CFAR's Highlights from Virtual CROI - Tuesday 3/10

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.

Plenary on Sex Differences
On this National Women and Girls HIV/AIDS Awareness Day, Eileen Scully from Johns Hopkins (and CNIHR Awardee) presented a tour de force, explaining the immunologic basis for sex differences in HIV (and other virus infections including coronaviruses), highlighting the under-representation of women in pathogenesis-oriented studies in HIV, and demonstrating that one can rapidly recruit women into such a study (A5366) which enrolled only cis-gender women (first of its kind in the HIV cure world). Her plenary abstract is found at following link, and the A5366 study was presented in a themed discussion here:

Special Coronavirus Session
There was a simply outstanding session on coronavirus today at CROI featuring Zunyou Wu (Chief Epidemiologist, Chinese CDC); John Brooks from the U.S. Centers for Disease Control and Prevention; Ralph Baric from the University of North Carolina; and Anthony Fauci from NIAID/NIH. This excellent session is publicly available and found at the following link:

Cardiometabolic and Pulmonary Complications (oral symposium) and “Focus on Fat” (themed discussion)

  • Predicted 10-year risks of diabetes and cardiovascular disease in the ADVANCE trial. Andrew Hill from the University of Liverpool presented data from the ADVANCE trial on the projected 10-year risk of diabetes and cardiovascular disease. The ADVANCE trial randomized treatment naïve patients with HIV in South Africa to efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) versus dolutegravir (DTG)/TDF/FTC versus DTG/tenofovir alafenamide (TAF)/FTC and found increased weight gain among participants randomized to the latter regimen (especially among women). In this study, weight, lipids, fasting glucose, and blood pressure (BP) were measured at baseline and week 48, and used to calculate 10-year risks of CVD and type 2 diabetes using the Framingham, and other cardiovascular risk equations. Treatment with TAF/FTC+DTG led to greater rises in weight, lipids, and glucose than TDF/FTC+DTG, with small predicted 10-year risks of CVD and diabetes; metabolic syndrome rates were higher on DTG/TAF/FTC than EFV/TDF/FTC regimens. A follow-up study in the same session (Griesel et al.) suggested that CYP2B6 polymorphisms in African populations may lead to higher efavirenz concentrations and an inhibition of weight gain on EFV-based regimens.
  • Greater weight gain after switch to INSTI-based regimen from NNRTI versus PI regimens. John Koethe from Vanderbilt University examined weight over time among people with HIV (PWH) switched to an INSTI (but before TAF was approved in 2016) in the NA-ACCORD study. The analysis was restricted to those with virologic suppression for 2 years and included 877 participants switched to an INSTI-based regimen from an NNRTI-based regimen or a PI-based regimen. The ADVANCE trial was conducted among patients naïve to therapy, not switched to INSTI-based regimens. In this study, significant weight gain (1.13 kg/year) was seen from a switch to an NNRTI to an INSTI (but not from a switch from PI to an INSTI) with the weight gain difference being driven among those switched from an NNRTI to DTG (1.73 kg/year).There was no analysis of bictegravir since this study was conducted prior to its approval. Weight gain with switch to raltegravir or elvitegravir was not significant. This increase in weight in the NNRTI to INSTI switch group was primarily driven by an increase in the weight slope among women, non-whites, and older PWH (>50 versus <50 years). There seems to be a heterogeenous effect of ART class and agent on body weight regulation.
  • Body composition changes over the menopausal transition in HIV+ and HIV- women. UCSF’s own Phyllis Tien presented this abstract from the WIHS that was able to compare weight changes and changes in waist circumference among women living with HIV (WLWH) and without HIV. Although body mass index (BMI) increases WLWH after the menopausal transition, this expected BMI increase was not seen among WLWH in the WIHS study. However, waist circumference did increase among WLWH after menopause, and this change in visceral obesity may be a better measure of body changes after menopause in this population than BMI.

Targeting the persistent HIV reservoir (oral symposium) and Cure Strategies: Trials and Tribulations (themed discussion)

  • Total body imaging of the HIV reservoir is arriving – and UCSF is out in front!: UCSF’s own Timothy Henrich presented on behalf of his team including Henry Van Brocklin a talk demonstrating that one can detect radio labeled VRC01 (a neutralizing anti-HIV antibody) in the lymph nodes of people with HIV using PET/MRI and has now moved on to using the most sensitive PET technology in the world (at UC Davis), the PET EXPLORER.
  • CMV-and HIV-specific CD4 cells may contribute to expanded clones of HIV-infected cells. Francesco Simonetti from Johns Hopkins, in collaboration with the CFAR Clinical Core/SCOPE cohort, showed that CMV- and HIV-specific T cells contribute to clonal expansion of HIV-infected reservoirs. As one might expect, the normal function of T cells (antigen-driven proliferation) is a barrier to HIV eradication.
  • Intact provirus seems to preferentially persist in “epigenetic graveyards” in HIV controllers. Chenyang Jiang from the Ragon Institute presented compelling data suggesting that in elite controllers, intact provirus tends to persist in regions of the genome that are rarely transcriptionally active. Infection of cells isolated from elite controllers vs. healthy volunteers showed no difference in integration sites (and it occurred outside of the “graveyard” regions), consistent with the possibility that the preferential persistence in epigenetic graveyards observed in vivo may reflect immunologic selection in vivo.
  • Intact Proviral DNA levels decline in people with HIV on ART. Rajesh Gandhi from Massachusetts General Hospital (that last name seems familiar…) presented data from the AIDS Clinical Trials Group (ACTG) 5321 study which follows patients with long-standing virologic suppression on ART. Proviral DNA was measured at median of 7.1 yr after ART initiation (time point 1) and again a median of 3.7 yr later (time point 2).This study shows that intact proviral DNA levels decline significantly (half-life 6.5 yr), whereas total proviral DNA remains stable over the same time period (half-life 22.9 yr). Some individuals even had a decline in intact proviral DNA to undetectable levels. The overall decline in intact proviruses implies that cells containing replication-competent proviruses are being lost, which can help inform strategies to accelerate HIV reservoir depletion.
  • CARs: Blake Rust from the Fred Hutchinson demonstrated impressive suppression of rebound in some SIV-infected monkeys getting HIV-specific CARs, which use the extracellular CD4 motif as the “antibody” recognizing HIV envelope.
  • bNAbs+TLR agonists: Denise Hsu from the US Military Research program in Thailand presented a study demonstrating that combining a TLR7 agonist with 2 bNAbs seemed to result in a delay in viral rebound in SHIV-infected macaques.
  • “Kitchen sink” approach in monkeys (Ad26/MVA vaccine + TLR7 + bNAbs): In a study led by Dan Barouch from Beth Israel Deaconness Medical Center, this combination intervention resulted in synergistic control of viral rebound during ATI, with the majority of monkeys in the “kitchen sink” arm controlling. This highly important study has a very similar design to our own amfAR Institute’s trial in people with HIV (led by our own Steve Deeks and Michael Peluso), which should begin enrolling within the next few months.
  • Novel interventions to block HIV transcription. UCSF’s own Sara Moron-Lopez (UCSF/VAMC; 2018 CFAR Mentee and 2019 CFAR Awardee) showed that a novel antiviral ABX464 being developed by Abivax reduced HIV transcription in infected cells and lowered HIV DNA levels in 11 ART-suppressed PWH. While the effects were reversed with drug withdrawal (i.e., no “block and lock”), this type of agent may have a unique role to address the inflammatory state if it can truly reduce HIV expression in vivo.
  • Why settle for a regular CAR when you can have a Convertible CAR? Our own Eytan Herzig (Gladstone and 2017 CFAR Awardee) presented his work on convertible CAR T cells, a promising advance in getting genetically engineered T cells to improve the sensitivity and specificity of genetically engineered HIV-specific cells, featured in his recent Cell paper.

Prevention 2020: Agents, Options, and Outcomes oral symposium

  • Near-Perfect Accuracy of a Real-Time Urine Tenofovir Test Compared to Lab-Based ELISA. UCSF’s own Matthew Spinelli (2017 CFAR Mentee and 2019 Early Career Excellence in Clinical Science Awardee) presented data in the PrEP oral symposium on a novel point-of-care assay to assess adherence to tenofovir disoproxil fumarate (TDF)-based PrEP regimens. Since self-reported adherence can be biased and since more routine pharmacologic metrics of adherence (drug levels in plasma, dried blood spots, hair) require expensive liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based methods, antibody-based assays to tenofovir have been recently developed. These assays allow point-of-care testing for tenofovir in urine (like a urine pregnancy test). This abstract shows the high performance of the point-of-care lateral flow assay developed from this antibody compared to laboratory-based testing among diverse populations of heterosexual men and women on PrEP (in Partners PrEP) and transgender individuals on PrEP (in the TRIUMPH study). This real-time assay is now ready for further field testing.
  • Longer-term safety of F/TAF and F/TDF for HILONGER-TERM SAFETY OF F/TAF AND F/TDF FOR HIV PrEP: DISCOVER Trial Week 96 results. Onyema Ogbuagu from Yale University presented the 96-week safety and efficacy results from the DISCOVER trial, which enrolled (mainly white, 84%) MSM in a trial comparing TAF/FTC to TDF/FTC-based PrEP. The efficacy at 96 weeks between the two regimens in preventing HIV remained similar. In terms of safety, More significant declines in bone mineral density (>3%) were seen in those on TDF/FTC compared to TAF/FTC. Weight gain was 0.5kg in those on TDF/FTC versus 1.7kg on TAF/FTC over 96 weeks, adding to the data on weight gain with TAF.

Follow-up on GEMINI study (poster)

  1. DTG/3TC versus DTG + TDF/FTC (GEMINI 1&2): Confirmed Virologic Withdrawals through Week 96. The GEMINI study looked at the combination of DTG/3TC for the initial treatment of HIV infection, with the 48-week data of the GEMINI 1 and 2 studies that were published in The Lancet in 2019; this poster summarizes the 96-week data from the GEMINI 1 and 2 studies. In these studies, a total of 1433 patients were randomized to DTG/3TC versus DTG/3TC/TDF. At Week 96, 86.0% (616/716) of participants in the DTG/3TC group and 89.5% (642/717) in the DTG/TDF/FTC group achieved HIV-1 RNA <50 copies/mL. Overall, 11 participants taking DTG/3TC and 7 taking DTG/TDF/FTC met confirmed virologic withdrawal criteria through week 96, but none had treatment-emergent resistance mutations. Of note, those with CD4 less than 200 continued to have lower rates of virologic suppression (consistent with the 48-week data). The 96-week data of GEMINI 1 and 2 studies were also recently published in JAIDS.

HIV is on our Minds (oral symposium)

  • Cerebrovascular complications and NeuroHIV in the Global Setting. UCSF’s own Felicia Chow (2013 CFAR Awardee) gave an overview of HIV’s contribution to stroke risk and the rising incidence of cerebrovascular complications among people living with HIV worldwide, but particularly in East Asia and Sub-Saharan Africa. Her talk touched on the role of cerebrovascular function in cognitive performance among PLWH and she advocated for clinicians to address traditional stroke risk factors in the care of PWH in LMIC in order to lower stroke risk in this vulnerable population.