AND SCIENTIFIC ASPECTS
Sonya Norris, Alan Nixon, William Murray
Science and Technology Division
Revised 18 December 2001
BACKGROUND AND ANALYSIS
Epidemiology of HIV/AIDS
The Human Immunodeficiency Virus (HIV)
The Immune System and the Etiology of HIV Infection
E. HIV Vaccines
The Krever Commission
AIDS: MEDICAL AND
Acquired Immune Deficiency
Syndrome (AIDS) was first described in the United States in the summer
of 1981 and was initially associated with cases of Pneumocystis carinii
pneumonia (PCP) and Kaposis sarcoma (KS) in homosexual men who
were also immunocompromised. The first case of AIDS in Canada was
reported in February 1982. Since then the incidence of AIDS has
grown significantly. Worldwide 36.1 million people are infected
with HIV, and more than 14,000 new infections occur daily. The
vast majority of those infected live in the developing world, particularly
in sub-Saharan Africa, southeast Asia and the Asian sub-continent.
It is estimated that nearly 22 million people have died from AIDS and
13.2 million children have been orphaned by the disease.
However, exact numbers are difficult to obtain because of under-diagnosis,
incomplete reporting and reporting delays in many countries.
As its name suggests, AIDS
involves the breakdown of the bodys immune system, leaving the victim
vulnerable to unusual and fatal diseases. The human immunodeficiency
virus (HIV) the virus that is now known to cause AIDS was
discovered in 1983. HIV is not highly contagious and its transmission
is easily preventable, but prevention is predicated on behavioural change
among populations at risk. The virus is unusual: it has a
very high mutation rate and, although it is the subject of intense research
scrutiny, its mode of action is not fully understood. An effective
vaccine against HIV is not expected for a number of years and, until relatively
recently, no effective therapies existed. In mid-1996, the results
of a number of clinical trials investigating the effect of mixtures of
multiple anti-HIV drugs were reported. Early observations show that
drugcocktails of three or more drugs can overcome the rise
of drug-resistant mutants; in many cases, HIV concentrations in the blood
have fallen below the level of detection. It is too soon to say
that a cure for HIV/AIDS is at hand; however, it now appears that it may
be possible to transform HIV disease into a chronic, controllable condition.
BACKGROUND AND ANALYSIS
In the years that have passed
since the identification of AIDS in 1981, many advances have been made
in understanding the disease, how it is spread, and how it may be prevented.
The disease will be discussed under the following headings: epidemiology
of HIV/AIDS; the human immunodeficiency virus (HIV); the immune system
and the etiology of HIV infection; associated diseases; HIV vaccines;
and anti-HIV drugs.
Epidemiology of HIV/AIDS
Since the first AIDS case
was diagnosed in Canada in 1982, the disease has spread widely.
By 31 December 2000, a total of 17,594 Canadians had been diagnosed
with full-blown AIDS and 70.6% (12,419) of those had died. Health
Canada states that the significant delay in the reporting of AIDS cases,
together with under-reporting, affects the accuracy of the figures quoted
above. Following initial infection, HIV disease is characterized
by a long asymptomatic period that can last for ten years or more before
full-blown AIDS develops. In 2000, 2,104 positive HIV tests were
reported in Canada, bringing the cumulative total of reported tests between
1985 and the present to 48,014. It is estimated that at the end
of 2000, there were well over 50,000 HIV-positive (HIV+) people
in Canada (including those living with AIDS). Of these, an estimated
30% are unaware of their infection.
Health Canada now reports
statistics on the incidence of HIV and AIDS in the publication HIV
and AIDS in Canada. This document, published biannually, covers
material formerly presented in two separate reports: HIV in Canada
and AIDS in Canada; it reflects an integrated approach to HIV and
Among other statistics,
HIV and AIDS in Canada allocates all reported Canadian AIDS cases
to an exposure/risk category. As of 31 December 2000, of
all adult AIDS cases attributed to identifiable risk categories, 72.3%
were attributed to homosexual activity and a further 4.8% consisted of
men who identified a combination of homosexual activity and intravenous
drug use as risk factors. The balance of adult cases
attributed to identifiable risk categories were allocated as follows:
intravenous drug use, 6.5%; recipient of blood, 1.6%; recipient
of clotting factor, 1.7%; and heterosexual contact, 11.6%. For adults
with no identifiable risk factors, 581 cases of AIDS have been reported
(3.3% of total cases). Children under 15 years of age accounted
for 203 cases of AIDS (1.2%).
The above data serve only
as a snapshot of the Canadian HIV epidemic; they do not identify which
Canadian groups are being infected today. Only in Canada and the
developed nations of Europe and Australasia does AIDS remain a disease
where the majority of those afflicted are gay. The incidence of
new HIV infections among Canadian gay men has fallen, with the most significant
decrease taking place among older gay men who have witnessed the deaths
of friends and loved ones. Unfortunately, young gay men are less
likely to practise safe sex and they continue to have a relatively high
rate of infection. As the epidemic in the gay population slackens,
it is intensifying among young heterosexuals. By the end of 2000,
women accounted for 7.7% of the total cumulative adult cases of AIDS.
They represent an increasing proportion of the HIV infections and
AIDS cases reported each year among adults. In 2000, 22.9% of
new HIV infections reported in adults were in women. Between
1985 and 1994, HIV infections in women accounted for only 9.8% of the
The profile of newly diagnosed
HIV infections has changed considerably since it was first identified.
Essentially three-quarters of all infections between 1984 and 1995 were
due to the high-risk activity of men who have sex with men. This
changed over subsequent years as the proportion of females infected rose
and the contribution of intravenous drug use to the spread of the virus
increased. Between 1994-1995 and 1999 general trends of decline
were observed in the number of: HIV infections reported; AIDS diagnoses;
and AIDS-related deaths. However, in 2000, the number of new AIDS
cases reported increased for the first time since 1994. Additionally,
there has been an increase in both the reported number and relative proportion
of positive HIV tests attributed to men who have sex with men, corroborating
the increased HIV incidence reported for this group in 1999.
In the United States,
AIDS ceased being primarily a disease of gay men in the early 1990s.
Data from the United States Centers for Disease Control and Prevention
show that the proportion of newly reported HIV cases among homosexual/bisexual
men steadily decreased from 43% in 1996 to 41% in 1997 to 40% in 1999.
However, this tread reversed in 2000 and the rate jumped back to 43%.
The percentage of new cases for white adults, which had in the past declined
and then remained constant at 32% between 1998 and 1999, has now increased
to 37.3%. At the same time, the rate of infection among women and
minority groups has continued to rise, similar to the situation in Canada.
AIDS cases among women have been increasing over the years, accounting
for 13.0% of all total AIDS cases in 1993, and rising to 17.4% in 2000.
The percentage of U.S. blacks with AIDS continues to increase, rising
steadily from 31.8% of all cases in 1993 to 37.8% in 2000. These
are alarming statistics, given that only 12.3% of the population is black.
Similarly, Hispanic Americans accounted for only 12.5% of the population,
but 18% of AIDS cases in 2000. For Americans aged 25-44, HIV was
the fifth leading cause of death in 1999; among blacks it was the number
one cause of death in this age group.
Sexual intercourse is the
principal means of HIV transmission. Unprotected anal or vaginal
intercourse poses the greatest risk of infection as the epithelial tissue
of both the vagina and anus/rectum contain cells that are susceptible
to invasion by HIV. Scientific studies have shown that in heterosexual
transmission of HIV, women are at least twice as susceptible as men; however,
lack of circumcision increases the risk for men. Oral sex is believed
to be a less risky sexual practice because viral entry is limited to access
through oral cuts, abrasions or inflamed areas; however, HIV has been
found capable of infecting Langerhans cells present on tonsil epithelial
tissue. The virus is destroyed by stomach acids. The use of
non-latex condoms for all sexual acts involving the exchange of body fluids
significantly reduces the risk of HIV transmission.
Although only 6.5% of
all AIDS cases diagnosed up to 31 December 2000 were directly attributable
to intravenous drug use, it is a high-risk activity when shared needles
are involved. This means of transmission is increasing in Canadas
major urban centres. Canadian studies have shown that low-income
inner-city residents with unstable housing are twice as likely to become
infected with HIV than are wealthier drug users. It has also been
observed that people who inject cocaine more than four times a day are
2.4 times more likely to become infected than are those who inject other
drugs. In the United States, intravenous drug use is a major cause
of new HIV infections. A February 1995 analysis conducted by the
United States Centers for Disease Control and Prevention found that approximately
75% of the 40,000 newly infected with HIV in the United States in 1994
self-medicated with illegal drugs.
The AIDS virus can be transmitted
in whole blood and blood products. Factor VIII, a coagulation product
originally prepared from blood plasma, has been responsible for a large
number of HIV infections. Approximately 1,200 Canadians were infected
by HIV from contaminated blood and blood products in the 1980s.
By 1 November 1985, the Canadian Red Cross had fully instituted testing
of all donated blood for HIV antibodies. Earlier, the Red Cross
had instituted donor screening to eliminate persons in high-risk groups.
The Canadian blood system now is as safe as any in the world. Canadian
Blood Services, in operation since September 1998, tests all blood donations
for the most common strains of HIV (HIV-1 and HIV-2), using a very sensitive
test; this test produces no false negatives, i.e., no infected
samples are missed. However, the test can produce infrequent false
Infants born to mothers
infected with HIV are at risk of contracting the virus. Mother-to-infant
transmission of HIV perinatal transmission may
occur in three ways: (1) infection in utero in cases where
the virus moves across the placenta; (2) exposure of the baby to infectious
blood and vaginal secretions during labour and delivery; and (3) postpartum
transmission through breast-feeding. The rate of infection varies
considerably, but may be as low as 13% or as high as 40%. In a
U.S. study, the incidence of perinatal transmission was reduced from 25.5%
to 8.3% when AZT was administered to HIV+ women during pregnancy
and delivery and to newborns for eight weeks after birth. It is
believed that further improvement can be achieved by means of combination
therapy using three or more anti-HIV drugs. By 31 December 2000,
a total of 158 cases in which perinatal transmission of HIV had progressed
to AIDS had been recorded in this country. This mode of transmission
accounts for by far the largest proportion of AIDS cases in children less
than 15 years of age (83.6%).
of HIV is of greatest concern in the medical and dental professions and,
to some extent, also in areas of emergency assistance where persons come
into contact with blood. HIV transmission has occurred in hospitals,
usually through needle-stick injuries with contaminated syringes.
Invasive surgical procedures also involve some risk of transmission through
cuts caused by surgical instruments or bone fragments, but the incidence
of infection by this means is very low. No instances of HIV transmission
from a health-care worker to a patient have been recorded.
The transmission of HIV
by dentists to patients has been given prominence as a result of the case
of a (now-deceased) Florida dentist who may have infected as many as five
patients. Dentistry is not thought to be a major risk to the public,
however, and procedures have been developed to sterilize dental equipment
to protect patients. As in the medical profession, the risk is greater
for dentists and their assistants who treat HIV-infected persons, but
this risk is regarded as very small.
The AIDS virus has been
isolated in many body fluids, including saliva, but transmission of HIV
by this route is very low-risk, if it exists at all.
B. The Human
Immunodeficiency Virus (HIV)
HIV is unlike most of the
viruses that infect human beings in that it is a retrovirus whose genetic
material is ribonucleic acid (RNA), rather than deoxyribonucleic acid
(DNA). There are two major types of HIV: HIV-l is the commonest
strain worldwide, while HIV-2 is prevalent in West Africa. Of the
two, HIV-l produces the more severe disease. To date, nine genetically
distinct subtypes of HIV have been identified and designated subtypes
A through H, and O.
HIV is the most studied
virus in history but much remains to be learned about it. A single
HIV virus particle, or virion, is roughly spherical in shape.
It has an outer coat, or envelope, consisting of a double layer
of lipid (fat) molecules. The envelope is studded with proteins.
Some of these are of human origin and are known as major histocompatibility
complex (MHC) protein molecules, which are important components of
the human immune system.
The virion envelope also
has numerous protein spikes, each of which contains a protein
called gp120 on the outside and gp41 embedded in the envelope. The
prefix gp stands for glycoprotein, meaning that the proteins
are linked to sugars. The number refers to the mass of the protein.
The gp120 envelope glycoprotein is derived from a precursor molecule called
gp160. The gp120 protein is known to bind tightly to the CD4 molecule
on the surface of immune cells, thus facilitating entry of HIV into the
cell. Recent research has suggested that a second protein on the
cell surface, an enzyme designated CD26, may serve as the actual entry
point for HIV into the cell. Within the gp120 protein is a loop structure
called the V3 loop and this is believed to be important in
the infective process of HIV. Two other proteins have been identified
inside the envelope, and designated p17 and p24. The core, or capsid,
of the virion contains the genetic material of the virus, in the form
of two strands of RNA. A number of enzymes essential to the infective
cycle of HIV have been identified. These are described in detail
in a later section.
Immune System and the Etiology of HIV Infection
A major impediment to a
full understanding of HIVs role in the development of AIDS is the
fact that the functioning of the human immune system is still incompletely
understood. A brief discussion of the immune system follows.
The human immune system
consists of two sub-systems: humoral immunity and cell-mediated
immunity. Humoral immunity is based on the production of antibodies
by B lymphocytes, or B cells, which are produced in the bone marrow
and circulate in the bloodstream. The B cells are extremely versatile
and, in total, represent millions of antibody genes which direct the production
of equal numbers of different antibodies. These lymphocytes, carrying
any one of millions of different antibodies on their individual cell surfaces,
constantly roam the body, ready to meet an invading antigen.
(An antigen is a foreign protein or carbohydrate toxin, which may be produced
by a pathogenic organism.) When an antigen meets a B cell carrying
a matching antibody, that B cell is stimulated to divide rapidly and to
secrete large numbers of antibodies to attack the invader. The antibody
need not match the antigen exactly to be effective.
Cell-mediated immunity involves
a type of lymphocyte, known as the T-cell, that originates in the thymus
gland. Unlike a B cell, a T-cell cannot see the entire
antigen, but receptors on its cell surface recognize protein fragments
of antigens called peptides. These peptides, which are short linear
sequences of amino acids, may even include the inner part of a microbes
structure. A major histocompatibility complex (MHC) protein molecule
processes and presents the antigen fragment to the T-cell.
T-cells comprise two sub-populations,
the CD4 helper and CD8 killer T-cells. The latter also are known
as cytotoxic T-cells because they literally kill infected
cells, thus limiting the spread of a virus. The CD4 helper T-cells
respond to the chemical signal from the antigen fragment on the MHC protein
and produce a large amount of chemicals called cytokines (or lymphokines).
Interferons and interleukins are two of the various classes of cytokines
produced. These chemicals stimulate the immune system and the inflammatory
response of body tissue that is a part of the immune reaction.
The complement system
is another important part of the immune system. This sub-system
involves the interaction of more than 18 protein fractions which augment
the bodys immune defences when antibodies combine with invading
antigens. Among other things, the complement system facilitates
the lysis (break-up) of cells of invading pathogens.
The B and T-lymphocytes
form a tightly interwoven system which has positive and negative feedback
loops. The T-cells stimulate the B cells into an active state where
they divide rapidly and produce large quantities of antibodies.
In turn, the B cells process antigens into a form to which T-cells most
readily respond, stimulating the T-cells into an active state.
Some understanding of the
immune system is necessary in a discussion of AIDS because the dominant
theory of the disease is that the CD4 T-lymphocytes are affected by the
virus, producing functional abnormalities and reduced numbers of cells,
leading eventually to the profound immunosuppression that characterizes
advanced HIV disease. Other cell types, notably large scavenger
cells called macrophages, are also infected by HIV, and these may
serve as important reservoirs of HIV outside the blood, and as carriers
of the virus to other organs (the Trojan horse effect).
It is generally accepted
that HIV infection proceeds through a number of stages leading up to the
condition known as AIDS. In 50 to 70% of persons with primary HIV
infection, after three to six weeks an acute syndrome develops which is
similar to mononucleosis and is marked by fever and general malaise.
There is also a high level of viremia (virus in the blood) at this
Within a week to three months
after initial infection, the body mounts an immune response to HIV.
At the same time, it is possible that the virus becomes widely disseminated
in the body, particularly in the lymphoid organs. The immune reaction
results in a large decline in viremia but is unable to suppress HIV reproduction
completely. The virus becomes almost undetectable in the peripheral
blood cells, but remains detectable in the lymph nodes.
The mechanism(s) leading
to the dysfunction and decline of CD4 T-cells is not well understood.
The simplest hypothesis is that the T-cells are directly killed by the
virus after infection. It also has been shown, in vitro,
that an infected T-cell will fuse with a number of uninfected cells to
form clusters called syncytia, a process which leads to the death
of all the affected cells. Syncytia formation has rarely been seen
in vivo, however.
CD4 T-lymphocytes also may
be killed through an HIV-specific immune response involving both the humoral
and cellular sub-systems. A number of viral proteins have been identified
which stimulate antibody formation; HIV-infected T-cells that express
these proteins on their surfaces may be selectively killed by cytotoxic
T-cells. The immune system also may be disrupted without actual
cell death: infected cells may not function properly, the result being
a compromised immune system. It has also been hypothesized that
some sort of auto-immune reaction may be causing the death of the
There is evidence that a
significant number of individuals infected by HIV do not progress to AIDS;
in some studies, about half the persons remain free of AIDS 10 years after
becoming infected by the virus. One study in San Francisco found
that 8% of men infected for between 10 and 15 years remain clinically
normal, exhibiting only minor abnormalities of the blood and immune systems.
A research group in Britain suggests that up to 25% of persons infected
with HIV will survive for 20 years without developing AIDS.
There is evidence that viral
burden the amount of virus in the body is an important
factor in progression to AIDS. Persons with a high viral burden,
both initially and as the infection continues, seem to progress more rapidly
to AIDS. Why some people have a higher viral burden than others
is not known, but the answer to that question may produce important insights
into the etiology of the disease and could point the way to improved therapies.
In summary, despite a number
of hypotheses about how HIV produces the pathogenic events that eventually
lead to AIDS, there is no completely satisfactory explanation as yet.
The emerging majority view of AIDS is that the disease is caused by a
progressive HIV burden in the infected person, involving an incompletely
effective activation of the immune system, followed by the eventual destruction
of that system by the virus.
It is now recognized that
HIV infection leads to a continuous disease process that starts with the
initial exposure and terminates in the advanced forms of immune deficiency,
the state typically known as AIDS. Death results from the complex
interactions between the HIV infection itself and the secondary opportunistic
infections and cancers that are commonly associated with the syndrome.
The first stage of infection
is known as the acute retroviral syndrome and is characterized
by fevers, pharyngitis, headache, malaise and a rash. The symptoms
are often mistaken for influenza or infectious mononucleosis. This
phase begins about one to three weeks after infection and may last for
one to two weeks. During this period, there is a burst of viremia
in the person, who is now infective. It is important therefore that
counselling be initiated immediately to prevent HIV transmission.
In the next stage of the
disease, most people enter a period of clinical latency.
In a large study of homosexual men, the median time from estimated initial
infection to the development of full-blown AIDS was 10.8 years.
This period varied from as little as 12 months to more than 11 years.
In fact, the virus is not really inactive during this period, so the term
latency is not really appropriate. Virtually all infected persons
suffer a gradual deterioration of their immune system, particularly depletion
of CD4 T-cells in the peripheral blood; also, lymphadenopathy
swelling of the lymph nodes typically occurs at this time.
In January 1995, a review
article on the population dynamics of HIV in infected persons suggested
that the long period of clinical latency associated with HIV/AIDS
is a period of great activity during which cells are being infected and
dying at a high rate and in large numbers. A steady-state
model is suggested, during which infection, cell death, and cell
replacement are in balance. This further suggests that the virus
goes through an extraordinarily large number of replication cycles, a
turnover that drives both the pathogenic process and the development of
great genetic variation within the virus. The great accumulation
of mutations accounts for the resistance that invariably develops to antiviral
The next stage of the disease
is called early symptomatic HIV disease. This designation
has largely replaced the older AIDS-related complex (ARC)
terminology. In this stage, the CD4 T-cell count has dropped significantly,
and there is an increase in infectious diseases, although these are usually
not life-threatening. A variety of chronic or intermittent symptoms
may occur, and almost every organ system may be affected. The observed
symptoms include: fever, night sweats, chronic diarrhoea, fatigue,
minor oral infections, and headache.
Another factor that can
be important in this phase is the development of adverse effects to antiretroviral
drugs such as zidovudine (AZT). At this stage also, the virus may
become increasingly resistant to such drugs.
In the late symptomatic
stage of HIV disease, the CD4 T-cell count declines even further, and
the infection rate for serious opportunistic diseases increases.
Antibiotics are available to treat most diseases effectively, but these
drugs often have side effects, and there is a risk of drug resistance
by the various pathogens. Pneumocystis carinii pneumonia
(PCP) is common during this stage but is susceptible to treatment.
Treatments for other infections including cryptococcal meningitis, cytomegalovirus
(CMV) retinitis, central nervous system toxoplasmosis, and Mycobacterium
avium-intracellulare tuberculosis are under development or in the
The final stage of the illness
is familiarly referred to as full-blown AIDS. Some medical
workers prefer advanced HIV disease as more appropriate.
In this stage, the CD4 T-cell count drops to below 50 cells/ml and
the probability of death rises greatly. Opportunistic diseases remain
as the greatest threat for morbidity and mortality. Careful and
regular expert medical care is essential at this stage.
E. HIV Vaccines
Vaccines are the most cost-effective
means of reducing infectious disease; the ideal solution to the HIV/AIDS
epidemic would be an effective and affordable vaccine for general use
in all countries and among all population groups. Although HIV transmission
is almost completely preventable through the use of appropriate prophylaxis,
this approach requires major behavioural modification in the areas of
sexual activity and intravenous drug abuse, where this is notoriously
difficult to achieve. The international vaccine research program
is very active; currently, more than 20 experimental AIDS vaccines are
in various stages of human testing.
When HIV was first discovered
in 1983, there was a burst of optimism about possible vaccines; however,
because HIV is different from most viruses for which vaccines have been
developed, it presents special challenges. The body mounts an early
immune response to acute HIV infection but lasting immunity does not develop
and the immune system eventually is destroyed.
HIV is perhaps the most
genetically variable virus yet discovered. HIV-l, the predominant
viral group in most of the world, differs greatly from HIV-2, the viral
group responsible for AIDS in West Africa. Worldwide, there are
at least nine distinct subtypes of HIV-l. Within the subtypes the genetic
diversity of HIV is vast, and any given population of virus within a host
includes a large proportion of defective viral genomes. An asymptomatic
HIV+ person might have at least one million genetically distinct
variants of HIV; a person living with AIDS might have 100 times that number.
The source of the variation lies in the enzyme reverse transcriptase which
has no editing mechanism to correct the errors in transcription
which occur during viral reproduction. Thus, a vaccine effective against
one strain of HIV will not necessarily confer immunity against the mixture
of strains encountered in nature.
Experimental animals (animal
models) are needed for vaccine development, as well as for study
of the disease process in AIDS. The ideal animal model would be
an inexpensive laboratory animal in which HIV induces an AIDS-like condition.
At present, there is no such model. Chimpanzees can be infected
with HIV, but they have to be infected with the most virulent strains
before they develop AIDS-like symptoms. Their use is held to be
valuable for vaccine development. The simian immunodeficiency virus
(SIV) is related to HIV, and is very closely related to HIV-2. SIVs
occur naturally in a number of African nonhuman primates but the virus
is not normally pathogenic. However, SIV will cause an AIDS-like
condition in macaques, a simian group that includes the familiar rhesus
Various types of HIV vaccine
are currently under development. The standard approach is the use
of a prophylactic vaccine to prevent individuals becoming infected.
Another approach is the use of a therapeutic vaccine to modify
the disease in infected persons. An additional approach is to develop
a vaccine to prevent transmission of HIV from mother to fetus during pregnancy,
an important consideration because more women are becoming infected with
There are two classic approaches
to vaccine development for virus diseases:
First, the vaccine may
be based on a live virus that has been genetically altered, or attenuated,
to eliminate its ability to cause disease. Examples include
vaccines to prevent polio and measles. This option has some
potentially serious safety problems with HIV. The virus, as
noted, mutates extremely rapidly and is known to recombine with other
HIV strains, and potentially with other viruses, raising the possibility
that the altered virus could regain its pathogenicity. Further,
because there is no reliable animal model in which to study HIV disease,
an attenuated strain of the virus cannot be tested for pathogenicity.
Second, vaccines also
may be based on inactivated, or killed, whole virus.
Testing of inactivated SIV vaccines in nonhuman primates has yielded
some success in producing a protective response, but the protection
has been brief and has been effective only against virus delivered
by intravenous inoculation. Also, there is no evidence that
any such HIV vaccine has generated the cytotoxic-T-lymphocyte response
believed to be necessary for successful immunity to HIV.
A number of novel approaches
to vaccine development are also being pursued with HIV/AIDS. Recombinant
DNA (rDNA) technology is being used to produce large quantities of viral
proteins and peptides, and even viral genes, which can be used as immunogens
for vaccine production. Their new approaches include the use of
various attenuated microorganisms, such as the vaccinia virus, containing
an HIV gene encoding an HIV protein.
Only one such vaccine has
entered trials so far and is described as a gp120 subunit
vaccine. The designation gp120 refers to a subunit of
the envelope glycoprotein produced by the virus which it uses to latch
on to susceptible cells. The vaccine has been shown to be safe for
humans on the basis of small-scale trials in Europe and the United States.
However, recent research suggests that the current generation of gp120
immunogens (i.e., antibodies to gp120) may not be effective against HIV.
Instead, scientists are producing a better antibody to gp120. What
is needed is a line of cells that mimic HIV by having the gp120 protein
on their outer membranes. The hybrid cells are then activated
by mixing them with cells susceptible to HIV. The hybrid cells are
then fixed at this point with formaldehyde in a fusion-competent
form which is then used to produce antibodies in mice. It has been
shown to neutralize several strains of HIV.
Much research is still needed
to surmount the numerous problems that exist with HIV vaccines.
In animal studies, vaccine protection lasts only for a short period and
only against a virus identical to the one used to make the vaccine.
This is a major problem, given the huge genetic variation among HIV populations:
vaccines will have to provide immunity against the extreme genetic diversity
of HIV observed in humans, a property known as cross-reactivity.
It remains to be determined whether a special type of immunity
is required to protect against mucosal exposure to HIV, such as would
occur during sexual intercourse, as opposed to exposure through the bloodstream.
Also, protective immunity will need to be achieved against both cell-free
and cell-associated virus particles because humans are rarely infected
by cell-free virus.
Finally, the trials of any
prophylactic HIV vaccine will be both difficult and controversial.
To provide a good test of vaccine efficacy, an unprotected
control group would have to be involved. The prospect of using such
a group, without doing everything possible to prevent their becoming infected
by the virus, raises very difficult ethical and moral issues.
The most publicized news
out of the 1996 XI International Conference on AIDS was in regard to the
successes achieved in combating HIV by means of combination therapies
consisting of two to four anti-HIV drugs given at one time. There
is now a good indication that HIV infection will become a controllable
chronic condition, and there is also the hope that a real cure may actually
be possible in the future.
The genetic material of
HIV contains nine genes, three of which code for essential enzymes.
The first enzyme, reverse transcriptase (RT), copies the viral RNA into
the more common genetic material DNA. The second enzyme, integrase,
snips the hosts DNA and inserts the viral DNA sequence. Thus,
through the normal operations of the host cell, the HIV sequence is read
and translated into a long HIV protein strand. Finally, the third
enzyme, protease, cuts the protein strand at the correct points releasing
all the protein subunits needed for the virus to self-assemble a new virus
particle. In this manner, one infected CD4 cell can produce and
release hundreds of new HIV particles.
The focus of anti-HIV drug
development has been the design of drugs that specifically target the
function of one of these enzymes. To date, most work has focused
on two classes of drugs to defeat RT. The most common RT drugs,
the nucleoside analogues, include AZT, ddI, ddC, 3TC, and d4T. In
addition, there is also a group of non-nucleoside RT inhibitors, of which
nevirapine, loviride, and delavirdine have been studied in most detail.
Some success also has been achieved in developing drugs to inactivate
the protease enzyme. The major protease inhibitors include saquinavir,
ritonavir, indinavir, amprenavir and nelfinavir. As yet, only a
few drugs have been designed to interfere with integrase activity.
These anti-integrase drugs, as well as a number of additional RT and protease
inhibitors, are in the early stages of testing. As many as 20 anti-HIV
drugs can be used in a large number of effective therapeutic combinations.
Since the first anti-HIV
drug, AZT, came on to the market, the HIV virus has been able to defeat
drug challenges by developing drug-resistant mutants. It has been
estimated that each time HIV genetic material is duplicated, at least
one, and perhaps even two or more, duplication mistakes are made.
Every progeny virus that is different from the parent virus is a mutant.
Some mutations are deleterious to the virus, making it less infectious
or able to replicate; other mutations may benefit the virus. However,
the vast majority of mutations have little or no effect. Due to
the rapid rate of viral reproduction and the huge quantity of virus that
may be present in the body, a few viral particles that are resistant to
a specific drug may already exist in the body, even though the virus has
never come in contact with that drug. When this happens, the drug
may kill off the susceptible virus and the amount of virus in the blood
(viral load) will drop dramatically. The resistant virus, however,
is given a selective advantage; after a few months, it proliferates and
previous viral levels are again attained. Alternatively, no resistant
mutants may be present, but the anti-HIV drug may not completely suppress
viral replication. Viral load will drop, but a low level of viral
reproduction continues and eventually a drug-resistant mutant appears
Mathematical analyses have
shown that drug resistance to monotherapy (use of one drug) can arise
in only a few months. There is also a high possibility of a double
mutation that results in drug resistance to combined two-drug therapy;
however, there is an extremely low to negligible chance of a triple or
quadruple mutation that would lead to drug resistance to combination therapies
of three or more drugs. If HIV is challenged with high doses of
three or more drugs, viral replication should be completely arrested so
that reproduction cannot take place and triple or quadruple mutations
cannot accumulate over time. It is now recommended that aggressive
combination therapy be initiated as soon after initial infection as possible,
before the immune system has been severely degraded and while the viral
load is still relatively low and a wide variety of mutants have not yet
accumulated. This is called Highly Active Anti-Retroviral Therapy
It is now recognized that
any combination of drugs should include both AZT and 3TC. AZT is
a very potent anti-HIV drug. Although 3TC is less potent, the 3TC-AZT
combination acts as a toggle switch against resistance. AZT resistance
may arise, but 3TC keeps viral replication in check until resistance to
it occurs. Luckily, the mutation that confers resistance to 3TC
is the reverse of the mutation that gave AZT resistance, and the HIV becomes
susceptible to AZT again. AZT and 3TC combined with ddI or the
non-nucleoside RT inhibitor, nevirapine, have been found to reduce viral
load to nearly non-detectable levels; however, even better results may
be possible if AZT and 3TC are combined with a protease inhibitor.
On their own, the protease inhibitors have been found to be very potent
against HIV replication; however, resistant mutants quickly arise.
Resistance does not appear to be a problem when optimum levels of protease
inhibitor, AZT, and 3TC are used. For example, in clinical trials,
the continued use of a combination of indinavir, AZT, and 3TC resulted
in a sustained drop in viral load below detection level and a sustained
gradual increase in CD4 count.
It is theorized that an
early aggressive attack on HIV will stop replication, allow the immune
system to heal and, over time, allow the body to clear itself of virus.
There is some indication that severely damaged immune systems may not
completely heal, which leaves the difficult option of remaining on the
harsh drug therapies for a lifetime. A more appealing alternative
is to restore the immune system; this is being pursued by work on interleukin-2
and granulocyte-macrophage colony stimulating factor (IL-2 and GM-CSF).
Although combined therapy of these drugs is believed to invigorate the
immune system, substantial work remains to be done in this area.
No one yet knows how long
it will take to clear HIV from the body, if indeed this is possible.
Some long-lived body cells can function for three years before they are
replaced, and dormant HIV might shelter in them. In addition, some
clinicians fear that dormant HIV might shelter indefinitely in certain
specialized nerve cells or in the brain. Accordingly, only trial
and error experimentation in humans will tell when or if combination therapy
can be terminated. On a positive note, no evidence of HIV was seen
when lymph node biopsies were conducted on six patients after 78 weeks
on a combination of AZT, 3TC, ddI, ddC and interferon-alpha therapy.
In spite of the good news,
it is estimated that combination therapy will cost more than $13,000 per
patient per year, which will put a financial strain on the health-care
budgets of developed nations. This is a minor concern, however,
when compared to the plight of those living with HIV in developing nations.
The developing countries of the world contain 90% of all HIV infections,
and the poor who live there have no hope of ever affording anti-HIV therapies.
Unless the cost of anti-HIV drugs can be drastically reduced, the recent
successes in combination drug therapy will have virtually no effect in
stemming the world AIDS pandemic.
In September 1993, following
the annual meeting of federal-provincial-territorial ministers of health
in Edmonton, it was announced that the alleged failures of the Canadian
blood system to protect Canadians adequately from HIV infection would
be the subject of an inquiry. Mr. Justice Horace Krever, Justice
of the Ontario Supreme Court and Member of the Ontario Court of Appeal,
was named commissioner of the inquiry, which began 22 November 1993
and was conducted pursuant to Part I of the federal Inquiries Act.
On 14 February 1994, testimony
began at the inquiry into Canadas blood system. Public hearings
were held in every province. Prior to the start of the public hearings,
however, Canadas deputy health ministers suggested that major changes
be made to the blood system and recommended that the Canadian Red Cross
no longer control the purchases of blood products. A report by the
deputy ministers suggested that the Canadian Blood Agency assume this
The Krever Inquirys
485-page Interim Report was released on 24 February 1995. In addition
to making recommendations for improving the safety of Canadas blood
system, the report recommended that hospitals should contact individually
the estimated 3.5 million Canadians who had received blood transfusions
between 1978 and 1985, to inform them of the risks of HIV infection from
the transfusions and of the advisability of being tested.
In December 1995, as required
by section 13 of the Inquiries Act, Judge Krever issued notices
to a number of individuals informing them that the final Commission report
might assign blame to them. The right of the Commission to assign
blame was challenged in the Federal Court of Canada by the Canadian Red
Cross, the federal government, six provinces, five pharmaceutical companies,
and a number of individuals. In June 1996, Mr. Justice John Richard
allowed allegations of potential misconduct to stand against 17 Red Cross
and federal officials; however, he forbade the inquiry to assign blame
to 47 other people, including former health ministers and senior bureaucrats.
When the Commission was
established, its mandate was to investigate and assess the problems and
shortcomings of the Canadian blood system and make recommendations.
The Commissions recommendations were then to be used by the federal
and provincial governments to reorganize the Canadian blood system to
help ensure that such a tragedy would not occur again. Due to the
many delays experienced by the Commission, federal, provincial and territorial
health ministers felt the safety of the Canadian blood supply could not
wait until receipt of the final report. On 10 September 1996,
these ministers announced that a new national authority would be established
within one year, at arms length from all governments, to operate
the blood system.
On 26 November 1997, the
Health Minister released the final report of the Krever Commission, on
behalf of the federal government. Judge Krevers report dealt
with major topics related to the AIDS crisis, including:
the Canadian response
to threats to the safety of the blood supply caused by the emergence
safety in blood products
and plasma derivatives;
to the risk of HIV in the blood supply; and
the need for reform
of the current blood system.
In response to the Krever
Commissions recommendations, Canadian Blood Services (CBS) was set
up as a charitable, not-for-profit organization, to provide a safe and
reliable blood supply for Canadians. (Quebec has established its
own blood supply system called Héma-Québec.) CBS assumed responsibility
for the operation of Canadas blood supply system on 28 September
On 28 May 1998, the Health
Minister announced details of the new Canadian Strategy on HIV/AIDS (CSHA).
A significant feature of the new strategy is that, unlike previous HIV/AIDS
initiatives (Phases I and II of the National AIDS Strategy), it will not
be time-limited and will receive annual funding of $42.2 million from
the governments A-budget. Other elements of CSHA include:
a new policy to make
promising drug products available sooner to Canadians;
additional funding for
Correctional Service of Canada (CSC), directed toward the prevention
of the spread of HIV infection and the treatment of inmates in federal
correctional institutions who have AIDS; and
the establishment of
a 15-member Ministerial Council on HIV/AIDS, with membership drawn
from all areas of HIV/AIDS and representing broad expertise.
The Council is intended to provide the Minister of Health with advice
on the effective and efficient implementation of a shared national
HIV/AIDS strategy and will replace the National Advisory Committee
Parliament has produced
several reports on AIDS. In May 1986, the House of Commons Standing
Committee on National Health and Welfare tabled a report entitled AIDS
in Canada. In June 1990, the Parliamentary Ad Hoc Committee on AIDS
released its report, Confronting A Crisis. In November 1992, the
House of Commons Standing Committee on Health and Welfare, Social Affairs,
Seniors and the Status of Women held public hearings in the form of a
roundtable discussion with the Parliamentary Ad Hoc Committee on AIDS
to focus on renewed federal funding for the national AIDS strategy.
On 26 November 1992, the
Sub-Committee on Health Issues of the House of Commons Standing Committee
on Health and Welfare, Social Affairs, Seniors and the Status of Women
began public hearings on a study of HIV-infected blood and other
related matters. The Sub-Committees report, entitled Tragedy
and Challenge: Canadas Blood System and HIV, was tabled in the
House of Commons in May 1993 and made nine recommendations. The principal
recommendation was for a public inquiry into Canadas blood system.
The efficiency and safety of the system was the primary focus of the report,
which included a full examination of the events of the 1980s when the
blood supply became contaminated by HIV.
The House of Commons Sub-Committee
on HIV/AIDS was formed in December 1994; its first report, entitled A
Study of the National AIDS Strategy: Report of the Sub-Committee
on HIV/AIDS, was presented to Parliament one year later. The
report contained 23 recommendations aimed at strengthening the federal
governments response to the AIDS epidemic. The Sub-Committee
then examined the issue of compassionate access to experimental drugs
for people who are catastrophically ill and, in October 1996, submitted
their findings to Parliament in the report entitled Compassionate Access
to Investigational Therapies: Second Report of the Sub-Committee
on HIV/AIDS. This document made eight recommendations focused on developing
mechanisms to liberalize access to unproved drugs while still maintaining
the rigour of clinical drug trials.
June 1981 - AIDS was first
reported by the Centers for Disease Control (CDC) in the United States
and was incorrectly attributed only to promiscuous homosexual activity
February 1982 - AIDS was
first reported in Canada.
June 1982 - CDC reported
that 20% of the U.S. patients were heterosexual IV drug abusers of
July 1982 - CDC reported
that hemophiliacs had contracted AIDS through blood products.
May 1983 - AIDS virus
LAV (lymphadenopathy associated virus) was discovered in France.
September 1983 - National
Advisory Committee on AIDS was established in Canada.
April 1984 - AIDS virus
HTLV-III (human T-cell lymphotropic virus III) believed to be the
same as the LAV virus was discovered in the U.S.
March 1985 - U.S. approval
of the first commercial screening test for the presence of AIDS virus
antibodies in blood.
May 1985 - Heat treatment
for hemophilia blood complexes was initiated in Canada (100% in place
by June 1985).
November 1985 - Blood screening
of donated blood for AIDS virus antibodies began in Canada.
1 May 1986 - Minister of
National Health and Welfare announced a $39-million, five-year plan to
support activities dealing with AIDS in Canada.
8 June 1988 - The Minister
of National Health and Welfare allocated an additional $129 million
over five years to the federal governments AIDS program.
16 October 1989 - The Minister
of National Health and Welfare announced that a new HIV Clinical Trials
Network would be developed in Canada by the University of British Columbia
at St. Pauls Hospital in Vancouver. The Network would improve the
access of patients and physicians to clinical trials of drugs and vaccines
for treatment of AIDS and HIV infection.
24 April 1990 - The Minister
of National Health and Welfare announced the federal governments
intention to establish a National Treatment Registry for persons with
HIV/AIDS. The Registry would be known as the Treatment Information
System for AIDS and HIV Infection (TISAH) and be based at the University
28 June 1990 - The Minister
of Health and Welfare, Mr. Beatty, presented the National Strategy on
AIDS. The Strategy did not include any new federal funding; existing
funds were re-allocated.
October 1990 - Anonymous
blood testing of 67,078 newborn babies born in Ontario between October
1989 and July 1990 showed that 21 tested positive for HIV antibodies,
for an indicated infection rate of 3.1 per 10,000. This rate was about
double that anticipated. Where a blood test indicates that the mother
is infected with HIV, the newborn has a 30-50% probability of being infected
30 October 1991 - The Minister
of Health and Welfare, Benoît Bouchard, announced that the Federal Centre
for AIDS would be phased out and its duties assumed by other units of
the department. A national AIDS Secretariat was created to serve
as the departmental focal point of HIV/AIDS issues. The Laboratory
Centre for Disease Control would carry out AIDS surveillance and epidemiological
research as well as biomedical/laboratory research. The Health Services
and Promotion Branch would handle AIDS education and prevention strategies
and funding for national and community-based groups as well as for non-governmental
organizations. A new unit of the Branch would be created to address
care and treatment issues.
January 1992 - The Ontario
Ministry of Health set up anonymous HIV-testing centres across the province.
The program was to cost $600,000 and be part of a $2.1 million AIDS program
announced by the government in October 1991. Many AIDS workers believed
that the anonymity of the testing would encourage persons at risk to come
forward to be tested.
July 1992 - At the VIII
International Conference on AIDS in Amsterdam, a topic of major interest
was the possibility that AIDS, or a condition similar to AIDS, may occur
in the absence of infection by either HIV-l or HIV-2, the viruses believed
to be responsible for the disease.
15 April 1993 - The Hospital
for Sick Children in Toronto announced that it would notify the families
of children who received blood transfusions between 1980 and 1985 that
they might have been exposed to HIV. It was estimated that some 17,000
former patients might be involved. The program was to start by sending
letters to some 1,700 families of former pediatric heart patients.
The program was to be expanded if the initial effort was successful.
In mid-June, the Hospital announced that six former patients had been
found to be HIV+.
24 November 1993 - The Hospital
for Sick Children in Toronto announced that 17 of the 1,700 pediatric
heart patients contacted in April 1993 had tested positive for HIV.
This 1% infection rate was higher than had been expected. The hospital
set up a hot line for parents seeking information on transfusions
during the 1980-1985 period.
7 June 1994 - At its annual
meeting in Halifax, the Canadian Hospital Association announced that it
would develop a national campaign urging persons who had received blood
between 1978 and 1985 to be tested for HIV. The campaign would involve
individual hospitals, and the federal and provincial governments.
Three weeks later, the Ontario Hospital Association launched a province-wide
campaign urging blood recipients from the period in question to be tested
25 June 1994 - After two
years of discussion and debate, the Canadian Red Cross Society formally
announced plans to construct a $150-million blood-processing plant near
Halifax. The plant would be run jointly by the Red Cross and Miles
Incorporated, a subsidiary of the German pharmaceutical company, Bayer
AG. The plant was scheduled to open by 1997.
July 1994 - A paper in the
journal Science quoted a WHO estimate that, worldwide, at least
3 million people had developed AIDS and that, cumulatively, at least 15
million people had been infected by HIV. It was estimated that, cumulatively,
by the year 2000, a total of 30 to 40 million people would have been
infected by HIV since the start of the epidemic.
19 July 1994 - A Reuter
report in The Globe and Mail stated that the U.S. National Task
Force on AIDS Drug Development had been told that some medical firms planned
to terminate their AIDS research if the current approach to finding a
therapy proved fruitless. The most recent avenue of research focused
on protease inhibitors; protease is an enzyme essential to
the replication of HIV. This announcement was in line with information
presented at the X International Conference on AIDS (see below).
7-12 August 1994 - The X
International Conference on AIDS was held in Yokohama, Japan, the first
ever in Asia. The conference included few reports on new results
of AIDS drugs or therapies, and no indication that vaccine development
was a realistic hope for the near future. One important announcement
was that zidovudine (AZT), given to HIV-positive pregnant women, can protect
their babies from infection. The dominant theme of the conference
was that more resources needed to be directed to basic research on the
virus and on the human immune system. There was an indication that
the U.S. National Institutes of Health might divert some funds away from
clinical trials of AIDS drugs towards basic research, although vaccine
research and testing might not be affected. The conference organizers
planned to stage the conference every two years in future, instead of
continuing the annual format.
31 August 1994 - A report
in The Globe and Mail stated that the federal Laboratory Centre
for Disease Control estimates that in Canada between 940 and 1,440
persons became infected due to transfusion in the period 1978-85
and that as many as 245 persons might still be unaware of their HIV-positive
status. The figure of 1,440 was described as the worst case
16 December 1994 - The WHO
announced that the first major human tests of AIDS vaccines would be carried
out with heterosexual male drug users in Thailand and homosexual men in
Brazil as the key volunteers.
1 May 1995 - The Secretary-General
of the Canadian Red Cross Society stated that, although Canadas
blood supply today is as safe as that of any developed country, blood
recipients still have approximately a 1-in-50,000 chance of contracting
HIV through blood and blood products. This continuing small risk
of infection is in part due to the fact that a blood donor may be infected
by HIV but test negative for HIV antibodies at the time of donation.
29 June 1995 - Health Minister
Diane Marleau announced funding for a national HIV/AIDS Treatment Information
Network to be administered by CATIE, the Community AIDS Treatment Information
Exchange of Toronto. The network would provide information on:
the diagnosis and treatment of HIV and AIDS; clinical advances in the
field; drug and non-drug therapies; medical and complementary therapies;
and where to obtain care. Health Canada would provide $4.9 million
over three years to establish the Network, which would be operational
by the end of 1995.
7-12 July 1996 - Vancouver
hosted the XI International Conference on AIDS. Data presented at this
conference showed that it should be possible to transform HIV/AIDS from
a terminal disease to a chronic controllable condition through the use
of drug cocktails of three or more anti-HIV drugs.
10 September 1996 - Federal,
provincial and territorial Ministers of Health agreed to establish, within
one year, a new national authority to operate Canadas blood system.
The new blood authority would operate at arms length from all governments
and be responsible for managing all aspects of an accountable and fully
integrated blood system. Quebec decided to establish a separate
agency of its own.
September 1997 - Health
Canada in close collaboration with national stakeholders involved
in HIV/AIDS issues and under the direction of the Minister of Health,
Allan Rock began a national consultation process to obtain input,
suggestions and advice, from both organizations and individuals, to help
Health Canada shape the direction and priorities for Phase III of the
National AIDS Strategy which became known as the Canadian Strategy on
HIV/AIDS (CSHA). CSHA was to begin in April 1998 and continue for
a further five years following that date.
September 1998 - Canadian
Blood Services took over the operation of Canadas blood supply.
AIDS: The Unanswered
Questions. Science, Vol. 260, 28 May 1993, pp. 1219,
Canada, Health and Welfare.
Building an Effective Partnership: The Federal Governments Commitment
to Fighting AIDS. Ottawa, 1990.
HIV and AIDS:
Canadas Blueprint. Ottawa, 1990.
Canada, House of Commons,
Standing Committee on National Health and Welfare. Report on
AIDS In Canada. 9 May 1986.
DeVita, Vincent T. Jr.,
Samuel Hellman, and Steven A. Rosenberg. AIDS Etiology, Diagnosis,
Treatment and Prevention. Third Edition. J.B. Lippincott
Greene, Warner C.
AIDS and the Immune System. Scientific American,
Special Issue, September 1993, pp. 98-105.
MacDonald, Hon. David. Chairperson.
Confronting A Crisis: The Report of the Parliamentary Ad Hoc Committee
on AIDS. June 1990.
Nossal, Sir Gustav J.V.
Life, Death and the Immune System. Scientific American,
Special Issue, September 1993, pp. 52-63.
Pantaleo, Giuseppe, Cecilia
Graziosi, and Anthony S. Fauci. The Immunopathogenesis of
Human Immunodeficiency Virus (HIV) Infection. The New England
Journal of Medicine, Vol. 228, No. 5, 4 February 1993, pp. 327-335.
Royal Society of Canada.
AIDS: A Perspective for Canadians. Summary Report and Recommendations,
* The original version of this Current
Issue Review was published in November 1993; the paper has been updated
regularly since that time.