Vaginal Ring Provides Partial Protection from HIV in Large Multinational Trial

NIH-Funded Study Finds Protective Effect Strongest in Women over Age 25
February 22, 2016

​A ring that continuously releases an experimental antiretroviral drug in the vagina safely provided a modest level of protection against HIV infection in women, a large clinical trial in four sub-Saharan African countries has found. The ring reduced the risk of HIV infection by 27 percent in the study population overall and by 61 percent among women ages 25 years and older, who used the ring most consistently.

These results were announced today at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston and simultaneously published online in the New England Journal of Medicine.

"Women need a discreet, long-acting form of HIV prevention that they control and want to use," said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) and the primary funder of the trial. "This study found that a vaginal ring containing a sustained-release antiretroviral drug confers partial protection against HIV among women in sub-Saharan Africa. Further research is needed to understand the age-related disparities in the observed level of protection."

Women accounted for more than half of the 25.8 million people living with HIV in sub-Saharan Africa in 2014. Finding effective HIV prevention tools for adolescent girls and young women in particular is critical, as one in four new HIV infections in sub-Saharan Africa occur in this group.

The ASPIRE study, also known as MTN-020, aimed to determine whether the experimental antiretroviral drug dapivirine could safely and effectively prevent HIV infection when continuously released in the vagina from a silicone ring replaced once every 4 weeks. The study, which began in 2012, enrolled more than 2,600 HIV-uninfected women ages 18 to 45 years who were at high risk for HIV infection at 15 sites in Malawi, South Africa, Uganda and Zimbabwe. The women were assigned at random to receive either the dapivirine ring or a placebo ring. No one knew who received which ring until the end of the trial.

All study participants received a package of HIV prevention services at each study visit, including HIV risk-reduction counseling, partner HIV testing, treatment of sexually transmitted infections in participants and their partners, and free condoms.

The investigators found that the dapivirine ring reduced the risk of acquiring HIV by 27 percent among all women enrolled in the trial. But when the scientists excluded data from two sites where it was apparent early on that many women were not returning for study visits or using the ring consistently, the ring reduced the risk of HIV infection by 37 percent.

Furthermore, the investigators found that the dapivirine ring reduced the risk of HIV infection by 61 percent in women ages 25 and older, but provided no statistically significant protection in women younger than 25 years. These younger women appeared to use the ring less consistently than other participants, based on the amount of dapivirine measured in volunteers' blood during study visits.

To explore this age-related effect further, investigators performed analyses that were not originally planned and found that the ring reduced the risk of HIV infection by 56 percent in women older than 21 years, but provided no protection for women ages 18 to 21 years. More research is needed to determine whether behavior, biology or a combination of factors contributed to the lack of significant protection for younger women.

Finally, the investigators found that the rate of adverse medical events was similar among women who received the dapivirine ring compared to those who received the placebo ring, as was the frequency of antiretroviral resistance in women who acquired HIV.

"To help bring about an end to the HIV/AIDS epidemic, women-especially those in sub-Saharan Africa-need multiple options for HIV prevention," said Jared Baeten, M.D., Ph.D., who co-led the study for the NIH-funded Microbicide Trials Network (MTN). "The ASPIRE study was an important step towards determining whether the dapivirine ring could become one such option." Dr. Baeten is a professor of global health, medicine and epidemiology at the University of Washington in Seattle.

"The ASPIRE study is the first to demonstrate that a sustained drug delivery product that slowly releases an antiretroviral drug over time can offer partial protection from HIV," added Thesla Palanee-Phillips, Ph.D., who led the study with Dr. Baeten. Dr. Palanee-Phillips is the director of network trials and research center programs at the Wits Reproductive Health and HIV Institute in Johannesburg, South Africa.

An ongoing large multinational clinical trial called The Ring Study also tested the dapivirine ring for safety and efficacy in women. Similar to ASPIRE, The Ring Study investigators found an overall effectiveness of 31 percent, with a slightly greater reduction in risk of HIV infection among women older than 21 years. The results of The Ring Study also were announced today at CROI.

NIAID plans to consult with a panel of outside experts to determine next steps for research on the dapivirine ring, which the International Partnership for Microbicides (IPM) developed and provided for both studies as their regulatory sponsor.

The ASPIRE study was funded by NIAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all part of NIH, and conducted by MTN.

The Ring Study is being funded by the Bill and Melinda Gates Foundation, the U.S. President's Emergency Plan for AIDS Relief, the U.S. Agency for International Development, and several European governments and organizations, and is being conducted by IPM.

ClinicalTrials.gov using study identifier NCT01617096, and the MTN press release. For more information about The Ring Study, please see the IPM press release.

Question & Answer: 

The ASPIRE HIV Prevention Study

What was the ASPIRE study?

ASPIRE (“A Study to Prevent Infection with a Ring for Extended Use”) was a large, multinational Phase 3 clinical trial designed to test the effectiveness and extended safety of a drug-infused vaginal ring for preventing HIV infection in women. Also known as MTN-020, the trial was part of ongoing research to develop a safe, effective and desirable microbicide for women.

What are the recently announced findings of the ASPIRE study?

The study determined that a silicone ring that continuously releases the experimental antiretroviral drug dapivirine in the vagina provides partial protection against HIV infection in women.
For more information about the study results, please see the answer to question 10.

What is a microbicide?

A microbicide is a form of HIV prevention applied topically inside the vagina or rectum. Vaginal microbicides have been formulated as a ring, gel, film or suppository. No microbicide has been approved for use outside of research studies.

Who participated in the ASPIRE study?

The ASPIRE study team enrolled 2,629 HIV-uninfected women ages 18 to 45 who were sexually active but not pregnant and were at high risk for HIV infection.

Where did the ASPIRE study take place?

he ASPIRE study took place at 15 sites in Malawi, South Africa, Uganda and Zimbabwe.

When did the ASPIRE study begin and end?

The ASPIRE study began in July 2012 and data collection ended in September 2015. The study results were reported in February 2016 at the Conference on Retroviruses and Opportunistic Infections (CROI) and published online on Feb. 22 in the New England Journal of Medicine.

Who funded and sponsored the ASPIRE study?

The National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH), all part of the National Institutes of Health (NIH), funded the ASPIRE study. The clinical trial was sponsored by the International Partnership for Microbicides (IPM), which developed the dapivirine vaginal ring and provided it for the study.

Who conducted the ASPIRE study?

The ASPIRE study was conducted by the Microbicide Trials Network, which is funded by NIAID with co-funding from NIMH and NICHD.

Protocol chair Jared Baeten, M.D., Ph.D., professor of global health, medicine and epidemiology at the University of Washington in Seattle, and protocol co-chair Thesla Palanee-Phillips, Ph.D., director of network trials and research center programs at the Wits Reproductive Health and HIV Institute in Johannesburg, South Africa, led the study.

What was the study design?

Participants in the Phase 3 clinical trial were assigned at random to receive a flexible silicone ring containing either 25 mg of dapivirine or no drug (a placebo ring). Neither the participants nor the study team knew who received which type of ring until the trial ended. During participants’ monthly study visits, staff counseled the women to insert a new ring into the vagina once every 4 weeks for at least 12 months.

All study participants received a package of HIV prevention services at each study visit, including HIV risk-reduction counseling, partner HIV testing, treatment of sexually transmitted infections in participants and their partners, and free condoms. Also during study visits, the women received HIV tests, pregnancy tests and a new silicone ring. Women who became HIV-infected during the study were counseled to discontinue using the vaginal ring and were referred to local medical care and support services.

What are the results of the ASPIRE study?

The dapivirine ring reduced the risk of acquiring HIV by 27 percent among all women enrolled in the trial. When the scientists excluded data from two sites where it was apparent early on that many women were not returning for study visits or using the ring consistently, the ring reduced the risk of HIV infection by 37 percent. Both of these findings were statistically significant.

Investigators also found that the dapivirine ring reduced the risk of HIV infection by 61 percent in women ages 25 and older but provided no statistically significant protection in women younger than 25 years. These younger women appeared to use the ring less consistently than other participants, based on the amount of dapivirine measured in volunteers’ blood during study visits.

To explore this age-related effect further, investigators performed analyses that were not originally planned and found that the ring reduced the risk of HIV infection by 56 percent in women older than 21 years, but provided no protection for women ages 18 to 21 years.

Finally, the rate of adverse medical events was similar among women who received the dapivirine ring compared to those who received the placebo ring, as was the frequency of antiretroviral resistance in women who acquired HIV.

Taken together, these results indicate that the dapivirine vaginal ring safely conferred partial protection from HIV in women in sub-Saharan Africa.

These results were reported in February 2016 at the Conference on Retroviruses and Opportunistic Infections (CROI) and published online on Feb. 22 in the New England Journal of Medicine.

 

What will happen next with the dapivirine ring?

NIAID plans to consult with a panel of outside experts to determine next steps for NIH-funded research on the dapivirine ring.

Why is the ASPIRE study important?

The ASPIRE study is important because women need a discreet, long-acting HIV prevention method that they control and want to use. This would be particularly helpful in situations where it is difficult or impossible for women to refuse sex or to negotiate male condom use with their sexual partners. Women make up more than half of all people worldwide living with HIV, and in sub-Saharan Africa, women represent nearly 60 percent of all people living with the virus. In most cases, women become infected with HIV through sex with an infected male partner. Finding effective HIV prevention tools for adolescent girls and young women in particular is critical, as one in four new HIV infections in sub-Saharan Africa occur in this group.

How did the study team ensure the safety of study participants?

The safety of study participants was evaluated at multiple levels beginning with the clinical staff at each clinical research site. Clinical research teams performed thorough checks on the health and safety of participants during each study visit. Safety also was monitored by a team at the MTN statistical and data management center, which assessed incoming reports of adverse events daily, as well as by a protocol safety review team that provided monthly oversight.

In addition, an independent Data and Safety Monitoring Board (DSMB) carefully monitored participants’ safety. A DSMB is an independent group composed of clinical research experts, statisticians, ethicists and community representatives that meets periodically during a study to review safety and efficacy data as it is gathered. A statistician who is not part of the study team presents interim data to the DSMB. Because the study team is blinded to interim study data, they are excluded from portions of meetings when data are presented. The DSMB alerts the study team if anything appears to compromise the safety of study participants, if there is compelling evidence that the study intervention is effective, or if it becomes clear that the study cannot answer one of the questions it was designed to address.

What is the relationship between the ASPIRE study and The Ring Study, and what are The Ring Study’s results?

The ASPIRE study and The Ring Study are both Phase 3 clinical trials designed to test whether a silicone ring that continuously releases the experimental antiretroviral drug dapivirine in the vagina can safely and effectively prevent HIV infection. Both studies have tested the same microbicide ring developed by IPM, and both have taken place in sub-Saharan Africa. Together, the two studies enrolled more than 4,500 women.

The Ring Study investigators found an overall effectiveness of 31 percent, with a slightly greater reduction in risk of HIV infection among women older than 21 years. These results were also reported at CROI in 2016.

IPM is conducting The Ring Study, which began in 2012 and is expected to end in 2016. The study is being funded by the Bill & Melinda Gates Foundation, the U.S. President’s Emergency Plan for AIDS Relief, the U.S. Agency for International Development, and several European governments and organizations. For more information about The Ring Study, please visit the International Partnership for Microbicides website.

Why were two Phase 3 clinical trials of the dapivirine ring necessary?

Positive results from at least two Phase 3 efficacy trials usually are needed for regulatory authorities to consider approving a new pharmaceutical product for licensure. That is why the ASPIRE study and The Ring Study both were launched to test the safety and efficacy of the dapivirine ring.
More information about the ASPIRE study is available at ClinicalTrials.gov using study identifier NCT01617096.

Content last reviewed on February 22, 2016