E-DRUG: Unethical clinical trials in developing countries? (4)
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Dear e-drug friends,
The following note asks for reflection on design of
HIV research in Africa.
David Gisselquist
IS THIS ETHICAL? Researchers follow HIV-positive
African adults who do not know they are infected to
study HIV transmission to spouses, AIDS-related
illness and death, and infant and child mortality
david_gisselquist@yahoo.com
16 March 2006
INTRODUCTION
The purpose of this note is to stimulate a dialogue
about HIV epidemiological research in sub-Saharan
Africa that has tested and followed people who do not
know they are HIV-positive. At least seven large HIV
research projects have followed HIV-positive African
adults who were not aware of their HIV status and have
examined HIV transmission to spouses, infant and child
survival, and/or the study participants own health
and survival.
Ethical guidelines for medical research can be found
in many places, including the Nuremberg Code
(available from:
http://ohsr.od.nih.gov.nuremberg.php3) and the World
Medical Association Declaration of Helsinki (available
All of the studies reviewed in this note have been
approved by ethical review boards. In the projects
discussed in this note, researchers have with some
exceptions given research participants the option to
learn their HIV status. Characteristically, projects
offer participants a free additional HIV test at a
nearby clinic; many participants do not go. From this,
the researchers defense for not telling has been that
participants did not want to know their HIV status,
and that warning a spouse that their partner is
HIV-positive would violate the participants right to
privacy (and even laws in some countries).
But there is another way to approach the issue. Two
parties are involved: the participant and the
researcher. If a prospective participant does not want
to receive results of an HIV test, the researcher has
options as well. If following without telling is
unethical, the project can remain ethical by testing
and enrolling in follow-up research only people who
agree to learn their HIV status, and to share it with
their spouse.
While the information gathered from research discussed
in this note has been useful, this should not weigh in
the balance in considering whether it is ethical, and
whether it should be allowed. If research is
unethical, whether it is useful should not be an
issue. Furthermore, not sharing knowledge of HIV
status with research participants has obstructed
understanding of Africas HIV epidemic. For example,
it obstructs tracing the source of infections in
persons found to be HIV-positive, and so leaves
unanswered questions about how to explain and how best
to prevent HIV incidence.
The following seven projects followed people who did
not know they were HIV-positive and have studied HIV
transmission to spouses and/or the participants
health and/or child survival.
MALAWI, RURAL KARONGA, general population cohort,
1982-continuing according to latest available
information [Funding: Welcome Trust, British High
Commission in Malawi, DfID]
This project began with retrospective HIV tests on
blood samples collected to study leprosy and
tuberculosis in 1981-84 and 1987-89 in two areas of
Karonga District.[1,2] Retrospective testing of sera
from 1981-89 identified 197 adults with HIV
infections, including 56 serodiscordant couples.[3] In
1998-2000, researchers were able to trace almost all
persons who were HIV-positive in 1981-89 plus controls
(who were HIV-negative in earlier surveys) together
with their spouses and children.
During the 1998-2000 survey, Field staff were not
aware of the HIV status of the individuals
Individuals [adults only] were interviewed, examined,
and HIV tested (after counseling and if consent was
given) (page 1546, reference 3). Field workers
arranged return visits to give post-test counseling to
those who wanted to know their HIV results (page
1818, reference 2).
The 1998-2000 round identified 92 births between
1981-2000 to women known to be HIV-positive
mothers,[3,4] and 36 currently serodiscordant
couples.[3] One 2003 source reports a follow-up survey
planned in 2004, which is expected to provide
information on survival of children and mothers
according to mothers HIV status.[5]
TANZANIA, RURAL MWANZA, general population cohort,
1991-94 [Funding: Commission of European Communities,
Center for International Migration and Development,
Germany, DfID, MRC of UK]
This prospective study, which followed roughly 9,000
adults,[6] observed 6 incident HIV infections in 43
discordant couples.[7] In most prospective studies,
intensive counseling of discordant couples has
resulted in the adoption of safer sexual practices,
and this has limited their capacity to examine risk
factors and transmission rates. In the Mwanza
study
cohort members were only informed of their HIV
status if they accessed a parallel voluntary
counseling and testing service. Only a small number of
participants pursued this service (page 77, reference
7).
TANZANIA, URBAN MWANZA, male workers and wives,
1991-96 [Netherlands Ministry for Development
Cooperation]
In the full cohort of nearly 2,500 adults, few of
those who were HIV-positive were aware of their HIV
status. In line with the national policy on informing
patients, HIV test results were only provided if the
study participant had requested it. Full-time pretest
and posttest counseling was offered through a
counselor at the study clinic. This involved a
separate blood sample and a result-reporting system
not linked [to] the study (page 195, reference 8).
During 1991 to 1994, 21.5% of study participants had
requested and received pretest counseling but only
half of those returned for the final result (page
195, reference 8). The project observed 9 incidence
infections in 88 serodiscordant couples.[8]
TANZANIA, RURAL KISESA, general population cohort,
1994-continuing according to latest available
information [UNICEF, Netherlands Ministry for
Development Cooperation, USAID MEASURE Evaluation
Project]
In a general population cohort, three serosurvey
rounds have been completed in 1994-95, 1996-97, and
2001.[9] One 2003 source reports that a fourth round
was planned for 2004.[5]
In the 1994-95 and 1996-97 surveys,
all adults aged
15-44 were asked to come to a central point in the
village for an interview and to give a blood sample
for HIV testing for each survey
HIV counselling and
testing were offered in the second survey. (page 261,
reference 10). In both the second and third surveys,
counselling and testing were offered by a qualified
counsellor, who followed up with those wanting to know
their HIV test results (page 2646 of reference 11).
However, very few individuals wanted to know their
HIV status (page 2650, reference 11).
A paper reporting child survival according to
HIV-status of the mother during 1994-2000 reports 123
children born to HIV-positive mothers.[4,9]
According to a recent report, Kisesa will become the
principal location for monitoring and evaluating the
uptake and impact of the antiretroviral program that
a Global Fund 4th round grant supports in
Tanzania.[12] Availability of antiviral treatment may
motivate participants in the Kisesa project to ask
about their HIV status.
UGANDA, RURAL RAKAI, general population cohort,
1988-continuing according to latest available
information [Funding: NIAID NIH, Rockefeller
Foundation, USAID, National Institute for Child Health
and Development, Johns Hopkins Population Center,
World Bank STI Project, US NIH, Fogarty Foundation;
Glaxo-Welcome Foundation]
In Rakai, Uganda, researchers have bled and questioned
a rural cohort roughly every 10 months from 1989 and
continuing. This research included the 1994-98 Rakai
trial of improved treatment of sexually transmitted
disease (STD) to reduce HIV incidence. Numbers bled
increased from 1,292 in 1989 to more than 20,000 in
1994-99.[13]
A report of 1989-90 Rakai research[14] does not say
whether and how the project offered information about
HIV status to study participants. A report of 1990-91
research (page 746 or reference 15) states All
individuals are offered counseling and HIV results are
readily available on request. However, Among
serodiscordant couples, only 10 men (12.7%) and six
women (7.2%) requested both counseling and their HIV
test results during 1990-91 (page 748 of reference
15).
From 1989 to 1990, the project followed 21 discordant
couples, and observed 2 incident infections.[14] In
1990, the project identified 83 men and women with
HIV-positive partners; a year later, the project
observed incident HIV infections in 6 of these men and
women.[15]
During 1994-98, the project offered all study
participants free condoms and voluntary, confidential
serologic testing for HIV-1 and counseling by trained
project counselors (page 922, reference 16). Among
monogamous serodiscordant couples, 56% of
HIV-1-positive partners
had requested and received HIV
counseling, and 25% stated that they had informed
their spouses (page 1152, reference 17). During this
period, the project observed 90 incident infections in
415 initially serodiscordant couples.[16]
During 1994-98, the project observed 230 HIV-positive
pregnant women; 46% of all pregnant women received
test results and counseling, but no information is
available about how many HIV-positive pregnant women
did so.[18]
UGANDA, MASAKA, general population cohort,
1989-continuing according to latest information
[Funding: UNICEF, MRC of UK, DfID]
Ugandas Medical Research Council established a
general population cohort in Masaka in 1989. Towards
the end of the 1990s, roughly 15,000 were bled in
annual serosurveys.[19] The study is continuing.
HIV test results were provided to study participants,
on request, by experienced counselors employed by
[Ugandas Medical Research Council] MRC and stationed
in the study area. During annual serological surveys,
all adults were encouraged to visit a counseling
station (page 1084, reference 20). However, during
1989-97, less than 10% of all adults make use of
counseling
[W]e do not know whether individuals who
come for counseling share their test results with
their spouse, although they are encouraged to do so.
Although we had only limited data on condom use, it is
noteworthy that none of the HIV-negative adults in
discordant marriages reported using a condom (page
1088, reference 20).
During 1989-97, the project observed 34 incident
infections in 121 adults known to have HIV-positive
spouses.[20] During 1989-90, the project observed 218
children born to mothers known to be
HIV-positive.[4,21]
In 1989, the the Masaka research team established a
natural history cohort of participants with and
without HIV selected purposively from the full study
cohort to include many HIV-positive subjects, their
HIV-negative partners, and HIV-negative controls; the
cohort was continued through 1998.[22,23] Study
managers identified people to be enrolled in cohort
according to HIV status, but all field and clinic
staff who worked with the participants were blind to
their status. Comprehensive counseling services were
provided in study villages away from the clinic for
safe-sex education and HIV testing. Participants were
actively encouraged to use these services, but were
told that they should not inform or discuss their HIV
status with the clinic staff (page 635, reference
23). The study, in other words, tried to ensure that
clinic staff treating HIV-positive participants
remained blind to their HIV status, even when patients
were aware.
Masaka project staff assessed project relations with
study participants during 1994-2000, during which time
the project divided the cohort into two intervention
arms and a control arm to study the impact of sexual
behavior change interventions and improved STD
treatment on HIV incidence.[24] Residents in the
intervention arms received sexual behavior change
interventions with or without improved STD treatment;
residents in the control arm received benefits not
related to sexual behavior or STD treatment. Notably,
in the control arm the lack of an obvious link
between the control arm activities and the evaluation
meant that the survey had to be explained more
vaguely
(page 1085, reference 24). Deciding the
appropriate level of detail to disclose when obtaining
informed consent is an acknowledged ethical dilemma
(page 1088). Project staff considered whether to
clarify misconceptions among subjects giving blood
that they were participating in the search for an AIDS
cure (page 1089): Whether it is necessary or
desirable to refute this misconception
is a dilemma.
Deception of research subjects is morally
questionable, but this must be weighed against
pragmatic factors. For instance, more detailed
explanations risk biasing the reported behavior if
they become unblinded to the aim of the trial to
study impact of interventions on HIV transmission.
ZIMBABWE, MANICALAND, general population cohort,
1998-continuing according to latest information
[Funding: Wellcome Trust; UNAIDS; Royal Society,
London; DfID; World Bank; Southern African AIDS Trust]
The Manicaland HIV/STD Prevention Project began with a
baseline survey in 1998-2000 and completed one
follow-up survey in 2001-03. According to a report
from the baseline survey, Written informed consent
was sought as a condition for enrolment and a separate
free voluntary HIV counselling and testing service was
made available (page 1897, reference 25). Neither of
two reports from the 2001-03 follow-up provide any
information about arrangements to tell participants
their HIV status.[26,27]
By design, this research is unable to observe HIV
transmission to spouses: A maximum of one member of
any given marital group was selected to participate to
increase the statistical power of an embedded
randomized controlled trial (page 718, reference 26).
One of the objectives of the research is To quantify
and describe orphan incidence (page 717, reference
26). Information from the baseline and first follow-up
surveys shows that 83% of childrens fathers and 82%
of childrens mothers who died in the inter-survey
period had been HIV-positive at baseline (page 719,
reference 26). The project has reported numbers and
ages of children at first follow-up and mortality
among children, but has not reported this information
according to HIV-status of mothers.
CONCLUSION
During 1989-2003, at least seven research projects in
Africa followed research participants who were
HIV-positive without telling them so. According to
information available in the public sector, additional
follow-up surveys were or are expected in five
projects (Karonga, Malawi; Kisesa, Tanzania; Rakai and
Masaka, Uganda; and Manicaland, Zimbabwe).
Following research participants who have a
life-threatening condition such as cancer or diabetes
and not telling or treating them would be unusual in
medical research in rich countries, and even more so
if the condition were an infectious disease.
Throughout Africa, governments and donors in the early
21st century have been aggressively extending programs
to reduce mother-to-child transmission and to provide
antiviral treatment to people infected with HIV. These
programs are improving access to HIV tests and
increasing incentives to test. These efforts to extend
testing and treatment contrast with research projects
that have tested and followed people sometimes for
many years who do not know they are HIV-positive.
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