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Are We Ready For Circumcision: The Role of Circumcision as a Potential Preventive Measure to Stop the Spread of HIV Infection
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Reported by Jules Levin
13th CROI, Denver, Feb 5-8, 2006
"Circumcision and HIV Transmission: The Cutting Edge"
Thomas C Quinn
NIAID, NIH and Johns Hopkins Med Inst, Baltimore, MD, US
Quinn delivered a long talk about the effort to use circumcision as an HIV prevention tool in third-world countries. He reviewed studies showing significant benefit, and ongoing randomized trials whose preliminary results show significant potential benefit. He reviews the risks including low rates of complications and cultural barriers, stigma, and criticism. He also reviews modeling to predict significant benefits to men & women and significant reductions in HIV transmission rates. But he also discusses the risk that men may feel too secure & increase sexual activity with multiple partners & potentially increase HIV transmission rates despite circumcision. This report reviews all this information in depth including current policy recommendations on making circumcision available by UNAIDS & WHO.
......We have not embraced circumcision because of the attempt to balance the potential benefits, and they appear great, against the potential risks, but it can reduce STI & HIV transmission, it can be cost effective & protective long-term for men & for women.....
Quinn says if you combine treatment with ART and circumcision you would have an even greater impact.
"...HIV is a global pandemic with 40 million people living with HIV...it's not slowing down....last year more than any other year more people became HIV infected, 5 million people became newly infected, and it's not slowing down...there are many factors, biological determinants, that drive the transmission of HIV (see table below)...there are many variables or determinants present in the person transmitting HIV and variables or determinants in the person acquiring HIV....common to both is this finding of a lack of circumcision that seems to increase infectiousness of the infected man, but it also appears to increase the susceptibility of the uninfected individual.....there are 3 randomized clinical studies launched several years ago, one finished & 2 ongoing, all intended to find that circumcision could play an important role in preventing the spread of HIV....if that is true, and if they all come to the same finding, we need to start developing the policy of how we might implement circumcision as a preventive modality. One has to look at the safety of the procedure in young adults, acceptability to the populations at risk....in europe very few men are circumcised
....circumcision is the most common surgical procedure among humans....20-25% of men worldwide are circumcised....in the USA now 55% of newborn infants are circumcised...it's much higher in adult men...it's a simple procedure that does entail some risks despite the health benefits (see picture below) it offers...it has to be considered within the cultural context, will it be accepted within certain cultures and that is a major issue....in African & Asian countries where male circumcision is practiced HIV prevalence remains low, but there are confounding factors in these 'ecological' studies reporting this information.....
....cohort and cross-sectional studies show at times dramatic results suggesting that circumcision is protective find, but these types of studies are problematic in that they have confounding factors....circumcision of men may protect women from getting HIV from these men as well as protect men from HIV acquisition, significant if his viral load was <50,000 (0 females infected; see study below in table)......Reynolds presented study at CROI: female partners of circumcised men have much lower prevalence of HIV & certain STDs but not all STDs (see table below)....uncircumcised men appear more vulnerable to HIV-infection because of the presence of cells more susceptible to HIV infection under the foreskin while circumcised men appear to have a protective coating on penis.
Due to the risks associated with circumcision no one wanted to recommend the procedure for prevention so there are three trials ongoing. These are large studies and interest in the studies appear good. Most of these studies are looking at HIV-negative men and looking at HIV acquisition, but one study is looking at HIV+ men. The South Africa study was stopped by the DSMB after an interim analysis in Nov 2004 due to 'dramatic' benefits observed. The study results have been published. The Rakai study in South Africa is circumcising HIV+ men and looking to add their female partners to see if they are reducing transmission.
From population-based studies and couple studies, the probability of HIV transmission and acquisition has been associated with the blood and genital viral load, male circumcision, sexually transmitted diseases, stage of disease, genetic haplotype, viral subtype, and levels of mucosal immune response. This presentation will review the relationship between male circumcision and HIV transmission and discuss policy implications in promoting circumcision as a prevention modality.
This review synthesized information from published and unpublished epidemiologic studies, clinical trials, and mathematical models.
A systematic meta-analysis of 38 studies, mostly in Africa, found that circumcised men appear to have a 50% or more reduction in HIV infection than did uncircumcised men. A sub-analysis of 16 of these studies found a 70% reduction in HIV infection among higher-risk men. Mapping of the HIV epidemic has demonstrated a strong correlation between regions with higher rates of HIV infection and those with lower circumcision rates. A 2-year cohort study of male partners of HIV-positive women in Rakai, Uganda, found that 40 of 137 uncircumcised men became infected compared with 0 of 50 circumcised men over 2.1 years (p = 0.0004).
Biological explanations include greater ability of the internal foreskin to absorb HIV more efficiently due to the greater presence of Langerhans and other HIV target cells and its greater susceptibility to tears, abrasions, and consequently infection by sexually transmitted diseases and HIV. One randomized controlled trial in South Africa demonstrated that circumcision afforded a 61% (95%CI 34 to 77%) reduction in HIV incidence even after controlling for behavioral factors; and 2 similar trials in Uganda and Kenya are in progress.
Quinn concluded that these epidemiologic, biological, and clinical trial results provide strong evidence that male circumcision significantly lowers the risk of HIV acquisition. Mathematical models of implementing male circumcision in countries with high incident rates suggest marked reductions in HIV incidence in men with subsequent decreased transmission rates to women. Policy implications of recommending male circumcision to populations in high-risk countries need to take into consideration cultural norms, religious traditions, national and local laws. Circumcision may represent one important biological intervention to decreasing the acquisition of HIV, but will need to be carefully integrated into other HIV prevention and sexually transmitted disease control programs prevent subsequent behavioral disinhibition among circumcised men.
South AFRICA STUDY RESULTS
......There were 49 seroconversions in the control arm, people without circumcision, over a 21 month period, compared to 20 seroconversions in the intervention arm men who were circumcised. That shows a dramatic difference in incident rate: 2.1 vs 0.85, much lower in the circumcised group. Unadjusted RR, relative risk, of 0.40 means there is a protective rate of 60% for circumcision, consistent with the literature. This is an Intent To Treat analysis. But, if you include the crossovers, just looking at the circumcised vs the uncircumsized men, just looking at the physiological finding of efficacy you get a relative risk reduction of 0.25 that means a protective rate of 75%, "very dramatic". The adverse events were low but they were present, 3.8%. (see table of events below) The adverse event rate was 8.2% in HIV+ men. So, the first completed randomized clinical trial that "completely supports" the previous data, it shows a strong protective effect, a reduction of female to male transmission, it's partial protection as there were some seroconversions, the followup has only been 1 year so we can only say short-term effect, it was only done in sub-Saharan Africa so will it work in Asia or other places, its consistent with expectations, and it begs the question---what should we do about circumcision as a public health intervention. UNAIDS & WHO have weighed in on this, they recommend to see what the other two trials find, & their interim analysis will be in June & July of this year. In the meantime "make safe circumcision available to men who request it but do not promote it yet for HIV prevention" until yet until we see the results from these two trials.
researchers have modeled the potential benefits in reducing HIV incidence in males & females. Quinn said—"As you can see the models see a reduction in HIV incidence in men & women. The potential impact on women according to the modeling is even greater because it would decrease transmission to women and circumcised men are less transmissible at lower viral loads (<50,000 c/ml) and therefore you would get a better impact on the pandemic in Africa".
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