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Past Issues
Volume 15, number 6
June 2001
Contents
Justice Cameron Speaks
South African jurist's address to GMHC audience, June 11, 2001
How to Read a Scientific Paper
The final installment of "How To Read A Scientific Paper"
Bare Bones to Cell Phones...
There are many ways to treat. A Treatment Issues editorial
Life, Health and Justice
in the AIDS Epidemic
By Mr. Justice Edwin Cameron
Supreme Court of Appeal, South Africa
It is a very particular pleasure and an honor to be speaking at
GMHC. Summer in New York City is a wonderful time. But, for the
gay men of this city, the summer of 1981 was not. It was a time
of disquiet, alarm, panic and increasing horror as the realization
spread that a new disease was affecting growing numbers of the community.
If we travel back over twenty years to August 1981, when Larry Kramer
hosted the first meeting that lead to the founding of GMHC, it is
hard to imagine the sense of devastation that beset the founders
of this organization. The bodies of gay men were being marked and
crippled and crumpled by a new syndrome.
What was more, their infirmity and death seemed to threaten the
life of the gay body politic itself. All that the boisterous ascendance
of gay liberation had attained since the late 1960s seemed at peril.
Not only were gay men themselves threatened with debility and death
on an as yet unknowable scale, but the new disease portended public
opprobrium, fear and revitalized hatred and prejudice of fearful
dimensions. The notion of homosexuality as a contamination, a disease,
a sinful abomination punished by nature and the deity, seemed to
have received conclusive microbial and epidemiological support.
It was the challenges arising from this stark and frightening situation
that GMHC was created to meet. GMHC was founded on certain signal
moral premises and practical insights. They were that —
- inaction breeds despair;
- despair leads to defeat; and
- in the face of AIDS, defeat could only mean death.
GMHC was therefore born from practical necessity. But however dire
the situation its founders faced, its objectives were bathed in
hope. Activism in its essence implies a recognition that the world
is wrong and, together with that, a determination to change it.
More importantly, activism is premised on a belief in our own and
others' capacity to change what is wrong. It is this belief that
makes many activists inspiring, and it is their conduct in pursuit
of that belief that gives us hope.
So it was, and so it still is, with GMHC. Activism lies at the
core of GMHC's commitment in the AIDS epidemic over the last twenty
years. And it is the tradition of principled activism that must
lie at the core of our response to the epidemic in the next twenty
years.
There have been fundamental changes since those dark days of 1981.
AIDS no longer is what it seemed then, a "gay plague." It is a heterosexual
"plague" that passes over cultures and continents and sexuality
and age and gender. Overwhelmingly, today, the most brutal impact
of AIDS is felt amongst the poor populations of Africa and elsewhere
in the third world.
The current demography of the epidemic is increasingly reflected
in a small mirror within North America itself, where poor and relatively
marginalized inner-city communities, mostly black, account for an
unsettling preponderance of new infections1; and it is
to be noted that GMHC, true to its activist roots, has confronted
this demographic change directly and truthfully. It has transformed
itself from a sectoral organization serving an embattled gay, mainly-white
community, to a cross-sectoral organization serving embattled, deprived
and marginalized communities regardless of gender and color and
orientation.
I said "a small mirror." That is because by any standard the preponderant
reality of this epidemic is now located in Africa. New Yorkers who
have died of AIDS number about 70-75,000. That is about one-fifth
or one-sixth of the total number of Americans — some 448,0602
— who have died of AIDS. In the whole of North America there
are estimated to be fewer than one million people living with HIV
and AIDS, with about 40,000 new infections per year.3
Dismaying as these figures are, the bigger epidemiological picture
dwarfs them. UNAIDS estimates that, worldwide, 22 million people
have already died of AIDS. This makes AIDS, in the simple words
of Dr. Anthony Fauci, "one of the most destructive microbial scourges
in history." As the Harvard Consensus Statement of March 2001 put
it, AIDS is "the worst worldwide pandemic in 600 years."4
The problem with AIDS in Africa has always been one of scale. The
figures numb comprehension. The statistics of death, debility, of
orphans, professionals, mothers, rural workers, infants, pregnant
women, the projections of economic decline and industrial losses
and systemic collapse, threaten to overwhelm our capacity for sympathetic
imagination. At the end of 2000, a national antenatal clinic HIV
sero-survey in my country showed that 24.5% of pregnant women presenting
for treatment at HIV clinics were infected with HIV. In the Manzini
district of Swaziland, a small neighbor of South Africa, the prevalence
was 41.0%. These figures reflect an agonizing reality throughout
Central and Southern Africa5, where more than two-thirds
of the world's estimated 36-38 million persons with HIV/AIDS live.
Nearly 10 million children in Africa have been orphaned by AIDS.
My country has the world's highest population of people with HIV/AIDS
— nearly 5 million, including nearly 20% of the population
between 15 and 45. Last year alone it was estimated that 350,000
South Africans died of AIDS.
If Larry Kramer could term AIDS in America a "holocaust"6,
then the situation elsewhere defies the capacity of language to
describe it.
Just as the known demography of the epidemic was shifting from
the gay communities of the white north to the black communities
of sub-Saharan Africa, a second change came about. It was even more
momentous than the first. It was the breakthrough in medical treatment,
heralded in December 1995 when the Food and Drug Administration
licensed protease inhibitors for the first time.7 Medical
science at last seemed resurgent; and real hope arose that HIV infection
could be treated and contained and possibly even defeated in the
longer run.
The new drugs are not a miracle. But they are very close to miraculous.
They have conferred the gift of life and wellness on many millions
with HIV and AIDS who previously faced only the slow degeneration
of cancers and infections and fungal outbreaks and weight loss and
vital organ collapse that foreshadowed death.
The statistics here are as vivid as those of demography8
— sickness and death from AIDS have been reduced dramatically;
lives are being saved and quality of living restored; families,
couples, communities that faced premature bereavement have been
made whole again.
Yet this hope has not reached sub-Saharan Africa and other communities
in the developing world. In the midst of hope, a calamity of huge
proportions threatens them. For them, the reality of AIDS today
is as stark and fearsome and life-depriving as what confronted the
gay men of New York City twenty years ago. For the overwhelming
majority of poor Africans, AIDS still means stigma, suffering and
death. For them treatment remains inaccessible. Death rates are
rising. HIV prevalences continue to defy acceptance or belief. Hope
is not a word that lies on their tongues.
In my own life I have felt these facts with pressing force. As
an affluent white gay man, on a continent where the epidemic most
acutely affects poor black heterosexual women, I discovered in the
mid-1980s that I was infected with HIV. I experienced the dread,
the fear and the self-loathing that internalization of the meaning
of infection entails.
I exercised my entitlement to silence because I was terrified of
the consequences of disclosure. I fought against stigma and discrimination
and for equality and justice in the epidemic. But I did so as a
human rights lawyer involved in a larger struggle for justice within
my country. As someone who was myself living with HIV I found the
prospect of disclosure too daunting.
There were too many battles within myself, within my own mind and
my own body, to feel that I had the strength to fight off, also,
the prejudice and stigma I feared if I made my status known as someone
living with HIV.
The primary battle for me was to try to stay well — and I
hoped, against hope, that I would do so. But, like too many others,
my body's own defenses eventually proved ineffectual against the
virus. In October 1997 — twelve years and six months after
I was infected — I fell seriously ill. I had four of the symptomatic
markers of AIDS. I felt death in my lungs, death in my mouth, death
in my throat and in my limbs and muscles and guts.
But as a relatively affluent professional, on the salary of a judge
I could afford to start triple combination therapy. This I did in
November 1997. Within weeks, the drugs that I was taking contained
and repelled the virus. I started to recover my strength and vitality
and life interest. I gained weight. I could exercise again. I could
climb the two flights of stairs between the judges' common room
and my 8th Floor Chambers in Johannesburg without having to stop,
gasping for breath, at every landing.
I experienced, as never before, the awesomely simple and momentous
drama of being alive. I have been blessed by good health and vigor
these last three and a half years, when, without the drugs, if I
had been a statistic on the median of gay men in their mid-40s after
the onset of full-blown AIDS, I would have died some time late last
year.
I contrasted my affluence and privilege, my protection and support,
with that of other South Africans who were poorer than me. One of
them, Gugu Dhlamini, disclosed on 1 December 1998 that she was living
with HIV. Three weeks later, her fellow township-residents stabbed
and stoned her to death. I felt I had to speak publicly about privilege
and protection and how these had conferred life on me, when millions
of others, no less entitled to life and health than I, faced only
debility and death. With the assurance and impetus and energy that
a successful drug regimen gave me, I was able to do so in April
1999.
I have therefore been more than a spectator in the debates about
drug access and equity in Africa. I have been a beneficiary of the
iniquity that gives life to the affluent and the well-connected,
and withholds it from the poor and the powerless. As a white and
privileged African, I stand in the wind of a world system that deprives
poor black Africans of equitable access to global resources and
that keeps them impoverished through maintenance of disabling debt
burdens.
It is the interplay between these two facts about AIDS — its
demography and its treatment — that presents the fundamental
moral challenge of the next years of the epidemic. Treatment exists
that can save people from death by progressive immune system collapse,
but it is available only to those rich enough, or who live in countries
rich enough, to afford it. In effect, life is being withheld from
millions of poor persons because they are poor. This presents a
moral iniquity of very significant proportions.
A year ago, this was not a view widely held in governments or international
organizations or corporations. In an age of globalization, where
corporate profit and corporate control are seen as beacons to international
prosperity and growth, it was all too tempting for those living
in the affluence of North America and Western Europe to shut themselves
off from the reality that AIDS presents to nearly 30 million Africans.
All too easily, then, it was assumed that anti-retroviral drugs
were and would remain unavailable to poor Africans affected by the
epidemic, and that pricing, access and infrastructural impediments
were simply unalterable premises in a world with AIDS.
A year after the XIIIth International AIDS Conference in Durban,
the debate has undergone fundamental changes. An international consensus
has formed that AIDS in sub-Saharan Africa and elsewhere in the
developing world is an international crisis. In large measure, the
changed perceptions have been the direct product of inventive, determined
activism. Courageous activists in my country and North America and
elsewhere have confronted pharmaceutical corporations and forced
them to make practical commitments to drug availability, price reductions,
increased manufacture and devolved licensing and manufacturing arrangements.
There has been no more heartening change in the epidemic than the
growing chorus of world and national leaders, strategists and economists9
and generals and security advisers and businessmen and women, who
have begun to recognize that means must be found to bring to those
who need them the lifesaving drugs that can halt the damage that
HIV does in the human body.
AIDS is now recognized not just as a problem of human suffering
or of medical treatment, but as an issue with economic and security
implications that affect the entire world. In Washington, the new
administration acknowledged promptly that the epidemic poses problem
to the national security of the United States.10
A number of influential Harvard academics released a detailed statement
contending that scientifically monitored treatment for AIDS in poor
countries is "feasible, affordable and highly effective." That statement
has substantial shortcomings. First, it puts governmental cooperation
and commitment as a precondition to the implementation of its plan.
That makes people with HIV and AIDS the hostages of their governments'
attitudes. Second, the statement does not address critical questions
such as the rights of developing countries to initiate compulsory
licenses and undertake parallel imports of drugs under World Trade
Organization regulations and within their own legal frameworks.11
Despite this, the Harvard statement is visionary, powerful and
compelling. It represents a critical breakthrough in the debate.
It is an authoritative affirmation of the practicability of and
necessity for large-scale treatment initiatives to be undertaken
in Africa and other poor regions affected by AIDS.
It is hardly coincidental that since the statement's release, the
Secretary-General of the United Nations has launched a Global AIDS
and Health Fund12 aimed at garnering U.S. $7 - 10 million
per year to combat disease in poor countries.
But the single most important event has been the dramatic reduction
in drug prices achieved over the last 12 months. Through energetic
coalitions and campaigns, and assisted by perceptive and well-researched
reporting13, a small group of activists in Africa and
North America have turned public opinion. They have shamed the international
drug companies into taking significant action to make the drugs
whose patents they control more accessible to those who most need
them. The result has been that the cost of several combination therapies
has come down by 80%.
So the landscape has changed immeasurably. Almost every day seems
to bring new good news. Only last week, on Wednesday, June 6, Pfizer
announced that it would be making its drug Diflucan available free
of charge to the 50 least-developed countries affected by AIDS.
Anyone who has ever suffered systemic thrush, and felt the almost
immediate relief that Diflucan brings, appreciates the immense humane
significance of this offer. That it has been made is almost certainly
due to the crusade of the Treatment Action Campaign in South Africa,
which launched an international campaign that made it literally
intolerable for Pfizer to continue profiteering from Diflucan.
The debate has also moved in other ways. A year ago, prevention
of new HIV infections was often counter-poised with treatment of
those already infected, as though prevention and treatment were
at odds with each other. It is now widely accepted that the dichotomy
is false.14 Physiologically, treatment is a form of prevention.
This is most dramatically evident in mother to child prevention
programs, where administering drugs to a mother in parturition has
a good chance of preventing transmission to her baby. There is also
good physiological evidence that an effective course of anti-retroviral
medication prevents or substantially inhibits sexual transmission
of the virus.
Psychologically treatment also enhances prevention, since it affords
those already infected with an incentive to come forward to be tested,
to receive counselling, and to engage fruitfully with the complexities
of behavior modification. But, third and most important, treatment
also enhances prevention socially. By treating people we offer them
hope. And by offering hope in this epidemic, we dispel the notion
that AIDS spells doom, that confronting it is fraught with failure,
and that once infected the subject can face only debilitation and
death.
In short, treatment has irreversibly broken the equation between
AIDS and death. It allows us to begin to undo the social stigmas
and phobias that make prevention so difficult to talk about frankly,
and to practice effectively.
So the scene has been set for dramatic and immediate action. And
yet actual progress on implementation has been too, too paltry.
For those living with and dying from AIDS in Africa, these have
been victories without real triumph; movement without any visible
progress. The drugs that bring life and restore health and replenish
strength remain unavailable to all but an infinitesimal minority
of Africans who need them. Price reductions have made them accessible
to more; but to most they remain prohibitively expensive.
What I called last year at the Durban AIDS Conference a "collusive
paralysis" between drug companies and African governments continues15,
though its form has subtly changed. Governments and corporations
blame each other for inaction in the face of a fearsome calamity;
and seem rely on each other's default to legitimate their own.
As the shameful unacceptability of high drug pricing has been demonstrated
to the world, those who favor inaction have begun to shift their
arguments.16 They now focus on difficulties of providing
access, of deficiencies in health infrastructure, of complexities
of regimen and compliance and monitoring, and the real possibility
of resistant strains of the virus coming to the fore. Problems of
drug quality are cited as a reason for not using generic substitutes.
These problems are real. About that there can be no dispute. The
question however is not whether they exist, but how we are to tackle
them. For too, too many decision-makers in government and the corporate
world, these difficulties, substantial as they may be, provide a
further excuse to postpone urgent and immediate action.
In my own country, a government that has led the way in human rights
observance and in creating humane and just legislative protections
for people with HIV and AIDS is still dithering about the most elementary
steps to provide drugs for South Africans with HIV. We are the best-resourced
nation in Africa, with the most sophisticated health and distributional
and medical and scientific infrastructure. Every day, 200 babies
are born with HIV in South Africa. Yet we still do not have even
a national plan, let alone a national program, to inhibit transmission
of the virus from mother to child.
This is an appalling state of affairs; and in it we stand shamed
by our smaller and less-populous neighbor, Botswana17,
which already implements at national level anti-retroviral treatment
to prevent mother-to-child transmission. And on Wednesday, June
6, 2001, the government of Botswana announced a major scheme to
provide anti-retroviral medication in the public sector to people
living with HIV and AIDS.
By contrast, in South Africa, even the decision whether to use
Nevirapine [Viramune] — a drug with incontestable efficacy
in reducing transmission from parent to child — has been referred
from the governmental agency overseeing drug quality and safety
back to the Cabinet. To call this disappointing is inadequate. It
is distressing beyond comprehension.
Over all this looms the ambivalence of South Africa's President
Mbeki who last year gave public sustenance to discredited theories
propounded by those who deny that AIDS exists at all as a virally
caused syndrome. In October last year, after 12 months of nurturing
dissident beliefs about HIV and AIDS, the President appeared to
have backed off his stand. But in a television interview on 24 April
2001, he was asked whether he would take an HIV test. He said No,
because that would merely be "setting an example within the context
of a particular paradigm." He then went on to reiterate discredited
skepticism about what he called "unknown toxicities" involved in
administering drugs to people with HIV and AIDS.18
That we in South Africa should still be debating what "paradigm"
is or should be applicable to the AIDS epidemic represents a national
calamity of profound and grievous proportions. As Professor Malegapuru
Makgoba, President of South Africa's Medical Research Council, recently
stated in the Second James Hill Lecture to the National Institute
of Health, Bethesda, Maryland, "Whenever politics takes center stage,
manipulates science and scientific truths for its ends, opts for
the wrong scientific advice, and erodes the independence and rigor
of the scientific methods in any country, the consequences have
been dire."
Professor Makgoba has been unflinching in his condemnation of "quackery"
and of the apparent succor given to "discredited, pernicious and
dissident ideas, unethical practices and unscientific experimentation."
He states that "Africa's inability to have a strong science, engineering
and technology base can be placed on unwise political choices,"
and unequivocally sketches out the cost to our country and to the
continent of the controversy, inspired by presidential ambiguity
and doubt, regarding HIV/AIDS. This cost includes —
- Undermining all the good strategies that have a proven record
of effectiveness;
- Sending mixed signals and messages to all those that have dedicated
themselves to the alleviation and eradication of this epidemic;
- Having a negative impact on affected patients and families;
- Undermining and eroding scientists and the scientific method
in developing countries;
Professor Makgoba's warning is uncompromisingly dire: "If, as Africans,
we do not heed the implications, history may say we have collaborated
in the greatest genocide of our time."
The language of 'holocaust' and 'genocide' is not inapposite. The
moral issues are unambiguously clear, and the imperative to action
is unequivocal. Treatment must be provided to Africans with HIV
and AIDS. What is at issue is how best to bring this about, and
whether we, in this world, have the will and the courage to tackle
the solutions that we know are there.
Now that the issue has been identified, the huge scale of the effort
involved in tackling it effectively, as with the figures, threatens
to overwhelm our capacity for sympathetic imagination and constructive
action.
It is in this regard that we must view with scepticism the efforts
by some economists and commentators, pharmaceutical executives and
even certain African leaders to sketch the difficulties involved
as insuperable.19 The scale of the problem is huge. But
that does not suggest inaction. It calls imperatively to intervention
now. Studies increasingly show that anti-retroviral medication can
feasibly be supplied, accessed, administered and monitored in poor
African settings.20
There are millions in Africa with AIDS. There are tens and tens
and tens of thousands being infected every day — nearly 2,000
new infections in South Africa alone on every new day. Hundreds
of thousands of people in my country are dying of AIDS each year.
Every day more people feel sick, begin to lose their strength, feel
the stark reach of death beginning to embrace their lungs and muscles
and bowels.
Whatever we can do, now, will begin to help some of those people,
now. This is not a time for indecision and prevarication. It is
not a time for preoccupation with supposedly insuperable difficulties.
Nor is it a time for indefinite plan-making. It is — especially
— not a time for grandiose schemes designed to attain perfection.
It is a time for immediate further price reductions from the drug
corporations. It is a time for immediate agreement on manufacture
of generic substitutes. It is a time for immediate agreements on
drug provision in individual African countries. It is a time for
immediate funding, on massive scale, of drug access, provision,
supervision and monitoring projects. It is a time for immediate
implementation of feasible schemes along the lines of that outlined
in the Harvard Statement.
The arguments of the skeptics present a classic case of the supposedly
"better" being the enemy of the good. It is unlikely that in our
lifetimes we will attain perfection in Africa. Let us attain something
less than perfection in the lives of enough Africans to save them
from death by AIDS.
It is all too easy for us, in retrospect, to condemn other ages
who faltered when confronted with moral challenges. Ordinary Germans
under the Nazi regime, and white South Africans under apartheid,
are two all-too-easy examples. Other examples abound. What of those
western countries, including the United Kingdom and the United States,
that were reluctant to take Jewish refugees during the 1930s, as
Nazi persecution of the Jews started the dire march toward the final
solution of the death camps? No doubt, the plight of the German
Jews was inconvenient. The world economy had barely survived its
worst post-agrarian depression. Unemployment in Western Europe and
America was still a significant problem. Moral ambiguities seemed
to too many to affect the plight of the Jews. And there was too
much antipathy amongst informed western leaders to those who were
seeking to help them.
What can these complex and painful memories from the not-too-distant
past of our own cultures teach us? They can teach us that when a
situation calls for our action, we should respond to it with immediacy
and with urgency and without temporizing because of supposed difficulties
in the way of action.
I am a guest in your country, but you must permit me to say that
the USD $200 million that President Bush has offered as the contribution
of the United States of America to Secretary-General Kofi Annan's
Global AIDS and Health Fund is pitiful indeed. It is like a rich
man offering a starving person a penny when the meal that will save
his life will cost only a dollar.21
The intervention urged in the Harvard Statement envisages as a
first objective getting 1 million Africans with AIDS on treatment
within three years, reaching a cost of US $1.1 billion annually
by year three, and US $3.3 billion by year five. Given the wealth
of the nations from whom support for the plan is sought, outlay
of this order is readily attainable.22 It is not a question
of resources, but will, and that will must be supplied and reinforced.
It is here that the activist traditions of the gay men of New York
City and San Francisco and London and Sydney and Johannesburg can
teach those committed to wider justice in the epidemic so much.
In the face, twenty years ago, of an unparalleled threat to an emerging
and vulnerable community, they banded together. They created strategic
alliances. They gave of their energy, their time and their resources.
They created community, counselling, advocacy, resource and treatment
organizations. They challenged apathy and inaction. They confronted
bigotry and hatred. They changed not only the way in which the world
viewed AIDS, but the way in which informed opinion now views public
health and the treatment of any disease. Ultimately, they changed
the way in which gays and lesbians themselves are viewed in society.
GMHC embodies the history of principled activism, strategic alliances,
concerted lobbying and individual acts of personal courage through
which the gay male populations of twenty years ago countered and
eventually contained the deadly threat of AIDS — even while
suffering terrible losses. Those same challenges, even more starkly,
face Africa and the developing world today. Courage and activism
and international commitment of even more heroic proportions will
now be needed.
The problem of AIDS in Africa and the developing world calls us,
imperatively and urgently, to a similar commitment to collective
action. We who know best what AIDS means in our bodies and in our
communities can best impel the western world to take the action
it must, in regard to patents, in regard to granting licenses, in
regard to provision of drugs, in regard to provision of funding
and personnel. We are the heirs of a tradition that dramatized the
history of activism itself. Let us apply it, with new vision and
new courage, in the world at large.
Footnotes:
- 1 Bob Herbert, "It hasn't gone away," New York Times
31 May 2001. The Morbidity and Mortality Weekly Report for 1 June
2001) vol 50 no 21, records that by 1996 more AIDS cases occurred
in America amongst blacks than any other racial/ethnic population.
- 2 Morbidity and Mortality Weekly Report 1 June 2001,
vol 50 no 21.
- 3 Fauci, AS "The AIDS Epidemic: Considerations for the
21st Century," Global Issues vol 5 no 2, 7/2000.
- 4 Consensus Statement on Anti-retroviral Treatment for
AIDS in Poor Countries by individual members of the Faculty of
Harvard University.
- 5 The MMWR for 1 June 2001 estimates national prevalence
of HIV infection amongst persons 15-49 years in sub-Saharan Africa
at 8.8%.
- 6 Kramer, L Reports from the Holocaust: The Story of
an AIDS Activist (1994).
- 7 Information accessible at www.fda.gov/oashi/aids/virals.html.
- 8 The MMWR for 1 June 2001 has telling graphs and figures.
- 9 For example Dr James Wolfensohn, President of the World
Bank, writing in the op-ed columns of the Washington Post 18 April
2001.
- 10 "AIDS a 'National Security Problem,' Powell says,"
Reuters, accessed at www.reuters.com
on 4 February 2001. See also Jordan S Kassalow, "Why Health is
Important to US Foreign Policy" Council on Foreign Relations/Milbank
Memorial Fund, 2001.
- 11 See the critiques by Dr Hans Binswanger, President
and founder of AIDS Empowerment and Treatment International, in
a communication direct to the signatories (www.aidseti.org);
and by the Treatment Action Campaign of South Africa, available
at www.tac.org.za.
- 12 United Nations (New York) Press Release 18 May 2001.
Secretary-General Kofi first proposed the Fund when he addressed
an African summit meeting in April 2001.
- 13 Including Mark Schoofs in the Village Voice and Wall
Street Journal, Tina Rosenberg of the New York Times; Barton Gellman
and Jon Jeter of the Washington Post; columns by Anthony Lewis
in the NYT.
- 14 Distressingly, however, some commentators still write
as though to suggest that treatment is counter-posed to prevention.
See for instance Thomas L Friedman, "It Takes a Village," New
York Times 27 April 2001.
- 15 Jonathan Mann Memorial Lecture, Keynote Address at
XIIIth International AIDS Conference, published as "The Deafening
Silence of AIDS" in Health and Human Rights (2000) vol 5 no 1
pp 7-24.
- 16 Compare The Economist, editorial, 17 February 2001,
pages 21-2; Andrew Sullivan, "Profit of Doom?", New Nation 26
March 2001.
- 17 See Rachel Swarns, "Free AIDS Care Brings Hope to
Botswana" New York Times 8 May 2001.
- 18 The African National Congress's on-line journal, ANC
Today, in vol 1 no 13, 20-26 April 2001, uses the caution expressed
in the US Government's "Guidelines for the Use of Anti-retroviral
Agents in HIV-infected Adults and Adolescents" updated 5 February
2001, to conclude that "the US scientists argue that the certainties
about HIV/AIDS that are trotted out in our country everyday rest
on a very shaky scientific basis," and that they "mean" that "further
and urgent scientific work and debate is required to confront
the serious problem of AIDS."
- 19 See for instance Alan Whiteside, "Drugs: The Solution?"
AIDS Analysis Africa vol 11(6) April/May 2001.
- 20 To the evidence set out in the Harvard Statement should
be added Msellati, P and others, "Socio-economic and behavioral
evaluation of the UNAIDS-Ministry of Health Initiative on Drug
Access for HIV Infection in C™te d'Ivoire," Preliminary Report
dated May 2000, supplied to me by Prof Didier Fassin of Universitˇ
Paris-13 Nord.
- 21 See the stringent criticism directed at the plan by
Africa Action, the oldest advocacy organization in the United
States concerned with African affairs, in a media release dated
14 May 2001.
- 22 See the authoritative analysis by Dr. Hans Binswanger
"HIV/AIDS Treatment for Millions" Science vol 292, 13 April 2001
221-3, available in an expanded version at www.aidseti.org.
How to Read a Scientific
Paper
By Carlton Hogan, University of Minnesota, Coalition for Salvage
Therapy
(Last of a three-part series)
In Part 2 of this series, we learned from flipping coins that:
1. That the more experimental observations you make, the more precise
your answer will be.
2. That even though more precision is nice, after a while there
is a diminishing return as results from the study continue to fall
within a very small range (a range around the "true" value).
While enrolling everyone on earth in a trial would produce a highly
precise result, we can be satisfied with the results of a far less
ambitious study. For example, if we wanted to know if a drug could
reduce viral load, we may only need to enroll a few dozen people.
This is because laboratory endpoints are highly reproducible, easy
to quantify and respond quickly to changes in virus levels in the
blood.
But if we wanted to know if a treatment prevented AIDS, we'd be
more interested in knowing how many symptoms occurred while participants
were in the trial. Clinical endpoint trials such as this may require
enrolling several hundred people or more. Thankfully, rates of HIV
disease have declined and AIDS symptoms are far less common than
they once were, but this means that the study's size must be very
large if it is to yield enough events for us say if the treatment
had an effect or not.
Uncontrolled Trials
Let's revisit our imaginary HIV drug, X-100 for a minute. When
we do a trial of a treatment in people, it's similar to flipping
a series of coins, except that the coins have been modified (treated).
If there is a difference in outcomes between heads and tails from
what we'd expect, we can attribute it to the modification. Now imagine
each person in a trial becomes a "coin flip." Rather than heads
or tails, let's measure something else that has only two possible
outcomes. In HIV trials, viral load results are often expressed
as being above or below the limit of detection. This is an example
of a binary value (that is, one that can have one of two possible
outcomes). Let's say "heads" means undetectable virus and "tails"
means any detectable value. We measure how many people have undetectable
virus in our trial of X-100 treatment in order to say something
about how many people out in the real world can expect a similar
result.
It's important to note we're not yet talking about a controlled
trial, where modified coins are compared to normal coins or X-100
is compared to other drugs. We are simply looking at what happened
to these people who took X-100. This is sometimes called a case-series
or an uncontrolled trial. Obviously, whether X-100 is "good"
or "bad" in the real world depends on what it is compared to. It
may be better than no treatment, yet not as good as standard treatment.
It may even be worse than no treatment. That's why it's so hard
to interpret studies that aren't controlled: they may alert us to
a severe toxicity or reveal a miracle cure, but mostly they only
tell us what happened in that group of people who took X-100. They
are not generalizable. Sometimes a case series is matched with a
series of similar people on another treatment, but we can never
be sure if the comparison is meaningful.
Our gullible alien decides to become an AIDS researcher and does
his first X-100 trial in one person—who soon develops an undetectable
viral load! Visions of the Nobel Prize — or at least making
the cover of Newsweek — dance in his head. But our skeptical
alien wants to give X-100 to several more people before he makes
any conclusions. The second volunteer becomes undetectable, but
the third does not. Does this sound familiar? Heads, heads, tails?
As the trial proceeds, it starts to mirror our coin flip series,
finally yielding a high probability that X-100 works in about 50%
of trial participants, and by extension, persons like them. This
isn't so bad if these results are applicable to patients who are
failing their current treatment. But I'd feel more confident if
we could see how X-100 stacks up against treatments we are already
familiar with.
Treatment Arrives
A new alien joins the scene. Her name is Carol and she appears
on earth with an incredible new ray gun she invented that makes
coins be heads, no matter what.
"Cool!" we say, "let's try it!"
The first coin is flipped, Carol blasts it, and it comes up heads.
"Wow," says the gullible alien, "It works!"
"Hmmm," the skeptic says. The second coin is flipped: heads. Third
coin, heads. Fourth and fifth coins: heads. Our friend is looking
less skeptical now, even though he knows all this just shows is
that coins are very likely (5/5, based on the available data) to
come up heads when blasted with Carol's ray gun.
"So what do you think?" Carol asks.
"Well," says the skeptical alien, "on the first coin, you had a
fifty/fifty chance. With two flips, the odds that it was a fluke
and that the ray gun did nothing went down to 25%. And after five
flips, there was only a 3% chance that those five heads occurred
based solely on chance. Hmm, five heads in a row might happen occasionally,
but it's pretty unlikely.
I believe it is highly probable that this ray gun actually works.
If 5% probability, or .05 is good enough for the New England
Journal of Medicine, then it's good enough for me!"
Is There Some Significance to This? (P value)
Now I need to explain what's so special about 5%. When you are
reading a research report or hearing a lecture you will often come
across the term "P value." Simply put, the
P value is the probability that the findings in the study
could have occurred as a matter of chance, instead of reflecting
a real change from the expected average. P value is also
called significance, and generally the two terms are interchangeable
— unless you are talking to a very picky statistician. In our
case, the odds of getting five heads in a row was 3% or 0.03. Carol
claims that her ray gun was, in fact, the reason that they got five
heads and no tails.
Notice that no one has proven that the ray gun works; they have
simply decided that it is very, very likely that it does. In the
same way, no clinical trial can "prove" how well a particular treatment
does, but it may, however, give an answer that you feel fairly confident
about. Remember that, before Carol and her ray gun appeared, the
probability of getting heads was 50%, or 0.5, not a very convincing
P value — in fact, no better than flipping a coin!
I have never seen a good explanation for how and when it was decided
that a P value of 0.05 (5%) was the magic cut-off for statistical
significance. Who decided that if there is less than a one in twenty
chance of a result being due to chance, then the effect is real?
Somehow this number has been elevated to oracle status, where 0.05
is the dividing line between success and failure. If your study
shows results with a P value of 0.046, you'll be published
in NEJM and address the plenary at a big conference in a warm climate.
But show a P value of 0.055, and you're dismissed in disgrace.
It's kind of silly. There's absolutely nothing magic about one-in-twenty
except that it's become a standard. Like speed limits: why 55 mph,
and not 57 or 53? It's just a nice even number.
The basic rule of thumb is, the smaller the P value, the
better. You can even make up your own personal P value for
significance, depending on your innate skepticism. Maybe you think
that one-in-twenty odds are too forgiving, so you decide to remain
unconvinced unless P values are less than one in 50 (P <0.02).
You go!
Controlled Trials
Let's bring this back to earth, and start talking about controlled
trials. A trial is controlled when the experimental treatment is
compared to one of known benefit — a control. And the
safest way to do a controlled trial is to allocate the study treatments
to trial participants by a random process. Randomization helps ensure
that investigators will not consciously or unconsciously influence
the outcome of a trial due to personal preferences or beliefs. For
example, if treatments are not randomly assigned, there is a risk
that a doctor might choose to put her sicker patients on X-100 so
they can get the latest drug. Or the investigator may think it's
too risky to give experimental drugs to sicker patients and assigns
them to the known treatment. Either way, a doctor's personal opinions
can affect or bias the comparison. If sicker patients were preferentially
given X-100, the drug could appear to be less effective because
sicker patients tend not to respond as well to treatment. In the
second example, the reverse would occur. The point is that you can
never know all the factors that might influence patient selection.
Therefore the only way to ensure a fair comparison is to randomly
assign treatments. When treatments are compared in this way —
ensuring that both treatments groups are selected without bias —
it is called a randomized controlled clinical trial.
Let's take a harder look at our imaginary X-100. We suspect it
has real benefits. After all, half the people taking it had undetectable
virus afterwards. But we're not sure that this might not have happened
anyway. And even more importantly, if there are already other treatments
for HIV, we want to know if X-100 can add any benefit to what is
otherwise available. To answer this question we need to conduct
a randomized controlled clinical trial. Since the case series study
of X-100 was promising, it is decided to test X-100 plus HAART against
HAART by itself. But how many people do we need to enroll in our
trial to get results we can count on?
Sample Size ("N")
To decide on a sample size (or "N") for a clinical trial, a trial
investigator must first establish standards for the precision of
their measurements, then they decide how much comparative benefit
from the drug would be meaningful or possible to observe. Finally
they calculate the number of people that should be enrolled in order
to obtain useful results with the kind of precision they demand.
In the same way that P <0.05 is a convention for describing the
likelihood of randomly getting some result, there are a couple of
other common conventions for stating how precisely the results were
measured. One convention that we discussed in Part 2 is power, or
the likelihood of detecting a benefit that is really there. Power
of 80% or 90% is typical for clinical trials. Another important
convention is called alpha, which is an estimate of how likely it
is to falsely detect an effect when there is none. Alpha, also known
as the significance level, is often set at 5%. A good, but not entirely
accurate analogy for power and alpha is sensitivity and specificity.
If you think about it, the more stringently alpha is set to avoid
falsely detecting an effect, the more likely it becomes to fail
to detect a true effect. In other words, there is an inherent tradeoff
between alpha and power.
Next, investigators must decide how much of a treatment effect
they'd like to be able to capture with the precision allowed by
their power and alpha. A difference of 15%-20% between compared
treatments is a common expectation in AIDS trials. In order to detect
smaller differences between treatments, the sample size must include
a sufficient number of patients receiving each treatment. One of
the dangers of too-small studies is that they have too little power.
A small study may be able to confidently report: "X-100 plus HAART
was no better than HAART" — with "better" meaning at least
20% better. But so what? The trial's sample size does not allow
confirming or rejecting the possibility that X-100 is 10% or 15%
better than HAART alone — something that would be good to know.
If a disease affects hundreds of thousands of people, then a treatment
that offers even one or two additional percentage points of benefit
can have an important impact on a lot of people. However, if a relatively
small number of eligible trial participants limits the achievable
sample size, then perhaps detecting a 20% difference is the best
that can be hoped for.
So, assuming that HAART gives you a 50% response rate and that
we are looking for a 20% difference, we would like at least 60%
of participants taking X-100 to have an undetectable viral load
(20% of 50 is 10; 50% + 10% is 60%).
One more point. It's important to try to estimate beforehand how
many people are likely to drop out or crossover (take the other
arm's treatment) during the trial. This can have a major impact
on the power of the trial. It's as if the coins are changing from
heads to tails in mid-air and vice versa. If dropouts and switching
start to make the treatment groups look more and more alike, then
the trial's power to detect a difference between groups is watered
down.
These factors (power, alpha, size of difference to be detected
and expected dropout and switching rates) plus a few others all
go into determining a trial's sample size. And all of these statistical
considerations are presented in that easy-to-skip "methods" section.
But now you know enough to dive in and decide for yourself if the
researchers had realistic expectations or if they were just starry-eyed
and gullible.
Confidence Intervals
Finally, there's one bit of information found in most science papers
that might help you get a better grasp on trial results than just
the P value alone. The "95% confidence interval" or "95%
CI" is a range of possible results within which you can be 95% sure
that the "real" answer lies. So to end up with a "true answer" of
50% (as in the coin flips) the 95% CI could start out very wide.
On the first flip it stretches from 0% to 100%, but as you do more
and more flips, the 95% CI narrows until it covers just a tiny increment
above and below 50%. You might see this written in the literature
as 95% CI = (49.99, 50.1). The narrower the interval, the more certain
you can be about where the "true" answer lies. Looking at the 95%
CI will often give you a far better intuitive understanding of the
certainty of the results. With our coins, if you saw "Odds of a
head = 50% CI = [20%, 90%]," you would know that the result is almost
worthless — it could be anywhere inside that wide margin. But
if you see "Odds of a head = 50% CI = [48% - 52%]" you can be far
more confident that 50% is a good result.
That's it for the statistical stuff. No one grasps all of these
concepts the first time through, but they offer the clearest and
least ambiguous way of measuring research precision and accuracy.
Understanding their meaning is essential for critical reading. Now
lets wrap up this series by looking at a far less quantifiable measure
of a report's significance.
Where Does It Appear?
Not all trial reports are equally trustworthy. In Part 1 we looked
at who wrote the paper, now we're going to look at who has reviewed
and published it. The "gold standard" for publication is the peer-reviewed
journal. Peer-review means that other experts in the field have
had an opportunity to go over the work in detail and ask the authors
for clarification or additional information. Not only are articles
in these important journals reviewed by peers before publication,
they are subjected to intense scrutiny by the journal's readers.
It can be amusing to follow one of the well-mannered "flame-wars"
that sometimes break out in the Letters section of a respected medical
journal. The lesson is that no single paper decides scientific truth;
general agreement comes about slowly, by consensus — and sometimes
that's a rocky process.
Scientific conferences produce an abundance of reports and papers.
Many major conferences have several different levels of review.
Oral presentations and especially plenary talks (meetings attended
by all conference participants, as opposed to special interest "breakout
sessions") may undergo a peer-review process as stringent as a journal
paper does. Posters (which are really just oversized abstracts)
and "break-outs" typically undergo less scrutiny. So it's especially
important when reviewing conference presentations to consider them
in context. If they make sense and tend to "fit together" with peer
reviewed papers, they may offer some novel insights or greater detail
to what has gone before. But if, say, a poster substantially disagrees
with the peer-reviewed literature, a careful look is merited before
breaking out the party hats. This doesn't mean the poster data is
wrong — revolutionary ideas are often rejected until they become
more familiar. But if what you read sounds too good to be true,
it's worth looking a little deeper into the disagreement.
More and more frequently, the pharmaceutical and other industries
create "front groups" that sound as if they are independent scientific
organizations, when in fact they are mostly, or entirely staffed
and supervised by employees or consultants of a company. It's important
to not only look at who sponsors a conference, but also who is on
their "scientific advisory board." Most of the major conferences
actually list these advisers on their letterhead. If it's not obvious,
or hard to find out who is providing scientific leadership, be very
cautious. It's quite possible the conference is in effect a very
detailed, complex advertisement.
Unfortunately, conflict-of-interest regulations have been weak
or missing in biomedical science, so we see scandals like investigators
who hold patents on a drug chairing federally funded research projects
into that same drug. Fortunately, there is greater and greater interest
in this issue, and many organizations are drafting guidelines requiring
investigators to disclose any stock, consulting, or other fiduciary
arrangements with any entities that have a stake in their research.
Many, if not most major scientists have consulted for various companies
at one point or another and there is a "revolving door" between
the National Institutes of Health (NIH), industry, and academia.
So while it may be virtually impossible to eliminate all conflict
of interest, evaluating possible conflicts has now become an inescapable
part of assessing research findings.
This is a lamentable state of affairs, but this is where peer review
is essential. Before publication in any major journal, experts in
the relevant field pay particular attention to the "methods" section
of the paper we described before. While there is always the slim
possibility that investigators simply made the data up (which has
occurred), knowing that standardized, well-tested methods and tools
were employed helps to detect "fudging" and disingenuous conclusions.
A whole new set of complications comes with the rapidly evolving
field of "web publishing," as research appears on the Internet without
having first appeared in a peer-reviewed journal. With a disease
as deadly as AIDS and in a field that's evolving as rapidly as HIV
research, it's understandable to want the freshest information as
quickly as possible. Paper-based distribution is inherently slow,
but we shouldn't sacrifice quality for speed. It will be critical
over the next few years for to work out rational and workable guidelines
for responsible web publishing. Many sites are already taking the
initiative and have started using many of the same safeguards (scientific
advisory boards, peer review, etc.) that distinguish respected paper-based
publications.
Let the reader beware... but let the reader be ruthless. As you
practice reading abstracts and full-length papers you will start
to recognize the signs of quality research as well as the signs
of slipshod work. Keep at it. The more mysteries we can dispel about
this disease, the sooner we can stop its progress.
A Treatment Issues
Editorial
Learning from Experience
"HAART is no less miraculous in rural Haiti than it is in Boston."
—Dr. Joia Mukherjee, Partners in Health
When Brazil committed to treat all of its HIV-positive citizens
in 1996, it called upon a domestic drug industry that had been making
low cost generic versions of expensive patented drugs for years.
Reducing the cost of essential HIV medicines in Brazil altered the
course of the epidemic there. AIDS deaths peaked in 1998 and continue
to fall. About 100,000 people are currently receiving treatment
and diagnostic monitoring in Brazil.
In Uganda, the number of clinics qualified to give antiretroviral
therapy increased from three to ten over the past three years. Dr.
Peter Mugyenyi "broke the rules" when he imported generic versions
of HIV drugs, but today, he estimates, more than three thousand
people in his country are receiving treatment. Recently Botswana
and Gabon have joined a few other African nations who say they will
strive to provide universal therapy. Still, the biggest obstacle
facing all of these initiatives is the prohibitive cost of drugs
and diagnostics.
In rural Haiti, a tuberculosis treatment program operated by Partners
in Health is providing HIV drugs to about 70 people. With no recourse
to CD4 counts or viral load tests this bare bones approach evaluates
symptoms to make treatment decisions. Drugs are administered by
directly observed therapy (DOT) with the involvement of community
members. Compliance is good and once desperately ill individuals
have returned to productive lives.
All of these efforts pressed ahead with what they had — they
did not wait for court cases, TRIPS compliance or the generosity
of lawful patent owners to begin offering treatment and hope. Corporate
controlled discount plans and drug giveaways have met with less
success. Over a year ago Boerhinger-Ingleheim, the makers of nevirapine,
announced a five-year plan to donate their drug to treat HIV-positive
women in labor. But steep administrative hurdles meant that very
little medicine was actually given — and thousands of children
were infected needlessly. Meanwhile, the initiative of one small
non-profit organization, Global Strategies for HIV Prevention, has
provided purchased nevirapine to several thousand mothers with minimal
red tape.
Against this background of struggling but significant progress,
large international health organizations have been meeting with
industry, governments, foundations and community representatives
to develop guidelines for the medical management of antiretroviral
therapy in the developing world. Wide ranging opinions are debated
at these meetings — some maintaining that comprehensive healthcare
should be in place before treatment arrives, others demanding full
diagnostic monitoring or clinic-based DOT, and some arguing that
low-tech syndromic management is sufficient. Every meeting begins
with a recitation of how many lives will be lost, but who talks
about how many lives have been saved?
How many would be alive today if industry had made affordable drugs
available last year instead of stalling over theoretical points
of law? How many new infections would have been prevented? How much
larger would the foundation be for the next stage of treatment initiatives?
Perhaps the tragedy of this lost year is how much we failed to
learn about what works and what doesn't. Can home care networks
distribute drugs? Is DOT feasible? Are diagnostic tests necessary?
Are side effects manageable? Does clinical recovery follow patterns
seen in developed countries? Is additional nutritional support necessary?
We can only learn about these questions through experience and operational
research. And not every answer will work everywhere. The number
of efforts needs to proliferate.
The experience of non-governmental organizations should also be
reported. How many people has Medicins Sans Frontieres (MSF) treated
with antiretroviral therapy since the International AIDS Conference
in Durban? The World Health Organization? UNAIDS? Have drug-recycling
programs been successful? What have we learned?
Most agree that a massive airlift of antiretroviral drugs with
no plan for distribution is not likely to succeed. But while the
big organizations focus on big solutions to the big problem, too
little has been done on a small scale — as if saving a few
lives is pointless if you can't save them all. In addition to those
few precious lives lost, though, we've squandered an opportunity
to supplant theory with experience, creativity and insight from
a broad range of many modest efforts. Let's do better next year.
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