Wednesday, December 5, 2012

Problems with RCT's & Circumcision

What you'll find those with a pro-circumcision agenda doing is that they cite that only data derived from RCT research is valid in determining the validity of any circumcision research outcomes. ie. if its not RCT derived it is not valid.

While RCT's tend to be the gold standard of research studies, they are not without fault, and can lead to very misleading future predictions, particlularly when the assumptions they are based on are incorrect.

1. The first incorrect assumption of the African RCT circumcision trials was blaming the male foreskin as the cause of HIV infections.  Because some African population groups of non-circumcised men, had higher HIV infection rates than circumcised populations, the male foreskin was seen as the predominant cause of the differences in HIV infection rates.  What the researchers ignored was the fact that many African circumcised populations had higher hiv infection rates than non-circumcised populations.  Therefore the correct assumption about the cause of sexually transmitted  HIV infections has to be behavioural, eg. unsafe sex with multiple sex partners.

2. The second incorrect assumption was that circumcision confers an absolute lifetime protection against HIV infection, and that an 18 to 24 month trial was enough to prove this.  WRONG, the studies needed to have been longitudinal, over a complete lifetime, to determine the validity of circumcisions protective effect over a lifetime. If as seems to be the case that circumcision in a highly controlled environment with extra resources, than are normally available in aAfrica, can confer a small delay in time before infection occurs, then the assumption of life-time protection is also WRONG.  The desperation of researchers, and particularly the WHO in trying to do something about the HIV epidemic in Africa, has led to premature endoresment of something the research did not find or prove, ie. lifetime protection against HIV.  The RCT's did not prove a lifetime protective effect from circumcision, there is no evidence from the RCT';s of this claim. 

3. The third incorrect assumption is that men wont change their behaviour after circumcision, believing they are protected from HIV, and therefore disinhibiting their behaviour and practicising less safe sex behaviour.  Recent evidence from Africa confirms behavioural disinhibition is already occurring.  Therefore the assumption that men wont change their behaviour which will increase risk is also wrong.

The WHO has endorsed medical circumcision in Africa becuase it is claiming circumcision will reduce millions of infections, but this is made on an assumption that is not proven and most probably incorrect.  If you just change the assumptions slightly, ie. that circumcision may increase behavioural dis-inhibition and increase in unsafe sex behaviours, then the reduced infections become meaningless.  If as most data shows, that circumcision does not provide a lifetime protective effect against infection, then the protective effect of circumcision is incorrect, and again the predictions of reduced infections are meaningless.

Lets look at some research evidence which disputes the lifetime protective effect of circumcision. For instance,there is much data from around the world that shows some circumcised populations have higher HIV infection rates, than non-circumcision populations.  The EU where circumcision is uncommon has much lower rates of HIV than the USA where circumcision is very common. What this tells us, is that over a lifetime, whatever protective effect circumcision may have, is insignificant over a whole life, and meaningless in populations where circumcised groups have higher HIV infections than non-circumcised pouplations.

Therefore if you set up RCT's to last 18 to 24 months, end them early, and resource them in ways that will never be available in real life, and the reality is that the protective effect of circumcision is only short term, lets say 12 to 24 months, & not effective over a lifetime of 30 to 50 years of sexual activity as claimed, And you advertise and convince men that the protective effect of circumcision is for a lifetime, then you have made a grave public health error. What you have done is created a false sense of securty, and potentially created an environment where behavioural disinhibition occurs, where circumcised populations begin to practice less safe sex, & you end up with a public health disaster with higher HIV infections.

RCT's as with Computers, are only as good as the theoretical assumptions they are based on, or the data that is put into them.  Its Basically garbage in & garbage out!!!!!!!!!!

Wednesday, November 21, 2012

Fully Informing Africans about Medical Circumcision

There are a number of reports emerging out of Africa that many men who have elected medical circumcision now believe they are protected from HIV, and are having unprotected sex with women.  In the rush to promote medical circumcision Africans have not been fully informed about the true effectiveness of circumcision which is very limited, nor the true nature and causal spread of the HIV virus.

It is important that Africans in the 21st century, have access to education & are fully informed as the 21st century is the informtion age.  Partially informing Africans to promote circumcision is Unethical.

Lets start an internet campaign to Inform Africans about HIV & Medical Circumcision.

Important Information is as follows =

  1. Circumcision does not prevent HIV infection, Circumcised men all over the world are infected with HIV.  Many circumcised populations have higher infection rates than populations that do not practice circumcision.
  2. The HIV reduction risk via circumcision has been poorly explained, or just plainly over-stated. At best (and this is debated in the scientific literature) the widely publicised 60% reduction in HIV infections  (which is the most optimistic figure) from medical circumcision,  can mean that if you have sex with 10 women who are HIV infected, you can be infected by 4 of them.  Or if you have 10 sexual encounters with a single woman who is infected with HIV, you will get infected on 4 of those occassions.  Therefore the 60% figure that is talked about is very misleading, and over a lifetime you are still at significant risk of becoming infected with HIV even if you have medical circumcision.
  3. Africans have also not been fully informed that for women having sex with a circumcised man can increase the risk of HIV infection by up to 54%, particularly if sex occurs within several months of the circumcision.  Also not explained is that if a circumcised man has HIV, circumcision offers zero protection to a woman.
  4. Without knowing someone's HIV status when you have sex with them ( which is the true cause of sexually acquired HIV) you are at risk becoming infected with HIV circumcised or not.
  5. HIV virus does not hide in the foreskin itself, it hides in human blood, and human semen.
  6. The major cause of sexually acquired HIV infections is having unprotected sex with a person who is infected with HIV, and therefore Without behaviour change the HIV epidemic in Africa will never be defeated.
  7. Behaviour is the cause of HIV infections in adult sexual relationships. Having unprotected sex with a partner who is infected with HIV is the cause of infections, and having unprotected sex with multiple sex partners multiplies HIV infection rates greatly, and the cause of Epidemics.
  8. Exposure to contaminated blood is also a common way of becoming infected with HIV.
  9. The male foreskin does not cause HIV infections, therefore it is OK if your cultural tradition is to remain intact and refuse circumcision.
  10. HIV infections are caused by contact with the virus, usually through bodily fluids such as blood or semen.
  11. The only ways to eliminate contact with the virus sexually= is through avoidance (ie. Do not have sex with a person who is infected with HIV) or using a barrier method during sex, between your body and the virus.
  12. Condoms are a barrier method, which form a barrier between the exchange of bodily fluids such as blood and semen during sex, and is the only way to ensure protection from the HIV virus.  Circumcision is not a barrier method, skin contact and bodily fluid can & does occur with a circumcised penis.
  13. Condoms are ethical, they provide barrier protection from the HIV virus to both the man and the woman, this is particularly important as women get zero protection from male circumcision.
  14. Having sex in a monogomous relationship where neither partner is infected by HIV, makes it impossible to become infected with HIV via having sex with your partner alone.  Circumcision is not required.
  15. If you make the choice to have sex with multiple sex partners, be the new modern African, be fully informed and use a barrier method such as a condom, and use it properly to ensure no contact or exposure to the virus occurs.

  • Slogan options?
  • "I'm a 21st Century African & I'm Fully Informed about HIV"
  • "I'm a 21st Century African & I use condoms"

Tuesday, October 30, 2012

Giving up psychological defenses for circumcision

In order for future generations of males to be free of circumcision and its losses, harms and deprivations, currently circumcised men, as those in the intactivist movement have already done, have to give up their psychological defences of justifying circumcision in order to mitigate against the harms done.  It hurts less to be in denial about circumcision's losses and deprivations, it feels better to tell yourself that having a circumcised penis is fantastic, that its better! Psychological defenses work But........' The cost of mainataining this psychological defence is that circumcision's harms, losses and deprivations will continue forever generationally.   Therefore the psychological pain about the truth of circumcision's harms losses and deprivations, has to be endured by this current generation of men in order to end it for future generations of men. 

Bravery and courage awards to the men who break thru their own psychological defences, & feel the pain of what was done to them and what was taken from them, and who fight for furure generations of men to be free of circumcision, and fight for future men to have the freedom to make the choice for themselves.  These men have to fight the dominant ideology of their culture, they face ridicule, but they do not flinch, truly BRAVE!!!

Suspending human rights & Requiring balance in debating

Its funny how only on the subject of infant male circumcision are we required to suspend human rights and and demand BALANCE to both sides of the argument,  In female circumcision, or genital cutting or FGM, no such suspension of human rights or balance ever seems required (in western nations), its rightly denounced with no excuses for it. One word HYPOCRACY!!!!

A ritual nick on the genitals of a female child is seen as a human rights violation (No tissue is lost, sexual function is unaltered), but you can slice off the whole of the male foreskin, a functional male sex organ which is lost forever in male circumcision, and the subject of human rights is to be suspended, and balance is required?  My morals and ethics tells me there's something disgustingly wrong in all this!! Some people call it cultural relativism, that because male circumcision has been common, and it is part of certain religious or tribal practices then it is to be tolerated.  Well if there;s such a thing as human rights, then they are either universal to both male and female, and the right to genital integrity is fundamental to both sexes, or human rights are just meaningless.

Monday, October 29, 2012

Narcissism & Circumcision

Its just been re-highlighted to me, the narcissism thats involved in the circumcision of children.  We have a talentless TV & Radio personality here in Australia, who creates outrageous stunts to entertain, because he's basicly just talentless narcissist. Several Years ago he had his son circumcised, and he bought his son's foreskin into the radio studio to shock his fellow disc jockey's and his audience, making fun of his son's foreskin. 

I mean......... How Narcissistic is that, a complete lack of empathy for his son, and what his son may feel about this radio stunt one day if he finds out?  The stunt It was all about him and his needs, getting fame, noteriety at his son's expense.  Obviously the decision to circumcise, was a narcissistic one, because in Australia the RACP Australia's authority on circumcision of children, recommends against the procedure less than 10% of newborns are circumcised, so he did it because "he" wanted his son circumcised.  Narcissism pure and simple, putting his own interests ahead of his sons, with no empathy for what his son might have wanted, and also growing up circumcised, in a country where most of the boys are left intact.  Pure Narcissism.

This is also another reason why circumcision still happens, the Narcissism of the parents, putting their own needs ahead of their childs.  If they were really empathic & enlightened parents they would investigate not only what circumcision is/was, but also its harms, and the role and function of the foreskin which is lost to circumcision.  Given the male foreskin has a functional role in male sexuality, to remove this from your son, because its your preference is just pure Narcissism.

Thursday, October 25, 2012

The AAP has a Gross sense of Entitlement

What a Gross sense of Entitlement the American Academy of Pediatrics  has, demanding the freedom to cut babies genitals something babies cannot protest to, and then try and deny freedom of speech to demonstrators who protest routine infant circumcision..... Shows u the blinkered vision and mentality of these priveleged unethical doctors.

At the 2012 AAP annual conference, Intact America was banned from having a booth at the conference, and the Police were called to move and ban the protesters from exercising their right to freedom of speech and protest.  WOW....... Ya want the freedom to cut kids, yet ya wanna deny freedom to those who protest this!!!!!!  WHAT A SENSE OF ENTITLEMENT!!

Tuesday, September 25, 2012

Women in Europe are more safe from HIV & STI's than American Women

With all the latest ProCirc Propganda extolling the virtues of circumcision, and how it lowers STI's, well lets look at some facts, which is that Women in Europe where circumcision is uncommon are safer from HIV & STI's, than women in the USA where circumcision is very common.  In fact the countries with lowest HIV STI's are all non-circumcision cultures eg New Zealand, Japan, Finland.

Looking at available data on Sexually Transmitted Infections we find  The USA has 1200% higher HIV infections than No-Circ Finland (in Press) has 500% higher HIV infections than No-Circ Germany & 300% higher HIV infections than no-circ Holland. . The USA has 2.7 times the Syphillus infections than than no-circ Holland. . The USA has 33 times the Gonnoreah infections than than no-circ Holland. . The USA has 19 times the Chlamydia infections than No-Circ Holland. Infant Circumcision has failed the USA on the health measure of STI Infection rates, so if you are a woman you sre safer in Europe, where circumcision is uncommon.
(Advocates for Youth data) http://www.advocatesforyouth.org/storage/advfy/documents/fsest.pdf

Sunday, August 26, 2012

Critique American Academy of Pediatrics 2012 Circumcision Policy

As you are all aware the AAP has released its 2012 circumcision policy and it is very  pro-circumcision.

My response to the AAP is as follows:

  1. You have failed your patients which are American Children, and not Parents, not Doctors, not Hospitals, and not Religious groups. 
  2. You have failed to represent the interests of baby boys.
  3. You have failed to account for the human rights of baby boys.
  4. You have failed to account for medical ethics and how it applies to non-therapeutic amputative surgery of a non-consenting minor.
  5. You have failed to mention the male foreskin is a functional sex organ in its own right.
  6. You have failed to mention all of the scientific literature which contradicts the protective effects of circumcision for STI & HIV prevention.  A basic tenet of the scientific method is to use all available to data to disprove your theory, and not to selectively choose data which supports your theory.
  7. You have failed to mention the large body of evidence which documents the harms of circumcision from injury & infection to death in children, to sexual dysfunction in adults, and adult resentment of their infant circumcison.
  8. AAP your 2012 Circumcision Policy is a FAIL, and I hope it brings you both internal and international shame.
Is there a greater moral failing than to fail defenseless children?

Friday, July 27, 2012

German Dr's letter on circumcision translated


Undue Suffering Circumcision for Non-Medical Reasons Is Wrong


A Commentary By Dr. Maximilian Stehr

As the debate over the medical ethics of circumcision rages in Germany, some have argued that the practice provides health benefits. But many in the medical community disagree. Circumcision is not in the best interest of boys who undergo the procedure.

Info

In July 2011 a mother took her 2-year-old son to a pediatric clinic in Munich. Up to that point he had been the picture of health. There was absolutely nothing wrong with him. His parents simply wanted him to be circumcised at a medical facility on religious grounds.

But something went wrong when the boy was anesthetized, and the surgical team suddenly couldn't ventilate him anymore. The oxygen levels in his blood dropped, and his heart stopped beating. A dramatic scene unfolded in the minutes that followed, as the doctors tried to reanimate him, eventually calling in the emergency pediatric specialist. By the time the specialist arrived, the boy's body had been starved of oxygen for at least 10 minutes. The team finally managed to resuscitate the boy, and he was taken to our hospital by ambulance. But the child never regained consciousness. The lack of oxygen had caused too much damage to his brain.

I'm not telling this story to be sensationalist. I'm telling it because it moved me deeply. A healthy child that had probably happily crawled out of his bed that very morning had been anesthetized unnecessarily a few hours later, and by midday he lay in our intensive care unit, severely disabled for the rest of his life.

This shocking tale makes one thing absolutely clear: We doctors must never unnecessarily endanger the patients entrusted to our care. After all, had this boy not been circumcised, there would have been no emergency during his anesthetization. Every surgical intervention and every anesthesia is associated with a certain amount of risk. In this case the risk is not very great, but should nevertheless be taken only when justified. Under no circumstance should the dangers be overlooked because we think "It's only a minor operation." It's not.

'First, Do No Harm'

Munich's university hospital, the Klinikum Grosshadern, stopped circumcising boys without medical indication back in 2001. Many renowned pediatric hospitals had taken similar steps even before the Cologne Regional Court recently declared religious circumcision of children illegal. The medical community has been debating the issue for almost a decade. It's only thanks to the judges in Cologne that the matter has been brought to the attention of the public.

One of the fundamental principles of medical ethics is that no one should be harmed. The oath formulated by Hippocrates (approx. 460-370 BC) and sworn by all doctors includes the following statement: "I will prescribe regimens for the good of my patients according to my ability and my judgment and never do harm to anyone." Another key idea lies at the heart of all ethical behavior by medical personnel: "Primum nihil nocere," or "First, do no harm," a phrase coined by Scribonius Largus, a doctor at the court of the emperor Tiberius Claudius. The treatment of patients must be with their welfare in mind, and must therefore have priority over other interests, such as science, financial gain or profit.

Medically unnecessary circumcision causes damage because it results in an irreversible loss of healthy bodily tissue. Some people may consider it insignificant because the foreskin serves no discernible purpose. But the foreskin does indeed have a number of functions, although very few of the people engaging in the debate are aware of them.

No Medical Benefit

After birth, the foreskin protects the head of the penis (the glans) and prevents the external urethral orifice from abrasion and drying out. Following circumcision, the surface of the glans regularly thickens and calluses. This can lead to a constriction of the opening of the urethra, the most common complication associated with circumcision in infancy, occurring in up to 30 percent of cases. It's not unusual for several operations to be required before affected children can empty their bladder properly.

The foreskin also plays a role in arousal. In contrast to the glans, which has deep sensitivity, the foreskin has what are known as tactile corpuscles which can only be found in similar density in the tips of the fingers, the lips and the eyelids. It's therefore hardly surprising that the foreskin is considered a male erogenous zone. A significant majority of men who are circumcised in adulthood, and are therefore in a position to make comparisons, say they are less sensitive in this area after surgery. But that's not the only reason why circumcision affects sexuality: Couples in which the man is circumcised uniformly report a loss of male secretions during sex and therefore greater friction and resulting pain. It can therefore be assumed that circumcision can indeed have a negative impact on sexuality and the sex life of both circumcised men and their partners. These findings are not new. Major studies and surveys have been conducted and published as far back as the 1990s.

But the direct consequences of an operation must also be considered. Post-surgical complications occur in between 0.19 and 2 percent of circumcisions, but rise to 11 percent for patients circumcised in infancy. These complications primarily involve secondary bleeding or infection. In rare cases the urethra or the glans may be damaged or even need to be amputated. I see such complications time and again at our clinic, even though they occur in less than one percent of medical procedures. They mean painful surgery for the child.

Often enough, circumcision is deemed to be of medical benefit, for instance in preventing infectious diseases or cancer. But it's worth taking a closer look at the figures and the findings of related studies: Circumcised infants may have only a tenth as many urinary tract infections in their first year, but these infections generally occur so rarely that 100 circumcisions would be needed to prevent a single urinary tract infection. This doesn't make sense in otherwise healthy babies. There is no medical benefit to routine circumcision.

Wait For Consent

Nor does it reduce the likelihood of passing on or contracting sexually transmitted diseases. As early as 1855, a study suggested a possible link between circumcision and the transmission of venereal diseases. Since then, more than 30 studies have been published on the matter. However, the findings of these studies are extremely inhomogeneous. In effect, circumcision doesn't have any effect on the incidence of most sexually transmissible diseases (gonorrhea, syphilis, herpes and AIDS).

In 2007, the World Health Organization recommended circumcision as a prophylactic measure against HIV infection. This recommendation was based on studies from Kenya and Uganda that suggested that the risk of infection with HIV was 50 percent lower in circumcised heterosexual men than in non-circumcised ones. But demands for routine or blanket circumcision don't take into account the fact that the WHO considers circumcision only for adult males who can decide for themselves and are at a high risk of infection.

From an epidemiological perspective, the practice makes no sense for Germany. Furthermore, circumcision for this purpose could also be carried out at an age at which the person in question can make their own decisions. The same concern also applies to the supposed preventative nature of circumcision with regard to penis carcinoma or even cervical cancer: If circumcision had an unambiguously positive influence -- and not all scientists agree it does -- this operation would only make sense at an age when the man is sexually active, in other words at an age when the young man can consent himself.

A Chance For Dialogue

Medically, there is no evidence of advantages for boys. Therefore non-medically indicated circumcision is not in the child's best interests either. This is the key argument against the inadmissible comparison of circumcision with a recognized vaccine. The effectiveness and therefore the utility of the vaccine for the child have been scientifically proven.

Doctors have to weigh potential risks and benefits. There are no medical benefits to circumcision on religious grounds. For this reason it's all the more significant that it's a serious surgical procedure fraught with risks and complications. Whether it's carried out under local or general anesthetic, circumcision causes boys undue suffering. This procedure must therefore be rejected from both a medical and an ethical perspective.

As a devout Catholic, I have great respect for the concerns of religious communities. As a scientist, I feel discredited by Chancellor Angela Merkel's comments about how the circumcision ruling makes Germany "a laughing stock." The Cologne Regional Court presented us with an opportunity to work together with the various religious communities to consider the rights of physical inviolability and religious freedom. Some Muslims have already shown a willingness to accept that boys be circumcised only when they are old enough to give their consent. But in Berlin the debate is at risk of being stifled politically, robbing us of the chance for dialogue.

Translated from the German by Jan Liebelt



Tuesday, July 3, 2012

Women at greater risk with circumcised men

 There are now 2 Research studies that show women who have sex with a circumcised man are at greater risk for contracting HIV!!!!!! Why no Awareness campaigns no Publicity, WHY?  My additions are in Bold type.

Randomized Trial of Male Circumcision in HIV-infected Men: Effects on HIV Transmission to Female Partners, Rakai, Uganda

Abstract

Background

A randomized trial of male circumcision (MC) was conducted among HIV-infected males to test the hypothesis that MC would reduce HIV transmission to female sexual partners.

Methods

This randomized, unblinded trial, conducted in Rakai District, Uganda, enrolled 922 uncircumcised, HIV-infected asymptomatic men aged 15–49 with CD4 counts ≥350. Men were randomly assigned to immediate circumcision (intervention) or circumcision delayed for 24 months (control). Concurrently enrolled HIV-negative female partners were followed up at 6, 12 and 24 months, to assess HIV acquisition by male MC assignment (primary outcome). An intention-to-treat analysis assessed women’s HIV acquisition using survival analysis and Cox proportional hazards modeling. The trial was registered in the Clinical Trials.gov Protocol Registration System (NCT00124878).

Findings

The trial was terminated for futility (Why for futility? It was an important finding male circumcision may be a risk factor for women?). Ninety three concurrently enrolled female partners of intervention arm (Circumcised Men) men and 70 partners of control arm men (Intact) provided follow up data. Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7–33.4) in the intervention arm (Circumcised Men) and 13.4% (95% CI 6.7–25.8) in the control arm (Intact men) (adjusted hazard ratio= 1.49, 95% CI 0.62–3.57, p = 0.368). At 6 months, intervention arm male-to-female transmission in couples who resumed intercourse ≥5 days prior to certified surgical wound healing was 27.8% (5/18), compared to 9.5% in couples who abstained longer post-surgically (6/63, p = 0.06) and 7.9% in control arm couples (5/63, p = 0.04)  (Wht not state here that there is a 50% to 60% increase in hiv infections with a circumcised man, and beginning intercourse early creates a 400% increase in HIV infection risk)

Interpretation

Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months, and transmission risk may be increased with early post-surgical resumption of intercourse. (Why not state the truth and say that evidence exists that male circumcision increases the risk of HIV for females) Longer-term effects could not be assessed. (They could'nt be assessed because you ended the trial early, male circumcison might be an important risk factor for females, dont women of the world need to know this?)  Post surgical sexual abstinence and subsequent consistent condom are essential for HIV prevention.
Keywords: Male circumcision, randomized trial, HIV-infected men, female HIV acquisition, Uganda

 

1994 Apr;23(2):371-80.

Risk factors associated with prevalent HIV-1 infection among pregnant women in Rwanda. National University of Rwanda-Johns Hopkins University AIDS Research Team.

Source

Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205.

Abstract

This study evaluated risk factors associated with prevalent HIV-1 infection among pregnant women in a semi-rural but densely populated area surrounding the town of Butare in Rwanda. Overall seroprevalence was 9.3% in 5690 pregnant women who sought antenatal care at one of five health centres. Factors associated with higher seroprevalence of HIV-1 included history of multiple sexual partners, history of at least one sexually transmitted disease (STD), relatively high socioeconomic status (SES), being unmarried, young age at first pregnancy, and low gravidity. Women who had used oral contraceptives, smoked more than one cigarette per day, whose partners were circumcised, and had had sex to support themselves were also at higher risk of being infected. A history of blood transfusion in the past 5 years was not associated with HIV-1 infection. History of multiple sexual partners, history of STD, high household income, partner circumcision, and past oral contraceptive use remained strongly associated with HIV-1 infection even when simultaneously controlling for other covariates. Among legally married women who lacked sexual behaviour risk factors, history of STD, high SES, young age at first pregnancy, and low gravidity were significantly associated with HIV-1 seroprevalence.

PMID:
8082965
[PubMed - indexed for MEDLINE]

 

 

 

 

 

 

 

 

Introduction

Three trials of male circumcision (MC) in HIV-negative men, including one conducted in Rakai, Uganda, showed that circumcision reduced male HIV acquisition by 50–60 () and MC is now recommended for HIV prevention in men.() As programs scale up, it is inevitable that HIV-positive men will also request MC, partly to avoid stigmatization. We previously reported that MC was safe and reduced rates of genital ulcer disease (GUD) in asymptomatic HIV-infected men with CD4 cell counts ≥350.(,). Given the social considerations and clinical findings, WHO/UNAIDS has recommended that surgery be provided on request to HIV-infected men unless there are medical contraindications.()
A prior observational study in HIV-discordant couples in Rakai suggested a lower rate of male-to-female HIV transmission from circumcised HIV-infected men, particularly if their HIV viral load below 50,000 copies/mL.() Two other observational studies also reported an association between MC and reduced female HIV risk.(,)
In parallel to the trial of MC in HIV-negative men referenced above, we conducted a randomized trial of MC in HIV-infected men and enrolled their female partners. Trial objectives were to assess MC safety and efficacy for STI prevention in HIV-infected men, (,) and to test the hypothesis that MC would reduce HIV and STI transmission from HIV-infected men to their HIV-uninfected female sexual partners. This paper reports trial results in the women partners of HIV-infected men, , including HIV incidence and rates of STI symptoms and vaginal infections.

Methods

The trial was conducted in Rakai District, Uganda, between 2003 and 2006.

Male participation

Trial procedures for HIV-infected men, including consent, randomization, and data and sample collection, were the same as those previously reported in the MC trial of HIV-negative men;() and are briefly summarized here. Men received an explanation of study goals and provided written informed consent for screening and HIV testing. Prior to screening and throughout the trial, men were offered HIV results, counseling and information on HIV prevention. They were informed that the effects of MC on HIV/STI transmission to women partners were unknown and that adherence to safe sexual practices was imperative.
In all, 1,151 HIV-positive eligible uncircumcised men were identified, of whom 922 consented and were enrolled. Eligibility criteria included being HIV-infected, uncircumcised, aged 15 to 49 years, having no medical indications or contraindications for circumcision and, because the safety of MC in HIV-infected men was unknown, no evidence of immunosuppression (WHO clinical stages III or IV, or a CD4 count below 350 cells/ml3). Men with genital infections or a hemoglobin ≤ 8 gm/dL were treated and rescreened prior to enrollment.
Participants were randomly assigned to be circumcised within approximately two weeks (intervention arm) or after 24 months (control arm). Random assignment was in blocks of 20, with replacement.() Prior to circumcision men were provided with detailed instructions on postoperative wound care, hygiene, abstention from intercourse until complete wound healing had been certified and safe sexual practices thereafter. They were given an information sheet with these instructions to share with their sexual partners. Circumcisions were performed using the “sleeve” procedure.(,) Postoperative follow up visits were scheduled at 24–48 hours, 5–9 days and 4–6 weeks, and predefined adverse events (AEs) were recorded.(,) Men whose wound was not fully healed at the 4–6 week visit were followed weekly until healing was certified.
At each postoperative follow up, participants were interviewed and the wound was inspected. Participants were asked about resumption of sexual intercourse; those who resumed sex were asked when intercourse first occurred following surgery and whether condoms were used. The sexual risk reduction information, including post-surgical sexual abstinence until completed wound healing, was reiterated at each postoperative visit. Male participants in both arms were then followed at 6, 12 and 24 months post-enrollment; interviewed regarding sexual behaviors, health and related issues; and examined. Venous blood samples and penile swabs were collected.

Female partner participation

Male participants in the trials of MC in HIV-infected and HIV-uninfected men were asked to invite their wives or permanent consensual partners (subsequently referred to as female partners) to enroll in a study to assess the efficacy of MC for prevention of male-to-female HIV and STI transmission. Enrolment and follow up procedures were the same for female partners regardless of the male’s HIV status. Results reported in this paper are for the partners of HIV-positive men.
Female partners were informed of study goals and procedures, were told that the effects of MC on transmission of HIV or STIs were unknown, and were counseled on HIV and STI prevention (including consistent condom use) and on the need to refrain from sexual intercourse following MC until completed wound healing was certified. All women participants provided written informed consent for enrolment and follow up.
Female partners were followed at 6, 12 and 24 months post-enrolment. At baseline and each follow up visit, women were administered a detailed sociodemographic, behavioral, and health interview and provided venous blood samples and self-collected vaginal swabs. Interviews were conducted in private, by trained same-sex interviewers fluent in Luganda.
At each study visit, participating men and their female partners were provided with intensive HIV/STI prevention education including abstinence, faithfulness and consistent condom use; were offered free condoms, and voluntary HIV counseling and testing (VCT) and couples counseling and testing (cVCT). Participants could enroll even if they declined to receive their HIV results or accept cVCT. Intensive efforts were made throughout the trial to facilitate individual and couples counseling and disclosure of HIV results, including the creation of couples’ support clubs. Participants were informed of the advantages of receiving HIV results including, as of 2004, access to free antiretroviral therapy offered by the RHSP through the President’s Emergency Program for AIDS Relief (PEPFAR).
In addition to the information provided to all participants, community meetings were conducted to inform the population of the trial and of the need for safe sexual practices regardless of the male partner’s circumcision status.
The protocol was reviewed and approved by the Uganda National Council for Science and Technology, and by three Institutional Review Boards (IRBs): the Science and Ethics Committee of the Uganda Virus Research Institute; the Committee for Human Research at Johns Hopkins University, Bloomberg School of Public Health; and the Western Institutional Review Board, Olympia, Washington. Trial oversight was provided by an independent Data Safety and Monitoring Board (DSMB). A Community Advisory Board (CAB) provided guidance on study design, conduct and the dissemination of results to the community. The trial was conducted in accordance with Good Clinical Practices and International Clinical Harmonization (GCP-ICH). Women were compensated for their time and travel costs, equivalent to $3.00 per visit, for a total of $12.00 for completion of all study visits. The CAB, DSMB and IRBs approved this compensation as appropriate.
The parallel MC trial in HIV-negative men was closed on December 12, 2006, following an interim analysis which demonstrated the efficacy of MC for HIV prevention in men.() Participants in both trials, as well as Rakai communities, were informed of this finding. Because continuation of the trial in HIV-infected men could result in stigmatization of participants, enrolment of HIV-positive men was paused and the investigators requested an unscheduled interim review and guidance from the DSMB. The DSMB determined that the conditional power to detect 60% efficacy, as specified in the study protocol, was only 4.9% and recommended that enrollment be closed. The investigators were unblinded, and study participants (men and women) were informed of the finding. However, the DSMB recommended continued follow up of enrolled participants. The DSMB reviewed the follow up data on Dec 17, 2007 and recommended that follow up of HIV-positive men and their partners be closed. The current analysis is based on results to that date.

Laboratory methods

HIV status was assessed by two enzyme immunoassays (EIAs): Vironostika HIV-1 (Organon Teknika, Charlotte, North Carolina, USA] and Murex Biotech [Central Road Temple Hill, Darford, UK). Discordant EIA results and seroconversions were confirmed by Western blot (Calypte Biomedical Corporation, Rockville, MD, USA). Male HIV viral load was measured by reverse transcriptase polymerase chain reaction (RT_PCR) assay (AMPLICOR HIV-1 MONITOR version 1.5, Roche Molecular Systems, Branchburg, N.J.). Women’s self-collected vaginal swabs were assessed for Trichomonas vaginalis by InPouch TV culture (BioMed Diagnostics, San Jose CA). Vaginal flora was quantified by the Nugent method;() a score of 7–10 was classified as BV.
To ascertain whether females had acquired HIV from their linked partner, viral sequence data were generated from both individuals for portions of the gag and gp41 fragments(). The genetic distance of the viral sequences between the two partners was compared to the variation between epidemiologically unrelated individuals in the Rakai population.(, ).

Statistical analyses

The primary endpoint was male-to-female HIV transmission. Based on our prior observational data,() the study was powered to detect an incidence rate ratio of 0. 41 for HIV transmission from intervention compared to control arm HIV-positive men. We estimated that 220 couples would provide 80% power to detect this reduction over two years, adjusting for losses to follow up and crossovers. We also hypothesized reduced transmission in couples in which the circumcised HIV-infected man had a viral load <50,000 cps/mL and estimated that the study had >90% power to detect >95% efficacy in this subgroup. No interim analyses were planned.
Enrolment characteristics of males and females in concurrently enrolled couples were assessed using Chi-square tests for differences in distributions between study arms. The effect of MC on male-to-female HIV transmission was assessed in an intention-to-treat analysis using Kaplan-Meier estimation, based on the time to the follow up visit at which the female partner was first HIV-positive. An overall risk difference and risk ratios were calculated at the end of follow-up, with 95% confidence intervals (95%CI) based on Greenwood variance estimates. Cox proportional hazards models were used to estimate the adjusted hazards ratio (adj HR) of HIV detection in female partners, after adjustment for covariates which differed between study arms at enrollment at p < 0.15. We evaluated male-to-female HIV transmission by female reported characteristics and behaviors at enrollment and follow up. Female risk behaviors were also compared between arms at each follow up visit. We determined the prevalence of vaginal infections and symptoms during follow up, and estimated the prevalence risk ratios using modified Poisson regression with robust variance estimation to account for repeat observations.
After unblinding the study, the DSMB requested further analyses, including male-to-female HIV transmission in intervention arm couples by timing of resumption of intercourse relative to certification of wound healing. Given the schedule of postoperative visits, timing of healing could not be precisely determined, since healing preceded certification (i.e., there was an unknown interval between actual and observed healing). We assumed that men who resumed sex within the 5 days prior to or after certified healing had initiated intercourse when the surgical wound was likely to be intact; and were classified as “delayed resumption of sex.” Couples who resumed sex more than 5 days prior to observed healing, when scar formation were less likely to have been complete, were classified as having “early resumption of sex”. We then assessed male-to-female HIV transmission in intervention arm couples reporting early and delayed resumption of sex.
After the study was unblinded, we examined HIV viral load (VL) prior to and after MC among consenting control arm men who received circumcision as a service, in order to assess whether the stress of surgery might upregulate HIV VL. Eighty nine men not on ART and 25 men on ART provided blood immediately prior to surgery and at the one month post surgical visit. (During the trial, bloods were not collected between the time of surgery and the 6 month follow up visit.) We estimated within-individual change in log10 HIV VL copies/mL after MC, relative to the preoperative levels, using a paired t test.

Trial registration, funding, role of the funding source and study collaborators

The trial was registered in the Clinical Trials.gov Protocol Registration System (NCT00124878) and was funded by The Bill and Melinda Gates Foundation as an investigator-initiated grant (Grant # 22006). Additional support for laboratory analyses and training were provided, respectively, by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health and the Fogarty International Center (grants 5D43TW001508 and D43TW00015) The study was conducted by the Rakai Health Sciences Program, a research collaboration between the Uganda Virus Research Institute, and researchers at Makerere and Johns Hopkins Universities. FM and LHM had full access to all data until trial closure. All other investigators were blinded until trial closure and had access to data thereafter. RR from the Gates Foundation maintained oversight of progress, participated in open DSMB sessions and in the interpretation of data. The research team conducted data analyses at Johns Hopkins University and at the Rakai Health Sciences Center. The corresponding author had final responsibility for preparing results for publication.

Findings

The trial profile is shown in figure 1. A total of 7,274 men were screened of whom 1,151 (15.8%) were HIV-infected and eligible; of these, 922 (80.1%) consented and enrolled. Among 474 HIV-infected men randomized to the intervention arm, 374 (78.9%) were currently married or in a consensual union: 291 (77.8%) of their female partners consented and enrolled, of whom 122 (42.0%) were HIV-negative at the time of enrolment. Of these HIV-negative women, 93 (32.0%) enrolled concurrently with their husbands and 92 had at least one follow up visit over 24 months. Among 448 HIV-positive men randomized to the control arm, 348 (77.6%) were in a current marriage/consensual union; 239 (68.7%) of these female partners consented and enrolled, of whom 100 (42.0%) were HIV-negative at the time of enrolment. Of these women, 70 (29.3%) enrolled concurrently with their husband and 67 had at least one follow up visit over 24 months. The 92 intervention arm couples and 67 control arm couples with concurrent female and male enrolment and at least one female follow up visit constitute the primary population for determining male-to-female HIV transmission.
Figure 1

Figure 1

Trial Profile.
An additional 29 HIV-negative female partners of intervention arm men and 30 HIV-negative partners of control arm men entered the study six or more months after their husband's enrollment. These women were excluded from the primary male-to-female HIV transmission analysis since, unless women enrolled at the same time as their partner, we did not know their HIV status at the time of their husband’s enrolment. Thus, we could not determine which HIV-infected late-enrolling women had seroconverted since their husband’s enrolment, and this could thus result in bias if HIV transmission in the first six months differed by study arm. The couples with delayed female enrollment were assessed in secondary analyses.
Table 1 shows the enrollment characteristics of HIV infected men and concurrently enrolled HIV-uninfected partners. There were no significant differences between arms in male characteristics or behaviors at enrollment. Female partners of men in both arms were comparable with respect to numbers of sexual partners in the past year, alcohol use and STI symptoms. However, intervention arm female partners were somewhat younger (p = 0.067) and less likely to report condom use in the past year (p = 0.017). At enrollment, 97.7% of intervention arm and 94.1% of control arm men had received their HIV results and post-test counseling. Among female partners, 68.8% in the intervention arm and 74.3% in the control arm accepted HIV results and post-test counseling at time of enrolment, and an additional 16.4% of intervention arm and 16.2% of control arm women reported they had previously received their results (i.e., 85.2% intervention and 90.5% control females had received HIV results). All participants received intensive HIV prevention education. Female retention rates were comparable in both arms at the 6, 12 and 24 month follow up visits. (Table 2)
Table 1

Table 1

Enrollment characteristics of HIV-infected men and HIV-negative women in couples enrolled concurrently.
Table 2

Table 2

Female Partner Retention Rates
Figure 2 shows the Kaplan-Meier cumulative probabilities of female HIV acquisition in couples with concurrent male and female enrolment. Over the 24 month follow up, the cumulative probability of female HIV acquisition was 21.7% (95%CI 12.7–33.4%) in the intervention arm and 13.4% (95%CI 6.7–25.8%) in the control arm (unadjusted HR=1.58, 95%CI: 0.68–3.66, p=0.287). After adjustment for differences in enrollment characteristics by Cox proportional hazards regression, the adjusted HR was 1.49, 95% CI 0.62–3.57, p = 0.368). When female partners who enrolled six months or more after their husband are included, the cumulative probability of infection was 17.4% in the intervention arm and 15.8% in the control arm (HR = 1.22, 95%CI 0.59–2.54, p = 0.65). There were no male crossovers among couples in the primary analysis. There were three crossovers among men whose female partner had delayed enrolment, but none of these crossover men transmitted to their partners.
Figure 2

Figure 2

Cumulative probability of Female HIV acquisition.
In a subanalysis (not specified in the protocol), we assessed whether HIV transmission in intervention arm couples was associated with the timing of resumption of intercourse relative to wound healing (Table 3). HIV acquisition, observed at six months, occurred in 27.8% (5/18) of women in intervention arm couples who resumed sex early, compared to 9.5% (6/63) of women in couples with delayed resumption of sex (RR = 2.92, 95%CI 1.01–8.46, p = 0.06). The proportion of women acquiring HIV by 6 months in intervention arm couples who delayed sex (9.5%) was comparable to the proportion of newly HIV-infected control arm women ( 7.9%[(5/63]; p = 1.0). However, the rate of female HIV acquisition at 6 months in intervention arm couples with early post-surgical resumption of sex (27.8%) was significantly higher than in control arm women (RR = 3.50. 1.14–10.76, p = 0.038).
Table 3

Table 3

Proportions of women with observed HIV acquisition at the 6 month follow-up visit in the control arm, and in the intervention arm by timing of resumption of intercourse in relation to post surgical wound healing.
There were no significant differences in HIV transmission between study arms by enrollment covariates, nor by female-reported sexual risk behaviors during follow up (data not shown). Among women whose partner’s enrollment viral load was <50,000 cps/mL, the cumulative probability of HIV acquisition was 15.7% (11/70) in the intervention arm and 10.6% (5/47) in the control arm (HR = 1.48, 95%CI 0.55–3.98, p = 0.43). Among couples with a male enrollment viral load > 50,000 cps/mL, female cumulative HIV acquisition was 27.3% (6/22) in the intervention arm and 15.0% (3/20) in the control arm (HR = 1.82, 95%CI 0.52–6.32, p = 0.34)
There were no statistically significant differences in female-reported number of sexual partners, condom use, or use of alcohol with sex during follow up (Table 4). In the intervention arm, 75.3% (70/93) of HIV-infected men disclosed their serostatus to their female partner; and in the control arm, 77.1% (54/70) of men disclosed their serostatus (p = 0.38).
Table 4

Table 4

Women’s sexual behaviors during follow up, by study arm
The proportions of follow up visits at which female partners reported STI symptoms or had laboratory diagnosed BV in the intervention and control arms, respectively, were: GUD, 16.4% (37/225) versus 16.1% (26/161), p=0.95; vaginal discharge, 36.4% (82/225) versus 32.3% (52/161), p=0.50; dysuria, 15.5% (35/225) versus 14.9% (24/161), p=0.89; and BV, 55.8% (121/217) versus 51.9% (83/160), p=0.54. Trichomonas was detected in 6.5% (9/138) of follow up visits in intervention arm women and 15.2% (17/112) of visits in control arm women (PRR = 0.43, 95%CI 0.18–1.02), which was of borderline statistical significance (p = 0.056).
Among 25 couples in which the female partner seroconverted during the trial, sequence data for both partners were available for 13 pairs. In all 13 couples, the genetic distance of the viral sequences between partners was < 0.5% , which was less than two standard deviations below the median distance of sequences between unrelated individuals in Rakai, indicating probable HIV acquisition within the partnership.()
We assessed pre- and postoperative HIV VL in 89 ART naïve control arm participants receiving MC as a service. Among 80 men with detectable VL prior to surgery, the mean VL log10 cps/mL was 4.30 (SD 0.83) preoperatively, and 4.50 (SD 0.74) at the fourth postoperative week, a mean increase in intra-individual VL of 0.20 log10 cps/mL (p = 0.002). All 9 men with undetectable VL load prior to surgery remained undetectable at week four. In 25 control arm men who had initiated ART prior to circumcision, we observed no increase in VL in the 21 (84.0%) who had an undetectable VL prior to surgery, nor in the 4 men who had detectable preoperative VL.

Discussion and interpretation

Circumcision of HIV-infected men did not reduce HIV transmission to their uninfected female partners (Figure 2), and we cannot exclude the possibility of higher transmission in couples who resumed intercourse before complete healing of the surgical wound (Table 3). Since study duration was limited and not all women completed 24 months of follow, we could not assess long term benefits or risks to women. The findings indicate that strict adherence to sexual abstinence during wound healing and consistent condom use thereafter must be strongly promoted when HIV-infected men receive MC. .
These findings have important implications for MC programs. The WHO and UNAIDS recommend that HIV-positive men who request MC be provided with the service unless there are medical contraindications.() Despite the lack of MC efficacy for HIV prevention in women, we agree with these recommendations for the following reasons. If programs excluded HIV-infected men it could result in stigmatization, and it is likely that HIV-positive men would seek surgery from potentially unsafe sources to mask their serostatus. Conversely, circumcised HIV-negative men could use their MC status to negotiate unsafe sex. Additionally, circumcision reduces genital ulcer disease() and human papillomavirus infection in HIV-infected men, (pc RG) which constitute direct health benefits.
Our finding that resumption of intercourse prior to complete healing may increase the risk of HIV transmission to women makes it imperative that circumcised men and their female partners be clearly instructed to abstain from intercourse until wound is healed. We previously reported that wound healing was complete in 73.0% of HIV-positive men at 4 weeks and 92.7% at 6 weeks after MC() Thus, it would be prudent to recommend abstinence for a minimum of six weeks following surgery and to reexamine men to assess healing prior to advising that sexual intercourse may resume. It should be noted that the possible short-term increase in transmission to partners of circumcised HIV-positive men if sex is resumed early is unlikely to have a substantial effect on the HIV epidemic: the exposure period of possible increased risk is short and the number of HIV-positive men with uninfected female partners who resume sex early will generally represent a small proportion of MC program clients. Nonetheless, comprehensive MC programs should, wherever feasible, promote and offer condoms, VCT and cVCT, and MC-related health messages for women. Offering MC to infants and to boys prior to sexual debut would mitigate the challenges of MC in HIV-infected men, but would require careful attention to consent and assent by parents and minors.
We observed an increase in HIV viral load among ART naïve men following surgery, which could result in higher infectivity.( ), Our post-surgical assessment was conducted at 4 weeks, and additional research is needed to determine whether MC affects VL beyond this period.
We were disappointed that the trial did not show protection from HIV infection in women, as was expected from observational studies.(). One possible explanation is that most men in the observational studies had been circumcised in childhood and did not initiate intercourse until long after completed wound healing. However, it should be noted that this trial did not show any trend towards protection at 12 and 24 months after surgery.
We previously reported that female partners of HIV-negative men randomized to MC had lower rates of GUD, trichomonas and BV.() In partners of HIV-positive men, MC was associated with lower rates of trichomonas (PRR = 0.42, 95% CI 0.18–1.02, p = 0.056),similar to the PRR in partners of HIV-negative men.() However, MC in HIV-positive men was not associated with lower rates of female partners’ STI symptoms or BV.
There are limitations to this study. The trial was underpowered, in part because the number of enrolled male HIV-positive/female HIV-negative discordant couples were lower than anticipated from prior Rakai cohort studies. Although the proportions of married men were comparable in both study arms (Figure 1), a higher proportion of intervention arm female partners enrolled (77.8%) compared to control arm partners (68.7%, p = 0.007). This suggests differential motivation to participate between arms, which may have introduced bias. However, with the exception of somewhat lower condom use reported by intervention arm women, there were no statistically significant differences in female baseline characteristics (Table 1) and adjustment did not materially affect the estimates of efficacy. The study was closed early and this limited our ability to assess longer-term effects. In addition, 29 wives in the intervention arm and 30 in the control arm were enrolled six or more months after their husbands, and were excluded from the primary analysis, however, inclusion of these late enrollees did not alter the results. Finally, for reasons of safety, we excluded HIV-positive men with CD4 cell counts less than 350 or WHO Stage III or IV disease. Thus, we cannot determine possible effects on female partners of MC in men with more advanced HIV infection.
It is important to note that this was not a classical discordant couples trial, in which participants enroll as a couple. HIV-positive males enrolled and were randomized as individuals, and were asked to invite their partners, who also enrolled as individuals. Participants were strongly encouraged to accept couples VCT at enrollment and throughout the trial, but about a quarter in each arm did not disclose their serostatus. In our prior experience, acceptance of cVCT is relatively low in this rural population and is more frequent in persons who know they are HIV-uninfected. HIV transmission rates in this study, particularly in the first six months, were high compared to studies of HIV-discordant couples enrolled after receiving cVCT. Such couples may represent a self-selected and motivated subpopulation and may be more likely to adopt preventive behaviors() than the individuals in this trial. For example, consistent condom use was uncommon at enrollment (Table 1), increased over time, but was still relatively low at 24 months (50.0% in the intervention arm and 36.4% in the control arm), despite repeated health education and the provision of free supplies.
It would be difficult to conduct another trial of MC effects on male-to-female HIV transmission. Given our results, such a trial would have to be powered to detect a low efficacy, requiring a very large population of male-infected HIV-discordant couples and protracted follow up. Given the potentially higher transmission rates in the post-surgical period, additional follow up visits and interim safety analyses would be needed. Thus costs, logistics and limited expectation of efficacy probably render such a trial unfeasible.
In conclusion, circumcision of HIV-infected men did not reduce HIV transmission to female partners, and the possibility of higher risk of transmission in couples who resumed intercourse before completed wound healing cannot be excluded. Wherever possible, MC should be offered in conjunction with HIV counseling services, condoms, and HIV prevention education for men and women, to optimize the health and safety of MC patients and their partners. However, the efficacy of MC for prevention of HIV in uninfected men is clear,() and reductions in male HIV acquisition attributable to circumcision are likely to reduce women’s exposure to HIV-infected men.(,) MC programs are thus likely to confer an overall benefit to women.

Acknowledgements

We thank the members of the Data and Safety Monitoring Board, as well as the institutional review boards that provided oversight (the Science and Ethics Committee of the Uganda Virus Research Institute; and the Western Institutional Review Board). We are also grateful for the advice provided by the Rakai Community Advisory Board. We wish to thank Dr. Edward Mbidde, Director, Uganda Virus Research Institute for his support. Finally, we wish to express our gratitude to the study participants whose commitment and cooperation made the study possible.
Funding: The trial was funded by The Bill and Melinda Gates Foundation (Grant 22006). Additional support for laboratory analyses and training were provided, respectively, by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health and the Fogarty International Center (grants 5D43TW001508 and D43TW00015)