AIDS in the Developing World
Erica Seiguer
On 23 April 1984 United States Secretary of Health
and Human
Services Dr. Margaret Heckler proclaimed that
the world would have a
vaccine for HIV, the Human Immunodeficiency Virus
that causes the
Acquired Immunodeficiency Syndrome (AIDS), by
the mid 1980s.
Thirteen years later there is still no vaccine
to prevent the spread of the
virus, and there are those who believe that the
discovery and
development of a vaccine are unlikely.1 Moreover
the high-cost of HIV
therapies, the so-called "cocktail" treatments,
makes palliative care
inaccessible to the 90% of the world's HIV-infected
population who live
in developing countries. Peter Piot, director
of UNAIDS, the Joint
United Nations Program on AIDS, has cautioned
against complacency in
the face of recent successes with the triple
therapies. Addressing the
Fourth Conference on Retroviruses and Opportunistic
Infections in
January 1997, Piot stressed that "the epidemic
is not over, despite what
you may hear. I strongly believe that without
a vaccine we will not be
able to stop this epidemic."2
AIDS highlights many of the painful differences
between the developed
and developing worlds. Wealthier nations such
as the United States have
been able to stem what could have been a catastrophic
epidemic; in the
US, HIV incidence has been almost exclusively
confined to high-risk
groups such as intravenous drug users and homosexual
men.3 In the
developing world, the ravages of HIV have been
more pronounced.
Globally, by the year 2000, 40 million people
will be infected and
between five and ten million children under ten
years of age may be
orphaned, having lost their parents to the disease.
UNAIDS has
estimated that each day over 1,000 children are
infected with HIV and
that if the spread of the virus is not contained,
by the year 2010, AIDS
may increase infant mortality by 25% and under-five
years mortality by
more than 100%.4 AIDS threatens to decimate entire
populations. In
Mumbia (formerly Bombay), India, about 50% of
sex workers are
HIV-positive. In Manipur, also in India, 55%
of drug users are infected
with the virus.5
AIDS also has far-reaching consequences for uninfected
individuals. The
age group most affected by AIDS includes those
individuals in their most
economically productive years of life; HIV is
rapidly becoming the
leading cause of death for men aged 25-44 years.6
The World Bank has
estimated that AIDS will lead to a 0.6% annual
per capita slowing of
growth in countries in sub-Saharan Africa.7 Researchers
have studied the
effects of rising morbidity and mortality in
Thailand which is arguably one
of the nations hardest hit by the AIDS epidemic.
By the year 2000,
Thailand expects to spend $8.7 billion as a result
of the demographic
effects on worker productivity, savings loss
and medical costs.8 Aside
from its adverse effects on labor productivity
and health care
expenditures, AIDS is predicted to lead to a
decrease in allocations for
human capital investment such as education and
a lower savings rate as
individuals, health care professionals and government
administrations
dedicate greater resources to taking care of
the those who are infected
with HIV.
Why is there no vaccine for HIV? Aside from the
biological obstacles the
virus presents, there are political, economic
and social realities that have
limited progress in HIV vaccine design. Moreover,
even if a vaccine is
developed, we can expect there to be tremendous
difficulties in getting
the prophylactic drugs to those populations that
need them most. Issues
of payment, delivery and changes in risk behavior
have not been
adequately addressed although most scientists,
pharmaceutical
executives, activists and public health officials
are aware that these
questions must be resolved.
The Current State of AIDS Research
By employing several anti-viral drugs at once,
scientists have been able to
reduce the replication of the virus to such low
levels that the virus cannot
mutate rapidly enough to develop resistance to
the drugs. When the most
promising results of triple therapies were unveiled
to the world at the 11th
International AIDS Conference in Vancouver in
July 1996, some at the
conference raised concerns about the lack of
progress on the vaccine
front and voiced their frustration with the fact
that the therapies had no
practical application in the developing world
where the majority of those
with HIV live. In Uganda, for example, the average
citizen makes less
than $1 per day, and the total annual government
health expenditure is $3
per person.9 At approximately $15,000 a year,
the treatments that have
been able to restore health to many individuals
are not affordable even to
comparably wealthier patients in the US. Not
only are the cocktail
therapies financially inaccessible to those living
in the developing world,
but they are extremely difficult to administer,
requiring a patient to take
dozens of pills as part of a demanding regime.
For destitute AIDS
sufferers, such treatments are unrealistic. According
to consensus, the
therapies are not a solution. Moreover, resistant
strains of HIV will most
certainly develop and the current arsenal of
antivirals will not be effective
in combating the mutated strains. The only real
answer to HIV is a
vaccine. Scientists who aim to develop an effective
vaccine are currently
employing various strategies.
In the United States, before a drug is made available
to the American
public, it must be approved by the Food and Drug
Administration
(FDA). The drug must pass several stages of trials,
described as Phases
I, II, and III which are completed in human subjects.
Phase I tests for
safety and immunogenicity. The researchers will
compare any
vaccine-related side-effects with the side-effects
induced by the placebo.
The second phase of trials are the initial evaluation
of safety and
immunogenicity in the target population. Phase
III studies determine
whether the vaccine has protective efficacy-in
the case of an HIV
vaccine-and whether it will prevent an exposed
individual from becoming
infected.
Since 1987, over 40 HIV vaccine trials have been
conducted in the US
and abroad. However, no potential vaccine has
ever advanced to Phase
III trials. In 1994 an advisory council from
the National Institute of
Allergy and Infectious Diseases (NIAID) at NIH
along with the
Congressionally-mandated AIDS Research Advisory
Committee
(ARAC) decided not to proceed with a 4500-person
efficacy trial on the
two most promising vaccines of the day. Despite
this decision reached by
ARAC, the World Health Organization (WHO) and
the International
AIDS Vaccine Initiative (IAVI) considered the
pressing need for
progress in HIV vaccines for the developing world
and WHO decided to
proceed with Phase III trials.
The US Response
The United States funds approximately 85% of the
worldwide public
sector investment in HIV research. The bulk of
federal dollars allocated
to HIV research has been devoted to therapies
and not to prophylaxes.
According to the Rockefeller Foundation, less
than 5% of the $4 billion
spent on AIDS-related research worldwide is directed
toward vaccine
research.10 Perhaps due in part to the recent
evaluations of the NIH
AIDS research effort, the search for an AIDS
vaccine has attracted the
attention of the media and politicians. In a
May 1997 graduation address
to students at Morgan State University in Baltimore,
President Clinton
urged the development of a vaccine for HIV within
ten years.
Why should the United States devote vast resources
to AIDS research
when the virus is disproportionately concentrated
in the developing
world? The virus presents both a scientific and
a humanitarian challenge.
In addition, because of increases in international
travel, the US is aware
that it cannot isolate itself from more virulent
strains of HIV. There are
already documented cases of certain clades of
HIV, previously thought
to be restricted to Africa and Asia, that have
surfaced in the US.11
Despite the fact that the US may be experiencing
a decline in AIDS
cases, those in the field are concerned that
in the developing world the
epidemic may be just beginning.
The International Response
To better coordinate the UN's efforts to combat
HIV, in January 1996,
WHO replaced its Global Programme on AIDS (GPA)
with UNAIDS,
the Joint United Nations Programme on HIV/AIDS
which is composed
of several sponsoring UN bodies. Each of these
organizations has a role
to play because AIDS is intimately connected
to poverty, migration, the
status of women and other societal factors.12
UNAIDS, through its
Ethics Review Committee (ERC), also intends to
build a nation's capacity
to review the ethical implications of the disease.
UNAIDS has emphasized the importance of adhering
to a number of
ethical principles in all HIV and AIDS related
research. These ethical
principles include beneficence, equity/distributive
justice, confidentiality,
respect for autonomy, and informed consent. In
the case of HIV vaccine
trials, the Ethics Review Committee is well-aware
of the ethical
considerations of testing a potential vaccine
in the developing world.
An AIDS vaccine will need to be tested in the
developing world for a
variety of reasons. For biostatistical purposes,
scientists need to have a
test group comprised of patients who do not currently
have HIV and
who are at
high risk for acquiring the virus. The subjects
in the trial, through their high
risk behavior, will be more likely to be exposed
to the virus thus enabling
scientists to determine in a relatively short
period of time whether the
vaccine is preventing infection. A vaccine trial
would not be nearly as
effective in a random sampling of adults in the
US because the incidence
among the general population of risk behavior
for HIV
| UNAIDS includes: |
| UNDP |
| UNESCO |
| UNFPA |
| UNICEF |
| WHO |
| The World Bank |
In the United States, when an individual learns
of his HIV status he is
immediately referred to a physician who can prescribe
the cocktail
therapies. Since this protocol has become a standard
of care in the US,
medical assistance usually pays for these treatments
according to Dr.
Ruth Macklin, Chair of the Ethics Review Committee
and professor of
Bioethics at Albert Einstein College of Medicine.13
Thus, if one were to
conduct a vaccine trial in the US, once an individual
in the trial had tested
positive for HIV, the researchers would be obligated
to refer that
individual to a physician. This makes it very
difficult to measure whether
the vaccine prevents progression to disease.
The results would be less
clear and the study would require more participants
than if the trial were
conducted in the developing world where the therapies
are too expensive
and are not made available to infected individuals.
In these populations
scientists can better assess what the long-term
effects of the vaccine will
be. For example, researchers may discover that
although the individual
tests HIV-positive, he may never develop AIDS.
Recently, there has been great public debate concerning
the ethics of
having a placebo control group in the maternal-infant
HIV transmission
studies currently underway in countries such
as the Ivory Coast. The goal
of these trials is to determine the effectiveness
of lower doses of the
anti-HIV drug zidovudine (AZT) in preventing
transmission of HIV from
mothers to children. The full regimen, known
as the 076 regimen, was
shown in the US in 1994 to reduce transmission
of the virus by as much
as two-thirds. However, the treatment is not
affordable to most of the
developing world at a cost of $800 to $1000 per
mother. In an effort to
reduce the number of children infected with HIV,
researchers are
attempting to determine to what extent altered
regimens might prevent
transmission.
In studies conducted in the United States the
placebo-control group was
disbanded after the reduction in mother-child
transmission was confirmed
in the 1994 study. Currently, the drug is offered
to pregnant women who
test positive for HIV. In September 1997, the
executive
editor of the
New England Journal of Medicine (NEJM), Dr. Marcia
Ansell, argued
on the editorial pages of the journal that the
trials currently being
conducted in developing nations were unethical,
and she asserted that
including a placebo group violated WHO's international
ethical guidelines
for biomedical research involving human subjects.
The same ethical
principles that guide research protocols in the
sponsoring nation must be
upheld in other nations in which clinical research
is conducted. A primary
issue of concern
raised by Angell and others is whether or not
the subjects in the studies
are aware of what the study is testing, what
a placebo is, and thus
whether they are able to provide informed consent
to participate. In
interviews in The New York Times, many of the
women appeared
confused about the trial but consented to it
in order to avail themselves
and their children of the health care provided
by the doctors and
researchers conducting the studies.14 The Center
for Disease Control
(CDC) and NIH have defended the trials, insisting
that review and
approval from UNAIDS, NIH, CDC and host countries
prior to the start
of the trials was achieved after debate and discussion
of many other
ethical issues. The directors of the CDC and
NIH, Dr. David Satcher
and Dr. Harold Varmus, responded with a defense
of the trials in
progress in the NEJM, asserting that the studies
are being conducted
according to widely accepted bioethical principles
and guidelines and that
they are supported by the local populations.
15
UNAIDS is not the only international organization
working to combat
AIDS. The International AIDS Vaccine Initiative
(IAVI), formed in
August 1995, has been working to promote research
and development
of a vaccine for HIV. IAVI has identified some
of the major obstacles to
the design of a vaccine for HIV which include
the lack of market
incentives for pharmaceutical and biotechnology
companies to invest in
research on HIV vaccines.
The Private Sector
In 1994, there were eleven companies in the US
and abroad with active
HIV vaccine research programs. Today there are
only a handful of US
firms committed to developing a vaccine for HIV.
IAVI has been at the
forefront in attempting to address the issues
of market size and liability.
Of primary concern to private sector researchers
and executives is the
feasibility of creating an effective vaccine.
It is unclear whether a vaccine
can ever be developed due to a variety of biological
characteristics of the
virus, including its high mutation rate and the
uncertainty over what kind
of immune response would guarantee that an individual
would not be
infected upon exposure. Moreover, because there
are at least nine
different clades of HIV, it has yet to be determined
whether a vaccine
against one or all of the strains of HIV will
be needed. There are
disagreements over the level of efficacy that
a vaccine will be able to
guarantee; few believe that the vaccine will
be 100% effective.
Market size
Beyond the scientific challenges faced by researchers,
the private sector
must also weigh the potential profitability of
each drug it produces. In the
case of a vaccine for HIV, industry is well aware
that the market in the
developed world will be limited. In countries
such as the US, it is likely
that use of a vaccine will be limited to high
risk groups such as
homosexual men and IV drug users. IAVI estimates
that five million
courses of an HIV vaccine will be needed to vaccinate
the sexually active
homosexuals and IV drug users in the developed
nations and that less
than 150,000 additional doses per year will be
needed for those
individuals entering the two risk groups.16
For those in the developing world who stand to
benefit the most from a
vaccine, manufacturers worry about payment for
their products. Thus,
the developed countries will have to bear the
cost of providing a vaccine
to those who cannot afford it. Merck Vaccine
Division President R.
Gordon Douglas stresses that the pharmaceutical
companies are not
responsible for vaccinating the world.17
Liability
IAVI and other groups dedicated to the development
of a vaccine for
HIV have analyzed issues of liability at the
various stages of vaccine
production. During the clinical trial period,
various side effects
attributable to the candidate vaccine may be
identified. At the
post-licensure stage, vaccine manufacturers are
concerned about the
effect of the vaccine on healthy individuals
who might develop malignant
tumors because the class of viruses to which
HIV belongs is known to
cause cancers.18
Conclusions
AIDS, perhaps unlike any other disease encountered
thus far by
scientists, accentuates the gap between the rich
and the poor. Although
the vast majority of those with HIV reside in
the developing world, most
of the financial support for research on the
virus is in the hands of the
developed countries. As the epidemic progresses,
it become clear that a
vaccine is the only means through which the developing
nations will be
able to combat HIV. Research priorities until
very recently have been
heavily weighted in favor of therapy rather than
prevention, perhaps
because of the disincentives, both biological
and financial, to develop
vaccines.
Although most HIV-infected individuals live in
the developing world,
there is great impetus for the West to work toward
a vaccine. A higher
standard of living and longer life expectancy
in the developing world will
mean larger markets for Western goods and services.
Western
researchers, pharmaceutical executives and public
health officials should
consider both the humanitarian concerns and the
economic realities
presented by HIV as they attempt to solve the
problems that HIV
creates.
Notes:
1 Albert B. Sabin. "Improbability of effective vaccination against Human
Immunodeficiency Virus because of its intracellular
transmission and
rectal portal of entry," Proceedings of the National
Academy of
Sciences, Vol. 89, September 1992, pp. 8852-8855.
2 "UNAIDS chief: Only a vaccine can end AIDS,"
AIDS Weekly Plus,
February 10, 1997.
3 Norman Hearst and Jeffrey S. Mandel. "A research
agenda for AIDS
prevention in the developing world," AIDS, 1997,
11 (suppl. 1), S1-S4.
4 Thalif Deen. "United Nations: AIDS to hit one
million children warns
UN," Inter Press Service, July 13, 1997.
5 IAVI Report, Vol. 2, No. 2, Summer 1997, p. 10.
6 Barry Bloom, Hearing of the Foreign Operations
Subcommittee of the
Senate Appropriations Committee, May 15, 1997.
7 Thomas C. Quinn. "Global burden of the HIV pandemic,"
The Lancet,
Vol. 348, July 13, 1996, pp. 99-106.
8 Craig Emmott. "The economic impact of AIDS in
Thailand: A
comparison to Tanzania," from <http://www.nectec.or.th/users/>
9 Danstan Bagenda and Philippa Musoke Mudido.
"A look at...Ethics
and AIDS. A reaction: We're trying to help our
sickest people, not
exploit them," The Washington Post, September
28, 1997, p. C03.
10 AIDS Alert, "Vaccine development moves to front
burner: critics say
president's vaccine plan inadequate," March 1997.
11 Lisa M. Krieger. "New AIDS strain worries researchers;
Vaccines no
match in Africa, Asia," The San Francisco Examiner,
March 22, 1996.
12 UNAIDS: An Overview.
13 Interview with Dr. Ruth Macklin, Chair, Ethics
Review Committee,
UNAIDS, October 31, 1997.
14 Howard W. French. "AIDS research in Africa:
Juggling risks and
hopes," The New York Times, October 9, 1997.
15 David Satcher and Harold Varmus. "Ethical complexities
of conducting
research in developing countries," The New England
Journal of
Medicine, Volume 337, Number 14, October 2, 1997.
16 IAVI, Financial and Structural Issues: Summary
Report and
Recommendations of an International Meeting,
August 17, 1995, The
Rockefeller Foundation, p. 6. These figures are
based on the assumption
that 2% of adult males are sexually active homosexuals.
17 Erica Seiguer. "Curing AIDS in the midst of
politics and science: The
search for a vaccine continues..." Business Today,
Spring 1997, p. 11.
18 IAVI, Financial and Structural Issues: Summary
Report and
Recommendations of an International Meeting,
August 17, 1995, The
Rockefeller Foundation, pp. 6-7.
