Download The Andean pre-exposure prophylaxis (PrEP) study is a Phase IIb

Introduction To The Cape Town
PrEP Study
Pre-Exposure Prophylaxis (PrEP) and HIV
The global toll of new HIV infections - more than four million new HIV infections
occurred in 2006 alone - demonstrates the urgent need for effective new HIV
prevention tools. Existing prevention methods such as education, counseling, and
condom use are important in reducing the number of HIV infections, but have not been
sufficient to stop the epidemic. Moreover, other potential prevention methods, such as
a safe and effective vaccine against HIV, are still many years in the future.
Pre-exposure prophylaxis (PrEP), therapy taken to prevent rather than treat an infection
or illness, is one strategy being studied by the NIH as part of its effort to develop new
HIV prevention tools. In monkey studies, treatment with HIV antiretroviral drugs
significantly reduced infections among monkeys exposed to the simian version of HIV.
In humans, HIV has also been shown to be vulnerable to this type of pre-infection
intervention. For example, antiretroviral treatment of an HIV-infected mother during
childbirth reduces an infant’s chance of contracting the virus by about 75 percent.
Treatment with anti-HIV drugs can also significantly reduce the risk of infection when
taken immediately after exposure to the virus (PEP).
The Cape Town PrEP Study
The Cape Town PrEP study is a Phase IIb “proof of concept” study sponsored by the
National Institutes of Health (NIH) and funded by the Bill and Melinda Gates
Foundation, both in the United States. This study is designed to determine whether use
of the HIV antiretroviral drug Truvada® (tenofovir disoproxil fumarate and
emtricitabine) may help prevent HIV infection among people at high risk for HIV
infection, when combined with safer sex counseling and condoms. A highly qualified
team of researchers in Cape Town is conducting this study.
The study will enroll 200 healthy, sexually active HIV-negative men who have sex with
men (MSM) who are at high risk of HIV infection. The study will be conducted at the
Desmond Tutu HIV Foundation in Cape Town. Potential volunteers are extensively
interviewed to ensure that they understand the study and that their participation is
completely voluntary.
All study participants will receive condoms and counseling on how to prevent HIV
infection, along with medical care for any sexually transmitted infections.
Approximately half will also receive the study drug Truvada® once daily, and half will
receive a placebo. Neither the study personnel nor the volunteers will know who is
receiving the drug and who is receiving placebo. Study volunteers will receive safer sex
counseling and will be tested for HIV and for other sexually transmitted infections
monthly. In addition to extensive safer sex counseling, volunteers will be counseled
that, even if they receive the study drug, there is no assurance that the drug will offer
any protection against HIV - meaning safer sex precautions should always be used.
At the end of the study, the investigators will compare the number of HIV infections in
the group that received the drug to those in the group that received placebo, to
determine if Truvada can effectively help to prevent HIV infection when used in
combination with safer sex counseling and condoms. Finding a potential difference
between the two groups requires a large number of volunteers because the extensive
risk-reduction counseling provided to study volunteers generally lowers HIV risk
behavior in both study groups.
Volunteers will be carefully monitored throughout the 24-month study period and for 6
months afterwards. In addition to the possible usefulness of Truvada® in HIV
prevention, the study will also assess the effects of taking a daily pill on HIV risk
behaviors; adherence to and acceptability of the regimen; and whether use of the drug
for prevention causes drug resistance in volunteers who become infected with HIV.
Volunteers will be monitored monthly for any possible side effects or abnormalities, and
the study drug will be promptly discontinued if any serious concerns are identified. If,
despite extensive safer sex counseling and the availability of condoms, a volunteer
becomes HIV-positive during the study, they will receive full medical care, including
treatment for HIV infection if needed.
Truvada was selected for the Cape Town PrEP study because it has been shown to be a
safe and effective treatment for HIV, with few side effects in studies involving more
than 15,000 people worldwide. Tenofovir®, one of the component drugs of Truvada®,
was approved by the Food and Drug Administration (FDA) in the United States in 2002.
The tenofovir plus emtricitabine combination pill used in this study was approved for
use in the United States in 2004, and in South Africa by the Medicine Control Council
(MCC) in 2007. More than 100,000 HIV-infected people around the world have now
used these drugs.
A trial of tenofovir for HIV prevention has been recently completed by Family Health
International in West Africa. This study confirmed the safety of tenofovir used daily in
HIV uninfected women, and found that the HIV risk behavior of volunteers declined
during the study, likely because of the counseling provided. Eight women became
infected during the study: 6 in the placebo group and 2 in the tenofovir group. The
West African study provides a solid basis for larger studies needed to learn whether HIV
PrEP can effectively prevent HIV.
Commitment to HIV Prevention in Cape Town
Investigators at the Desmond Tutu HIV Foundation have an outstanding record of
conducting HIV prevention research. The Cape Town study site has recruited more
than 1,000 people at risk of HIV into research studies since 1996, and has
demonstrated outstanding compliance with international clinical trial standards.
Another reason for conducting this study in Cape Town is the impact of HIV among
MSM here. Studies indicate that prevalence of HIV infection in MSM is 10% in town and
up to 35% in townships – underscoring the need to conduct HIV prevention research in
the communities in which new prevention tools are needed most.
Consultation with and the participation of local affected communities has been a
cornerstone in developing the Cape Town PrEP study. Researchers consult regularly
and on all aspects of the study with a Community Advisory Board (CAB) comprising
leaders of HIV/AIDS service organizations, LGBT community activists, and members of
the at-risk community. CAB members have participated in the developing the study
design, the informed consent process, and study recruitment strategies; as well as in
educating the community about the trial. The government of South Africa has also
helped oversee the development of the study. Finally, the study investigators have
consulted widely and on an ongoing basis with community leaders and government
officials to ensure that the Cape Town study is responsive to the needs of people in the
region who are at risk of contracting HIV.
The NIH is sponsoring, and the Bill and Melinda Gate Foundation is funding the Cape
Town PrEP study through a grant to the J. David Gladstone Institutes, a non-profit
independent research organization affiliated with the University of California, San
Francisco. The study is being conducted at the Desmond Tutu HIV Foundation at the
Institute of Infectious Disease and Molecular Medicine, University of Cape Town Faculty
of Health Sciences. The NIH and the Bill and Melinda Gate Foundation are currently
supporting other studies of HIV PrEP among MSM in the Brazil, Ecuador, Peru, Thailand,
and the United States.
Data from the Cape Town PrEP study are expected to be available in 2010.
For questions, please contact Earl Burrell at [email protected] or on
021.650.6969.
Frequently Asked Questions
1. What is the purpose of the Cape Town PrEP study?
The Cape Town PrEP study is a Phase IIb “proof of concept” study designed to
determine whether Truvada®, a drug that is already being used to treat people with
HIV infection may also help prevent HIV infection in people who are HIV-negative.
2. Why are new HIV prevention methods needed?
More than four million people became infected with HIV in 2006, indicating that current
HIV prevention methods are not adequate. While HIV prevention counseling has been
shown to reduce HIV infections, education and counseling are not sufficient to stop the
epidemic, and other prevention methods - such as a safe and effective vaccine - are not
likely to be available for many years. The need for new prevention methods is critical,
particularly in places where HIV is spreading rapidly such as Africa, which is the most
impacted continent.
3. What is Truvada®?
Truvada® is a medication for HIV infection that combines two drugs, tenofovir and
emtricitabine, in a single tablet taken once daily. Truvada® has been approved by the
MCC in South Africa and the FDA in the United States and is used around the world to
treat HIV/AIDS.
4. Why was Truvada® selected for this study?
Truvada was selected because it has been shown to be safe and effective with few side
effects in studies involving more than 15,000 people worldwide, and because the drug
was shown in studies to prevent the transmission of the monkey version of HIV (simian
human immunodeficiency virus, or SHIV) without serious side effects. Truvada® is
taken orally only once daily, remains in the bloodstream for many hours, and was well
tolerated in safety trials involving people not infected with HIV. More than 100,000
persons have taken the drug since its approval.
5. Has this approach to prevention been studied before?
Yes. Drugs are taken to prevent malaria, and can be used to reduce the risk of
developing tuberculosis and meningitis.
The possibility that a drug for HIV treatment could be used to prevent HIV infection has
been studied in monkeys with very positive results. In addition, drugs used to treat HIV
reduce transmission of the virus from mother to child by about 75 percent.
6. Where else are PrEP studies being conducted and who is supporting them?
PrEP for HIV is being studied among MSM in Brazil, Ecuador, Peru, Thailand, and the
United States. These studies are being sponsored by the NIH and funded by the NIH or
the Bill and Melinda Gates Foundation.
A study in at-risk women in Cameroon, Ghana, and Nigeria that was completed in 2006
confirmed the safety of tenofovir, a component of Truvada®, the drug being studied in
the Cape Town trial. That study was sponsored by Family Health International with
support from the Bill and Melinda Gates Foundation.
7. How will the Cape Town PrEP study work?
The study is designed to determine whether Truvada® is effective in preventing HIV
infection when combined with safer sex counseling and condom use. The study will
also examine side effects from the study drug.
The study will enroll 200 HIV-negative MSM in greater Cape Town. Participants will be
randomly divided into two groups. Both groups will receive medical care for any
sexually transmitted infections, along with condoms and counseling on how to prevent
HIV infection. One group will also receive the study drug Truvada® once daily, while
the other will receive a placebo (sugar pill). No one, including the study personnel, will
know who is receiving the treatment and who is receiving the placebo until the study is
finished.
Participants will receive intensive counseling in safer sex practices. They will be
monitored for the 24 months in which they receive study drug or placebo, and for 6
months afterward.
8. How will study participants be selected?
Study volunteers must be men who have sex with men, at least 18 years old, HIVnegative, healthy, sexually active, and at high risk for HIV infection. Volunteers are
extensively interviewed to ensure that they understand the study and are participating
voluntarily. They receive complete information about HIV infection risk behaviors, the
study drug, the purpose of the study, and what is required of them.
Volunteers will be recruited through outreach to the MSM community. Information
about the study will be made available at community events, over the Internet, and
through recruiters who visit places where MSM meet. All outreach efforts emphasize
that participation is voluntary.
9. Who is conducting the Cape Town study?
The study’s principal investigators are Dr. Robert Grant (University of California, San
Francisco, and the Gladstone Institutes, United States) and Dr. Javier Lama (IMPACTA,
Peru). The co-investigator is Dr. Linda-Gail Bekker (Desmond Tutu HIV Foundation,
South Africa).
10. Who is sponsoring and funding the study?
The Cape Town study is being sponsored by the Division of AIDS at the National
Institute of Allergy and Infectious Diseases (NIAID), which is part of the NIH in the
United States. The study is being funded by the Bill and Melinda Gates Foundation in
the United States, through a grant to the J. David Gladstone Institutes, a non-profit
independent research organization affiliated with the University of California at San
Francisco. The company that manufactures Truvada®, Gilead Sciences, is donating the
study drug but is not providing funding for the trial.
11. What is the role of the drug company, Gilead Sciences, in the study?
Other than donating the drug, the company that makes Truvada® has no role in the
design, implementation, or evaluation of this study.
12. Where will the study be conducted?
The study will be conducted at the Desmond Tutu HIV Foundation, Institute of
Infectious Disease and Molecular Medicine, University of Cape Town Faculty of Health
Sciences. This site was selected for its strong experience in clinical research; its
capacity to involve their communities in carrying out this study; and its capacity to
comply with all regulatory aspects of the study, including providing safeguards for
participants. This is a not-for-profit organization that has no financial ties to the drug
manufacturer.
13. Why is this study being conducted in MSM?
This study is being conducted among MSM in Cape Town because it is important to
ensure that Truvada® is safe and effective in those populations most in need.
Conducting the study in a population that would be most likely to benefit, such as MSM,
will also establish a strong infrastructure that will help ensure that the drug reaches the
people who need it in the future, should it prove safe and effective. PrEP for HIV
prevention is being studied in the populations most at risk in other countries as well –
among MSM in Brazil, Ecuador, Peru, Thailand, and the United States.
Study volunteers are active and informed participants and contributors to the study. All
volunteers will undergo an intensive informed consent process that lays out the details
of the trial and its potential benefits and risks. All participants in the study will receive
intensive counseling and free condoms, which is expected to reduce the risk of infection
in both the study drug and placebo groups. Participants are encouraged to ask
questions and to discuss the trial with others they trust, including other medical
experts, and are free to leave the trial at any time without repercussions.
14. Why is the study being conducted in Cape Town?
Cape Town was selected for this study because MSM in Cape Town are highly affected
by the epidemic. Studies indicate that prevalence of HIV infection in MSM is 10% in
town and up to 30% in townships.
Investigators in Cape Town have an outstanding record of conducting HIV prevention
research, with high recruitment and retention rates of study volunteers. The Cape
Town study site has recruited more than 1,000 people at high risk for HIV into research
studies since 1996. The Cape Town site has also outstanding compliance with
international clinical trial standards.
The government of South Africa has taken strong leadership roles in HIV prevention,
and understands the importance of HIV research and how it can benefit its’ citizens. It
is essential that prevention research take place where the epidemic is. Since 90% of
new HIV infections occur in Africa, Asia, and Latin America, it would not be correct for
this research to be done only in the United States and Europe.
15. How has the community been involved in the study design and planning?
Consultation with and the participation of affected communities has been a cornerstone
of the development of this study. Study investigators consult regularly and on all
aspects of the study with a CAB comprising leaders of HIV/AIDS service organizations,
LGBT community activists, and members of the at-risk community. Discussions with
the CAB began with the start of study planning (June 2007), continue today, and will
continue throughout the study. CAB members have participated in the development of
the research design; development of the informed consent process; recruitment; and in
educating the community about the trial. In addition, the investigators consult widely
and on an ongoing basis with others, including community leaders and government
officials.
16. Is this study fully compliant with all ethical standards?
Yes. The study is fully compliant with the Declaration of Helsinki and all other ethical
standards.
17. How are study volunteers protected?
Volunteers are protected through extensive scrutiny of the study before it is
implemented, extensive briefing to ensure they understand the study and all of their
rights as volunteers, and careful monitoring both during and after the study period.
All study plans and materials have been extensively reviewed by the Institutional
Review Boards (IRBs) at the University of Cape Town in South Africa and the University
of California, San Francisco. These institutional review boards meet all applicable
international standards. The study was also reviewed and approved by the MCC in
South Africa and the NIH and FDA in the United States.
Study volunteers are extensively counseled about the purpose of the study and how it
will work, the fact that they might receive a placebo, and the need to strictly maintain
safer sex precautions. All volunteers must sign an informed consent document and are
required to pass a comprehension test to demonstrate that they understand the study
and their rights as volunteers.
All volunteers will receive regular HIV testing, risk reduction counseling, and condoms
throughout the study and will be closely monitored for any concerns or problems - such
as the emergence of toxicities or drug resistance. Volunteers are free to withdraw from
the study at any time and for any reason.
The study will be monitored by a Data and Safety Monitoring Board (DSMB), an
independent group of clinical research experts, statisticians, and other representatives
of the international academic research community, including representatives from South
Africa. This group is independent and is not part of the research staff of the study.
The DSMB may recommend that a trial, or part of a trial, be stopped if there are safety
concerns, or if they believe that the trial objectives either have been achieved or cannot
be achieved.
18. What compensation will study volunteers receive?
Participants will be reimbursed for their transportation expenses to go to the study clinic
and for the time spent at each study visit. Participants will also receive treatment as
needed for curable STIs at no cost. Hepatitis B vaccination, a preventive public health
intervention, will be offered at no cost to those participants who need it.
19. Why does this study use a placebo?
No one knows whether PrEP with Truvada® will be effective in protecting people from
HIV infection. Reliable information about the effectiveness of PrEP with Truvada®,
which is needed to guide public health authorities at the national and international
levels, can only be obtained by comparing the active drug with a placebo among people
who all receive standard prevention interventions.
20. Do you need people to become infected to demonstrate whether PrEP
works?
Study personnel are committed to helping volunteers reduce their risk of HIV infection.
Some persons will learn to protect themselves with intensive counseling, but some will
not - which is why we look for new prevention methods such as PrEP or a vaccine. If
infections are lower in the group that received Truvada®, it may mean that Truvada®
is effective as a PrEP intervention. If the rate of new infections is low in both groups,
very valuable information will have been gained about ways to provide counseling that
effectively reduce HIV risk. The large size of the prevention studies helps assure that
some information will be learned even if the great majority of people learn to protect
themselves.
21. What happens if a study participant becomes HIV positive during the
study?
If, despite safer sex counseling and provision of condoms, a participant becomes
infected with HIV during the study, infectious disease specialists with expertise in HIV
care will follow him at the study clinic. The study will provide primary care and
laboratory testing for viral load, CD4 T-cell counts, and drug resistance, which are often
the most expensive parts of HIV treatment. If antiretroviral therapy is warranted, the
government of South Africa’s free ART rollout clinics will provide them.
22. Does Truvada® have side effects?
While all HIV drugs have some side effects, Truvada® is a widely used in part because
its side effects are generally mild. In previous studies in HIV-infected individuals, less
than 1 percent of study participants stopped Truvada® therapy because of side effects.
The most commonly reported side effects from use of Truvada are nausea, vomiting,
diarrhea, and flatulence. These effects have largely been reversed after use of the drug
was discontinued. The study will monitor the health of the participants very carefully,
and will stop the study drug if there is any sign of illness due to participation in the
study. Anyone who has trouble will be monitored and cared for until the signs of illness
resolve.
23. What is HIV drug resistance and why is it a concern in this study?
Like many pathogens, HIV can develop resistance to drugs used to treat it.
Theoretically - if a person is receiving a drug to prevent HIV infection and becomes
infected - the fact that the virus is exposed, even briefly, to the drug being taken for
prevention could cause it to develop resistance to that drug, making that drug, and
possibly others like it, less effective for treatment.
Previous studies indicate that it is more difficult to develop resistance to Truvada® than
to other HIV drugs. In studies involving tenofovir, a component drug of Truvada®,
animals that eventually became infected despite exposure to the drug for prevention
did not develop drug resistance. Drug resistance also generally does not occur when
drugs are used to prevent malaria, tuberculosis, or pneumonia.
24. What precautions are being taken to minimize the risk of developing HIV
drug resistance for volunteers in the study who become infected with HIV?
The Cape Town study involves several safeguards designed to reduce the risk of drug
resistance. Volunteers will be tested for HIV twice before starting the study, and
participants will be tested for HIV frequently throughout the study to ensure that, if
they do become infected, the study drug is stopped before resistance can occur. The
fact that this study employs a combination of two drugs also makes it less likely that
resistance to both drugs will occur.
Any participant who becomes infected with HIV during the trial will receive appropriate
medical treatment. The study will provide viral load testing and CD4 T- cell counts, as
well as drug resistance testing using three different laboratory tests (genotype,
phenotype, and a sensitive point mutation assay).
Although drug resistance is not expected to occur during the study, any unexpected
evidence of drug resistance will be reported to an independent DSMB, which will
recommend whether the trial should continue.
In the unlikely event that a study volunteer develops any resistance to Truvada®, many
therapies would still be fully active to treat their HIV infection, including AZT,
nevirapine, and efavirenz, and all protease inhibitors, which block HIV replication at a
different point than Truvada®.
25. What medical care is provided for study volunteers?
Careful medical monitoring and care is provided to volunteers throughout the study. In
addition to primary medical care and treatment of sexually transmitted infections, study
volunteers will receive all appropriate laboratory tests to monitor for possible HIV
infection or any other blood abnormalities. These tests are known as CD4 T-cell, viral
load, and drug-resistance testing. Volunteers will also be monitored and treated if
needed for any side effect that may be related to the study drug.
If a volunteer contracts HIV during the study, treatment with antiretroviral drugs will be
available through government programs. The government of South Africa’s free ART
rollout clinics will help provide antiretroviral treatment to all who require it.
26. How will participants and the community benefit from the study?
Study participants will benefit from extensive and ongoing HIV prevention education
and counseling, including provision of free condoms at every visit. Volunteers will also
receive testing and treatment for HIV and sexually transmitted infections, and testing
for hepatitis B. Volunteers whose laboratory tests show that they are susceptible to
hepatitis B will be offered free vaccination.
If Truvada® is proven to be safe and effective in preventing HIV infection, some study
participants will have been among the first to receive it. All participants, regardless of
the study results, will make an important contribution to future HIV prevention efforts
in their own community.
27. If Truvada® prevents HIV infection in the study, will it be practical for
broad use? How will it be made available?
If Truvada® is found to be highly effective at preventing infection with no serious side
effects in the Cape Town study and at other sites, the Cape Town study team will work
closely with national and international health organizations to develop guidelines for use
of the drug for HIV prevention in high risk persons who are also receiving counseling,
condoms, and care for sexually transmitted infections. These efforts would include
additional research to optimize counseling for people at risk and use of the drug for
prevention. The study investigators are also working with drug manufacturers and
Departments of Health to help ensure that effective drugs will be available for both
treatment and prevention. Tenofovir, one of the drugs being used in this study, is
already available from generic drug manufacturers.
28. Is there a risk that people in the study will feel that they are protected
and will increase their risk behavior during the study?
Study volunteers will be counseled that PrEP with Truvada® is experimental, and that it
is not known whether it will protect them against HIV infection. Still, there is a concern
that some people may feel protected and may relax safer sex precautions.
This concern was also expressed when HIV preventive vaccine trials were first
introduced, and after the advent of PEP. However, analyses of risk behavior during
vaccine trials and studies of PEP indicate that risk behavior actually decreases during
these studies because of the counseling provided. Volunteers in other PrEP studies
have reported fewer sexual partners and increased condom use during the study, which
likely reflects the benefits of counseling and condoms.
Several steps are taken in this study to ensure that volunteers continue to protect
themselves. Volunteers are counseled that the pill they receive may not protect them,
and the investigators will not allow a potential volunteer to enroll in the study unless he
understands what a placebo is and the importance of following HIV risk-reduction
measures.
In addition, the investigators will closely evaluate risk behavior and the incidence of
sexually transmitted infections during the trial, and will alter the counseling provided to
volunteers if they detect an increase in overall risk behavior.
29. Why have other PrEP studies been stopped?
Studies of Truvada® or one of its component drugs, tenofovir, are successfully under
way in the United States, Botswana, and Thailand and this PrEP study has been
successfully launched at the Ecuador and Peru sites. Another study has been
completed in West Africa. However, PrEP studies were halted before they began in
Cambodia and Malawi for a variety of reasons, including misunderstanding and
miscommunication about the purpose of the study, and what care would be available
for participants who become HIV positive despite the provision of intensive risk
reduction counseling and condoms. Sites in which studies are now successfully under
way have learned from the experience of other study locations and have made
extensive efforts to address and prevent the types of concerns that arose at those sites.
The investigators and sponsors of the Cape Town PrEP trial are committed to open
communication, provision of comprehensive prevention measures to all participants,
and appropriate treatment of any illnesses or side effects that result from participation
in the study and for any volunteer who becomes HIV-infected during the study.
Eligibility Criteria
The target population for this multi-centre trial was developed to capture homosexual
men who self-identify, are aged 18 years or older, who are at especially high-risk for HIV
infection, and who consent to participate in this study.
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Male sex (at birth). This study aims to study the toxicity and efficacy of
chemoprophylaxis for the prevention of HIV transmission in men only
Willing and able to provide written informed consent as required by GCP and the
ethical standards of South Africa
Age 18 years of age or older in keeping with the legal age of Informed Consent
in South Africa
HIV-1-uninfected as necessary to determine toxicity and efficacy of
chemoprophylaxis for the prevention of HIV-1 transmission
Evidence of high risk for acquiring HIV-1 in order to ensure an adequate number
of primary outcome observations (HIV-1 infection) to power the study and
statistically determine the efficacy of the chemoprophylaxis being tested. These
criteria include any ONE of the following:
o No condom use during the last receptive and/or insertive anal intercourse
with a male HIV-positive partner or a male partner of unknown HIV status
during the last 6 months
o Anal intercourse with more than 5 male sex partners during the last 6
months
o Exchange of money, gifts, shelter, or drugs for anal sex with a male
partner during the last 6 months
o Sex with a male partner and STI diagnosis during the last 6 months or at
screening
o Sexual partner of an HIV-infected man with whom condoms are not
consistently used
Able to provide a street address of residence for themselves and one personal
contact who would know their whereabouts during the study period to enable
study staff to retain recruited MSM cohort and contact participants in order to
convey any pertinent information pertaining to the study
Ability to understand and speak a local language (English, Xhosa, or Afrikaans)
for which an informed consent form has been approved by the University of
Cape Town, Ethics Review Board as well as the University of California, San
Francisco, Institutional Review Board before use
These inclusion criteria were developed with previously gathered information from
previous research conducted by the Desmond Tutu HIV Foundation within this
demographic in Cape Town, input from local LGBT social advocacy groups, as well as in
coordination with our international partners.