HOPE – The HIV Open-label Prevention Extension Study
What is the aim of the HOPE study?
HOPE (HIV Open-label Prevention Extension, or MTN-025) was designed to provide former ASPIRE participants the opportunity to use the dapivirine ring in the context of a study that would build on the results of ASPIRE. HOPE is collecting additional information about the ring’s safety, how women use the ring knowing that it has reduced women’s risk of HIV in theASPIRE and Ring Study Phase III trials, and the relationship between adherence and HIV prevention. HOPE also seeks to understand why some women choose not to enroll in HOPE, and why some who choose to enroll do not want to use the ring. By including all women, researchers hope to better understand why the ring may work well as an HIV prevention strategy for some but not for others, how this might change over time or in different circumstances, and what influences women’s decisions about the ring. A similar study, called DREAM, is being conducted for former participants of The Ring Study.
What exactly is the dapivirine ring?
The dapivirine ring is similar to vaginal rings commonly used for contraception except that it contains an ARV – dapivirine – instead, which gets slowly released into the vagina during the month that it is worn. Women can insert and replace the dapivirine ring themselves. Dapivirine, also known as TMC-120, belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors that bind to and disable a key protein that HIV needs to make copies of itself. IPM holds an exclusive worldwide license for dapivirine from Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), which is designed to ensure that women in low-resource settings have affordable access to any dapivirine-based microbicide.
Where is HOPE being conducted and who is leading the study?
HOPE is being conducted at 14 MTN-affliliated trial sites in Malawi, South Africa, Uganda and Zimbabwe where ASPIRE was conducted. Jared Baeten, M.D., Ph.D., of the University of Washington in Seattle, is leading HOPE, with Thesla Palanee-Phillips, MMed Sci, Ph.D., M.Sc., of the Wits Reproductive Health and HIV Institute, Johannesburg, South Africa; and Nyaradzo Mgodi, MBChB, MMed, from the University of Zimbabwe College of Health Sciences in Harare, Zimbabwe.
When did HOPE start, and when is it expected to be completed?
HOPE enrolled its first participants in August 2016 and completed formal enrollment mid-September 2017. To date, 1,432 women have enrolled. The study expects to complete all follow-up by October 2018 and report results in 2019.
How is HOPE designed?
In ASPIRE, participants were using a vaginal ring for the first time and had no knowledge of its efficacy or long-term safety, nor whether they had been randomly assigned to use the dapivirine ring or a placebo ring (that looked the same but had no active drug). In HOPE, there is no randomization and no placebo ring. All women, if they choose, receive the dapivirine ring. Women are in the study for about a year; visits are monthly for the first three months and quarterly thereafter – a schedule more in keeping with a public health service delivery model. Periodically, participants receive individual test results that reflect the amount of drug released from the ring to facilitate discussions on adherence and how it relates to protection.
Why enroll women who don’t want to use the ring?
By including all women, researchers hope to better understand why the ring may work well as an HIV prevention strategy for some but not for others, how this might change over time or in different circumstances, and what factors influence women’s decisions about the ring. All participants who join HOPE contribute valuable information to the study, including how to help women use the ring successfully in the future.
What were the results of ASPIRE?
ASPIRE enrolled 2,629 sexually active HIV-negative women ages 18-45, and was conducted between August 2012 and June 2015 at 15 clinical research sites in Malawi, Uganda, South Africa and Zimbabwe. Primary results of both ASPIRE and The Ring Study were reported in February 2016. Overall, the two studies found the ring was well-tolerated and reduced women’s risk of acquiring HIV by about 30 percent overall (by 27 percent in ASPIRE and by 31 percent in The Ring Study). In ASPIRE, HIV incidence, which represents the number of women who are newly infected for every 100 participants in a given year, was 3.3 in the group assigned to use the dapivirine ring and 4.5 among those in the placebo group. Higher levels of protection were seen in women who used the ring most consistently, and the ring was not effective among younger women ages 18-21, who used the ring least regularly. Results of an exploratory analysis of ASPIRE data reported at AIDS 2016 found the level of HIV protection for those who appeared to use the ring most consistently was at least 56 percent and as high as 75 percent or more with near perfect use.
Is the expectation that women will use the ring more consistently in HOPE?
Researchers are hopeful that women will feel more at ease about the ring in HOPE and that those who choose to accept the ring will use it as consistently as possible, knowing that its regular use may reduce their risk of HIV. In similar open-label extension studies of daily oral PrEP, adherence to product use increased, and as a result, the level of effectiveness was higher than in the original Phase III trials, in which participants did not know whether they had been assigned to use the active product or a placebo. At the same time, women in HOPE are free to choose the ring or not, and to change their minds at any time during the study, without judgement.
What have researchers learned so far in HOPE?
Preliminary results of HOPE are based on a planned interim review of study data that took place in October 2017, one month after the study had closed enrollment. At the time of the review, 1,407 former ASPIRE participants had been enrolled, and the majority (92 percent) had accepted the ring when they joined the study. The review also indicated women’s adherence to ring use was higher in HOPE than in ASPIRE, with 89 percent of returned rings indicating the ring was used at least some of the time within the last month (based on residual drug levels) compared to 77 percent seen in ASPIRE. Moreover, the interim review found the rate of new HIV infections was 1.9, considerably lower than what was seen in ASPIRE. HIV incidence, which represents the number of women who are newly infected for every 100 participants in a given year, was 3.3 in the group of ASPIRE participants assigned to use the dapivirine ring and 4.5 among those in the placebo group. Using statistical modeling based on the placebo group in ASPIRE, the researchers estimated the rate of new infections would have been 4.1 had women otherwise not been able to take part in HOPE and be offered the ring. The difference in incidence rates represents a 54 percent reduction in HIV risk. The research team reported HOPE interim results at the Conference on Retroviruses and Opportunistic Infections (CROI) in March 2018. Interim results of DREAM, which were also reported at CROI, are remarkably similar. While these findings are encouraging, they must also be considered in light of inherent limitations, such as the lack of a true placebo group in either study.
How is DREAM, the open-label access study for The Ring Study, different from or the same as HOPE?
As an open-label extension study for former participants of The Ring Study, DREAM (Dapivirine Ring Extended Access and Monitoring) is very similar to HOPE. It, too, is designed to collect additional safety information, explore when, why and how women use the ring, and to help understand how adherence may affect the product’s efficacy. DREAM began in July 2016 and has enrolled 940 women at six sites in Uganda and South Africa where The Ring Study was conducted. All women who participate in DREAM are followed for about a year. The study is expected to complete in December 2018 and report final results in 2019. Both studies are also interested in understanding why some women do not want to use the ring.
At the Trial Site
What approvals were needed to conduct the study?
HOPE underwent extensive and rigorous review by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the U.S. Food and Drug Administration (FDA). Moreover, before any site could begin the study, approvals were required of government and drug regulatory authorities in the trial site country and by the site’s Institutional Review Board (IRB) or Ethics Committee (EC). IRBs and ECs ensure that studies are scientifically valid and ethically sound and provide oversight throughout the duration of the trial.
Who may participate in HOPE?
Former ASPIRE participants could take part in HOPE provided they were not HIV-infected, pregnant or breastfeeding at the time of enrollment, and they agreed to use contraception during the study. Of the 2,629 women who were in ASPIRE, researchers estimated that about 2,400 would be eligible. Ultimately, about 1,500 of those women who could be contacted were screened for the study, and more than 1,432 have enrolled to date.
Why would some former ASPIRE participants not enroll in HOPE?
It may be that some women are not able to join HOPE because they have acquired HIV or are pregnant and/or breastfeeding. Others may have moved away or are unable to be reached by the trial site. Some women may be eligible to enroll in HOPE but choose not to. Researchers hope to understand the reasons for declining to join the study among women who agree to participate in one-time questionnaires and/or in-depth interviews.
Did women participating in HOPE provide informed consent?
Yes. As with any research study, women who volunteer to join HOPE are informed about all study procedures, possible risks and time requirements. Study staff also explain that women do not have to take part in the study and may leave it at any time, without consequence.
Is safety still being monitored in HOPE?
Results of ASPIRE and The Ring Study showed the dapivirine ring to be well-tolerated and have a strong safety profile. Nonetheless, one of the reasons for conducting HOPE is to collect additional information about the ring’s safety. In HOPE, women are monitored in much the same way as they were in ASPIRE, with routine laboratory tests, including HIV testing, and assessment of any ongoing or recent medical conditions at each study visit. Unlike ASPIRE, which involved monthly visits throughout the study, women in HOPE are seen monthly for the first three months, and then visit the clinic quarterly (every three months) thereafter. Participants with special concerns or needing more immediate attention may contact the trial site at any time.
What happens if a participant becomes HIV-positive while in HOPE?
Women in the trial who test positive for HIV stop using the ring immediately and are counseled and referred by study staff to local HIV care and support services. Women are encouraged to remain in the study and continue with routine study visits but are also invited to participate in another MTN study called MTN-015. MTN-015 does not provide HIV treatment, but offers laboratory tests indicating how the infection is progressing and how women are responding to treatment. Results from these tests may help local treatment providers better manage their clinical care.
Does HOPE provide antiretroviral therapy, or ART, to women who acquire HIV?
MTN receives funding to conduct clinical trials only, and cannot provide HIV treatment. However, all MTN trial sites are required to have agreements with local service providers so that if a study participant acquires HIV she can be referred to the appropriate services and care in her community.
Can women who are pregnant or breastfeeding use the ring in HOPE?
Researchers don’t yet know how dapivirine might affect a woman’s pregnancy or the development of her fetus, so HOPE participants must not plan to become pregnant during the study and are required to use effective contraception. If a participant becomes pregnant during the study, she will stop use of the ring, but may remain in the study and continue with all trial site visits.
The MTN recognizes the need for information about the safety of the ring in women during pregnancy and breastfeeding. As a first step, it conducted a safety study in the United States, which found only a very small amount of dapivirine is absorbed into breastmilk. Additional studies involving both pregnant and breastfeeding women are being planned to take place in Africa. If the ring is approved, its intended use will be for sexually active women ages 18-45 – women of reproductive age. Understanding its safety during pregnancy and breastfeeding will be especially important.
What are the medical benefits for women participating in HOPE?
Study participants receive free laboratory tests and physical and pelvic exams, HIV prevention counseling and free condoms. STI risk-reduction counseling, testing and treatment are also provided at no charge to women, and HIV testing and STI treatment is offered to their partners. In addition, HOPE provides effective barrier and hormonal contraception and monthly pregnancy and HIV testing. Women are referred to local service providers for ongoing treatment, management and care for any medical issues that cannot be managed at the clinical research site.
How will women be protected from HIV after they leave HOPE?
The reality is that participants live at high risk of acquiring HIV and their options for protection are limited. That is exactly why researchers are doing this work—to expand the prevention options available to women. Before exiting the study, participants will receive counseling on different HIV prevention options, including how to access certain services after they leave the study. Options may include: using condoms, using oral PrEP (if accessible), reducing their number of sexual partners, engaging in lower-risk sexual behaviors, having frequent HIV and STI testing (and receiving treatment for STIs, if infected), and encouraging their partners to be tested and treated for HIV and STIs.
Regulatory approvals, new studies and next steps
What are IPM’s plans for seeking regulatory approval of the dapivirine ring?
IPM is seeking regulatory approval of the dapivirine ring for women ages 18-45. IPM’s first application was submitted to the European Medicines Agency (EMA) in June 2017, under a procedure called Article 58 in which the EMA, in cooperation with the World Health Organization (WHO), is asked to provide a scientific opinion on the safety, efficacy and quality of the dapivirine ring for use specifically in low- and middle-income countries. Should the EMA grant a favorable opinion, IPM will then seek WHO pre-qualification. This is important because drug regulatory authorities in many developing countries often rely on WHO pre-qualification to determine which new products or drugs to consider for approval.
Separately, IPM plans to submit applications next to the South African Health Products Regulatory Authority (formerly the Medicines Control Council) and to the U.S. Food and Drug Administration (FDA). And, if WHO pre-qualification is granted, IPM will also proceed with applications to drug authorities in several African countries, including countries where ASPIRE and The Ring Study were conducted.
What is MTN’s role?
The MTN is a clinical trials network that receives its funding from the NIH for the expressed purpose of designing and conducting the kind of studies needed to support potential licensure and regulatory approval of promising HIV prevention products. In this regard, the MTN has supported the regulatory process by conducting several key studies of the dapivirine ring that are included in the dossier of data that IPM is submitting to regulatory authorities. In addition to the ASPIRE Phase III trial, these studies include those conducted in the United States: MTN-023/IPM 030, a Phase IIa safety study of the ring in adolescent girls; MTN-024/IPM 031, a Phase IIa safety study of the ring in post-menopausal women; MTN-012/IPM 010, a Phase I penile safety study of dapivirine involving sexually abstinent men; and MTN-029/ IPM039 in lactating women.
The MTN is planning additional studies of the monthly dapivirine ring, including REACH (MTN-034), which will evaluate both the ring and oral PrEP among adolescent girls and young women, and studies in breastfeeding and pregnant women (MTN-042, MTN-043), so that if approved, the ring can be considered for use by these populations of women who are particularly vulnerable to HIV.
When is a decision expected?
IPM anticipates receiving EMA’s opinion later this year (2018). If the EMA renders a positive opinion, and WHO subsequently provides pre-qualification, IPM is hopeful that the first regulatory approvals in Africa could come in 2020.
Why does it take so long?
The application, or dossier, that IPM submitted to the EMA included data from more than 250 laboratory and clinical studies, detailing nearly 15 years of research into 260,000 pages. Applications being prepared for other regulatory submissions are likely to be of similar length and complexity. Moreover, because dapivirine is a new drug, the review process may be more complex and take longer than for a drug like Truvada, which was already approved for the treatment of HIV when it was under review for use as prevention, an approach called pre-exposure prophylaxis, or PrEP.
If the ring is approved, when and where will it be available?
If the ring is approved, IPM has indicated that it would prioritize rollout in sub-Saharan Africa, where women are at the greatest risk of HIV.
How much is the ring expected to cost?
If approved, the ring would likely be publicly funded and provided to women at low or no cost, similar to other HIV prevention services.
Is there need for the dapivirine ring when PrEP is already approved in many countries?
Daily use of an ARV tablet called Truvada (oral PrEP) is an approach now approved in many countries, including in Africa, and recommended by WHO for persons at substantial HIV risk. PrEP is highly effective with consistent use. But taking a daily tablet can be challenging for some people. Others may have concerns about the stigma associated with taking an ARV pill. No single method will suit everyone, nor suit everyone at all times. As with contraception, the more HIV prevention options available to women, the more likely one will and can be used.
If approved, the monthly dapivirine ring would be the first biomedical HIV prevention product developed specifically for women – and the first long-acting product. Importantly, it would represent another option from which they may choose. Globally, more than half of all people currently living with HIV are women, and in sub-Saharan Africa, women account for nearly 60 percent of adults with HIV, with unprotected heterosexual sex the primary driver of the epidemic. Women need and deserve a range of safe and effective approaches to protect themselves against HIV.
Are other studies of the dapivirine ring being planned?
Other studies of the ring are planned, including REACH, which will enroll 300 young women ages 16-21 at five trial sites in Kenya, South Africa, Uganda and Zimbabwe. REACH (Reversing the Epidemic in Africa with Choices in HIV prevention, or MTN-034) will evaluate how young women use the monthly dapivirine vaginal ring and Truvada as daily PrEP, and their preferences for either or both approaches. The study, which will start in 2018, will also collect information on the safety of these methods in young women. This is especially important for the dapivirine ring. While IPM is seeking its regulatory approval for use by women ages 18-45, data specifically on the ring’s safety and use among women under 18 would be required if the ring will be made available to this population.
MTN researchers are also planning studies in Africa to determine whether the ring is safe to use during pregnancy (MTN-042) and breastfeeding (MTN-043), when the risk of acquiring HIV from an infected partner may be particularly high. Another study, MTN-041, will explore attitudes about ring and PrEP use during pregnancy and breastfeeding among women, male partners and community stakeholders.
What about next generation rings?
While a ring used for a month at a time may appeal to some women, others may prefer a product they replace every three months, or a ring that provides contraception in addition to protecting against HIV. Studies of these next generation rings are ongoing or planned in the U.S., including a study of a three-month ring (MTN-036/IPM 047) and studies of the dual-purpose ring (MTN-030/IPM 041, MTN-044).
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More information about HOPE and other MTN studies are available at http://www.mtnstopshiv.org/news/studies.
About the Microbicide Trials Network
The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners whose work is focused on the development and rigorous evaluation of promising microbicides – products applied inside the vagina or rectum that are intended to prevent the sexual transmission of HIV – from the earliest phases of clinical study to large-scale trials that support potential licensure of these products for widespread use. More information about the MTN is available at http://www.mtnstopshiv.org.