Dear CFAR community,
Monica, Mallory, Lauren, Peter
IMPORTANT ABSTRACTS FROM SEARCH SAPPHIRE STUDY AT UCSF
Elijah Kakande, 124: RANDOMIZED TRIAL OF COMMUNITY HEALTH WORKER DELIVERED DYNAMIC CHOICE HIV PREVENTION
Elijah Kakande, James Ayieko, Helen Sunday, Edith Biira, Marilyn Nyabuti, George Agengo, Jane Kabami, Gabriel Chamie, James Peng, Melanie Bacon, Moses Kamya, Diane V. Havlir, Maya Petersen, Laura Balzer Research Group: SEARCH Study Team
In one of many important SEARCH abstracts presented at CROI 2023, the group hypothesized that a dynamic choice prevention (DCP) intervention, including flexibility to move between PrEP and PEP and delivered by community health workers (CHW), would increase HIV biomedical prevention coverage among persons at risk in Uganda and Kenya. SEARCH conducted a cluster randomized trial among persons (≥15 years) with current or anticipated risk of HIV, with intervention villages receiving DCP delivered by CHW with clinician support with 1) product choice (daily oral PrEP [TDF/XTC] or post-exposure prophylaxis [PEP]) with the option to switch over time, 2) service location choice, 3) HIV self-testing option, 4) 24/7 phone access to clinician, and 5) CHW & provider training on client-centered care. Control villages received standard of care prevention referrals. The primary outcome was biomedical prevention coverage: proportion of 48-week follow-up with self-reported PrEP/PEP use. From May-July 2021, the group enrolled 429 people (212 intervention; 217 control) in 16 villages; 57% were women and 35% aged 15-24 years. 58% of intervention participants chose PrEP and 58% chose PEP at least once over 48 weeks. Choice of self-testing increased from 52% at baseline to 71% at week 48. Choice of out-of-facility (vs. clinic) delivery was ≥98% throughout. Among 413 (96%) participants with primary outcome ascertained, average biomedical prevention coverage was 28% in intervention vs. 0.5% in control (27.5% absolute increase; 95%CI: 23.0-31.9%, p < 0.001). Effect sizes were similar in men and women. Coverage during periods of HIV risk was 36.6% in intervention vs. 0.9% in control (35.7% absolute increase; 95%CI: 27.5-43.9%, p< 0.001).
Conclusion: In this cluster randomized trial, the intervention increased biomedical coverage by 28%; however, substantial time at risk of HIV remained uncovered by biomedical prevention, highlighting the need for additional interventions.
Moses Kamya, Abstract 128: RANDOMIZED TRIAL OF DYNAMIC CHOICE HIV PREVENTION IN ANTE/POSTNATAL CARE CLINICS
Jane Kabami, Catherine Koss, Helen Sunday, Edith Biira, Marilyn Nyabuti, Laura Balzer, Shalika Gupta, Gabriel Chamie, James Ayieko, Elijah Kakande, Melanie Bacon, Diane V. Havlir, Moses Kamya, Maya Petersen Research Group: SEARCH Study Team
Women seen for ante and postnatal care (ANC) remain at risk for HIV in rural sub-Saharan Africa, despite routine access to PrEP. Patient-centered prevention delivery models that offer structured choices in product, testing and visit location may increase coverage. The SEARCH team conducted an individually randomized trial among women (≥15 years) with current or anticipated risk of HIV infection seen at ANC clinics in rural Kenya and Uganda to evaluate the effect of a dynamic choice prevention (DCP) model (intervention) versus standard of-care (control). DCP included: 1) product choice (daily oral PrEP [TDF/XTC] or post-exposure prophylaxis [PEP]) with option to switch over time; 2) service location choice; 3) HIV self-testing option; 4) 24/7 phone access to clinician; and, 5) provider training on patient-centered care. The primary outcome was biomedical prevention coverage over 48 weeks (proportion of months with self-reported PreP or PEP use); self-reported use during months a client retrospectively reported HIV risk was a secondary outcome. 400 women were enrolled between April and July 2021 (203 intervention, 197 control); 38% were pregnant; 94% reported no PrEP or PEP use for prior 6 months; 52% were aged 15-24y. Among 384/400 (96%) of women with outcome ascertained, the intervention increased biomedical prevention coverage by 40.2% (95%CI: 33.8%-46.7%; p< 0.001); mean coverage was 70% in intervention vs. 29% in control. The intervention also increased coverage during months at risk of HIV: 81% in intervention vs. 43% in control (38.1% absolute increase; 95%CI: 31.2%-45.0%; p< 0.001). Among intervention participants, 100% chose PrEP and 11% chose PEP at least once during 48 weeks. Choice of off-site visits increased over time (61% selected out-of-facility delivery at week-48 vs. 22% at baseline), as did choice of HIV self-testing (59% selected self-testing at week-48 vs. 34% at baseline). Therefore, in this impressive randomized study from SEARCH, a patient-centered dynamic choice intervention that provided flexibility in product modality, testing and service location more than doubled biomedical HIV prevention coverage in a high-risk population already routinely offered access to biomedical prevention options.
James Ayieko, Abstract 200: RANDOMIZED TRIAL OF DYNAMIC CHOICE HIV CARE FOR HIGHLY MOBILE PERSONS IN EAST AFRICA
James Ayieko, Colette Inviolata, Elijah Kakande, Fred Opel, Erick Wafula Mugoma, Laura Balzer, Jane Kabami, Elizabeth A. Bukusi, Carol Camlin, Edwin Charlebois, Melanie Bacon, Maya Petersen, Diane V. Havlir, Moses Kamya, Gabriel Chamie Research Group: SEARCH Study Team
Persons with HIV (PWH) with high mobility face multiple obstacles to HIV care engagement and viral suppression due to planned and unplanned travel away from their clinics’ catchment areas. In an individual randomized trial, the SEARCH study evaluated the effect of a mobile PWH-centered HIV care intervention on viral suppression vs. Ministry of Health standard care (control) among mobile adults (≥15 years old; and ≥2 weeks out of community in prior 12 months) with either viral non-suppression or recent missed visits in Kenya and Uganda (SEARCH NCT04810650). The intervention included dynamic choice of a “travel pack” (emergency 14-day ART supply, discrete ART packaging and travel checklist), multi-month (up to 6-month) and offsite medication refills, facilitated transfer to out-of-community clinics, and routine screening for travel and hotline access to a mobility coordinator who oversaw intervention delivery. The primary outcome was HIV viral suppression (viral load < 400 c/mL) at 48-weeks. Secondary outcomes included retention in care (proportion of time in care; “out of care” time starting 14-days after missed scheduled visit) and ART possession over 48 weeks. From April-July 2021, 201 participants (102 intervention, 99 control) were enrolled: 109 (54%) were female, 101 (50%) from Kenya, median age was 37 (IQR: 29-43), and 91 (45%) of participants (46% intervention, 44% control) had a VL >400 c/mL in the year prior to enrolment. At enrolment, viral suppression was 80% in intervention and 85% in control. Of 196 (98%) participants analysed at 48 weeks, there was no significant difference in viral suppression between the intervention (85%) vs. control (86%) arms. However, this person-centered intervention did significantly improve
retention in care and ART possession, which may confer long term benefit.
Catherine Koss, PS 975: RANDOMIZED TRIAL OF DYNAMIC CHOICE PREVENTION AT AN OUTPATIENT DEPARTMENT IN EAST AFRICA
Catherine Koss, James Ayieko, Jane Kabami, Laura Balzer, Elijah Kakande,
Helen Sunday, Marilyn Nyabuti, Erick Wafula Mugoma, Melanie Bacon,
Elizabeth A. Bukusi, Gabriel Chamie, Maya Petersen, Moses Kamya,
Diane V. Havlir
Dynamic choice models for delivering HIV prevention may increase coverage for persons at risk. Outpatient departments (OPD) in health facilities in rural sub-Saharan Africa account for a high proportion of new HIV diagnoses, but are an understudied entry point to biomedical HIV prevention, including dynamic choice models. The SEARCH group conducted an individually randomized trial of a dynamic choice HIV prevention (DCP) intervention vs. standard-of-care referral to prevention services (SOC) among adults with current or anticipated risk of HIV exposure seen at OPD clinics in rural Kenya and Uganda. DCP included 1) product choice (daily oral PrEP [TDF/XTC] or post-exposure prophylaxis [PEP]) with option to switch over time, 2) service location choice, 3) HIV self-testing option, 4) 24/7 phone access to clinician, and 5) provider training on client-centered care. Primary outcome over 48 weeks was biomedical covered time (proportion of follow-up covered by PrEP/PEP), assessed via self-report; secondary outcomes included coverage during periods of retrospectively self-assessed HIV risk. 403 participants were enrolled from April-July 2021, (197 DCP, 206 SOC): 61% women, 37% ages 15-24 years, 25% serodifferent partner, 88% HIV status unknown partner, 7% with prior PrEP or PEP use. In the DCP arm, 86% ever chose PrEP, 13% PEP over 48 weeks; selection of HIV self-testing increased from 26% to 51% and of out-of-facility visits from 8% to 52% during follow-up. Among 376/403 (93%) with outcomes ascertained, mean biomedical covered time was higher in DCP (47%) vs. SOC (18%); a difference of 29.2% (95% CI 22.7-35.7%; p < 0.001). Therefore intervention effect on coverage during periods at risk of HIV was larger; mean at-risk covered time was 65% in the DCP arm vs. 26% in SOC (difference 38.6%; 95%CI: 31.0-46.2%; p < 0.001). In fact, the choice of PrEP/PEP, visit location, and HIV testing, plus client-centered care resulted in two-fold greater time covered by a biomedical prevention option compared to SOC among both men and women at elevated risk of HIV seen in a general outpatient department.
Sarah Puryear. PS 883: RANDOMIZED TRIAL OF BRIEF ALCOHOL INTERVENTION FOR VIRAL SUPPRESSION AND ALCOHOL USE
Sarah Puryear, Florence Mwangwa, Fred Opel, Gabriel Chamie, Laura
Balzer, Jane Kabami, James Ayieko, Elijah Kakande, John Schrom, Melanie
Bacon, Sarah Woolf-King, Maya Petersen, Diane V. Havlir, Moses Kamya,
Judith A. Hahn
Unhealthy alcohol use is a major contributor to viral nonsuppression among persons with HIV (PWH), and a significant source of morbidity globally. It is unknown whether brief behavioral interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy
alcohol use in sub-Saharan Africa (SSA). As part of the SEARCH study, an individually randomized trial in Kenya and Uganda of a brief, culturally-adapted skill-based alcohol intervention among PWH with HIV viral non-suppression, missed visits, or out of care, and with
self-reported unhealthy alcohol use was performed. The intervention included in-person counseling sessions at baseline and 3-months, and booster phone calls every 3-weeks in the interim. The primary outcome was HIV viral suppression (VL < 400 copies/mL) at 24-weeks. Alcohol use at 24-weeks, assessed via self-report (AUDIT-C, prior 3 months) and phosphatidylethanol [PEth], an alcohol biomarker, was a secondary outcome. 400 persons (197 intervention, 203 in control; 57% in Uganda) were enrolled from April 2021 through September 2021. There was no difference in viral suppression between arms at 24-weeks, but unhealthy alcohol use (AUDIT-C ≥3/female; ≥4/male or PEth≥50 ng/mL) declined from 100% at enrollment to 73% in intervention and 84% in control arms at 24-weeks (RR: 0.86, 95% CI: 0.79-0.94; p< 0.001). Therefore, brief alcohol interventions have the potential to improve the health of PWH in SSA.
IMPORTANT BASIC SCIENCE ABSTRACTS FROM CROI
Adam Capoferri, Oral Abstract 106: THE FRACTION OF CELLS WITH UNSPLICED HIV RNA IS NOT ASSOCIATED WITH PLASMA VIREMIA
Adam A. Capoferri, Ann Wiegand, Francis Hong, Jana Jacobs, Jonathan Spindler, Andrew Musick, Michael J. Bale, Wei Shao, Michele D. Sobolewski, Anthony Cillo, Rebecca Hoh, Steven G. Deeks, John M. Coffin, John W. Mellors, Mary F. Kearney
Using samples from the SCOPE cohort (CFAR clinical core), Adam Capoferri (NCI-Frederick) showed that – regardless of the level of control of viral replication – about 5-20% of infected CD4 cells produce unspliced HIV RNA. This suggests that viral control (in the presence or absence of ART) is largely determined by events downstream of proviral transcription initiation and that viral replication in plasma is largely determined by a small subset of HIV-transcribing cells with a high “burst size.”
Ashley George, Themed discussion 337: NK CELL BIOMARKERS THAT PREDICT TIME-TO-REBOUND IN HIV+ INDIVIDUALS UNDERGOING ATI
Ashley F. George, Tongcui Ma, Min-Gyoung Shin, Reuben Thomas, Mauricio Montano, Satish Pillai, Martin Tolstrup, Ole S. Søgaard, Jonathan Z. Li, Davey M. Smith, Steven G. Deeks, Katherine S. Pollard, Warner C. Greene, Nadia R. Roan
Ashley George (Gladstone Institutes, Roan lab) presented an interesting CyTOF-based analysis of NK cell phenotypes associated with time to rebound among people with HIV interrupting ART, leveraging samples from the ACTG 5345 and Vacc4x cohorts. She found that higher levels of an atypical subset of NK cells (CD56-CD16+) and anti-RT Ab levels were associated with delayed time to viral rebound, suggestive of a possible role of NK cells in the temporary control of replication during early rebound. These findings are of particular interest given an NK cell signature previously reported in post-treatment controllers.
Nadia Roan, Pre-Conference Workshop (Frontiers in Laboratory Technologies) Oral Abstract 2: SINGLE-CELL ANALYSIS OF THE RNA, PROTEIN, AND GLYCAN FEATURES OF HIV-INFECTED CELLS
Nadia Roan (Gladstone Institutes) presented a talk in the preconference workshop describing her lab’s CyTOF-based approach to identifying the multidimensional surface phenotypic characteristics (analogous to “facial recognition”) of latently HIV-infected cells using a novel bioinformatic adaptation of a “nearest neighbor” analysis she calls PP-SLIDE. Using this approach to enrich for HIV reservoir cells, she has now applied scRNAseq and proteomic approaches to more carefully reveal features of HIV-infected cells, including increased gene expression of cell survival, immune evasion, and cytolytic pathways.
Michael Peluso, Oral abstract 33 (COVID symposium): WHAT WE KNOW NOW ABOUT LONG COVID SYNDROMES
Michael Peluso (HIV, ID, Global Medicine division), the leader of the LIINC cohort at ZSFG, provided an exceptional state-of-the-art overview of “long COVID,” from its clinical manifestations to hypotheses about pathogenesis being explored in ongoing research. If you want a great summary of the field, make sure to watch this along with the Q&A at the end.
Michael Peluso, poster 273: DIFFERENTIAL ASSOCIATION OF CYTOMEGALOVIRUS WITH ACUTE AND POST-ACUTE COVID-19
Michael J. Peluso, Harry Pickering, Fay Chan, Gabrielle C. Ambayec, Gabriele Beck-Engeser, Katherine Wick, Michael Matthay, Carolyn Calfee, Jeffrey Martin, Steven G. Deeks, Smita Iyer, Holden Maecker, Timothy Henrich, Elaine F. Reed, Peter W. Hunt
Michael Peluso (HIV, ID, Global Medicine division), demonstrated that asymptomatic CMV co-infection was associated with a 2-fold increased risk of hospitalization and systemic SARS CoV-2 antigen burden among people with acute COVID-19 after adjustment for other clinical and demographic risk factors, but a 50% decreased risk of long COVID, particularly with neurologic symptoms. These findings highlight important interactions between chronic viral infections with COVID-19 pathogenesis.
Kyrlia Young, poster 343: POLYFUNCTIONAL SARS-CoV-2-SPECIFIC T CELLS PERSIST IN TISSUE OF COVID19 CONVALESCENTS
Kyrlia C. Young, Ashley F. George, Matthew McGregor, Xiaoyu Luo, Rebecca Marquez, Kailin Yin, Tongcui Ma, Trimble Spitzer, Nadia R. Roan
Kyrlia Young (Gladstone Institutes, Roan lab) assessed SARS-CoV-2-specific T cell responses in endometrial tissue as well as maternal and cord blood specimens from women after delivery who experienced earlier COVID-19 during pregnancy. She found a much higher frequency of tissue-resident SARS-CoV-2-specific T cells in endometrial tissue up to 5 months after infection than in peripheral blood, suggesting prior viral exposure at that site and the likelihood that the long-term persistence of these cells may help protect against infections during future pregnancies.
Kailin Yin, poster 346: UNIQUE DIFFERENTIATION AND HOMING FEATURES OF T CELLS IN INDIVIDUALS WITH LONG COVID
Kailin Yin, Michael J. Peluso, Reuben Thomas, Jason Neidleman, Xiaoyu Luo, Rebecca Hoh, Scott Lu, Sarah A. Goldberg, Sulggi Lee, Kara Lynch, John D. Kelly, Jeffrey Martin, Steven G. Deeks, Timothy Henrich, Nadia R. Roan
Kailin Yin (Gladstone Institutes, Roan lab) used a CyTOF-based approach to assess phenotypic differences in SARS-CoV-2-specific T cell responses between those with and without long COVID in the LIINC cohort, finding increased exhaustion and tissue homing properties in those with long COVID, consistent with the possibility that viral persistence in tissues might contribute to pathogenesis.
Tongcui Ma, poster 380: CD103 EXPRESSION ON CD8 T CELLS PREDICTS LONGER TIME REBOUND OF HIV AFTER ATI
Tongcui Ma, Ashley F. George, Min-Gyoung Shin, Mauricio Montano,
Satish Pillai, Katherine S. Pollard, Jonathan Z. Li, Davey M. Smith, Steven G.
Deeks, Reuben Thomas, Warner C. Greene, Nadia R. Roan
Tongcui Ma (Gladstone Institutes, Roan lab) used a CyTOF-based analysis of CD8+ T cell phenotypes associated with time to rebound among people with HIV interrupting ART, leveraging samples from the ACTG 5345 and Vacc4x cohorts. They found that higher CD103 expression on T cells was associated with delayed rebound, suggesting a possible role of cells with this “tissue residency” marker in delaying rebound or an association between these cells with a lower “active” reservoir (as CD103 is induced by the immunoregulatory TGFb signaling pathway).
Akshay Gala, poster 381: THE CIRCULATING CELL-FREE DNA METHYLOME PREDICTS HIV POST-TREATMENT CONTROL
Akshay Gala, Zain Dossani, Prerna Dabral, Michael J. Peluso, Steven G. Deeks, Jonathan Z. Li, Satish K. Pillai
Akshay Gala (Vitalant Research Institute, Pillai lab) demonstrated that prior to ATI, post-treatment controllers had significantly higher levels of plasma cell-free DNA levels, which also tended to be more hypomethylated, than non-controllers or in people without HIV. These findings suggest both an active cell killing mechanism that may be contributing to post-treatment control of HIV and the possibility that similar measures might be developed to predict the likelihood of viral control following ATI in HIV cure studies.
Zichong Li, poster 439: A NUCLEOSOMAL MODIFICATION COMPLEX FOR SILENCING HIV
Zichong Li, Melanie Ott, Warner C. Greene, HOPE Collaboratory
Zichong Li (Gladstone Institutes, Ott and Greene labs, for the HOPE collaboratory), extending his recent early investigator talk at February’s CFAR seminar, identified a novel mechanism involving a BAF-NSL super-complex, which appears to promote HIV silencing in HIV-infected cells. These findings can be leveraged for novel silencing or latency-reversing approaches.
Prerna Dabral, poster 448: INTERLEUKIN-2-INDUCIBLE T-CELL KINASE (ITK) INHIBITION PREVENTS HIV LATENCY REVERSAL
Prerna Dabral, Li Du, Mohamed Bouzidi, Richard Miller, Steven G. Deeks, Satish K. Pillai
Prerna Dabral (Vitalant Research Institute, Pillai lab) presented some nice work demonstrating that ITK inhibition may prevent latency reversal in HIV-infected cells following polyclonal T cell receptor stimulation. It also seemed to inhibit T cell proliferation to a greater degree in HIV-infected than in uninfected cells, identifying this pathway as a potential target for antiproliferative and/or block and lock strategies.
Li Du, poster 549: TARGETING THE HOST-VIRUS INTERFACE TO BLOCK SARS-CoV-2 ASSEMBLY IN AIRWAY CELLS
Li Du, Fred Deiter, Mohamed Bouzidi, Jean-Noël Billaud, Graham Simmons, Prerna Dabral, Suganya Selvarajah, Anuradh Lingappa, Maya Michon, Shaofeng Yu, Kumar Paulvannan, Vishwanath Lingappa, Homer Boushey, John Greenland, Satish K. Pillai
Li Du (Vitalant Research Institute, Pillai lab) identified anti-SARS-CoV-2 activity in a pan-respiratory virus small molecule inhibitor of viral protein assembly, PAV-104, highlighting its potential as a potential therapeutic.
Michael Peluso, poster 282: PLASMA-BASED ANTIGEN PERSISTENCE IN THE POST-ACUTE PHASE OF SARS-CoV-2 INFECTION
Michael J. Peluso, Zoe Swank, Sarah A. Goldberg, Yasmeen Senussi, Scott Lu, Rebecca Hoh, Khamal Anglin, Beatrice Huang, Matthew S. Durstenfeld, John D. Kelly, Timothy Henrich, Steven G. Deeks, David V. Glidden, David Walt, Jeffrey Martin
Michael Peluso (HIV, ID, Global Medicine division) and colleagues, assessed the degree to which plasma N or S antigen tended to persist in people with long COVID in the LIINC cohort. Those with long COVID were slightly more likely to have detectable antigen in plasma at least one timepoint (10%) than those without any long COVID symptoms (8%), suggesting that viral persistence might contribute at least somewhat to long COVID pathogenesis.
Julie Frouard , poster 421: T-TRACE ENABLES SINGLE-CELL MULTI-OMICS ANALYSIS OF HIV RESERVOIR CELLS FROM TISSUES
Julie Frouard, Xiaoyu Luo, Jason Neidleman, Kailin Yin, Sushama Telwatte, Steven Yukl, Jennifer Cohen, Anastasia Polos, Carol Thuman, Rebecca Hoh, Steven G. Deeks, Pavitra Roychoudhur, Sulggi Lee, Phyllis C. Tien, Nadia R. Roan
Julie Frouard (Gladstone Institutes, Roan lab) presented data implementing their T-TRACE protocol which integrates scRNAseq and CITE-seq to characterize the active reservoir in gut vs circulating infected CD4 T cells. Intriguingly, shared clones in blood and gut were transcriptionally and phenotypically quite different, and HIV-expressing cells were enriched for effector and cytolytic gene signatures.
Michael Peluso, Abstract 435: REBOUND DYNAMICS FOLLOWING IMMUNOTHERAPY WITH AN HIV VACCINE, TLR9 AGONIST, AND bNAb
Michael J. Peluso, Amelia Deitchman, Gesham Magombedze, Meghann Williams, Nitasha Kumar, James Mullins, Barbara K. Felber, George Pavlakis, Rowena Johnston, Jackie Reeves, Lucio Gama, Michel C. Nussenzweig, Timothy Henrich, Rachel L. Rutishauser, Steven G. Deeks, Harriet L. Robinson, Marina Caskey, Romas Geleziunas, Christos J. Petropoulos, Devi Sengupta
Michael Peluso, Steve Deeks (HIV, ID, Global Medicine division) and colleagues presented the results of perhaps the most ambitious and trailblazing HIV cure intervention ever attempted to date. In the amfAR HIV Cure Institute’s “kitchen sink” trial, ten participants with ART-suppressed HIV underwent combined therapeutic vaccination, latency reversal with TLR9 agonist, and combination bNAbs in an incredibly intensive trial conducted in the middle of the COVID-19 pandemic. The intervention included: (1) Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost vaccination, followed by (2) a combination of two broadly neutralizing antibodies (bNAbs; 10-1074, VRC07-523LS) and a TLR-9 agonist (lefitolimod) and then (3) two bNAbs given at the time of treatment interruption. While there could not be a placebo arm given logistical challenges, an impressive 5/10 participants achieved plasma viral load setpoints <1,000 copies/ml, significantly better than has been seen in historical cohorts, and were unexplained by differences in bNAb exposure or susceptibility patterns. One participant remained off ART with undetectable viremia for at least 18 months. While a sterilizing cure was not achieved in any participant, the striking findings suggest that this combination of interventions may get us one step closer to a functional cure, and will no doubt be followed up by future controlled trials.
Lily Zemelko, poster 408: IMMUNE FEATURES ASSOCIATED WITH HIGHER T-CELL RESPONSES TO AN HIV THERAPEUTIC VACCINE
Lily Zemelko, Naseem Sadek, Kara W. Chew, Mansi Purwar, Laurent Humeau, David V. Glidden, Matthew H. Spitzer, David B. Weiner, Steven G. Deeks, Rafick P. Sékaly, Jeffrey A. Tomalka, Rachel L. Rutishauser
Lily Zemelko (DEM, Rutishauser lab) presented a CyTOF- and whole blood RNAseq-based analysis of circulating immune cell phenotypes associated with a more robust HIV-specific T cell response to a DNA-based therapeutic vaccine for HIV in the PENNVAX trial. She found that higher expression of genes involved in T cell homeostasis and innate sensing were associated with more robust T cell responses to vaccination. They also found that this vaccine boosted not just cytotoxic CD8+ but also cytotoxic CD4+ T cell and gamma-delta T cell responses to HIV.
Tyler-Marie Deveau, poster 414: IMPACT OF SARS-CoV-2-MEDIATED CD4 T-CELL ACTIVATION AND HIV DNA PERSISTANCE IN VIVO
Tyler-Marie Deveau, Michael J. Peluso, Amanda M. Buck, Sadie Munter, Jane Srivastava, Rebecca Hoh, Nitasha Kumar, Rachel L. Rutishauser, Steven G. Deeks, Timothy Henrich
Tyler-Marie Deveau (DEM, Henrich lab) presented an AIM-based analysis of SARS-CoV-2-specific CD4 T cell responses in ART-suppressed people with HIV before and after SARS CoV-2 infection. They found an expected expansion of memory SARS-CoV-2 CD4+ T cells two months following COVID-19 in most participants, and in sorted SARS-CoV-2-specific CD4s, a significant expansion of HIV DNA was observed in one participant, suggesting that clonal proliferation of HIV-infected SARS CoV-2-specific CD4s may sometimes occur as a consequence of COVID-19.
PLENARY: Janet Siliciano, “HIV Reservoirs: Obstacles to a cure”
Dr. Siliciano gave a beautiful overview talk on HIV reservoirs. She discussed new approaches to measuring the reservoir and recent insights in the field characterizing the various ways in which HIV persists in cells and tissues (including clonal proliferation and homeostatic mechanisms). She also highlighted the fact that, in cure studies, it is essential to analyze the coordination between viral dynamics and host immune responses in order to fully identify potential mechanisms of control that can be harnessed in therapeutic approaches.
Abbas Mohammadi (Li Lab): “Viral and host mediators of persistent low-level viremia” and Fengting Wu (Simonetti Lab): “Proviruses in self-reactive CD4+ T cells are a common source of residual HIV viremia”, Abstracts #137 and #138
Abbas Mohammadi, Behzad Etemad, Xin Zhang, Yijia Li, Steven G. Deeks, Michael M. Lederman, Sigal Yawetz, Daniel Kuritzkes, Mathias Lichterfeld, Athe Tsibris, Mary Carrington, Zabrina Brumme, Jose R. Castillo Mancilla, Gaurav Gaiha, Jonathan Z. Li
Some people have persistent low-level viremia that cannot be suppressed with ART. These two talks explored the potential origin of the virus in these cases. They found that virus is being produced by infected cells, but does not appear to be infecting new cells (replication is blocked completely, in some cases due to defective provirus). Cells producing viral mRNA appear to be hard-wired to survive. In some cases, viral production may be coming from autoreactive CD4+ T cells.
Paul Rubenstein: “HIV-1 host reservoir reactivation after a CCR5d32/32 allogeneic hematopoietic stem cell transplant”, Abstract 434
Four cases of sustained antiretroviral-free remission after CCR5delta32/32 homozygous allogeneic stem cell transplantation have been reported (Berlin, London, Dusseldorf patients after bone marrow transplant, and a case reported at CROI 2022 of a cord blood transplant – all done for cancer treatment). The case reported at CROI 2023 was of a 67y/o with AML who received a stem cell transplant from a CCR5d32/32 homozygous donor with 100% chimerism (no detectable wt CCR5 DNA), and underwent antiretroviral treatment interruption 15 months later. HIV plasma RNA was detectable 2 months after ART was stopped with R5 tropic virus, suggesting virus arose from virally-infected wildtype CCR5 cells and highlighting the very high barrier of immune system replacement required for consistent maintenance of ART-free remission.
Ole Sogaar: “The impact of 3BNC117, 10-1074, and lefitolimod on HIV-1 persistence: The Titan Trial”, Abstract 136
The Titan trial is one example of an HIV cure study in which combinations of different therapies are given to people with HIV on ART to try to induce changes in the immune system to promote control after ART is stopped. In this study, two broadly neutralizing antibodies (bNAbs) were given with or without a drug that stimulates the innate immune system (a TLR9 agonist, lefitolimod) around the time of treatment interruption. The administration of the two bNAbs did delay viral load rebound and may have led to lower viral loads in some participants; further studies are ongoing to determine the impact of the interventions on the immune system.
Mothe et al “A placebo-controlled trial of the HTI immunogen vaccine and vesitolimod”, Abstract 433
Beatriz Mothe Pujades, Adrià Curran, Juan Carlos López, Julen Cadiñanos, Ignacio De Los Santos, Juan Ambrosioni, Arkaitz Imaz, Santiago Moreno, Pere Domingo, Yanhui Cai, Romas Geleziunas, Devi Sengupta, Ian McGowan, Christian Brander, Jose R. Arribas, Álvaro Aranguren, Margarida Garcia-Garcia, Isabel Leal, Heinz Lubenau
The AELIX-002 therapeutic vaccine, aimed at eliciting HIV-specific T cell responses that target regions of HIV associate with natural control of infection (the “HTI” insert), was recently found to lead to altered post-ART viral load dynamics (vs placebo) when given to people with HIV on ART (Bailón, Nat Med, 2022). Here, the AELIX-003 study is reported, in which HTI-containing vaccines were given in combination with vesitolimod, a TLR7 agonist. The vaccine regimen induced HTI-directed T cell responses, but did not alter post-ART viral load dynamics. Amongst vaccinated participants, higher HTI-specific T cell responses correlated with lower viral levels.
Ana Enriquez (Fromentin): “Single infusion of stem-like CCR5-modified CD4 T cells provide long-term HIV control”, Abstract 182
Ana B. Enriquez, Ashish Arunkumar Sharma, Joumana Zeidan, Gary Lee, Slim Fourati, Khader Ghneim, Gabriela Sanchez, Francesco Procopio, Robert Balderas, Nicolas Chomont, Dale Ando, Steven G. Deeks, Rafick P. Sékaly, Rémi Fromentin
Here, the authors report the outcomes of two clinical studies, SB-728-902 (n=9) and SB-728-1101 (n=9) in which individuals with HIV on ART were provided a single infusion of autologous CCR5-modified T cells (by Zinc finger nuclease disruption). Infusion of these cells resulted in the persistence of high frequencies of these cells with a stem-like phenotype, reduced HIV DNA levels, and 5 participants maintained control of plasma viremia for one to six years.
PEDIATRIC HIV CURE - Roger Shapiro: “Progress in clinical trials of pediatric HIV cure”
Nice summary of ongoing clinical trials in pediatric cure (complimented by additional talks in the session reviewing the knowledge about pediatric HIV infection and NHP studies). Key points: (1) Starting ART near birth leads to very low viral reservoirs and almost no detectable intact virus by 2 years of age (=> there is a great need to expand birth diagnostic programs to get children on ART sooner); (2) bNAb treatment studies are ongoing – they show safety, tolerability, sustained viral suppression but it’s difficult to assess the reservoir because blood volumes and the size of the reservoir both are low; (3) children have unique reservoir biomarker patterns that may be useful in ongoing and future cure studies in this population.
INTERVENTIONS TO IMPROVE HIV AND ASSOCIATED CONDITIONS’ CARE OR INEQUITIES
Gabriel Chamie. OA 112: RCT OF ECONOMIC INCENTIVES FOR REDUCED ALCOHOL USE AND INH ADHERENCE AMONG PWH
Gabriel Chamie, Judith A. Hahn, Allen Kekibiina, Nneka Emenyonu, Brian Beesiga, Kara Marson, Robin Fatch, Sara Lodi, Julian Adong, Harsha Thirumurthy, Michael McDonell, Monica Gandhi, Kendall Bryant, Moses Kamya, Winnie Muyindike
Presenter: Gabriel Chamie, UCSF
On Monday, UCSF’s Gabe Chamie (and Judy Hahn and others) presented results from a 2x2 factorial RCT among PWH on ART with latent TB infection and hazardous alcohol use in Uganda. The intervention included escalating financial incentives v. no incentives for either/or INH adherence (via electronic medication monitoring) and/or alcohol abstinence (or reduction in levels of hazardous drinking). Results showed that escalating financial incentives contingent on reduced alcohol use and/or INH adherence by monthly POC testing led to significant reductions in biomarker-confirmed alcohol use, but no change in INH adherence among PWH with latent TB infection and hazardous alcohol use receiving INH. This is the first to show efficacy in the use of financial incentives to reduce alcohol use in sub-Saharan Africa.
Bassler JR, PS 877: IMPACT OF REDLINING ON TIME TO VIRAL SUPPRESSION AMONG PERSONS DIAGNOSED WITH HIV
Lauren J. Ostrenga, John R. Bassler, Dustin M. Long, Mariel Parman, Michael J. Mugavero, Ariann F. Nassel, Emily B. Levitan, Aadia Rana, D. Scott Batey
The ongoing impact of “redlining” neighborhoods (residential districts often inhabited by primarily racial/ethnic minoritized groups that were historically classified by the US government as “hazardous” and marked red) has been linked to observed inequities within chronic diseases such as obesity and diabetes. This study examined the association of structural racism from historic redlining policies with the amount of time to reach viral suppression among people newly diagnosed with HIV (PWH) in Louisiana. City boundaries defined by the 2020 U.S. Census Bureau were spatially joined with historically redlined-graded neighborhood data, and residences of new HIV diagnoses from 2011-2019 were determined from the Louisiana HIV surveillance data. Of the 3,227 PWH included in the analysis, 929 (28.8%) lived in a redlined neighborhood. Results showed that the adjusted median time to viral suppression among PWH in redlined neighborhoods was 262 days (95% CI: 219- 294), significantly longer than the 195 days (95% CI: 182-207) among PWH in non-redlined neighborhoods. Additionally, PWH in redlined neighborhoods were 0.88 (95% CI: 0.81-0.95) times as likely to reach viral suppression vs PWH in non-redlined areas. Findings suggest that generational and structural inequities, as well as the physical environment, continue to impact present-day health outcomes of PWH.
Perazzo JD, PS 1082: A RANDOMIZED CONTROL TRIAL OF AN HIV CARE INTERVENTION BUNDLE FOR PEOPLE WITH HIV
Joseph D. Perazzo, Tamilyn Bakas, Qutaibah Oudat, Joshua Lambert, Carl
Patient navigation and case-management services to improve care are well-supported interventions that have mostly been tested in isolation. This poster presents findings from a longitudinal randomized control trial that examined the effectiveness of a pre-/post-visit telehealth bundled-services intervention towards participant time to viral suppression and visit-related outcomes. Participants were randomized to receive the standard of care (n=20) or the bundled-services intervention (n=20), which consisted of up to seven additional telehealth sessions with a registered nurse that provided psychosocial and educational support, health system navigation, and enhanced health care communication. Results of the study showed that participants within the intervention arm reached viral suppression more quickly, were more likely to be undetectable at the 12-month time point, were more likely to complete scheduled visits, and less likely to be lost to follow-up in the first year. Findings suggest that telehealth bundled-services interventions that occur pre- and post-visit can help patients reach viral suppression sooner and remain engaged to clinical care.
Susan Graham, PS 535: US PATIENT PREFERENCES FOR LONG-ACTING HIV TREATMENT: A DISCRETE CHOICE EXPERIMENT
Susan M. Graham, Douglas Barthold, Brett Hauber, Aaron Brah, Enrique Saldarriaga, Ann C. Collier, Rodney Ho, Vincent C. Marconi, Jane Simoni
Long-acting antiretroviral therapy (LA-ART) has the potential to provide new HIV treatment options with longer durations that can address adherence barriers. This study utilized a discrete choice experiment (DCE) to elicit preferences for key attributes of potential LA-ART modalities among people with HIV (PWH) in Atlanta, Georgia, and the western Washington State. The DCE presented three options (two systematically generated hypothetical LA-ART regimens and an opt-out option) over 17 choice scenarios. LA-ART regimen descriptions focused on four different treatment modalities (oral tablets, injections, and implants) with varying product characteristics (e.g., pain, dosing frequency) and administration locations (clinic, pharmacy, home). 700 participants were enrolled (median age 51 years, 70% identified as male), and findings suggest that a long-acting oral tablet will be preferred by many participants over their current treatment, with annual implants and injections being the next most preferred modalities. As advances in LA-ART continue, these results indicate that treatment modalities with longer time between doses and administration at their home can facilitate uptake of future novel LA-ART regimens.
Bow Suprasert. SPS 864 NOT GETTING TO ZERO HIV FOR PEOPLE WHO INJECT DRUGS
Moranda Tate, Bow Suprasert, Danyion Reagan, Katherine Gao, Katherine McNaughton, Raul Ruiz, Kassandra Miller, Alexander Marr, Kelly D. Taylor, Willi McFarland, Erin C. Wilson SFDPH’s Moranda Tate, Bow Suprasert, and UCSF/SFDPH colleagues presented a poster using data from NHBS survey of people who inject drugs (PWID) in San Francisco. They highlight an increase in new HIV infections among PWID despite decreases in the epidemic overall. Data demonstrate that San Francisco is not on course to get to zero HIV infections according to previously-projected timelines, citing stigma towards drug users in healthcare settings and systems as an important and recalcitrant barrier.
Hannah Leslie. PS 937: OVER-AND UNDER-REPORTING IN HIV TESTING, STATUS, AND TREATMENT IN RURAL SOUTH AFRICA
Hannah H. Leslie, Chodziwadziwa Kabudula, Rebecca West, Mi-Suk Kang Dufour, Aimée Julien, Nkosinathi Masilela, Stephen Tollman, Audrey Pettifor, Kathleen Kahn, Sheri Lippman
UCSF’s Hannah Leslie presented a poster that evaluated the accuracy of self-reported HIV testing, HIV status, and HIV treatment compared to population-based survey data and clinic records in rural South Africa. Findings suggest that survey-based self-report methods substantially overestimate recent HIV testing and underestimate HIV prevalence.
Matthew Spinelli. PS 1011: PREVALENCE AND CORRELATES OF SARS-CoV-2 VACCINE - HESITANCY AMONG US PEOPLE WITH HIV
Matthew A. Spinelli, Mallory O. Johnson, Nadra E. Lisha, Jennifer P. Jain, Carlos Moreira, David V. Glidden, Greer Burkholder, Heidi Crane, Jeffrey Jacobson, Edward Cachay, Kenneth H. Mayer, Sonia Napravnik, Richard Moore, Monica Gandhi, Katerina Christopoulos
Using data from the CFAR Network of Integrated Clinical Systems (CNICS), UCSF’s Matt Spinelli reported SARS-CoV-2 vaccine hesitancy among 7% of PWH in routine clinical care in the US. Hesitancy was higher among female and Black patients, but hesitancy decreased over time during the COVID-19 pandemic. Findings suggest a need for tailored and targeted interventions in the future.
Jose Gutierrez. PS 1055: IDENTIFYING PREFERRED PROGRAM DELIVERY ATTRIBUTES FOR LONG-ACTING INJECTABLE ART
Jose Gutierrez, Elizabeth Montgomery, Moira McNulty, Jonathan Colasanti, Mallory O. Johnson, Torsten Neilands, Kimberly Koester, John Sauceda, Samantha E. Dilworth, Xavier Erguera, Kaylin Dance, Manami Diaz Tsuzuki, John Schneider, Elvin Geng, Katerina Christopoulos
In a poster focused on patient preferences for delivery of long-acting injectable ART, UCSF’s Jose Gutierrez presented data from the UCSF Modern ART study. Using a discrete choice experience, results indicated that the most important considerations included cost (no cost preferred over co-pay) and injection visit location (HIV clinic preferred over mobile van or other options).
Hong-Ha Truong. PS 1026 Prevalence of chlamydia and gonorrhea among adolescents in Kisumu, Kenya
Hong-Ha M. Truong, Elsa Heylen, Kevin Kadede, Sayo Amboka, Damaris Odeny, Maurice Opiyo, Marion Hewa, Fidel Opondo, Beatrice Otieno, Hanningtone Odhiambo, David Ogolla, Mary Guzé, Lara E. Miller, Craig R. Cohen, Elizabeth A. Bukusi
In a poster detailing data on the prevalence of chlamydia and gonorrhea among 15–19-year-olds in Kisumu, Kenya, UCSF’s Hong-Ha Truong presented compelling survey results (for > 3000 adolescents) and STI testing data for approximately a third of the sample who reported sexual activity. STI prevalence overall was 9.6% and higher among girls and adolescents who reported recent sexual activity, transactional sex, or forced sexual contact. Most adolescents who tested positive were asymptomatic and thus would likely have gone undiagnosed and untreated, a finding that underscores the importance of routine STI testing in this setting for this population.
HIV PREVENTION ABSTRACTS
Mark Marzinke Abstract 159: CABOTEGRAVIR PHARMACOLOGY IN THE BACKGROUND OF DELAYED INJECTIONS IN HPTN 084
Mark A. Marzinke, Xu Guo, James Hughes, Brett Hanscom, Estelle Piwowar-Manning, Craig Hendrix, Scott Rose, Jim Rooney, Alex R. Rinehart, Susan Ford, Adeola Adeyeye, Myron S. Cohen, Mina Hosseinipour, Sinead Delany-Moretlwe
HPTN 084 is a phase 3, randomized, placebo-controlled trial which demonstrated the superiority of long-acting injectable cabotegravir compared to oral TDF/FTC for reduction in HIV incidence among individuals assigned female at birth. In this study, Marzinke and colleagues examined the impact of delayed injections. Cabotegravir injections are normally given every four weeks for the 2 loading doses and then every eight weeks after that. Delays were considered type 1 (if the second loading dose occurred >8 weeks after the first injection, but not more than 14 weeks) or type 2 (if subsequent injections occurred 12-18 weeks after the preceding injection). One participant experienced HIV seroconversion after a 16-week delay between injections 8 and 9, with CAB concentrations <4x PA-IC90. There were an additional 194 participants experiencing 19 type 1 delays and 205 type 2 delays. For type 1 delays, 100% of occurrences given at 8-10 weeks yielded cab levels ≥ 4x the PA-IC90, but those >10 weeks only 25% were ≥ 4x the PA-IC90. For type 2 delays, 98% at 12-14 weeks and 90% at 16-18 weeks were ≥ 4x the PA-IC90. In summary, there may be up to 6 weeks of forgiveness for individuals female at birth who receive delayed CAB-LA injections, with quarterly dosing likely feasible in this population.
Sue Eshleman Abstract 160: THE LEVI SYNDROME: CHARACTERISTICS OF EARLY HIV INFECTION WITH CABOTEGRAVIR FOR PrEP
Susan H. Eshleman, Jessica M. Fogel, Estelle Piwowar-Manning,
Brett Hanscom, Alex R. Rinehart, Myron S. Cohen, Marybeth McCauley,
Jennifer Farrior, Adeola Adeyeye, Mina Hosseinipour, Beatriz Grinsztejn,
Mark A. Marzinke, Sinead Delany-Moretlwe, Raphael J. Landovitz,
HPTN 083 and 084 demonstrated the superiority of long-acting injectable cabotegravir to oral TDF/FTC for HIV prevention in cisgender men and transgender women who have sex with men; and cisgender women; respectively. Twenty breakthrough HIV infections were detected during the blinded phase of the 2 trials (5 baseline, 15 incident; 16 of 20 occurred in HPTN 083). Long-acting Early Viral Inhibition (LEVI) Syndrome is a novel phenotype of HIV breakthrough infection with extremely prolonged negative antigen/antibody testing after HIV infection, which can be detected early only with repeated HIV RNA testing. Of these 20 infections, 7 did not have cab exposure within 6 months, with standard HIV antigen/antibody testing algorithms behaving normally and no INSTI resistance detected. Of the remaining 13 cases, 12 exhibited delayed detection with standard algorithms, with INSTI mutations occurring in 10 (major mutations for 7). Retrospective RNA testing and genotyping indicated that most cases of INSTI resistance could have been prevented via earlier detection of breakthrough infection. RNA testing, when available, should be used for HIV monitoring when using cabotegravir for PrEP.
Sybil Hosek Abstract 162 CAB LA FOR HIV PREVENTION IN AFRICAN CISGENDER FEMALE ADOLESCENTS (HPTN 084-01)
Sybil Hosek, Erica L. Hamilton, Julie Ngo, Yuqing Jiao, Brett Hanscom, Sinead Delany-Moretlwe, Nyaradzo M. Mgodi, Bekezela Siziba, Ishana Naidoo, BRENDA G. MIREMBE, Betty Kamira, Mark A. Marzinke, Cynthia McCoig, Hans Spiegel, Lynda Stranix-Chibanda
HPTN 084-01 is a Phase 2B safety study examining injectable cabotegravir for PrEP among 55 adolescent women. Overall, injectable cabotegravir was well-tolerated in this population with no safety signals. While oral cabotegravir adherence was sub-optimal, nearly all cabotegravir injections were on time except for 1 at week 9 and 2 at week 33. Overall, 94% of participants elected to continue CAB-LA via HPTN 084 Open Label Extension. In summary, Cab-LA is an attractive PrEP option for adolescent women given challenges with adherence to oral PrEP options in this population.
Hyman Scott Abstract 161 CABOTEGRAVIR FOR HIV PrEP IN US BLACK MEN AND TRANSGENDER WOMEN WHO HAVE SEX WITH MEN
Hyman Scott, Brett Hanscom, Craig Hutchinson, Jonathan Lucas, Aditya Gaur, Colleen Kelley, Debora Dubar, Paul Richardson, Jim Rooney, Alex R. Rinehart, Adeola Adeyeye, Beatriz Grinsztejn, Raphael J. Landovitz, Sheldon Fields
HPTN 084 is a phase 3, randomized, placebo-controlled trial which demonstrated the superiority of long-actine injectable cabotegravir compared to oral TDF/FTC for reduction in HIV incidence among cisgender men and transgender women who have sex with men. At U.S. sites, of 1698 individuals enrolled, 844 (50%) were Black. Among Black men and transgender women who have sex with men in the TDF/FTC arm, the HIV incidence was 2.11 per 100 P-Y vs. 0.62 in non-Black participants in the TDF/FTC arm. In the CAB-LA arm, the incidence was 0.58 per 100 P-Y in Black participants vs. 0 in non-Black participants. In conclusion, HIV incidence was high in the TDF/FTC arm among Black participants in HPTN 083, however, there was consistent higher protective efficacy of Cab-LA vs. TDF/FTC among Black participants, indicating that this is a powerful prevention tool for reducing HIV incidence among Black MSM and transgender women.
Shannon Riddler # 164 SAFETY AND PK/PD OF A TENOFOVIR ALAFENAMIDE/ELVITEGRAVIR INSERT ADMINISTERED RECTALLY
Sharon A. Riddler, Clifton Kelly, Craig Hoesley, Ken Ho, Jeanna Piper, Stacey Edick, Faye Heard, Yuqing Jiao, Gustavo F. Doncel, Sherri Johnson, Ratiya Pamela Kunjara Na Ayudhya, José Bauermeister, Craig Hendrix
A fast-dissolving insert containing 20mg of TAF and 16mg of elvitegravir (EVG) demonstrated efficacy in rectal/vaginal SHIV challenge studies among non-human primates. In this Phase 1 open label study, the safety and PK of 1 and 2 inserts was tested among humans, with ex vivo HIV infectivity studies of rectal tissue performed. Twenty-one participants of whom 71% were male at birth were recruited, with the inserts well tolerated, with one episode of anal erythema determined related to product. EVG and TAF were detected in nearly all rectal tissue samples at 2 hours post dose. EVG concentrations declined and were below the limit of quantification in 50% vs. 30% for those with 1 vs. 2 inserts at 24 hours whereas TFV was measurable in the majority of samples for 72h. Compared to baseline, median log10 HIV p24 antigen was significantly reduced at all timepoints for both 1 and 2 inserts. TAF/EVG inserts are a promising on-demand rectal microbicide for HIV prevention.
Alessandro Grattoni # 165 ULTRA LONG-ACTING REFILLABLE ISLATRAVIR IMPLANT FULLY PROTECTS NHP AGAINST SHIV
Fernanda Pons-Faudoa, Nicola Di Trani, Corrine Ying Xuan Chua, Lane Bushman, Simone Capuani, Jocelyn Nikita Campa Carranza,Kathryn Shelton, Pramod Nehete, Joan Nichols, Jason Kimata, Peter L. Anderson, Roberto C. Arduino, Alessandro Grattoni, Charles Dobard, Gerardo Garcia-Lerma
In this implant strategy, a titanium implant silicone membrane controls drug release. Nano-channel systems works like an hourglass; it releases drug in a constant and sustained fashion at a constant rate through an electrostatic reaction. In this study an islatravir nanofluidic implant was placed in 4 macaques, with islatravir triphosphate levels remaining constant over 20 months, and 100% efficacy demonstrated via weekly rectal/vaginal low dose SHIV challenges. Mild local tissue inflammation occurred but there were no signs of systemic toxicity. Islatravir nanofluidic implants are a promising technology for HIV prevention that can achieve therapeutic levels for long periods with minimization of sub-therapeutic tail concentrations which may select for resistance in cases of HIV breakthrough.
Katherine Bunge # 127 DELIVER: a safety study of a Davipirine vaginal ring and oral PrEP during Pregnancy
Katherine E. Bunge, Jennifer Balkus, Felix Mhlanga, Ashley Mayo, Lee Fairlie, Clemensia Nakabiito, Luis Gadama, Catherine Chappell, Nyaradzo M. Mgodi, Jeanna Piper, Nahida Chakhtoura, Daniel szydlo, Barbra Richardson, Sharon L. Hillier
DELIVER is a safety study of pregnant individuals using the dapivirne ring and TDF/FTC PrEP during pregnancy as early as 30 weeks of gestation. Overall, enrollment was stratified approximately 1:1 to those 30-36 weeks and those 36+ weeks of pregnancy. 307 participants were enrolled with women randomized approximately 2:1 to the dapivirine ring within both of these cohorts. Overall, one stillbirth and one neonatal death occurred in the TDF/FTC arm (occurring <36 weeks), and one stillbirth and one neonatal death occurred in the dapivirine arm (occurring >36 weeks). These adverse pregnancy outcomes are similar to the background rate in the populations enrolled and support investigation of dapivirine earlier in pregnancy.
Susan Buchbinder MOSAICO Study Report-Back: Phase 3 Study Results from a Mosaic Adenovirus26 -based HIV vaccine
MOSAICO is a Phase 3 Study which tested a tetravalent mosaic adenovirus 26 vector HIV vaccine which was administered at two timepoints (months 0 and 3) which was followed by an additional dose of the Ad26 tetravalent mosaic vaccine and a Gp140 bivalent vaccine at months 6 and 12. Overall, 3,900 participants were enrolled, including cisgender men and trasgender women who have sex with men. Those who wanted PrEP were referred to programs and were not enrolled in the study. Unfortunately, in interim analysis, the HIV incidence was 4.1 per 100 person-years in both the vaccine and placebo arms, indicating 0% efficacy. In a follow-up presentation by Dr. Larry Corey, he reflected that the Mosaico study demonstrates that vaccine approaches which generate non-neutralizing antibodies are unlikely to be a viable strategy for an HIV vaccine, and instead, we will need to work on immunogens that generate broadly neutralizing antibodies to more than one site.
COMORBIDITIES AND HIV
Matthew Durstenfeld, poster 666: EXERCISE CAPACITY IS REDUCED IN HIV INDEPENDENT OF SARS CoV-2 INFECTION
Matthew S. Durstenfeld, Michael J. Peluso, Matthew A. Spinelli, Danny Li, Erica Sander, Shreya Swaminathan, Victor Arechiga, Rebecca Hoh, Mandar A. Aras, Carlin S. Long, Steven G. Deeks, Priscilla Hsue
Matthew Durstenfeld (ZSFG Cardiology) presented an analysis of exercise capacity in the convalescent COVID-19 LIINC cohort and explored differences by presence of long COVID symptoms and HIV status. He found that while those with and without long COVID had similar exercise capacity, people with HIV had significantly lower exercise capacity than those without HIV, suggesting that HIV – or unmeasured factors linked to it - likely has a more significant effect on objectively measured exercise capacity than long COVID.
Rebecca Abelman, poster 679: ASSOCIATION OF SEX HORMONES WITH INCIDENT DIABETES IN WOMEN WITH AND WITHOUT HIV
Rebecca A. Abelman, Michael Schneider, Christopher Cox, Jennifer C. Price, Mardge Cohen, Deborah Gustafson, Michael Plankey, Anjali Sharma, Phyllis C. Tien
Rebecca Abelman (HIV, ID, Global Medicine division), working with Phyllis Tien and the MACS-WIHS CCS found that higher total testosterone and lower sex homone binding globulin tended to be associated with a shorter time to develop Type 2 diabetes, independent of BMI. Future analyses will address whether these effects are any different in post-menopausal women.
Helen Byakwaga, Oral Abstract 150: HIV-RELATED KAPOSI SARCOMA IN EAST AFRICA: CONTEMPORARY UPDATE ON STAGE AND SURVIVAL
Helen Byakwaga, Aggrey Semeere, Miriam Laker-Oketta, Megan Wenger, Elyne Rotich, Charles Kasozi, Winnie Muyindike, Philippa KadamaMakanga, Sigrid Collier, Hilda Muwando, Toby Maurer, Esther Freeman, Samson Kiprono, Andrew Kambugu, Jeffrey Martin
In a contemporary East African cohort, with active surveillance for Kapsoi’s Sarcoma, Helen Byakwaga (IDI, Kampala, Uganda) and Jeffrey Martin (UCSF, Epi/Biostatistics, CFAR Clinical Core) showed that from 2021-2022, despite modern ART regimens, updated guidelines and availability of early ART initiation and Kaposi’s Sarcoma (KS) chemotherapy, many people with HIV diagnosed with KS in this setting continue to present with advanced KS, with a shockingly high mortality rate of 38% at 8 months. These findings highlight the need for earlier case identification and chemotherapy options for people with HIV and KS in East Africa.
Felicia Chow, Oral abstract 183: SEX MODIFIES THE ASSOCIATION OF AGE AND VIREMIA WITH STROKE RISK IN HIV
Felicia C. Chow, Robin Nance, Emily Ho, Andrew Huffer, Rizwan Kalani, Christina Marra, joseph zunt, Laura Bamford, Greer Burkholder, Edward Cachay, Mari Kitahata, Sonia Napravnik, David Tirschwell, Joseph Delaney, Heidi Crane
Felicia Chow (UCSF Neurology), presented an intriguing study from the CFAR Network of Integrated Clinical Systems (CNICS) network, where she evaluated the clinical predictors of stroke in over 13,000 people with HIV on ART. She found that women had a 2-fold higher risk of stroke than men, but only at younger ages. She also found that viremia and methamphetamine use were stronger predictors of stroke in women than in men. These observations may shed light on differential behavioral and biologic drivers of stroke in women and men with HIV, identifying potential interventional targets.
Cecile Lahiri, Abstract 610, Liver Steatosis and Fibrosis in Women with HIV by Integrase Inhibitor Use
Cecile D. Lahiri, Michael Yu, Logan Gerig, Cyra C. Mehta, Joffi Musonge-Effoe, Jennifer C. Price, Phyllis C. Tien, Amanda B. Spence, Svenja Albrecht, Maria L. Alcaide, Adaora Adimora, Audrey French, Michael H. Augenbraun, Kathryn Anastos, Jessica A. Alvarez
In this study from the MACS-WIHS Combined Cohort Study, Lahiri et al. investigated whether hepatic steatosis and fibrosis in women with HIV (WWH) differed following switch to integrase inhibitors (INSTI) compared to those who were continued on a non-INSTI regimen. The investigators included WWH who had been on ART for at least two years and were virally suppressed and excluded women who were HBSAg positive, had untreated HCV, decompensated cirrhosis, or heavy alcohol use. FibroScan was conducted at varying time points post-INSTI switch or at a comparable time point in the non-INSTI group. Liver steatosis, liver stiffness, and FibroScan AST (FAST) Score were evaluated after adjustment for age, CD4%, BMI, TDF or TAF use, pre-switch anchor ART class, alcohol use, and time since switch. Women who switched to INSTIs had a greater increase in weight, BMI, and waist circumference, but no differences were seen between groups beyond one year. Interestingly, WWH on INSTI had 3.6 greater odds of having hepatic steatosis within one year of switch as compared to women who did not switch to an INSTI-based regimen. No difference was seen in moderate fibrosis. Hepatic fibrosis measurements and FAST scores were only minimally higher in the INSTI group at one year. This study suggests that WWH switching to INSTIs have greater odds of having hepatic steatosis (but notably not hepatic fibrosis), providing evidence that providers should have a lower threshold for non-invasive hepatic fibrosis testing among WWH on INSTI-based regimens.
Bernard Surial, Abstract 149, Cardiovascular Disease Events in Treatment-Naïve PWH Starting INSTI-based ART
Bernard Surial, Frédérique Chammartin, José Damas, Alexandra Calmy,
David Haerry, Marcel Stöckle, Patrick Schmid, Enos Bernasconi, Philip Tarr,
Huldrych F. Günthard, Gilles Wandeler, Andri Rauch In this elegant Swiss HIV Cohort Study, Surial and colleagues sought to determine whether CVD events were increased among treatment-naïve PWH who were started on an INSTI-based regimen. This was in direct response to the Neesgaard et al. study in Lancet HIV in 2022 through the RESPOND cohort that showed that INSTI initiation was associated excess incidence of cardiovascular events in the first two years after INSTI exposure, even after adjustment for cardiovascular risk factors (although notably this cohort included both treatment-naïve and treatment-experienced PWH). This study included treatment-naïve Swiss HIV Cohort participants after 5/2008 (when INSTIs were introduced in Switzerland) who were randomized to either an INSTI-based ART regimen or other ART. They were subsequently followed until the first cardiovascular disease event. Among those randomized to an INSTI-based regimen, the majority were on DTG (53%) or BIC (18%). Among those who were not on an INSTI-based regimen, 52% were on boosted PIs and 43% were on NNRTI-based regimens. One hundred and sixteen cardiovascular events occurred within 4.9 years (IQR: 2.4 – 7.4). No difference was observed in adjusted CV event incidence between INSTI-based ART versus other ART. This reassuringly suggests that among ART-naïve PWH, there is no difference in the rate of CVD events between those who start INSTI-based ART versus those starting other regimens.
Darrell Tan, Abstract 146, Weight and Metabolic Changes After Switch from BIC/FTC/TAF to LA CAB+RPV
Darrell H. S. Tan, Andrea Antinori, Beng Eu, Maria José Galindo,
Clifford Kinder, Donna Sweet, Cornelius N. Van Dam, Kenneth Sutton,
Denise Sutherland-Phillips, Alessandro Berni, Feifan Zhang,
William R. Spreen, Harmony P. Garges, Parul Patel, Ronald D’Amico.
This was a sub-analysis within the SOLAR study, a randomized trial comparing the efficacy, safety, and treatment satisfaction of switch to CAB + RPV Q2M to continuing oral BIC/TAF/FTC in virally-suppressed PWH. Metabolic and weight outcomes were compared from baseline to 12 months. Of note, only 17% and 18% of the participants in the LA CAB + RPV and BIC/TAF/FTC groups, respectively, were natal females and at baseline, 59% of the participants were overweight or obese in both groups. At 12 months, 3% of those in the LA CAB + RPV arm experienced a weight increase ≥10% versus 4% of those in the BIC/TAF/FTC arm. There were no significant changes in the proportion of patients in different BMI categories in both groups. There were no clinically relevant changes from baseline to month 12 in the proportion of participants with metabolic syndrome or insulin resistance in either arm. These findings suggest that a switch from BIC/TAF/FTC to LA CAB + RPV will not provide significant weight loss or changes in metabolic outcomes as compared to remaining on BIC/TAF/FTC. Of note, no sex-stratified analysis was available at the time of the presentation.
Bronwyn Bosch, Abstract 671, Weight Loss and Metabolic Change After Switching from TAF/FTC + DTG to TDF/3TC/DTG
Bronwyn E. Bosch, Godspower Akpomiemie, Nomathemba Chandiwana, Simiso Sokhela, Andrew Hill, Kaitlyn McCann, Ambar Qavi, Manya Mirchandani, Francois Venter The objective of this study, conducted as a follow-up study from the ADVANCE trial, was to evaluate whether weight gain seen with TAF + DTG use was reversible after changes in ART. Participants were initially in the ADVANCE trial (1053 treatment-naïve participants in South Africa), who were randomized to either TAF/FTC + DTG, TDF/FTC + DTG, or TDF/FTC/EFV for 192 weeks. Then, as part of the follow-up CHARATERISE study, participants were switched to the open-label TDF/3TC/DTG (TLD) for at least 52 weeks. Changes in weight, lipids, fasting glucose, Hgb A1c, and HIV RNA were followed over time. Women who were on a TAF-based regimen in ADVANCE and subsequently switched to TLD experienced a median weight loss of 1.6 kg. A similar weight loss was not seen in the male participants. Participants who were on EFV-based regimens gained a median of 2.9 kg after switch to TLD, with similar results by sex. Overall, the cohort had a slightly improved glucose and lipid profile after switching from TAF to TDF.
Sophie Degroote, Abstract 672, Favorable Metabolic Outcomes 48 Weeks After Switch to DTG/3TC
Sophie Degroote, Sophie Vanherrewege, Els Tobback, Els Caluwe, Lara Vincke, Wim Trypsteen, Mareva Delporte, Evy Blomme, Linos Vandekerckhove, Marie-Angélique De Scheerder
This study was a randomized, open-label controlled trial with PWH who were either switched to DTG/3TC, switched to BIC/TAF/FTC, or continued on BIC/TAF/FTC. Participants were followed up for 48 weeks with measurements of weight, BMI, waist circumference, lipids, insulin resistance, DXA scan, and FibroScan. Linear mixed models with covariance patterns were used and the analysis was an intention-to-treat exposed analysis. A total of 134 participants were randomized. Weight, waist circumference, and BMI were different at baseline, with higher metrics seen in the DTG group more than in the BIC group. After adjustment for baseline BMI, a larger mean difference from baseline to week 48 in both groups were seen in ALT, HDL, lean trunk mass, trunk fat mass, and fat percentage. There were no significant differences with respect to the other outcomes. Greater treatment-mediated differences in trunk fat mass were seen in people with BMI >30 kg/m2 in both groups. These results suggest that switch to DTG/3TC may improve metabolic outcomes at week 48 when compared to BIC/TAF/FTC, particularly if other metrics to evaluate body composition are used.
Myrthe Verburgh. Abstract 673, Reversibility of TAF- and/or INSTI-associated Weight Gain
Myrthe L. Verburgh, Ferdinand Wit, Anders Boyd, Peter Reiss, Marc van Der Valk This study aimed to determine the reversibility of >7% TAF and/or INSTI-associated weight gain in virally suppressed PWH. Taking place as part of the ATHENA cohort in the Netherlands, the investigators selected virally suppressed individuals who had either switched to TAF only, switched to an INSTI only, or to both TAF + INSTI and had gained >7% body weight within 24 months of switch. Then, they selected individuals who had discontinued only TAF, only an INSTI, or both TAF + INSTI after the weight gain had occurred. A control group of individuals who experienced >7% weight gain within 24 months of switch but who continued on their regimen was used. Mean weight changes prior to and after switch were recorded and modeled. Sixty-nine PWH switched from TAF and/or an INSTI-based regimen. Within the cohort, 79.7% were male and the median BMI at discontinuation of TAF and/or INSTI was 25.7 kg/m2 (IQR 23.7-28.0). Within 24 months prior to discontinuation, weight gain was: 3.20 kg [95% CI, 1.02, 5.40] among those who discontinued TAF only, 5.89 kg [3.37, 8.89] among those who discontinued only INSTI, and 5.64 kg [2.03, 9.23] in the TAF + INSTI group. In the first 12 months after discontinuation, weight change was: -1.30 kg [-2.94, 0.15] in the TAF group, -2.55 kg [-4.48, -0.73] in the INSTI group, and -1.69 kg [-4.93, +1.26] in the INSTI + TAF group. Notably, after 12 months, weight loss stabilized in all groups. These results suggest that weight gain from TAF/INSTI use appears to be only partially reversible after discontinuation.
Sangwon Kim. Abstract 147, A Loss of Erα Attenuates DTG-mediated Disruption of Thermogenesis in Brown Adipocytes
FIkrak Jung, Sunghee Jin, Becky Tu-Sekine, Frederick Anokye-Danso,
Todd T. Brown, Sangwon Kim
Building on prior work that demonstrated that two-week administration of DTG to female mice reduced energy expenditure and decreased UCP1 expression in brown/beige adipose tissue (Jung et al, JID, 2022), this study aimed to evaluate whether INSTIs may interrupt adipose function via the estrogen receptor. Estrogen receptor-mediated transcriptional activity was measured by luciferase reporter containing estrogen response element in the presence of DTG, DOR, and EFV. Estrogen receptor α (ERα) deficient cells were created from primary preadipocytes isolated from female mice and were subsequently treated with DTG for eight days as differentiation into mature white or brown adipocytes occurred. Mature adipocytes were then analyzed for lipid accumulation by Oil Red O staining, adipogenic markers by qRT-PCR, and immunoblotting. The investigators found that DTG treatment reduced estrogen-mediated ERE-reporter activity in a dose-dependent manner, whereas DOR and EFV had no effect. While genetic deletion of ERα alone did not affect overall adipogenesis, loss of ERα attenuated DTG-mediated suppression of UCP1, which is essential for the thermogenic process in brown/beige adipocytes. Other brown adipogenesis markers were decreased in ERα suppression and lipolysis was blunted in those with deleted ERα. These findings suggest that DTG inhibits the estrogen receptor-mediated transcriptional regulation pathway and may provide a potential sex-specific mechanism by which INSTIs may lead to weight gain.
Kassem Bourgi, Abstract 674, Weight Gain Among Participants Switching to a DTG-based HIV Regimen in Kenya
Kassem Bourgi, Susan Ofner, Beverly Musick, Kara Wools-Kaloustian, Lameck Diero, Constantin Yiannoutsos, Samir Gupta
This study aimed to evaluate whether there are differences in the rate of weight gain following switch to DTG in Kenya. Participants enrolled in the Academic Model Providing Access to Healthcare (AMPATH) program in Kenya who were on an NNRTI for greater than or equal to 24 months prior to switching to DTG were included in the study. Changes in the rate of weight gain were measured following switch to DTG and stratified by sex and baseline NNRTI regimen. Overall, 23,131 participants were included in the analysis. Thirty four percent were on EFV as the baseline NNRTI drug and 29% were on NVP. The rate of weight gain for overall participants was 0.35 kg/year pre-switch followed by 0.7 kg/year post-switch. Among female participants, the rate of weight gain was 0.44 kg/year pre-switch as compared to 0.9 kg/year post-switch. Among males, the rate of weight gain was 0.23 kg/year pre-switch and 0.5 kg/year post-switch. Participants switching from EFV-based regimens exhibited a significant increase in weight gain following DTG switch (0.44 kg/year pre-switch versus 1.2. kg/year post-switch) whereas participants switching from NVP-based regimens had no changes in the rate of weight gain.