Male Circumcision and HIV

Future Medicine: Male Circumcision is not the HIV vaccine we have been waiting for!

The May issue of Future Medicine carries an editorial authored by Lawrence W. Green of UCSF's Department of Epidemiology & Biostatistics, Ryan G. McAllister of Georgetown University, Kent W. Peterson of Virginia-based Occupational Health Strategies, and John W. Travis of North Carolina-based Wellness Associates.

The abstract to the aptly entitled article Male circumcision is not the HIV 'vaccine' we have been waiting for!:

Over the past several months, some researchers and health organizations [101] have proclaimed circumcision to be a compelling and important new HIV tool. A recent commentary claims that circumcision is “at least as good as the HIV vaccine we have been waiting for, praying for and hoping to see in our lifetimes” [1]. Thousands of African men now line up to get circumcised in the mistaken belief that it will save them from HIV, as some developing nations – lacking even rudimentary medical care and clean drinking water – rush to implement mass circumcision programs with encouragement and millions of pledged dollars from the US government [2, 102, 103]. In addition, there are calls for implementing mass neonatal circumcision [104].

The push to institute mass circumcision in Africa, following the three randomized clinical trials (RCTs) conducted in Africa [3-5] , is based on an incomplete evaluation of real-world preventive effects over the long-term – effects that may be quite different outside the research setting and circumstances, with their access to resources, sanitary standards and intensive counseling. Moreover, proposals for mass circumcision lack a thorough and objective consideration of costs in relation to hoped-for benefits. No field-test has been performed to evaluate the effectiveness, complications, personnel requirements, costs and practicality of proposed approaches in real-life conditions. These are the classic distinctions between efficacy and effectiveness trials, and between internal validity and external validity [6].

Campaigns to promote safe-sex behaviors have been shown to accomplish a high rate of infection reduction [7], without the surgical risks and complications of circumcision, and at a much lower cost. For the health community to rush to recommend a program based on incomplete evidence is both premature and ill-advised. It misleads the public by promoting false hope from uncertain conclusions and might ultimately aggravate the problem by altering people’s behavioral patterns and exposing them and their partners to new or expanded risks [8] . Given these problems, circumcision of adults, and especially of children, by coercion or by false hope, raises human rights concerns.

You can read the article online here. You can download it here: Download mcnotavaccine.pdf.

This article states the case very well. Among the bullet points presented:

• All three of the studies were halted early
• The durations of the experiments were short
• No long-term follow-up has been or can be done
• A large number of participants were lost to follow-up
• Many infections appear to be from nonsexual sources

Other important confounding factors considered:

• Condom use and safe-sex practices were repeatedly reinforced
• Participants were provided 2 years of free medical care
• Participants were paid to participate
• Participants were solicited who wanted to be circumcised, and who may, therefore, not be representative of the general population
• The trials were conducted in atypically sanitary and well-resourced settings that are unlikely to be replicated in mass African circumcision campaigns   

The authors conclude:

Regardless of whether circumcision might offer some heterosexual males a partial degree of protection from HIV, numerous other issues need to be thoroughly considered before instituting mass circumcision campaigns.

In short, given the large number of unknowns, confounding factors and lack of long-term follow-up in the three RCTs, it is premature to recommend circumcision as an HIV-prevention strategy. Much more evidence must be gathered on real-world efficacy of male circumcision as a prevention tool before mass surgeries are implemented.

An objective scientific assessment must be conducted to determine if the three RCTs are applicable in real-world settings. And, to determine the true cost of a circumcision campaign, there must be a comprehensive resource analysis of the plan. These mass circumcision costs also must be compared with the opportunity costs of funding ABC campaigns.

As part of these assessments, the very real risks of circumcision surgery, including directly increasing HIV transmission to men as well as indirectly increasing transmission to women, surgical risks such as hemorrhage, other infections, meatal stenosis, need for repeat surgery and even death, must be considered.

Finally, the value and function of the foreskin as an integral part of the male sexual organ [31] and the ethical issues surrounding such surgery, including informed consent, the possibility of coercion and the dangerous implications of conveying erroneous messages of HIV immunity, must also be carefully considered in any analysis.

ABC programs offer nearly full protection from HIV infection, yet even if circumcision’s effectiveness matches the 50–60% effectiveness the RCTs reported, it only partially protects men, does not protect women at all, and leaves women more vulnerable to unsafe sex practices being forced upon them.

Those promoting circumcision argue that circumcision is an additional tool that will ultimately reduce infections more than just relying on condoms, monogamy and abstinence. However, African males are already lining up to be circumcised, thinking they will no longer need to use condoms. Rather than complementing ABC programs, promoting circumcision will undermine the ABC approach by diverting funds and encouraging risk compensation behavior, ultimately leading to an increase in HIV infections.

The world community must cautiously review and carefully consider the long-term consequences of mass circumcision campaigns, from the risk of increasing deaths and infections to human rights violations. In the rush to save lives, many may instead be lost and human rights trampled in the stampede. Circumcision is not the panacea the world has been waiting for in the battle to stem the HIV crisis.

At long last, members of the academic and health policy community, a sector from which much of this is emanating, have stepped forward with a systematic analysis of the problems and issues associated with the widespread promotion of circumcision for the purposes of addressing the HIV epidemic. We need more like this one.

Wired Magazine: Why Medicine Should Care Less About 'Sick,' More About 'Normal'

Have you ever known an elderly person who fell ill and decided to live out their final days without treatment? The idea behind refusing treatment by the elderly would seem to be that no intervention, particularly costly and uncomfortable invention, is necessary where the final outcome is predetermined by normal parameters, such as life-expectancy. How much pain and discomfort, not to mention inconvenience, are "worth it" to gain an extra year or two of life?

Similar questions are starting to be asked in younger people. A seemingly classic example might be UTIs in infants. For example, instead of asking whether a UTI in the first year of life is cause for long term concern, doctors tend to think in terms of pre-emptive treatment to reduce the risk - at least in the case of neonatal circumcision. But is the prevention of a single UTI in one child out of a 100 + children worth 100 circumcisions if one UTI in a 100 is within normal parameters? Most would say no, especially given easy treatment with a weak antibiotic.

Similar questions should be asked of HIV infection. How many new infections can be expected with a normal level of fully deployed proven prevention efforts? This number may be hard to come by and even more controversial to assert, given the level of funding at stake. Unlike UTIs, HIV occupies a center-of-gravity in the funding universe.

This very state of affairs may explain the irrational rush to promote circumcision in sub-Saharan Africa. Wherever there are doubt and confusion about what is normal and expected given the circumstances, there will be those who rush in to fill the void with whatever they can. However, what would be different if we knew the expected rate of infection with clean water? Better neonatal care? Regular STD screening? Regular HIV testing? Adequate nutrition? Full employment? Greater empowerment of women? The list is really endless.

In the absence of all these things, I suspect the circumcisionists would say their solution is the best stop-gap. But is it? I rather believe that stop-gaps are excuses to fail in the provision of these other important improvements whose benefits extend much further beyond merely reducing HIV infection.

And with that, the following article talks about the idea behind "distinguishing between a condition within normal parameters — which doesn't require intervention — and an anomaly, which demands it."

Link: Why Medicine Should Care Less About 'Sick,' More About 'Normal'.

We've seen the cart, now here comes the horse.

Aidsmap has recently reported on an emerging realization among HIV prevention researchers that asking about anal intercourse is important to rule out this confounding factor in prevention studies based in Africa.

Studies into sexual behaviour in Africa have often neglected to enquire about anal sex, and sex between men. There has either been an assumption that such behaviour was not prevalent, or a sensitivity to cultural taboos and prejudices means that investigators are reluctant to enquire about such behaviour. But studies are now suggesting that anal intercourse is common in Africa in both heterosexual and homosexual contexts and is an important mode of HIV transmission.

Excuse me, but could we get a do-over on those African circumcision trials?? This problem has been suggested before, but I think saying it out loud in the literature ought to get some attention. In studies where the numbers are small, but the difference in infection rate is great (precisely because the numbers are small), the problem of failing to account for all the confounding factors is greatly magnified. The African circumcision trials fall squarely into this trap. Now, will we hear calls to re-examine the studies? Unlikely, and as usual the responsibility to call them out on it will fall to the lay person. That would be most of you who read this blog.

In related news, Aidsmap is also reporting that HIV+ gay men with HPV, or ano-genital warts, have presented in Australia with abnormal cells in the anus that could indicate greater rates of cancer and/or HIV infectiousness. Combine this with the recent survey that demonstrated almost twice the rate of HPV among circumcised men in the USA, and we may be on to something.

The Preventioneers: The Biggest Challenge to HIV Prevention

With every new wave of HIV prevention initiatives comes a lament. The new (and not so new) researchers complain that lives are being lost, efforts are being wasted, and governments and policy makers don't "get it."

A recent perspective article published in the New England Journal of Medicine represents the worst of these agony aunt pieces. The authors dwell on the "enormous challenges," the "staggering loss of life," and the "repeated failures of biomedical interventions" except of course that of circumcision, and carry on how we must invest more money, do more research, change the paradigm.

By now, male circumcision has been absorbed into the scientific community's canon of received wisdom. Yet as we shall see in another post, the wisdom is really both a desperate hope and an unwillingness to upset the apple cart of fellow researchers. After all, these people rely on each other for support in their pursuit of new projects and funds to carry them out.

Yet this old song and dance reminds me of that age old (and highly localized) symbol of San Francisco. No, not the Golden Gate Bridge. I'm talking about the haggard man on the corner with his hand out, pleading poverty and helplessness, in a city with 27 places serving free food every day of the week, every day of the year. It's a sympathy play to our most basic instinct for compassion.*

Nevertheless, the authors make some important points. First, they point out that artificial end points and speculative estimates of expected infection rates make drawing conclusions exceedingly difficult. Second, they say that poor trial infrastructure results in participant attrition and lack of follow up, further hampering interpretation of data. Thirdly, they complain about the confusion ethical considerations that require providing safer sex education, condoms and follow up have on determining efficacy.

Now, I'm not an epidemiologist. And I'm not a scientist or statistician. But I am someone who makes a living figuring things out. And to my mind, every single one of these issues applies to the circumcision trials. First, the end points were decided by the researchers and supervisory infrastructure entirely arbitrarily based on "ethical considerations" instead of at a biomedical event, as the authors of this article suggest is desirable. These "ethical considerations," mind you, didn't seem to bother them at the beginning of the trials.  The small number of infections yielded mildly statistically significant differences at 18 months. However, the question whether those numbers would or wouldn't close the gap, or even widen over time, will never be answered.

Second, participant attrition was interpreted as enhancing the efficacy despite the fact that the problem of the control group not receiving the same level of traditional prevention interventions (condoms, education, routine medical care providing further opportunity for reinforcement) was never adequately controlled for. If the control group has less contact with study personnel, wouldn't their attrition rate likely be greater? And if so, how do you factor this in? Follow up was another problem. Has there been any follow up? What do we know about the two groups more than a year after the trials were ended? Very little is the answer because many of the control group were removed therefrom by circumcision. A biomedical event, if you will, that ended any future meaningfulness to follow up.

The third issue is so obvious, so blatant that it hardly needs analysis. Simply put, you cannot adequately separate safer sex messages from the biomedical outcome of circumcision when they are delivered together. This was a problem in a Cambodian microbicide trial that ended in failure, confusion and controversy around the same time.

So what is the answer to HIV/AIDS? It is this. We have prevention technologies that do not involve issues of informed consent, mixed messages (i.e. condoms are still necessary), or complications and botched surgeries where health care infrastructure is lacking or non-existent. They are effective. They are cheap. And they are freely available to enlightened communities. Condoms, encouraging fewer partners and discouraging multiple concurrent partners, frequent testing leading to early detection, and treatment itself. This is not a hard problem on the scientific plane. It is enormously difficult on the political plane, both among governments and scientific organizations because HIV competes with those groups' professional, economic, and organizational agendas.

Reference

N Engl J Med. 2008 Apr 10;358(15):1543-5. Challenges to HIV prevention--seeking effective measures in the absence of a vaccine. Lagakos SW, Gable AR. Harvard School of Public Health, Boston, USA.

Photo credit: Isabella Valentine

*And yes, some homeless are doing the best they can. I understand that. After all, I do indigent criminal defense and am closer to the problem than most. So please no hate mail.

A Curious Thought: Nigerian State Bans Contraceptives, Including Condoms ... Circumcision Next?

The Nigerian state of Anambra has banned contraceptives of all types including condoms because, to paraphrase, contraceptives encourage immorality. I wonder if the state will consider banning circumcision because it too might encourage "immorality." A curious thought.

Link: Global Challenges | Nigerian State Bans Promotion, Distribution of Contraceptives, Including Condoms - Kaisernetwork.org.

Notebook: What happens when we realize a vaccine isn't possible?

The HIV/AIDS research community has finally come to the conclusion that a vaccine will likely never come. More than one expert has said this in the last year. A few elder statesmen of long experience in the infectious disease research community have come out and said that HIV/AIDS is a disease easily avoided with a long period of incubation, usually past the years of child-bearing and most of those of child-rearing, that in most countries affects a small number of people engaging in very specific contagious behavior. Nature and evolution simply do not find this disease to be a major problem. Hence, it is less a threat to world humanity than a personal tragedy to individuals and those countries hardest hit.

We have entered a new period in the development of the HIV/AIDS era. The emphasis will now be on prevention. The HIV/AIDS research world is awash in money. If the donor community accepts that a vaccine is not possible, billions of dollars will flow elsewhere. Economics dictates that the recipients of donor largesse will have to shift their research and activities to continue receiving these huge sums of money, recipients being institutions rather then individuals. Hence, we saw the World Health Organization endorse male circumcision. Then we saw the United Nations add their voice as well.

More than a few people were perplexed at the apparently bizarre interest the vaccine activist community  had in male circumcision. The AIDS Vaccine Advocacy Coalition and the International AIDS Vaccine Initiative both became positively giddy at the prospect of male circumcision. I now question whether they have concluded privately that the vaccine effort's days are numbered. Closer than anyone to the effort and more dependent on donors than even the research institutions, which usually have more than one focus, they perhaps see an opportunity for continued viability in the promotion of genital surgeries.

The evidence for male circumcision is weak. Its efficacy in a clinical setting is unclear. Its effectiveness in the general population is negligible. No one seems ready to acknowledge that all the players in the male circumcision push have vested interests. Yet, the United States Centers for Disease Control (CDC) appears ready to endorse it, falling in line with the United Nations and the World Health Organization. Given the condescending attitude of most US government institutions, I suspect the CDC is more than a little annoyed that they were beaten to the punch.

The CDC condemned the new Swiss guidelines on HIV+ infectiousness almost immediately. More than eight years of evidence went into the formulation of the new guideline. In prevention terms, why support male circumcision so quickly and condemn the proven prevention value of ARV therapy? The CDC will eventually come around to support the Swiss viewpoint. Right now, the new guidelines are an uncomfortable, counterintuitive change in direction. But it is fundamentally a technical question of prevention. Male circumcision on the other hand is an American cultural norm that evokes a fierce commitment to its continued practice in the United States. However, it is new to the HIV/AIDS scene. Hence it has attracted interest as it involves the creation or expansion of new organizational structures and materials, and provides a new opportunity for advocacy and the allocation of resources.

So where is the world now viz HIV/AIDS and male circumcision?

If the experts have concluded both that a vaccine is not possible and that HIV is little more than a personal tragedy for individuals in the developed world, I think we can expect a mad scramble for prevention funds. This will likely involve all sorts of new and innovative efforts, of which more than a few will involve genital mutilation. We can likely look forward to continued forced circumcisions of children and scaremongering to induce submission in adults. Much like the early period of HIV/AIDS, ethics and human rights will take a hit.

[This article has been reprinted as a news item on the European AIDS Treatment Group website.]

Swiss recommendations now state that HIV positives on effective anti-retroviral treatment not infectious

This post is coming a little late to the fore. Nevertheless, I still wanted to mention it briefly.

Swiss public health officials have issued new guidelines (original in French and German [pdf warning]) regarding the infectiousness of HIV+ individuals on effective anti-retroviral therapy. Basically, the new guidelines state that condoms are unnecessary in serodiscordant (one positive, the other not) couples under a narrow but widely applicable set of circumstances. These circumstances are:

• The HIV+ individual must consistently adhere to the anti-retroviral therapy regimen and the effectiveness of the therapy must be monitored at regular intervals by his or her treating physician according to officially accepted guidelines;
• The viral load must be below the limit of detection (<40>)
• The HIV+ person must not be suffering from any other sexually transmitted infections.

Again, under these very narrow circumstances, serodiscordant couples needn't use condoms during sexual intercourse. Read the English translation here [pdf warning].

This is in accord with a study presented at the Fifteenth Conference on Retroviral and Opportunistic Infections. That study concluded that provision of ARV therapy to African nations could reduce HIV infection over all by 90%.

[This post was picked up by Reuters through Blogburst.]

AP ridicules South Africa for proceeding with caution on circumcision

The Associated Press has issued an article dripping with ridicule in tone and use of selective quotes  regarding South Africa's reluctance to "run roughshod" over the traditional values of certain ethnic groups that "frown" on circumcision by recommending the procedure.

Stephen Lewis, who is described as a former UN AIDS envoy, accused South Africa of being "addicted to folly" for refusing to jump on the bandwagon. Lewis repeats the lie that there is "overwhelming evidence" supporting circumcision as an AIDS "prevention."

The AP does not mention the numerous doubts expressed by AIDS organizations in Australia, Europe, and Canada over encouraging a genital surgery to deal with HIV/AIDS. It also fails to mention the cultural, economic and historical reasons that HIV has made such massive inroads in South Africa.

The article additionally makes no mention of the fact that circumcision likely increases HIV among women, disempowers women to negotiate condom use, and provides no protection for men who have sex with men.

The AP completely omits any mention that multiple, concurrent partnerships are the primary vector for HIV in sub-Saharan Africa, which has explained why countries such as Zimbabwe, Uganda, and South Africa suffer high rates of the disease compared to other parts of the continent.

The article does however tack on the obligatory line that "circumcision does not provide complete protection," thereby acknowledging the inherent problem of encouraging a procedure that harms many and may help some.

Contact the AP and Stephen Lewis.

AP Headquarters
450 W. 33rd St.
New York, NY 10001
info@ap.org
+1-212-621-1500

Attn. Stephen Lewis
Stephen Lewis Foundation
info@stephenlewisfoundation.org

Full fair use AP story after the fold.

Failed Merck vaccine may have made intact men more vulnerable; rethink is in order, researchers say [updated]

[Dr. Susan Buchbinder] reported at the [15th CROI] conference today that further analysis of the Merck study results found that uncircumcised volunteers who received the vaccine ran nearly 4 times the risk of infection than those who were given a placebo.

Buchbinder said one possible explanation is that the vaccine somehow activated white blood cells near the surface of the foreskin - known HIV targets - making them more vulnerable to infection. She told reporters that she would not recommend at this time that study participants who are uncircumcised and received the vaccine, rather than a placebo, be circumcised as a precaution.

Follow-up research has also shown that the slight trend toward higher infection rates among all those who took the vaccine has not yet abated. But the number of infections involved is so low that there remains a possibility that the higher infection rates among uncircumcised men was purely the result of chance.

A vaccine trial that made volunteers more vulnerable to HIV that then would encourage circumcision is insult to injury for the unfortunates who received the ill-fated vaccine candidate.

A rethinking is in order, no doubt about it. But the rethink, at least in the developed world, is that HIV/AIDS is 100% avoidable. This virus may be beyond us, but it is infinitely containable. We know more than enough to shift some of the burden that researchers are feeling onto the shoulders of the community. We all have to take responsibility for avoiding this virus.

If some ADULTS want circumcision as part of this process, they should have it. The challenge then is how to maintain the responsibility on the adult individual, the only place where it can work. The danger is that the temptation will be to shift the decision from the individual to someone else, such as doctors and parents. Ethically, that is the wrong path to take, and ultimately another ill-effect of the virus, but which is within the power of humans to avoid.

Link: Failure to find AIDS vaccine has researchers seeking new directions.

Aidsmap, the best source of information on HIV/AIDS in the English language, has a better analysis of the Merck vaccine failure. Their article includes details of a discussion that the failed vaccine may have deactivated the protective mechanism in the mucosal tissue of the foreskin.

I think it is important to realize what the difference between the intact and circumcised seroconverters was in real numbers: 49 versus 33, respectively, out of 930 male volunteers. That's a tiny group, conclusions from which would seem ill-advised.

UPDATE: Forty-nine people in the vaccine trial group seroconverted. Thirty-three in the control group also seroconverted. Therefore, the difference between the circumcised and intact group who seroconverted is even smaller than the difference between the trial and control group. The numbers here are miniscule with no statistical significance. That wasn't made clear in the earlier reports. And it was glossed over by the largely circumcision positive press.

Link: Aidsmap | CROI: AIDS vaccine: additional [increased] infection risk restricted to uncircumcised men.

Aciclovir treatment for genital herpes as proxy for circumcision?

If circumcision reduces ulcerative genital diseases in men and ulcerative diseases such as HCV infections are a co-factor for HIV infection, then the effect should be lower HIV infection rates over all. That's one of the theories anyway behind prophylactic circumcision. Yet a large study presented at the 15th Conference on Retroviruses and Opportunistic Infections using Aciclovir to suppress HCV in infected individuals should in theory also have reduced HIV infection in the HCV infected group and their partners. That didn't happen.

This failure of theory to deliver in practice raises numerous questions about the alleged benefit of circumcision to reduce HIV infection. If suppression of HCV doesn't reduce HIV infection, maybe HCV infection isn't the cause of the higher HIV rates. Could it be that HCV infected individuals are also behaving in ways that expose them to HIV rather than the HCV infection being a vector for the infection?

The head spins, thinking about how confused the research is in the area of understanding correlation and cause and effect in HIV transmission. Aciclovir may have made a good proxy for circumcision if it indeed had had the effect of reducing HIV infection. Because it didn't, it calls into question whether the mechanism for reduction in risk in circumcised men has anything to do at all with alleged lower HCV rates in these men.

Link: Aidsmap | Aciclovir treatment for genital herpes does not reduce HIV acquisition in men or women, major trial shows.