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Past Issues
Volume 15, number 9
September 2001
Contents
Boundless Compassion (ignore the
fine print)
Is Catholic healthcare stressing dogma at mercy's expense?
Gettin' Snippy
New York State's HIV SNPs are coming
Fiddling While Lagos Burns
Will Nigeria's emerging national tragedy finally be addressed?
Don't Slam the Door on Your Way Out
"Endpoints" in HIV clinical trials don't mean the end of the line
Taking the Air in Buenos Aires
Treatment strategies evolve at Argentina conference
When Conscience Limits Care
By Kelly Safreed Harmon
An HIV-positive woman elects to have a Cesarean section to minimize
the risk of infecting her baby. She asks the surgeon to tie her
tubes during the procedure to prevent further pregnancies. He refuses
and tells her she will have to have a separate operation at a different
hospital at another time if she wants a tubal ligation. She later
finds out her insurance won't pay for this operation at any hospital
— and that it won't pay for birth control pills, either.
A woman has been sexually assaulted and is rushed to the nearest
emergency room for care. The risk of HIV infection is discussed
and she takes a test, but she is not told that using condoms during
the next few months could prevent her husband from becoming infected.
She is also not offered emergency contraception or told that a different
hospital might give her something to keep her from becoming pregnant.
Since emergency contraception must be provided within 72 hours of
sexual intercourse, not knowing about this option resulted in her
pregnancy — and placed her in a painful personal dilemma of
deciding whether to have an abortion.
These aren't real stories, but they could be. Many people do not
realize that the extent of care offered by medical facilities that
operate under the guidance of the Catholic Church may not be equal
to care available from other, non-Catholic, health providers. Some
interpretations of Catholic healthcare guidelines may prohibit medical
staff from educating patients about condom use to avoid HIV infection,
from honoring a patient's end-of-life requests and from even mentioning
the option of abortion or providing referrals to other providers
who will.
These exceptions to comprehensive care may not become apparent
until a medical need arises and a requested service is denied. In
cases where the full range of medical options is not discussed and
no referral is offered, the gap in care may not become apparent
at all. This is a particular problem for people with HIV, who often
have complicated and intertwining needs for treatment, diagnosis,
counseling and support. It has been recognized — and mandated
in some states' HIV care guidelines — that services for HIV-infected
people should be bundled together in facilities that enable one-stop
shopping for personal and family healthcare. It's also widely recognized
that barriers to care — whether geographic, economic, cultural
or social — limit the quality of care that people receive,
which can result in poorer outcomes for individuals and their families.
Finally, the experience of the HIV community has made it clear that
an individual's full and free participation in treatment decisions
encourages a greater investment in the outcome of those decisions
— and restricting patient choice undermines the engagement
of patients with their health needs.
What the Church Guidelines Mean
The guidelines that limit services at Catholic healthcare facilities
are derived from elemental Church doctrines about the sacredness
of human life; that life begins at the moment of conception and
that interfering with the natural order of reproduction, life and
death is wrong. Based on these core convictions, the personal behavior
of Catholics is regulated by Church edicts against artificial contraception,
artificial fertility techniques, abortion, euthanasia and the death
penalty. In addition, the Church attempts to limit its complicity
in these activities by not enabling or facilitating their practice
by agencies and resources under its control.
The National Conference of Catholic Bishops, which represents the
Roman Catholic Church in this country, has produced a document known
as "Ethical and Religious Directives for Catholic Health Facilities."
Often referred to as "The Directives," it is the authoritative basis
for limiting the medical services that Catholic healthcare providers
may offer.
While Catholic providers must "adopt these Directives as policy,
[and] require adherence to them ... as a condition for medical privileges
and employment," in practice, various decision-makers are able to
interpret and apply the Directives differently. Generally, it is
the responsibility of a local bishop to determine how the Directives
will translate into policy at institutions under his purview. A
conservative diocese may interpret the Directives narrowly and demand
full adherence, while facilities under less strict jurisdiction
may skirt some guidelines and tease out loopholes in others. Individual
providers may choose to ignore certain prohibitions altogether.
Because interpretations of the guidelines are determined regionally,
and because it is difficult to obtain quantitative information about
the extent to which restrictions are actually imposed or evaded,
no one can precisely assess to what degree the Directives are limiting
access to comprehensive healthcare. But from different parts of
the United States, both studies and anecdotal reports indicate that
this is not a hypothetical issue.
Many people don't realize that a significant number of hospitals
and other healthcare facilities in their community may be obligated
to follow Church ethical guidelines. An individual may select a
doctor from a list of in-plan providers without understanding that
the doctor admits patients to a hospital with limited care. Many
people, because of geographical constraints, may have no convenient
alternative to Catholic healthcare. Still others may find their
medical options limited because of where an ambulance took them
for emergency care.
Catholic facilities and agencies do not always make it clear in
advertising and patient handbooks what aspects of care they restrict.
Depending on a bishop's direction, the facility's administration,
or an individual provider's conscience, some or all of these options
may not be available:
- Medical staff may be prohibited from educating patients about
using condoms to prevent HIV and STD infections — even patients
who are in sero-discordant sexual relationships. The prohibition
may also extend to people having homosexual intercourse where
conception is not an issue. Some providers may also refuse to
discuss harm-reduction techniques for active drug users.
- HIV-positive women with multi-drug resistant virus could possibly
be denied access to an experimental drug if a clinical trial requires
that birth control measures be used.
- Unfortunately, it is common for women to find out they are HIV-positive
at the same time they learn they are pregnant. At a Catholic facility,
the provider may be forbidden to discuss a woman's option to abort
the pregnancy.
- Staff at a Catholic facility may refuse to honor a patient's
end-of-life request to reject artificial nutrition and hydration.
- Some Catholic facilities may not offer referrals — or even
inform patients about the opportunity for services they do not
provide. This leaves the least informed patients with an impression
that no other options exist. Even facilities that choose to provide
referrals can create unreasonable barriers by requiring that patients
go elsewhere for important aspects of their care.
Healthcare advocates are also concerned about Church lobbying to
restrict research on stem cells, restrictions on in vitro
fertilization, artificial insemination, sterilization and tubal
ligation. The experimental technique of "washing" sperm to safely
allow an HIV-infected man to father a child may also fall outside
of Church guidelines for natural insemination.
Merger Mania
While healthcare providers affiliated with other religious bodies
may impose limits on certain aspects of care, primarily abortion,
a national organization called The MergerWatch Project asserts that
none are as restrictive as Catholic healthcare providers. More than
11 percent of the nation's community hospitals are Catholic facilities,
and they account for more than 16 percent of community hospital
beds, according to the Catholic Health Association of the United
States. Some Catholic hospitals and hospital networks further extend
their ethical reach by applying the guidelines to all affiliated
outpatient clinics and even to non-Catholic tenants of Church-owned
office facilities.
Today, many financially secure non-profit Catholic hospitals have
become key players in what some have called "merger mania." As the
trend to consolidation within the healthcare industry continues,
an increasing number of resources are coming under the control of
a relatively small number of decision-makers. When secular healthcare
organizations agree to merge or form partnerships with Catholic
hospitals and healthcare systems, the terms of these agreements
can extend Catholic ethical policies to the non-Catholic facilities.
For a secular organization pressed to merge out of financial necessity,
adopting the Catholic restrictions as part of an alliance that keeps
the doors open may seem like a small compromise.
Other quasi-business entities that affect people's healthcare can
also be governed by religious guidelines. Non-profit HMOs and insurance
companies guided by Church policies have been allowed to limit the
care available to their customers. Some insurance beneficiaries,
including people who receive health insurance through Medicaid,
have been shuttled into these HMOs without being told that they
will not receive comprehensive medical care.
For non-Catholic hospitals entering business relationships with
Catholic hospitals, one strategy to preserve family planning services
has been to negotiate exceptions to the rules at the non-Catholic
sites. But recently, the National Conference of Catholic Bishops
has become more assertive with its members and their healthcare
facilities about implementing the Directives. At a June 2001 conference
in Atlanta, the Conference declared sterilization to be "intrinsically
immoral" — implicitly telling Catholic hospitals that their
non-Catholic partner hospitals should not be providing sterilization
services at all.
Lois Uttley, vice president of The Education Fund of Family Planning
Advocates of New York State (MergerWatch's parent organization),
suggests that the Conference "cracked down" as a direct response
to some of the creative compromises that have been used to skirt
Catholic regulations. "I think what this signals is a tightening
of the hold of the hierarchy," she warns.
With Catholic providers strengthening their control over an increasingly
large portion of the healthcare marketplace, it is reasonable to
anticipate that denials of service arising from ethical mandates
will multiply in the future.
Where the System Breaks Down
It's often suggested that the best accommodation between reality
and the restrictions is a "work-around" tactic commonly used by
sympathetic medical personnel at Catholic healthcare facilities.
It's not known how many or how often providers sidestep their employers'
rules and simply share information they deem appropriate with patients
on a private basis, but some say this is the best way to help patients
without making waves.
Uttley holds that this is no solution at all."I call it the 'don't
ask, don't tell' policy in healthcare, and it's a very dangerous
policy,"she says. "It opens the door for anti-choice or anti-gay
people in the hospital to 'rat on' physicians who are violating
the [restrictions]." Physicians and nurses can face grave repercussions,
including dismissal — particularly those who signed statements
pledging adherence to the hospitals' ethical policies. Refusing
to sign such a statement is not necessarily an effective means of
protection. At least two physicians who did so have been fired or
refused admitting privileges, according to Uttley.
Religious exemptions from city, state or federally mandated standards
of care have been granted in exchange for pledges to refer patients
to appropriate service providers when ethical restrictions limit
that care. Yet the mechanisms for monitoring and enforcing the effectiveness
of these makeshift solutions have received little attention. How
can the funding agency insure that people are properly referred
or even informed that referrals are available? Furthermore, referral
may not be practical or humane in some cases. A terminally ill patient
who has requested that artificial nutrition and hydration be removed
may not realistically be able to arrange for care at another facility
during his or her last days.
Uttley also cautions about grave shortcomings in the referral policies
that some Catholic facilities enact to mollify their critics. She
points to New York State's policy of providing Catholic facilities
with blank envelopes containing referral lists compiled by the state
department of health. "This envelope is simply handed to the patient.
In our view it's an unconscionable compromise. An appropriate referral
is to say, 'I don't have this service available, but let me call
such-and-such a place and make an appointment for you.'" Some feel
an even better accommodation would be to provide transportation
to and from the off-site provider.
GMHC's Director of Health Policy, Susan M. Dooha, agrees. "The
problem with referral schemes is that they compromise the 'one-stop
shopping' principle that has been proven essential to effective
healthcare, and creates additional barriers for already overburdened
HIV-positive people."
Dooha maintains that accepted standards of care should be maintained
when church-affiliated healthcare providers enter into contracts
with government. "The state," she says, "which represents you and
me, shouldn't allow watered-down care to be paid for with our tax
dollars. If a hospital receives Medicaid funding, for example, the
public should expect to find a full range of Medicaid-covered services
offered. And if an HIV provider is dependent on public money, it
should be expected to provide barrier-free care. If you ask people
to jump extra hurdles to access essential services that should be
part of a package, then you can expect that someone will be harmed
when they don't get the care they need. Government has a duty to
prevent that harm."
How Healthcare Advocates Are Responding
Healthcare advocates, especially those focusing on reproductive
rights, have formed networks that oppose religiously influenced
healthcare on the local, state and national levels. Different groups
are working on various priorities and strategies. MergerWatch, for
example, monitors business transactions that threaten reproductive
healthcare and helps community members fight to retain reproductive
health services in the new networks.
On a different front, California advocates scored a victory in
2000 with legislation to mandate that consumers are informed about
providers with restrictive policies. The legislation requires insurers
to clearly disclose in provider guides and promotional materials
which services may be restricted.
Many established groups and coalitions actively working on these
issues offer HIV/AIDS organizations and concerned members of the
public an array of resources and opportunities for local action.
Lourdes Rivera of the National Health Law Project recommends that
local advocates "really scrutinize the services currently available
in the community." By doing an inventory of what is and isn't provided,
advocates can arm themselves to fight efforts to further reduce
patients' options.
MergerWatch's Uttley urges people to document cases in which patients
have been denied information or services. MergerWatch and other
groups utilize this information in their campaigns. (To report cases
to MergerWatch, go to www.mergerwatch.org.)
This information can also be used to alert the community about
objectionable policies already in place. "Look at how a community
hospital advertises itself," says Rivera, who is managing attorney
of her organization's Los Angeles office. A hospital may claim to
offer a "full" array of HIV/AIDS services or reproductive services,
for example, while it actually adheres to religious restrictions.
People make choices about care for themselves and their families
"based on what the institutions say they are providing," Rivera
states.
The reproductive health community has been actively alerting affected
communities, including those involved with HIV/AIDS, to the public
health implications of religious-based limits on access to care.
GMHC's Dooha encourages HIV/AIDS organizations to grapple with this
issue, noting that dealing with restrictions to access can help
make specific prevention and care measures more effective. "People
with HIV don't need single services in a vacuum," she says. "Quality
HIV care involves the whole ball of wax."
An Introduction to New York's HIV
Special Needs Plans By Naomi
Seiler
An HIV Special Needs Plan, or HIV SNP (pronounced "HIV snip"),
is a new kind of Medicaid plan for people with HIV in New York State.
Medicaid is the government health insurance program that provides
coverage for people with limited incomes. (Medicaid is not the same
as Medicare, which is a federal health insurance program that provides
for people who are elderly or disabled.) Medicaid is the source
of healthcare coverage for more than 65% of New Yorkers with HIV/AIDS.
Why Were Medicaid HIV SNPs Created?
When it began, Medicaid was a fee-for-service program. This means
that the government pays providers, like doctors, clinics and hospitals,
for each of the services they give to people with Medicaid. In most
states, Medicaid has been shifting to a managed-care system in recent
years. In a managed care Medicaid plan, the government pays a health
plan a certain dollar amount for each Medicaid beneficiary enrolled,
and in return the plan provides for most of the enrollee's care.
This change was designed to help control costs within the Medicaid
system.
New York's HIV SNPs are a type of Medicaid managed care plan. But,
they are only for people with HIV and their children. These special
plans were proposed to coordinate the complex array of medical and
social services needed to help support the health of people living
with HIV. SNPs will be expected to manage HIV disease comprehensively
by offering medical care and supportive social services, like treatment
education and adherence programs, all under the supervision of a
case manager. Medical and social service providers specializing
in HIV have been forming networks and contractual relationships
among themselves in preparation for the SNPs. As New York pioneers
this HIV-specific managed care plan, Medicaid programs in other
states will be watching closely.
In New York State, as in many other states, managed care is changing
from a voluntary to a mandatory system. New Yorkers with Medicaid
have been receiving notices that they must choose a Medicaid managed
care plan. However, people with HIV are exempt from this shift to
mandatory managed care and, for now, they can choose to stay in
traditional, fee-for-service Medicaid.
Will People with Medicaid and HIV in New York Have to Join an
HIV SNP?
Initially, New York's HIV SNPs will be voluntary. This means that
people with HIV who have Medicaid can either stay in regular Medicaid,
choose a "mainstream" Medicaid health plan, or choose an HIV SNP.
They will not lose their Medicaid benefits if they do not enroll
in an HIV SNP.
But sometime in the next few years, managed care for New Yorkers
with HIV may become mandatory. This means that people with HIV who
receive Medicaid may have to choose an HIV SNP or a Medicaid "mainstream"
health plan, and won't be able to stay in fee-for-service Medicaid.
Some groups of people, such as those who are homeless, will still
be exempt from mandatory managed care and will be allowed to stay
in traditional Medicaid if they wish.
What Are the Differences between Traditional Medicaid, "Mainstream"
Medicaid Managed Care Plans, and HIV SNPs?
HIV SNPs are different from traditional Medicaid in several ways.
First of all, they are managed care plans. Like "mainstream" Medicaid
health plans that already serve people with and without HIV, HIV
SNPs receive a certain amount of money from the government for each
person enrolled. In turn, HIV SNPs provide their enrollees with
most of their healthcare.
Here are some similarities and several important differences.
1. Benefits: People in HIV SNPs and Medicaid managed care plans
get all the same benefits as people in traditional Medicaid. Most
of the benefits are given directly by the SNP, but others are given
outside the SNP. For example, a SNP may provide addiction counseling
directly, but refer a client to an outside methadone program.
2. Case management: An HIV SNP is supposed to create an "umbrella"
of services to meet the special needs of people with HIV and their
children. So, HIV SNP enrollees will have case managers to help
coordinate all of the medical and social services that members should
receive.
3. Providers: In traditional Medicaid, people can see any providers
(doctors and hospitals) who take Medicaid. In an HIV SNP, enrollees
can usually only go to providers who participate in the health plan.
These providers make up the health plan's network.
4. Primary Care Providers: Members of an HIV SNP have one doctor
who is a primary care provider, or PCP. The PCP coordinates the
enrollee's medical care, and if the enrollee wants to see a specialist,
she or he usually has to get a referral from the PCP. In an HIV
SNP, all primary care physicians are "HIV specialists," which means
they have at least a minimal amount of training and experience in
treating people with HIV/AIDS.
5. Specialists: People in traditional Medicaid can see any specialist
who takes Medicaid. People in "mainstream" Medicaid managed care
plans, including SNPs, will usually need a referral from their primary
care physicians and can only see specialists in the plan's network.
Questions? Contact GMHC's Managed Care Coordinator: 212/367-1126
Be Aware of Barriers to Care: Family Planning Services
HIV SNP enrollees are supposed to be able to get family planning
and reproductive health services from any Medicaid provider, whether
or not the provider is a part of the SNP's network. Enrollees do
not need a referral from their PCP or approval from the plan. The
SNP must tell every enrollee of childbearing age about this right,
and must give her a list of family planning providers.
One network that has applied to become an HIV SNP in New York is
Fidelis Healthcare, a Medicaid health plan sponsored by the Catholic
Church. Because Catholic healthcare directives forbid offering most
family planning services, the Fidelis SNP must refer its enrollees
to out-of-network providers. In the past, religious healthcare providers
have sometimes refused to inform beneficiaries about the full range
of family planning options and some have refused to supply the mandated
referrals or have created other barriers to care. Enrollees in the
Fidelis SNP should be especially careful to insure they are offered
comprehensive care and the full range of services.
Family planning services include:
- Contraception
- Sterilization
- Screening, diagnosis, and referral to participating providers
for pregnancy
- Medically necessary abortions and, for NYC residents, elective
abortions.
- Pap smears
- Pelvic and breast exams
- STD testing and treatment
These services include all necessary education and counseling.
Family planning services also include pre- and post-test HIV counseling
and blood testing, when it's part of a family planning appointment.
HIV SNPs have to provide counseling for all pregnant women, prenatal
care including treatment to prevent transmission of HIV to the baby,
plus testing to diagnose or rule out HIV infection in exposed infants.
Minors have the same right to family planning services in HIV SNPs
as adults. The plan must keep all information about family planning
confidential, for both adult and minor enrollees.
It's Not Too Late to Start Saving
Lives in Nigeria By Yinka Adeyemi
Courtesy of AIDS News Service, Vol. 3, No. 2, a publication of Journalists
Against AIDS (JAAIDS) Nigeria. www.nigeria-aids.org
In January of 2001, Mauritania, a country with one of the lowest
reported HIV prevalence rates in Africa, took a step that Nigerian
leaders neglected to take more than 15 years ago: The country's
Senate held a Special Session on HIV/AIDS, inviting experts to speak
on the nature of the epidemic, and to suggest ways to nip it in
the bud, even as the epidemic ravages the rest of the African continent.
The Mauritanian Senate recognized the urgency of concerted action
against the epidemic, and suggested the introduction of sexual education
in schools as well as a privately managed national agency to play
an advocacy role. It is a refreshing, bold step from a country about
the size of a few local government areas in Nigeria.
About 1989, when neighboring countries were reporting an outbreak
of HIV/AIDS, Nigeria reported only 11 cases of HIV infection. Officials,
unwisely and against every historical epidemiological trend, diverted
attention from the virus, focusing instead on mosquitoes and malaria.
As they did so, and fuelled by apathy and delusion, the virus silently
crept into the nooks and crannies of Nigeria, infecting millions
and killing thousands.
Due to bad policy, many Nigerians will have to suffer, and many
will die from the virus, barring the sudden development of an efficacious
vaccine. Today, even if we take the grossly underestimated figures
used by the Nigerian government, the country has a whopping 2.6
million HIV/AIDS cases. And this is primarily the result of callous
inaction and arrogance on the part of government. Information was
adequate, but officials simply refused to use it or even take it
seriously.
It was a familiar pattern in many African countries, with the possible
exception of Uganda and a few East African countries. Indeed, rather
than begin early intervention to educate and stem the spread of
HIV/AIDS, African countries initially engrossed themselves in a
wasteful debate over the origin of AIDS.
It all probably started in 1985, at the First International Conference
on Virus-related Cancers in Dakar, Senegal, in which I participated
along with co-discoverer of HIV, Dr. Robert Gallo, and the head
of the OAU Scientific Commission, Dr. Williams. It was at this conference
that respected scientists articulated their theory about Africa
as the origin of not only AIDS, but of many other frightening diseases
also. For instance, Dr. Kevin De Cock argued that Ebola virus, Marburg
virus and Lassa fever, all thought to be new diseases, "turned out
to have been endemic in Africa." Meanwhile, Gallo aired his African-Monkey
Connection theory.
Said Gallo at the Dakar Conference: "Viruses closely related to
HTLV (Human Type Lymphotropic Virus), but distinct from it, have
been isolated from Old World monkeys. This and other facts led us
to propose that the ancestral origin of HTLV is Africa."
As I wrote in a syndicated column in 1985, to a people who, barely
20 years earlier were under the yoke of Western colonialism, the
Africa-Monkey argument was another indication of racism by Western
scientists. Therefore, because of our history of colonialism and
slavery, the first impulse of African leaders and opinion formers
was to defensively repudiate such Western claims with a display
of nationalistic garb.
But while Africans were engaged in this needless debate, intense
anti-HIV/AIDS efforts were going on in the West. Pressure groups
were forming and national education campaigns on HIV were being
launched everywhere.
In Nigeria of 1985, it was difficult to meet one person who did
not view HIV/AIDS as a "disease of the white man," and the African
connection theory as more evidence of the Western association of
Africa with everything negative. Well-meaning people who dared to
preach abstinence or condom use as a way to curb the spread of HIV
were routinely laughed at as victims of malicious Western propaganda.
In the prevailing environment, therefore, many did not see the need
for behavioral change. Unfortunately, that attitude persisted for
years. Yet, many science writers knew that a major outbreak in Nigeria,
with its 100 million people, was only a matter of time.
Such was the prevailing attitude in Nigeria, and it was the principal
reason the National Action Committee on AIDS (NACA) was not inaugurated
until last year. The Committee's work is cut out for it, and the
challenges are daunting.
Although the death of popular musician Fela Anikulapo-Kuti and
the admission by his world-renowned physician brother, Professor
Olikoye Ransome-Kuti, that the musician died of AIDS has promoted
some awareness and encouraged the use of condoms, many Nigerians
still remain unpersuaded. A survey of some Nigerians, selected randomly
over two weeks in January 2001, suggests that many are armed with
information about the disease. But even those who reported adequate
knowledge said they did not see any reason to wear condoms because,
"I do not sleep around" or "I know the people I sleep with." Less
than 5 percent said they would consider voluntary testing, while
the majority said they would rather not know about their HIV status
in order not to be ostracized by friends and family.
That is not an irrational fear in Nigeria today. Fela's brother
suffered unprecedented assault in the press by commentators who
accused him of a criminal vendetta against the more popular musician.
Worse than ostracism is the likelihood of an HIV-infected person
being fired from gainful employment.
There appears to be no recourse in Nigeria for such people who
are wrongfully dismissed from their jobs. In a shocking case that
resonated throughout Nigeria, a judge on January 22, 2001, disallowed
a former hospital worker, Georgiana Ahamefule, who was dismissed
from her job, from appearing in her defense out of fear that she
would spread the virus in court! Her case remains unresolved.
The attitude of the judge underscores a desperate need in Nigeria
for a national education program on HIV/AIDS, along with comprehensive
programs to combat the virus, including condom use, vaccine tests,
counseling and treatment.
Political leaders should begin to speak openly about the virus
and participate in public blood screenings. Of course, it is probably
too late for 2.6 million Nigerians, who, unfortunately, will eventually
become the cadavers next door. But far too many Nigerians remain
at risk. And they must be saved.
*Yinka Adeyemi is a Columnist for the Daily Times of Nigeria
and author of "A Media Handbook for HIV Vaccine Trials for Africa"
published by UNAIDS.
Death as an Endpoint
By Carlton Hogan, University of Minnesota, Coalition for Salvage
Therapy
Killing PWAs for Science, or Providing Information to Prolong
Life?
In clinical trials of HIV drugs, the term "endpoint" is often misunderstood
as meaning the end of the trial or the end of a participant's enrollment
in the trial — Sayonara, Baby. This can be the case, but not
necessarily. As we learn more about the long-term effects of HIV
and the drugs used to treat it, follow-up after the main endpoints
have been reached appears increasingly important to ascertain the
overall risk/benefit ratios of various treatments over time.
"Endpoints" are actually just the key data items a trial is focused
on. Or to put it another way, they are the data necessary to prove
or disprove the trials' central hypothesis. They can be events in
a person's life that serve as meaningful milestones for deciding
if a treatment is effective. Some common endpoints are viral load,
CD4 count, toxicity, quality of life, opportunistic infections (OIs),
and death. If, at the end of a randomized trial, there is a difference
between the tallies of endpoints in a treated group compared to
an untreated group, it is attributed to the effect of the treatment.
In the early days of AIDS research, there were vehement and vocal
protests against clinical trials that used death as a key data item.
Loud sloganeering protested "killing for science," but in fact,
while these trials may or may not have shortened or lengthened life,
the outcomes were due to the disease and the drugs being tested
— not the choice of the endpoint. Using the "death endpoint"
simply meant that dates of deaths were recorded, and that ample
numbers of people were enrolled so that if, in fact, there were
a difference in death rates, the trial would be able to measure
that. Since deaths occur less frequently than, say, opportunistic
infections (OIs), it takes more people in the trial to measure a
meaningful difference.
In many ways an impact on mortality was, and remains the most critical
attribute of an anti-HIV medication. Sure, I personally would want
to take a drug that reduced my viral load more. But this is only
because earlier research has established that viral load is a good
predictor of one's risk of death (it's also a partial surrogate
marker, which is not exactly the same thing). The numbers of my
viral load test have meaning only because they predict advancing
disease and death. Otherwise, I really couldn't care less.
We here in the US learned that lesson the hard way — and some
of us are still learning it. Two early ACTG trials, 019 and 016,
investigated AZT in persons who were asymptomatic or had early symptoms.
These trials were halted too soon to give a clear insight into the
limitations of AZT monotherapy — tragically, that had to be
learned mainly by patient experience. There were very small reductions
in opportunistic infections in the AZT groups of those trials, but
this benefit was more than offset by a greater number of adverse
events (life threatening toxicities). A more important lesson, though,
was the fact that those trials were neither large enough, nor lasted
long enough to determine AZT's effect on survival except among a
small number of very rapid progressors.
Concorde, the European trial of AZT in asymptomatic patients, by
contrast, was much larger, and followed patients for three or more
years, as opposed to the year and a half in the ACTG trials. Concorde
revealed that there was indeed a "blip" of transient benefit at
time points similar to the ACTG trials, but that by three years,
long before most asymptomatic participants would have progressed
to overt disease, the blip disappeared, and any benefit from AZT
monotherapy was lost. The only remaining characteristic of those
on the AZT arm was a much higher rate of toxicity. Of course, now
we know that AZT resistance sets in fairly rapidly when it is used
as monotherapy, but these trials took place long prior to resistance
testing.
Critics of death as an endpoint often argue that for trials with
early asymptomatic patients, death is likelier to occur due to common
causes like automobile accidents, ODs, and homicide. This criticism
was fed by the US Veteran's Administration (VA) study number 298:
a study of AZT in asymptomatic people, conducted after the earlier
AZT trials but before Concorde reported its results. The VA trial
too showed little or no benefit from AZT monotherapy, but the drug's
advocates worked hard to find a methodological flaw to blame this
on, since Concorde had not yet spoiled the party. In particular,
they pointed to the fact that a majority of the deaths were not
"HIV associated." This criticism reflects a fundamental lack of
understanding about the role of randomization. While randomization
does not absolutely guarantee there will be exactly the same number
of auto accidents in the AZT arm and the no-AZT arm, it does mean
that the differences will be very small (if, in fact, AZT has no
effect on risk of auto accident). But more importantly, random allocation
of people between the treatment arms provides a sound basis for
clarifying whether the difference in auto accidents was a matter
of chance, or likely due to the drug. Skeptics used to point to
suicide (which tragically has been all too common in AIDS trials)
to criticize and ridicule the idea of using death as an endpoint.
Now, with a greater appreciation of psychiatric side effects that
has accompanied the growing use of Sustiva/Stocrin, differences
in suicide rates related to treatment assignment is not as humorous
or as irrelevant as once thought.
The Lady or the Tiger?
In the post-HAART world, AIDS-related OIs are increasingly rare.
Generally opportunistic infections only occur in persons who don't
know they have HIV until they get sick, or to those who have already
failed multiple treatment regimens. Yet death rates remain alarmingly
high in the HIV community; some common causes are liver failure,
cardiovascular disease and cancer. There is little agreement about
the relative contribution of HIV versus the HIV drugs in the development
of these conditions; most likely both are culprits. But it's clear
that in some people, at least, HAART itself may be a significant
source of morbidity, and even mortality.
Imagine two treatments that perform virtually identically in their
viral load effect at 48 weeks, yet have very different clinical
performances over longer periods of time. A relatively tolerable
regimen might allow years of good health, and a more toxic one could
prevent HIV- related conditions, yet eventually poison you. The
initial approval of the first protease inhibitors (PIs) offers some
interesting insights. Despite those who claim that the age of clinical
endpoint trials is over, the initial ritonavir study, conducted
by William Cameron, and ACTG 320, which investigated indinavir,
each showed dramatic reductions in both infections and deaths among
patients taking PIs. Of course, now that there are several HAART
regimens to choose from, and with OI rates having plunged even further
from the dual-nucleoside days, similar trials would need to be far
larger and longer if they were to be conducted today. An exception
to this might be among salvage patients, who unfortunately are at
immediate or near term risk of OI, which allows the clinical benefits
of treatments to be more rapidly assessed.
There's another instructive lesson to be learned from the initial
PI trials. Not one of the trials that led to FDA approval of the
current PIs showed evidence of lipodystrophy or insulin resistance
during the study period. These syndromes — both with life threatening
potential — only began to appear after a year or more on treatment.
So it's not enough to know that a treatment reduces your viral load.
You also need to have some sense of whether the treatment itself
is likely to kill you. Early on in the first days of protease euphoria,
Keith Henry of Regions Hospital in Saint Paul wrote an article describing
several previously healthy patients in their twenties who suffered
alarming rises in lipids (cholesterol and triglycerides), and then
suffered heart attacks after initiating protease therapy. These
particular patients were relatively immunologically healthy. It
would have been highly unusual if they had suffered an OI during
that brief period. For them, at least, the treatment may have been
worse than the disease. In the absence of clinical endpoint studies,
we may never know how common an occurrence this is.
The issue is further muddied by the rapid approval of HIV drugs
based on viral load changes over 48 weeks, as specified by the initial
accelerated approval regulations. The situation is even worse today
when drugs are approved based on 24 week data — significantly
short of half a year. The possibility of detecting slowly developing
toxicities in such a short time is almost nil. After all, even 48
weeks was too short to observe lipodystrophy or insulin resistance
in the initial PI trials. Also, 24 week data short-changes us on
resistance information as well. It is quite possible for PI resistance
to not fully develop within the first six months.
Obviously everyone wants new treatments to become available as
soon as possible, but there's a crucial component of accelerated
approval that has been neglected by the drug companies. Rapid approval
based on virologic data was supposed to be only the first step to
gaining full approval. Longer-term clinical follow up was supposed
to continue after rapid approval. Drug company commitments to do
post-marketing studies have for the most part been abandoned or
done in a lackluster fashion. There is very little information published
in the scientific literature that derives from longer-term post-market
trials. Although post-market study is a formal obligation, written
into the accelerated approval regulations, most companies simply
ignore it, and the FDA unfortunately cannot, or will not force the
issue.
What About the Ethics?
It's very important to rebut the remnants of the "killing for science"
legacy. No one should be compelled to go on a trial just to get
a new drug and any coercion to join a trial with a promise of drug
access is unethical. Since any trial of treatment effectiveness
must compare one treatment to the absence of that specific treatment,
simply joining a trial is no guarantee of getting a new drug. Furthermore,
it may compromise the scientific purpose of the trial if people
who join just to get drug access drop out when they are assigned
to an arm that does not contain the treatment they desire. That's
why there must be expanded access to experimental drugs for persons
who are in imminent danger of disease progression if, for no other
reason, to ensure that all trial participants are willing research
partners. But for those who are truly uncertain whether a new treatment
is in their best interest, clinical trials are a way to help advance
the science. And if such trials are properly and ethically conducted,
patients in all arms must have a good chance of benefiting.
Unfortunately, the public antipathy to including death as an endpoint
contributed to a case of science being clouded by human desperation
as well as business interests. People with AIDS needed new treatments
as soon as possible, but if the FDA only agreed to review trials
with mortality endpoints, then new drug approvals would be delayed.
Neither the community nor the drug companies wanted that. Yet as
we've seen, by foregoing death as an endpoint and by not following-up
long-term there's an increased risk that a drug might slip through
that actually shortens life.
Censored
In the early days of AIDS clinical research, the single most common
endpoint was "progression of disease or death." Another reason death
was included was to avoid a possibly serious source of bias that
could lead to false conclusions. Suppose that success or failure
of a treatment was defined by the number of OIs that occurred in
people who received an experimental drug compared to those who received
a placebo: The primary endpoint would be progression to disease.
Now suppose that people taking the experimental drug actually died
much, much faster than those on placebo, so much faster, in fact,
that they died before developing OIs. Meanwhile, the people on placebo
were living long enough to get one of the classic AIDS OIs. This
creates a paradoxical result: If OIs are the only endpoints that
matter, then people who took the experimental drug will appear to
have done much, much better — despite the fact that they died.
In statistical terminology this is called "censoring." The deaths
on the experimental arm are "censoring" the possibility of observing
other endpoints for those people. When there were no good treatments,
patients were dying so frequently and so fast that an endpoint that
didn't record death stood a good chance of yielding deadly, deceptive
results. There are all kinds of mathematical adjustments statisticians
can make to try and come up with a more accurate answer, but at
the end of the day, real data trumps everything.
Nowadays, of course, viral load is the most common endpoint in
an antiretroviral drug trial — although it can be used in several
different ways. One way is to find the percentage of participants
whose viral load is undetectable, or below the level of quantification
(BLQ). This is a nice simple case of what's called a binary endpoint:
something that can have only one of two possible values. The viral
load is either detectable or not and that's all we know. Death is
also a binary endpoint. We could still have the same censoring problems
with viral load endpoints as with OI endpoints, but happily, people
on treatment no longer die the way they did in the eighties. Nonetheless,
censoring by death can be a significant source of bias.
One of the most common ways of dealing with censoring bias is to
employ a "non-completer equals failure (NCF)" analysis. This is
used when people in a trial are not available to have their viral
load drawn, whether due to death, dropout or any other reason. The
missing value is recorded as a "failure" — in this case, detectable
virus. Clearly, this also has its problems. An NCF analysis can
possibly cause the drug's potency to appear understated. But that
is preferable to believing a drug is effective when it is actually
ineffective, or even killing people despite their having no detectable
virus to measure. It also, some believe, adds a "reality factor."
If many people stop taking one drug but not the other in a trial,
or people on that drug just drop off, this suggests an underlying
reason. The drug may be very toxic, difficult to take, or otherwise
unattractive. So while NCF analysis may give a poorer estimate of
the biological activity of a drug, many feel it can provide a preview
of its effectiveness in the real world.
There are other ways to use viral load as an endpoint for a clinical
trial. Using an average of viral load values for everyone in a trial
can actually provide much more information than a simple binary
(detectable/undetectable) result. But now there is a real problem
about what to do with people who are in fact undetectable. If we
decide to average the viral loads of all participants, what value
do we set for those who are undetectable? There are a number of
ways of dealing with this problem such as predicting what an undetectable
value should be from the slope of past values or assuming that the
undetectable value is at some point the middle of the undetectable
range.
One drug company had its hide nailed to the wall by some sharp-eyed
activists a few years ago. For the purposes of their trial, the
company assumed that everyone who was undetectable was at the bottom
of the range; they were assigned a viral load of 1. Viral load tests
in those days were only able to detect virus levels above 500, so
in this trial, the minute someone went undetectable, their statistical
shenanigans made it seem like there had been a huge 2.7 log drop!
"What a great drug!" crowed the company. "Not so fast!" said the
activists. Despite this not-so-sly effort to cook the books, it's
a real challenge figuring out how to deal with data and still come
up with useful, scientifically valid answers.
No, This Doesn't Mean Duesberg Is Right
These days, liver and heart disease are of great concern to the
HIV-positive community, but since there is nothing HIV-specific
about these diseases, the actual rates of their occurrence are slipping
through the cracks. There is clearly a serious problem though, especially
for people with other risk factors like hepatitis or obesity. In
the last two years five major figures in the AIDS activist community,
that I am aware of, have died after surviving a decade or more of
HIV — yet none of these were counted as "AIDS deaths." Still,
it seems obvious to those close to these people that treatment toxicity
played at least some role in their deaths.
But although death is still uncomfortably common in our community,
it's nothing like it was in the eighties and early nineties, when
gay men, injection drug users, and female sex partners of positive
men were dying by the dozens every day. The last thing I would want
this article to do is to flat out discourage someone from accessing
treatment. Nonetheless, attitudes are rapidly changing, and many
clinicians are wondering if putting people with high CD4 counts
on these powerful drugs is a great idea. The Community Program for
Clinical Research on AIDS (CPCRA)* is beginning a trial later this
year to try and address some of those questions. The "SMART" trial
will assemble one group of patients whose treatment is managed so
as to keep viral load as low as possible at all times. Their endpoints
will be compared to another group that will try to hold off treatment
until their CD4 cell counts approach (but not too closely) dangerous
levels. This is going to be a very large, very long-term trial,
so definitive answers are years away. Meanwhile, as through so much
of the epidemic, we are going to have to rely on the educated best
guesses of our doctors and ourselves. Happily, even with treatment-associated
illness, death rates are a small fraction of what they once were.
As wonderful as this is in a human sense, it makes the science more
difficult. "All cause mortality" is a very reasonable and useful
candidate endpoint for clinical research. But with deaths on the
decline, such studies will be very large and long. We can only hope
that risk of iatrogenic (treatment caused) disease does not continue
to increase with duration of exposure to antiretrovirals.
The protease inhibitors, non-nucleoside reverse transcriptase inhibitors,
and the classic nucleosides gave us a mini-miracle. It would be
hard to think of any disease where progress in treatment has been
so swift and decisive. Unfortunately, everything comes with a price,
and these very powerful drugs have substantial toxicities. It remains
to be seen how many people can survive after five, ten, or fifteen
years on these drugs. The challenge for antiretroviral clinical
research, then as now, is to create endpoints that are meaningful
for today. If future trials are to be relevant and provide us with
the information we need to make safe, sound health choices, these
tough questions about appropriate endpoints will have to be grappled
with again and again.
*The author needs to disclose that he works for the Statistical
and Data Management Center of the CPCRA, and is, in fact, on the
SMART protocol team. However I am writing this piece as an individual,
and nothing I say should be construed as an official CPCRA position.
International Hit Parade
By Mark Harrington
In Buenos Aires the midwinter days are short and the weather cool
like summer in San Francisco. The International AIDS Society (IAS)
chose Argentina to initiate its new pathogenesis and treatment biennial,
which will fall during the off-years between the much larger International
AIDS Conferences. Although new data was sparse, here is a look at
three of the meeting's "greatest hits."
Hit Even Harder
David Ho treated us to a review of career highlights from his work
on viral dynamics during the five years since his earthshaking Vancouver
presentation. In doing so he proved that — as Prince observed
in a song from Graffiti Bridge — there is indeed joy
in repetition. At the end of the talk he showed us that a five-drug
regimen consisting of lopinavir/ritonavir with 3TC, efavirenz and
tenofovir can cut the first phase of viral decay from 14 days (shown
with AZT/3TC/ritonavir back at Vancouver) to just seven days. It's
too soon to say whether this regimen will also accelerate subsequent,
slower phases of decay, which David attributes to virus produced
from macrophages. It's remarkable just how little research has been
done on this second compartment. Macrophages are terminally differentiated
and found in tissue, not blood, and thus are much harder to sample
than the latently infected CD4 T cell about which so much has been
written. If the five-drug regimen also accelerates the second and
third phases of viral decay, then perhaps we can look forward to
eradicating HIV from the body by taking HAART without a single slip-up
in only thirty years instead of sixty. What fun!
Hit Even Later
Julio Montaner, updating us on the British Columbia HIV cohort,
showed that baseline CD4 count when starting treatment is highly
predictive of hospitalization, AIDS, and survival — with baseline
CD4 count below 200 being bad and one below 50 very bad indeed.
However, if baseline CD4 counts are adjusted with data for adherence,
then, remarkably, people who started treatment with CD4 counts below
50 — if they'd been highly adherent to their regimens —
had survival results equivalent to those of people who entered the
cohort at higher CD4 counts.
This reminds us that individuals with quite low CD4 counts can
be rescued. John Mellors just hates this data, though it doesn't
in the least undermine the prime lesson from his important analysis
of the prognostic value of viral load levels using banked blood
samples from 1985. The Mellors data showed that viral load shortly
after infection strongly predicted the rate of CD4 cell loss and
hence the rate of disease progression. Montaner's data show that,
in the short term at least, CD4 count, especially at low levels,
is more predictive of clinical outcome. These data don't prove that
it's better to start later — but they don't support the notion
of hitting at levels much above 200 CD4 cells either. That shredding
sound represents five years of misguided guidelines being ripped
to pieces.
Hit Intermittently
Tony Fauci kicked off the conference proper with an update on structured
intermittent therapy (SIT) using a long cycle (60 days on treatment,
30 days off) and a short cycle (7 days on, 7 off). The long cycle
was less than optimal since viral loads tended to rebound during
the off phase and did not always decline fully after restarting
treatment — which in some cases apparently led to drug resistance.
The short cycle SIT, however, at 32 cycles (64 weeks) into the
experiment, continues to look pretty good. Ten people who had achieved
good viral control on HAART were enrolled. For the eight remaining
in the study after 60 – 64 weeks, there was no change in absolute
CD4 count, CD4 percentage, CD8 count, activation markers, plasma
HIV RNA, cellular HIV RNA, proviral HIV RNA, or latently infected
CD4 cell count. The data were "obvious and monotonous" in these
respects, commented Fauci. Lymph node biopsies were similarly unremarkable
and unchanged. No drug resistance mutations had appeared. So far,
so good. The really interesting part was that triglycerides, total
cholesterol and LDL cholesterol all dropped significantly from week
0 to week 24 and continued dropping out to week 52. So, at least
in this handful of patients, the short-cycle SIT appears to preserve
antiviral efficacy while reducing common and potentially serious
HAART-associated toxicity. Larger randomized, controlled studies
are urgently needed.
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