too great. They have
successfully shown that it can work. Compliance is 90 percent, which is
fantastic. It's because of the way the do it. Before they start you on
drugs you go several times for training. After they give you the medication,
they follow-up, and they follow-up on opportunistic infections. Having been
in the field, they are able to detect the problems much faster. PWAs are
involved in their teams; they are in fact the counselors and the people who
follow up. Quite a number of MSF patients become educators.
SVILEN KONOV, BULGARIA
In Bulgaria, the only medications we can use are the originator's products.
There are no generics. Unfortunately there is only one center where
HIV-positive people are treated and the center has only two doctors. With
the money from the Global Fund, the national coordinator on HIV/AIDS claims
that the system will be decentralized, but so far we see no measures taken
in that direction. Doctors outside of that center have no experience and
no real knowledge about treatments. Even a rich person would have a hard
time getting special care. If you are knowledgeable you can ask for a
better combination, but you can not get anything exceptional.
DELME CUPIDO, NAMIBIA
The Government has taken up the drug donation offer made by Boehringer.
They are using brand name drugs at the moment through the donation programs,
which is problematic because I'm not sure now sustainable that is. The
Government has said to us the intention is to roll out treatment across
the country, to expand it to the 13 regions and at the end of it they are
hoping to roll out to something like 55 sites across the country. They are
doing a progressive realization type of plan; you get the donation then
you are able to treat so many people. We are going to get funds from the
Global Fund which can then finance the roll-out to other sites. We are on
the cusp of getting treatment for a quite a number of people. When that's
going to happen, who knows?
KARYN KAPLAN, THAILAND
Because of the Global Fund grant, the government announced a plan to
scale-up from 2,000 to 70,000 by 2005. At a cost of about 30 dollars
per month, GPOvir (3-in-1 nevirapine, lamivudine, stavudine) is available
for 80 percent of the people who can tolerate it. They are planning
comprehensive care centers where a person with HIV coming in will
immediately meet and be counseled by another person with HIV. Their
entire treatment support will come from another person with HIV and
this is a key component of the plan. They are already seeing that
adherence is better with support that includes equal involvement
of PLWAs.
Participants:
David Ananiashvili, Georgian Plus Group, Georgia
Augustine Chella, NAP+—Network of African People
Living with HIV/AIDS, Zambia
Ben Cheng, Forum for Collaborative HIV Research, USA
Lei Chou, ATAC—AIDS Treatment Activist Coalition, USA
Polly Clayden, HIV i-Base, UK
Rachel Cohen, MSF—Médicins Sans Frontières, USA
Simon Collins, HIV i-Base, UK
Delme Cupido, Legal Assistance Centre, AIDS Law Unit, Namibia
John Daye, NAPWA—Australia
Roman Dudnik, AFEW—AIDS Foundation East-West, Russia
Olive Edwards, JN Plus—Jamaican Network of Seropositives, Jamaica
Lobna Ibrahim, PATAM—Pan African Treatment Access Movement, Egypt
Gregg Gonsalves, GMHC—Gay Men's Health Crisis, USA
Chris Green, Spiritia Foundation, Indonesia
Mauro Guarinieri, EATG—European AIDS Treatment Group, Italy
Mark Harrington, TAG—Treatment Action Group, USA
Bob Huff, GMHC—USA
James N Kamau, PATAM—Kenya
Anastasia Kamlyk, Positive Movement Belarus, Belarus
Karyn Kaplan, TTAG—Thai AIDS Treatment Action Group, Thailand
Hanna Khodas, All-Ukrainian Network of PLWH, Ukraine
Svilen Kolev Konov, Plus and Minus' Foundation, Bulgaria
Rolake Nwagwu, Nigerian Treatment Access Movement,, Nigeria
Germán Perfetti, Asociación Líderes en Acción,
Colombia
Subhasree Sai Raghavan, SAATHII—Solidarity and Action Against
the HIV Infection in India, India
Richard Stern, Agua Buena Human Rights Association, Costa Rica
Paisan Suwannawong, TTAG—Thailand
Vladimir Zhovtyak, All-Ukrainian Network of PLWH, Ukraine
|
News From the Bench
By Bob Huff
Resistance to RNAi inhibition of HIV
Atze Das and colleagues from the University of Amsterdam reported
in the Journal of Virology that they had successfully expressed small
interfering RNAs (siRNA) targeted to the HIV Nef gene that blocked viral
replication in long-term experiments. RNA interference is a recently
discovered natural process where short (22 base pair) double strands
of RNA can target complementary sequences of messenger RNA and prevent
their translation into proteins. Previously, siRNA has been shown to
be an effective HIV-inhibitor in short-term assays. But the inhibition
of replication is not complete, apparently, since escape mutants were
observed to appear after several weeks in culture. The resistant
viruses had changes or deletions in the Nef sequence, which could evade
control by the experimental siRNA. One way around this problem might
be a form of combination therapy, where multiple variants of the anti-Nef
siRNA sequence are introduced that would block the common resistant
mutations as they emerged.
Das A, et al. Human immunodeficiency virus type 1 escapes from
RNA interference-mediated inhibition J. Virol. 2004;78 2601–2605
Assay for Less-Fit Phenotype?
An experimental phenotypic drug-resistance assay could potentially
model complex viral properties with much more clinically relevant
information than current assays offer, particularly for people with
multi-drug resistant virus. Commercially available phenotypic resistance
assays evaluate drugs individually but may miss synergies resulting
from combinations. A flow cytometry-based assay developed by Haili Zhang
and colleagues, from Johns Hopkins University, not only reports susceptibility
to complete regimens in a physiologically relevant way, but incorporates
a measure of replication capacity. Some drug-resistant mutants are less
replication-competent than wild-type HIV and certain "salvage" patients
may benefit from remaining on therapy despite virologic failure. The assay
would allow clinicians to identify which drugs in the regimen were selecting
the "less fit" virus, and allow them to stop non-contributing drugs. The assay
could also report if a drug combination had residual virologic effect despite
the apparent lack of activity by its components.
Zhang H, et al. Novel single-cell-level phenotypic assay for
residual drug susceptibility and reduced replication capacity of
drug-resistant human immunodeficiency virus type 1. JVirol, Feb 2004,
1718–1729.
Doctors Organize to Protest
Abbott's Norvir Price Hike
The annual Retrovirus Conference, the most important scientific meeting
of the year on HIV/AIDS, held this year in San Francisco from February
8-13, is not usually an occasion for social or political expression. In
fact, the organizers actively discourage demonstrations and leafleting
and reward any interruptions with banishment. This year's conference was
remarkable for the manifestations of anger and protest at pharmaceutical
maker Abbott Laboratories over a 400% increase in the price of their HIV
drug, Norvir, announced in December of 2003. Even more remarkable was that
the most visible protest leaders were a group of HIV doctors from around
the country who have organized a new coalition to speak out about the
Abbott outrage as well as on ADAP budget cuts and other threats to their
ability to rationally care for people with HIV.
During an afternoon break on the second day of the conference,
about 30 physicians representing the newly formed Organization of HIV
Healthcare Providers gathered in front of the Moscone West Center and
marched two blocks to a press conference at the San Francisco AIDS
Foundation where Drs. Bill Powderly, of Saint Louis, Benjamin Young, of
Denver, and Edwin DeJesus, of Miami, explained the necessity of resisting
the Norvir price hike. Addressing the cameras of CNN and San Francisco
news outlets in the packed meeting room, the physicians pledged to boycott
Abbott's sales representatives, resign from Abbott advisory boards and
refuse to participate in non-essential Abbott research. The Providers have
obtained over 200 pledges to support the boycott, said New York physician,
Howard Grossman. The press conference was organized by the AIDS Treatment
Activists Coalition (ATAC).
Earlier in the week, members of the two large HIV doctor's organizations,
the 1,600 member American Academy of HIV Medicine (AAHIVM) and the HIV Medical
Association (HIVMA), which had each issued strong letters criticizing the
Abbott move, held an unprecedented joint meeting to strategize support for
adequate funding for HIV care programs. Members of the new Organization of
HIV Healthcare Providers group are planning "white coat" visits to Congress
in the coming months to lobby for ADAP and Medicaid funding.
|
Boosted Reyataz: 48-Week
Results
By Bob Huff
Atazanavir (ATV, Reyataz) is the first once-a-day (QD) protease
inhibitor (PI) to be marketed in the United States. The drug was approved
in mid-2003 at a dose of 400mg QD, to be taken with food. The pivotal
studies of atazanavir compared it to the two current standard-of-care
drugs for first-line regimens, efavirenz (Sustiva) and ritonavir-boosted
lopinavir (Kaletra). Although atazanavir suppressed HIV RNA as well as
efavirenz in previously untreated patients in a 48-week trial, it did
not perform as well as Kaletra in 24-week data from a comparison of
unboosted atazanavir with ritonavir-boosted lopinavir (Kaletra) in
treatment-experienced patients. At the time of its consideration by
the FDA Antiviral Drugs Advisory Committee shortly before approval,
there was concern expressed that low and widely varying trough blood
levels of atazanavir may often fail to provide adequate viral suppression,
especially in those with pre-existing PI resistance.
To address those worries, the sponsor showed the Committee some
preliminary, 24-week data from a comparison of Kaletra with ritonavir-boosted
atazanavir (ATV 300mg/RTV 100mg QD) in treatment-experienced individuals
with multiple prior protease inhibitor resistance mutations. Although the
FDA was not able to review this data for inclusion in the prescribing
information, the early data suggested that when atazanavir blood levels
were boosted by 100mg of ritonavir, the viral load reductions seen at 24
weeks were equivalent to those produced by Kaletra in this highly
treatment-experienced population.
At the 11th Annual Retrovirus Conference, Edwin DeJesus and colleagues
have now reported on 48-week data from the comparison of ritonavir-boosted
atazanavir with Kaletra (BMS AI424-045). Approximately 120 patients were
randomized to each arm of the open-label trial. A third arm offering
atazanavir plus saquinavir failed to perform as well as the ritonavir-boosted
PIs. The nucleoside backbone was composed of tenofovir (300mg) and one other
drug.
The mean reduction in viral load at two weeks was -1.18 log copies/mL
for boosted atazanavir and -1.31 log copies/mL for Kaletra. At 48 weeks,
the mean viral load reduction was equivalent between the arms, at -1.93
log copies/mL for atazanavir/ritonavir and -1.87 for Kaletra. While the
proportion of individuals responding with HIV RNA reductions below 400
log copies/mL was equivalent between the groups at about 57 percent,
slightly more persons on Kaletra experienced reductions below 50 copies
(46% vs. 38%).
Mean changes in CD4 cell counts were similar in the two groups
although the Kaletra group showed a tendency to a greater rise during
the first 16 weeks of the trial. At 48 weeks, the mean increase in CD4
cell count was 121 cells/mm3 in the Kaletra group and 110 cells/mm3 in
the boosted atazanavir group.
Atazanavir (ATV) is distinguished among protease inhibitors by having
little impact on blood lipid levels such as cholesterol and triglycerides.
Patients in this study who had developed high lipid levels after taking
other protease inhibitors experienced normalization of lipids after
switching to atazanavir. Lipid levels, especially triglycerides, increased
or remained stable in those receiving Kaletra. A dose-limiting side effect
of atazanavir may be the development of jaundice or yellowing of the eyes
due to bilirubin increases that occur in a large proportion of treated
patients. Bilirubin elevations were not associated with hepatotoxicity
and did not result in any discontinuations in
this trial.
DeJesus E, Grinsztejn B, Rodriguez C, et al. Efficacy and safety
of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) vs
lopinavir/ritonavir (LPV/RTV) in patients who have experienced virologic
failure on multiple HAART regimens: 48-week results from BMS AI424-045.
Program and abstracts of the 11th Conference on Retroviruses and Opportunistic
Infections; February 8–11, 2004; San Francisco, California. Poster 547.
Fortress NIH
By Gregg Gonsalves
Back in 1992, I co-authored a report about the AIDS research program at
the National Institutes of Health (NIH) documenting redundancies and gaps
in the effort and the lack of leadership in the program as a whole. Subsequently,
Senators Edward Kennedy and Orrin Hatch with Representative Henry Waxman passed
a bill substantially re-organizing the AIDS effort at NIH based on our report's
recommendations. When the Clinton Administration took office, a new Director of
the Office of AIDS Research (OAR) at NIH was appointed. That Director, the
eminent immunologist William E. Paul presided over a new era of AIDS research,
in which the best scientists in the U.S. and around the world, in consult with
community groups, came together to provide strong outside oversight and advice
for the nearly billion dollar program.
Paul was a strong force for reform at the NIH but he paid for it dearly
— after pushing too hard for change in the NIH vaccine program, the
bureaucrats struck back and Paul was pushed from power. However, his successor,
noted virologist Neal Nathanson proved no more palatable to the NIH good old boys
(and girls) as he continued to seek change. With the ascent of George Bush
in 2000, reform came to an end as the scientific leaders of the Clinton years
fled back to academia.
The NIH under Bush is notable for its inability to attract senior scientists
of the caliber of Paul and Nathanson willing to accept administrative positions.
It has also been under siege from conservative ideologues who would like to
privatize research or who regularly conduct witch hunts for research on sexual
behavior and drug use. The AIDS program at the NIH since 2000 has retreated
to the bad-old-days of insular decision-making by second-rate administrators
who regularly dole out bad advice, or, like toadies at the court of Louis the
XIV, tell their leader, Anthony Fauci, what he wants to hear. Strong
countervailing voices of senior scientists like Harold Varmus, David Baltimore,
Paul and Nathanson are now generally locked out of decision-making at NIH.
This was clearly evident in the NIH's decision to go ahead with a large
phase III trial of two discredited vaccine candidates in Thailand. Despite
howls of protest from the best AIDS researchers in the country, NIH has
decided to push ahead with the $100 million folly, claiming a duty to the
Thai researchers.
The second boondoggle to emerge from NIH over the past few months has
been the plan to renew funding for its major AIDS treatment and prevention
clinical trials networks, both in the U.S. and in the developing world. In
a fleeting moment of courage a few years ago, the NIH arranged for all of
the networks' grants and contracts to expire during 2004/2005 so a
comprehensive plan could be considered and the entire system reshaped to
meet current and future challenges in HIV research. Most of the networks
were set up well over a decade ago, and although they've undergone minor
changes, their leadership is restricted to a small group of investigators
who run the show, each playing musical chairs with the other when their
terms on important committees expire.
NIH could have brought in a group of non-network scientists, including
experts in newly relevant fields (e.g. hepatitis; TB; operational, outcomes,
and health services research; tropical medicine), and a diverse collection
of community groups, to offer independent review and analysis and intelligently
plot a course for the years ahead. This kind of open, scientific debate
on the future of HIV clinical research would have been good for the field
and good for the process, but NIH caved in to the political strength of
the entrenched network leadership and cut back-room deals with them, reinforcing
their power by creating a mega-network with a coordinated leadership structure,
putting the good old boys in charge of everything.
So the pendulum has swung. From the reforms of the early 90s, we're now
seeing the reaction: NIH has turned inward, neglecting and even spurning the
advice of outside scientists and community groups, while relying on its own
limited in-house expertise to shuffle around millions of dollars in research
money. Such inbred thinking and opaque decision-making is not what AIDS research
needs right now. We need greater openness, input and transparency and we need
to demand it again, like we did in 1992.
© 2004 Gay Men's Health Crisis |
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