Pediatric HIV Research Ethics

1
Pediatric HIV Research Ethics

• Ann J. Melvin MD
• 5/18/06

2
Four major principles in 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.

3
Four major principles in 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

4
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

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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
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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
7
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

8
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
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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

10
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.

11
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

12
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.

13
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

14
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

15
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

16
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

17
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
18

• 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

19

• 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, it any should be assured of
  the best proven diagnostic and therapeutic method

Lurie P, Wolfe S. NEJM 1997337853-856.
20
Arguments against placebo controlled ZDV trials

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

21
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

22
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
23
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
24
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.
25
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

26
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
27
Outcome

• Revision to Declaration of Helsinki
• Wording in clause 29 changed from proven to
  current
• In 2002 a note of clarification was added
  saying that a placebo could be substituted for
  proven efficacious therapy if there were
  compelling and scientifically sound
  methodological reasons why its use is necessary
  and in situations where the condition being
  studied is minor and patients getting placebo
  will not be subject to risk of serious or
  irreversible harm

28
Questions

• Should the Declaration of Helsinki have been
  revised to weaken the requirement regarding
  standard of care for control arms
• Why or why not?

29
Questions

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

30
Questions

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

31
Single-Dose Nevirapine vs Ultra-Short AZT -
HIVNET 012 Guay L et al. Lancet 1999354795-802
Jackson B et al. Lancet 2003362859-68.
Transmission 14-16 Wks 18 Mos
13.5 15.7 22.1 25.8
Efficacy 42 41
Breastfed Infants
INTRA
POST
Nevirapine
2 mg/kg x1
200 mg x1
versus
Ultra-Short AZT
INTRA
POST
4 mg/kg bid x1 wk
300 mg q 3 hr
32
NVP Resistance at 6-8 Weeks after Single-Dose
NVP for PMTCT in Women/Infants HIVNET 012

• Eshleman S et al. JAIDS (2004) 35126-30
• In final analysis of women in NVP arm (279/306,
  91 evaluable), NVP resistance mutations detected
  in 25 (70/279) of women at 6 weeks postpartum.
• Eshleman AIDS (2000) 151951-7
• As part of a substudy of HIVNET 012 including
  evaluation of infected infants, NVP resistance
  detected in 46 (11/24) of infected infants.

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Prolonged NVP Exposure after Single-Dose
Intrapartum NVP Increases Risk Resistance

• Several studies demonstrate persistence of
  detectable NVP levels after single-dose exposure
  in women for gt3 weeks.
• Prolonged duration of NVP levels after a one dose
  forms basis for
• Prolonged efficacy of SD NVP through early BF
  period but also
• Selection of NVP resistance after a single dose.

34
Prolonged NVP Levels Post Single Dose
Persistent Early BF Period Efficacy but Increases
Risk Resistance NVP Levels can Persist for 2-3
Weeks Following Single Dose
Cressey TR et al. JAIDS
200538283-8
Lower limit assay quantification 50 ng/mL
35
Single-Dose NVP Prophylaxis is Associated with
NVP Resistance Acquisition in Mothers
2 doses
SD NVP
AZT SD NVP
gt2 NRTI SD NVP
SD NVP 7 d AZT/3TC tail
Time 6wk 6 wk 4 wk 2 wk 6 wk
7 wk 4 wk 7 wk 8 wk 4-6 wk
8 wk Clade C B E,B
E,B A,D B,G,F CRF,A C
E,B C C
36
Single-Dose NVP Prophylaxis is Associated with
NVP Resistance Acquisition in Infants Failing
Prophylaxis
SD NVP
AZT SD NVP
SD NVP, no maternal SD NVP

Clade E,B C A E,B
C E,B C C A,D C
C CRF01,
06
37
NVAZ Study, Malawi - Infant NVP Resistance
Influence of Maternal SD NVP and Infant
AZTEshleman S et al. J Infect Dis
2006193479-81
of Infected Infants with NVP Resistance
Mother Infant
Stratified Early Presenter (got maternal
NVP) Taha JAMA 2004 Late Presenter Taha
Lancet 2003
87 (20/23) 74 (14/19)
IP NVP
NB NVP
6 wk tx 14.1
AZT 1 wk
IP NVP
NB NVP
6 wk tx 16.3

57 (12/21) 27 ( 4/15)
NB NVP
6 wk tx 20.9
NB NVP
AZT 1 wk
6 wk tx 15.3
38
Frequency of K103N Variants in Maternal Plasma by
Time Post SD-NVP (Allele-Specific Sensitive
Assay) Loubser S et al. AIDS 200620995-1002
Median K103N Frequency
10.8 5.9 1.2 0.7
39
18 Month Virologic Outcome With and Without SD
NVP Exposure with RNA lt50 Lallemant M. 3rd
IAS Meeting, Rio de Janeiro, Brazil 2005 (
TuFo0205)
p 0.04 0.15
0.05
NVP exp 221 202 194
191 NVP, no exp 48
45 44 44
40
In light of the previous discussion of standard
of care for control arms Is it ethical to
include a nevirapine only arm in clinical trials
investigating strategies to prevent the
acquisition of nevirapine resistance?
41
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

42
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

43
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

44
Can children who dont know they have HIV truly
provide assent to participate in HIV treatment
trials?
45
Clinical case

• Born 26 wks 570 gms
• NEC with subsequent short gut, ROP
• Diagnosed at HIV at age 2 yrs.
• Short stature
• Mild cognitive delay
• Age 9 - Cardiomyopathy probably ZDV related

46
Clinical case - cont

• Age 13 benign plasmacytoma removed
• Age 17 breast lymphoma eventual mastectomy
• Age 18 cryptococcal meningitis
• Recurrent zoster
• Chronic sinusitis
• Chronic headaches

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Clinical case - cont

• Antiretroviral history
• Zidovudine age 6-9
• ddI age 9-13
• Stavudine lamivudine age 13-16
• 4 agent HAART started age 16
• Sporadic adherence associated with major
  illnesses
• Refused all ARVs at about age 18
• Died age 19

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Right to refuse treatment

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

49
4 Box method (Jonsen, Clinical Ethics)
Patient Preferences
Medical Indications
Contextual features
Quality of Life
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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

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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

52
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

53
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

54
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

55
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.