TRACKING DRUG RESISTANCE IN SOUTH AFRICA
Andrew McIntyre on Thabo Mbeki’s determination to buck conventional wisdom
on AIDS
By Andrew McIntyre
The Australian Financial Review 31 March 2000
In late October last year, South African President Thabo Mbeki, under
pressure to supply the anti-AIDS drug AZT to thousands of rape victims in
the country, let off a bombshell by strongly criticising the drug and
declaring in Parliament that there exists a large volume of scientific
literature alleging, among other things, the toxicity of this drug is such
that it is in fact a danger to health".
While the news was briefly reported in Australia and elsewhere, the extent
of the reaction and the furious debate that has followed in South Africa,
has largely escaped international attention.
Mbeki claimed that AZT was being challenged by court cases in the US,
Britain and South Africa and asked for an official inquiry into the issue
by the Minister for Health, Dr Manto Tshabalala-Msimang.
His announcement produced bafflement and intense anger amongst health
professionals who maintain that AZT is safe and believe Mbeki has
political motives. The drug’s manufacturer, Glaxo-Wellcome, responded that
it was unaware of any such lawsuits. AZT is the mainstay of international
efforts to treat AIDS patients and to prevent the transfer of the virus
from HIV positive mothers to their babies.
Dr Joseph Perriens, the head of the care and support division of the UN
AIDS program in Geneva, suggested Mbeki "inform himself better... [and]
recast the debate in terms of cost". Dr Salim Abdool Karim, the head of
AIDS research at the Medical Research Council, said, "I think [that] if
the President doesn’t want to provide AZT, he should find an excuse based
on fact."
The South Africa Government has come under increasing pressure to provide
expensive Western drugs like AZT that it cannot afford. There has been a
bitter dispute over the rules which protect worldwide patents of
pharmaceuticals. However, Mbeki’s questioning of the drug was initially
sparked by an Australian research group in Perth, headed by Eleni
Papadoupoulos, which claims its work shows that AZT is, pharmacologically,
a failure.
The drug manufacturers and clinical AIDS specialists claim that the drug
improves "quality of life" and can reduce transmission of HIV. But Mbeki’s
statement has added momentum to critics of AZT who argues that the cure
might just be worse than the disease. There is a growing number of
scientists and medical professionals claiming that not only is there no
clear scientific proof that AZT kills HIV or cures AIDS, but that there is
ample evidence that it kills humans.
As evidence, they cite the 1994 publication of results from the Concorde
trial, the most thorough double-blind randomised comparison of two
policies of AZT treatment. This involved 1,749 symptom-free, HIV-infected
individuals from centres in the UK, Ireland and France. The 347 deaths
during the trial outnumbered the total of those in all other published
trials in symptom-free and early symptomatic infection. The results showed
there was no statistically significant difference in clinical outcome
between the two therapeutic policies. In 1995, extended results of the
Concorde study showed a significant increased risk of death among those
patients treated early. However, despite this evidence that patients
treated with AZT may continue to develop AIDS diseases, that the
side-effects of AZT may mimic AIDS and that AZT given to non-HIV-infected
babies causes the AIDS-defining pneumonia PCP, AZT continues to be the
most commonly prescribed anti-HIV drug. Glaxo-Wellcome has described the
Concorde study as flawed and said that its findings would not affect
medical practice.
However, there are some eminent professionals ringing alarm bells. Dr
Donald Abrams, professor of medicine and director of the AIDS program at
San Francisco General Hospital has observed, "I have a large population of
people who have chosen not to take any anti-retrovirals ... I’ve been
following them since the very beginning... They’ve watched all of their
friends go on the antiviral bandwagon and die." What united long-term
survivors of AIDS was their resolve not to take AZT and other
anti-retrovirals.
An article in last year’s June New Scientist reported that French doctors
had linked a rare but fatal childhood neurodegenerative illness to
exposure to AZT while still in the womb and during or shortly after birth.
Dutch AIDS specialist Kees Brinkman, of Amsterdam’s Onze Lieve Vrouwe
hospital, claims that several other side-effects may be explained by the
drug’s ability to block the production of mitochondria, the
energy-producing, semiautonomous organelles that are found in every living
cell in the human body. "When continually assaulted, only weakness and
eventual death can follow," he said. In a paper in Lancet last year, he
and his colleagues added that there were other common side-effects, such
as nerve and muscle damage, pancreatitis and decreased production of blood
cells. Brinkman concluded, "I strongly believe that [these anti-viral
drugs] are much more toxic than we considered previously."
An Italian study published last May in the journal AIDS claimed that
HIV-positive mothers who took AZT had children with "a higher probability
of developing severe disease or severe immune suppression and a lower
survival [rate]" than those whose mothers had refused this treatment. A
September Lancet article reported the cases of eight children with the
obscure-sounding condition of "mitochondria dysfunction", two of whom
died.
Building on this evidence, AZT critics say that the very symptoms of AIDS
we have become familiar with, particularly severe wasting, may not be
caused by the AIDS virus attacking the immune system but by the very drug
claimed to cure it. If it is true that the treatment remains better than
the disease, it is reasonable that doctors and researchers continue to
recommend AZT. But could they be wrong? AZT was originally designed to
kill cells indiscriminately. And to make matters worse, most people who go
onto anti-retrovirals, including AZT, are completely symptom-free at the
start. In fact, the main targets for the makers of these drugs are those
without symptoms.
Dr Stephen Kent, senior research fellow at the AIDS pathogenesis research
unit of the Macfarlane Burnet Centre for Medical Research in Melbourne,
argued recently in The Australian (February 4) that the effectiveness of
these drugs in reducing morbidity and mortality had been shown in
countless studies since 1996. Dr Kent described the belief that HIV was
not the cause of AIDS as a conspiracy with the potential to ‘mislead
vulnerable people who are struggling with life-saving but
difficult-to-manage HIV treatments".
Sceptical scientists claim the contrary — that there is still no study
proving that any of these cocktails, separately or together, can extend
life. In South Africa, material critical of AZT has become central to the
debate, with claims that senior members of the AIDS medical establishment
are unaware of the latest scientific literature. In a pointed rebuke of Dr
William Makgoba, head of the Medical Research Council and a personal
friend of Mbeki’s, the President said, "What do you do if professors won’t
read articles about subjects they write about?"
Dr Kent has described the debate questioning existing treatments and
research as "irrelevant" and "a disgraceful waste of time and resources".
In a South African TV debate, a Glaxo-Wellcome representative said, "We
find it unusual that these allegations of safety aspects on AZT have
suddenly arisen in South Africa. They have not surfaced in any other
country around the world, in over 100 countries where the drug is
registered." To which the South Africa’s health minister replied "If it is
the first time, then somebody has to start"
With billions of dollars in drug-company profits and research grants at
stake, not to mention reputations, Mbeki is under enormous domestic and
international pressure. Just two weeks ago his office bitterly accused
Western drug companies of enriching themselves from the AIDS epidemic and
compared them to warmongers "who propagate fear to increase their
profits". In the face of nearly 20 years of research and the largest
amount of money ever spent on a single virus (with precious little to show
for it), it is surprising that the Western media is not taking more of an
interest in these difficult questions.
Andrew McIntyre is a Melbourne writer who has written on HIV and AIDS for
several years.
On Fri, 18 Feb 2005 20:46:28 -0500, "PaulKing"
<aimulti@aimultimedia.com> wrote:
Wow. This is a real piece of yellow journalistic bullshit!!!
Phew....let's begin.
OK--so this was written nearly 5 years ago. Recently, unfortunately,
he reiterated his resistance to access to ARV for pregnant women.
http://news.bbc.co.uk/1/hi/world/africa/1808986.stm
But he clearly seems to think HIV exists and causes AIDS at this
point. He isn't that stupid.
Yeah. Boy, is she ever a piece of work.
Ah, this was inaccurate even then. AZT monotherapy is used for
preventing mother-to-child transmission. Or a single dose of
nevirapine. It works pretty well for that (AZT) but may result in the
mother developing resistance.
LOL. If Mbeki DID buy the ravings of Papadoupoulos, he is a bigger
idiot than I thought. She's never actually done any research!! Just a
lot of armchair theorizing.
However, there IS a big issue with regard to costs of the drugs, and
the pharma held notion that intellectual property rights trump human
life.
Wow. Dead cold lies here.
Concorde studied AZT monotherapy and discovered it doesn't do much for
people as a monotherapy. No one disputes that.
However, combinations of antiretrovirals have since proven that the
drugs do work to slow disease progression and vastly reduce mortality.
So this is disingenuous in the extreme.
This is probably a very old quote. A lot of people wait to do ARV and
now the data show that waiting until the CD4 count falls between
200-300 is probably the best time to start. Early intervention is not
really all that useful.
What data?
The drugs ARE toxic. No question. AIDS is MORE toxic. It's about risk,
benefit and limitations.
It's not so obscure any more. This is why the use of nutritional
supplements to minimize mitochondrial damage make sense and require
further clinical evaluation.
This is also a distorition of current clinical practice in places
where ARV is available. He acts like AZT is the only HIV medicine.
Idiot.
Dr. Kent is correct.
Nonsense....see:
The fact that AIDS is killing so many young adults in Africa should
give them a clue.
Mbeki should be under pressure. His policies are as sick and insane as
the pharmaceutical industry's blocking of generic antiretrovirals.
Well, he should retire. He's about as dumb as Gina Kolata. Maybe
dumber, if that's conceivable.
Abstracts relevant to my comments below.
George M. Carter
**
Vermund SH. Prevention of Mother-to-Child Transmission of HIV in
Africa.Top HIV Med. 2004 Dec-2005 Jan;12(5):130-4.
The University of Alabama at Birmingham, Birmingham, AL, USA.
HIV infection and mortality rates in African children are
astoundingly high. Risk factors for mother-to-child transmission of
HIV include maternal plasma viral load and breastfeeding. With regard
to the latter, current data indicate that mixed feeding (breastfeeding
with other oral foods and liquids) is associated with the greatest
risk of transmission. Studies are under way to determine if exclusive
breastfeeding with rapid early weaning can reduce transmission rates
in the absence of exclusive formula feeding for all infants. Perinatal
transmission rates have been dramatically reduced with the use of
single-dose nevirapine, but this strategy protects only approximately
50% of infants, and more than 75% of women receiving nevirapine
develop a major nevirapine resistance mutation. In developed areas of
the world, antiretroviral therapy has reduced perinatal transmission
by more than 90% compared with 1993 rates. Improved HIV-related care
for HIV-infected women in Africa is needed to reduce rates of HIV
infection in children and to prevent maternal mortality. This article
summarizes a presentation by Sten H. Vermund, MD, PhD, at the
International AIDS Society-USA course in Chicago in May 2004.
**
Imamichi T. Action of anti-HIV drugs and resistance: reverse
transcriptase inhibitors and protease inhibitors. Curr Pharm Des.
2004;10(32):4039-53.
Applied and Development Research Program, National Institute of
Allergy and Infectious Diseases at Frederick, Science Applications
International Corporation-Frederick, Inc., Frederick, MD 21702, USA.
timamichi@niaid.nih.gov
Currently, 20 drugs have been approved for Human Immunodeficiency
Virus type-1 (HIV-1) clinical therapy. These drugs inhibit HIV-1
reverse transcriptase, protease, or virus entry. Introduction of a
combination therapy with reverse transcriptase inhibitors and protease
inhibitors has resulted in a drastic decrease in HIV-1 related
mortality. Although the combination therapy can suppress viral
replication below detection levels in current available assays, low
levels of on-going viral replication still persist in some patients.
Long-term administration of the combination therapy may increase
selective pressure against viruses, and subsequently induce emergence
of multiple drug-resistant HIV-1 variants. Attempts have been made to
design novel antiretroviral drugs that would be able to suppress
replication of the resistant variants. At present, several
investigational drugs are being tested in clinical trials. These drugs
target not only the resistant variants, but also improvement in oral
bioavilability or other viral proteins such as HIV-1 integrase,
ribonuclease H, and HIV-1 entry (CD4 attachment inhibitors, chemokine
receptors antagonists, and fusion inhibitors). Understanding
mechanism(s) of action of the drugs and mechanisms of drug resistance
is necessary for successful designs in the next generation of
anti-HIV-1 drugs. In this review, the mechanisms of action of reverse
transcriptase- and protease-inhibitors, and the mechanism of
resistance to these inhibitors, are described.
**
Pereira CF, Paridaen JT. Anti-HIV drug development--an overview. Curr
Pharm Des. 2004;10(32):4005-37.
Eijkman-Winkler Center, Hp G04.614, University Medical Center
Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
c.f.pereira@lab.azu.nl
Highly active antiretroviral therapy (HAART) has markedly
decreased mortality and morbidity in the developed world. HAART
consists of a combination of three or more of the following classes of
antiretroviral (ARV) drug: reverse transcriptase inhibitors, protease
inhibitors and a recently approved fusion inhibitor. However, HAART
cannot completely eradicate HIV from the body, results in long-term
toxicity and eventually leads to the emergence of drug-resistant HIV
strains. These problems prompt the search for potent new drugs that
are active against drug-resistant viral strains and that can safely be
combined with other ARV drugs. The aim of this review was to give an
overview of new compounds in preclinical or early clinical development
that interact with various steps in the HIV life cycle: virus-cell
attachment; gp120-CD4 binding; gp120-coreceptor binding; viral fusion;
viral assembly and disassembly; reverse transcription; nuclear import
of the pre-integration complex; proviral integration; viral
transcription; processing of viral transcripts and nuclear export;
assembly of new virions; cellular factors involved in HIV replication.
There's lots more...
