HIV-related lipoatrophy (fat loss under the skin) is a clinical
problem that affects many people living with HIV. Lipoatrophy can
cause substantial loss of buttock tissue, veiny legs and arms,
and facial wasting. Lipoatrophy can happen alone or in combination
with lipohypertrophy (fat accumulation) in the visceral (organ)
and dorsocervical (back of the neck) area. These body changes,
with or without blood level alterations of cholesterol, triglycerides,
lactic acid, glucose, and insulin, is called HIV-related lipodystrophy
syndrome.
Many of these body changes occur normally with aging, but being
HIV positive seems to accelerate their development. Many observational
cohorts and studies to determine the causes and potential treatments
of lipodystrophy have been performed since 1997, the first year
when we realized that living longer with HIV may be accompanied
with side effects like body changes. Even though there is not yet
a consensus-based case definition for lipodystrophy, there are
many things that we have learned since then. One is the potential
impact of nucleoside thymidine analogs like d4T (Zerit, stavudine)
and AZT (zidovudine) on subcutaneous (under the skin) fat wasting.
Studies in which patients were switched from these drugs to abacavir
(Ziagen) or tenofovir (Viread) have produced encouraging results
in reversing lipoatrophy, even if at a slow rate. Other studies
looking at using insulin sensitizers like rosiglitazone (Avandia)
to reverse lipoatrophy have produced conflicting results. It seems
that the use of Avandia in combination with Zerit or AZT does not
allow for regrowth of subcutaneous fat tissue. Fortunately, good
news came to patients with lipoatrophy in the U.S. when the FDA
approved Sculptra (polylactic acid) injections in August 2004 for
the treatment of HIV related facial lipoatrophy. Although this
option does not treat the root cause of the problem, it can give
patients the hope of restoring a healthy appearance once again.
David Nolan is a clinician and researcher based at Royal Perth
Hospital in Western Australia, where he works at the Centre for
Clinical Immunology and Biomedical Statistics. He has a broad range
of interests relating to HIV and its treatment, with a particular
emphasis on lipoatrophy where he has explored associations between
NRTI therapy, mitochondrial toxicity and fat tissue pathology.
He has published more than 30 research papers and reviews, covering
the broad topic of lipodystrophy as well as related topics including
mitochondrial toxicity syndromes, metabolic complications of HIV
protease inhibitor therapy, hyperlactatemia syndromes, genetic
susceptibility to abacavir and nevirapine hypersensitivity reactions,
and the effects of HIV and treatment on bone density.
On the other hand, AIDS wasting associated with untreated HIV
predominantly affects lean body mass while having less of an effect
on fat tissue. The only exception here is that women with advanced
HIV disease tend to lose fat as well as muscle, although again
this has different characteristics. Loss of fat in AIDS wasting
in women tends to be generalized (i.e., the same all over the body)
as with any weight loss, while part of the reason that lipoatrophy
is so noticeable in both men and women is the way in which fat
loss is so "unevenly spread" over the body. For women in particular,
the preferential loss of fat over the legs and buttocks associated
with lipoatrophy is quite unusual.
This is a very interesting question and one where there is no
definitive answer yet. The adipocyte depletion findings tell some
of the story, although the clinical data are probably more important
in showing how significant the effect of AZT is in terms of lipoatrophy
risk. Overall, the severity of fat loss — and the risk of
clinical lipoatrophy — is approximately halved with zidovudine
treatment compared to stavudine. This means that in "ball park" terms,
the risk of developing noticeable fat loss is 15 percent to 20
percent after 3 to 5 years of zidovudine treatment.
My own view (and again there is no consensus opinion available
as yet) is that the impact of zidovudine treatment is not sufficient
to minimize its use for first-line therapy in industrialized countries.
There are a number of reasons:
Again, a very interesting question. I think it is fair to say
that any triple-NRTI drug regimen needs to include AZT to have
a good chance of success, given the poor outcomes that have been
associated with NRTI combinations such as tenofovir/abacavir/lamivudine
or tenofovir/didanosine/lamivudine (very poor efficacy), or stavudine/didanosine/abacavir
(poor efficacy and high toxicity) [reviewed in 1]. In
these regimens, it appears that these drugs all tend to favor the
emergence of a similar pattern of resistance mutations, so that
there is very little barrier to the emergence of K65R or L74V/I.
AZT appears to counteract this effect, as it "pulls in another
direction," actually becoming more potent when these resistance
mutations start to emerge. This means that the virus has more difficulty
becoming broadly resistant to both AZT and the other NRTI's (most
commonly lamivudine and abacavir) within the NRTI combination.
As stated above, I think the risk of lipoatrophy associated with
AZT can be managed in a rational way that minimizes the chances
of developing problematic fat loss, and in this particular case
(when triple NRTI therapy is desired) there really is no effective
alternative drug at present.
I think there is strong evidence that delaying treatment until
CD4+ T cell counts fall below 200 increases the risk of a number
of drug-related toxicities, including lipoatrophy (if using d4T
or AZT) and neuropathy (which can be associated with HIV itself
as well as the use of d4T or ddI) [reviewed in 2]. There
is also a concern that low HDL-cholesterol levels associated with
more advanced HIV disease may predispose patients to metabolic
complications and the potential for a greater risk of cardiovascular
disease [3]. I would argue that treatment should be initiated at
higher CD4+ counts (i.e., 200–350) and should be focused on:
I think the mitochondrial toxicity at a cellular level is reversible,
as it is likely that the toxicity of these drugs is mediated specifically
by their effects on mitochondrial DNA depletion. The more worrying
problem is that severe lipoatrophy represents a profound loss of
adipocytes (fat storing cells) within the fat tissue through cell
death (apoptosis). The TARHEEL study showed very nicely that you
can "turn off" this process of cell death by switching from d4T
to a non-thymidine NRTI (i.e., far fewer cells are killed), but
you are then left with the problem of having to replace the cells
that have been lost. While the non-thymidine NRTI's are obviously
not toxic to fat tissue, they do not actively encourage new cells
to grow, and treatments that may be anticipated to help this process
of regeneration (such as rosiglitazone) have not performed well
to date. This problem is further complicated by the fact that lipoatrophic
fat tissue contains a large number of macrophages, inflammatory
cells that are probably there to "mop up" the adipocytes and their
stored fat after cell death, and these may also inhibit the growth
and development of new fat cells.
With regard to the micronutrients you mention, there is no evidence
that they improve any clinical outcomes if used as a preventive
treatment. They have been used in the management of lactic acidosis
(usually in an intensive care setting) although, because these
events are so rare, the benefits are not really known. Uridine
treatment (in the form of a sugar cane extract called "Mitocnol" or "Nucleomaxx")
has shown a lot of promise as a preventive treatment that may limit
the toxicity associated with either stavudine or zidovudine without
compromising the effectiveness of these drugs against HIV, but
these results have been obtained primarily from the laboratory.
Clinical experience with this extract is minimal at present and
the cost of treatment is about $100 per month. I'm sure more information
will be available in the next year or so, which will be watched
with interest.
This is an important area, but one where it has been difficult
to obtain good data. Facial lipoatrophy is obviously one of the
most stigmatizing aspects of lipodystrophy, and this is an area
where people really want to see improvement following NRTI switching.
We do see improved facial appearance associated with NRTI switching,
although in general the more severe the initial lipoatrophy (prior
to switching) the more limited the improvement. This is a frustrating
aspect of the syndrome, as it is a case of "first affected, last
to improve." This means that less affected areas (such as the arms
and trunk) tend to improve before more badly affected areas such
as the face and legs. Also, because the process of "regrowing" populations
of fat cells seems to be slow, improvements happen over years rather
than months.
My own opinion is that we need to put this issue on the agenda
and keep it there — particularly in the case of stavudine,
where there is a substantial concern about toxicity issues. There
is a rationale that stavudine may be better tolerated in non-white
populations — and certainly this is an anecdotal opinion that
is expressed by clinicians who look after mainly African-American
patients. However, the potential toxicity of these drugs needs
to be assessed carefully and quickly in the developing world, before
the development of severe and widespread complications. We have
already seen the burden of disease associated with severe lipoatrophy
in our own communities — this history should not be reproduced
in developing countries.
Besides lipoatrophy, what other long-term health implications
does having decreased mitochondrial DNA or impaired function mean
to someone with HIV?
In truth, probably very few implications. The effects of NRTI
drugs on mitochondrial function appear to be very tissue-specific,
so in the case of lipoatrophy it is very likely that the "damage" is
limited specifically to fat tissue. For example, it is notable
that stavudine treatment — which has been consistently associated
with severe mitochondrial DNA depletion in adipocytes — has
no significant effects on mitochondrial DNA in blood cells. Also,
the mitochondrial toxicity associated with NRTIs appears to be
readily reversible, in the sense that mitochondrial DNA depletion
goes away quickly after ceasing/switching NRTI therapy.
Some historical data exists suggesting that ddI treatment is not
associated with lipoatrophy. For example, an early study of dual
NRTI therapy by Thierry Saint-Marc (published in 1999) included
a number of patients receiving didanosine in both stavudine (d4T/ddI
= 13/27, 48%) and zidovudine treatment groups (AZT/ddI = 13/16,
81%) that were well-matched for NRTI therapy duration. In this
study, use of stavudine remained the most significant risk factor
for lipoatrophy (relative risk 1.95 compared with zidovudine),
while no significant didanosine effect could be demonstrated [4].
More recently, results from the FTC-301A study also suggest that
the once-daily NRTI drug emtricitabine (FTC) compares favorably
with stavudine (each combined with ddI-EC and efavirenz) in terms
of lipoatrophy risk over 72 weeks (n=571), while maintaining equivalent
efficacy and improved overall tolerability. Average loss of fat
was noted only in the stavudine group, despite the fact that ddI
was used in both study arms [5]. More long-term data are awaited
in this study.
In your experience, does tenofovir have the same or different
benefits when it comes to lipoatrophy reversal/prevention as abacavir?
How about when it comes to lipids?
We have observed the same "non-toxic" effects on adipocyte's mitochondrial
DNA levels for these drugs, and the study data certainly suggest
that tenofovir and abacavir are not associated with risk of lipoatrophy
(both with an incidence of <3% over 3 years). In this respect,
neither drug will have a particular advantage. With regard to lipids,
the "lipid lowering" effect of NRTI switching appears to basically
represent the effect of removing stavudine from the HAART regimen
(in NRTI switching strategies) or of removing PI drugs such as
indinavir, rather than any special attribute of tenofovir or abacavir.
There was some attempt to differentiate the effects of abacavir
and tenofovir on lipid/lipoatrophy outcomes in presentations at
this year's 12th Retrovirus Conference, but I think these will
come to nothing once other confounding factors are taken into account.
From the "lipodystrophy" point of view, including both metabolic
and lipoatrophy outcomes, these are both good drugs.
Probably the best way to conceive of the difference between subcutaneous
fat and these other fat depots is that subcutaneous fat is the
ideal storage site for dietary fat, while visceral fat tends to
function as an "overflow" system if the fat-storing capacity of
the subcutaneous fat tissue is exceeded.
This means that subcutaneous fat responds very effectively to
the insulin stimulus that is associated with eating a meal. What
happens in this transition from a "fasting" to a "fed" state, therefore,
is that:
The whole idea of this process is that fat stores are created
while there is food around, so that there is an energy source available
for a period of fasting (e.g., overnight, for those who don't have
late-night snacks!). As you can imagine, this is a system that
has evolved over thousands of years — when fast food hadn't
been invented and the next meal wasn't always guaranteed!
In this context, visceral fat is different in that it doesn't
respond to insulin so strongly — which means that it doesn't
generally compete with subcutaneous fat tissue for the storage
of dietary fat. It is also much more "labile," in that fatty acids
are also released back into the circulation much more readily from
visceral fat than from subcutaneous fat. Its purpose is probably
to create a short-term store of fat that can be used again quickly,
without running the risk of letting excess fatty acids build up
in tissues such as muscle and liver where they can be quite damaging.
So, from a metabolic point of view, there are a couple of important
points to make here. One is that you can create excess visceral
fat by eating more fat than your subcutaneous stores can cope with.
The second is that "insulin resistance" — which means that
tissues (including subcutaneous fat but also liver and muscle)
don't react to the presence of insulin appropriately — reduces
the ability of subcutaneous fat to store fat in the most efficient
way. This leads to the accumulation of fatty acids in all the wrong
places (muscle, liver) and also creates a reservoir of fatty acids
(from visceral fat) that is released at all the wrong times (e.g.,
even when you've just eaten and there is already plenty of metabolic
fuel available).
Visceral fat accumulation (around the organs) is one part of the "Metabolic
Syndrome" that also includes insulin resistance and dyslipidemia,
and these three elements cluster together quite strongly.
- Excessive dietary intake of saturated fats and sugars contributes
to the development of visceral obesity by exceeding the capacity
of the subcutaneous fat to store dietary fat in an appropriate
way. Lack of exercise also leads to fat not being "burned" as a
source of energy. This means that you don't have to have HIV infection
and/or PI therapy to get these problems — and indeed about
30 percent of U.S. adults are affected by Metabolic Syndrome.
- Once visceral obesity is established it makes it harder to "recover" from
insulin resistance, as there is always a source of fat that must
also be "burned" along with dietary fat before the system can go
back to efficient functioning.
- One of the least understood areas is whether having lipoatrophy
also contributes to the risk of insulin resistance and visceral
obesity. This would make some sense, as having less and/or poorly
functioning subcutaneous fat would be likely to make it easier
to "overload" the capacity of this organ to store fat. Some recent
data from the Netherlands [van Wijk JP, et al J Clin Endocrinol
Metab. 2005 Mar 22; Epub ahead of print] support this possibility,
indicating that more severe lipoatrophy increases the risk of insulin
resistance. I think this is an example of how we need to think
carefully about how to look after the health of those who are affected
by severe lipoatrophy into the future.
Getting back to the original question, it is not really known
why stavudine and zidovudine don't affect visceral fat in the way
that they cause lipoatrophy. One explanation may be that visceral
fat is intrinsically more resistant to mitochondrial toxicity,
because (1) it doesn't rely so much on energy-requiring processes
such as triglyceride synthesis, and (2) because it expresses "anti-apoptotic" proteins
(one is called cIAP) that make visceral fat cells less susceptible
to mitochondrial toxicity and subsequent cell death. At this stage,
no one has collected fat samples from this fat depot in HIV-infected
patients.
Besides serving as caloric storage and protection against
cold weather, what other function does subcutaneous fat have?
This is currently a booming area in medical research, as it becomes
increasingly recognized that subcutaneous fat actually functions
as an active metabolic organ rather than as an inert storage site.
There are many examples of how this plays out, but the case of adiponectin
might be a good starting point. Adiponectin is basically a hormone
that is released only from subcutaneous fat, which profoundly influences
the way that fatty acid metabolism is regulated by the body as a
whole. When subcutaneous fat tissue is healthy (and not affected
by insulin resistance) it releases increased amounts of adiponectin
into the system, which acts as a signal for the body to efficiently "burn" the
fat that is present in muscle and liver. This means that adiponectin
acts to protect against insulin resistance. However, when subcutaneous
fat is not functioning properly, adiponectin levels go down and this
then becomes part of the problem of insulin resistance — fat
is allowed to build up in the wrong places and is not efficiently
burned.
There is a lot more to this story, but to summarize, it is certainly
true to say that subcutaneous fat is an integral player in metabolism
generally — and is likely to be just as important to "metabolic
health" as muscle or liver.
To contact Nelson Vergel: www.facialwasting.org.
References
1. Arribas JR. The rise and fall of triple nucleoside reverse transcriptase
inhibitor (NRTI) regimens. J Antimicrob Chemother. 2004;54:587–92.
2. Keswani SC, Pardo CA, Cherry CL, Hoke A, McArthur JC. HIV-associated
sensory neuropathies. AIDS. 2002;16:2105–17.
3. El-Sadr WM, Mullin CM, Carr A, Gibert C, Rappoport C, Visnegarwala
F, Grunfeld C, Raghavan SS. Effects of HIV disease on lipid, glucose
and insulin levels: results from a large antiretroviral-naive cohort.
HIV Med. 2005;6:114–21.
4. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere
O, Lang JM, Gastaut JA, Touraine JL. A syndrome of peripheral fat
wasting (lipodystrophy) in patients receiving long-term nucleoside
analogue therapy. AIDS. 1999;13:1659–67.
5. Saag MS, Cahn P, Raffi F, Wolff M, Pearce D, Molina JM, Powderly
W, Shaw AL, Mondou E, Hinkle J, Borroto-Esoda K, Quinn JB, Barry
DW, Rousseau F; FTC-301A Study Team. Efficacy and safety of emtricitabine
vs stavudine in combination therapy in antiretroviral-naive patients:
a randomized trial. JAMA. 2004;292:180–9.
Treat the World
By Bob Huff
Against all odds, treatment for HIV is expanding in Africa and
elsewhere in the developing world. Beginning in the late 1990s,
Brazil showed the way by making affordable generic antiretroviral
(ARV) drugs produced in their own factories available to all of
its HIV-positive citizens. By daring to break the monopoly of the
multinational patent holder companies, Brazil dropped the average
price of a year's therapy from $10,000 to under $600 and made it
available for free to 140,000 Brazilians. India's historically
flexible patent laws allowed generic drug makers there to export
affordable drugs to Africa, where non-governmental (NGO) treatment
programs run by organizations like Doctors Without Borders (MSF)
soon proved that providing HIV treatment in severely resource-limited
settings was feasible and therefore conceivable for African governments
to undertake. Competition among the Indian generic manufacturers
soon pushed the average price of therapy to under $350 per year
then to as little as $140. Thailand followed up an aggressive prevention
campaign in the 1990s with a treatment program based on Thai-made
generic drugs. Funding from the new Global Fund for AIDS, Tuberculosis
and Malaria (GFATM) and other sources have encouraged governments
to expand the scope of their health programs. The United States'
President's Emergency Plan for AIDS Relief (PEPFAR) has funded
another track of treatment, largely based on drugs from originator
companies, with prices now reduced to the cost of manufacture.
Other treatment programs in Africa, funded by charities, religious
groups and businesses, continue to grow, using donated drugs from
the multinational companies, heavily discounted branded drugs and
purchased generics. The treatment landscape in Africa in 2005 has
evolved beyond what many people thought possible just five years
ago, yet it still falls far short of what is needed.
Despite the progress, the overall picture of HIV treatment in
the developing world is spotty, with only about 12 percent of those
who need ART receiving by at the end of 2004. The World Health
Organization's (WHO) ambitious "3 by 5 Plan" to treat three million
people by the end of 2005 is likely to wind up treating about 1.2
million. Disbursements from the GFATM are lagging. One bright spot
is the fast-growing PEPFAR program, which is ahead of schedule
in bringing 470,000 people under care by June of 2006.
Although low cost generic drugs made these gains possible, it
is becoming increasingly clear that the infrastructure — the
facilities, staff, equipment and supplies — needed to assure
the quality and sustainability of these fledgling treatment efforts
is not available at a similar discount — where it is available
at all. And, even as these programs struggle to their feet, economic
developments and legal changes in the Indian patent laws that made
generic drugs possible, threaten to knock them back down. The continued
expansion of ARV therapy in Africa and elsewhere is at risk of
collapse unless problems with funding, staffing, administration
and drug supply are addressed. Despite the good start, the lives
of millions of people with HIV remain at risk unless sustainable
solutions to these problems are found.
Proof of Concept
When the multinational drug companies realized what was happening
in Brazil they lashed back at the threat by mounting an all-out
campaign to defeat the affordable drugs movement. While major
pharmaceutical companies like GSK and Bristol Myers Squibb had
charity programs for AIDS operating in Africa since the mid-1990s,
those programs were largely focused on support for specific medical
facilities or services for orphans. If they were available at
all, major label ARVs in Africa were priced at the same stratospheric
level as in the North or given away with so much red tape that
few got them. One of the first obstructionist tactics the big
companies rolled out was a whispering campaign to reinforce the
conventional wisdom that offering treatment in Africa was a fantasy.
Experts knowingly pointed to gaps in African infrastructure,
citing the lack of trained staff and clean water (and, bizarrely,
even the lack of wrist watches) as insurmountable barriers. Of
course, many of their observations were valid and infrastructure
is proving a formidable challenge, but the naysayers served a
political purpose by implying treatment was futile unless every
underlying problem could first be solved. Artificial controversies
were sparked that pitted prevention against treatment; that claimed
treatment was not cost-effective; that claimed if drugs were
dumped on Africa then drug resistance would spread around the
world. Against this onslaught a few groups worked to demonstrate
that treatment in Africa with affordable drugs and minimal infrastructure
was achievable. Their success was a necessary step in convincing
northern governments and funders to undertake "3 by 5." It could
not have happened without generic drugs.
As the propaganda war slipped away from them, the pharmaceutical
companies turned to lawsuits before finally capitulating and grudgingly
offering their branded drugs at no-profit prices or through charity
programs. It may be that they ceded ground because they realized
that the only battlefield that mattered was in the domain of international
trade law, where they enjoyed overwhelming superiority.
The big drug companies obstructed affordable generic medicines
not because they feared the loss of markets — there was essentially
no market in Africa — but because they feared losing control
of their patent monopolies: their intellectual property. And it
was not even intellectual property in Africa that was the great
concern, since few companies had bothered to patent their drugs
there. More likely they were terrified of seeing the example spread
elsewhere. Compulsory licensing in Brazil; generic production in
India; the threat of re-importation of low cost or charity drugs
from Africa to the European markets were portents of doom. What
if consumers in the United States began demanding affordable medicines?
It is the principle of ownership, everywhere, with no limits on
monopoly control that has been the real battle prize.
Quality Counts
India's generics companies make drugs for the world including the
United States. Most of the Indian ARV makers use factories that
are inspected by the U.S. Food and Drug Administration (FDA)
and its European equivalents. Questions about the quality of
Indian generic drugs have mostly been fueled by the multinational
companies as part of the campaign to protect intellectual property.
But there are legitimate issues of quality that need to be addressed.
The WHO maintains a list of prequalified drugs supplied by sources
that have been vetted for quality and consistency. Drug regulatory
experts inspect the methods and materials that are used to make
the finished drug product in pill form. Large government and
NGO purchasers look to the list when deciding what to buy.
In 2004, a number of drugs that were certified by the WHO under
its prequalification program were removed from the list, which
caused ripples of uncertainty in the patient community and titters
of glee from the pharma lobby. Some of the drugs were de-listed
voluntarily after the WHO uncovered discrepancies in the reports
of bioequivalence testing, clinical studies designed to prove that
the generic version of a drug delivers the same amount of medicine
to the blood that the brand name does. The story goes that one
of the Indian research organizations contracted to perform these
studies simply evaluated a single patient then essentially photocopied
the result to make up the 15 or so tests the study required. Whether
the drug company was neglectful or complicit in this fraud is unclear.
Nevertheless, the bioequivalence data on all drugs performed by
this research company fell under suspicion and several Indian drug
makers withdrew their products from the WHO prequalification list
until the studies could be repeated and verified.
Prequalification is a valuable status to have. Many government
programs are unable to evaluate the quality of drugs and rely on
the WHO to identify reliable sources. But the WHO program has its
limits. Currently, it only inspects the production of the finished
form of generic ARVs but not the factories that produce the bulk
drug product, called the active pharmaceutical ingredients (API).
The U.S. PEPFAR program has set even higher standards for the
drugs it will spend taxpayer dollars on. PEPFAR says it will only
pay for drugs that are good enough for Americans; those that have
been approved by the FDA. Generally, the Indian companies don't
object to this, seeing FDA approval as the ticket to greater market
acceptance. Many critics, however, saw FDA involvement as a redundant
barrier erected to protect the U.S. pharmaceutical industry — after
all, the head of its international AIDS effort is the former chief
of the Eli Lilly pharmaceutical company. Still, the U.S. government
has said that generic drugs will be acceptable to PEPFAR as long
as they have been okayed by the FDA. The first of the Indian generic
drugs will soon have cleared this hurdle and critics will be watching
to see if they will join the brand name drugs dispensed by PEPFAR
doctors in Africa and elsewhere.
The Weight
Just as competition among the pill makers brought prices down,
having multiple sources of the the bulk active ingredients — the
APIs — that go into the pills should also produce competition
that will reduce prices. Most APIs used in generic drugs are
made in Brazil, India and increasingly, China.
The manufacture of bulk drug APIs is measured in tons. For example,
a ton of lamivudine will treat about 8,000 persons for one year.
If all eight million people who need treatment were to take lamivudine,
they would consume nearly 1,000 tons per year. The world's current
capacity for the production of bulk lamivudine is about a third
of that. Drugs with high daily doses require much more physical
product than drugs with lower doses. For example, an individual
taking nelfinavir consumes about two pounds per year whereas the
yearly dose of stavudine is only about three-quarters of an ounce.
Increasing and sustaining the industrial capacity to produce sufficient
quantities of APIs at competitive prices has yet to be addressed.
While there is currently sufficient capacity to supply APIs for
the drugs most often used in the developing world, that capacity
is lagging for badly needed second-line drugs such as efavirenz
and tenofovir.
Drugs and More Drugs
The most common generic ARV regimens currently in use in the developing
world are based on nevirapine and supported by lamivudine plus
d4T or AZT. Although the decision to roll out these drugs was
driven by their low cost, the regimens are effective, even if
problematic for many. Nevirapine in particular can be tricky.
Close monitoring is recommended during the first several months
to avoid liver toxicity, especially in women. Many believe that
nevirapine is not suitable for people who are taking certain
tuberculosis medications. Efavirenz might be a better choice
for them, but so far the generic price for efavirenz is no better
than the price from the patent holder. Nevirapine is also not
very forgiving of interrupted or intermittent dosing and resistance
to the drug is quick to appear when drug concentrations are not
maintained. When a nevirapine-based regimen fails, there are
few good choices in the developing world. Ideally, a switch would
be made to a protease inhibitor, such as Kaletra. But the ritonavir
needed to boost this and other PIs requires refrigeration, which
can't be guaranteed in many settings. A Kaletra-based regimen
is far more expensive than nevirapine and there is currently
no generic version of Kaletra available. A new generation of
Kaletra that does not require refrigeration should be approved
within the year, though there is no word on its price yet. If
it chooses to get involved in this great effort, Abbott Laboratories,
the makers of Kaletra, will be in a position to help revolutionize
therapy in resource limited settings.
Tenofovir is an attractive replacement for stavudine or AZT because
of its potency and minimal side effects profile. But tenofovir
is not yet available from the Indian generic makers and it is questionable
if it will be if it turns out to be protected under the new Indian
patent regime. Tenofovir is available as second-line therapy in
some PEPFAR and other programs, supplied under Gilead's no-profit
program for countries that can't afford it otherwise. Gilead has
taken steps to increase its capacity to provide the developing
world with tenofovir and its fixed-dose combination of tenofovir
and FTC. They have recently licensed a South African generic maker
to supply the 95 countries in its no-profit access program. As
one of the fastest growing ARV makers over the past few years,
Gilead can afford to be generous, but one wonders about the sustainability
of no-profit pricing in the long run. Voluntary licenses with modest
royalty payments to the patent holder would be a better approach,
some think. Multiple manufacturers might create more competition
and drive prices down by stimulating greater demand for the raw
materials. Yet some fear that competition would also increase the
incentive to cut corners on quality.
Currently, the no-profit price of Gilead's tenofovir is about
$25 a month, which compares to a price of about $3.30 for generic
d4T from India. But with reports starting to stream in about d4T–associated
facial wasting in Thailand and peripheral neuropathy in Kenya,
when does the cost of the cheapest drugs become too great?
We may be seeing the emergence of two tiers of treatment in Africa:
PEPFAR, with its newer, less toxic drugs and full service monitoring,
and the generic-based programs that use less monitoring and older,
cheaper drugs with more side effects. Both are keeping people alive,
but one is a rich program and the other is struggling with limited
means. If PEPFAR leaps ahead as the largest treatment provider
in Africa, the trickle-down benefits may eventually appear in the
other efforts as staff is trained and knowledge transferred to
more people. But critics charge that PEPFAR is already sucking
the life out of some government programs by luring trained staff
away with higher pay. Nevertheless, retaining staff is a huge structural
problem that is not easily solved. A recent news report claimed
that 1,000 nurses leave Kenya each year for jobs in Europe. It
could be that a well-to-do program like PEPFAR that pays superior
wages may ultimately help keep talent in the country.
The Future
The Clinton Foundation negotiated a breakthrough low price for
generic ARVs, but this has not been followed up with purchase
orders that would meet the criteria for obtaining this price.
Still, the promise to provide a year of ARV treatment for $140
has given confidence to government programs that feared undertaking
an unaffordable commitment.
Economies of scale may bring the price of generic drugs down to
Clinton levels, even without the conditions of sale required under
its cash-on-the-barrelhead terms. But if companies do not receive
payment, then they will have little incentive to continue offering
their products. Several Indian generic companies have complained
that certain African governments are slow to pay and that the cost
of bearing this risk must be passed along to their other customers.
Also, corruption persists as a problem in Africa. Some countries
require a local agent to purchase and receive the drugs for resale
to the government. This is an opportunity for big markups and kickbacks
to government officials with little transparency of the final price
paid for the drugs.
There are still some barriers to reaching the lowest possible
price for ARVs — import duties, taxes, local distributor markups — but
it's not clear that even halving the cost of drugs will increase
the numbers treated at this point. Low cost generics primed the
pump and made AIDS treatment in Africa conceivable, but even free
drugs won't make it into bodies without the supporting infrastructure.
In mother-to-child transmission programs, it appears that the cost
of providing single-dose nevirapine, a simple protocol now recognized
to be fraught with problems, is not much less than sustaining a
program to provide more complex protocols, or even continuous treatment.
Yet it was the single-dose plan that allowed the bureaucrats and
investors to consider treatment in these difficult settings possible
at all.
What Could Possibly Go Wrong? There is reason
to be optimistic about the prospects for treating HIV in Africa — and
some say they dare not consider the alternative. Momentum is finally
building, but now the course is shifting to difficult terrain.
If there is the will to purchase and pay for the drugs, then it
is likely that they will continue to be supplied by someone, somewhere.
But who is going to transport them, store them, inventory, reorder,
and dispense them? Who will pay for training more doctors, nurses,
medical officers and peer counselors, more administrators and more
accountants? There is a need to educate many more patients and
many more educators. There is a need to simplfy and reduce the
cost of diagnostics; to settle on new guidelines for treatment;
find better second-line, third-line and less toxic regimens. There
is a need to tackle corruption and to build political will and
donor confidence and lift the crushing burden of debt. The cost
of drugs may have receded as the main challenge, but it threatens
to reemerge if the supply is cut off or if there is a spike in
prices due to world economic events. Will donor fatigue slowly
strangle the life from the effort? The GFATM donors are already
backing away from their commitments. A fragile government's earnest
health plans can be disrupted overnight by disaster or war. The
PEPFAR dollars could be cut off by the whim of Congress — and
there is fear that the top notch infrastructure erected by PEPFAR
will collapse more quickly and completely than more modest, independently
established programs. But no matter why or how, when the money
stops or the drug shipment does not arrive, the impact will be
slow devastation and a slide back into despair.
World CAB II
This Time It's Generic
By Bob Huff
In January 2005, an unprecedented meeting was held in Mumbai,
India, between four manufacturers of affordable generic antiretroviral
medicines and 30 advocates for HIV treatment access drawn from
every region of the world. This was the second meeting of a worldwide
HIV community advisory board (CAB) with drug companies; the first
was held in San Francisco in 2004 with several multinational pharmaceutical
firms. The meetings were organized by iBase of London and GMHC.
The companies meeting in Mumbai included Cipla, the pioneer manufacturer
of low-cost antiretroviral (ARV) drugs; Hetero, a large supplier
of the bulk drug substance to many other generic drug makers; Strides,
a small supplier of ARVs with historical ties to the African market;
and Ranbaxy, an emerging powerhouse with ambitions of joining the
ranks of the multinational, research-based pharmaceutical industry.
The advocates traveled from Africa, South America, the Caribbean,
Eastern Europe, Southeast Asia, as well as from India and Nepal,
to press for lower prices and assurances of quality products.
Within the span of three years competition from the Indian generic
drug industry has caused the price of ARVs to fall from over $8,000
per year, offered by the multinational originator companies, to
under $200 per year, thus making large-scale plans for treating
millions of people throughout the developing world feasible. But
if lowered prices have brought plans to the table, the realities
of actually providing therapy to so many have proven formidable
and many problems remain. The meeting in Mumbai was intended to
explore some of the problems that the generics industry can address,
including the need for pediatric formulations of generic ARVs;
the need for equally affordable second-line therapy for use when
one's initial ARV regimen is not tolerable or has been compromised
by resistance; and the need to address sometimes radical disparities
in pricing that occur from country to country.
A key topic of discussion was the recent withdrawal of several
important ARVs from a quality assurance list maintained by the
World Health Organization (WHO) that many governments rely upon
when purchasing large quantities of drugs. At issue was the performance
of several clinical studies designed to show that the generic drugs
are absorbed into the bloodstream as well as the brand name versions.
Inspectors from WHO uncovered certain irregularities with the conduct
and reporting of several of these bioequivalence studies, which
called into question results from all such studies performed by
the Indian drug makers. This was a delicate issue for the generic
companies, and while no consistent explanation for the problems
uncovered by WHO were obtained, the affected companies all pledged
a rapid return to the critical list.
The future of low-cost generic ARVs also came under discussion.
New patent rules going into effect in India may change the way
the industry does business. Low-cost generic drugs have been possible
because Indian patent law does not protect the final drug product,
only the process of making the product. This means the generic
makers have been free to copy expensive Western-developed drugs
by coming up with a new manufacturing process. Under the new rules,
patent protection will be granted to final products first known
after 1995, which means that newer ARV drugs, like Viread and Reyataz
may never become available at the kind of prices the generic makers
are able to deliver. Products known before 1995 will not be affected.
All of the implications of the new patent laws are not clear, but
Dr. Hamied of Cipla, the only of the four companies serving the
private ARV market within the country, thinks the outcome will
hurt India by introducing monopoly patents, "It's going to be a
disastrous situation for India ten years down the line."
Representatives from India pressed the manufacturers on one of
the most vexing contradictions they face, "Why are drugs made in
India cheaper in Africa than at home?" Each company added its piece
to the puzzle, variously blaming import duties on raw materials,
taxes and an indifferent Indian government. But all agreed that
the key barrier to achieving lower prices, whether in India or
Nigeria, is the lack of a consistent, growing commercial demand
for their production. Despite widely announced plans for scaling-up
treatment to reach three million people by the end of 2005, last
year, one maker said, only 40,000 new patients were added to the
treatment rolls. Yet with Cipla now claiming an average price of
$160 per year, it may be that drug cost is no longer the limiting
factor. Until the barriers of inadequate healthcare infrastructure,
training and finance are removed, many fear that attainment of
the kind of large-scale purchases than can bring ARV costs below
$100 per year will remain unlikely.
The following are condensed excerpts from the discussions
held in Mumbai.
The Price of Drugs in Delhi
Loon: I'm proud India is making these drugs. I am a consumer
of these products. But I am paying $280 per year while people in
other countries are paying $180 per year. I'm pissed off about
this.
Strides: The only way we can get costs down is to get volume and
to manufacture the API (Active Pharmaceutical Ingredient), which
we are pursuing. The government should remove sales tax and statutory
levies that increase the consumer price. Wholesale and retail margins
are about 20 percent, but 36 percent is going to agencies of the
government. If you supply to the government of India, sales tax
is exempted. But if you supply to an NGO, then you are charged
16 percent. The government has to be lobbied. It took us years
to remove the taxes for TB products. We need to do that for ARVs.
Loon: Can the price for the stavudine/lamivudine/nevirapine
combo be brought down?
Strides: I don't think you will find that the price of Strides,
Ranbaxy, and Cipla will be very different from one another. Certain
costs are fixed: the API, the manufacturing costs. We have all
agreed to keep profits down. Just because it is a generic doesn't
mean the manufacturing process is compromised. It is a Rolls-Royce
product. You can only hope to reduce price if the volume becomes
larger. Only 40,000 patients for ARVs were added last year. The
economies of scale have not yet been demonstrated.
Loon: Could you have non-profit prices in India for people
who pay out of pocket?
Strides: It is very difficult to make small sales. It would be
good if all the communities would get together and have a common
basket for procurement. It then becomes much easier for us to work
out a better price. If you have a buyer's club, then we can do
that.
Thomas: Will you sell to buyer's clubs? What will be the process?
Strides: It's all about numbers. If someone asks for 50 bottles,
I may or may not be able to offer it to them. You have different
packaging specifications in different countries. In Nigeria it
must have a code on it. What I produce in Nigeria, in English and
French, I can't sell to Costa Rica. When you register, you include
the label in the language and you can't deviate from that. Each
country's label is different. You also have to have a minimum batch
size. If you all get together, you can get the price advantage
and better service, too. If 500 individual buyers get together
the freight is the same as for ten.
Marie Mendene: Have you had any discussions about regional
procurement?
Strides: Many people talk about this proposal. It would make our
life simpler.
The Clinton Price
Marie de Cenival: What is the quantity and the price that was
offered to the Indian government under the Clinton Foundation agreement?
Ranbaxy: The Clinton prices are theoretical prices based on volumes
that have not materialized. They said they would reach 100,000
patients after 2004, then 200,000 after 2005. We said our price
is based on 40,000 patients. This is where we could enter into
contracts with our suppliers. But the volumes haven't been realized
yet.
Marie: Which countries have really gotten the Clinton price?
Ranbaxy: Very few. In Rwanda the price went from our NGO price
to the Clinton price but there was no increase in volume. Only
the distributor lost out because his commission shrank.
Cipla: If you want to treat a million patients, we can manufacture
2 million tablets a day. But where will you get the API? The bottleneck
in the large scale supply of ARVs in is the manufacture of active
ingredients. You need 30 tons of stavudine; 146 tons of nevirapine
per year. If you change to efavirenz, you need 220 tons annually.
Nelfinavir, you need 900 tons annually for a million patients.
Who is there to finance these quantities? One hundred companies
like Cipla can not cope with this situation. The problem is the
manufacture of the actives.
Gopa: It was a year ago that we heard of the Clinton price
at $140 per year. What assumptions went into that pricing? Are
those assumptions still in effect?
Cipla: We were told that seven countries were in partnership with
Clinton for supplies, and that the total demand would be 2 million
patients in the next two years. On that basis we arrived at a price
of $140 per patient per year for Triomune. But that was a conditional
price. They announced that price but not the conditions.
The conditions were: the price of the APIs were fixed; no payment
of royalties or licensing fees; no litigation over patent infringements;
the specification of the product was fixed; any variations were
higher. Supplies were point to point; no intermediates. These were
subject to large confirmed irrevocable orders. Payment terms were
to be agreed in advance: advance payment or against supply. Then
the fluctuation in currency would be considered. If the dollar
went down, the price would increase. The dollar is already down
25 percent. It was without shipping, for only three products in
only seven countries.
So they are nice people at the Clinton Foundation, but I don't
know how effective as an NGO they are, because no business has
developed from them.
Marie de Cenival: So the market is not what we thought. I'm
surprised that you believed what Clinton told you.
Cipla: He is a very good talker.
Planning for the future
Marie. The Clinton deal is not working. Can we talk about what
will work?
Cipla: First, who will invest in the API? I'd suggest the Global
Fund and World Bank should invest in API. The South African government
has given a loan of $50 million to a company to make APIs. I think
it is a public mission to fund this.
Marie: What is the best price you can give?
Cipla: Why do you only talk about pricing? There are other issues.
What is the cost of medication? The medicine is only a small part
of the costs of treating the people.
Loon: Will we ever get below $140 in India?
Cipla: India is in a unique position — we have a large industry,
over 20,000 pharmaceutical companies — but there is also a
public drug sector. I suggest that the public sector takes over
ARVs. We have reduced the price dramatically in Triomune over the
last four years. If the duties go away, then the price will be
lower.
Estella: What are the opportunities for reducing the price
of APIs?
Cipla: Twelve to fourteen APIs are being used extensively for
ARVs. It is not humanly possible for any one company to produce
all of them. Understand the scale of operation: stavudine requires
30 tons but nelfinavir requires 900 tons. If I make Triomune for
1 million patients I need 110 tons of lamivudine. Last year GSK
consumed 26 tons of lamivudine, and their sales were $135 million.
We import and make APIs and intermediates. We sell very few APIs.
From India, the countries buying APIs are Brazil and maybe Thailand.
The problem will come when WHO begins to inspect APIs; that will
be a major problem. Before they said they only approve the end
product. The responsibility for the API was ours. Now they are
going to inspect the API factories. If we have to use FDA approved
factories, it will be difficult.
Marie de Cenival: I take your suggestion is to get the World
Bank to fund API production.
Cipla: What you should do is have a consortium that sets up a
manufacturing base. Choose a least developed country with no patents
until 2016. Bangladesh, Ceylon, Mauritius. If governments do not
actively participate, then little can be done. You need a long-term
partnership because it is a life-time illness. Why doesn't the
Indian government use its factories? Let me ask you an important
question. What contingency plans do you have to assure that you
have medications 20 years down the line? One of our main partners
in producing ARVs is China. If China decides to stop supplying
chemicals for ARVs then we are all out of business. The China patent
rule is that they can not sell the patented drug in China but they
can export it to countries where it is legal to sell, like India.
That could change. Today the China currency is linked to the dollar.
Tomorrow, if the currency is delinked and starts floating, the
prices of all ARV drugs will raise very high. What happens if the
companies stop selling at cost? If they leave the field? If China
stops selling APIs? What contingency plans do you have?
Quality
Asia: We want to talk about the crisis over WHO prequalification.
The entire Ranbaxy ARV portfolio has been withdrawn from the
WHO pre-qualified list. This has caused disruptions to treatment
programs. Nigeria is deregistering all Ranbaxy products. We saw
that a new CRO (Contract Research Organization) was contracted
for PEPFAR purposes. This seems to establish two tiers of quality.
Can you comment on the apparent double standard?
Ranbaxy: Double standard? We didn't realize our delisting would
be interpreted that way. PEPFAR was knocking at the generics' door — due
to your pressure. We have good relations with the U.S. FDA. We
understand that process very well. They have approved 100 of our
products. We were in middle of assessing data for the FDA and we
wanted to harmonize everything to the U.S. market and consolidate
manufacturing in one place. If a product is approved by the FDA
then it is accepted anywhere. It's not a double standard, but exactly
the same product made at the same locations.
Gregg: You need to get these drugs back on the WHO list and
not wait for FDA. You are creating havoc until they are re-listed.
Ranbaxy: The two are not linked. The U.S. asks for less stability
data than the WHO does, so filing for WHO prequalification could
actually happen later. WHO requires certain additional data to
be generated which is being generated. There are bioequivalence
studies running today and you cannot be 100% sure when the data
will come out.
Marie de Cenival: What really happened?
Ranbaxy: Those three products were supported by bioequivalence
data from a particular CRO in India, which had been used by several
different companies, pharmaceutical and others, doing various kinds
of analyses, including bioequivalence studies. It was a very reputable,
publicly listed company. The CRO had some issues with GCP (Good
Clinical Practice) and GLP (Good Laboratory Practice) and consequently
those studies were not passed by WHO. And WHO de-listed the products.
Marie de Cenival: What issues? If we know what happened, then
maybe we can calm down the concern that you are selling bad products.
Can you be more specific?
Ranbaxy: What I can say is there were issues with noncompliance
and handling of data. This issue has caused everyone a lot of trouble.
It has been a breach of faith and a breach of contract and once
everything settles down we might need to take legal action against
the CRO. Anything I say now would be a breach of confidentiality.
Strides: We are happy with our CRO — it is approved by Brazil,
inspected by the FDA and WHO. Monitoring of the bioequivalence
protocol is the responsibility of the drug company, not the CRO.
No CRO objects to having a company-appointed monitor in place.
There are absolutely no issues with our bioequivalence studies.
Let me explain the process of developing a product. We do preformulation
studies; we study the compatibility with excipients, do dissolution
tests, etc. We compare with the innovator product. There is no
pharmacopoeia, so there are no reference standards other than by
comparison with the innovator. Twelve months of stability studies
are required by WHO. From the day you identify a product to having
approval is 18 months to 2 years. We are underway with efavirenz
and will be ready by the end of the year.
We have sent stavudine/lamivudine to the FDA. The problem with
FDA has been their inability to accept bioequivalence studies that
were carried out using European innovator products. They don't
have the right of reference. This means every bio study has to
be repeated with U.S. approved innovator product. We just completed
a bioequivalence study with one.
Marie Mendene: There was news in Cameroon that the drugs were
of poor quality. We were embarrassed. What are you doing to address
these concerns in our communities?
Hetero: We have traveled to several countries and are educating
people. We met with the Ministry of Health in Cameroon. We want
to eliminate any ambiguity. We could not survive in this business
if they weren't good quality.
Marie Mendene: We are glad to hear that you have resubmitted
your products to the WHO. But we are concerned about the other
products that you have not yet submitted.
Cipla: Are you aware that WHO hires out inspectors for prequalification?
We have been disillusioned by the type of inspectors coming to
inspect. There are two types of qualification: the facilities and
the products. When we give work to an outside agency, then we need
to have them independently certified. We asked WHO, why not certify
Contract Research Organizations (CROs) too?
Also, WHO does not qualify the active ingredient going into the
end product. So any prequalification is meaningless unless they
also qualify the APIs. Now they are going to start qualifying the
APIs and the cost will double. We will have to produce every API
according to FDA good manufacturing practice (GMP).
Patents
Cipla: After India's independence in 1947, the multinational companies
were very strong in India and we were following the British Patent
Act of 1911. We started fighting to change the patent law and
we succeeded in 1972. We decided you can only patent a process,
not a product, and then only for 7 years for health and food
products. That gave us the legal freedom to make whatever we
wanted. Now Indian companies now control 80% of Indian market.
Unfortunately, as of January 1, 2005, the situation has changed
concerning products invented after 1995. Whatever was known prior
to 1995, we can still produce.
Gopa: Have you assessed the impact of the new patent regime on
ARVs?
Ranbaxy: Most individual ARV drugs are pre-1995. Only patent applications
filed after January 1995 are affected by the new law. The drugs
in our portfolio are okay except for tenofovir and abacavir. But
certain combinations such as lopinavir/ritonavir might be restricted.
Atazanavir will be a problem. If there is a need for efavirenz
in a triple combo, there could be a problem, but most products
in the portfolio will not be affected. We have to take it as it
comes.
German: When world patents come to India that protects products
for 20 years, what will this do to the generics industry?
Strides: Well, you have to find ways to manufacture that are non-infringing.
The cost will be higher, but you will have higher returns because
there will be less competition. But the preferred way will probably
be to get into partnership with voluntary licenses. We will live
with it. This is going to happen and there's nothing we can do
about it. This is happening the world over.
Asia: You say that partnership with the multinationals is
preferred but sometimes the terms of licensing will not be acceptable
if they don't serve the interests of patients.
Strides: Some multinationals are extremely good and others not
so. But getting into litigation is not the way to go. I think non-confrontation
way is the way to go. I'm not rejecting compulsory licensing, but
I have no comment now. I think we should give voluntary licensing
another shot.
Gopa: The other companies said they are going to live with
the new patent regime. What will you do?
Cipla: I think amendment of the patents is a big mistake on the
part of the government. We require a permanent compulsory licensing
system for the developing world. We are willing to pay a 4% royalty,
but I cannot allow a monopoly in a country the size of India. It
is going to be a disastrous situation for India 10 years down the
line. I would prefer an automatic patent: a 5% royalty on net sales
is equivalent to a 25% ownership position.
There should be no monopoly. Evergreening of patents is the most
dangerous thing. AZT was invented in 1963. It was claimed in 1985
as an AIDS drug with a patent until 2005. GSK has said AZT should
only be marketed in combination, with a patent that goes to 2017.
That's 54 years of monopoly for AZT. We should oppose this.
Drugs for Children
Elena: In Romania there are many AIDS cases in children; I
am the mother of a child with HIV; there are no generics, although
the government is obligated to pay for ARVs. I want to know what
is planned for pediatric formulations in Romania and the rest of
the world?
Ranbaxy: Romania follows the European Union, which requires different
kinds of data for registration that we haven't done yet, but we
will.
On pediatrics, I want to have your suggestions on what kinds of
products we should develop. The costs of pediatric drugs are higher.
For example, carrying liquids in glass across the globe raises
the cost. We have dedicated resources in R&D that we can put to
work on developing pediatric formulations.
Polly: What pediatric formulations do you have so far?
Ranbaxy: We have conventional zidovudine, and are working on a
stavudine. These are available in India and produced in Nigeria
for local use. Volumes are very low and economy of scale will be
slow.
Olive: Are you working on a pediatric triple combination?
Ranbaxy: The ratio of the drugs in the combination changes with
the child's weight. We can't get people to agree on the needed
doses, so we decided on a product which will exclude some age groups.
It will apply to a weight of about 20–30kg, but not above
and not below. Some pediatricians agree with this and some don't.
If we develop something that is not necessary we will lose a lot
of time and resources. Another challenge is to create a formulation
that is not a liquid. But then access to clean water becomes an
issue.
Simon: You know that in practice, children are being treated
by crushing adult formulations. This is due to cost and also
lack of availability.
Ranbaxy: That's off-label use. To get it approved, you have to
clinically prove it, and that is where the challenge is.
Polly: What are your plans for developing pediatric formulations?
Strides: We made a proposal to WHO a year and a half ago for a
triple drug pediatric formulation. WHO never got back to us. We
need people to tell us if we are doing the right thing, making
the right doses; but not much has happened. We can develop granules
in sachet, which UNICEF was excited about. Clean water is still
an issue. Temperature and humidity are issues. The granules can't
clump together.
What's in the pipeline?
Svilen: What new medications do you have in the pipeline?
Hetero: The latest is lopinavir/ritonavir and tenofovir.
Simon: Atazanavir is listed in your book. What about the legal
problems?
Hetero: The APIs for atazanavir and tenofovir are absolutely ready
today, but we have to see what will happen with the patent situation.
We can do anything we want in R&D, but for commercialization, patents
are an issue.
Gregg: What else is in the pipeline? We need tenofovir, and
a better formulation of ddI.
Strides: On tenofovir, it depends on the patent mailbox. We don't
want to market these then get into litigation. We want work with
the innovator companies. The best thing is if they give voluntary
licenses, then we will make them. They need to be more considerate
with giving voluntary licenses. There is an advantage for them,
too. The cost of making tenofovir in India would be much cheaper.
It works both ways.
Svilen: What about older products like abacavir and nelfinavir?
Strides: Nelfinavir is in the pipeline. WHO has said not to pay
much attention to abacavir. Also there is less API available. The
cost is prohibitive because the raw materials must be from an approved
source. The Chinese are good at making materials at a low cost
but their standards are not accepted. They don't have DMFs (Drug
Master Files) that are acceptable to WHO or the FDA. So we depend
on a few Indian API makers.
With our soft gel capabilities, we have ritonavir and lopinavir/ritonavir
and saquinavir. Two are prequalified and five more are under evaluation.
We expect prequalification in the next three months. Bioequivalence
studies are completed.
Loon: What are your new products?
Ranbaxy: We are close to introducing lopinavir/ritonavir and nelfinavir.
But these won't be triple fixed dose combinations (FDCs) because
there are problems with some combinations. Second-line is based
on PIs, which have high doses, and frequent doses.
Gregg: The price of generic efavirenz needs to match the price
for nevirapine. Why is there such a great difference?
Ranbaxy: Prices of originator efavirenz were lower than the generic
because our price could not match the innovator's cost. If we start
getting volume we can improve the price. We sold at a loss for
a while to match the innovator until we could lower our costs.
But not much was purchased at 95 cents. If you look at the volume
of efavirenz supplied to Africa, it is very small at this time.
Simon: What about abacavir, zidovudine, 3TC? The market is
for use in TB patients.
Ranbaxy: Abacavir is not widely used because doctors in India
don't like to use it. A small number use it but it is growing slowly.
We found that in Latin America governments are asking for abacavir.
Gregg: Will the patents for tenofovir and FTC stop you from making
them?
Cipla: FTC was known before 1995; tenofovir is 1997. I think we
can make it and see how it works out. I'm a firm believer in the
automatic patent of right. You don't have to ask, you just pay
a fair royalty. Until they joined NAFTA, Canadians were able to
copy any drug they wanted and pay a 2 percent royalty.
I think it is very important to work out what drugs you want for
the future. What are your criteria? T-20 costs $20,000 per year.
I can make T-20 for $5,000 a year. Are you interested in T-20?
You have to look at efficacy and affordability side by side. We
go by what is the easiest to produce, but that may not be what
you need.
Copies of the complete World CAB II Report can be obtained at
www.i-base.org.uk
Are We In It for the Long
Haul?
By Gregg Gonsalves
Many AIDS activists have been enraged by the export abroad of
conservative American morality on sex, drugs and prostitution through
HIV/AIDS programs funded by the U.S. government. Particularly galling
is that it replaces accepted, evidence-based public health policies
with ideology. But if there is one thing this U.S. government hates
more than fags, junkies, hookers, condoms and clean needles, it's
socialized medicine.
Quietly, the President's Emergency Plan for AIDS Relief (PEPFAR)
and other bilateral initiatives are exporting the HMO-ization of
AIDS in Africa and elsewhere on the planet, in which a network
of private institutions are being built up to provide antiretroviral
therapy (ART) to the millions who need it. In the short term, this
will not be a bad thing. Circumventing crumbling or rudimentary
public health systems in developing countries probably means that
more people will get treated more quickly.
However, in the long run the vast investment in non-governmental
and faith-based organizations to provide care will drain whatever
resources are left in the public sector, take governments off the
hook for providing care to their citizens and enforce a fee-for-service
health sector system when the donors eventually tire and move on
to other crises in these countries leaving only those who can pay
for it with the care they need to survive.
If it's good enough for the United States, it must be good for
Africa, Asia, and the Caribbean. Right? Sadly, the American model
of health care will leave close to a third of the population of
this country uninsured by 2013.
The sustainable scale-up of antiretroviral therapy in the developing
world depends on the simultaneous scale-up of the public health
sector in these countries, yet this is a task that repulses the
United States and many other donor countries, as they try to pare
down their own lavish welfare states. Furthermore, in 2005, demanding
health care as a public right and a public good is virtually a
revolutionary act. Most people are just too busy trying to survive
to speak up and demand what they need.
The difficulty of the current moment is that there is no clearly
described acceptable alternative to the vertical programs that
are rolling out all across the globe. Although the Global Fund
to Fight AIDS, Tuberculosis and Malaria (GFATM) is funding public
sector programs against these diseases (which is a welcome relief
from the American franchising of health care), it too has the potential
to distort the health care landscape in these countries since it
isn't a sector-wide approach.
I recently asked a health systems researcher in Mumbai to describe
a middle ground between the short-term need to get as many people
on ART as quickly as possible and the long-term need to strengthen
health systems. I was told that these were incompatible goals.
In fact, this is the mantra of many health systems researchers
and this is as unhelpful as the privatization agenda being promulgated
by the U.S. We need to find the middle ground and find it quickly.
In several reports over the past year, the drastic shortage of
doctor, nurses, clinical officers, community health workers, has
been described as one of the key factors in slowing the scale-up
of antiretroviral therapy. But this shortage is also being acknowledged
as one of the broader problems facing the health sector in developing
countries. It is here that the twin needs to roll out ART quickly
and to strengthen the overall health sector is being recognized.
The recommendations for dealing with the shortage of health care
workers though are varied and some have the potential of once again
distorting the health care environment in developing countries.
In particular, a bill proposed by Senator Bill Frist would send
doctors as U.S. federal employees and private sector professionals
as volunteers to developing countries. This new Global Health Corps,
instead of providing incentives for local health workers now migrating
in droves to richer countries to stay home, is yet another way
that the U.S. will further weaken local capacity. As UNAIDS' Peter
Piot has said: "Isn't it a bit absurd that we then send nurses
and doctors to fill slots in Africa that have been emptied by our
recruitment policies?"
The dialogue on the shortage of health care workers in developing
countries has put health systems and HIV/AIDS experts together
to identify solutions to this problem. We now need a broader discussion
on how to strengthen other aspects of health systems as we scale-up
ART. HIV therapy is a lifetime commitment and so should our commitment
to seeing that AIDS is the beginning of creating better health
for all across the globe. It is only within functioning health
systems that ART can be sustained over the long haul.
© 2005 Gay Men's Health Crisis
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