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eBriefing

Long-Acting HIV Prevention Methods

Long Acting HIV Prevention Methods
Reported by
Ann Griswold

Posted January 22, 2018

Overview

The development of antiretroviral drugs for HIV treatment, and in more recent years, for prevention has dramatically reduced disease burden for millions of people with access to adequate treatment and prevention programs. However, UNAIDS reports that 25 million people in Sub-Saharan Africa are still living with HIV, accounting for more than two-thirds of the infected population worldwide, and that young women (aged 15–24) in this region are disproportionately impacted. Importantly, the number of young women nearing or in this age range is currently very high, placing us at a critical juncture. Without adequate intervention and a reduction in the rate of new infections, the most likely outcome is a resurgence of the HIV epidemic.

The scientific community must develop new and effective prevention strategies to reduce HIV transmission in order to prevent this devastating outcome. Taking into consideration economic, social, and cultural barriers to current HIV prevention strategies, approaches such as long-acting therapies are a promising path forward; however key questions remain before this approach can be put to use in community settings. On September 22, 2017, the Bill & Melinda Gates Foundation and the Academy’s Microbiology and Infectious Diseases Discussion Group gathered scientists, policy makers, and community leaders to address current scientific barriers to development of long-acting prevention methods for HIV.

Speakers

Long Acting HIV Prevention Methods
Emilio Emini, PhD, The Bill & Melinda Gates Foundation
Long Acting HIV Prevention Methods
Mitchell Warren, AVAC
Long Acting HIV Prevention Methods
Alex Rinehart, PhD, ViiV Healthcare
Long Acting HIV Prevention Methods
Trevor Hawkins, MD, Gilead
Long Acting HIV Prevention Methods
Zeda Rosenberg, ScD, International Partnership for Microbicides
Long Acting HIV Prevention Methods
Tom Hope, PhD, Feinberg School of Medicine, Northwestern University
Long Acting HIV Prevention Methods
Nitin Joshi, PhD, Massachusetts Institute of Technology
Long Acting HIV Prevention Methods
Marina Caskey, MD, The Rockefeller University
Long Acting HIV Prevention Methods
Bruce Kerwin, PhD, Just Biotherapeutics

Presented by

Introduction

Despite generous funding from domestic and international donors, nearly 40 million people are infected with HIV—and only about half of them are receiving antiretroviral treatment. Scientists have identified several HIV prevention strategies over the past three decades, ranging from condoms to antiretroviral drugs. However, with 2 million new cases per year, stronger HIV prevention efforts are needed.

Toward this goal, the Bill & Melinda Gates Foundation has accelerated efforts to curb new infections in eastern and southern Africa, which accounts for 43% of the global total of new HIV infections. Some of the biggest challenges are reaching people who are infected but not being treated; reaching high-risk groups, including young people aged 15–24; and finding drugs that are stable in extreme temperatures, not prone to resistance, and effective against multiple viral strains.

Prevention efforts must overcome the stigma associated with HIV, provide increased access to healthcare and education, and improve adherence to existing methods. Among young people aged 15–24, especially, a cultural shift is needed from promoting risk reduction and changing perception to understanding what people want and need. A strategic agenda could bring together commercial drug manufacturers and suppliers with an advisory committee of stakeholders, and promote more effective planning and implementation at the national level. This agenda could also create a demand for HIV prevention tools through public affairs, policy, and communications.

Novel drug delivery technologies may drive the development of long-lasting targeted drugs. A removable implant is being used to deliver tenofovir alafenamide (TAF) and cabotegravir (CAB) to allow for slow, controlled release of the drugs. New encapsulation techniques are being used to embed TAF into fibers of biodegradeable molecules through self-assembly, extending their stability. Luciferase is being used to label and track the movement of HIV under various drug interventions to identify gaps in prevention methods.

Researchers are also developing novel small molecule prevention interventions. One of these is Cabotegravir Long-Acting, an integrase inhibitor that has low solubility and a long half-life, is stable for three years at room temperature, and does not require cold chain storage. Another is GS-CA1, which inhibits the development of the viral capsid and prevents movement of nuclear material into cells. MK-8591 (EFdA) is a nucleoside translocation and excision inhibitor that inhibits reverse transcription and can prevent drug resistance. The 30-day dapivirine ring may support adherence for those who find daily methods a challenge. The ring has a five-year shelf life and is inexpensive to manufacture.

Novel biological interventions, such as antibodies, may help fill prevention gaps. The potential use of antibodies for HIV prevention was first described in 2009; less than a decade later, clinical trials are underway. Studies reveal that a single antibody is not sufficient to cover a range of HIV strains or have a long enough half-life, so researchers are exploring combinations of antibodies. Engineering will likely be needed to respond to resistant strains of HIV. To succeed on the market, antibodies must safely target 98%–100% of HIV strains, have a half-life of 3–4 months at a low dose, and cost less than $50 per year, per person.

Session 1: The Challenge of Effective Anti-HIV Biomedical Prevention

Speakers

Highlights

  • The UNAIDS 90-90-90 goal is inadequate; greater efforts are needed.
  • Creating a demand for HIV prevention tools can expedite prevention efforts.

Control of the HIV Epidemic: The Challenges and the Potential for Failure

Emilio Emini, of the Bill & Melinda Gates Foundation, called for greater efforts to develop a long-acting prophylactic for HIV. Prevention programs have significantly reduced the incidence of neonatal HIV, but Emini cautioned against declaring success just yet. Despite generous funding from domestic and international sources, nearly 40 million people around the world remain infected—and only half of these individuals are undergoing antiretroviral treatment. Emini noted the limitations of defining success in terms of the UNAIDS 90-90-90 goal (i.e., identifying 90% of HIV-infected individuals, treating 90%of those identified, and reaching full suppression in 90% of those treated). If successful, this strategy would reach only 75% of those infected, leaving a big gap and potential viral reservoir. With 2 million new cases around the world each year, greater efforts are needed.

UNAIDS 90-90-90 HIV testing and care continuum

UNAIDS 90-90-90 HIV testing and care continuum

The Foundation aims to reduce the incidence of HIV infection in eastern and southern Africa, where nearly half of all HIV infections exist. Although HIV-related deaths have decreased by 40% over the past 6 years, 750,000 people still become infected every year, and 60% of them are women and girls. The problem is the cycle of infection, Emini says. An estimated half of infected men in their 20s are not aware that they have HIV, and infect young women during sex.

The cycle of HIV infection in African women and men

The cycle of HIV infection in African women and men

These infected women are more likely to be identified than the men who infected them. That’s because as these women age, many become pregnant and visit healthcare facilities, where they are diagnosed and receive antiretroviral treatment. Men, however, have limited access to healthcare systems and continue to infect others in their communities. Young people ranging from 15 to 24 years old are at the highest risk of infection. Because this population has grown considerably, Emilio says, “We will have more people living with HIV 15 years from now than we had 15 years ago.”

The HIV community will need to address several key challenges for HIV in Africa, Emini says. For example, an effective vaccine could curb the virus at childbirth and a cure could halt the need for long-term treatment. It is also crucial to study the high-risk age group in more detail, by gathering regional epidemic and transmission characteristics, background prevalence, stigmas, and rates of transactional sex. Lastly, there’s a need to provide programs and services to prevent HIV, such as voluntary circumcision and other strategies that reach beyond active prophylactic options like condoms and oral contraceptives that can be forgotten in the moment.

Learnings from the Use of Currently Available Biomedical Interventions

Mitchell Warren, of AVAC, emphasized that despite recent strides in local infection control, the HIV community has not yet reached the finish line. Toward this end, AVAC invests in the three-pronged approach of delivering, demonstrating and developing strategies for curbing infection. Warren states, “We have never, in 35 years of the epidemic, had as robust a pipeline in clinical trials, let alone, early product development.”

Menu of HIV prevention products under development

Menu of HIV prevention products under development

The HIV community may find inspiration in stories of the painstaking translation of other health-related products such as the tampon, which took 20 years to move from concept to market. Voluntary medical male circumcision (VMMC), for example, did not become popular until a decade after its introduction, when a toolkit was created to stimulate demand. Oral PrEP, too, took a while to gain momentum. Some experts initially worried that PrEP would discourage condom use, but that appeared not to be the case. Studies soon showed a 96%–97% efficacy rate among gay men and the product was recommended by the World Health Organization (WHO). The big shift, though, occurred in 2015 when Kaiser Permanente California reported that none of the men taking PrEP became infected with HIV.

These stories reveal four take-home lessons for HIV prevention, Warren says. First, remember that clinical trials are not the same as real life; rather, these studies reveal more about how people feel about the trial than they reveal about the actual products. Second, focus on what people actually want and need rather than focusing solely on risk perception. Third, create a demand for products and go big with investment, rather than focusing on small demonstrations. Lastly, take time early on to build a toolbox of strategies to engage people, peers, providers, partners, and policymakers in HIV prevention.

Speaker Presentations

Controlling the HIV Epidemic: The Challenges and the Potential for Failure


Emilio Emini (The Bill and Melinda Gates Foundation)

What's New; What's Next: Learning from Current Interventions to Inform the Future


Mitchell Warren (AVAC)

Session 2: Novel Small Molecule Prevention Interventions

Speakers

Highlights

  • Several potential HIV therapies are in the commercialization pipeline: CAB LA, TAF, GS-CA1 and MK-8591 (EFdA), and the monthly dapivirine ring.
  • The next step is ensuring that these drugs are safe, accessible, and affordable.

Cabotegravir Long-Acting (CAB LA) Intramuscular Injectable Suspension: A New Candidate for HIV Prevention

Alex Rinehart, of ViiV Healthcare, highlighted key features of Cabotegravir Long-Acting (CAB LA) suspension that make it a potentially useful drug for HIV prevention and HIV treatment (in combination with a long-acting injectable suspension of rilpivirine). CAB LA is an injectable integrase inhibitor with low solubility, a long half-life, a three-year shelf life at room temperature, and no requirement for cold chain storage. The drug has also shown evidence for potent anti-HIV activity and a high barrier to resistance. Rinehart highlighted the results of two CAB LA Phase 2a studies in low-risk, HIV-uninfected patients that had similar designs: one with men (ECLAIR) and one with men and women (HPTN 077).

Menu of HIV prevention products under development

Menu of HIV prevention products under development

The ECLAIR study showed a faster decline in plasma levels than had been predicted, with absorption rates halved in males with the highest BMIs compared to those with lower BMIs. The injectable was generally well tolerated in both studies, with very few discontinuations due to injection site reactions. For both men and women, the Phase II studies revealed that a 600-mg dose every 8 weeks was more effective than the 800-mg dose every 12 weeks at achieving steady state trough and IC90 target levels.

These studies have given way to a pair of ongoing Phase III prevention efficacy trials. The first trial, HPTN 083, is a double blind, double dummy international, non-inferiority study of high-risk, uninfected men who have sex with men and transgender women. Participants will receive either a single, active CAB injection every 8 weeks and an inactive tenofovir disoproxil fumarate/emtricitabine pill every day or a single, inactive CAB injection every 8 weeks and an active tenofovir disoproxil fumarate/emtricitabine pill every day. The second trial, HPTN 084, is a superiority trial with a similar design as HPTN 083 that includes at-risk, uninfected women in seven sub-Saharan African countries. Rinehart emphasized that these studies may not yield results for some time, but will hopefully lead to a product that could offer an additional viable choice for HIV Prevention.

Promising Single Agent ARVs for Prevention

Trevor Hawkins, from Gilead, brought the audience up to speed on three HIV prevention agents: TAF, GS-CA1, and MK-8591 (EFdA). The first agent, TAF, is a useful prodrug that aids absorption of Tenofovir. Studies suggest that TAF is less likely to cause renal toxicity and has greater plasma stability than the traditional prodrug TDF.

Plasma stability and mechanisms of action for TDF and TAF

Plasma stability and mechanisms of action for TDF and TAF

The DISCOVER study is underway to compare oral TAF with Tenofovir in 5,400 participants.

The second agent, GS-CA1, is an extremely potent and fairly stable inhibitor that will move into clinical trials next year. This drug inhibits the development of the viral capsid and prevents movement of nuclear material into cells. It sidesteps the issue of viral mutations that faces existing drugs, can be administered in a low dose with a low injection volume, and has low aqueous solubility. The challenge is getting GS-CA1 into a low-dose tablet.

The third agent, MK-8591 (EFdA), is a nucleoside translocation inhibitor that offers broad coverage for a number of HIV viruses. It prevented HIV infection for 180 days in rats. Monkeys with EFdA did not become infected with HIV when exposed, nor did they develop virus-specific antibody responses.

Hawkins advocates for an a la carte menu, noting implants should last for at least one year. He states that TAF is the most promising agent, while GS-CA1 could be used for subcutaneous injection, and EFdA is highly active against a number of resistant mutants.

Dapivirine Ring: Clinical Data and Delivery Plans

Zeda Rosenberg, from the International Partnership for Microbicides (IPM), gave an update on the status of the dapivirine ring. The simple technology—a silicone ring that slowly releases the antiretroviral drug dapivirine over a 30-day period—was the first long-acting method to reduce the risk of HIV in Phase III trials. The ring may support adherence if daily methods are a challenge, is stable for five years, and can be inexpensively manufactured. Two Phase III trials, IPM 027 (The Ring Study) and MTN-020 (ASPIRE), showed a 27%–31% overall efficacy rate and strong safety profile among 4,500 participants at 22 sites in sub-Saharan Africa. Greater risk reduction (45%) was seen among women who used the ring at least some of the time. No risk reduction was seen in women under age 21, likely due to low product use. Additional studies have assessed drug-drug interactions, the ring’s pharmacokinetic profile, condom function while using the ring, and safety in adolescents and post-menopausal women. Open-label extension studies called DREAM and HOPE are underway to provide the ring to former Phase III participants; and another planned study called REACH, will assess young women’s use of and preferences for the monthly ring and daily oral PrEP.

The ring is now under regulatory review. To expand affordable access to the ring, if approved, IPM is collaborating with its manufacturing partner QPharma; Johnson and Johnson, which granted IPM exclusive rights to the drug; donors and implementing organizations; an access advisory committee; and other key stakeholders. IPM is also developing a three-month dapivirine-only ring, which may reduce annual costs and increase convenience, as well as a three-month dapivirine-contraceptive ring designed to simultaneously prevent HIV and unintended pregnancy.

Phase III Pooled Results

Phase III Pooled Results

Speaker Presentations

Cabotegravir Long-Acting (CAB LA) Intramuscular Injectable Suspension: A New Candidate for HIV Prevention


Alex Rinehart (ViiV Healthcare)

Promising Single Agents for Long Acting HIV Prevention


Trevor Hawkins (Gilead)

Dapivirine Ring: Clinical Data and Delivery Plans


Zeda Rosenberg (International Partnership for Microbicides)

Session 3: Drug Delivery Technologies

Speakers

Nitin Joshi

Massachusetts Institute of Technology

Highlights

  • Injectables are challenging because they must be delivered during a specific window of viral sensitivity.
  • Implants are challenging because of hydrophobicity and other chemical issues.
  • HIV retreats to certain body tissues during specific types of treatments.

Challenges of Developing Sustained Release Formulations of Antiretrovirals for PrEP

Tom Hope, of the Feinberg School of Medicine at Northwestern University, began by noting that antiretroviral therapies (ARTs) should ideally provide an individual with one year of protection against HIV. This was the rationale behind creating SLAP-HIV. At the start of the work, there were only two potentially long-acting ARTs: TAF and CAB. Then the NIH organized the SLAP-HIV design competition, which challenged researchers to develop longer-acting ARTs. The three competitors were injectable TAF, biodegradable implants, and a removable implant for delivering TAF and CAB. The winner, the removable implant, would then go to phase I trials.

Hope explained the pros and cons of each therapeutic approach. The injectable is challenging, he says, because researchers must mix different formulations together to fill gaps during windows of virus sensitivity. This makes it difficult to get the bulk material into an injectable product. For the biodegradable implant, Hope explained, “We can treat a beaker…but when we put it in an animal, things behave differently.” The biodegradable implant could be a good backup plan, he notes. The winner, the removable implant, was comprised of a sealed tube with slow-release pellets inside. But a complication arose: TAF and CAB are hydrophobic, so pressure builds on the end caps of the tubes and eventually pops them off like a cork from a bottle. Researchers eventually found a better way to seal the tubes. The advantage of the implant is that once the polymer and release rates are figured out, the tube can easily be changed to accommodate the best number of pellets.

Hope then described the challenges of PrEP. While the HIV community considers IC 90 a goal, 10% of the drug cannot stop the virus. He then set out to understand where the virus disappears to during clinical trials. Hope’s lab uses luciferase as a viral tracking device, allowing scientists to track transmission by zooming into tissues and detecting the glowing HIV viruses. “We are mapping susceptibility of the organ for the virus to get through the barrier,” Hope notes.

TFV Levels, Luciferase, and PCR results in IVR treated animals

TFV Levels, Luciferase, and PCR results in IVR treated animals

Using this approach, his group detected HIV in the upper reproductive system and ovaries, even with the IVR. With this information in hand, his lab has begun tracking the virus in people using the IVR and oral PrEP. With the IVR, infected cells took cover in the uterus; with the oral PrEP, 90%–95% of cells were not infected. It appears that the ring protects against HIV infection where it is placed, but if the virus breaks through the drug wall of the ring, it can move into the upper reproductive system. On the other hand, oral PrEP produces the “herd effect” seen in vaccines where most of the cells cannot be infected and because of this, viral spread is difficult.

Self-Assembled Hydrogels as Long-Acting Injectables

Nitin Joshi, an Instructor with Jeff Karp at Harvard Medical School, noted that Karp Lab has spent the past seven years developing long-acting injectables, but mostly for inflammation-related disorders. With support from the Bill and Melinda Gates Foundation, Joshi and Karp have focused on TAF. They aim to build a long-acting injectable form that does not have an initial burst or prolonged PK tail, is shelf stable, cost-effective, easy to use and easy to scale up for manufacturing.

At the start, they needed to overcome the challenge of weak hydrophobicity in TAF. The Karp group reviewed the FDA’s Generally Recognized as Safe chemicals (GRAS) for small molecules that are amphiphilic in nature with hydrophobic tail and hydrophilic head and enzyme cleavable part. Through this process they developed a library of 20 molecules.

Target molecule characteristics to combine with TAF

Target molecule characteristics to combine with TAF

Karp’s group then developed a process for the selected GRAS molecules to self-assemble as injectable gels. As they assemble, their fibers tangle together and encapsulate the therapeutics inside. As the fibers break down, the enzyme degradation slowly releases the drug.

Fibers of GRAS molecule woven together to encapsulate drug

Fibers of GRAS molecule woven together to encapsulate drug

This process has worked for a range of drugs with locally targeted effects, such as treating ulcers and arthritis. These self-assembled gels can address a number of the goals of the study such as long-term stability; cost effectiveness; simple and scalable manufacturing; sustained concentrations; and biodegradability. To maximize the concentration of TAF in the gel, Karp's group mixed the GRAS amphiphile with larger TAF, then with oil, to create an organogel or hydrogel. There are now 20 formulations that encapsulate at 180-360 mg in 2 mls of gel. The fiber capsule also protects TAF from degradation for up to two weeks, which is one week longer than without encapsulation. This work is now transitioning to in vitro release with the goal of in vivo release in dogs and rats.

Speaker Presentations

Challenges of Developing Sustained Release Formulations of Antiretrovirals for PrEP


Tom Hope (Feinberg School of Medicine, Northwestern University)

Further Readings

Tom Hope

Spreen WR, Margolis DA, Pottage JC Jr.

Curr Opin HIV AIDS; 2013; 8:565-571.

Andrews CD, Spreen WR, Mohri H, et al.

Curr Opin HIV AIDS; 2013; 8:565-571.

Fowers K.

ReGel Hydrogels for In Vivo Applications.

In Polymeric and Self Assembled Hydrogels. The Royal Society of Chemistry.

Liu J, Ghneim K, Ghneim K, Sok D, et al.

Science. 2016;353(6303):1045-1049.

Kiser PF, Johnson TJ, Clark JT.

AIDS Rev. 2012;14(1):62–77.

Stieh DJ, Matias E, Xu H, et al.

Cell Host & Microbe. 2016; 19(4):529-40.

Session 4: Novel Biological Interventions

Speakers

Highlights

  • Single antibodies rarely cover a sufficient range of HIV strains or have a long enough half-life to serve as effective therapies.
  • Antibody combinations can be safely used to increase therapy half-life and extend effectiveness.
  • Manufacturing optimization may be necessary to overcome the instability seen in antibody combinations.

Broadly Neutralizing Antibodies for HIV Prevention

Marina Caskey of Rockefeller University is studying two antibodies, NC117 and 10-1074, as potential components of a vaccine that safely inhibits HIV with at least 90% coverage. Marina initiated side-by-side studies of 3BNC117 and 10-1074 for the first time in humans. Her findings revealed that the antibodies are safe. However, the antibodies have a half-life of 2–3 weeks, after which time viral loads increase. Viral resistance was found in both studies, but combining the antibodies somewhat staunched the spread of resistance.

Caskey’s group explored whether antibodies can provide an alternative to antiretroviral therapy. She found that people who received antiretroviral therapy without the antibody rebounded in 2–3 weeks, while those who received VRC01 after retroviral therapy rebounded in 4 weeks. The rebound was delayed to 8 weeks in people who received 3BNC117 after retroviral therapy, however. Further study revealed a possible reason for the disparity: two-thirds of the participants showed a pre-existing sensitivity to 3BNC117, while only one-third of the participants showed pre-existing sensitivity to VRC01.

In another study, Caskey found that viruses derived from patient peripheral blood mononuclear cells were less sensitive to five different antibodies, including 3BNC117 and 10-1074, than published pseudovirus panels. “We think that perhaps the pseudovirus panels that were originally used to characterize the antibodies may overestimate breadth and potency of different bNAbs against circulating viruses. This might have implications when thinking of dosing regimens for future studies,” she says.

Comparison of IC50 curves for original published pseudovirus panels with viruses derived from patient PBMC samples

Comparison of IC50 curves for original published pseudovirus panels with viruses derived from patient PBMC samples

Caskey is now performing phase I studies with NC117 and 10-1074 in 44 HIV-positive participants. The antibody combinations show similar safety and efficacy as the individual antibodies, she says, suggesting that the antibodies do not interfere with each other. Furthermore, engineering an antibody to carry a LS mutation, which alters FcRn affinity, can delay infection after HIV exposure by 16 weeks for NC117, and up to 27 weeks for 10-1074. Delivered in combination, the LS-carrying antibodies can delay infection for 5 months. Such a strategy could provide a 4–6 month window for administration of low-dose antibodies. Clinical trials are now underway to evaluate the safety and pharmacokinetics of LS mutations.

Optimizing bNAbs for Manufacturability and Stability

Bruce Kerwin of Just Biotherapeutics described the challenge of commercializing antibodies in a way that ensures affordability for individuals at the highest risk of HIV. Ideally, the drugs should cost less than $20 per gram for a 3 mg/kg dose. Currently, they cost $150–$200 per gram, based on the drug’s concentration. To cut costs, Just Biotherapeutics is engineering new antibodies and developing less expensive manufacturing plants. Kerwin believes that their process can reduce costs to $40 per gram. As more patients are added, the cost could drop further, so long as bioreactors could produce 2–3 grams per liter, per day.

Drug stability remains a concern, however. Drugs may need to be stored in places like sub-Saharan Africa, where electricity is not available and temperatures reach beyond 100 degrees Fahrenheit. Most drugs break down in these conditions, particularly those carrying mutations such as LS. Just Biotherapeutics used a novel screening strategy to identify 26 amino acid residues that influence antibody stability. They’ve tested these antibodies to assess aggregation, pH, and thermal stability during the production process. This approach has improved antibody stability at low pH stability, increased the speed and robustness of viral inactivation, and improved thermal stability for storage by six-fold.

Biophysical analysis of variants is used for evaluating potential behavior during production and storage

Biophysical analysis of variants is used for evaluating potential behavior during production and storage

Speaker Presentations

Broadly Neutralizing Antibodies for Prevention


Marina Caskey (The Rockefeller University)

Further Readings

Marina Caskey

Nishimura Y, Gautam R, Chun TW, et al.

Nature. 2017;543(7646):559-563.

Caskey M, Schoofs T, Gruell H, et al.

Nat Med. 2017;23(2):185-191.

Scheid JF, Horwitz JA, Bar-On Y, et al.

Nature. 2016;535(7613):556-60.

Bar KJ, Sneller MC, Harrison LJ, et al.

N Engl J Med. 2016;375(21):2037-2050.

Gristick HB, von Boehmer L, West AP Jr, et al.

Nat Struct Mol Biol. 2016;23(10):906-915.

Open Questions
  • How will scientists, policy makers, and community leaders address the need to reach high-risk young people, aged 15–24?

  • How can scientists and researchers bridge the gap between clinical trial results and real-life product use?

  • Which social science questions and approaches can help researchers understand what people want, so that products are successfully delivered to and used by individuals with HIV? How can these strategies be accelerated?

  • How can the research community work with unknown endpoints? Will resistance develop? Will people remain engaged?

  • How can formulations best deliver multiple drugs in a compact format?

  • What is the meaning of the pharmacokinetic tail, and is it important?

  • Which combination of drugs or antibodies offer the greatest protection and lowest potential for resistance?

  • Which species of HIV should be used in macaques?