Setting the Standard: New prevention trials in the era of oral PrEP

There’s a lot going on in the world of HIV prevention research right now. The HIV vaccine field has launched a second efficacy trial—HVTN 705/HPX 2008—investigating a mosaic vaccine that could protect against clades of HIV from around the world. HPTN 084, a second trial comparing injectable cabotegravir to oral PrEP as prevention, this one among women, also recently launched across Southern and East Africa. These two trials join five other efficacy trials currently looking to expand the range of new prevention options.

At AVAC, we came out with our annual AVAC Report on December 1–our attempt at trying to untangle the mixed messages that have been circulating, and offer solutions to confront them head on.

The report touches upon an issue that has gained a lot of attention: how participants might access oral PrEP as part of HIV prevention trials. In the midst of all this activity, we thought it necessary to dive deeper into this issue. It may seem simple: trial participants have the right to the highest standard of HIV prevention and care as part of participation. Both the WHO/UNAIDS ethics guidance and the UNAIDS/AVAC Good Participatory Practice Guidelines for biomedical HIV prevention trials clearly outline this point. But the ethics, trial design issues and the mechanisms by which interventions are provided as standard of care are quite complex. Opinions differ and politics abound.

On November 2-3, the South African Medical Research Council (SAMRC) held a summit in Cape Town to discuss this very issue of standard of care in prevention and treatment trials in Southern Africa. Before the summit, members of the Vaccine Advocacy Resource Group (VARG) convened an Imbizo—a South African term for a gathering led by a traditional leader to discuss policy issues—to develop their position on what standard of care should be in prevention trials, and the role that communities and advocates should have in these decisions. AVAC attended both the Imbizo and summit to support the VARG and engage in the discussions.

The topic and tensions–and, for the most part, the players—are not new. Standard of care, and particularly when and how to integrate new interventions into the prevention package, has been discussed and debated for nearly as long as the research itself. What is new is stakeholders across prevention research coming together to reach consensus on not only the package, but on how it should be delivered. Traditionally, these conversations have been siloed. Ethicists made decisions based on their guidelines, statisticians based on trial design considerations, researchers on national context and available resources. Excitingly, there is a way forward from the summit that integrates the different interests of a broad range stakeholders. This is Good Participatory Practice in action!

The summit arrived at some concrete next steps. The SAMRC and the Fred Hutchinson Cancer Research Center (FHCRC and home of the HIV Vaccine Trials Network) will establish a trial-agnostic fund to cover the cost of oral PrEP and HIV testing for HIV prevention trial participants for the duration of the trial; trial sites and their communities will decide how to provide PrEP at their site—and this will likely look different at different sites; sites will be encouraged to work with implementing partners to optimize PrEP access and to support adherence; and South Africa researchers will work with the National Department of Health’s (NDOH) PrEP Technical Working Group to support establishment of demonstration projects closer to trial sites.

These are commendable and essential steps—and advocates, AVAC included, will be following them closely. As we continue to reflect, these are the questions and issues that remain at the fore for AVAC.

How ‘standard’ can standard of care be?

Decisions about provision of oral PrEP in clinical trials as standard of prevention, in particular, are happening as PrEP is being rolled out with great variability in the very countries in which the trials are happening. This creates operational and ethical complications—as well as exciting opportunities. Is there undue incentive if participants are offered PrEP in the trial, but PrEP is not available in the communities? Are researchers filling for the role of government—which is responsible for setting and improving the national standards of care? Within the same country, South Africa being an example, availability of PrEP can differ even between trial sites, potentially creating inequality in how participants in the same trials and in the same country get access.

The consensus from the summit is that rigid standardization is likely impossible; community and trial context have to be taken into account. Some sites do not have the capacity to provide PrEP on site, while some do. Some are close in proximity to demonstration projects and implementation sites and can create efficient linkages, while others cannot. The agreement is that trial sites, in collaboration with communities and local and national advocates, will work together to define a model of provision that ensures all participants who want PrEP can access it. This variability presents an exciting opportunity for sites to be innovative, and for the field to learn from different models of PrEP provision in real time.

But researchers, regulators and communities must also monitor execution of the PrEP plans to ensure that variation does not lead to inequality in access—and stakeholders at all levels must be linked and coordinated so there is constant learning and more efficient collaboration.

How should coordination look different moving forward?

As we move from discussion to action, partnerships are a must. Meaningful coordination will be especially critical among:

  • Advocates and researchers: Civil society is key to the HIV response at national levels. They can, and should, play a concrete role in how to connect prevention programs to trials. As both the ethical guidance and the GPP guidelines highlight, advocates and civil society should have voice in these decisions, and it was good to see that happen in the summit. True engagement, though, doesn’t just mean one meeting. It means a comprehensive, transparent plan for the ongoing role for advocates.
  • Trial sites and governments: Science does not happen in a vacuum; national policies have great impact on trial conduct, and as we have seen with HVTN’s proactive and progressive stance with regards to treatment in HIV prevention trials in 2003—researchers can also have an impact on national policy. SAMRC has committed to working with the South African National Department of Health to set up demonstration projects closer to trial sites.
  • Trial sites and local and national PrEP implementation and research activities: If PrEP cannot be provided onsite, mechanisms must be developed to connect participants to PrEP delivery programs and initiatives. Data and existing capacity from the research and implementation activities should also inform messaging and enhance counseling and adherence support.
  • National advocates and community advisory boards (CABs): To ensure PrEP plans are developed with meaningful and inclusive engagement, that CABs need to be linked to national advocacy agendas, and national advocates, in turn, to the clinical trial objectives and activities. VARG members are planning to follow up with CABs and community engagement personnel to ensure coordination and synergy across sites and communities in South Africa.
  • Regulators, ethics review bodies and funders: The decisions from the summit stand to impact trials happening across Southern and East Africa and those being implemented by multiple clinical trial networks. To promote equity and ensure adherence to core ethical and scientific values, regulators, funders and ethicists need to be coordinated across geographies and networks.

So, what?

AVAC’s position, as we outlined in our new report, is clear: while one research organization, product developer or funder cannot reverse global inequities in HIV prevention or care, researchers have an obligation—and an opportunity—to try to narrow the equity gap. Trialists must grapple with PrEP provision in clinical trials head-on; they should work with program implementers and communities to develop, implement and assess high-quality prevention and treatment models for participants in research programs, and can encourage the development of sustainable community access to good quality, comprehensive HIV prevention.

The summit was a good starting place. As advocates we will be following the implementation of the plans set out by MRC and HVTN—we will be making sure that stakeholders involved and affected by the decisions (from advocates to regulators to trial site staff) are engaged in a sustained manner, that trial sites are communicating with PrEP programs in their contexts, and that there is equity in access across trial sites and across countries.

As we anticipate how the next generation of PrEP products and other HIV prevention modalities will further complicate standard of care conversations, it is partnerships and transparency that will make research smoother and more relevant to the real-world context.

Further resources

NIH-Funded HIV Trial Networks: A family tree

This graphic provides a visual history of the DAIDS Networks and a look at what’s proposed for the next funding cycle. It appears in AVAC Report 2017: Mixed messages and how to untangle them.

Total Global HIV Prevention R&D Investment by Prevention Option, 2015–2016

This graphic shows the percentage of total global investment in HIV prevention spent on different interventions in 2015 and 2016. For much more on HIV prevention research & development funding, visit www.hivresourcetracking.org.

US HIV Research: A family tree

This graphics shows a family tree representing HIV research in the United States. It appears in AVAC Report 2017: Mixed messages and how to untangle them.

Timeline for DAIDS HIV Trials Network Recompetition

This graphic looks ahead from 2017 through 2027 at the DAIDS HIV Trials Network Recompetition process. It appears in AVAC Report 2017: Mixed messages and how to untangle them.

New HIV Prevention Trials Hold Promise for New Prevention Options for Women

Just ahead of another World AIDS Day, two new efficacy trials officially launched in Africa today with the potential of additional HIV prevention methods in the future.

The two trials – one studying a new vaccine strategy from Janssen/Johnson & Johnson that could protect against multiple strains of HIV and the other with an injectable antiretroviral PrEP strategy every two months from ViiV/GSK – join five other efficacy trials that are hoped to expand the options available to meet the varied needs women and men have for HIV prevention over the course of their lives.

“It is unprecedented to have so much diverse activity in the field, with nearly 25,000 trial participants to be enrolled across all of these trials around the world. As we commemorate World AIDS Day, it’s important to pause and be thankful for the many thousands of women and men around the world who have stepped up to volunteer for clinical trials that have given us the means to respond to this epidemic, in whose footsteps the 6,000 African women who will take part in these two new trials now follow,” said Mitchell Warren, executive director of AVAC, a global HIV prevention organization.

“Equally unprecedented is the level of pharmaceutical engagement within these trial partnerships. While both of these new trials are jointly funded by the US National Institutes of Health and the Bill & Melinda Gates Foundation, the two product developers are active financial partners,” said Warren. “We hope that the examples of ViiV and Janssen will prompt additional and sustainable industrial partnerships in HIV prevention research.”

“These new trials come at one of the most dynamic times for HIV prevention. There are more trials of new concepts; more programs beginning to deliver daily oral PrEP; a vaginal ring going through regulatory review; record numbers of people on HIV treatment; new guidelines reflecting the scientific evidence behind undetectable = untransmittable; and real-world evidence from Uganda that scaling up treatment and voluntary medical male circumcision can reduce new HIV infection at a population level,” said Warren.

This dynamism also makes the field far more complex than ever before, as these multiple signs of progress co-exist and compete for resources. Later today, AVAC will be releasing its annual “state of the field” report—Mixed Messages and How to Untangle Them—which addresses these realities. The report will be available online at www.avac.org/report2017.

“Both new trials could pave the way for valuable new long-acting prevention options—in addition to, not instead of, the interventions we have today. As the AVAC Report describes, now is the time to structure research agendas and networks, oral PrEP programs and comprehensive approaches to HIV prevention in such a way that they lay the groundwork for strategies like those being tested in these trials,” Warren said.

Press Release

New HIV Prevention Trials Hold Promise for New Prevention Options for Women

Contacts

Mitchell Warren, mitchell@avac.org, +1-914-661-1536
Kay Marshall, kay@avac.org, +1-347-249-6375

New York — Just ahead of another World AIDS Day, two new efficacy trials officially launched in Africa today with the potential of additional HIV prevention methods in the future.

The two trials – one studying a new vaccine strategy from Janssen/Johnson & Johnson that could protect against multiple strains of HIV and the other with an injectable antiretroviral PrEP strategy every two months from ViiV/GSK – join five other efficacy trials that are hoped to expand the options available to meet the varied needs women and men have for HIV prevention over the course of their lives.

“It is unprecedented to have so much diverse activity in the field, with nearly 25,000 trial participants to be enrolled across all of these trials around the world. As we commemorate World AIDS Day, it’s important to pause and be thankful for the many thousands of women and men around the world who have stepped up to volunteer for clinical trials that have given us the means to respond to this epidemic, in whose footsteps the 6,000 African women who will take part in these two new trials now follow,” said Mitchell Warren, executive director of AVAC, a global HIV prevention organization.

“Equally unprecedented is the level of pharmaceutical engagement within these trial partnerships. While both of these new trials are jointly funded by the US National Institutes of Health and the Bill & Melinda Gates Foundation, the two product developers are active financial partners,” said Warren. “We hope that the examples of ViiV and Janssen will prompt additional and sustainable industrial partnerships in HIV prevention research.”

“These new trials come at one of the most dynamic times for HIV prevention. There are more trials of new concepts; more programs beginning to deliver daily oral PrEP; a vaginal ring going through regulatory review; record numbers of people on HIV treatment; new guidelines reflecting the scientific evidence behind undetectable = untransmittable; and real-world evidence from Uganda that scaling up treatment and voluntary medical male circumcision can reduce new HIV infection at a population level,” said Warren.

This dynamism also makes the field far more complex than ever before, as these multiple signs of progress co-exist and compete for resources. Later today, AVAC will be releasing its annual “state of the field” report—Mixed Messages and How to Untangle Them—which addresses these realities. The report will be available online at www.avac.org/report2017.

“Both new trials could pave the way for valuable new long-acting prevention options—in addition to, not instead of, the interventions we have today. As the AVAC Report describes, now is the time to structure research agendas and networks, oral PrEP programs and comprehensive approaches to HIV prevention in such a way that they lay the groundwork for strategies like those being tested in these trials,” Warren said.

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About AVAC: Founded in 1995, AVAC is a non-profit organization that uses education, policy analysis, advocacy and a network of global collaborations to accelerate the ethical development and global delivery of AIDS vaccines, male circumcision, microbicides, PrEP and other emerging HIV prevention options as part of a comprehensive response to the pandemic.

Evolving Context for HIV Prevention Research (Map)

A global map showing selected HIV prevention research and oral PrEP status.

Global HIV Prevention R&D Investment by Technology Category, 2000-2016

In 2016, funding for HIV prevention R&D decreased by 3 percent (US$35 million) from the previous year, falling to US$1.17 billion. Funding in 2016 signals the lowest annual investment in HIV prevention R&D in more than a decade.

New Report: Investment trends for HIV prevention and cure R&D

It is said success breeds success. 2016 was a year of encouraging progress, indeed success, on a number of HIV prevention fronts. Two trials of the dapivirine vaginal ring showed efficacy, a spate of new vaccine and antibody trials began, and a trial of long-acting injectable PrEP launched.

Those developments are successes by any measure, and yet this year’s funding report from the Resource Tracking for HIV Prevention Research & Development Working Group (Working Group) shows that prevention funding continues to slowly decline overall. Over the same time, cure research got a big bump from global funders. A separate cure-focused brief from the Working Group, developed in partnership with the International AIDS Society (IAS), showed investment in cure research tripled since 2012.

Global HIV Prevention R&D Investment by Technology Category

Released today, the Working Group’s latest annual report on global investment in biomedical HIV prevention shows that overall funding for HIV prevention research and development (R&D) has fallen to its lowest level in a decade.

The prevention research report notes that funding for preventive vaccine research constituted the bulk of all investments, followed by investments in cure, microbicides, prevention of mother-to child transmission (PMTCT), PrEP, medical male circumcision (VMMC), treatment as prevention (TasP) and female condoms. Over half of the HIV prevention option tracked by the working group experienced a decline. These trends are somewhat reflective of the cyclical nature of large-scale clinical trials—when trials end, funding drops off. Likewise, as some interventions enter full-scale rollout, like PrEP, VMMC and TasP, research in this area can be expected to slow down. Nevertheless, the overall trends bear close watching and strong advocacy to ensure that research continues. The progress of this research in the context of flat funding should not be misconstrued. Flat funding will not get us where we need to go next.

Taking stock of all that’s been accomplished with a decade of flat funding, it’s important to note that two million people continue to be infected each year. To achieve control of the epidemic, the field must also take stock of what could be achieved with the right priorities.

The right products need to be tested in the populations who need them most, and research does not always connect well to the people who are most at risk. The report explores the demographic breakdown of almost 700,000 participants in ongoing HIV prevention trials in 2016, with the majority of these volunteers residing in sub-Saharan Africa, most notably in treatment as prevention trials in Botswana, Uganda, Kenya and South Africa. Only one in eight trial participants in 2016 belonged to a population most affected by HIV, including MSM and transgender women, injection drug users and cisgender women.

An intensifying trend towards a small number of large investors is concerning. Together, the US public sector and the Bill & Melinda Gates Foundation (BMGF) represented 88 percent of the total global investment in 2016, compared to 81 percent in 2015. Simply put, for every dollar spent on HIV prevention R&D in 2016, 88 cents came from just two donors.

On a hopeful note, global investment in research toward an HIV cure increased to US$268 million, a 33 percent increase over 2015 levels, with a number of new funders, and an expanded research portfolio at the US National Institutes of Health. The majority of investments (US$253.2 million) came from the public sector with US$13.8 million invested by philanthropies such as Aids Fonds, amfAR, CANFAR, the Bill and Melinda Gates Foundation, Sidaction and Wellcome Trust.

This is a vigorous period in research and development, reflecting a growing recognition from the global community that research has to be part of the long-term fight to end the HIV epidemic. Now is the time to support continued progress with additional, well-targeted resources.

The Resource Tracking Working Group hopes these reports will serve as tools for advocacy and be used to develop public policy that accelerates scientific progress. We thank all of the individuals who contributed data to the report and who gave time and effort as trial participants.

Check out the report, share it with your fellow advocates, and be sure to let us know if your organization is either a funder or recipient of HIV prevention grants or if you have further questions or information about resource tracking at all!