The first ever HIV drug, AZT, has a chequered history: its toxicity killed patients yet it paved the way for successful med combos. What next for the drug as it comes off patent in the UK?
Words Chris O’Connor
This
month, AZT, the first ever HIV drug, loses its patent protection in the UK.
In simple terms, this means AZT’s brand owner, GlaxoSmithKline (GSK),
can no longer keep the drug’s formula to itself, opening up the market
for other drug companies to produce generic versions and undercut the price.
In the US, where Retrovir (AZT) came off patent in September 2005, Ranbaxy
has already entered the market with a generic version.
But why should anyone, apart from drug companies and the NHS, care who makes
the drug? Surely as long as it works, it doesn’t really matter? Patenting
of HIV drugs generates strong emotions in a way rarely seen with drugs for
other serious conditions like diabetes and cancer. The reason lies in the
history of AZT’s development, which has been no spectator sport. People
with HIV have paid with their lives.
Failed
cancer drug
AZT, or azidothymidine, was first developed in 1964 as a cancer drug by Dr
Jerome Horwitz at Wayne State University, Detroit. The drug was developed
with funding from the US National Institutes of Health, a
factor that later led a number of court cases questioning Burroughs Wellcome’s
exclusive rights to make and sell it. Wellcome filed a patent to protect AZT
in 1985 after lab results showed that it appeared to retard the development
of HIV. A population decimated by Aids started demanding speedy access to
the new drug. A Reaganite government agreed and a large-scale drug trial,
ACTG 019, was arranged, bypassing many of the regulatory barriers. The parent
companies of Glaxo Wellcome and Smith Kline Beecham merged in 1995.
Fast-track optimism
To great excitement, the trial reported in the New England Journal in 1987
that AZT could delay progression to severe symptoms of HIV or Aids. That August,
former US health secretary Louis Sullivan declared: “Today we are witnessing
a turning point in the battle to change Aids from a fatal disease to a treatable
one.”
The drug received fast-track approval for people with advanced HIV before
any long-term toxicity trials in animals had been completed. The very next
day Burroughs Wellcome’s stock rose 32 per cent. But the cost of AZT,
around $7,000 for one year’s supply, enraged activists and ACT UP (Aids
Coalition To Unleash Power) in the States, staged a number of protests. By
September the cost of the drug was cut by 20 per cent.
Across
the Pond
Although not licensed in the UK until 1992, many people with HIV here had
their first taste of AZT through the controversial Anglo-French Concorde trial
in 1988, when the drug quickly became a byword for the good, the bad and the
ugly side of HIV medication. Whereas the earliest studies tested AZT in people
with Aids, Concorde studied AZT in people who had not yet developed symptoms,
to see if the drug could slow HIV progression.
HIV positive since 1984, UK Coalition’s Andrew Little first took it
in 1989 as part of Concorde. When asked about AZT 17 years on, he says quietly:
“Has it been that long? It’s the one we loved to hate.”
“My partner and I both joined the trial. I’d been told I wouldn’t
live beyond 1987; I was living on borrowed time. I didn’t expect a cure.
It was the beginning of the notion that I’d rather die fighting the
thing than die of the thing itself.”
Not so double-blind
Concorde was a double-blind trial, with some patients receiving AZT and others
a placebo. Neither the researchers nor the patients knew what they were taking.
In the States there were accusations that the double-blind ACTG 019 was compromised
because it was alleged it had been ‘un-blinded’ by patients who
quickly realised they were either on AZT or taking placebo.
The same could have been said about Concorde. “My partner had very bad
side effects,” said Little, “so we figured he was on it. I had
no side effects, so I could have had AZT with no side effects or placebo.
“What happened next could have been intuitive or just plain lucky. A
friend, who was dying of Aids at the end of 1989, made me promise to him that
I would take half of my partner’s drugs. ‘Give yourselves half
a chance,’ he said, ‘take half of it’.” In May 1990,
ACT UP was protesting again, this time about the drug itself. Two years earlier
they had demanded fast-track access, but now many of the gay activist leaders
who had experienced an initial good response to the drug were finding it was
no longer working and that it was also highly toxic. Some people were unable
to tolerate it at all, suffering vomiting, muscle pain and searing headaches.
Many needed blood transfusions.
A
bombshell hits
By 1993, the Concorde trial showed that there was no benefit in terms of survival
if people started AZT before they had symptoms, compared to waiting until
symptoms developed. Simply put, early use of AZT alone did not slow down the
progression to Aids or improve survival. The results were a bombshell.
“The Concorde results were a shock,” said Andrew. “At that
time I had bought into the philosophy that I would rather die trying to beat
this thing. If the drugs work along the way, so much the better.”
In the UK, the findings triggered a picket outside Terrence Higgins Trust
premises staged by the group Gays against Genocide, angered by the charity’s
publication in 1991 of four glossy brochures aimed at people with HIV or Aids
in conjunction with Wellcome with their logos side by side. The picket resulted
in the imprisonment of two HIV positive activists, Karl Burge and Michael
Cotterell.
Andrew Little said: “I’ve never had any truck with people being
angry with the drug companies over AZT. Later on, when we started fighting
for access to the drugs, there was a quid pro quo: they may or may not work.
We went into it with our eyes open, they kept some people alive longer.”
Legacy
of suspicion
Not everyone agrees. Long-term survivor Michael Crookes never took AZT but
had first-hand experience of it in trials. “I started 1987 on a high:
a fabulous job as a classical dancer and a partner, Ashley, I adored.”
Michael remembers the Concorde trial vividly: “AZT was more or less
thrust down patients’ throats and they were told not everyone was going
to know whether they were getting it. I witnessed violent physical changes
and severe loss of quality of life that would have become impossible for Ashley,
had he lived.” Ashley, who took AZT, died of chronic renal failure in
1989. For Michael, and many like him, the lasting legacy was one of suspicion.
“I made a pact with myself: never take any HIV treatments from doctors,
until I have no other choice.” Dr Jyoti Dhar, an HIV consultant at Leicester
Royal Infirmary, recently came across some old documents on AZT when researching
a presentation: “We were
discussing whether people should be setting their alarms for a sixth dose
of AZT that day; it’s unbelievable now,” she says. Dr Dhar also
remembers how people would take doses of up to 1.2g a day in 1990. Today’s
typical dose is 250mg or 300mg, twice-daily.
A long-term survivor
Despite these setbacks and the apparent failure of AZT monotherapy (the drug
as a single therapy), the first ever HIV drug proved to be a long-term survivor.
In 1992 the US FDA (Food and Drug Administration) approved use of ddC (Hivid)
in combination with AZT for adult patients with advanced HIV showing signs
of immune deterioration; the first successful use of combination therapy for
the treatment of Aids. Two years later, another study showed AZT reduced the
transmission of HIV from HIV positive women to their babies by two-thirds.
With the advent of protease inhibitors and HAART (highly active antiretroviral
therapy) in 1995, AZT got a new lease of life. This time in combination with
other potent drugs that fought the virus in a
different way. Despite its controversy, AZT steadfastly remained at the frontline
of the armoury of HIV treatments.
AZT: the money spinner
Few doubt that AZT has not only made a massive contribution to the fight against
Aids over the last decade but also to GSK’s profits. That said, GSK
spokesman Chris Hunter-Ward described the estimated £41m in sales last
year as “minimal”. AZT’s ‘spin offs’, the co-formulations
Combivir (AZT/ 3TC) and Trizivir (AZT/3TC/abacavir) last year made £593m
and £303m respectively.
But branded AZT no longer has the market place to itself. Generic manufacturers
of the drug are expected to inject stiff price competition. GSK acknowledge
that in Europe and the US it will be difficult to maintain the current cost
of AZT. Hunter-Ward said: “Prices tend to drop when things go generic,
but it shouldn’t have an impact on Combivir. People could take separate
pills but that would be a step back.”
How great that drop could be is suggested in the comments of one buyer in
the US. He told PN he was sourcing the generic brand Viro Z from Ranbaxy “for
10 per cent of what AZT costs”.
AZT activism of the 80s has had a long-lasting effect on the pricing of other
drugs, especially in the West. Recently a manufacturer of thalidomide, a drug
that worked poorly for HIV, discovered that it could fight certain types of
cancer. When priced for treating HIV/Aids patients it was $6 for a 50mg capsule.
The cancer-treating capsule, exactly the same as the HIV one, was priced at
$11. The company’s chief executive told PN: “Our pricing people
said if you charge more than $3,000 per year, they (HIV/Aids activists) will
show up at the door.”
Beginning
of the End?
AZT is entering a new stage. In the US, the price of Retrovir when it hit
the market was $10,000 a year. This has dropped to around $2,200 and there
may be more cuts to come.
Steve Sherman, co-ordinator for an Aids Drug Assistance programme in North
Carolina, told PN his programme was obligated to source the lowest prices
for meds. It now purchases generic AZT, Viro Z, from Ranbaxy, unless a clinician
specifies otherwise.
“We are now dispensing a product that is 10 per cent of the cost of
branded AZT (Retrovir). We have no concerns from clinicians or patient groups.
As far as Combivir is concerned, Sherman has been the subject of much discussion
among US drug assistance programmes.
“The pill burden is important. We have decided, though not mandated,
that’s it’s the clinician’s decision if they prescribe Viro
Z and 3TC separately, or Combivir.”
Sherman’s district in North Carolina has 800 people in a programme that
will run out of money in six months. “Any nickel we’re able to
save on one drug allows us to serve more clients and provide more medication.”
Other
challenges
In South Africa, where AZT is a second-line treatment, GSK was forced by the
South African government to license it to Aspen Pharmacare and MedPro generic
producers. They are also entitled to export generic AZT to other sub-Saharan
countries. Jonathan Berger, a lawyer with the South African Aids law project,
told PN that South African generic AZT had not been reaching the other African
markets because of registration problems in those countries. According to
the Desmond Tutu Clinic in Cape Town, Aspen AZT is priced at 80 Rand (£7.40)
in public clinics for a month’s supply of 300mg tablets. Retrovir in
public access is 124 Rand (£11.40).
The US-based Aids Healthcare Foundation (AHF), which runs clinics across sub-Saharan
Africa, has accused GSK of not producing enough Retrovir to meet increased
demand. AZT requirements have been boosted by the US aid plan, PEPFAR, which
has increased its funding for ARVs in the developing world.
AHF President, Michael Weinstein, said: “It’s obvious: it’s
not a coincidence that this happens at this point in time, as patents expire.
They (GSK) were producing in ample supply until they lost their stranglehold."
AHF claim that GSK, expecting increased competition from generics and a decrease
in prices, intended to profit before the patent expired. However, generic
manufacturers have been unable to meet the increased demand for the drug leading
to a shortfall in supply. A GSK spokesperson told South African HIV news service,
PlusNews: “We have seen an increase in orders since PEPFAR, we think
that is great news, but we didn't know how fast PEPFAR would be implemented
and how fast governments would place orders.”
A
final fall from grace?
Anticipating the loss of the AZT patent in the UK, the British HIV Association
(BHIVA) is also taking a fresh look at drug pricing. The 2005 guidelines discuss
three co-formulated drugs, Combivir, Kivexa and Truvada, in the context of
pricing, and note: “While [co-formulation] adds to the
convenience of the regimen, the committee did not feel that this was sufficient
to pay a large premium for a combination pill rather than using the components
individually.”
But ultimately AZT’s fall from grace will be triggered by clinical considerations.
Last year, BHIVA revised its guidelines so AZT-containing combos were no longer
recommended for someone starting HIV therapy. This was because growing evidence
suggests AZT may contribute to fat loss. The rationale was that any cost-savings
achieved by having access to generic AZT would be cancelled out by the high
cost of treating lipoatrophy (body fat loss). The guidelines now recommend
that people already taking AZT should be offered the option of switching to
tenofovir or abacavir. “Until the situation becomes clearer, the increased
likelihood of lipoatrophy mitigates against the choice of AZT as initial therapy,”
they state.
Ed Wilkins, HIV consultant at North Manchester General Hospital, who sits
on the board at BHIVA, said he, as a doctor, has no problem about using generics:
“But we are at the behest of the PCT. If someone was on tenofovir and
AZT, and it was cheaper, we would use generic AZT.” Wilkins predicts
that when 3TC (the other active drug in Combivir) comes off patent in several
years time, the London HIV consortium might persuade someone to make a formulation
of generic AZT and 3TC in a clinical setting.
“I think it [AZT] is going to be an ‘also-ran’. Lipodystrophy
concerns are always going to be there and this can be very costly to treat.”
However,
AZT is still very much a part of BHIVA guidelines when it comes to pregnancy.
Dr Jyoti Dhar told PN: “We have delivered over 100 babies with positive
mothers and in the last six years only two were born with HIV. The success
rate is very gratifying, and that partly has been down to AZT.”
Activism and AZT go hand in hand. The history of the drug, and the HIV epidemic
it shadowed, set the template: find or develop, then patent new drugs, price
them high and market them aggressively, but then risk the wrath of highly
politicised Aids activists making waves globally. But the relationship remains
schizophrenic.
As Joan Tallada of European Aids Treatment Group puts it: “I have conflicting
feelings about AZT. I feel that it is a symbol of greed and of the mistakes
we made as activists and doctors. On the other hand, combining it with other
drugs saved many lives and opened up the path for the nukes (NRTIs). For many
people this meant life.”
