The Role of Adult Male Circumcision in the Prevention

Transcription

Goldstuck, Androl Gynecol: Curr Res 2014, 2:3
http://dx.doi.org/10.4172/2327-4360.1000123
Andrology & Gynecology:
Current Research
Review Article
The Role of Adult Male
Circumcision in the Prevention
of HIV/AIDS- Does the
Technique Make a Difference?
Norman D Goldstuck1*
Abstract
The co-evolution of the Human Immunodeficiency virus (HIV) and
the human male foreskin have in part enabled the spread of HIV.
This is due to the affinity of the HIV virus for the Langerhans cells
of the inner foreskin. Voluntary Medical Male Circumcision (VMMC)
is a means of breaking this link. The techniques available include
standard surgical techniques or one of the many types of necrotising
rings and clamps or by removal of the foreskin with a Gomcolike disposable device. The best device to use will be one which
is most amenable to VMMC programmes so that it must be safe,
easy to learn, to use and to teach, disposable and non-re-usable,
affordable, and easy to store. Only the Gomco Clamp or a Gomcolike disposable device allowing healing by primary intention, which
when used with tissue adhesive, avoid the necessity for routine
follow-up visits as with other methods and may make VMMC more
cost effective and well suited for up-scaling circumcision. A clinical
comparison of the Gomco devices with surgical methods and rings
and clamps is needed.
Keywords
HIV; Prevention; Circumcision; Surgical; Devices
Introduction
The most powerful tool for understanding biological phenomena
is the Darwinian theory of evolution. In this review we will use this and
other medical technological advances to focus on the understanding
of the problem and routes to prevent the spread of HIV/AIDS in
Africa. We will use this to evaluate one of the presently available
modifiers of the transmission of HIV/AIDS in adult heterosexuals,
namely circumcision. In order to know where we want to go, it is
useful to know how we got here. To do this we need to understand the
power of evolutionary forces to change biological tissues.
Elephant embryos have nephrostomes in their kidneys and a
trunk, which was a snorkel, proving they were once aquatic [1].
Molecular genetics shows their nearest relatives are the hippopotami,
still largely aquatic, and whales who are totally aquatic. Sea mammals
are thus the descendants of land mammals whose pre-mammalian
ancestors came from the sea. Evolution often takes a circuitous route.
Similarly, in humans appendages have evolved and devolved like
*Corresponding author: Norman D Goldstuck, Faculty of Medicine and Health
Sciences, Department of Obstetrics and Gynecology, Stellenbosch University
and Tygerberg Hospital, Western Cape 7505, South Africa, Tel: +27823418200;
E-mail: [email protected]
Received: March 25, 2014 Accepted: May 19, 2014 Published: May 23, 2014
International Publisher of Science,
Technology and Medicine
a SciTechnol journal
the male nipple and the appendix. Could it be that the human male
foreskin also no longer has a beneficial function and that like the
appendix it remains and has the capacity to become subtly diseased,
and act as a transmitter of disease? The question of why the foreskin
evolved and its role in aiding HIV transmission in heterosexuals is the
key to understanding the role that circumcision can play in helping
stop the spread of heterosexual HIV / AIDS in Africa in particular and
in the world in general. We examine whether aiding the ‘devolution’
of the foreskin by surgical means can prove beneficial in disrupting
the transmission of HIV/AIDS in heterosexuals and how this is best
achieved. General immunity also plays a role in preventing acquisition
of HIV/AIDS and a genetic history of increased immunity to other
diseases where the pathogen has to pass through cell membranes e.g.
bubonic plague may confer partial immunity. This review will not
examine the role of infant circumcision in the possible prevention
of HIV and other medical disorders; although similar in principle,
the circumcision techniques and complications differ from adults.
The benefits in terms of HIV prevention are many years delayed. It
is adult circumcision programmes that will give the most immediate
return on capital and effort employed.
Evolution of the Foreskin
Darwinian Theory tells us that any physical characteristic that
persists is the subject of natural selection [1]. That physical feature
may now be redundant, e.g. appendix, male nipple, but at some
stage it conferred an advantage. Using this logic the foreskin must
either presently or previously have provided an advantage. Since we
know that currently the foreskin is involved in causing phimosis and
pain, increased urinary infections and latterly the transmission of
heterosexual HIV / AIDS, it appears to be deleterious to, rather than a
contributor to human male health. There must have therefore been a
time when it was advantageous for a human male to have a foreskin.
Cox [2] has proposed that the presence of a tight foreskin causing
phimosis and other problems, led to delayed sexual experience in
males who were already of reproductive age. This meant that they
could establish themselves as hunter- gatherers so they would be in
a better position to support their offspring when they did eventually
become sexually active and begin a family. Analogously in females
a tight hymen, making first coitus more difficult, was favoured. In
older sexually active males the foreskin often does not cover the
flaccid phallus. Therefore, in adulthood it would not be needed and its
evolutionary selective role would be over. This ‘male virginity’ sign- a
tight foreskin - is no longer present today because of circumcision and
the education of males (and the caregivers of young male children)
to avoid foreskin strictures by pulling it back and freeing adhesions.
Male virginity is now cultural rather than physical. We can speculate
that had an HIV-like virus been around 10000 years ago, that human
males would all now be foreskinless, as smaller foreskins would have
conferred an evolutionary advantage leading to its disappearance.
The Evolution of Circumcision
With the possible exception of trepanning, circumcision is the
oldest known surgical operation performed by humankind. We know
this from texts and cave drawings, which go back for 5000 years or
more [3]. It was common to many ancient societies around the world.
All articles published in Andrology & Gynecology: Current Research are the property of SciTechnol, and is protected by
copyright laws. Copyright © 2014, SciTechnol, All Rights Reserved.
Citation: Goldstuck ND (2014) The Role of Adult Male Circumcision in the Prevention of HIV/AIDS- Does the Technique Make a Difference?. Androl Gynecol:
Curr Res 2:3.
doi:http://dx.doi.org/10.4172/2327-4360.1000123
The mucosal epithelium of the inner foreskin allows HIV infected
cells to form apical viral synapses with the dendrites of Langerhans
cells (Figure 1) [4].
What happens next depends on whether the cells are weakly
or highly infected. HIV entry into T-cells requires co-factors such
as chemokine receptors including CCR5. A few individuals carry a
mutation known as CCR5-Δ32 in the CCR5 gene, protecting them
against these strains of HIV.
Figure 1: The infected T-cells cannot pass through the keratinized outer
foreskin or penile skin. In the inner foreskin the highly infected T-cells are
able to transfer HIV via the Langerhans cells to dermal T-cells and cause
systemic infection [4].
The weakly infected T-cells go through the epithelial layer and
attach to the dendrites of the Langerhans cells. The inner foreskin
produces tumor necrosis factor- α which stimulates the Langerhans
cells via cytokines to produce an influx of CD4 and T-cells. The
Langerhans cells produce Langerin which binds the HIV and helps
the cells degrade it and transport the virus to the local lymph nodes.
This mechanism becomes overwhelmed at high viral loads. The
Langerhans cells then transfer the HIV particles to dermal T-cells
(below the epidermis) which then induce a systemic infection (Figure
2). Uncircumcised men are also prone to genital ulcerative disease.
This may be due to Herpes Simplex Virus -2 (HSV-2), Syphilis or
Chancroid. The HIV study in South Africa (Orange Farm) showed
that HIV was also increased in uncircumcised men at high risk for
Human Papilloma Virus (HPV) [5].
Evidence that Circumcision Reduces the Risk of HIV
Infection
Speculation that circumcision might play a role in reducing the
spread of HIV goes back to the early years of the epidemic. Fink [6,7]
first postulated that the foreskin may be involved in the acquisition of
and heterosexual spread of HIV by men, and that male circumcision
may exert a protective effect. This was followed by the publication
of observational studies [8-13]. As the name implies these studies
compared HIV rates in areas where the men were circumcised
with areas where they were not. Observational studies examined
the prevalence of HIV in sub-Saharan Africa with the practice of
circumcision. The methods of circumcision were medical (surgery
with primary healing) or religious or tribal or customary. Some of
these studies were cross sectional and a minority were prospective.
The highest prevalence of HIV is found in East- and Southern Africa
where men are not generally circumcised. These findings required
confirmation with randomized controlled studies (RCT).
Figure 2: The different types of circumcisions as described in table 1.
No other primitive body modification was as widespread. All the
evidence points to the fact that this symbolized manhood and that
sexual activity was now permitted. It was a “rite of passage”. These
traditions persist to this day. Traditional circumcision therefore
is carried out to enable young men to perform sexually. It is often
only partial and its role as a modifier of HIV transmission in these
circumstances (if any) is not clear.
Why are Uncircumcised Men at Higher Risk for
Infection?
Uncircumcised men appear to be at higher risk because the
inner foreskin layer is a largely non-keratinized mucosal epithelium,
unlike the outer foreskin and most of the dermis. Intact keratinized
epithelium is largely resistant to the passage of HIV infected T-cells.
Volume 2 • Issue 3 • 1000123
Three large randomized trials followed. They were carried out in
South Africa, Kenya and Uganda [14-16]. The trials were all ended
early as the evidence that the circumcised group was not seroconverting at the same rate as the control group was overwhelmingly
apparent during the interim analysis. These three studies later formed
the basis for a Cochrane review [17], which confirmed the value of
surgical circumcision with healing by primary intention, as a method
for preventing heterosexual HIV transmission, and reducing infection
rates by 60%. Although the studies were controlled for many variables,
including sexual partners, frequency of coitus, and condom use, only
the South African study explicitly stated that all the participants were
counseled regarding condom usage. This may have been implicit in the
other two studies, but it is not definitively stated. The control groups
did not use the condoms they were provided regularly and efficiently
otherwise the differences between those who were circumcised and
those who were not, would not have become apparent so quickly.
This is a comment that is not expressed very often. Despite counseling
and increased knowledge, the use of condoms remains sporadic. A
surgical method of circumcision (forceps guided or sleeve technique
• Page 2 of 7 •
Curr Res 2:3.
Table 1: Types of circumcision and their differences *considered preferable (Morris and Eley 2011).
Type
Inner foreskin
Outer foreskin
Sulcus
Smegma
Shaft skin tension
Comments
‘Low and loose’
largely removed
largely removed
not fully open
can accumulate
no
flaccid penis droops
‘Low and tight’
maximum removed
removed
fully open*
cannot accumulate
yes
considerable shaft skin is removed,
flaccid penis is semi-erect
‘High and loose’
largely retained
removed
+ shaft skin
not fully open
can accumulate
no
flaccid penis droops
‘High and tight’
largely retained
removed
fully open*
cannot accumulate
yes
inner foreskin assumes the role of
shaft skin as large amount of shaft skin
removed
Figure 5: Healing after the Unicirc method which allows healing by primary
intention (at 2 weeks).
Figure 3: Healing after 4 weeks with the Alis clamp which heals by secondary
intention.
Figure 4: Healing after conventional surgical circumcision (largely primary
healing) at 4 weeks.
with healing by primary intention) was used on the few thousand
subjects in these studies. Surgical circumcision has disadvantages for
performing circumcisions in very large numbers, for up-scaling and
reaching targets. Cost effective and efficient techniques are needed for
this, and will be examined later.
Mechanisms of Adult Circumcision
There are numerous ways of performing circumcision.
Volume 2 • Issue 3 • 1000123
Historically, shields, rings, and clamps of all types have been used
for performing circumcisions – ritual or otherwise. The different
types of surgical styles are given in Table 1 [13]. In addition to the
conventional surgical methods (forceps guided, sleeve and dorsal
slit), development of clamps and rings for circumcision using modern
materials began in the 1930’s. One of the earlier prototypes came
from the Goldstein Medical Company (Gomco), and another was the
Winkelman Clamp. Both of these allow the circumciser to remove
the entire inner foreskin. Presently, numerous devices, mainly plastic,
are being developed. Each appears to have its own advantages and
disadvantages.
One or more of these will be needed for the WHO Global
Health sector ‘Strategy on HIV / AIDS for 2011-2015’. This seeks to
drastically reduce HIV infections by 60%. The WHO were reporting
on the US President’s Emergency Plan for AIDS relief (PEPFAR)
and UNAIDS, who determined that scale-up of voluntary male
circumcision in appropriate settings constitutes a high impact
intervention with good value for money. They suggested scaling-up
male medical circumcision to 80% coverage for 15 to 49 year old
males in 14 priority countries in Sub-Saharan Africa by 2015. This
would require 20.5 million circumcisions, and would be expected to
avert 3.4 million new HIV infections through to 2025. It would cost
US$1.5 billion, but save US$ 16.5 billion of healthcare costs.
Surgical circumcision in adults requires time and skill because
of obtaining local anesthesia and homeostasis and then suturing to
allow for primary healing. While this may not be a problem in western
countries it is a huge problem in Africa. There is a desperate shortage of
skilled personnel & nurses and paramedical need to be able to perform
circumcisions if large numbers are required. We need devices which
will not only bring down the cost of circumcision but ensure that it
is a simple & safe procedure in relatively unskilled hands. Devices
• Page 3 of 7 •
Curr Res 2:3.
have the possibility of reducing the time needed and the skill of the
provider doing the circumcision and thus the cost. Existing plastic
ring and clamp devices appear to be cost effective, but the scheduled
return visits for removal of these devices negate some of the financial
benefits. Healing is also only by secondary intention which occurs
when the normal mechanism of tissue healing is impeded. This leads
to the outpouring of fibroblasts into the wound. Fibroblasts secrete
collagen & other proteins and factors which interfere with healing so
that it takes place more slowly and often with accompanying scarring
and thus delays which may negate some of the health benefits. The
risk of acquiring HIV infection during the prolonged healing phase
may be greater because of the presence of a granulating area. The
prolonged wearing of the device is uncomfortable and the necrosing
tissue produces a socially unacceptable odour which the subject must
endure for a number of days. Devices , especially those which allow
healing by first intention are therefore potential alternatives to the
surgical procedures, especially the sleeve resection method which
produces a good cosmetic result, but is time consuming to perform
and which is considered to be the gold standard. Figure 3-5 show
healing for the surgical and Unicirc methods (primary healing)
compared to the Alis clamp which has secondary healing.
The WHO is currently conducting a study on a ring device with
controlled radial compression, without local anesthesia in Rwanda.
WHO have also outlined their suggested protocols for evaluating
devices [18,19]. This is elaborated further in the Appendix. WHO
acknowledge that the problem with the ring is the delayed healing and
recommends that counseling should be given to the subjects to use
condoms until healed (≈ 6weeks) [19]. The 3 randomized controlled
studies and, more recently, the study which shows that anti-retroviral
protect uninfected partners (HPTN 052) [20] from infected ones
could not possibly have shown the differences which they did if the
males had used condoms properly, faithfully and consistently. This
means that the devices which produce delayed healing through
secondary intention are inherently riskier than those, which allow
healing by first intention. The features which the WHO considers that
an ideal device should have are given in Table 2.
A comparison of surgical circumcision and the different types of
devices is given in Table 3 [21]. In addition to being clinically suitable,
a preferred device should meet other WHO standards relating to cost,
simplicity of use, and the ability to be used by providers with limited
skills. A comparison of these technical features is given in Table 4 [19].
Table 2: Characteristics of the ideal circumcision device (after WHO).
Social
Technical
Clinical
acceptable to client
easy to store and distribute
minimal blood loss
acceptable to sexual partner
easy instruction
device removed immediately after procedure
acceptable to caregiver(as appropriate)
short procedure time
confirmed clinical results
good cosmetic result
reproducible results
healing by first intention
affordable to client
disposable
compatible with tissue glue
minimal or no follow-up
cannot be re-used
no post-operative follow up visits
no postoperative analgesia or medication needed
safe and simple to use
simple to apply and remove when performing procedure
cannot cause injury
no post-operative analgesics oranti-biotics
Table 3: Clinical comparison of circumcision devices.
Type of device
Clinical feature
`
Gomco-type
Surgical
Clamps
Rings
(Gomco, UNICIRC)
(Forceps guided, sleeve,
(Smart, Tara, Alis)
(Shang, ERCRC, Prepex)
secondary intention
secondary intention
dorsal slit)
Healing method
primary intention
primary intention
(3 weeks)
(6 weeks+)
Local anaesthesia
yes
yes
yes
yes (topical with Prepex)
possible with tight/ short frenulum
yes
yes
yes
yes (not Prepex)
Necrotic tissue after removal of device
no
N/A
4-5mm
4-5mm
Putrefaction of necrotic material (increases infection risk)
no
no
yes
yes
Pain on removal
no
N/A
yes
yes
Instruments for removal
no
N/A
yes
yes (most)
Return visit for removal
no
yes (wound check)
yes
yes
ERCRC-elastic ring controlled radial compression UNICIRC- Universal circumcision device
Table 4: Technical comparison of circumcision devices.
Type of device
Technical feature
Gomco-type
(Gomco, UNICIRC)
Surgical
(Forceps guided, sleeve, dorsal slit)
Clamps*
(Smart, Tara, Alis)
Rings*
(Shang, ERCRC, Prepex)
longest history of technique and method of use
yes(1935)
yes
1990’s
2003
Cost effective (price per pack)
yes
no
no
no
Easy to perform (little experience)
yes
no
yes
yes
*
*- devices generally safer, quicker, easier to use than surgical methods
Volume 2 • Issue 3 • 1000123
• Page 4 of 7 •
Curr Res 2:3.
The Gomco-like devices appear to most closely achieve the
requirements of the WHO. This is especially true of the Unicirc
device, a disposable Gomco-like device [22] (SA designed and
developed). From the foregoing it is clear that a 3-way study of
surgical versus Gomco-like device versus a compression device is
urgently needed. The Gomco Clamp has been in use since 1935, and
the technique and method used in this type of circumcision has been
tested and numerous publications attest to its safety of use [21]. This
type of study is now possible because of the availability of the Unicirc,
a Gomco like disposable device which has become available and is
discussed further in the next section.
The Role of Technique in ‘Scaling-Up” of Male
Circumcision Programmes
In order to conduct a mass programme of circumcision we
have to abandon the traditional surgical method and seek a much
faster, more efficient and more cost effective method. The challenge
is that with so many prospective candidates available, which device
should be preferred. The costs of doing formal studies to compare
them all would be prohibitive. The WHO has provided a guide to
evaluate Medical Male Circumcision for Eastern and Southern Africa
[23]. A theoretical study has shown that the benefits of mass male
circumcision programmes are substantial. Some devices (Prepex),
however appear to show no cost benefit for large-scale programmes,
and there has been a suggestion that all the ring and clamp methods
may be flawed [22].
The fact that a device method (Prepex) maybe faster to perform
than a conventional surgical method, does not guarantee cost savings
[24-26]. Recent comparative studies (surgical vs. Gomco plus tissue
adhesive) in Mozambique confirm that the procedure is safe, fast,
easy to learn and teach, and would be well suited to use for up-scaling
of VMMC [27,28]. A disposable Gomco-like device (the Unicirc),
which has an equivalent action of crushing and bonding (between the
mucosa and skin of the prepuce) and also produces the same degree
of homeostasis as the original has recently been evaluated [29]. It is
cost effective and does not require suturing. It will hopefully be fast
tracked by the Treatment Advisory Group to WHO on circumcision
devices for use in resource limited settings.
Discussion
The age of HIV/AIDS began in the early 1980’s. Initially there
were few options for the treatment and limited scope for prevention.
Since then we have a large number of effective medications and have
discovered the important role that circumcision can play in helping to
Table 5: Summary of types of WHO recommended trials for evaluation of circumcision devices.
Type of study
Subjects (n)
Protocol inclusions
End points
Comments
experienced surgeon
clinical adverse events
phase recruitment
device related incidents
6 week follow-up
technical difficulty and complications
time to healing documentation
(Range)
50
Case series*
(non comparative)
Comparative*
(25-100)
100
experienced surgeon
(50-300)
pain assessment
cosmetic results
as above plus
randomised comparison
client satisfaction
multi-site
six week follow-up
adverse reaction monitoring
reasons for declining
Acceptability sub studies
Pilot field study†
not specified
100
(50-200)
Cohort field study†
500
(250-100)
during device placement
incorporate into a subgroup
while in-situ(nocturnal erections and emissions
from the clinical research study
during removal
assess acceptability to subjects,
partners and guardians
trained mid-level providers provider training needs and acceptability
train at least 10 providers
non-physician providers
adverse events
data for reasons on declining
procedure and removal times
outcome recordings
trained mid-level providers as above plus
non-physician providers
practicality of device use (i.e. need to return to
clinic for removal)
safety of procedure and removal
systematic evaluation after every 100
procedure starts
all adverse reactions
compare costs of:
device
training
provider’s time
staff follow-up time
equipment needed for placement/
removal
Adverse event rates
monitor
*
(800-1500)
not planned studies
If and when statistical differences(If any) between
device and conventional methods appears
data gathered from continual monitoring
when program is running
These studies should be performed in the country of origin initially and then repeated in the country of intended use
†
These studies should be performed in the country (-ies) of intended final use
Volume 2 • Issue 3 • 1000123
• Page 5 of 7 •
Curr Res 2:3.
prevent heterosexual spread of the disease. While medication is simple
to deliver and administrate (in principle at least), the provision of
circumcision is complicated because it requires a surgical procedure.
Added to that is the fact that there is uncertainty over which type
of circumcision and how this procedure should be performed.
After reviewing the pathology and mechanics of heterosexual HIV
transmission, we conclude that there are two main reasons why the
techniques of circumcision are important. We know that surgical
circumcision reduces the chance of spread of HIV by 60% from the
3 randomized controlled studies [14-16]. Firstly we have shown that
most of the available devices have a different action from surgical
circumcision, the principle difference being healing by secondary
rather than by primary intention. This means that we cannot be sure
that the ring or clamp devices would give the same results, especially
because healing takes place by secondary intention and takes much
longer (6 weeks+). The subjects may be vulnerable to infection at this
time, and the likelihood of patients abstaining from sexual activity or
using condoms is remote.
The second reason of importance is that there is some evidence
that some devices may not be all that cost effective [25] and thus not
that well suited for mass circumcision programmes. We believe that
the answer may lie with Gomco and Gomco-like disposable devices,
like the Unicirc device which allow for rapid healing and are more
cost effective because they do not require scheduled follow-up visits.
The Unicirc procedure can be performed with topical rather than
injected local anesthesia which is another advantage. The ultimate
impact of whatever method proves superior will be dramatic [30].
Just recently [31], a study on the Prepex which also allows healing by
secondary intention has showed a longer delay than was previously
documented.
Conclusion
VMMC programmes require techniques that are safe, quick
to perform, easy to learn and to teach, allow for rapid healing, do
not require scheduled follow-up visits, and are cost-effective. A
disposable Gomco like circumcision device used with tissue adhesive
would appear to offer the best prospects. This is now available as the
Unicirc device.
Appendix
The WHO has laid down guidelines for the evaluation of
devices for use in male circumcision. Manufacturers (or potential
manufactures) and will need to follow these guidelines especially if
they want their device to be considered for mass programmes for
which international agency funding will be required. Initial studies
are expected to be performed in the country (countries) of origin of
the device and later more comprehensive studies should be carried
out in the countries of intended use.
A summary of the type of trials and trial programs suggested by
the WHO is given in Table 5. The WHO also outlines the type of
follow up and post-marketing surveillance that they expect will be
carried out, to ensure that the devices are successful. These studies will
help to define which circumcision technique is the most preferable.
References
1. Dawkins R (2004) The ancestor’s tale. Weidenfield and Nicolson.
2. Cox G (1995) De virginibus puerisque: the function of the human foreskin
considered from an evolutionary perspective. Med Hypotheses 45: 617-621.
3. Cox G, Morris BJ (2012) Why circumcision: From prehistory to the twenty-first
century in Surgical Guide to Circumcision. Springer-Verlag: London, 243-259.
Volume 2 • Issue 3 • 1000123
4. Morris BJ, Wamai RG (2012) Biological basis for the protective effect
conferred by male circumcision against HIV infection. Int J STD AIDS 23:
153-159.
5. Auvert B, Sobngwi-Tambekou J, Cutler E, Nieuwoudt M, Lissouba P, et al.
(2009) Effect of male circumcision on the prevalence of high-risk human
papillomavirus in young men: results of a randomized controlled trial
conducted in Orange Farm, South Africa. J Infect Dis 199: 14-19.
6. Fink AJ (1986) A possible explanation for heterosexual male infection with
AIDS. N Engl J Med 315: 1167.
7. [No authors listed] (1987) Circumcision and heterosexual transmission of HIV
infection to men. N Engl J Med 316: 1545-1547.
8. Lavreys L, Rakwar JP, Thompson ML, Jackson DJ, Mandaliya K, et al. (1999)
Effects of circumcision on incidence of human immune deficiency virus type
1 and other sexually transmitted diseases. A prospective cohort study of
trucking company employees in Kenya. J Infectious diseases 180: 330-336.
9. Gray RH, Kiwanuka N, Quinn TC, Sewankambo NK, Serwadda D, et al.
(2000) Male circumcision and HIV acquisition and transmission: cohort
studies in Rakai, Uganda. Rakai Project Team. AIDS 14: 2371-2381.
10.Reynolds SJ, Shepherd ME, Risbud AR, Gangakhedkar RR, Brookmeyer
RS, et al. (2004) Male circumcision and risk of HIV-1 and other sexually
transmitted infections in India. Lancet 363: 1039-1040.
11.Cameron DW, Simonsen JN, D’Costa LJ, Ronald AR, Maitha GM, et al.
(1989) Female to male transmission of human immunodeficiency virus type
1: risk factors for seroconversion in men. Lancet 2: 403-407.
12.Telzak EE, Chiasson MA, Bevier PJ, Stoneburner RL, Castro KG, et al. (1993)
HIV-1 seroconversion in patients with and without genital ulcer disease. A
prospective study. Ann Intern Med 119: 1181-1186.
13.Mehendale SM, Shepherd ME, Divekar AD, Gangakhedkar RR, Kamble SS,
et al. (1996) Evidence for high prevalence & rapid transmission of HIV among
individuals attending STD clinics in Pune, India. Indian J Med Res 104: 327335.
14.Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, et al. (2005)
Randomized, controlled intervention trial of male circumcision for reduction of
HIV infection risk: the ANRS 1265 Trial. PLoS Med 2: e298.
15.Bailey RC, Moses S, Parker CB, Agot K, Maclean I, et al. (2007) Male
circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised
controlled trial. Lancet 369: 643-656.
16.Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, et al. (2007) Male
circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial.
Lancet 369: 657-666.
17.Siegfried N, Muller M, Deeks JJ, Volmink J (2009) Male circumcision for
prevention of heterosexual acquisition of HIV in men. Cochrane Database
Syst Rev.
18.World Health Organization (2011) Framework for Clinical Evaluation of
Devices for Male Circumcision, Geneva.
19.World Health Organization (2012) Use of devices for adult male circumcision
in public health HIV prevention programmes: Conclusions of the technical
advisory group on innovations in male circumcision. Geneva.
20.Cohen MS, McCauley M, Gamble TR (2012) HIV treatment as prevention and
HPTN 052. Curr Opin HIV AIDS 7: 99-105.
21.Morris BJ, Eley C (2011) Male Circumcision: an appraisal of current
instrumentation in Biomedical Engineering from theory to Applications:
Biomedical Engineering - From Theory to Applications. 315-354.
22.Millard PS (2012) Circumcision--what’s wrong with plastic rings? S Afr Med
J 102: 126-128.
23.World Health Organization (2011) Joint strategic action framework to
accelerate the scale up of voluntary medical male circumcision for HIV
prevention in Eastern and Southern Africa 2012-2016. Geneva.
24.Mutabazi V, Kaplan SA, Rwamasirabo E, Bitega JP, Ngeruka ML, et al.
(2012) HIV prevention: Male circumcision comparison between a nonsurgical
device to a surgical technique in resource-limited settings: a prospective,
randomised, non masked trial. J Acquir Immune Deficiency Syndrome 61:4955.
25.Obiero W, Young MR, Bailey RC (2013) The PrePex device is unlikely to
• Page 6 of 7 •
Curr Res 2:3.
achieve cost-savings compared to the forceps-guided method in male
circumcision programs in sub-Saharan Africa. PLoS One 8: e53380.
26.Bitega JP, Ngeruka ML, Hategekimana T, Asiimwe A, Binagwaho A
(2011) Safety and efficiacy of the PrePex device for rapid scale up of male
circumcision for HIV prevention in resources limited settings. J Acquir
Immune Deficiency Syndrome 58: e127-e134.
27.Millard PS, Fumo A, Sabino E (2012) Minimally invasive childhood and adult
circumcision. Trop Doct 42: 23-24.
28.Millard PS, Wilson HR, Veldkamp PJ, Sitoe N (2013) Rapid, minimally
invasive adult voluntary male circumcision: A randomised trial. S Afr Med J
103: 736-742.
29.Millard PS, Wilson HR, Goldstuck ND, Anaso C (2013) Rapid, minimally
invasive adult voluntary male circumcision: a randomised trial of Unicirc, a
novel disposable device. S Afr Med J 104: 52-57.
30.Williams BG, Lloyd-Smith JO, Gouws E, Hankins C, Getz W and Hargrove
J et al. (2006) The potential impact of male circumcision on HIV in SubSaharan Africa. Plos Medicine 3: e262.
31.Feldblum PJ, Odoyo-June E, Obiero W, Bailey RC and Combes S, et al.
(2014) Safety, effectiveness and acceptability of the PrePex device for adult
male circumcision in Kenya. PLoS One 9: e95357.
Author Affiliations
Top
Faculty of Medicine and Health Sciences, Department of Obstetrics and
Gynecology, Stellenbosch University and Tygerberg Hospital, South Africa
1
Submit your next manuscript and get advantages of SciTechnol
submissions

50 Journals
21 Day rapid review process
1000 Editorial team
2 Million readers
Publication immediately after acceptance
Quality and quick editorial, review processing
Submit your next manuscript at ● www.scitechnol.com/submission
Volume 2 • Issue 3 • 1000123
• Page 7 of 7 •