Refining the NIH research enterprise

Every 7 years, NIH competitively renews its funding of the HIV clinical research networks operating in the United States and internationally….By establishing a forward-looking agenda to guide this process, NIH will determine the focus and priorities through 2027. Learn more with resources available on this site, and to join the conversation, go to: https://www.niaid.nih.gov/research/HIV-Research-Enterprise.

What to Expect for CROI 2017

The annual Conference on Retroviruses and Opportunistic Infections (CROI) kicks off next week in Seattle. This year’s program covers a range of topics of interest to advocates including new data on basic science, a look at clinical trial design, planning to end the epidemic in New York, applying good participatory practices in research, understanding HIV and substance use and more.

Whether you’re en route to Seattle for the four-day meeting or following the proceedings from your favorite wifi-enabled device, this update is for you. Read on to learn more!

A few events are at the top of our list.

On Sunday, AIDS Treatment Activists Coalition, AVAC, DefeatHIV,European AIDS Treatment Group, Project Inform and Treatment Action Group are sponsoring a day-long community cure workshop. The workshop brings together educators and advocates interested in learning about HIV cure research. Attendees spend half of the day hearing from leading researchers about developments in the HIV cure field followed by a strategy session dedicated to developing and increasing advocacy around those topics. The community event is open to all but is nearing capacity. Please be in touch if you are interested in attending.

Monday’s agenda includes the Martin Delaney Presentation (12:15pm in Room 6AB), held in honor of the late HIV activist Martin Delaney. This year’s lecture will focus on Good Participatory Practice Guidelines (GPP) and include presentations from AVAC staff and partners. Through a series of discussions, presentations and feedback from participants, this panel will provide global highlights of GPP and build awareness around their significance in the research process. Please be sure to add it to your Seattle agenda!

And please join fellow advocates and activists on Wednesday night for a community reception, 6-9pm at Tap House. Download the flyer for more information.

Real-time Coverage

CROI also offers excellent webcast coverage, including live reports of the press conferences (press conference schedule available here), as well as taped playbacks. Electronic posters will be available a week after the conference and webcasts of the sessions will be archived online. Visit their electronics materials page for more.

As in years past, Medscape and aidsmap will be covering the conference with their excellent in-depth reporting across a range of research areas, including HIV prevention. And you can follow all the latest on Twitter at #CROI2017 where AVAC and others will be tweeting the latest data in 140 characters or less.

As always, please be in touch with any questions, and we look forward to seeing some of you in Seattle—and working with all of you post-CROI to plot what’s next!

NIH/NIAID/DAIDS Council-approved FY 2018 Concepts

https://www.niaid.nih.gov/grants-contracts/opportunities

Webinar: “Time to Protection” on PrEP

UPDATE: The audio and slides from the webinar are now available. Or watch the webinar on YouTube.

Daily oral PrEP using TDF/FTC provides high levels of protection against HIV in people who take the pill regularly. But this protection doesn’t happen overnight. Instead, a person needs to take a number of doses to build up protective levels of the drug in the blood.

Just how many doses?

Right now, the answer to this question is an educated guess—and the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) have different answers about “time to protection” in their respective guidelines for oral PrEP use.

Please join us for a webinar on the data behind “time to protection for PrEP” on Thursday, February 9, 11am–12:30pm US Eastern Time (visit www.timeanddate.com for the local time in your area) to learn more. This webinar will include pharmacologists who have studied drug levels in the blood and tissue of PrEP users, as well as representatives from the WHO who were involved in developing the guidance on this topic along with advocates and implementers.

Register here.

The primary difference between US CDC and WHO guidelines on time to protection relates to women. Specifically, US CDC guidelines recommend that women complete 20 doses of daily oral TDF/FTC to achieve protective levels of the drug in the vaginal tissue. WHO recommends seven days for men (penile and rectal exposure) and women (vaginal and rectal exposure).

Both of these recommendations are based on measurements of the amount of drug that accumulates in blood and/or tissue over a specific period of time. The studies of how drugs are taken into the body and how they leave the body is called “pharmacokinetics” and “pharmacodynamics” or “PK” and “PD” for short, as explained in our primer for advocates (www.avac.org/pharmacokinetics-and-pharmacodynamics). There isn’t a single PK measurement that is associated with PrEP protection—so both WHO and CDC guidelines are based on inference.

When indirect measures are used for direct conclusions, advocates need to understand the rationale. We hope this webinar will further the conversation. Please join us.

Beta version of ClinicalTrials.gov available for testing

A new beta version of ClinicalTrials.gov is available for user testing. The test site can be accessed from a link on the homepage or directly at https://clinicaltrials.gov/beta/, and will be available for at least one month to obtain feedback from the public. The new version [provides] new features to support searching for clinical studies.

Announcing the 2017 AVAC Advocacy Fellows

AVAC is delighted to announce the 2017 AVAC Advocacy Fellows—the eighth class of Fellows selected from a pool of over 100 applicants from 20 countries in Africa, Asia and the Caribbean. Please join us in congratulating these seven talented advocates:

The 2017ers will plan their projects in a busy and exciting time for HIV prevention. As we described in our recent Px Wire, there are many issues to rally around. Will more countries be able to roll out PrEP, will PrEP affect the standard of prevention of new trials? Will prevention initiatives for the growing number of young women be innovative and address their needs? Will we be able to accelerate progress towards meeting the Fast Track goals? And, where resources for sexual and reproductive health and rights may be challenged, can we work to ensure that the voices of those who have most at stake are heard?

The 2017 Fellows have bold ideas to address many of these opportunities and challenges in their Fellowship year, beginning on April 1, and we hope you’ll find ways to collaborate with them. With this incoming class, the AVAC Fellows family has grown to fifty-seven, with Advocacy Fellow Alumni from ten sub-Saharan African countries and China. Please visit the Advocacy Fellows page and follow the P-Values blog to learn more about the new Fellows’ planned work for the year and to learn about the Alumni Fellows’ ongoing work.

We thank all of the applicants and their proposed host organizations for the time and effort put into this process. We’re also grateful to the independent review committee of advocates, scientists and former Fellows and Hosts who guided the decision-making process.

A Call for Applications for the 2018 Fellows Program will be announced this June with an application deadline in August. If you would like to be notified of the 2018 Call for Applications or have any questions, please email us at [email protected].

What’s New on AVAC.org

AVAC.org has a host of new resources providing concise updates, informed perspective and handy tools. Take a look at the highlights below and get up to speed on a range of strategic issues.

New Resources

  • AVAC, in partnership with the Clinton Health Access Initiative (CHAI), is taking on new work focused on supporting innovation in the prevention “market”—including the programs that deliver new products and the pipeline of products in trials. This two-page intro to the “HIV Prevention Market Manager” gives an overview of this new body of work.
  • To get a flavor of the work the Prevention Market Manager team is focused on, check out this new resource: End-User Research Landscape Mapping and Findings. The term “end user” is used by people who work on developing and marketing products. It refers to the individual who’s ultimately going to make the decision to seek out and use a given product or intervention. This resource gives a sense of the range of efforts trying to understand what is and isn’t known about one key set of “end users” for new prevention options—adolescent girls and young women in sub-Saharan Africa.

From the Infographics Gallery

  • Introduction to Long-Acting Injectables is an updated graphic to guide you through the basics of antiretrovirals that are being developed as long-acting injectables for both treatment and prevention.

Strong Voices in P-Values

  • Progress and justice for women and girls has come under attack by the new US administration via the reinstatement and proposed expansion of the Global Gag Rule. In Standing Together Against the Global Gag Rule the AVAC team reaffirms its commitment to the fight for bodily autonomy, for justice, for choice and voice for women and girls.
  • In New and Touted HIV bNAb: Big deal or news blip?, veteran science writer and HIV journalist Mark Mascolini delves into the nuances of vaccine research using broadly neutralizing antibodies. You will learn more than just what these are; Mascolini looks at the big promises and the small print.
  • Lindsay Roth, a long-time organizer and advocate for sex workers’ rights, gives any lay reader on the subject of sex work an opportunity to gain a deeper understanding of the issues at stake in Getting Set to Defend and Advance Sex Workers’ Rights in 2017 and Beyond. Roth’s reporting shows how HIV prevention, human rights and economic justice can only succeed together.

Standing Together Against the Global Gag Rule

Wherever you live in the world, you know this to be true: there can be no progress, no justice and no hope for an end to AIDS without progress and justice for girls and women. And this holds true for all people and all “key populations” who are overburdened by the epidemic and underserved by the response, including LGBT individuals, people who use drugs, and those who are incarcerated.

Today we are writing about women. We are writing as the AVAC team to share with our allies, of all genders, that we will not cease fighting for bodily autonomy, for justice, for choice and voice for women and girls.

We are writing this now because progress and justice for women and girls came under attack this week by the new US administration via the reinstatement and proposed expansion of the Global Gag Rule, also known as the Mexico City policy.

The proposed expansion of the Gag Rule now applies to all US global health funding. This has not been enacted yet. Yet. There are many questions about how the expansion might work. We are working to find answers and are tracking the issue closely, along with a growing coalition of partners who recently issued a joint statement. We will be posting a more detailed update and set of resources on <AVAC.org in the coming week.

First created under US President Ronald Reagan, and subsequently rescinded by every Democratic president and reinstated by every Republican president since then, the Global Gag Rule has historically prohibited foreign NGOs receiving US foreign assistance for family planning from talking about, providing, referring or advocating for the legalization of abortion.

This past version of the Gag Rule affected roughly seven percent of US foreign health dollars. And even then it had a destructive impact on women’s bodies and lives. Clinics that provide comprehensive sexual and reproductive health services lost funding. They closed. A study in South Africa documented the impact: Without access to contraception, rates of unintended pregnancy and unsafe abortion went up. The Kaiser Family Foundation has produced a great overview of the policy’s history and how it has been applied in the past, and they plan to update it as more details become available.

In the meantime, we stand together. We situate women and girls’ rights in the broader context of social, economic and health justice. We recognize and stand with the many groups coming under attack from this week’s executive orders. We will stand strong and we will fight harder, smarter and without fear because we know that all of our lives depend on it.

Px Wire’s Take on 2017: #Onwards #UntilTheEpidemicIsOver

2017 promises to be a year of big changes, but how the political winds will touch the field of HIV is still unknown. Amidst the uncertainty, long hard work advancing HIV prevention is pushing frontiers all over the world from the lab to the clinic to the household medicine cabinet.

This issue of Px Wire, AVAC’s quarterly update on HIV prevention research, looks ahead at a host of issues we are watching in 2017. Are we confronting “Fast Track” goals with the sober analysis they demand? Will oral PrEP guidelines translate into programs and will programs meet people’s needs? What progress can we expect from studies on the dapivirine vaginal ring, various vaccine candidates or on broadly neutralizing antibodies, which are garnering so much press attention of late? Will global leaders embrace policies that ensure data gaps on key populations will finally be filled?

Check out AVAC’s round-up of these and other questions that we think will define the state of HIV prevention in 2017. And this issue’s centerspread extends the story beyond 2017 with an infographic showing the status of large-scale prevention trials through 2020.

New and Touted HIV bNAb: Big deal or news blip?

Fervid research has uncovered dozens of antibodies that shield cells from HIV. These broadly neutralizing antibodies (bNAbs) protect monkeys from SHIV, the simian-HIV hybrid. Thousand-person human trials are already dripping bNAbs into high-risk men and women to see if they prevent HIV infection. And much work suggests bNAbs hold promise as keys to HIV vaccine design or as immune therapy delivered by passive immunization or viral vectors.

So what inspired the media handstands proclaiming the discovery of yet another bNAb—one explored so far only in lab tests, inflating a bNAb class already studded with candidates that show potential based on their antiviral activity in lab studies? While human trials of bNAbs are underway, this newest next-generation candidate is years away from human trials. So, does the world need even one probably costly, hard-to-administer bNAb when as-needed PrEP taken consistently before and after sex or PrEP plus antiretroviral therapy for HIV-discordant couples virtually eliminate HIV transmission?

It appears so. All the fuss focused on a bNAb tagged N6, isolated from a volunteer whose immune system had 21 years to mold and remodel the antibody into a form that neutralized 98 percent of global HIV strains Mark Connors and colleagues threw at it—the most ever harnessed by a single bNAb. The diverse and exacting studies performed by this team from the National Institute of Allergy and Infectious Diseases (NIAID) and other centers offer tantalizing evidence that N6 is indeed something special.

Previously studied bNAbs, Connors and coauthors note, are either strong (stalling HIV at a relatively low dose) or broad (blocking a high proportion of tested HIV strains). None claims both distinctions—but N6 does. The new bNAb boasts sweeping breadth, thwarting 98 percent of HIV strains tested, compared with 80 percent to 90 percent neutralization with other bNAbs in this class, which targets the CD4 binding site. But the other CD4-homing bNAbs, observe Scripps researchers Devin Sok and Dennis Burton, wield only “modest potency” compared with N6’s robust median 50 percent inhibitory concentration (IC50) of 0.04 µg/mL. A few other bNAbs in different classes flex even more inhibitory muscle than N6 (median IC50 0.003 µg/mL for bNAb PGDM1400) but have narrower breadth than N6 (83 percent of isolates neutralized by PGDM1400).

bNAbs affix themselves to some stretch of the HIV envelope protein that the virus uses to snag CD4 cells. But the gene that encodes the HIV envelope mutates manically to shirk the embrace of antibodies (and vaccines designed to elicit or transport antibodies). At the same time, HIV shrouds its envelope in a sugar coat poorly recognized by antibodies. So a key measure of bNAb prowess is how well it copes with HIV’s shape-shifting mutations. And by this measure, N6 is a star. Only 4 of 181 HIV strains tested (2 percent) proved highly resistant to N6. Among 20 HIV strains resistant to other bNAbs in the same class as N6, the new bNAb neutralized 16 (80 percent).

To learn how N6 dodges HIV’s resistance defenses, Connors and crew performed a series of rigorous structural analyses showing precisely how N6 seizes HIV’s envelope loops. N6 grabs HIV the same way we grab things—with a hand, or at least something that looks like a hand. Connors’s team asks us to visualize N6 and other antibodies in this class as an index finger and thumb that pinch a sugar-coated shape-shifting part of the HIV envelope called the V5 loop. To resist other CD4 binding site antibodies, HIV warps V5 in a way that pushes away these antibodies to prevent them from binding. Crystal structure analysis showed that, compared with the index finger and thumb of VRC01 (the most-studied bNAb in this class), the finger and thumb of N6 are shorter and differ subtly in rotation and tilt. These subtle changes allow N6 to avoid wrinkles in V5 that cause resistance to other bNAbs in the VRC01 class.

Besides clutching V5, bNAbs in this class finger two other HIV envelope regions, the CD4-binding loop and another loop labeled D. The twist and tilt of N6 relative to other bNAbs make it rely less on V5 and more on loop D to grip HIV. Because loop D shifts shape much less than V5, the N6 hand grabs it more reliably and firmly from one HIV strain to the next.

VRC01, the bNAb now in large placebo-controlled trials to prevent HIV infection in men and women, must be dripped into a vein for 30 to 60 minutes every 8 weeks. Because N6 is 5 to 10 times more potent than VRC01, simpler subcutaneous shots may be possible and at longer intervals. Connors and colleagues suggest the durability of N6 may be further tweaked by mutational manipulation. Anything that simplifies delivery of a preventive or therapeutic agent boosts its chances of successful clinical use.

Autoreactivity (sometimes called self-reactivity) occurs when an agent produced by an organism (like humans) works against that organism. Although autoreactivity may be a defining feature of bNAbs, researchers agree that it represents an obstacle to inducing bNAbs and may account for their rarity in people with HIV. Connors and colleagues performed four binding studies indicating minimal autoreactivity with N6, a benefit that bNAb experts Sok and Burton suggest may favor N6 use for prophylaxis or treatment.

To learn how N6 evolved in their volunteer, Connors and coworkers sequenced B-cell antigen receptors at three times—2012, 2014, and 2015. Hints from these studies and from phylogenetic (evolutionary) analyses may give researchers vital clues to targeting diverse HIV strains with vaccines or immunotherapies. Discovering features shared by N6 and other bNAbs could inform the design of better vaccine and immunotherapy candidates.

Together these propitious traits inspired Sok and Burton to proclaim N6 the “best-in-class” among CD4-binding bNAbs. And given the breadth and brawn of N6, it may not be a stretch to call it the best bNAb period. But caution remains the catchword for any agent at this earliest stage of research. So far everything we know about N6 comes from a single, though exhaustive, 14-page paper, plus supplementary online data. From this point agents like N6 typically require further lab work and studies in animals like mice and monkeys before starting small human trials to assess their safety and find the right dose. Only then can researchers test efficacy in bigger human trials. But bNAb development moves fast these days. The much-vaunted VRC01 got discovered in 2010, its first human trial began only 3 years later, and the above-noted phase 2 efficacy trials are recruiting HIV-negative volunteers right now. Connors told P-Values that several pharma and biotech companies are already collaborating with academic partners to develop N6 for potential clinical use.

Will N6 and other bNAbs play a practical role in global HIV control? A lab study testing seven bNAbs found that the CD4-focused antibody NIH45-46W neutralized 91 percent of 45 global HIV strains. Adding PGT128, a bNAb directed at the V3 loop of HIV’s envelope, crippled 96 percent of tested HIV strains. Supplementing that two-pronged attack with PGT121, another V3 loop grabber, neutralized all HIV strains tested. Perhaps N6 combined with just one more bNAb would protect CD4 cells from all HIV-1 strains.

But right now that approach would prove impractical as a vaccination strategy because large and costly vats of bNAbs would have to be brewed, delivered to big target populations, and injected (as things stand now) every few months. A phase 2 trial of PrEP with cabotegravir, the long-acting integrase inhibitor, is testing intramuscular shots given every 4 or 8 weeks. A PrEP bNAb duo that works when injected at longer intervals would hold a clear convenience advantage over cabotegravir, but potential costs remain unknown, and we have already ventured far into the realm of speculation.