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Past Issues
Volume 20, numbers 4, 5, 6, 7
April – July 2006
The World Needs Better HIV Drugs
Options remain slim where resources are scarce
The Global need for Kaletra
Price is a barrier to second-line therapy
Increasing Access to Tenofovir
World CAB meets with Gilead
Treating HIV and HCV in the Same Person
Many questions remain unanswered
Testing the Next Generation of HIV Drugs
Guidance needed from FDA
New HIV Drugs Needed for the Next Decade
By Bob Huff
The greatest unmet medical need in HIV medicine worldwide
is for better treatments for people starting treatment for
the first time (treatment-naïve patients). With 40 million
people infected worldwide and perhaps a quarter of them in
immediate need of treatment, the world has made great progress
in the past few years in bringing antiretroviral (ARV) drugs
to more than a million people in Africa and elsewhere in the
developing world. Yet a huge gap remains in the availability
of treatment, and over 7,000 people with HIV continue to die
everyday.
The most widely used ARV regimen in the developing world
contains nevirapine, stavudine, and lamivudine. While quite
effective at suppressing HIV, this regimen owes its popularity
to its low cost and availability in easy-to-use combination
pills from a number generic manufacturers. Yet, all things
being equal, this drug regimen would not be the first choice. In
the U.S., stavudine has fallen off the list of preferred
first-line drugs, and nevirapine was never on the list. The
standard first-line HIV regimen in the developing world urgently
needs a makeover.
Stavudine (d4T), although highly effective as an anti-HIV drug,
has been associated with body fat changes known as lipoatrophy, and
may have been one of the chief culprits in the epidemic of facial
fat wasting that affected so many people on ARVs during the first
decade of HAART. After only a few years of widespread use in the
developing world, reports are starting to appear of body fat
abnormalities in patients in Thailand and elsewhere. The appearance
of these highly visible side effects in people taking ARVs has
the potential to damage the sometimes fragile public perceptions
of HIV treatments. It would be tragic if ARVs came to be shunned
in some places because they were seen as the source of disfiguring
and stigmatizing side effects. Another serious side effect of
stavudine use in some patients is painful peripheral neuropathy,
which can cause a burning sensation in the toes and fingers. Zidovudine
(AZT), a more expensive cousin of stavudine, is an alternate drug
choice, although it too has been associated with the development
of fat wasting problems, albeit at a slower pace. Zidovudine also
can contribute to anemia, a serious problem for pregnant women
and many others in the developing world with suboptimal nutrition.
Tenofovir is now the most commonly used NRTI in the
rich countries because it is highly effective and causes
no serious side effects in the great majority of people
using it. Although tenofovir does not have tolerability
problems, it has been associated with a reduction in kidney
function and possibly with diminished bone mass, side effects
that are mild and stable in most people but ones that give
doctors a bit of worry and require monitoring, especially
in patients with prior kidney problems. Unfortunately, careful
monitoring is a luxury that can not be counted on in resource-poor
settings, although clinical trials of tenofovir in Africa have
not uncovered any serious problems when using the drug in routine
practice under limited conditions. One formidable problem,
however, is that tenofovir is many times more expensive than
stavudine, and although future competition between generic
manufacturers may lower the cost, tenofovir will likely never
be as cheap as the current standard. For the foreseeable future,
the developing world is stuck with stavudine.
The Non-nukes
In the North, initial non-nucleoside reverse transcriptase
inhibitor (NNRTI)-based regimens are most commonly anchored
with efavirenz and backed up by tenofovir and emtricitabine
(a drug very similar to lamivudine). These three drugs are
also now available in a convenient, once-daily, single tablet
from their brand name makers.
As anchor drugs of an NNRTI-based regimen, both nevirapine
and efavirenz share many similarities. They both effectively
control HIV and both remain in the bloodstream for extended
periods. But both are also susceptible to loss of activity
if HIV develops only one or two resistance mutations, and
developing resistance to one drug results in resistance to
the other. In the rich countries, efavirenz is more commonly
prescribed because it is considered more potent and because
nevirapine requires much closer monitoring when initiating
the drug in first-time patients due to severe and occasionally
fatal liver problems that have developed in a few people. Nevirapine
should not be initiated in women with CD4 counts higher than
250 cells/mm3 or in men with CD4 counts higher than 400
cells/mm3. Nevirapine is also a difficult drug to use in
combination with certain drugs used to treat tuberculosis,
one of the most deadly opportunistic infections in the
developing world.
But even the best available choices for privileged patients
in the North leave much to be desired. Efavirenz is a convenient
and highly effective drug and most patients probably find it
trouble-free over the long-term. But efavirenz can cause
profound sleep disturbances and exhaustingly vivid dreams
in many people who may tolerate these side effects for a
year or so, but are relieved when they finally switch to
something else. And because efavirenz has been associated
with birth defects, it should not be used in women who are
or want to become pregnant. For them, nevirapine or a protease
inhibitor is a safer choice.
In the developing world, the best price for an efavirenz-based
combo is five-times that of a generic nevirapine regimen, which,
for a national treatment program, means that fewer people can be
treated and that the population-wide response would be blunted.
Basing a regimen on a protease inhibitor adds additional costs.
For mass treatment programs conducted with limited public health
funds in very poor countries, pennies per day matter, and the
best price for the best available regimen is often still
too much.
After the First Drugs are Gone
Because resistance to nevirapine is relatively easy to produce,
and because nevirapine resistance also eliminates efavirenz as
an option, there is already a growing need for second-line therapies
based on the protease inhibitors for treatment programs in the
developing world. This need has not received a lot of attention,
partly because of the urgency of getting first-line therapies
rolled out to those who desperately need them, and partly because
the tools for monitoring first-line treatment failure are not
widely available outside of a few well-resourced ARV treatment
programs like the US Government's PEPFAR. But when the need for
switching patients to protease inhibitors is confronted it immediately
becomes apparent that the cost of treatment rises dramatically. The
cheapest, most practical, and most widely available protease inhibitor
in the developing world, Abbott's Kaletra, is 4-5 times more
expensive than nevirapine, despite the company's special no-profit
pricing program.
While there is an unmet medical need for safer, cheaper,
more potent, more durable, and more tolerable HIV drugs for
all of the world's HIV patients, it is the crushing burden
of HIV in the developing world that elevates the desirability
of better ARV drugs into a crisis of need.
Characteristics of an Ideal Regimen
What would an ideal HIV drug look like? Of course an ideal
new drug for treating HIV in the developing world must potently
suppress HIV replication. But it should also work against a
broad range of HIV subtypes and against virus that has lost
susceptibility to other drugs. Ideally, a new drug would target
a unique point in the viral lifecycle so critical to HIV's
survival that resistance mutations would be rare, or would
come with a cost of drastically impaired fitness. The drug
should remain in the bloodstream long enough to allow once-daily
dosing — and be relatively forgiving of the occasional missed
dose. Optimally, the drug would be so potent that it could
be used on its own, without NRTI support. Alternatively, it
would be easy to formulate together with other HIV drugs into
a single pill without any special technology.
It should also enter and pass through the body without
affecting the blood levels of other drugs or being much
affected by them in turn. Not only should the long term
safety profile of this ideal drug be benign, but it should
have few of the tolerability discomforts like mild nausea
or diarrhea that accompany so many other drugs. Doctors
need to feel confident that they can start a patient on
this drug and not have to follow up for several months or
more. Patients need to know that the drug can reliably
roll back their HIV disease without making life miserable
or increasing their risk for other medical problems.
Finally, an ideal new ARV for the developing world
must be cheap and easy to make, and the patent holder must
be willing to allow multiple generic manufacturers to make
abundant quantities available wherever they are needed. A drug
like this would be in demand in the rich countries too, and
that's where a company would expect to make its investment
pay off.
Coming in 2007
This is a tall order, but there are encouraging signs that
better drugs are in the pipeline. Merck is racing forward
with development of a new drug that works by inhibiting a
unique target in the HIV lifecycle called integrase. So
far, Merck's integrase inhibitor appears to be quite potent
and has not revealed any particular safety problems
(day-to-day tolerability remains to be seen, with some
trial participants complaining of increased flatulence). A
minor drawback for Merck's first offering in this new drug
class is a requirement for twice-daily dosing. The biggest
medical unknown yet to be answered by the clinical trials
in progress is whether or when resistance mutations will
arise that defeat the drug. The biggest commercial unknown
is how much it will cost to manufacture the integrase
inhibitor, how much Merck will charge in the developing
world, and what will be the company's policy on allowing
third-party generic drug makers to produce the drug for
low-profit markets. Merck's integrase inhibitor should
receive U.S. approval in 2007.
Another new drug due in 2007 that also blocks HIV
infection in a unique way is Pfizer's maraviroc, a CCR5
antagonist that prevents the virus from entering target
CD4 immune cells. Although data is limited, in preliminary
studies, the drug was effective and no safety or tolerability
issues have emerged so far. One limitation is that maraviroc
is only effective at blocking HIV that uses the CCR5
coreceptor. HIV variants using a different coreceptor are
not inhibited by the drug and these variants may be present
in 10%-60% of people with HIV, mainly depending on the
duration of their infection. This means that maraviroc
may not be reliable for use in broad populations without
expensive diagnostic monitoring.
New NNRTIs are also being developed by Tibotec that
address problems with nevirapine and efavirenz. TMC125,
also due in 2007, may have utility in settings where primary
nevirapine resistance is common.
There is an unmet worldwide medical need for better HIV
drugs for initial and subsequent therapy for all kinds of
patients, and a drug with these ideal qualities for the
developing world is also exactly what is needed in the North
by treatment-naïve patients and by highly treatment-experienced
patients who have developed resistance to nearly all of the
20-plus HIV drugs available to them. New drugs on the horizon
may meet some of these criteria but the ideal is still out of
reach. Barring the discovery of an effective vaccine or another
unexpected breakthrough, HIV drug researchers still have a
lot of important work ahead of them.
The State of Access to Kaletra
By Bob Huff
In parts of the developing world, particularly in Africa,
the price of antiretroviral drugs has come down dramatically
over the past four or five years. A generic combination of
nevirapine, lamivudine and stavudine used for first-line therapy
can be had for under $150 per year. While this is an effective
and lifesaving combination that has enabled a half-million people
to begin therapy, there are side effects associated with stavudine,
and resistance to nevirapine can arise quickly if adherence is
not near perfect. This means that, as the number of people going
on first line therapy grows, the number of people who are failing
or intolerant of those drugs is also growing, which, in turn,
creates a growing need for second-line therapy.
There are many problems surrounding switching to a
second regimen after the first and most affordable therapy
is no longer useful, not the least of which is the cost of
second-line — typically much higher than first-line drugs.
For example, Kaletra, a first-line drug in the US and
Europe, is considered second-line in the developing world
because it has required refrigeration and no affordable
generic version is available. Abbott Laboratories, the
makers of Kaletra, recently brought to market a new version
of the drug that does not require refrigeration, even in hot
tropical climates. Abbott will sell the drug in Africa and
in a few non-African developing countries at a no-profit
price of $500 per year, or about $42 a month. Yet even
this is too much for some national treatment programs to
justify paying, and it does not seem likely the price will
go much lower soon. Abbott says it is losing money at this
rate, and no generic drug maker from India or elsewhere
has developed a competing product that comes close to
Abbott's $500 a year price.
In August 2006 Abbott announced that it would begin
selling new Kaletra in the developing world under a new
name: Aluvia. The heat-stable Aluvia lopinavir/ritonavir
tablets would be identical to the new Kaletra tablets
sold in the US and Europe except for a color change in
the tablet coating: from yellow ochre to rose. Abbott
also announced a new, lower price for sales to a list
of lower-middle-income countries such as Ukraine and El
Salvador. At $2,200 per year, however, this program may
not bring relief to many of the increasing number of
people who have run out of rope on their first drug
regimen and are looking to Kaletra for a lifeline.
A group of treatment activists from the developing
world recently met with Abbott in London to discuss the
dismal situation for second-line therapy in their
countries. Here are some excerpts from a country-by-country
report on the availability of Kaletra for patients who
are running out of options.
Moldova: We have Kaletra for
only 10 people. Only one child takes Kaletra. By
2010 it is planned for 50 people. There is an urgent
need for the drug because ARVs have been available
for three years and there is now resistance. It is
purchased by the Global Fund for $390/month. The
government has no funds for purchasing Kaletra. We
are concerned that when the Global Fund leaves the
country in 2010, there will be no more drugs.
El Salvador: In some countries in Central America,
Kaletra is now provided by the government. Before, we depended on
relatives living in North America. Kaletra is used as a second-line
drug in cases where there is resistance. Kaletra is prescribed only
when clinical resistance has been diagnosed. But we don't have
labs to demonstrate resistance.
Prescriptions are restricted because the costs are so high. No
one is treated with Kaletra in El Salvador or Guatemala. Only 10%
of those who need it can get Kaletra in Central America.
Ukraine: In Ukraine Kaletra is used
as first-line. We have 200 patients on Kaletra but it is
expensive. It is the only brand name drug being procured
in Ukraine. The government first purchased it for post-exposure
prevention. We don't care about the formulation but we
have very high prices. The prices for the government and
the Global Fund are different. Global Fund's Kaletra is
cheaper than the government's. A package in Ukraine costs
$370 dollars for the Global Fund, $420 for the government. Today
we are planning procurement for 6th Global Fund round and
they wanted to exclude Kaletra.
We have a lot of side effects and a lot of resistance
so we are very interested in Kaletra monotherapy. In Ukraine
we have 10 people on Kaletra monotherapy.
Paraguay: In Paraguay, Kaletra is
provided to only 20 persons. Half are children and Kaletra
is first-line for them. The cost is about $440 per month
for one person. That consumes 25% of the budget for the
national program. Monotherapy is used in the private sector
if people can access their labs in Brazil or Buenos
Aires. Kaletra has been available since 2003. Storage
is a problem.
Croatia: In Southeast Europe there
is some access to the old Kaletra. In Croatia we have 70
patients paying 403 Euros per month. There is a problem
with access to Norvir in Croatia.
Suriname: Some people need to use
Kaletra now, but the poor people can't buy it. Rich
people can get it from Holland.
Zambia: Out of the 55,000 people on
treatment in Zambia, currently 240 people are on second-line
therapy and most depend on Kaletra. We have Kaletra but
you need to take food with it. A new formulation that does
not require food or refrigeration will be very good for
countries like ours in Southern Africa. If people are
hungry they won't take the drug until they have food. More
than 80% of Zambians live on less than $1 a day. Buying
drugs is more expensive than paying rent for most
Zambians. HIV comes with job losses and to people who
live where there is no electricity and refrigeration. Kaletra
is mostly used in MSF (Doctors Without Borders) clinics
or PEPFAR programs in the big towns. A doctor will not
prescribe it for someone in a rural area. The cost of
second line is $450-$500/month. If there is a new formulation
then it is high time to find out how Abbott is planning
to increase access to Kaletra so that it reaches the people
who need it. PEPFAR gives free access to Kaletra, but
if people must travel from another town and they must
eat during their journey, then access to the drug is
not really free.
India: As far as we know Kaletra
is not available from the government in India. People
only have access to Kaletra in India if they have
money. We have 36,000 people on first line, but there
is no second-line treatment for people on the government
programs. Unofficially, about 10% of these people need
second line. People don't know about Kaletra.
Uganda: I take Kaletra. Kaletra
has been a total nuisance in my life: The food restrictions,
the number of pills I must take every night and day. But it
has worked very well for me. Most people don't have
fridges. I'm looking forward to the new Kaletra but
it must be accessible to people in rural areas. The
price of $700 per year is very expensive. Why is this
not the $500 they say they give to Africa?
China: China does not have any Kaletra. We only have what we can carry in.
Bulgaria: Bulgaria has Kaletra and it is reimbursed.
Russia: In Russia Kaletra is available and
registered. The demand for second-line is not sufficient for the
company to make it a priority. The price is also different between
the government and Global Fund. Global Fund price is $290/month
and it depends on the number of patients. Even this price is too
expensive. The government tries to avoid Kaletra due to the high
price.
Estonia: We have access to Kaletra in
Estonia. Of 300 patients on second-line, 71 are on Kaletra. We
only have the old formulation. The cost is about $6,000/year. Next
year we need to put 2,000 patients on ARVs.
Peru: In Peru we introduced Kaletra in 2004. We
got a price of $1.88 per day ($677/year) but in Peru it is free for
the people. We have about 100 persons on Kaletra. We get generic
Kaletra from Cipla. We have 500 people on the drug at 1.20 per pill.
Morocco: In Morocco, we started treatment
early so second-line therapy is a big issue. We have Kaletra
at the $500 access prices but it is still expensive for the
Ministry of Health. It is free for the people. About 40 people
take it. It is recommended for doctors to not prescribe it
unless it is the only solution. So we try not to use it. We
need the new heat stable version because we are a hot
country. People travel in buses without air conditioning to
get their medications. Getting to the clinics is a problem.
We buy Kaletra from Abbott in South Africa. We have benefited
from the access prices since 2004 but $500/year is too much for
a country like Morocco. We pay about $250/year for generic
first-line therapy. This is a similar situation for other North
African countries.
Cameroon: Our data says there are more
than 3,000 people on ARVs and around 200 people on Kaletra. The
price is a problem. The government decided not to apply for the
next round of the Global Fund, so we are not sure what will
happen if that support goes away. If we don't have that money,
how can we access treatment? And we have so many people in
rural areas. My village is 300km from Yaounde. How can people
access these drugs? Everyday the need for treatment increases
— and the cost is the issue.
World CAB Meets with Gilead
By Bob Huff
In July 2006, members of the International Treatment Preparedness
Coalition's (ITPC) World CAB met with Gilead Sciences, the makers
of Viread (tenofovir) and Truvada (tenofovir/emtricitabine) to
discuss the company's plans for making their drugs available at
affordable prices to ARV treatment programs in the developing world.
Although the company put into place a special Access program
in 2002 to make its drugs available in a group of 97 countries
at a no-profit price, the price of tenofovir has remained 6-8
times higher than the price of generic stavudine. Furthermore,
the lack of registration with drug regulatory authorities in
most of these countries has limited the ability of treatment
programs to order and prescribe tenofovir.
In mid-2006, Gilead announced that it would grant licenses
to several Indian generic drug makers to manufacture Viread
for the Access Program countries as well as for the domestic
Indian market with the expectation that competition and increased
volume of sales would reduce prices.
Gilead's pricing policies differ based on the category
of country (determined by gross national income per capita
and weighted by HIV prevalence):
1) Access countries (97)
2) Lower middle income (LMI) countries
3) Upper middle income (UMI) countries
4) High income countries
Current Access country prices are $17/month for Viread and
$26.25/month for Truvada. The standard price for LMI countries
is $30/month and $45/month. There is no set price for UMI
countries and prices will be based on negotiations with
governments. High income countries pay full price.
Truvada is dark blue in US and light blue in the Access
Program. Atripla is salmon colored in US and white in the
Access Program. Both are FDA approved.
* * *
India: I hear you say that Gilead wants
the drugs accessible to as many people as possible in the
world. We like the drugs but why didn't you offer voluntary
licenses in 2002. Why did you file the patent application
in India? Why so slow?
Gilead: We were initially advised that
we would only need registrations in a dozen countries and
we could use the import mechanism for the rest. It was not
practical. In South Africa it is only available on a named
patient basis, in others it is not allowed at all. Gilead
finally decided we have to do these registrations.
We started by relying temporary import permits and
realized this was not working a year ago. A year ago, we
decided to register in all 97 of our Access Program
countries. We hope to complete by the end of the year.
India: Why are you seeking a patent in India?
Gilead: We can't offer a license without
a patent. But we filed in India because we don't think a patent
will inhibit access if it is not abused. If there had been a
patent earlier, there might be better access in India now. We
don't think the presence in India of a patent will slow this. The
generic companies we are licensing will have the right to sell
in 101 countries. The drugs will be approved by FDA and WHO. We
think the patent will help accelerate competition. The main
reason we filed in India was to protect markets like Brazil. The
patent in India is not to protect in India, but to prevent
Indian generics from importing into countries like Brazil.
India: If the patent is not granted then you
don't have the right to license.
Gilead: If the patents aren't granted then
the licenses are void. There were protests in May but we were
working on this plan before then. We have been talking to some
of the generic companies for two years. We could have started
the technology transfer sooner.
India: What is happening about access to the drugs in India?
Gilead: We are relying on those generic companies
to make drugs for India. We are seeking registration there. In India
no price will be set. Thailand is a LMI country. We will allow Indian
companies to sell there. Allowing the distributors to make a profit
should assure commercial access in places like Thailand. We will go
to free pricing and allow the generics and the Access Program to
compete on price. In Africa the generics must beat $17 to compete.
USA: Must the Indian companies also register in Africa?
Gilead: If the branded product is already
registered, then the generics only need to show bioequivalence. Indian
manufacturers will submit bioequivalence data. If we haven't received
registration in a country then it will be a problem for the generics too.
India: Our experience is that the generic
is priced higher in India than in other countries.
Gilead: We don't have the experience yet
within India but in other countries patents can impede access. We
have to pay a royalty on the FTC component of Truvada, but we are
not asking the generics to pay that.
China: If the prices are allowed to float
in countries like India or Thailand, could the price actually
go up? If you feel the price is out of line will you come in
and sell at $17?
Gilead: We will watch things and intervene
if there is abuse. We are filing in India because it gives us
the option of going in ourselves. But we can't tell the generics
what to charge due to antitrust reasons. The only tool we have
is to reserve the option to go in ourselves.
India: Most of the 97 Access countries
don't have patents anyway.
Gilead: We can't resolve our differences about
deciding to patent our drugs.
Cameroon: My concern is with price. Only
10% of patients need second-line therapy. But the price for
first-line is $6. The price for second-line is too high for
people to afford.
Gilead: We had anticipated higher volume
and lower prices by now. I think prices will end up around $12
for Viread and $18-20 for Truvada. The cost per mg is lower
for tenofovir compared to stavudine, but the low dose makes
stavudine cheaper.
We want to have multiple generic partners to help drive
cost down on the API (raw materials) side. Normally, companies
don't invest in process improvements because there is no economic
need with full prices. But the Access Program drove manufacturing
cost improvements. We have improved manufacturing yields.
Ukraine: Are you going to register tenofovir
in Eastern Europe and Ukraine? We are preparing a Global Fund
application. Can we plan for tenofovir?
Gilead: We should file later this year
after we finalize our agreements with Merck. The price will
be the Access price for Ukraine. There are no Indian generics
in Ukraine.
We have an agreement with (generic maker) Aspen Pharmaceuticals
to represent us in sub-Saharan Africa. They will manufacture the
drug supply for Gilead's Access Program. Aspen manufactures finished
product according to US GMP (good manufacturing process) for all
Access countries. They distribute products under their global trade
names in Africa. They will pursue registration approval in Africa
where it is not already registered. Aspen is free to buy API from anyone.
Portugal: Gilead acknowledged the delays in
the past, where are the bottlenecks now?
Gilead: The initial registration filings
are the easy part but following up and babysitting all the
applications is much harder. In Thailand you have a two-year
window to develop local safety data. In the past year, we filed
an average of three applications a day. It is a huge logistical
challenge. I'm not sure now smooth this will go.
This is an issue for all companies working in these
regions. The other companies have been communicating
between themselves. We would like to see registration
harmonization between countries in Africa. Not one of
these applications has required unique data. Only two
countries of the 54 African countries have harmonization.
Portugal: What is the status of
tenofovir getting on the WHO Essential Medicines List (EML)?
Gilead: Viread was turned down for
inclusion on the EML in 2005 as a result of poor
communications. It is not a transparent or standardized process.
They requested information that was confidential, which we
deal with all the time. After we submitted the data, they
said they were going to put it on the website. We said no,
and WHO removed the data from the application.
We think the interval for considering the EML every two
years is too long. In Zambia the government did not allow
PEPFAR to use Viread because it was not on the list.
After recognizing how important the EML is, we are now
prequalified and have good communication and will submit
in the fall of 2006. The next approval date will be in April
of 2007. We would like them to approve sooner.
The last time there was no proactivity at WHO, but this
time we are in communication. You can't submit for prequalification
unless WHO has asked for it in an expression of interest. You
need to be on one list to get on another list.
India: The several Indian companies will
be charged a royalty. How much? Are there any other restrictions?
Gilead: We are charging 5%, which is less than the law
allows, especially if you provide technology transfer. It
is enough to cover all of our activities for regulation and
hiring people who will work for us in these countries. Cipla
will have competition sooner than they expected. Others will
get to market sooner. This is not the easiest drug to make. We
will give them process descriptions so they can make it right away.
South Africa: There will be less competition
in the middle income countries because you have a monopoly.
Gilead: We are unapologetic about getting
a patent. Without patent protection there is no motivation to
seek therapies for certain diseases. I do think many companies
abuse their patents. But if we are responsible in our pricing
then I think it is fair.
China: Are there any other restrictions
on the generic producers?
Gilead: Five percent royalty. Must seek
registration for GMP for PEPFAR or WHO prequalification —
if they fail, then we sit with them and we will help them, but
if there are serious problems, we will suspend the license.
They can sell tablets in 97 countries plus Cuba and Thailand.
They can only sell API to licenses in India or to Aspen or Gilead.
Every one will have the same agreement.
There are no restrictions on prices and we will assist in registrations.
The license is for tenofovir. We don't have a patent for FTC in
India. They can combine it with other agents if they want to.
Portugal: What is the Brazilian deal?
Gilead: There were good discussions with
the Ministry of Health. The price is $114/month for Viread. The
$114 price is good for three years. There is a statement about
respecting our intellectual property rights. There are also
purchase quantity requirements.
India: Does that mean they could not oppose a patent?
Gilead: That is an issue for the patent
courts. But if they did oppose we would probably void their
contract.
South Africa: All avenues are blocked
for competition in Upper Middle Income countries.
Gilead: For example we have a patent in
Mexico. We just voluntarily reduced our price in Mexico by
50%. We are going back to countries and dropping the price.
Morocco: If there is a compulsory license?
Gilead: We would not let a compulsory license
happen. Brazil asked for a voluntary license but threatened a
compulsory license in the press. Their terms for making the drug
were the same as for buying the drug. A new Minister of Health
came in and found that his manufacturers were deficient so he
decided to purchase. Their biggest concern was continuity of
supply. And they have had problems with that. They saw the
potential of 100,000s of people adding tenofovir and wanted
assurances of supply. We offered a safety stock but eventually
they didn't need it. Some people wanted a compulsory license on
principle.
Optimizing Antiretroviral Therapy
for HCV Coinfected People
By Tracy Swan, Treatment Action Group
Antiretroviral therapy (ART) may delay liver disease
progression in people coinfected with viral hepatitis by
preserving immune function. Conversely, viral hepatitis
coinfection complicates HIV treatment, because it increases
the risk for treatment-associated hepatotoxicity (liver injury)
and discontinuation of antiretroviral therapy.
Despite concerns about hepatotoxicity, the benefits of
antiretroviral therapy clearly outweigh the risks for coinfected
people. In fact, ART may be a life-saving intervention for
some coinfected people, since serious HCV-related liver damage
is most likely to occur in people with less than 200 CD4 cells. The
majority of coinfected people do not experience serious
antiretroviral-induced hepatotoxicity. Clearly, HIV treatment
should not be withheld from people coinfected with viral
hepatitis, although careful monitoring for signs and symptoms
of hepatotoxicity is warranted.
What is Hepatotoxicity?
Some medications can cause liver injury, ranging from mild
to life threatening. Drug-induced liver injury may be asymptomatic,
but it usually can be identified by laboratory tests. Injury to
liver cells is indicated by abnormally high levels of two liver
enzymes, alanine aminotransferase (ALT) and aspartate amino
transferase (AST). Some drugs cause bile duct blockage, referred
to as cholestatic injury, which is indicated by elevated gamma-glutamyl
transferase and alkaline phosphatase levels. Although cholestatic
injury usually resolves after discontinuing medication, in rare cases,
liver failure may occur.
Antiretroviral-induced hepatotoxicity is characterized by
elevated liver enzyme levels with or without the following
additional symptoms of liver inflammation: jaundice, fatigue,
loss of appetite, abdominal pain, nausea, vomiting, diarrhea,
light-colored stools, and dark urine. In addition to these
symptoms, rash may precede or accompany nevirapine-induced
hepatotoxicity syndrome.
Hepatotoxicity often occurs within weeks of starting a
new antiretroviral regimen or agent, but may also develop
with continued drug exposure over a longer period of time. In
many cases, providers can closely monitor and "treat through"
hepatotoxicity. However, experts recommend that all medications
be discontinued when liver enzyme levels reach ten times the
upper limit of normal within the first four weeks starting of
a new ART regimen. Continued use of a hepatotoxic drug or
regimen may be life threatening.
Several drugs from the three major classes of antiretroviral
agents, NRTIs, NNRTIs, and PIs, have been associated with hepatotoxicity,
and, in 2005, severe liver toxicity was responsible for Glaxo
SmithKline stopping all clinical trials of its experimental CCR5
antagonist aplaviroc.
Mechanism of Hepatotoxicity
While coinfection with viral hepatitis significantly increases
risk for antiretroviral-associated hepatotoxicity, several additional
factors can also cause or contribute to liver toxicity. These can
include alcohol use, direct toxicity of a specific drug, and
interactions between ARV agents and medications used to treat
a range of HIV-related comorbidities, namely opportunistic
infections and psychiatric conditions. Genetic differences
in drug metabolizing enzymes and related host factors may
also affect an individual's risk for hepatotoxicity.
In coinfected people, ART-related immune restoration
may result in flares of symptomatic hepatitis, and certain
antiretroviral agents may exacerbate hepatic steatosis
(the accumulation of fat in the liver), a condition associated
with more serious liver damage in persons with hepatitis C.
The liver is involved in the metabolism of several antiretroviral
agents, and serious liver damage may alter the liver's metabolic
or excretory capacity. Yet the extent of liver damage can vary
widely among coinfected individuals, ranging from mild fibrosis
to serious liver scarring, known as cirrhosis. Coinfected people
with more serious liver damage (defined as Metavir biopsy score
of F3 or F4) are more likely to develop antiretroviral-associated
hepatotoxicity than those with lower Metavir scores (F1 or F2)
and less liver damage.1
For vulnerable persons with more advanced liver disease,
metabolic alterations may lead to increased or decreased drug
exposure, resulting in either the accumulation of toxic drug
levels — with accompanying increased risk for side effects
and toxicity — or a decline to subtherapeutic levels
and an increased risk for developing drug resistance. Metabolic
alterations may also increase the potential for drug-drug
interactions.
Antretroviral Drug Levels and Hepatotoxicity
Antiretroviral drug levels must be high enough for a drug to
achieve its effect without causing toxicity; the range between
a minimally effective dose and a toxic dose is known as the
therapeutic window. Doses above the therapeutic window may
aggravate side effects and increase toxicity, leading to
discontinuation, or worse. It is reasonable to assume that
some cases of hepatotoxicity result from chronic dosing
above the therapeutic window. Furthermore, the different
therapeutic window may vary in each individual depending
on coadministered prescription drugs and genetic, immunologic,
or environmental factors.
Pharmacokinetic (PK) studies assess what happens to
a drug in the body: how it is absorbed, distributed,
metabolized and eliminated. Pharmacodynamic (PD) studies
evaluate drug activity, or what a drug does to the body. Data
from both types of studies are needed to characterize the
hepatic safety and proper dosing of antiretroviral agents
in coinfected people. It is important that coinfected people
are included and closely observed in Phase II and Phase III
studies of new drugs so that longer-term data on hepatic
safety and tolerability of antiretroviral agents may be
collected.
Some data on drug levels in people with serious liver
damage are available. In 2003, FDA issued guidance to
industry for conducting pharmacokinetic (PK) studies in
persons with hepatic impairment (defined as mild-to-moderate
cirrhosis according to the Child-Pugh scoring system). FDA
recommends, rather than requires, these studies when hepatic
metabolism and/or excretion accounts for a substantial
portion (>20 percent) of the absorbed drug or elimination
of a parent drug or active metabolite. In addition, even
when the drug or active metabolite is eliminated to a
lesser extent than 20%, FDA strongly recommends that industry
conduct these studies whenever labeling, literature, or
available information suggests that the drug has a narrow
therapeutic range.2
Although hepatic impairment studies performed to
date have yielded useful information, their results do
not apply to all coinfected people — only those
who have developed cirrhosis. Antiretroviral drug levels
are not studied in coinfected people with mild to moderate
liver damage, and not all approved antiretroviral agents
have been studied in cirrhotics.
Prior to approval, FDA should require that PK studies
of antiretroviral agents are conducted in coinfected people
with varying degrees of liver damage, particularly those
with more advanced liver damage such as bridging fibrosis
and cirrhosis. Ideally, barring any significant concerns
about drug safety, PK studies in coinfected persons should
be underway before Phase III trials and Expanded Access
Programs are launched.
PK studies are only the first step towards optimizing
antiretroviral therapy for coinfected persons. Additional
data are needed, particularly longer-term assessment of
antiretroviral drug levels, side effects, safety, efficacy,
tolerability and liver disease progression in coinfected persons.
Biopsy Alternative Needed
However the major challenge in designing such studies is the
lack of a non-invasive and inexpensive method to assess liver
damage in research and clinical practice. Liver biopsy is the
best way to determine what is happening to liver tissue, but
it is expensive, invasive, can be painful, and carries a small
risk of complications; rarely, these have been
life-threatening. Ongoing research is evaluating several
alternatives to liver biopsy, but none have replaced the
gold standard.
One potential solution involves using a combination of
blood tests, known as serum biomarker panels, to assess
the extent of liver damage in clinical practice. Although
many experts do not believe that serum biomarker panels
are a viable substitute for liver biopsy, these panels are
likely be used in the clinic. One way to understand the
value of these panels would be to recruit coinfected people
who had been biopsied into PK studies, then compare results
from serum biomarker testing to biopsy. If a good correlation
between biopsy and serum biomarker panel results were found,
this would mean that valuable and clinically relevant data
could be collected.
Drug Levels Matter
More research on ARV drug levels in coinfected persons is
also warranted, particularly since conflicting data have
emerged from many scattered, small PK studies of single
drugs. For example, Dominguez and colleagues reported that
coinfected participants had significantly lower levels of
lopinavir/r vs. those with HIV alone in Hepadose, a recent
PK study measuring PI and NNRTI levels in 132 HIV-positive
people, 70 of whom were coinfected. Hepadose measured trough
PI and NNRTI plasma concentrations in 132 people (the trough
is the lowest level of a drug present in the bloodstream
immediately prior to the next dose). But a different study
from Dickinson and colleagues did not find significant
differences in plasma levels of lopinavir/r according to HCV
status, or even among cirrhotics.3,4
Hepadose also detected significantly higher trough
concentrations of efavirenz, nevirapine and nelfinavir
in coinfected people compared to people with HIV alone. In
particular, the study saw trough concentrations of efavirenz
and nevirapine that were significantly above therapeutic
range in 56% of coinfected patients with fibrosis scores
of F0 to F3, and a whopping 86% of those with F4 (vs. 24%
for those with HIV alone).3
Other studies have reported similar findings. Jeantils
and colleagues detected above-the-range trough concentrations
of efavirenz in six of twelve coinfected individuals. Accordingly,
the investigators successfully reduced daily efavirenz doses
from 600mg to 400 mg.5
Until more data are available on ARV drug levels in coinfection,
therapeutic drug monitoring (TDM) may be useful for coinfected
individuals, particularly those with advanced liver damage, and
persons experiencing elevated liver enzyme levels, side effects,
or virologic failure. TDM studies provide individualized plasma
levels of protease and/or non-nucleoside reverse transcriptase
inhibitors (nucleoside analogue drugs, which become active only
inside of cells, require intracellular assays to measure drug
concentrations). Dosing is adjusted accordingly, as needed. Unfortunately,
TDM is an individualized measurement, and not applicable to anyone
other than the person being studied. TDM is more commonly used in
Europe than the United States, where it is costly and difficult to
obtain outside of a clinical trial.
References
1. Aranzabal L, Casado J, Quereda C, et al. HAART-associated
hepatotoxicity in HIV/HCV co-infected patients with advanced chronic
liver disease or cirrhosis. Abstract TuPe1.1C38. 3rd International
AIDS Society Conference on HIV Pathogenesis and Treatment, Rio
de Janeiro, Brazil. July 2005.
2. Food and Drug Administration. Guidance for Industry. Pharmacokinetics
in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact
on Dosing and Labeling. May 2003.
www.fda.gov/cder/guidance/3625fnl.doc
(accessed on 7th October 2005)
3. Dominguez S, Peytavin G, Guiguet M, et al. The HEPADOSE Study: evaluation
of protease inhibitors and non nucleoside analogue plasma concentrations in
HIV/HCV and HIV infected patients. Abstract WePp0305. 3rd International AIDS
Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil.
July 2005.
4. Dickinson L, Micheli V, Meraviglia P, et al. The impact of co-infection
with Hepatitis C or Hepatitis B on lopinavir pharmacokinetics in
patients infected with HIV. Abstract WePe3.2C06. 3rd International
AIDS Society Conference on HIV Pathogenesis and Treatment, Rio
de Janeiro, Brazil. July 2005.
5. Jeantils V, Wade A, Touitou H, et al. Therapeutic drug monitoring
of efavirenz (EFV) in HIV-1 infected patients treated with efavirenz
containing regimen. Abstract H-1995. 43rd Interscience Conference on
Antimicrobial Agents and Chemotherapy. Chicago, Illinois. 2003.
Treating HIV and HCV in the Same Person:
More is Needed
Given the prevalence of viral hepatitis coinfection among
people with HIV, there is an urgent need for much more
information about drug levels, long-term safety and tolerability
of antiretroviral agents in this population. FDA should go
beyond recommending pharmacokinetic (PK) studies of antiretroviral
agents in persons with hepatic impairment by requiring PK
studies in coinfected persons with moderate-to-serious liver
damage prior to approval. When indicated, sponsors should
support PK studies of approved antiretroviral agents.
Longer-term data are needed, since drug levels may
accumulate over time or liver damage may progress, thus
changing the safety, tolerability and efficacy profiles
of antiretroviral agents. Coinfected people in Phase II
through Phase IV studies should be carefully monitored
if we are to better characterize the safety, efficacy
and tolerability of antiretroviral agents.
New tools are needed to simplify assessment of liver
damage, and make PK results clinically relevant to persons
who have not had biopsies. Public and private sector research
partnerships should support development and validation of
non-invasive serum biomarker panels. Designers and sponsors
of long-term cohort studies need to incorporate serum biomarker
panels as part of long-term follow-up of coinfected participants.
Advocates need to develop a research agenda for antiretroviral
drug development in coinfected persons and work with regulators
to beef up pre-and post-approval requirements. Drug labeling should
reflect lack of specific data in coinfected persons due to incomplete
pre-and/or post-marketing commitments.
More HCV recommendations at:
www.treatmentactiongroup.org.
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Path of Least Resistance
New Drug Development Guidance Needed from FDA
By Bob Huff
With a wave of new HIV drug approvals expected over
the next year or so, we may finally see a dramatic reduction
in the number of people with HIV who find themselves "unable
to construct a viable regimen"; the classic definition of the
so-called "salvage" patient who has developed resistance to
nearly every available antiretroviral treatment option.
In other words, the near decade-long salvage crisis
for highly treatment-experienced patients may finally be
ending. Of course, some will still develop resistance to
every new drug that comes to market, though—hopefully—those
patients will be few.
But anticipation of this welcome accomplishment has also
raised a perplexing question from drug developers: If there
are no salvage patients then how can we develop the next
salvage drug—or any new HIV drug, for that matter?
The last few HIV drugs to be approved were tested
in clinical trials that compared a standard, best-available
treatment regimen (optimized background therapy) with the
standard treatment plus the experimental drug. At the end
of 24 weeks, if viral load reductions were greater in the
group that received the test medication than in the comparison
group then the new drug was a winner. When the best available
background regimens could suppress HIV in perhaps 25% of
highly treatment-experienced trial subjects, it was not
hard to demonstrate the value of a new drug that could
double that rate.
But if this new wave of drugs now or soon-to-become
available for use in standard regimens can effectively
suppress viral load in 80%90% of highly treatment-experienced
patients, then how can a clinical trial show that adding
an experimental drug contributes any measurable benefit? If
we are wedded to the salvage trial design, nervous drug
makers are asking, how can we prove that a new drug works?
The "add-on" salvage trial design was an efficient and
successful drug development strategy for industry. Companies
scrambled to develop salvage drugs, not only because there
was a critical need in the US and Europe, but also because
the six-month salvage study offered a fast path to accelerated
approval — and that path was well understood. The FDA had made it
clear what needed to be done to get a salvage drug approved.
As a bonus incentive, accelerated approval also meant that a
new drug could start earning revenue a critical six months to
a year sooner than would be possible under traditional approval.
But with the salvage study population drying up, the
industry is becoming nervous about the feasibility of testing
a new generation of drugs. What will the FDA demand? Can
new drugs be studied in treatment-naive populations? (That
is where the greatest unmet medical need has now shifted to.)
Will additional safety hurdles have to be met before trials
in treatment-naive patients are permitted? Will future trials
need to be much larger or run for several years longer than
they have in the past?
Drug companies like to start planning for possible drug
development pathways many years in advance to help them anticipate
the potential risks and rewards of investing in a new drug. Decisions
are being made today about drugs that may not come to market
before 2012. Unanswered questions about the regulatory environment
tend to make investment decisions seem more risky.
We are entering a period of uncertainty about how the
next generation of HIV drugs can be developed. Until that
uncertainty is resolved, pharmaceutical makers may become
cautious about starting up major new HIV drug development
programs. That would be bad for the millions of people with
HIV in the world who have yet to go on treatment and for the
tens-of-thousands who will inevitably need to switch to a
better treatment—including present and future salvage patients.
The FDA needs make it clear to industry and advocates: What is
the best way to develop new HIV drugs in the post-salvage era? What
is the new path of least resistance?
© 2006 Gay Men's Health Crisis
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