Daniel Halperin
HSPH research scientist Daniel Halperin thought he might have more than a hunch. In 1999, while based at the University of California as an assistant professor, Halperin and his colleague Robert Bailey of the University of Illinois at Chicago published a review in the Lancet. They argued that male circumcision rates were associated with sub-regional differences in HIV infection rates, especially in Africa and Southeast Asia. That is, the fewer men in a country or area who were circumcised, the higher the HIV infection rate. The researchers also argued that the global health community should add male circumcision to its weaponry against AIDS.
The reaction to the Lancet piece was mixed, with some researchers in agreement and others in need of harder evidence. Now, more than seven years later, Halperin and Bailey have been proven right by three clinical trials showing that circumcision reduces a man's risk of contracting HIV by more than half. The evidence was so strong that in December the National Institutes of Health (NIH) ended two of the trials early, after a previous South Africa study was also terminated prematurely due to strong findings. The directors of two significant international funding programs, PEPFAR and the Global Fund for AIDS, TB and Malaria, suggested that the programs would consider paying for circumcisions to fight the spread of the disease.
Halperin, who is now with the HSPH-based Harvard Center for Population and Development Studies, said that the news is very exciting. He heard about the stoppage of the two NIH-funded studies in December while working with the United Nations Family Planning Association on an HIV prevention study in Zimbabwe. He predicted that many lives would be ultimately saved as word spread among African men.
"After 25 years of trying to fight this virus, it is sobering that we have only one intervention that is now shown by the very highest standards of public health-findings from multiple randomized trials-to reduce the sexual transmission of HIV,'' he said.
The association between uncircumcised men and increased HIV risk was documented in 1989 by a team led by William Cameron of the University of Ottawa. In a prospective study in the Lancet, the researchers showed that uncircumcised men in Kenya faced more than eight times the risk for HIV-1 infection than their circumcised counterparts.
Ten years after that study, Halperin and Bailey published their own paper in the Lancet. In their 1999 piece, they reviewed the decade of research that had ensued since the Cameron paper. Four out of six additional prospective studies had also shown significant relative risks for HIV infection among uncircumcised men. Twenty-seven of 38 cross-sectional studies found a significant association between lack of circumcision and HIV infection.
The pair highlighted the incredible differences of HIV infection rates within the same parts of the world, drawing attention to low rates in most of west Africa, as well as in the Philippines, Bangladesh, and Indonesia, compared to much higher rates in parts of east and southern Africa and in Thailand, India, and Cambodia. Halperin and Bailey argued that differences in surveillance and prevention efforts alone could not explain the patterns. In fact, they noted that nearly all men in the areas where there were low HIV infection rates had been circumcised, usually by puberty, whereas most men in the areas with high rates had not been circumcised.
And they described the research that presented a biological explanation for why circumcision decreases HIV risk during heterosexual sex. Circumcision seems to protect men because the underside of the foreskin "is like an Achilles heel for HIV infection in men,'' said Halperin. "The foreskin is vulnerable to tearing and bleeding during sex. And the inner surface of the foreskin is loaded with Langerhans, macrophage, and CD4 cells, which are targets of HIV.'' The uptake of HIV in those immune cells, due mainly to the lack of a hardened, or keratinized, skin coating over the inner foreskin mucosa, is about nine times greater than in the mucosa of the female cervix, which had long been thought to be the most vulnerable part of the body of cells to HIV infection, he said.
Halperin and a small group of like-minded researchers soldiered on. From 2001 to 2005, Halperin served as the senior Prevention Advisor for the Office of HIV/AIDS at USAID. One of his duties involved developing and overseeing pilot programs in Zambia, Haiti, and South Africa that introduced male reproductive health services, including the availability of safe adult male circumcision.
His colleague, Robert Bailey, with whom Halperin wrote the Lancet piece, went on to lead a randomized, controlled trial in Kenya investigating the association between circumcision and HIV risk. It was this trial, along with one conducted in Uganda by a different research team, that was halted in December 2006 because the results so strongly suggested that circumcision halves a man's risk of contracting HIV from a woman. Just last week, the Lancet published the final data from the Kenya and Uganda studies, which now suggest the reduction in risk could be as high as 65 percent.
Now, another study in Uganda funded by the Bill & Melinda Gates Foundation is looking at whether male circumcision directly reduces transmission rates among women. In any case, noted Halperin, if fewer men are infected, women would benefit indirectly.
The risk reduction provided by circumcision appears as good, if not better, than what may be expected from a still nonexistent HIV vaccine. "This virus is incredibly challenging for the development of a vaccine,'' said Halperin. "It mutates very quickly. It is very hard to pin down. The first vaccine trials have not been very promising so far, and most experts on vaccines don't believe we will find anything close to a 100 percent vaccine, even if we get one. It's not that kind of vaccine. If we get one, it will probably be only partly effective. Or it may only slow the progression of HIV to AIDS. And even the most optimistic researchers say we may not have one of those ready for use for another 10 or 20 years, at the earliest.''
Halperin continues to conduct and analyze research on global sexual behavior, in addition to investigating and publishing on the extensive data regarding male circumcision, including the real-world programmatic implications of that evidence. For several years, he has explored the use of the so-called "ABC" approach to HIV prevention (Abstinence, Be faithful/reduce partners, or use Condoms consistently). He is particularly focused on researching the "B" part of the approach, trying to determine the role that multiple and concurrent sexual partnerships play in HIV transmission, especially in high-prevalence regions of Africa.
Halperin emphasized that circumcision isn't going to be the complete answer to the AIDS epidemic in Africa or in the world. But, he added, it is likely to become one important piece of the prevention puzzle, at least in some regions of the world.
"Ideally, we would want not only that those men who wish to become circumcised can have access to safe and affordable services, but also for men and women to use condoms and-perhaps of greatest epidemiological importance-to have fewer partners or practice mutual fidelity,'' he said.
Copyright, 2009, President and Fellows of Harvard College
