Trial Information

Trial of Male Circumcision: HIV, STD and Behavioral Effects in Men, Women and the Community

STUDY DESCRIPTION:

The study is being carried out by the Rakai Health Sciences Program, a research
collaboration between the Uganda Virus Research Institute/Uganda Ministry of Health, Johns
Hopkins Bloomberg School of Public Health and researchers from Makerere University, Kampala,
Uganda.

- The study, being conducted in Rakai District, Uganda, has enrolled 997 HIV+ and
following a detailed informed consent process, randomizing them to receive either
immediate (within several days or weeks) or delayed (two years) circumcision. The goals
are to assess the safety and acceptability of male circumcision among HIV+ men, and to
assess potential effects of male circumcision on the acquisition of STDs such as HSV-2.
Hypotheses are that male circumcision will be acceptable to and safe in HIV+ men, will
reduce the rate of acquisition of STDs, and will reduce the frequency of STD symptoms,
such as genital ulceration.

- The study has also enrolled 500 men who, regardless of their HIV status, decline to
receive their HIV results, despite encouragement to do so. Hypotheses are that
circumcision will be acceptable and safe in men who decline their HIV results, and will
reduce the rate of acquisition of HIV and STDs, and the frequency of STD symptoms such
as genital ulcers.

- The study has enrolled 3,700 female partners of the men in groups 1 and 2 above, as
well as of 5,000 HIV-negative men enrolled in a complementary NIH-funded study of male
circumcision for HIV prevention (U1 AI51171 which is being separately registered).
Following informed consent, the women partners are being followed annually to assess
the acceptability and safety of male circumcision in female partners, and potential
effects of male circumcision on HIV and STD acquisition. The hypotheses are that male
circumcision will be acceptable to and safe in women partners, and will reduce the
acquisition of HIV and STDs such as HSV-2 and HPV (human papilloma virus which causes
cervical cancer.)

- Finally, the study is also following ~3,000 men and women in the ~50 communities where
the circumcision trials are taking place, in order to assess community attitudes
towards and knowledge of male circumcision, and to assess whether other preventive
behaviors (abstinence, monogamy, numbers of partners, condom use, etc...) change in the
community once circumcision becomes available. The hypothesis is that male
circumcision will be acceptable in the community and will not result in behavioral
disinhibition (increased rates of high risk behaviors).

The Gates-funded study being registered here is complementary to a separate NIH-funded trial
of male circumcision in HIV-negative men who accept their HIV results, being carried out by
the Rakai Health Sciences Program study team. The latter study, which is enrolling 5000
HIV-negative men, is designed to answer whether male circumcision is acceptable and safe in
HIV-neg men, and whether the procedure reduces the acquisition of HIV and STDs.

The complementary Gates-funded trial is designed to answer the following additional
questions:

- Is male circumcision acceptable to and safe in HIV-infected men, and will it reduce the
rates of acquisition of STDs in these men?

These questions are of great importance for future circumcision programs:

- Will such programs need to screen out HIV+ men (if circumcision is shown to be unsafe
in such men, potentially as a result of delayed healing) or should future programs
include HIV+ men, if the procedure is safe in them, and has potential benefits such as
reduced STD acquisition, improved genital hygiene and reduced rates of STD
symptomatology?

- Is male circumcision acceptable and safe in men who decline their HIV results, and will
it reduce rates of acquisition of HIV and STDS in these men?

From prior Rakai Program data, the researchers know that men who decline their HIV results
tend to have higher risk behaviors. Determining potential circumcision risks in these men
(such as, potentially delayed healing because of their higher risk behaviors) or benefits
(such as potentially, reduced rates of HIV and STD acquisition) is thus very important for
the design of any future large scale circumcision programs. From the public health
viewpoint, it will be important to know whether such programs should include or exclude men
who decline HIV results. (Please note: the Rakai Program strongly recommends and encourages
the receipt of HIV results, and provides the results confidentially and free of charge. The
great majority of Rakai Program research participants (85-90%) accept their HIV results, but
a minority continue to decline, although the latter group is getting smaller every year. In
addition, please also note that even if participants decline their HIV results, the Rakai
Program still provides them with detailed HIV prevention education and counseling.)
Enrollment of men who decline their HIV results is also congruent with Ugandan Ministry of
Health Policy, which encourages but does not force individuals and study participants to
receive their HIV results.

Enrollment of female partners is designed to answer important questions regarding potential
effects of male circumcision on women. Should male circumcision reduce HIV and STD
acquisition in women, this would represent an additional important public health benefit of
the procedure and would add to the cost effectiveness of male circumcision programs.
However, if the procedure is associated with increased HIV transmission (for example, due to
increased transmission before a circumcision surgical would is fully healed), it is crucial
that such a potential risk be identified rapidly within a trial, in order to prevent the
risk within trials and in any potential future circumcision programs.

Following enrollment, men in the circumcision arm are followed post-operatively at weekly
intervals until wound healing is fully certified, , at 4-6 weeks, 6 months, 12 months and 24
months. Men in the control arm are followed at 4-6 weeks and 6, 12 and 24 months. At
baseline and follow up, men respond to a detailed sociodemographic, behavioral and health
questionnaire, and provide biological samples (venous blood, urine, sub-preputial swabs
[prior to circumcision] and for circumcised men, foreskins are collected at time of
surgery.) Samples will allow assessment of multiple infections, including HIV, HSV-2,
gonorrhea, chlamydia and syphilis.

Women partners are followed annually, through the Rakai Community Cohort Study. Following
written informed consent, women are administered a detailed sociodemographic, behavioral and
health status questionnaire, and provide venous blood and self-administered vaginal swabs at
baseline and study follow up visits. The samples will allow assessment of multiple
infections and conditions, including HIV, syphilis, gonorrhea, chlamydia, trichomonas,
bacterial vaginosis, HSV-2 and HPV. Women partners of HIV+ men receive additional visita at
6 and 18 months post enrollment.

Community members (men not in the trials, and women who are not partners of men in the
trials) are followed annually through the Rakai Community Cohort Study.

Services offered by the Rakai Program to all study participants include HIV and STD
prevention education (information on behavioral risk factors and on abstinence, monogamy,
being faithful and condom use), free condoms, free HIV counseling and testing for
individuals and couples, free STD treatment, access to Rakai Program clinics for general
health care, access to Rakai clinics for free HIV antiretroviral (ARV) drug screening and
services, prophylaxis for opportunistic infections and nevirapine services for the
prevention of mother-to-child HIV transmission. Please note: residents in the 50 villages
where the circumcision trials are being conducted have access to Rakai clinics and ARV
services whether or not they consent to be in Rakai studies, in order to avoid undue
pressure to participate.