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Past Issues
Volume 17, number 5
May 2003
Contents
Showdown at the X4 Corral
One form of HIV seems to kill T cells at a distance
Nevirapine-Based Fixed-Dose
Combination ARVs
HATIP Special Report
Short Course
Notes on HIV Drugs in Development
Gilead's Viread International
Access Program
A no-profit program tries to cut the red tape
"Goodbye, America"
Gregg Gonsalves ponders the gap between here and Belarus
Showdown at the X4 Corral
By Bob Huff
For most people, HIV infection, if not treated, causes a long,
slow decline in immune capacity to a point when they become susceptible
to dangerous opportunistic infections. In some, this decline can
happen within a few years; for a few, it hasn't happened yet after
20 years. In the pre-treatment era, the average time for progression
to death was about 11 years. Nowadays, this can be delayed by successful
suppressive antiretroviral drug therapy, although, again, some people
have terrific, trouble-free results while others never manage to
get the full benefits of treatment.
This variability in the course of HIV disease and in the success
of treatment can be due to a number of complex, intertwining factors.
An individual's genetics may come into play: a small number of people
lack crucial receptors that HIV uses to infect new cells and there
are surely many more host factors involved that we don't know enough
about. Different viral genetics can make a huge difference: a flawed
HIV protein called Nef makes for a much less virulent virus, while
infection with drug-resistant HIV bodes poorly for the success of
therapy. The effectiveness of treatment can obviously guide the
impact that HIV has and treatment efficacy is influenced by both
host and viral genetics as well as personal and cultural factors.
But the virus one starts out with may not be the virus that causes
trouble down the line. Early in the epidemic scientists recognized
that HIV has two faces: one attacks a limited set of immune cells
slowly and steadily, wearing down defenses over time. This form
of the virus gives AIDS its reputation as a slow but relentless
killer. But another form of the virus, one that eventually develops
in about half of those with HIV, shifts the disease into high gear
as it begins taking out T cells aggressively, causing rapid immune
cell loss that can quickly plunge a person into a dangerous state
of AIDS.
The differences between the two forms of HIV have been traced to
a few simple mutations on one of the virus' outer envelope proteins
responsible for latching on to new target cells. Most of the mutations
occur in a region called the V3 loop of the gp120 protein. When
HIV first attaches to a potential target cell, the gp120 protein
hooks up with the cell's CD4 molecule, which is the main cellular
receptor for infection. But attachment is not enough; the gp120
also needs to plug into a co-receptor molecule on the cell that
helps pull the virus into contact with the cell's surface so the
two can merge. In the slow form of the virus, the V3 loop of gp120
is able to connect with a cellular co-receptor called R5 (CCR5).
This R5 co-receptor is found on mature T cells that have already
been primed to fight infection as well as on immune system sentinels,
the macrophages. The R5-using HIV may cause a slower-paced infection
because it has only a limited set of target cells to infect and
because it seems to replicate at only a moderate rate.
But if the V3 loop changes its chemical properties slightly, the
virus starts to be able to use a different co-receptor called X4
(CXCR4). The X4 co-receptor is found primarily on immature T cells
that are still being formed in the immune system's incubator, the
thymus, and on newly activated T cells that have recently met their
antigen. The shift to an X4-using virus speeds up T cell destruction
dramatically. One study saw the rate of T cell loss increase by
three. A classic sign that X4-using virus is on the loose is when
infected T cells clump together to form giant cells called syncytium;
X4 HIV used to be called SI type, for syncytium-inducing. But X4-using
HIV is also able to kill T cells in subtle and coldly effective
ways that are just being discovered.
T cell depletion is the central problem — and central mystery
— of HIV disease, and there are several contending theories
to explain what's going on. The earliest explanation held that HIV
infected and killed T cells directly, end of story. Then it was
noted that although most T cells never become infected, they were
still being removed. From the beginning, other scientists held that
excess immune activation was responsible for running the T cell
supply into the ground, possibly through exhaustion or self-attack.
Some now think that apoptosis (programmed cell death) triggered
by errant immune signaling, toxic viral byproducts or over-revved
regulatory systems, is the main actor. Others argue that the T cells
are simply retreating from the blood (where they are typically counted)
back into hiding in lymph tissue. Most likely, several of these
proposed mechanisms are overlapping and may operate at different
stages of infection or under different conditions. One thing that
surely heralds a change in the pace of T cell depletion is the shift
from R5 to X4-using virus.
When the Shift Comes Down
The shift from R5-using to X4-using happens in stages and there
are a few in-between forms of R5/X4 HIV that are able to use either
co-receptor. As virulent as the X4 virus is, one of the mysteries
of HIV is why newly infected people almost always carry the R5 virus
exclusively. This may be because only the R5 virus is able to infect
immune cells that patrol the mucous membrane frontiers where sexually
transmitted HIV first takes hold. Yet even in people infected with
blood-borne X4 HIV, there is a nearly immediate shift to the R5
variant in the new host. It's not clear why the R5 co-receptor is
preferred at first; some have proposed an inhibitory factor, others
think that macrophages are a preferred target, or it may be that
R5-bearing mature T cells replicate faster and have not yet been
exhausted in a healthy host. Although X4 T cells outnumber R5s,
they may be outposted to tissues and less available to infection.
Typically, the R5-using stage of infection can carry on for five
or more years.
The reason for the shift is not clear. Some believe that the virus
is trying to escape antibody attack directed at its R5-using site;
others think that the virus simply starts to look for different
co-receptors once the supply of mature R5-bearing T cells becomes
too scarce. Once the shift begins, however, the use of X4 becomes
more and more common until in a few people the body's predominant
strain of HIV is using X4 exclusively. Clinically, this is bad news,
for although antiretrovirals are able to suppress X4 HIV as well
as its R5-using ancestor, T cell destruction now proceeds at an
alarming pace. If the R5-using virus is like a sniper picking off
selected target cells, the X4 virus is a weapon of mass destruction
in the thymic maternity ward.
This may be one of the strongest reasons not to delay starting
antiretroviral therapy too long: once the shift to X4 virus begins,
it may be very difficult to recover lost immune capacity. One study
found the shift often occurring in the 400 – 500 CD4 cell
range. Another showed a greater rate of switching below 500 than
above, with those in the 250-500 range switching at a rate similar
to those in the 0 – 250 range. One day it could be common
to test for co-receptor usage in the clinic; Virologic has developed
a phenotypic test that classifies a virus as X4-using, R5-using,
or dual type that could be available by 2004.
What is X4-Using HIV Doing in there?
A recent paper published in the Journal of Virology may
shed some light on why the X4 strain is so destructive. Most of
what we know about HIV comes from experiments conducted under laboratory
conditions using cell systems and special viral strains that have
been adapted to live and reproduce under artificial conditions.
There is a limit to what these systems can say about a disease process
that affects the complex interactions of immunity in living beings.
This is why Andreas Jekle and colleagues from the Gladstone Institute
of Virology and Immunology in San Francisco decided to use a model
of infection that preserves much of the ecology of the T cell's
environment, including a mix of cells at all stages of maturity
carrying either the R5 or X4 receptors, or both.
They began with lymphoid tissue harvested from children's tonsil
operations then infected the tissue with various strains of X4-,
R5- and mixed X4/R5-using HIV. They were particularly interested
in looking for evidence of cell destruction caused by apoptosis,
a natural mechanism of cell death than can be triggered by a number
of internal or external factors. It had been recognized in the mid
1990s that apoptosis was a contributing factor in T cell depletion.
Furthermore, it was noted that not only infected cells but also
uninfected "bystander" cells were somehow receiving signals
to activate their self-destruct mechanisms.
Jekle and colleagues began by looking for a few characteristic
markers that appear whenever apoptosis has been activated. One of
the first things they noticed was that signs of apoptosis were far
more common among cells that were dosed with the X4- and dual X4/R5-using
strains than among cells infected with R5-using HIV. Soon after
apoptosis markers began to appear in the X4-infected system they
noted that a large number of CD4 T cells were being depleted. Meanwhile,
the R5-infected batch of cells only became slightly depleted. Although
some studies have shown that CD8 cells were depleted in the presence
of X4 HIV, in this study CD8 T cells were not depleted by either
type of virus.
They then looked at how many cells had actually become infected
with HIV. With the R5-using virus, the number of infected cells
was low, and apoptosis levels, as was seen before, were also low.
With the X4-using virus, the number of infected cells was similar
to that of the R5 virus, but, as seen earlier, the number of cells
with apoptosis markers was very high. It seems that the X4-using
virus was able to stimulate cell death without directly infecting
the cells. This phenomenon is called bystander apoptosis and in
a number of other experiments it was shown that X4-associated apoptosis
did not depend on establishing a productive infection, and that
X4, but not R5, viral strains could induce widespread apoptosis
in bystander CD4 T cells. Furthermore, the R5-using virus infected
only CD4 T cells that carried R5 and produced a low level of apoptosis
in these cells but caused no apoptosis in cells that lacked R5.
In contrast, X4-using virus caused extensive apoptosis, predominantly
in uninfected bystander cells, including some that also carried
R5.
Since the only difference between the X4-using virus and the R5-using
virus was a few changes in the V3 loop of the envelope protein,
the investigators theorized that the interaction of the viral envelope
with the cellular co-receptor was likely responsible for setting
off apoptosis. They tested this by adding drugs that block X4-using
virus from binding to the X4 receptor on T cells. They found that
blocking X4 effectively protected the cells from bystander killing
by X4 viruses. Treatment with an R5 blocker did not protect the
cells. The authors concluded that binding of the gp120 viral envelope
protein of an X4-using virus to the cellular X4 co-receptor was
the trigger for bystander apoptosis in their tissue culture system.
But is this true in living bodies as well?
In this experiment, a small number of X4 virus particles were
able to deplete a large proportion of CD4 T cells — even when
pre-treated by the reverse transcriptase inhibitor AZT. While AZT
could prevent cells from becoming infected, it could not prevent
apoptosis triggered by exposure to gp120. If this finding is also
true in people, then the rapid drop in T-cells seen after the switch
to an X4-using virus may be primarily due to the killing of bystander
cells that never actually become infected. This may explain why
some studies found that viral load does not soar when CD4 counts
drop soon after the switch.
Finally, since the immature T cells that are depleted by bystander
apoptosis are the precursors to the mature cells, attacking X4-bearing
cells may be shutting off the supply of T cells at its source. This
could be another reason why only modest rates of T cell decline
are seen during chronic infection with R5 virus, and why T cell
depletion speeds up so much once the shift from R5 to X4 occurs.
However, the authors caution, while the gp120 interaction with X4
seems to be necessary to induce apoptosis, there may still be other
unknown factors that contribute to this effect. It is also not yet
known if the gp120 must be bound to an intact virus for it to trigger
apoptosis or if freely floating particles have the same effect.
"Pop" Stoppers
If blocking the binding of gp120 to a cell's X4 co-receptor can
stop bystander apoptosis and the resulting rapid CD4 T cell depletion
that occurs for some during the dangerous later stages of HIV disease,
then X4 binding inhibitors could be a valuable form of salvage therapy
for tens of thousands of people with AIDS. So what do we know about
drugs that block X4?
A number of R5 binding inhibitors are being developed as HIV therapy.
The R5 receptor is an attractive target because R5-using HIV is
the predominant strain in life and has such a long, slow course
of infection. Also, because some people are born without R5 receptors
(a genetic anomaly that occurs in about 1% of Caucasians) and because
rats modified to lack R5 suffer no overt ill effects, it's hoped
that blocking R5 won't have toxic consequences. Effective blocking
of R5-mediated infection, some believe, could preclude the need
for having to ever deal with an X4-using strain. Yet there's been
a great deal of concern that blocking R5 binding would push the
virus to start using the X4 receptor, although that has not been
borne out in laboratory studies. Still, that possibility makes the
need for an X4 blocker even more important.
One of the drugs that Jekle and colleagues used in their experiment
to show that blocking X4 stopped bystander apoptosis is called AMD3100.
The drug had been recognized as an HIV entry inhibitor even before
the R5 and X4 co-receptors were discovered in 1996. By 2000, several
studies had shown that AMD3100 could not only block infection by
X4-using HIV but could also arrest HIV-associated apoptosis. AMD3100
was explored in phase I clinical trials with HIV-infected people
where it apparently showed limited activity against HIV. Unfortunately,
heart rhythm abnormalities were detected in several patients and
development of AMD3100 for HIV therapy was halted in 2001. The drug's
sponsor, Anormed, of British Columbia, Canada, is now developing
a new, orally available compound called AMD070 that is active in
the laboratory against X4-using HIV. Human testing of AMD070 should
begin this year.
One of the potential problems with blocking X4 is that, unlike
R5, it may perform some essential jobs in the body that shouldn't
be messed with. It is also found on a greater variety of cell types
than just immune cells. While mice born without R5 do okay, mice
with the X4 gene deleted can't survive. And although AMD3100 has
been scrapped for treating HIV, it has other kinds of biologic activity
and is still under investigation for inhibiting cancers and accelerating
recovery after heart attack — all of which suggests that indiscriminately
blocking X4 may have unintended consequences. Finding highly specific
medicinal molecules that block HIV co-receptor function without
stepping on the toes of any of the receptor's natural tasks is the
goal.
New Ideas, New Tools
The other type of X4 blocker used in the Jekle study was a monoclonal
antibody that attached to the receptor and blocked access by gp120.
One speculative idea is that perhaps a vaccine could induce the
body to make its own anti-X4 antibodies, thus using the immune system
to supply the therapeutic molecules.
A recent experiment has reported that "gene silencing"
through RNA interference was able to suppress expression of the
cell's X4 gene and block infection by X4 strains. This new technique
gives a powerful tool for understanding the role these receptors
play in the immune system and they may one day offer an approach
to therapy. Another study observed that the viral protein Tat caused
cells to display more CXCR4 receptors on their surfaces, possibly
making them more susceptible to X4 virus. If this is significant,
then perhaps a Tat inhibitor could be synergistic with an X4 blocker
by reducing the number of X4 targets on a cell's surface. Another
therapeutic avenue might be to stimulate the molecules that bind
to R5 and X4 receptors in nature. These chemical messengers, called
chemokines, send signals that also decrease the expression of the
receptors on cells.
Resistance is Always with Us
One issue with co-receptor blockers — as with every other
HIV drug — concerns the near certainty that viral resistance
will develop after a while — and resistance to AMD3100 has
already been shown to develop in laboratory experiments. When the
drug was used against an exclusively X4-using virus, gp120 accumulated
mutations that allowed it to use X4 in spite of the drug. But there
are also suggestions that the mutations that allow escape from the
drug also make the virus less fit and less pathogenic. In one experiment,
all of the X4 isolates that evolved resistance to AMD3100 after
serial passage in cell culture exhibited reduced fitness compared
to wild type. In a clinical trial of AMD3100 in patients with dual
X4/R5 HIV the virus simply switched over to using R5. Since all
previous strains of HIV are likely to persist in viral reservoirs,
blocking an evolved X4-using virus would probably tend to cause
an earlier R5-using strain to eventually re-emerge. While not a
perfect solution, having an active R5 strain may be better than
the alternative.
Receptor blocking is still in its infancy, although several R5
blockers are moving forward in clinical trials. While resistance
may be a problem, it may also provide an opportunity. One therapeutic
strategy that is likely to come into greater use may be called "guided
resistance," which seeks to back HIV into a corner of diminished
fitness and destructive potential. Indeed this is already the only
strategy left for many people with multi-drug resistant virus who
find that a failing regimen, if tolerable, is far better than no
regimen at all. Since the virus appears impossible to eradicate,
maybe shutting off one of its more destructive aspects, such as
the shift to X4 type, can help to keep expanding the possibilities
for living with HIV.
Until then, entry inhibitors will continue to have an important
role to play in helping scientists understand the basic science
of HIV pathogenesis and T cell depletion. It may be a race to see
which avenue first benefits the greatest number of people: another
new drug to suppress HIV or a new understanding that unlocks the
secret to something much better.
Jekle A, et al., In Vivo Evolution of Human Immunodeficiency
Virus Type 1 toward Increased Pathogenicity through CXCR4-Mediated
Killing of Uninfected CD4 T Cells. J Virol, May 2003, p. 5846
Nevirapine-Based Fixed-Dose
Combination ARVs By Julian Meldrum
With commentary by Dr. Vijay Anthony Prabhu and Dr. Desmond Martin
Excerpted from HIV & AIDS Treatment in Practice (HATIP) #2
HATIP is a biweekly email newsletter intended for providers in
resource-limited settings.
For the full version of this article or to subscribe, visit: www.aidsmap.com
Advisory panel members include Dr. Vijay Anthony Prabhu (Chennai,
India), and Desmond Martin (President, Southern Africa HIV Clinicians
Society)
Fixed-dose combination antiretrovirals (FDC ARVs) are products
that combine two or more active drugs in one tablet or capsule.
In many countries, they now offer the cheapest available route to
a complete and effective ARV regimen. There are many potential advantages
of using FDCs. The most obvious are the simplification of what is
supplied to and taken by individual patients and reduced potential
for inappropriate sharing of drugs.
In a managed healthcare system where costs are shared, as is planned
in Thailand, these drugs can free up resources to provide more expensive
second- and third-line treatment options to those who need them,
which is a universal benefit. Standardization of first-line regimens
carries further potential benefits, including the development of
simple education packages for healthcare workers and community members
and possible economies of scale in laboratory monitoring tests.
Limitations at present include the lack of pediatric equivalents,
inadequate provision for lead-in dosing and a number of other shortcomings
concerning availability, packaging and provision for reporting adverse
events.
This may be the right way to go for large-scale treatment programs,
but there is still a distance to be traveled before the products
are fully suited to that purpose.
Quality Issues and Availability
WHO's Essential Drugs and Medicines team has established a project
to document the procedures and certification of generic facilities
used to produce medicines for HIV and AIDS treatment that are not
registered with the U.S. Food and Drug Administration (FDA) or European
drug regulatory agencies recognized by the European Medicines Evaluation
Agency (EMEA).
The Global Fund to fight AIDS, TB and Malaria has signaled that
they will rely on this WHO list as a basis for approving the purchase
of generic ARVs and other medicines, so the inclusion of products
and of their makers on the list may have an increasing influence
on their availability.
The Indian companies Cipla and Ranbaxy already have ARVs on the
list; Hetero and Aurobindo products are being assessed. However,
most of the products named are not listed by WHO. Ranbaxy's AZT/3TC
is the one exception.
The Thai Government Pharmaceutical Organization makes drugs primarily
for domestic use, with a high level of attention to quality control.
It is supplying them in limited quantities to Cambodia, Sri Lanka
and Laos, and has recently agreed to supply them to Indonesia. It
is also supporting a number of African countries in establishing
local manufacturing. Argentina, Brazil, China, Mexico and Vietnam
are producing generic antiretrovirals, but with the exception of
some AZT/3TC, these do not seem to include fixed dose combination
products of the kind discussed here.
| Fixed-Dose Products Now Available
AZT 300mg + 3TC 150mg + NVP 200mg
DUOVIR-N (Cipla Ltd)
ZIDOVEX-L-N (Imunus Aurobindo)
For lead-in dosing (or if NVP must be stopped):
AZT 300mg + 3TC 150mg — use separate drugs, or:
COMBIVIR (GlaxoSmithKline)
DUOVIR (Cipla Ltd)
VIROCOMB (Ranbaxy Laboratories Ltd)
ZIDOLAM (Genix Pharma/Hetero)
d4T 30mg + 3TC 150mg + NVP 200mg
GPO-VIR S 30 (Thai Government Pharmaceutical Organization)
STAVEX-30 LN (Imunus Aurobindo)
TRIOMUNE-30 (Cipla Ltd)
VIROLANS [capsules, d4T 30mg version] (Ranbaxy Laboratories
Ltd)
For lead-in dosing (or if NVP must be stopped):
d4T 30mg + 3TC 150mg — use separate drugs, or:
LAMISTAR 30 (Genix Pharma/Hetero)
LAMIVIR-S-30 (Cipla Ltd)
VIROLIS [capsules, d4T 30mg version] (Ranbaxy Laboratories
Ltd)
d4T 40mg + 3TC 150mg + NVP 200mg
GPO-VIR S 40 (Thai Government Pharmaceutical Organization)
TRIOMUNE-40 (Cipla Ltd)
VIROLANS [capsules, d4T 40mg version] (Ranbaxy Laboratories
Ltd)
For lead-in dosing (or if NVP must be stopped):
d4T 40mg + 3TC 150mg — use separate drugs, or:
LAMISTAR 40 (Genix Pharma/Hetero)
LAMIVIR-S-40 (Cipla Ltd)
VIROLIS [capsule, d4T 40mg version] (Ranbaxy Laboratories
Ltd)
All of the medicines listed above are taken as one tablet,
twice daily (12 hour intervals), with or without food. |
Affordability
Whatever the drug combination used, its success for an individual
patient will depend on the ability of that person to take it consistently
as prescribed.
Where patients are paying for their own treatment as in Kampala,
inability to maintain those payments has emerged as the main reason
for breaks in treatment, as reported at the 10th Retrovirus Conference
in Boston by Byahihi-Tusiime. While the treatments discussed here
are priced as low as $35 a month, they are still a long way from
being affordable by most people with HIV. In Uganda, Molly Tumusiime
reports there have been times when people went short of food to
pay for ARVs, or missed out on ARVs to pay for monitoring tests.
This is a powerful case for subsidizing treatment to make it genuinely
affordable, as has been done in Senegal's pioneering treatment access
program (described in Boston by Dr. Salif Sow) — and as is
planned in Thailand.
Failing that, the strategy reported by YRG-CARE in India, of careful
and thorough discussion with patients of their financial circumstances
before starting on treatment may be helpful to some. However, this
is a difficult role for hard-pressed clinical staff to assume. There
has to be a limit to the clinic's responsibility, to ensure that
the patient understands what treatment they need and how much it
costs, and is able to access any support or discounts that may be
available to them. Beyond that, it must be a decision for the patient
themselves and their family.
Dr. Prabhu: ARV therapy has come a long way in
India. The financial burden has steadily decreased and remains at
around $35 per month for fixed-dose combination triple ARV therapy.
The pricing of these potent drugs has received widespread publicity.
Generic pharma companies proclaimed their social consciousness and
responsibility by introducing these fixed-dose ARV drugs at lower
prices. But in spite of intense pressure from different groups –
positive patient networks, activists and others – these companies
have not reduced prices any further, for a variety of reasons. The
government does not help matters and continues to impose a sales
tax on these drugs.
When patients are paying for their own treatment, I would agree
with the Boston report from Kampala, that the main reason for breaks
in treatment is the inability to maintain payments for ARV drugs
even at low prices. AIDS and poverty go together. There is definitely
a need for subsidizing treatment to make it genuinely affordable.
Availability
Dr. Prabhu: ARV fixed-dose drug combinations are
available in major metropolitan cities and towns in India. Since
only a handful of pharma shops dispense these ARV drugs, it is sometimes
difficult to find out where they are or who dispenses them. Patients
in the rural areas have to travel long distances to the neighboring
big towns or cities, spending huge amounts of money, just to gain
access to their drugs. Often the pharma shops run out of stocks
especially at the end of the month or stock only certain brands
and not others, not offering the entire range to the patients.
Dosing Schedules
Ideally, the only choices that should need to be made with these
regimens are whether to start with AZT or d4T, and if it is d4T
then to choose a dosage (40mg or 30mg) on the basis of body weight
(greater or less than 60kg). Unfortunately, it is not quite that
simple in practice.
Lead-in Dosing: Starter Packs Needed
When nevirapine (NVP) is first started, it should be administered
at half dose for the first 14 days, i.e. 200mg once a day instead
of twice daily. However, the other drugs in the combination should
be administered at full strength. It is clear that this often doesn't
happen as it should.
As described by Dr. Martin, below, some patients are still starting
on full-dose NVP, risking avoidable NVP reactions. Others have been
started on one triple combination tablet a day, so the nucleoside
analogues are under-dosed, risking selection for drug-resistant
HIV. Hosseinipour reported in Boston that this was done in Malawi,
when Triomune first became available in Lilongwe and Blantyre. Studies
are now under way to find out whether this led to any avoidable
drug resistance. Other patients are prescribed separate drugs for
the initial period of treatment. However, as Dr. Prabhu explains,
there can be serious problems with this, because the quantities
in which the drugs are sold are not matched to how they are meant
to be taken.
There is an obvious solution to all of these problems: combining
two different fixed dose combinations (with and without NVP) in
a blister pack, marketed as a "starter pack." Symbols
on a 7-day, 14-dose blister pack could make it clear which tablet/capsule
is the morning dose and which is the evening dose. This should be
reinforced by clear written instructions in local languages. 7-day
packs would also reinforce the point that the drugs must be taken
daily (including at weekends) and make them convenient to carry.
If patients have to pay for them, they should cost exactly the same
as the triple combination drugs so there is no incentive to continue
with the starter doses for longer than two weeks.
Dr. Martin: It is our experience (in southern
Africa) that with Triomune, patients begin on the higher dose from
Day 1. It appears that dose escalation is just too much bother for
the physicians to explain and the cost of buying the separate drugs
is not something they feel able to inflict on their patients.
Dr. Prabhu: The lead-in or build-up dosing schedule
of NVP in combination with d4T/3TC or AZT/3TC is confusing for some
patients. NVP is available separately in a container of 60 tablets,
which with the lead-in dosage schedule leads to a wastage of about
15 tablets in the initial pill box. Patients do not seem to understand
this and continue to consume NVP alone even when the LAMIVIR 30
mg pill box [which also contains 60 tablets] is empty at the end
of the month. They feel they must finish both boxes before starting
on the next and end up taking NVP alone [which carries a high risk
of selecting NVP-resistant HIV], even after any amount of explanation!
The patients end up paying hard-earned money for NVP that they cannot
and should not use.
Other Packaging Issues
Dr. Prabhu: Certain patients who live far away
[from where treatments are available] access their drugs through
mail or courier. But on arrival at their home, the tablets are in
powder form! These tablets are not packed for long journeys. Pill
box covers are very loose and fall off at the earliest opportunity,
making it very difficult to identify the drugs the patients are
on, especially since doctors who prescribe these drugs do so in
secret with no written prescriptions in the patients hands and no
means of identification on the tablets themselves. Certain companies
package their ARV drugs with a red AIDS logo boldly embossed on
the packaging material, which patients find difficult to use, especially
when they are traveling in public.
Supporting Adherence
No matter how simple the treatment, it is still vital to spend time
making sure that the patient understands how the treatment works.
Dr. Martin: It has been my experience that, provided
adequate counseling is given prior to the commencement of ARVs,
adherence to the regimens is remarkably good. This is often in the
face of difficult work circumstances related to shift-work but the
patients have been very innovative in developing strategies to remember
their drugs. Clearly simplified dosage forms are preferable (twice-daily).
Our experience has shown that the use of "the buddy system"
has been the most effective. I think that in our populations where
HIV is a rampant epidemic the patients who are able to access antiretrovirals
do so with a commitment that will lead to impressive compliance.
Peer counselors who themselves have had a turnaround in their disease
can be very helpful.
Managing Nevirapine Skin Rash
The main risk associated with NVP, especially in the early stages
of treatment, is a skin rash which in its most severe form (Stevens-Johnson
syndrome) can be life threatening. Liver toxicity is also of concern
and requires prompt action if detected.
If a rash develops, patients need to be advised to return to the
clinic to evaluate it. If the rash is mild, then it may be best
to try and treat through, so long as patients understand the need
to return if the rash gets any worse. Treatment with corticosteroids
does not help (in fact it may make it worse). If a rash is severe,
or getting worse, then NVP must be stopped. Ideally, the nucleoside
analogues should be continued for another week to try and prevent
the emergence of virus with resistance mutations to NVP —
so the possibility of using efavirenz (which is vulnerable to the
same mutations) is kept open for the future. Liver toxicity is also
a serious risk with NVP and monitoring for this is a key responsibility
for prescribers.
Dr. Prabhu: NVP skin rash is common, usually
mild to moderate. Especially when it affects women and girls, much
desperation sets in. The patients may already be suffering from
HIV-related pruritic papular dermatitis from which they are seeking
relief. Usually with the advent of ARV drugs, their rashes come
under control, which can be a good indicator of the success of treatment.
But if such a patient develops a NVP-associated skin rash, it becomes
exceedingly difficult to distinguish failure of therapy from adverse
drug reaction. Serial CD4 counts and HIV RNA viral loads are a luxury
few patients can afford. Liver Function Tests might shed light on
the subject by showing elevation of transaminases. Finally it boils
down to a clinical decision taken on the table, to stop NVP or persist
with it and manage the skin rash symptomatically. If the general
condition of the patient continues to deteriorate, then it is obvious
that ARV drugs are not working and NVP must be stopped and alternatives
chosen. A risk versus benefit analysis, and knowledge of any prior
ARV use, should guide the decision-making process.
Dr. Martin: Information regarding toxicities
involving the liver, skin rashes or Stevens-Johnson Syndrome are
lacking: while patients are warned, there is no proper system for
reporting adverse events for these unlicensed products. Because
these patients have limited financial means laboratory monitoring
(liver enzymes) is not carried out in the vast majority of cases.
Downsides to Simplified Treatment?
The idea that HIV treatment can be reduced to one tablet, twice
daily, is powerfully attractive to physicians as well as their patients.
One risk is that "familiarity breeds contempt."
Dr. Prabhu: Generic pharma companies are as keen
as any other to motivate and induce doctors to prescribe their drugs.
"Prescriptions, doctor, for our product," "cheap
and best," "reminders" are some of their slogans
we hear day in and out. With all this pressure from pharma companies,
and from patients who are desperate, it is very easy and simple
to prescribe, but it needs more than strong will power, at times,
to take a balanced decision not to prescribe.
I am no longer surprised to come across prescriptions for these
drugs for a short duration of time, sometimes as short as a week's
duration, as though we are treating a common cold! Sadly, the concept
that, where HIV is concerned, therapy is life long is missing amongst
a vast majority of general practitioners [in India]. So if one combination
does not work, they just change to the other — very simple
— with the result that we are soon back to where we started.
Dr. Martin: A source of concern is that the widespread
and often sub-optimal use of regimens containing nevirapine will
lead to resistance to the nevirapine component and compromise mother-to-child
nevirapine-based transmission interruption programs.
How Effective are these Combinations?
The major reason why NNRTIs such as nevirapine are preferred to
protease inhibitors for first-line treatment is that they are more
easily tolerated (despite carrying risks, of which patients and
providers must be aware). Superior virologic performance has also
been reported, almost certainly because these combinations are less
dependent than the protease inhibitors indinavir and nelfinavir,
in particular, on taking treatment correctly in relation to meals.
One limitation is that NNRTIs are not effective against HIV-2 or
HIV-1 group O viruses, so if these are present a protease-inhibitor
based combination is likely to be needed.
A randomized trial that compared NVP, efavirenz, and a combination
of the two drugs (the 2NN study, funded by nevirapine's maker, Boehringer
Ingelheim), was reported at the Boston Retrovirus Conference. It
found that NVP and efavirenz gave comparable results in terms of
viral suppression. However, there were two deaths (from liver failure)
among people treated with nevirapine, which reinforces the need
for care in its use.
Following a series of trials which have shown efavirenz to be
comparable or superior to protease inhibitors, these reports are
important for providers to have confidence that the fixed-dose combinations
now on offer can be as effective as more costly treatment options.
There is also some data on the equivalence of various NVP formulations,
including generic ones. So far, this is reassuring.
Stavudine (d4T) vs. Zidovudine (AZT)
There is a groundswell of medical opinion, in countries where people
with HIV usually start medical treatment at CD4 counts above 200,
against using d4T as a first-line therapy. The prevalence of neuropathy
and a (still-controversial) association between d4T and loss of
fat (especially on the face) have relegated the drug to second choice
for many. There is clearly a strong case not to prescribe higher
doses of d4T than are needed. If a patient weighs less than 60 kg,
the 30mg dose of d4T should be prescribed.
In settings where anemia is widespread (and closely correlates
with mortality risk) and patients usually begin treatment at very
low CD4 counts, the actual risks are different and it may not be
unreasonable for doctors to prefer d4T as their first-line treatment.
The reason why more combinations have been launched based on d4T
rather than AZT, is that the higher potency of d4T, by weight, makes
it cheaper (per dose) than AZT. At a retail level, this translates
to a difference of around $5 per month ($35 vs. $40), which clearly
makes treatment more sustainable where patients pay for it.
Lipoatrophy has been seen in Thailand and India, and must be presumed
to affect Asian populations as it does Caucasians/Europeans. There
is some evidence from both longitudinal and cross-sectional studies
that lipoatrophy is more frequent among Caucasians than among people
of African descent. So the extent to which it will occur among African
populations is still unclear. But for those who suffer from it,
the implications will be much the same everywhere.
Dr. Prabhu: AZT is used by a large number of
practitioners, though patient tolerance of AZT is low. Complaints
of myalgia and headache are common, but what is worrying is development
of severe anemia, for which blood transfusions are used enthusiastically
with all the attendant risks. Management of ARV drug toxicity is
difficult. When HIV is already far advanced and when clinical anemia
is obvious, then d4T is the preferred drug. Peripheral neuropathy
is painful and slow to respond. Cessation of d4T is sometimes the
option chosen, but because of other limited options, dose reduction
is attempted to see if it responds.
Dr. Martin: Scant attention is paid [in Southern
Africa] to differing dosage forms for Triomune so that a number
of patients are overdosed with the 40mg d4T dosage form and the
risk of drug-induced neuropathy is increased; d4T-containing fixed-dose
regimens used in the presence of treatment for tuberculosis will
lead to increased occurrence of neuropathy.
Pediatric Dosing
Best practice in pediatric treatment relies on liquid suspensions,
of which a limited range are available, often only in branded versions,
at very high prices. For example, in Uganda, no generic suspensions
are available, observes Dr. Henry Barigye. Even in India, there
is no suspension available for d4T. Yet many babies and young children
are anemic and have problems tolerating AZT.
Professor Norman Nyazema, a pharmacologist who has served as a
senior technical advisor to the Medicines Control Agency of Zimbabwe,
insists there can be no short cuts. Splitting tablets is unacceptable
as a basis for licensing a drug for use in pediatric treatment,
and if doctors use a drug beyond its license, the manufacturer cannot
be held liable for the consequences. Companies that claim they are
meeting public health needs by providing low-cost generic formulations
must be pressed to provide a full range, including suspensions for
pediatric use.
Dr. Prabhu: The lack of choice in pediatric formulations
is particularly worrying, since with the increasing number of MTCT
interventions that are taking place, more pediatric AIDS cases are
being diagnosed. Only AZT, 3TC and NVP suspensions are available.
Anemia, which is so common in children, makes it difficult at times
to persist with AZT. d4T is chosen, but with lack of availability
of pediatric formulations, adult tablets are split to provide for
pediatric doses. This is not good practice, but in the absence of
alternatives, we are left with no choice!
| Short Course —
Notes on HIV Drugs in Development Raz-ma-TAZ
On May 13, 2003, an FDA advisory committee met outside of
Washington, D.C. to consider the approval of a new protease
inhibitor, atazanavir (ATV). The drug was mostly well received
by the committee; efficacy in treatment naive patients was
applauded and a recommendation for approval voted unanimously.
The sponsor, Bristol-Myers Squibb (BMS), was congratulated
by the FDA for testing the drug in diverse treatment populations
and against formidable comparators.
But data for treating treatment-experienced patients was
wanting. Although BMS put up slides about 24-week safety and
efficacy of ritonavir (RTV) boosted ATV in treatment-experienced
patients, the FDA hadn't enough time to review the data, and
so it was not officially presented to the committee. Yet,
there it was. So, while unboosted ATV was clearly inferior
to Kaletra, no one can really say yet if boosting ATV with
RTV fixes the problem — although many were inclined
to believe that it does. There's a bit of mystery here, and
I think that suits BMS just fine.
The lipid-neutral qualities of ATV are nothing short of
amazing compared to others in the PI class, and this will
drive acceptance by physicians. There is a danger of the drug
being oversold as a remedy for lipodystrophy if BMS is willing
to allow confusion between lipids and lipoatrophy to settle
in — there's no proven link. Again, the lipid profile
of ATV boosted with ritonavir was left in the shadows.
The unique resistance profile in treatment naive people
is the icing on the cake. There's a lot more to learn about
ATV resistance, but so far it's surprisingly good news. Hints
of PI hypersusceptability after the I50L mutation emerges
are the sprinkles on the icing. However, for people with prior
PI mutations, none of this applies; they have their own pathway
that leads to PI cross-resistance.
The concern over high bilirubin levels that caused reversible
jaundice in a large proportion of trial participants is quieting
down; expert consensus says it's not a problem in itself.
But this drug is going to give quite a few people yellow eyeballs.
Patient acceptance will be key.
Atazanavir also has a new brand name: Reyataz. Apparently
someone thought this is better than Zrivada, the name that
BMS had previously announced. A lot of people already call
it "Taz" so the new name was probably selected to
take advantage of that. More details from the hearing in the
next issue.
Tipranavir Urgent Access
The Tipranavir (TPV) phase III clinical trial called RESIST
1 is in the process of opening at 31 sites in the U.S. for
individuals with multi-drug resistant HIV. In addition, a
small safety study has opened to provide access for people
needing TPV who are not eligible for the large trial or who
do not live near a city where the trial is being conducted.
Unfortunately, due to drug supply problems, only 140 individuals
will be accepted into the safety study, which has entry criteria
of CD4 count below 50 and HIV RNA above 10,000 copies. Applicants
who are eligible for RESIST 1 and live within 100 miles of
a trial site will be excluded from the safety study. Patients
on the safety study will be assessed monthly for tolerability
and toxicity by the same criteria used in RESIST. Tipranavir
is taken with 200mg ritonavir to boost blood levels of TPV.
The safety study will only supply tipranavir; participants
must obtain ritonavir from their treating physician.
A larger expanded access program that may be able to provide
tipranavir for several thousand patients is planned for early
2004 if all proceeds well with the Phase III trials. Approval
could possibly come by early 2005.
Patients who have access to Fuzeon (T-20) are eligible for
RESIST and will be randomized separately to assure their even
distribution within the trial, however patients may not add
T-20 after beginning their RESIST regimen.
Alphaville
Schering has pulled a switch in their CCR5 entry inhibitor
development program. SCH-C, which had been slowed by a concern
with QT heart rhythm prolongation problems, has been shuffled
back to let SCH-D take the fast track. Schering had downplayed
the heart issue in meetings with community members, but much
skepticism remained. SCH-D is a different molecule with much
better activity in laboratory studies and, so far, no safety
issues. Phase I trials are in progress. Recent reports indicate
that only 1/10th the amount of SCH-D had similar activity
to a given amount of SCH-C. Like every other HIV drug, however,
resistance to SCH-D has been produced in lab tests. The switch
is a disappointment because it pushes back Schering's entry
inhibitor program by at least a year, but so far the new candidate
seems to have a more realistic chance of achieving approval.
X4 Take 2
Anormed has filed an investigational new drug (IND) application
with the FDA for its CXCR4 entry inhibitor, AMD-070. A previous
Anormed compound, AMD3100, was dropped in 2001 after heart
rhythm problems appeared during its first human trials. AMD-070
is a completely new drug with high specificity for CXCR4.
In lab studies it effectively blocked HIV infection of X4-bearing
cells by both X4 and dual X4/R5-using HIV. The drug is orally
available and had a 10-hour half-life in dogs. First human
study should begin this year.
|
Gilead's Viread International
Access Program By Bob Huff
Last December Gilead Sciences announced a plan to make their nucleotide
reverse transcriptase inhibitor Viread (tenofovir) available to
clinics and treatment programs in the developing world at an affordable
price. Joe Steele, the architect of Gilead's plan, recently answered
questions about the logistics and motivation for the program.
Gilead, Steele says, recognized the potential need for tenofovir
beyond the U.S. because its dosing, safety and low-maintenance qualities
were likely to be attractive to providers in limited resource settings.
Wishing to avoid delay, they decided to launch a proactive access
plan in anticipation of the need.
Initially, the Gilead program will address Africa, the less-developed
countries (LDC), Latin America, Russia and Eastern Europe. The program
was designed by Axios International, a technical assistance consultant
specializing in healthcare issues for the developing world that
had set up similar programs for Abbott and Boehringer Engelheim.
But Gilead sought to design a program that could skirt some of the
problems that have limited the impact of earlier programs.
The price for Viread through the program is $39 per bottle, roughly
10 percent of the U.S. wholesale price of $360 per bottle. The price
does not include shipping, since purchasers may require flexibility
in how they receive the drugs.
The cost of the drug has been set as the cost of goods plus the
cost of administering the program. The mandate was to sell the drug
for as low a price as possible with no expectation of making money.
At this price, Gilead expects to lose money until 2006 or 2007,
depending on how quickly volume sales develop, when prices will
likely drop. With new money coming in from the Global Fund, the
Bush initiative, and the Gates Foundation, a more rapid uptake of
the program may lower prices sooner.
Recognizing that the standard commercial model of drug distribution
would not apply, particularly in Africa, Gilead decided to forego
traditional methods by not seeking product registration in the countries
they want to serve. Instead they will sell the drug directly to
NGOs, clinics and individual physicians to avoid the high mark ups
taken by pharmaceutical distributors. Gilead will follow a model
of named-patient sales to entities that have been vetted by Axios
or a panel of regional experts that Axios has assembled. When it
has been determined that a clinic is legitimate and has sufficient
funding to offer a sustainable treatment program, they will be sold
the drug.
The named-patient route avoids the need to gain full registration
for Viread in every country where it could be useful. Clinic doctors
need only to obtain an import license for their program's use. This
could be as simple as demonstrating that the drug they wish to import
has an approved package insert from the U.S. FDA.
After a program or clinic has been approved, and funds or a letter
of credit has been received, the drug will be shipped from Gilead
in San Dimas, California via DHL or a similar carrier. Reorders
can be placed though the Internet.
After discussions with the FDA, Gilead decided to produce a white
tablet version of Viread intended for the special program to distinguish
it from the blue tablet approved in the U.S. It's hoped that this
will offer some protection against diversion or re-importation of
the discounted product to countries where Viread is marketed conventionally.
It will be illegal to sell the white tablet in the U.S.
Who is this for?
This drug, while cheap, is not affordable to every program that
would like to offer treatment. Until the large funding streams come
online, the number of people receiving Viread is likely to be relatively
small. Gilead has projected the need for Viread by taking an estimate
of how many people in Africa need treatment currently, then estimating
the rate at which people currently being treated will need a second-line
or salvage regimen. Because of the cost, Viread will not be a first-line
choice for many programs. Yet because the treatment situation in
the next three years is so uncertain, Gilead plans to remain flexible
with its plans while maintaining the overall goal of making their
drug available to meet the need.
"Goodbye, America"
By Gregg Gonsalves
There was a joyous sing-along at a party closing the first regional
meeting on AIDS activism for 17 states of the former Soviet Union,
which took place in Minsk, Belarus, from May 7 – 10. Partially
fueled by the camaraderie of working together over four days and
partially by copious amounts of vodka, participants from each of
the countries sang their national favorites (the Americans sang
Lou Reed's, Walk on the Wild Side). There were two songs that all
the Russian-speaking participants knew by heart: the old national
anthem of the USSR and a song called "Goodbye, America."
Goodbye America is about disillusionment with the United States
and more broadly the West, in which the lure of Western culture
and its forbidden fruits during the Soviet era turns out to be a
mirage for contemporary Russians. "Goodbye, America —
The place where I'll never ever be," goes the song, testifying
to the fact that the "good life" the U.S. and the West
symbolize remain out of reach for most people in the region. I couldn't
help thinking that this song was an appropriate coda to a meeting
that stressed the stunning lack of access to basic HIV treatments
and diagnostics and the unwillingness of the West to intervene on
any appropriate scale to assist these countries on the doorstep
to Europe in confronting an epidemic that is exploding all around
them.
The conference, "Increasing Advocacy Possibilities for the
Rights of People Living with HIV/AIDS (PLWHA) in the Newly Independent
States," was sponsored by the International Harm Reduction
Development Program of the Open Society Institute, the Tides Foundation,
the Ford Foundation and the Joint United Nations Programme on HIV/AIDS.
Despite the grave situation in the region, the conference felt like
a watershed event for the PWLHAs, drug users, sex workers, and gay
men who gathered there from over 20 countries, to attend a training
on advocacy skills and to strategize together about the needs for
their communities.
While there are strong AIDS advocacy movements in a few countries
in the region, particularly Ukraine, the idea of "acting-up"
was new to many from the former Soviet states. By the end of the
four days, the diverse group had settled on a few priorities for
their work together: antiretroviral therapy access; access to harm
reduction and substitution therapy (e.g. methadone); the reduction
of stigma and discrimination towards PWLHAs and drug users; and
the improvement of social services. Despite the obstacles they face,
I was amazed by the participants' energy, intelligence and passion
to move forward. Advocacy projects on issues identified at the conference
will now be supported by a grant-making process. In a novel twist,
the scope of projects to be supported and the proposals themselves
will be reviewed by advocates from the region, with logistical support
provided by the Tides Foundation, which has raised money and set
up a fund to disburse the grants.
The former Soviet Union has the fastest growing epidemic in the
world, yet the West has only recently taken notice of the looming
catastrophe there. One cannot help think that there is a bit of
queasiness by Western donors for an epidemic that is largely fueled
by drug use. For instance, the U.S. government's aversion towards
harm reduction, specifically needle exchange, and its own domestic
policies on drug use, make it far easier to ignore what is happening
in Eastern Europe and Central Asia, than to confront the irrationality
of its approaches here at home. George Soros' Open Society Institute
is a vital exception in the region and funds 65 percent of the harm
reduction efforts there. Yet, in the context of the scarcity of
other funding, there is little support for services for PWLHAs,
much less HIV-positive drug users, which makes the harm reduction
effort stand out like a sore thumb, exacerbating tensions between
communities of drug users and those of PWLHAs.
The question "What is to be Done?" has a thorny history
in the former Soviet Union, but unless great change comes to the
region, the devastation will be tremendous. It's time for Western
donors to step up and confront what is happening with a commitment
of cash and resources, and particularly for the U.S. to give up
its radically conservative vision of how to deal with drug use.
Activists around the world also need to support our colleagues in
the East and stand in solidarity with them as they begin the struggle
that started to take shape a week ago in Minsk.
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