Pediatric HIV Ethics

1
Pediatric HIV Ethics

• Ann J. Melvin MD
• 5/17/06

2
Case 1
3
To tell or not to tell

• 11 y/o Ethiopian girl
• Diagnosed as HIV-infected at age 7
• Both parents are infected
• Has an uninfected younger sibling
• On a 3 drug antiretroviral regimen and doing well
• Parents dont want her to know she has HIV

4

• Should this child be told she has HIV?
• Who should tell her?
• What if she were 5 years old?
• 14?

5
Disclosure-arguments against

• Stigma- protection from rejection/discrimination
• If other people find out he will be teased
• Protection from fear or depression
• She is happy- why make her worry?
• Parental fear of rejection/sense of guilt
• He might hate me for giving this to him

6
Disclosure-arguments against

• Upset family dynamics
• shell know she is different from her sister
• Concern over community disclosure
• Im worried he will tell others

7
"concealing most things from the patient while
you are attending to him. Give necessary orders
with cheerfulness and serenity...revealing
nothing of the patient's future or present
condition. For many patients...have taken a turn
for the worse...by forecast of what is to
come." Hippocrates.
8
Disclosure arguments for

• Childs right to know
• autonomy
• Lack of disclosure interferes with adolescent
  emotional development
• tasks of adolescence - Establish identity,
  independence, non-family relationships
• Improved psycho-social health

9
Disclosure arguments for

• Improved ability on the part of the care team to
  provide education
• Improved adherence
• Secondary HIV prevention

10
Psycho-social consequences of disclosure

• Early disclosure leads to better psycho-social
  adjustment
• Decreased incidence of depression Improved
  self-esteem
• Greater understanding of illness
• Improved ability to offer support

Slavin 1982, Bose 1994, Funck-Brentano 1997
11
4 Box method (Jonsen, Clinical Ethics)
Patient Preferences
Medical Indications
Contextual features
Quality of Life
12
Medical Indications

• Improved adherence
• Secondary prevention
• If child was very ill
• utilitarian ethics futility

13
Patient Preferences

• Is patient's right to choose (know) being
  respected to the extent possible in ethics and
  law
• Patient's capacity, evidence of incapacity
• What has the patient expressed about preferences
  for treatment (disclosure)
• autonomy

14
Quality of Life

• What are the prospects with/without disclosure
  for continuation of patient's "normal" life
• Are there biases that might prejudice the
  provider's evaluation regarding need for
  disclosure
• What harm is the child likely to experience
  because of disclosure/non-disclosure
• beneficence / nonmaleficence

15
Contextual Features

• Are there family issues that might influence
  disclosure decisions
• Are there financial/economic factors
• Are there religious/cultural factors
• Is there any justification to breach
  confidentiality/parents wishes
• What are the legal implications of disclosure
  decisions
• justice, autonomy, root cause

16
Can children who dont know they have HIV truly
provide assent to participate in HIV treatment
trials?
17
System of Protection

• Independent scientific ethical review
• Additional safeguards for vulnerable persons
• Voluntary and informed consent
• Parental permission and child assent
• Responsible and Competent Investigators

18
Adequate Provisions for Assent

• Information
• the reasonable volunteer (child)
• Comprehension (respect for persons)
• opportunity to choose to extent capable
• Voluntariness
• conditions free of coercion and undue influence

45CFR46.408 21CFR50.55
19
What is assent?

• An affirmative agreement to participate in
  research
• Mere failure to object should not be construed as
  assent
• Assent may be waived if
• a child is not capable (age, maturity, and
  psychological state)
• prospect of direct benefit not available outside
  of research
• research involves no more than minimal risk

45CFR46.408 21CFR50.55
20
ICH E-6 (and children)

• Child assent (4.8.12)
• to the extent compatible with the subjects
  understanding

Step Four, May 1996
21
Research involving children

• The investigator must ensure that
• Childs assent obtained to extent of capabilities
• Childs refusal to participate or continue always
  respected, unless
• child needs treatment not available outside
  research
• investigational intervention shows promise of
  therapeutic benefit, and
• there is no acceptable alternative therapy

CIOMS Guideline 14 (2002)
22
Respect for Children

• Parental Permission (yet within limits)
• A parent should protect the health and safety of
  his or her child (i.e., beneficence)
• Child Assent (not as a right, but a benefit)
• A parent should nurture the moral growth and
  developing autonomy of his or her child
• National Commission (1977)

23
Declaration of Helsinki

• Clause 25 When a subject deemed legally
  incompetent, such as a minor child, is able to
  give assent to decisions about participation in
  research, the investigator must obtain that
  assent in addition to the consent of the legally
  authorized representative

24
Code of Federal Regulations rules concerning
research in children

• 45CFR46 subpart D
• 46.404 - Research not involving greater than
  minimal risk.
• 46.405 - Research involving greater than minimal
  risk but presenting the prospect of direct
  benefit to the individual subjects
• 46.406 - Research involving greater than minimal
  risk and no prospect of direct benefit to
  individual subjects, but likely to yield
  generalizable knowledge about the subject's
  disorder or condition

25
Code of Federal Regulations rules concerning
research in children

• 45CFR46 subpart D
• 46.407 - Research not otherwise approvable which
  presents an opportunity to understand, prevent,
  or alleviate a serious problem affecting the
  health or welfare of children

26
Code of Federal Regulations rules concerning
research in children

• 45CFR46 subpart D
• 46.408 - Requirements for permission by parents
  or guardians and for assent by children - In
  addition to the determinations required under
  other applicable sections of this subpart, the
  IRB shall determine that adequate provisions are
  made for soliciting the assent of the children,
  when in the judgment of the IRB the children are
  capable of providing assent

27
Case 2
28
Clinical case

• Diagnosed as HIV at age 2 yrs.
• Mild cognitive delay
• Age 9 - Cardiomyopathy probably ZDV related

29
Clinical case - cont

• Age 13 surgery for benign abdominal tumor
• Age 17 lymphoma chemotherapy, surgery,
  radiation
• Age 18 cryptococcal meningitis
• Recurrent zoster
• Chronic sinusitis
• Chronic headaches

30
Clinical case - cont

• Antiretroviral history
• Mono, Dual NRTI from ages 4-15
• 4 agent HAART started age 16
• Sporadic adherence associated with major
  illnesses
• Refused all ARVs at about age 18
• Died age 19

31
Right to refuse treatment

• Right to autonomy?
• Role of physician?
• What if she were 16?
• 12?
• 6?

32
4 Box method (Jonsen, Clinical Ethics)
Patient Preferences
Medical Indications
Contextual features
Quality of Life
33
Medical Indications

• Patients medical problem hx, dx, prognosis
• Acute/chronic critical/emergent/reversible
• Tx goals
• Probabilities of success
• Alternate plans in case of tx failure
• How can this patient be benefited/harm avoided
  through proposed care
• utilitarian ethics futility

34
Patient Preferences

• What has the patient expressed about preferences
  for treatment
• Has the patient been informed of benefits and
  risks, and understood and given consent
• Patient's capacity, evidence of incapacity
• Advanced directives
• If the patient is incapacitated, who is the
  appropriate surrogate? Is the surrogate using
  appropriate standards?
• Is patient unable or unwilling to cooperate with
  treatment
• Is patient's right to choose being respected to
  the extent possible in ethics and law
• autonomy

35
Quality of Life

• What are the prospects with/without treatment for
  return to patient's "normal" life
• Are there biases that might prejudice the
  provider's evaluation of the patient's quality of
  life
• What deficits are the patient likely to
  experience with successful treatment
• Is the patient's present or future condition such
  that continued life might be judged undesirable
  by them
• Plan and rationale to forgo treatment
• Plans for comfort/palliative care
• beneficence / nonmaleficence

36
Contextual Features

• Are there family issues that might influence
  treatment decisions
• Are there provider issues that might influence
  treatment decisions
• Are there financial/economic factors
• Are there religious/cultural factors
• Is there any justification to breach
  confidentiality
• Are there problems will allocation of resources
• What are the legal implications of treatment
  decisions
• Are there any provider/institutional conflicts of
  interest
• justice, autonomy, root cause

37
Cases 3 and 4
38
Right to refuse treatment

• Woman in Massachusetts
• Lost a daughter to HIV she was convinced that
  the cause of death was zidovudine
• When her second child was 2, physicians wanted to
  enroll him in a multi-drug treatment trial
• Mother refused

39
What should the physicians do?

• Take the mother to court to force her to treat
  the child?
• Remove the child from the mothers custody?
• Allow the mother to refuse treatment?

40
Who chooses treatment?

• Oregon woman diagnosed as HIV during pregnancy
• Declined antiretroviral therapy during pregnancy
• Declined zidovudine for her infant and decided to
  breastfeed

41
Mothers perspective

• Doesnt believe that HIV causes AIDS
• Concerned over toxicity of medication
• Long-term effects not known
• Benefits of breastfeeding

42

• Should the state mandate maternal treatment?
• Should the state mandate infant treatment?

43
Clarify medical benefits and harms

• What is the risk of transmission for this
  specific infant?
• What is known about the long and short-term side
  effects of zidovudine

Wolf LE. APAM 2001
44
Clarify social benefits and harms

• Harm to parent-child relationship
• Foster care system not necessarily better
• Making parents compromise their beliefs to stay
  out of legal system
• Harm to parent-physician relationship
• Compromising future care
• Parents may not be truthful about what they are
  really doing

Wolf LE. APAM 2001
45
Understand parents reasons for refusal

• Are the parents adequately informed?
• Are there cultural/social factors that could be
  addressed?
• Is the parent capable of making an informed
  decision?

Wolf LE. APAM 2001
46
Explore available options

• Are there any alternative treatments or
  prophylactic measures that would be acceptable to
  the parents?

Wolf LE. APAM 2001
47
Placebo Controlled Trial of ZDV to prevent MTCT
of HIV-1 (ACTG 076)

• ZDV mother
• 100mg po 5x/d after 14 wk gestation
• 2mg/kg iv x1 1 mg/kg iv/hr in labor
• ZDV infant 2mg/kg po q6h x 6w
• placebo n183 ZDV n180
• Transmission placebo 25.5
• Transmission ZDV 8.3

Connor EM et al. NEJM 19943311173-80
48

• Cost of 076 regimen - 800/pregnancy
• Short-course ZDV/placebo controlled studies
  designed and conducted by UNAIDS, WHO, US NIH and
  US CDC
• Côte dIvoire, Uganda, Tanzania, South Africa,
  Malawi, Thailand, Ethiopia, Burkina Faso,
  Zimbabwe, Kenya and Dominican Republic

49

• Use of placebo in these trials set off an
  international debate
• P. Lurie, S. Wolfe NEJM article claiming that
  these trials violated the Declaration of Helsinki
  guidelines worded at the time as in any
  medical study, every patient including those of
  a control group, if any should be assured of
  the best proven diagnostic and therapeutic method

Lurie P, Wolfe S. NEJM 1997337853-856.
50
Four major principles in research ethics

• The Principle of Non-maleficence Research must
  not cause harm to the participants in particular
  and to people in general
• The Principle of Beneficence Research should
  also make a positive contribution towards the
  welfare of people.

51
Four major principles in research ethics

• The Principle of Autonomy Research must respect
  and protect the rights and dignity of
  participants
• The Principle of Justice The benefits and risks
  of research should be fairly distributed among
  people

52
Belmont report

• National Commission for the Protection of Human
  Subjects of Biomedical and Behavioral Research
  established by the National Research Act in 1974
• A statement of basic ethical principles and
  guidelines that should assist in resolving the
  ethical problems that surround the conduct of
  research with human subjects

53
Belmont report

• Respect for persons Respect for persons
  incorporates at least two ethical convictions
  first, that individuals should be treated as
  autonomous agents, and second, that persons with
  diminished autonomy are entitled to protection
• An autonomous person is an individual capable of
  deliberation about personal goals and of acting
  under the direction of such deliberation

http//ohsr.od.nih.gov/guidelines/belmont.html
54
Belmont report

• Beneficence Persons are treated in an ethical
  manner not only by respecting their decisions and
  protecting them from harm, but also by making
  efforts to secure their well-being
• Two general rules have been formulated as
  complementary expressions of beneficent actions
  in this sense (1) do not harm and (2) maximize
  possible benefits and minimize possible harms

http//ohsr.od.nih.gov/guidelines/belmont.html
55
Belmont report

• Justice Who ought to receive the benefits of
  research and bear its burdens? This is a question
  of justice, in the sense of "fairness in
  distribution" or "what is deserved."
• An injustice occurs when some benefit to which a
  person is entitled is denied without good reason
  or when some burden is imposed unduly. Another
  way of conceiving the principle of justice is
  that equals ought to be treated equally

56
Declaration of Helsinki

• Adopted by the WMA in 1964 as a response to the
  atrocities conducted during WWII latest
  amendment in 2000
• a guide to every physician in biomedical research
  involving human subjects

http//www.wma.net/e/policy/b3.htm
57
Declaration of Helsinki

• Clause 11 Biomedical research involving human
  subjects must conform to generally accepted
  scientific principles and should be based on
  adequately performed laboratory and animal
  experimentation and on a thorough knowledge of
  the scientific literature

58
Declaration of Helsinki

• Clause 29 The benefits, risks, burdens and
  effectiveness of a new method should be tested
  against those of the best current prophylactic,
  diagnostic, and therapeutic methods. This does
  not exclude the use of placebo, or no treatment,
  in studies where no proven prophylactic,
  diagnostic or therapeutic method exists.

59
Declaration of Helsinki

• Clause 9 Research Investigators should be aware
  of the ethical, legal and regulatory requirements
  for research on human subjects in their own
  countries as well as applicable international
  requirements. No national ethical, legal or
  regulatory requirement should be allowed to
  reduce or eliminate any of the protections for
  human subjects set forth in this Declaration

60
Declaration of Helsinki

• Clause 19 Medical research is only justified if
  there is a reasonable likelihood that the
  populations in which the research is carried out
  stand to benefit from the results of the
  research.
• Clause 30 At the conclusion of the study, every
  patient entered into the study should be assured
  of access to the best proven prophylactic,
  diagnostic and therapeutic methods identified by
  the study.

61
Declaration of Helsinki

• Clause 8 Medical research is subject to ethical
  standards that promote respect for all human
  beings and protect their health and rights. Some
  research populations are vulnerable and need
  special protection. The particular needs of the
  economically and medically disadvantaged must be
  recognized. Special attention is also required
  for those who cannot give or refuse consent for
  themselves, for those who may be subject to
  giving consent under duress

62
Declaration of Helsinki

• Clause 5 In medical research on human subjects,
  considerations related to the well-being of the
  human subject should take precedence over the
  interests of science and society

63
Equipoise

• Different arms of a randomized study should be
  expected to offer comparable benefit or there is
  reasonable doubt or scientific debate as to which
  arm is better

64
Arguments against placebo controlled ZDV trials

• Placebo known (or could be reasonably surmised)
  to be inferior
• Violating principle of equipoise
• Not providing proven standard of care
• Double-standard
• Same trials would not be approved in wealthy
  countries

65
Arguments for placebo controlled ZDV trials

• Trials pose potential benefit but no risk
• Standard of care in the countries was nothing, so
  women not deprived of standard of care
• Participating women had the potential of benefit
  because without the trial they would get nothing
• Overall community benefits from answer to locally
  relevant question

66
Arguments for placebo controlled ZDV trials

• Claim the point of the relevant clause in
  Declaration of Helsinki is that research
  participants in control arms should not be denied
  proven effective treatments they otherwise would
  receive

Selgelid M. Developing World Bioethics.
200551471
67
Arguments for placebo controlled ZDV trials

• Comparing short-course ZDV to 076 regimen would
  only provide relative efficacy, not absolute
  effectiveness
• Placebo/controlled trials require smaller numbers
  and can provide the answer faster

Selgelid M. Developing World Bioethics.
200551471
68
Arguments against placebo controlled ZDV trials

• Historical controls would provide scientifically
  valid control arm
• Local standard of care dictated by prices set by
  Western pharmaceutical multinationals
• Answers to ethical questions should not be
  dictated by economic criteria.

Schüklenk U. Social Science and Medicine
200051969-977.
69
Arguments against placebo controlled ZDV trials

• Violates principle of autonomy
• Informed consent frequently not possible in the
  affected communities
• Educational barriers
• Language barriers
• Cultural values
• Role of physician
• Even in educated western communities few people
  understand randomization and placebo

70
Summary of arguments

• Critics argued for the upholding of a universal
  standard of care that guaranteed access to the
  best treatments anywhere in the world
• Trial defenders argued that this would harm both
  vulnerable individuals and vulnerable
  impoverished populations

Selgelid M. Developing World Bioethics.
200551471
71
Questions

• Regarding the placebo controlled short-course ZDV
  trials which arguments do you think should
  prevail?
• Why?

72
Questions

• Should one particular answer to the control arm
  question be set as the standard for all
  international research?
• Why or why not?

73
References

• 45CFR46 -http//www.nihtraining.com/ohsrsite/guide
  lines/45cfr46.html
• Belmont Report - http//www.nihtraining.com/ohsrsi
  te/guidelines/belmont.html
• Declaration of Helsinki - http//www.wma.net/e/pol
  icy/b3.htm

74
References

• Levine R. The need to revise the declaration of
  Helskinki. NEJM 1999341531-4.
• Lurie P, Wolfe S. Unethical Trials of
  Interventions to Reduce Perinatal Transmission of
  the Human Immunodeficiency Virus in Developing
  Countries. NEJM 1997337853-6.
• Angell M. The Ethics of Clinical Research in the
  Third World. NEJM 1997337847-49.
• Selgelid M. Module 4 Standards of care and
  clinical trials. Developing World Ethics
  2005555-72.
• Jonsen A, et al. Clinical Ethics A practical
  approach to decision making in clinical medicine.
  5th edition. McGraw-Hill 2002.
• Wolf LE et al. When parents reject interventions
  to reduce postnatal human imuunodeficiency virus
  transmission. Arch Pediatr Adolesc Med
  2001155927-33.

75
Further reading

• AAP. Disclosure of illness status to children and
  adolescents with HIV infection. Pediatrics
  1999103164-166.
• Gershon AC et al. Disclosure of HIV diagnosis to
  children when, where, why and how. J Pediatr
  Health Care 200115161-7.
• Wolf LE et al. When parents reject interventions
  to reduce postnatal human imuunodeficiency virus
  transmission. Arch Pediatr Adolesc Med
  2001155927-33.
• Burns JP. Research in children. Crit Care Med
  200331supplS131-S136.