By Meredith Wadman of Nature magazine

The recent finding that women in seven sub-Saharan Africa countries are nearly twice as likely to acquire HIV if they use a popular, long-acting injectable contraceptive, has incensed AIDS researchers. They say that fifteen years of literature has pointed to this increased susceptibility, but that the unwelcome news has been ignored.

The results of a study of 3,790 couples also found that uninfected men were nearly twice as likely to acquire HIV from a female partner using the contraceptive, whose active ingredient is progesterone. The injection, whose generic version costs about $US 1.08, is given every three months, and used by more than 90 million women world-wide. The study, published on 4 October in Lancet Infectious Diseases, also showed that oral contraceptive use by women increased the risk of HIV infection for both women and men with infected partners, but the numbers generated did not rise to statistical significance.

The findings are obliging epidemiologists, infectious-disease specialists and public-health experts to reassess the risks and benefits of the contraceptive, whose branded version, Depo-Provera, is made by Pfizer. The World Health Organization (WHO) is convening a technical consultation early next year at which experts will examine the literature. The aim is to decide whether the WHO's recommendation for the use of injectable contraceptives should be revised for HIV-infected women, and for female partners of HIV-infected men, in light of the new findings.

But AIDS scientists say that the writing has been on the wall since a study in macaques was published in Nature Medicine in 1996. "How many years has it been that the non-human primate model, and other researchers, have been warning about this and being ignored? What, 15 years now? Shocking," John Moore, an HIV scientist at Weill Medical College of Cornell University in New York City, wrote in an e-mail to colleagues and journalists on 5 October.

The 1996 study showed that female rhesus macaques with progesterone implants were 7.7 times more likely to be infected with simian immunodeficiency virus than macaques that had a placebo implant.

Preston Marx, a microbiologist at the Tulane National Primate Research Center in Louisiana and the first author on that paper, says: "It's not like we did our work and it was published in an obscure journal. There's absolutely no excuse for people doing contraceptive work to not have known this, and not to have taken this forward in the late '90s. We should have had this answered [in humans] ten years ago."

Experts have hypothesized that the thinning of the vaginal mucosa by progesterone (pictured) makes it easier for HIV to penetrate the vaginal wall in an uninfected woman, and, conversely, for an HIV-positive woman to infect her partner. Other mechanisms at play may include changes in the vaginal microbiota induced by progesterone -- specifically, a reduction in hydrogen peroxide-producing Lactobacillus, which can kill HIV. Another hypothesis is that progesterone boosts the population of Langerhans cells in the vaginal mucosa, thought to be one of the main targets of HIV in the female genital tract.

Marx believes that public-health and contraceptive experts were hostile to his findings because they did not want to have to cope with a threat to a cheap, accessible and popular contraceptive method that is highly important in the developing world. Instead, he says, they shot the messenger. "I was in one meeting accused of massaging the data. It was real heat."

He notes that intervening human studies have pointed to the same conclusion, particularly a ten-year prospective study of over 1,500 sex workers in Mombassa, Kenya.

Balancing act

Public-health experts and epidemiologists see the issue differently. Mary Lyn Gaffield, the WHO epidemiologist responsible for developing the organization's guidelines for family planning, notes that human studies performed since the mid-90s have had methodological limitations. For instance, the risk profile of sex workers is different from that of the general population. Potentially confounding factors, she adds, such as condom use, and the inherent unreliability of self-reporting, mean that "the quality of the evidence is very weak in many of the studies", Gaffield says.

In the current study, she says, "they controlled for many confounding factors, but still hormonal contraceptive use was very, very small. So it warrants us giving a very, very careful look at whether the study prompts a need to warn about the safety or not."

Gaffield notes that there is more in the balance than a woman's risk of HIV infection. Unwanted pregnancies, especially in poor countries, can lead to serious and even fatal complications.

Zdenek Hel, an immunologist at the University of Alabama at Birmingham, was first author on a 2010 review that explored the literature on whether hormone-based contraceptives increase a woman's vulnerability to HIV infection. The review noted that the question remains "highly controversial" and "a topic of intense discussion". It concluded that the epidemiological data thus far were "inconclusive" and that "more comprehensive clinical trials are urgently needed".

Now, says Hel, the new study "may reflect a real and important biological phenomenon and should be taken seriously. This may be the conclusive epidemiological study that we called for."

This article is reproduced with permission from the magazine Nature. The article was first published on October 7, 2011.