CFAR's Highlights from Virtual CROI - Wednesday 3/11

Special non-CROI announcements:

  1. CFAR seminar: The CFAR seminar scheduled for April 1st, 2020 with Dr. Michael Mugavero from the University of Alabama, Birmingham has been canceled in light of current travel restrictions and containment policies. We will inform you of the new date when it is rescheduled.
  2. Future Leaders Symposium: The CFAR Future Leaders in HIV Symposium has been postponed from April 14 and we will update you when it is rescheduled.
  3. NIH notices regarding COVID-19 related late submissions and other disruptions to NIH-funded work.

Courtesy of the CFAR leadership, we have decided to send you a short summary of notable abstracts from each day of the “Virtual CROI” conference. Please note that this summary is by no means meant to be a comprehensive overview of all the abstracts presented at CROI, but a highlight of the oral abstracts from each day with a focus on those presented from investigators from UCSF and our UCSF-Gladstone CFAR affiliates.

The CROI team continued to make progress in making the virtual conference a model for agility and productivity in a challenging context of remote conference administration. Today, live Q&A components to oral abstract sessions were introduced to bring a level of interaction that is otherwise hard to create in a virtual conference. Moreover, CROI sessions will be available for on-demand viewing by registered attendees by 9:00 PM Eastern Time tonight! Way to go, CROI organizers!

Plenary on Tuberculosis
Opening the final day of Virtual CROI, Gavin Churchyard of The Aurum Institute in Johannesburg, South Africa gave a comprehensive update on recent advances in diagnostics, treatment and prevention of TB. He began by expressing frustration in areas in which progress has been limited, citing that 4 of 10 people with TB worldwide are undiagnosed. He then illustrated important advances in the areas of point of care and community testing for people with HIV and TB, improvements in diagnostic accuracy across a range of assays, advances in vaccine development, and a growing body of evidence for different treatment strategies, including options for multi-drug resistant TB and shorter courses of treatment. He ended with a call to action to meet TB 2030 targets for prevention and treatment, which will involve a substantial increase in funding for research and development. His plenary is available online here:

Plenary on Engineering Vaccine Immunity
Shane Crotty from the La Jolla institute for Allergy and Immunology gave a plenary on engineering B cell vaccine strategies that are capable of eliciting broadly neutralizing antibodies. This state of the art talk provided a clear overview of the many challenges to developing an effective B cell vaccine for HIV and how many of these challenges are beginning to be overcome with sophisticated immune engineering approaches and novel immunogen delivery protocols. View the plenary here:

Tuberculosis, Opportunistic Infections, and HIV Testing Oral Symposium. This session featured presentations from three UCSF investigators!

  • Challenges of PrEP during HIV acquisition. Challenges of PrEP during HIV acquisition. UCSF’s own Mike Peluso (2018 CFAR Mentee) presented the potential impact of PrEP during HIV acquisition on reservoir establishment, viral load set points, and immune responses from the UCSF Acute HIV cohort led by Sulggi Lee (2018 CFAR Excellence in Translational Science Recipient and 2015 CFAR Awardee). He reviewed data on early HIV infection among 58 individuals in San Francisco with 24 having PrEP exposure, highlighting therapeutic and diagnostic challenges in this context. Focusing on three specific and illustrative cases, these data set the stage for a research agenda to explore seroconversions on PrEP and acute HIV infection moving forward. and
  • Financial incentives for HIV re-testing (abstract 141). Also from UCSF, our own Gabe Chamie (2008 CFAR Awardee) presented findings from a study of 524 at-risk adults in rural Uganda, in which offering financial incentives resulted in significantly higher HIV retesting rates, whereas offering deposit contracts did not increase retesting rates.
  • Community-based HIV testing. Rounding out the UCSF trifecta for this session, Hong-Ha Truong (2005 CFAR Mentee) described a community-based hybrid HIV testing approach in Kisumu, Kenya that was successfully implemented in an urban setting with a high-risk, impoverished, and highly mobile population. The testing approach and design drew on lessons learned from the multi-community SEARCH study in rural East Africa, adapted to an urban setting. Despite several challenges, 97% of eligible clients were tested, and 93% of newly identified HIV+ persons initiated same-day ART.
  • 3HP vs. 6H for TB preventive therapy. Weekly isoniazid (900mg) and rifapentine (900mg) for 12 weeks (3HP) has already been shown to be effective compared to daily isoniazid for patients without and with HIV. Gavin Churchyard (see morning plenary above) reported the results of a trial in South Africa, Ethiopia, and Mozambique (the WHIP3TB trial) comparing treatment completion rates and effectiveness of 3HP given annually versus once compared to 6 months of daily isoniazid (6H) as TB preventive therapy. The presenter concludes that treatment completion was higher in the 3HP arm (with annual/once arms collapsed) vs 6H and that annual 3HP did not provide additional benefit to people receiving ART in preventing TB.

Gone but Not Forgotten: HCV After Direct Acting Antiviral Therapy Oral Symposium

  • Dramatic outbreak of HIV in West Virginia, US. Robert McClung of the CDC reported on an HIV outbreak of 81 cases in West Virginia during the period of January 2018 through November 2019, representing a 2,285% increase over prior years. The vast majority of cases (99%) were among persons who inject drugs. This outbreak highlights the importance of coordinated and creative cluster and outbreak responses that includes comprehensive diagnosis, treatment, and prevention services.
  • HCV burden among pregnant women in New York State. Linda Styer of the NY State Department of Health reported that among 29,323 dried blood spot (DBS) samples from 25,871 unique babies in New York State, 148 DBS were HCV antibody reactive, for an overall seroprevalence of 0.8%. Premature birth (26%) and low birth weight (26%) were twice as common in babies born to HCV seropositive mothers than seronegative mothers. The study highlights that newborn DBS testing using a Luminex-based immunoassay is an effective method of assessing HCV burden among pregnant women.

Critical Issues in Maternal and Child Health Oral Symposium

  • Treatment safety and efficacy among pregnant women. Lamerck Chinula from UNC’s Project Malawi presented results of a trial comparing the safety and efficacy of dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) vs. DTG + FTC/tenofovir dispoproxil fumarate (TDF) vs. efavirenz (EFV)/FTC/TDF in 643 pregnant women in 9 countries. The take home from this impressive trial is that DTG-containing ART started at gestational age 14-28 weeks had superior virologic efficacy at delivery to EFV/FTC/TDF, consistent with recent treatment guidelines by the World Health Organization. DTG+FTC/TAF had the lowest frequency of adverse pregnancy outcomes. See related press release here.
  • Reducing vertical transmission. UCSF’s own Ted Ruel (2007 CFAR Awardee) reported on a universal testing and patient-centered care delivered via government clinics in 32 communities in rural Uganda and Kenya through the SEARCH study. Communities were randomized to either immediate ART, annual population level testing, and patient-centered HIV care or HIV care per national guidelines. Among 1,417 births to 1,332 HIV+ women, vertical transmission was 0.5% (0-1.3%) in the intervention arm compared to 3.7% (2.4-5.1%) in the control arm (p<.001), representing marked progress toward the elimination of vertical transmission in the large and representative SEARCH model of testing and care. Abstract 134LB.

Immunology and Pathogenesis of Lentivirus Infections Oral Symposium

  • The IL-6 inhibitor tocilizumab decreases immune activation in treated HIV infection (Abstract#113). Benigno Rodriguez (CWRU) presented a placebo controlled cross-over trial of the IL-6 receptor antagonist tociluzumab (TCZ, 3 monthly doses) in ART-suppressed PWH. IL-6 receptor blockade predictably increased measurable IL-6 in plasma, but decreased multiple markers of innate immune activation (CRP but also sCD14, sTNFR1) and plasma markers of endothelial activation (but not direct measures of endothelial function), as well as markers of T cell cycling and PD1 expression. It also increased CD127 expression on naïve and central memory T cells and CMV-specific T cell proliferation in response to TCR stimulation. On the other hand, other immune activation markers like T cell activation failed to decline or tended to increase (e.g., IP-10 and sCD163). There were some toxicities (one each with neutropenia and a grade 3 rash that resolved after treatment discontinuation), which may preclude clinical use, but this is one of the more encouraging targeted immune-based interventions to decrease the persistent inflammatory state studied to date. That said, the effect of the intervention on many, but not all immune activation pathways that are abnormal during ART-mediated viral suppression raises questions as to whether it is reversing all the pathways that need to be reversed to fully restore health. Michael Lederman also discussed these issues in the Inflammation symposium in the afternoon (#156).
  • A vaccine strategy inducing both nAbs and Tissue-resident memory (TRM) T cell responses appears to protect against infection in a SHIV model (#114). Prabhu Arunachalam (Pulendran lab, Stanford) presented a vaccine study in a SHIV model showing that a vaccine capable of eliciting nAbs can protect against mucosal SHIV challenge (~50% protection) and that the addition of a TRM-inducing vaccine apparently provided additive protection (2/3 of monkeys).
  • HIV-induced NK cell memory characterized for the first time (#115LB). Stephanie Jost (Reeves lab, Beth Israel Deaconess MC) showed strong evidence for HIV Gag-specific NK cell responses in PWH, and particularly in elite controllers, suggesting that these NK cells – in addition to CD8+ T cells - might plausible be contributing to control in vivo as has been suggested in earlier host genetic studies by Mary Carrington and more recent observations in the VISCONTI cohort of post-treatment controllers.
  • ImmunoPET imaging of reservoir in SHIV-infected macaques appears to identify gut tissue as a site of viral rebound during ATI (118). Veronica Obregon-Perko from Emory showed data from a SHIV model demonstrating that after 1 year of suppressive ART, as others have shown previously in SIV-infected macaques and humans with HIV, there is typically higher viral RNA content in the gut than in other tissue compartments. They were also able to image this in the gut with ImmunoPET (radiolabeled bNAb) and there was an increase in the ImmunoPET signal in the gut before virus became detectable in blood during ATI. This would be consistent with a gut source of viral rebound.
  • About half of virus in plasma during ART appears to originate from tissues (#119). Using thoracic duct sampling along with statistical modeling, Leticia Cervantes (Betts lab, University of Pennsylvania) demonstrated that at least half of the virus detected in peripheral blood in the presence and absence of ART comes from a tissue origin (i.e. from draining lymph as opposed to blood). They confirmed this prediction with a macaque study, applying an intervention that blocked lymphocyte migration (which depletes peripheral blood CD4 cells). While it was always assumed that the tissues was the primary source of persistent viremia, this elegant study proved this for the first time.   

The Long and The Short of It: What's Next for Long-Acting Drugs themed discussion
This session started with an overview by Ethel Wald from Johns Hopkins on why the time for long-acting ART has come and where we are for both the closest-to-market combination (intramuscular cabotegavir plus rilpivirine) and for long-acting ART agents in development
Cabotegravir and Rilpivirine PK following Long-Acting Treatment Discontinuation. Susan Ford from GlaxoSmithKline reported on CAB and RPV pharmacokinetics following long-acting treatment discontinuation in patients on ART who were put on alternative ART oral regimens following CAB/RPV IM discontinuation. Although the authors report that CAB and RPV plasma concentrations observed during long-term follow-up are consistent with the apparent absorption-rate limited half-life for each long-acting formulation, it is important to note that 8/25 participants (32%) and 25/25 participants (100%) still had detectable CAB and RPV levels, respectively, in the plasma at 12 months after discontinuation. Although there should not be significant drug-drug interactions with these lingering CAB/RPV ART levels and oral ART regimens, those are very long half-lives!

Antiretroviral Therapy: The Long Game
The final clinically-oriented symposium of each CROI is always immensely popular as it pulls together all the updates over the past year and the current CROI symposium on what the current-state-of-the-research means for the care of those living with or at risk of HIV.
This year’s symposium did not disappoint. An excellent and comprehensive talk was provided by Rajesh Gandhi from Massachusetts General Hospital on Novel Antiretroviral Agents: Transforming the Care of People with HIV where he summarized long-acting ART with CAB/RPV, and the upcoming and enrolling trials with islatravir (MK-8591); capsid inhibitors; entry inhibitors including fostemsavir, UB-421 and PRO 140; and bNAbs. His discussion finished up with an important discussion on reducing cost and increasing access to currently-available and novel ART and PrEP agents worldwide. The second talk by Carolyn Bolton Moore from CIDRZ, Lusaka, Zambia on Pediatric and Adolescent ART: A Road Less Traveled summarized the current state-of-the-art in treatment of pediatric and adolescent ART, including a sobering look at the limited formulations of ART available for young children. The third talk by Jordan Lake from the University of Texas in Houston entitled Metabolic Complications of HIV and its Therapies gave a sweeping overview of metabolic complications in HIV, including reviewing most of the studies on weight gain with INSTIs both from prior years and presented during CROI 2020. Finally, the fourth talk by Jose Castillo-Mancilla from the University of Colorado, Denver, called Getting it Right; Practical Approaches to Adherence with Modern ARVs provided an incredible summary of why adherence to ART and PrEP should be optimized and novel measures of assessing adherence objectively, including pharmacologic measures (such as drug levels in plasma, dried blood spots, hair and urine); sensor-based systems; and electronic medication monitoring systems.

Follow-up on the London Patient (poster)
Ravindra K. Gupta, MD, PhD, of University College London presented findings from the London Patient case in a poster presentation. 30 months after treatment interruption, tests have not found any replication competent virus, similar to the Berlin Patient. These results have also been published in the Lancet: