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.

Accepting Applications for the GPP Online Training Course!

AVAC is pleased to announce the fifth offering of its global Good Participatory Practice Online Training Course!

With biomedical research moving forward at a thrilling pace, getting stakeholders involved in clinical trial conduct has never been more important. As of 2017, clinical trials are underway globally around a range of HIV prevention options—long-acting injectables and next-generation PrEP, antibody-mediated prevention, and implementation studies of the dapivirine ring—to name a few. Global rollout of oral Truvada as PrEP is shifting the field’s thinking about clinical trial design. Other advances are also grabbing headlines. Ebola research has led to a safe and effective vaccine, and research continues. New trials are on the horizon for tuberculosis drugs and vaccines.

The Good Participatory Practice (GPP) Guidelines provide a framework for engaging a broad range of stakeholders throughout the clinical trial process, increasing their understanding, commitment and participation in biomedical HIV prevention research. Through interactive modules, online forums that allow for peer-to-peer interaction, webinars and practical assignments—all facilitated by experts in GPP—the course deepens participant capacity to effectively apply GPP in their own contexts.

The course offers two tracks:

Track A is designed for research implementers, or individuals directly responsible for GPP or community engagement at a trial site. All learners who complete the requirements for Track A will receive a GPP Implementer Certificate.

Track B is designed for stakeholders not directly responsible for GPP implementation but interested in understanding GPP concepts and applications, e.g., research coordinators, civil society advocates and regulators. All learners who complete Track B requirements will receive a GPP Course Completion Certificate.

What Former Participants are Saying

To date, 100 percent of previous course participants rank the course as “excellent” or “very good” overall and the majority would recommend it to a colleague. Learners report they consider the interactive modules and facilitator feedback highly valuable. They also tell us the course gave them the tools and confidence to implement GPP. To learn more about the course overall, please click here.

“Taking this course was the best investment of my time in all of 2016. I had a fundamental and intuitive understanding of the principles on which GPP is based, but now I have a structured framework and practical tools for helping to envision and implement the next generation of research advocacy.” –Mark Hubbard, Education Liaison, Tennessee Association of People with AIDS

This course offering will run from 23 January through 28 April 2017. Download the application and submit it to GPPonlinecourse@avac.org by 18 January 2017. For more information please contact Jessica Salzwedel (Jessica@avac.org) or Stacey Hannah (Stacey@avac.org).