February 17, 2022

CROI 2022 - Day Three Summaries

Dear HIV Research Community,

Courtesy of the CFAR leadership, we send you a short summary of notable abstracts from the third day of the Virtual CROI 2022 conference, February 16, 2022. Please note that this summary is by no means meant to be a comprehensive overview of everything presented at CROI 2022, but a highlight from today with a focus on presentations from CFAR-affiliated investigators. Thank you to Rand Dadasovich, MD for his contributions to the summaries!

Thank you!

CFAR Leadership

Clinical Plenary

NEW ANTIRETROVIRALS AND THE FUTURE OF HIV TREATMENT AND PREVENTION

Chloe Orkin, Physician and Professor of HIV/AIDS medicine, Queen Mary University of London.

Dr. Orkin gave a stellar talk on the future of HIV treatment and prevention, mainly discussing long-acting agents as the next frontier.  She started out with a statement on how “radical protest and disruption” in HIV drove this incredible progress over the past 40 years.  

She then went on to describe the progress mostly in long-acting treatment and prevention, with a nice layout of all the prevention and treatment options which are coming in the slide below. 

Dr. Orkin then discussed long-acting cabotegravir and rilpivirine with summaries of efficacy, adverse effects, virologic failure, resistance and the increasing evidence that the oral lead-in period is not necessary.  

Since the CALIBRATE study was discussed at this meeting (summarized in last CFAR dispatch), Dr. Orkin then went on to describe the lenacapavir treatment naïve study which showed a high response rate of all 4 arms, including the ones that included lenacapavir subcutaneous every 6 months out to week 54. 

Dr. Orkin then described the studies coming up of the long-acting PrEP studies with lenacapavir (PURPOSE 1 and PURPOSE 2)

She reminded us that islatravir long-acting trials were on hold due to a lowering of white blood cell counts seen in the treatment and prevention trials to date, ending with the top barriers to implementation for long-acting agents summarized by health care providers and ideal recipients. 

S12-OA135: DOLUTEGRAVIR WITH RECYCLED nRTIs IS NONINFERIOR TO PI-BASED ART: VISEND  

In this oral abstract, Dr. Lloyd Mulenga of University Teaching Hospital in Zambia presented 48-week results of the VISEND trial, a randomized, open-label, phase 3 noninferiority trial in Zambia of  HIV-positive adults with virologic failure who were switched from an NNRTI-based regimen to DTG-based regimens while maintaining an NRTI backbone. 

Participants were stratified into two randomization arms based on initial viral load. In Arm A, adults with VL <1,000 copies/mL were randomized to TDF/3TC/DTG vs. TAF/FTC/DTG. In Arm B, those with VL ≧1000 copies/mL were randomized to TDF/3TC/DTG vs. TAF/FTC/DTG vs. (LPV/r or ATV/r)/ZVD/3TC. Primary end point was VL <1,000 copies /mL at week 48. Of 1201 randomized adults, 88% adults in Arm A treated with TDF/3TC/DTG maintained virologic suppression compared to 87% for TAF/FTC/DTG [difference, -0.5%, 95% CI -6.9 - 5.9]. In Arm B, 82% TDF/3TC/DTG-treated adults achieved VS, compared to 87% for TAF/FTC/DTG and 76% for 3TC/ZDV/PI/r. At 48-weeks, TAF/FTC/DTG was non-inferior to TDF/3TC/DTG for participants with VL <1000, though TAF/FTC/DTG was associated with higher weight gain. 

For participants with baseline VL >1000 copies/mL, TAF/FTC/DTG was non-inferior to TDF/3TC/DTG at 48-weeks. TAF/FTC/DTG and TDF/3TC/DTG were both superior to the PI-based regimens. TAF/FTC/DTG was associated with higher weight gain among female participants with baseline VL >1000 but less weight gain in male participants compared to TDF/3TC/DTG.  

S12-OA136: A RANDOMIZED TRIAL OF SWITCHING TREATMENT-EXPERIENCED ADULTS FROM PI/r TO DTG

In this oral abstract, Dr. Loice Ombajo from the University of Nairobi presented data from the Second-line Switch to DTG (2SD) study, a switch study of suppressed adults in Kenya from a second-line protease-inhibitor-based regimen to a dolutegravir-based regimen. This study evaluated the efficacy and safety of switching virally suppressed adults from a second-line PI/r-containing regimen to a DTG-containing regimen without prior drug resistance testing. Eligible participants were HIV-1 infected adults (≥ 18 years) who were virally suppressed (VL < 50 copies/mL) for at least 12 weeks prior to enrolment and on a second-line regimen of PI/r + 2 NRTIs for at least 24 weeks, and without prior integrase inhibitor exposure. About 800 participants were randomized (1:1) to switch to DTG or continue their pre-enrollment PI/r; pre-enrollment NRTIs were continued in both arms. At week 48, the proportion of participants with HIV-1 RNA ≥ 50 copies/mL was 5.0% (20/397) in the DTG arm and 5.1% (20/394) in the PI/r arm (treatment difference [95% confidence interval], -0.04% [-3.09 to 3.02]), meeting non-inferiority criteria. No participants with protocol-defined virological failure had detectable genotypic resistance to the study drug at time of failure in either arm. Switching from PI/r to DTG may be an effective and safe strategy for treatment-experienced virally suppressed adults with no prior INSTI-exposure, even without resistance testing. 

S12-OA137: NUCLEOSIDES AND DARUNAVIR/DOLUTEGRAVIR IN AFRICA (NADIA) TRIAL: WEEK 96 RESULTS

Dr. Nicholas Paton from National University of Singapore presented 96-week data from the NADIA trial, a study evaluating second-line ART in adults failing NNRTI + 2 NRTIs across sub-Saharan Africa. 464 participants were randomized to DTG vs. DRV/r arms, and then further randomized by NRTI backbone: continuing TDF/3TC vs. switching to ZDV/3TC. Similar to 48-week outcomes shared last year, 96-week outcomes showed high rates of virologic suppression and non-inferiority of DTG compared to DRV/r even with a high prevalence of baseline NRTI resistance (K65R was observed in roughly half of all participants, M184V in 87%). Five more cases of virologic failure with emergent DTG RAMs were reported, bringing the total to 9. Of note, 6 of the 9 cases of emergent dolutegravir RAMs occurred in those whose NRTI backbone was switched from TDF/3TC to ZDV/3TC, an interesting observation that supports prior in vitro data showing that NRTI RAMs may protect against dolutegravir resistance. Importantly, no darunavir RAMs were observed in the darunavir group, a finding that may support a preference for a darunavir-based regimen over dolutegravir as second-line ART. There were lower rates of virological failure and rebound in the group that continued a TDF/3TC backbone compared to those that switched to ZDV/3TC; this finding conflicts with the current WHO recommendations for second-line NRTI therapy.  

S11-OA133: ACTG A5324: A RANDOMIZED TRIAL OF ART INTENSIFICATION FOR COGNITIVE IMPAIRMENT IN PWH

Scott Letendre from UCSD presented negative data from a study of ART intensification among virologically-suppressed patients with HIV and neurocognitive impairment as measured through neuropsychiatric testing. Patient were randomized to add dolutegravir + maraviroc, dolutegravir + placebo, or dual placebo in addition to continuing their background ART regimen. Repeat neuropsychiatric testing was performed at weeks 24, 48, 72, and 96. 191 patients were enrolled (80% from the U.S.) 

The primary outcome was change in neuropsychiatric testing performance from baseline at week 48. Secondary outcomes included HIV VL, CD4 and CD8 cell count, depressive symptoms, and blood and CSF biomarkers, analysis of which is ongoing. Participants in all groups showed improvement in cognitive performance, consistent with a practice effect, however ART intensification with DTG + maraviroc or DTG alone did not alter neuropsychiatric testing performance or depressive symptoms over time. 

#134 LB: IMPROVING INTESTINAL BARRIER USING GLP-2 AGONIST REDUCES ARTERIAL INFLAMMATION IN PWH

Janet Lo (MGH) presented a really important clinical trial for the inflammation agenda. The GLP-2 agonist teduglutide has previously been shown to increase intestinal epithelial cell growth and repair and in animal models reduces microbial translocation. She showed in a clinical trial of 28 ART-suppressed people with HIV, that this GLP-2 agonist reduces systemic AND vascular inflammation by FDG-PET/CT, representing the first demonstration that blocking microbial translocation in people with HIV reduces pathways associated with morbidity/mortality. The intervention had some gastrointestinal tolerability issues in some participants, so it is possible that a lower dose might be required in future studies, but this trial represented a major advance in interventions targeting microbial translocation in treated HIV.

HIV-1 remission with CCR5∆32∆32 haplo-cord transplant in a US woman: IMPAACT P1107

Oral abstract 65 (from Session 5)

Bryson Y et al.  CROI 2022, 12–16 and 22–24 February, virtual meeting. 

One of the most newsworthy cure presentations involved a potential cure in a woman who received a stem cell transplant to cure a malignancy. Briefly, this case – referred to now as the New York Patient - involved a 64-year-old woman of mixed race who started antiretroviral therapy (ART) during acute infection. She developed acute myeloid leukemia a few years later and needed a stem cell transplant. After fully ablative therapy, she received a transplant from two donors. The first donation was from a partially matched relative. The second donation was from a cord blood repository in which a donor who was born without CCR5 was identified (the donor was homozygous for the CCR5-delta32 deletion). As CCR5 is typically required for HIV to enter cells, these cells are resistant to HIV infection. Cord blood stem cells are easier to transplant as the degree of matching is not as stringent. Also, these cells are less likely to cause graft-versus-host disease (GVHD). Unfortunately, the number of stem cells in cord blood units is limited, and hence engraftment can be slow and might not happen.

The standard stem cells engrafted first, and then eventually, the cord blood took over by about 100 days. The procedure was relatively well-tolerated. Importantly, there was no reported GVHD. The woman eventually stopped ART and has now gone 14 months with a rebound. As most near-cures fail during the first year, there is reason to be optimistic that the person was indeed cured.

The study is notable for lots of reasons. First, this appears to be the first woman who was cured therapeutically. The use of cord blood made finding a match for someone of mixed race much more likely. Finally, the lack of graft-versus-host disease argues that a robust attack from the donor on the original immune system may not be needed for a cure (the Berlin Patient had severe GVHD, which may have contributed to his cure).

We now have four successful cures related to a stem cell transplant: the Berlin, London, Dusseldorf, and New York patients.

The Impact of 3BNC117 and romidepsin treatment at ART initiation on HIV-1 persistence.
Oral abstract 62 (from Session 5)

Gunst  JD et al.CROI 2022, 12–16 and 22–24 February, virtual meeting. 

Administration of 3BNC117 at ART Initiation Induces Long-Term HIV CD8 T-Cell Immunity
Oral abstract 122 (from Session 10)

Rosás-Umbert M et al. CROI 2022, 12–16 and 22–24 February, virtual meeting. 

There is great enthusiasm in the cure arena for broadly neutralizing antibodies (bNAbs). These antibodies are able to (1) neutralize HIV directly, (2) kill infected cells (with the help of the innate immune system), and (3) induce CD8+ T cells. This latter outcome is referred to as the "vaccinal effect" and involves the development of antibody/antigen complexes that stimulate the production and expansion of HIV-specific CD8+ T cells.

A collaboration between teams in Denmark and New York conducted an innovative randomized clinical trial using 3BNC117, a bNAb. The team also used romidepsin, a latency-reversing agent (LRA). LRAs are used to induce HIV production, making it easier for the immune system or immunotherapies to recognize and kill infected cells.

Previous mathematical models suggested that the reservoir might be more active and easier to kill just as antiretroviral therapy is initiated.

The team conducted a randomized clinical study ("eClear") in which 59 people who were starting ART were randomized to (1) ART alone (the control group), (2) two infusions of the bNAb (days 7 and 21), (3) the LRA alone (days 10, 17 and 24) and the (4) bNAB plus the LRA.

About half of the participants started ART early in their infection. Five were women. Importantly, about half of the cohort was later found to have a virus that was potentially resistant to the bNAb.

The viral load declined fastest in the group given the bNAb and the LRA, suggesting that the LRA resulted in the generation of more virus-producing cells and that these cells were in turn rapidly killed by the bNAb.

Several months later, a subset of the cohort (n=20) agreed to interrupted therapy. ART was resumed if the viral load increased above 5000 copies RNA/mL or at week 12.  Seven study participants remained off therapy for 12 weeks. Interestingly, one person who received the LRA/bNAb combination has had persistently low levels of viremia for many months. The reservoir in this participant seems to be declining over time, even in the absence of ART.

In a separate presentation, the team reported that the frequency of Gag-specific CD8+ T cells at month three of the study was significantly higher in individuals that received the bNAb. This is consistent with the vaccinal effect. These cells may have contributed to the control of HIV in the one individual who has remained off therapy.

Phase 1 Study of Long-Acting 3BNC117 and 10-1074 in Viremic Adults Living With HIV.

Oral abstract 140 (from Session 12)

Marina Caskey, Katrina Millard, Martina Turroja, Christian Gaebler, Erin Logue, Caroline Jiang, Leah Todd, Jackie Reeves, Christos J Petropoulus, Timothy Wilkin, Pablo Tebas, Michel Nussenzweig

There are many broadly neutralizing antibodies (bNAbs) being developed for prevention, treatment, and cure. The first-generation bNAbs had a short half-life. These antibodies are being modified to persist for weeks to months after a single infusion. Mutating the antibody to bind to receptors on certain immune cells protects them from being degraded. This "LS" mutation is now commonly used to improve many antibodies' pharmacokinetics.

In a small study of two common bNAbs (3BNC117 and 10-1074), the LS-modified versions were shown to persist above the therapeutic levels in blood for up to six months after a single infusion. The combination was able to reduce viremia in untreated people for weeks. One person has maintained an undetectable viral load for up to six months after a single infusion of the antibodies.

"CHIMERIC ANTIGEN RECEPTORS (CARs): WHAT'S NEXT?" interactive session

James Riley. NEW AND IMPROVED T CELL CARs FOR HIV ERADICATION OR CONTROL

A one-hour session was held to discuss the use of CAR-T cells for HIV cure. CAR-T cells are genetically modified cells that express receptors targeting a specific antigen. The first CAR-T cells were developed in the 1990s for HIV, and the first randomized study of this approach was developed and conducted at UCSF. These early studies showed some promise, but with the advent of ART, the entire field shifted to cancer, where these cells were subsequently proven to be very effective for certain blood cancers.

The CAR-T cell world is now returning to HIV, and there are studies being done at UCSF and the University of Pennsylvania. Jim Riley at UPenn has been a leading scientist in this area. In a panel discussion, he briefly summarized a series of three studies. The first two studies involved taking T cells from a person and using an enzyme to disrupt CCR5, making the cells resistant to HIV infection. They found that removing CCR5 from a subset of cells in the body (less than 5%) was safe and potentially effective in limiting virus rebound after ART was interrupted. Virus control may have been due to the production of HIV-specific CD4+ T cells that lacked CCR5 and hence were protected from HIV infection.

More recently, this same group conducted a study in which cells were obtained from a participant, genetically modified to express an HIV-specific CAR, and infused back. The approach appeared to be safe in 8 people studied to date.

One brave and committed study participant volunteered for all three studies. Remarkably, this person had viral rebound after the first two studies but not after the third. This study suggests that by making the environment unfriendly to the virus (reduced CCR5 on target cells) while at the same time providing more killing machines (the CAR- T cells), a durable remission might be achieved. It was noted during the discussion that this participant was heterozygous for the CCR5 deletion, which likely helped.

POSTER HIGHLIGHTS

INCLUDING Env IN AN HIV THERAPEUTIC VACCINE BLUNTS Gag/Pol-SPECIFIC T-CELL RESPONSES

Poster 284 (from Session D05).

Kara W. Chew1, Emma Reuschel2, Mansi Purwar2, Megan C. Wise2, Nilu Goonetilleke3, Elizabeth R. Wonderlich4, Faraz Zaidi2, Drew Frase2, Jean Boyer5, Laurent Humeau5, Rafick-Pierre Sékaly6, David Weiner2, Dave Glidden7, Steven G. Deeks7, Rachel L. Rutishauser7.

CONSERVED-REGION MVA VACCINES REDIRECT HIV T-CELL IMMUNODOMINANCE IN PWH ON ART

Poster 285 (from Session D05).

Nilu Goonetilleke1, Yinyan Xu1, Shahryar Samir1, Ann Marie Weideman1, Sallay Kallon1, Joanna Warren1, Maria Abad1, Alison Crook2, Lawrence Fox3, Michael Hudgens1, David M. Margolis1, Tomas Hanke2, JoAnn D. Kuruc1, Cynthia Gay1, for M&M Study Team.

Many cure studies are based on the use of a therapeutic vaccine aimed at killing infected cells during antiretroviral therapy and/or controlling HIV after therapy is interrupted.

A critical question in the field pertains to what parts of the virus to target therapeutically. For prevention, all of the focus is on using vaccines to produce antibodies that target the envelope protein, as this seems to be the best way to prevent infection. For cure, the goal is to target infected cells, which typically requires T cells that target conserved areas of the virus, most of which are not in the envelop gene.

To help untangle how best to design a therapeutic vaccine, Kara Chew led a two-center study at UCLA and UCSF where people with HIV on ART were randomized to receive a DNA vaccine encoding Gag/Pol, Gag/Pol/Env, or placebo. Forty-five participants were enrolled. Rachel Rutishauser (UCSF) directed the laboratory studies.

Inducing completely new responses to the virus in a person who has been infected has been a challenge. New HIV-specific T cell responses were uncommon in this study but did occur. More work is ongoing to define these responses' phenotypic and functional characteristics.

Compared to placebo, vaccination with Gag/Pol induced significantly higher responses. In contrast, Gag/Pol/Env did not induce such a significant response when compared to the placebo. Overall, 62%, 47%, and 20% of the Gag/Pol, Gag/Pol/Env, and placebo groups had a ≥2-fold increased magnitude of either vaccine-matched Gag- or Pol-specific T cell responses.

This study provided proof that de novo responses can be induced therapeutically. It also suggests that increasing the size of the "payload" (the amount of immunogen in the vaccine) can result in lower responses to specific regions. This issue of antigenic competition suggests that we may want to have very targeted vaccines in a therapeutic setting.

In another therapeutic vaccine study being conducted by Nilu Goonetilleke (UNC), a novel viral vector (MVA) and immunogen ("tHIVconsv," which encodes for highly conserved areas on Gag and Pol regions) were administered to people on ART. Using state-of-the-art assays, they found that the vaccine shifted the immune response from one that targeted the original infection to one that targeted the vaccine). Shifting the "immunodominance" of the T cells during ART will be critical for developing a potentially curative vaccine.

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