DURBAN, South Africa—Where Zuma Mabuza lives, in KwaZulu–Natal, getting HIV—the human immunodeficiency virus—can feel inevitable. “If people in the community talk about HIV, the conversation is usually about which treatment options are best,” says Mabuza, a 28-year-old woman who sells used clothes to provide for her young daughter. Mabuza is not her real name; we have changed it to protect her identity because she is part of a large medical test of anti-HIV drugs. In KwaZulu–Natal, which is in the eastern part of South Africa, almost four in 10 people test positive for the virus. Although AIDS deaths have plummeted because of antiretroviral treatments, the new infection rate has not. Mabuza’s boyfriend is HIV-negative, but the stakes are high when the disease is so common. If he had an affair with someone who carries the virus, Mabuza could get infected through trusted, unprotected sex or a broken condom. If she started a new relationship, her partner could bring her disease. If she was sexually assaulted, her assailant could be HIV-positive.

Two years ago Mabuza heard about a vaginal ring that could protect her, and she decided to enroll in the medical trial that was testing it. The ring looks like a gummy bracelet. It is inserted into the body to secrete a drug named Dapivirine—a reverse transcriptase inhibitor that blocks the ability of HIV to replicate. Every month Mabuza and about 2,600 other women in the trial went to clinics in South Africa, Malawi, Uganda and Zimbabwe, dropped off their used rings and picked up new ones. Half of the rings contained Dapivirine and half contained nothing.

The Dapivirine ring is one of scientists’ latest attempts to stem the new infections at the center of the HIV epidemic. Worldwide for the past decade 2.5 million people have gotten infected annually. In sub-Saharan Africa women account for the majority of new cases. About 5,000 young women and teenage girls there acquire HIV each week. In a survey in KwaZulu–Natal, 24 percent of females under age 21 tested positive for the virus whereas just 2 percent of males the same age did. These young women often infect their same-age partners later in life, who in turn transmit HIV through affairs with younger women, according to genetic analyses.

Researchers had hoped to break the cycle by giving young women HIV drugs before they are infected. It’s a mode of therapy referred to as preexposure prophylaxis, or PrEP. However, when PrEP was given to women as a pill, the results were discouraging because many study participants didn’t take it daily. And the first trial results for the ring are not spectacular. The numbers, reported in February, show that young women don’t adhere well to the treatments. Often, they took the rings out. The exact reasons are a puzzle, but many women may have found the insert uncomfortable, or worried about what the men they slept with would think.

In the face of this unexpected setback scientists are now trying to develop new, less invasive products as well as giving more forethought into the social circumstances surrounding PrEP use. “If women feel they cannot control their exposure to the virus, if they’ve seen their mothers get infected or their family members die from AIDS and they are afraid of that, we want to offer them protection,” says microbiologist Zeda Rosenberg, chief executive of the nonprofit organization developing the ring, the International Partnership for Microbicides.

Rosenberg has focused on women since the early days of the HIV epidemic in the late 1980s. “Even though the disease had started in homosexual men, we were worried because sexually transmitted diseases almost always affect women worse,” she explains. In 2003 Rosenberg and her colleagues published a report on a microbicide gel that killed HIV, which women could apply before sex. By the time they got the formula right, however, an unexpected problem emerged. It failed to protect women in large clinical trials because women rarely used it.

So in 2010 Rosenberg began to devote more attention on the vaginal ring. “We thought theoretically a ring should be easier because a woman just leaves it in,” she says. The partnership had licensed the HIV drug Dapivirine from Janssen in 2003 and spent years developing the ring version of the product. Then the National Institutes of Health and other donors funded clinical trials.*

In February the lackluster results of the largest trial—the one including Mabuza—were reported in The New England Journal of Medicine. During the study, 6 percent of the women got HIV—71 in the treatment group and 97 from a group that got a sham treatment. When researchers analyzed the rings women had returned to the clinic, they found high levels of Dapivirine, indicating that many had removed the rings from their vaginas at some point every month. Women between the ages of 18 to 21 were most likely to have taken the ring out whereas women aged 25 and older were more likely to have kept it in. When used, the ring worked; these older women were 61 percent less likely to get HIV compared with women in the sham ring group.

The researchers think the reasons for ring removal are that, in general, young women are not comfortable with the device. Vaginal rings are not common as birth control in Africa as they are in the U.S and Europe. The rings with Dapivirine can cause mild side effects such as mild nausea and fatigue. Women also might not have liked how the ring felt or their partners might have felt it and not wanted them to use it. In addition, women may not have been convinced that the ring worked. Basically, for women who were not sick, the hassles may have outweighed potential benefits

Women under 21 have not adhered well to another type of HIV-prevention, too. Daily antiretroviral pills, called Truvada, hardly worked for them in trials even though the same pills staved off HIV in gay men, intravenous drug users and sex workers who took them regularly. In 2012 the drug got a stamp of approval from the U.S. Food and Drug Administration based on data from these groups showing that it is up to 92 percent effective. Since 2012 Truvada has been prescribed to more than 50,000 adults in the U.S.—mostly gay men in their late 30s.

To improve compliance among women in Africa, researchers are now investigating products that may change the hassle–benefit equation. Within a year clinical trials will begin on an injection of an antiretroviral drug, called cabotegravir, to see if it prevents infection for four or eight weeks. Another injectable at an earlier stage of research could provide protection for three months. And a vaginal ring in the pipeline combines birth control with HIV drugs. Simply knowing that research shows that the ring does work, when used properly, could make a big difference. “I want the ring because we know it’s effective,” Mabuza says. “I hope other women will feel the same.”

At the same time, scientists have realized they need to support young women socially and economically as well as medically if they hope to reach them with drugs or any other intervention. “Until I know the context of a woman’s life I can’t make a difference,” says Gita Ramjee, director of the HIV Prevention Research Unit at the South African Medical Research Council. “We need to understand where she comes from, what happens when she gets home, what are the challenges she faces. Is she having sex because she likes sex or is she desperate and needs money?”

In a country where 23 million people live below the poverty line young women can be enticed by men who offer them goods ranging from food to a nice dress. And they have little power to demand condom use in such transactional relationships. In South Africa these men even have a positive-sounding name: blessers. Mabuza tells me that she worries about how her eight-year-old daughter will fend off blessers when she enters high school. “These men destroy a child’s future,” she says, “but there’s not much you can do to stop them.” Researchers are trying to lessen the problem by giving cash to young women in return for good grades or attendance at sexual education and empowerment sessions. But results have been modest. Some say it is because the amount of cash is small.

In a half dozen studies across eastern and southern Africa researchers are now testing various models of PrEP delivery to young women. At a small HIV clinic in the mountains of KwaZulu–Natal—one branch of the Center for the AIDS Programme of Research in South Africa (CAPRISA)—staff have discovered that trust is key. They’re now offering Truvada pills to 16- to 25-year-olds. In addition they hold educational sessions that provide teenagers with information along with a safe place to talk and peer-to-peer programs that instill feelings of self-worth. And clinicians have become involved in patients’ lives beyond the medical setting. “We find ourselves helping the girls apply to universities—it’s outside of science but it all matters,” says Célia Mehou-Loko, a research fellow at CAPRISA. “You start to realize that putting in an implant or giving a pill is not enough because their needs are so complex,” she says. “We need to show them we care.”

*Editor's Note (9/5/16): An error in this paragraph was corrected after posting to state that the International Partnership for Microbicides began work on an anti-HIV vaginal ring in 2003, not 2010. It also was edited to clarify that clinical trials had several funders, not only the National Institutes of Health.