| CROI 2022 - Day Two Summaries
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Dear HIV Research Community,
Courtesy of the CFAR leadership, we will send you a short summary of notable abstracts from each day of the Virtual CROI 2022 conference the following day. Please note that this summary is by no means meant to be a comprehensive overview of everything presented at CROI 2022, but a highlight from each day with a focus on presentations from CFAR-affiliated investigators. Thanks to Rebecca Abelman, MD, for assisting with the Tuesday summaries!
Thank you!
CFAR Leadership
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Clinical Plenary
UNDERSTANDING THE EPIDEMIOLOGY OF COVID-19: A GLOBAL PERSPECTIVE
Dr. Muge Cevik, Clinician Scientist in Infectious Diseases and Virology at the University of St. Andrews gave a comprehensive plenary on the global epidemiology of COVID-19. She started her talk justifiably indicating that the sheer volume of information on COVID-19 (303,169 publications so far!) was extraordinary but less so was the capacity to make sense of it given all the conflicting information.
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The global pandemic has had mixed patterns worldwide with different waves and degrees of illness but one consistency is that vaccines have significantly reduced the morbidity and mortality of the disease.
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Factors driving transmission are complex and include host, viral, environmental and structural factors as shown here but data consistently shows outside transmission rare. Finally, as understand that COVID-19 cannot be eradicated, but work on global vaccine equity, we have to be aware that part of a pandemic response is to work on recovery from the pandemic given the profound other health impacts such as loss of progress in TB, malaria, hunger, childhood education, etc.
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Basic Science Plenary
NEW INSIGHTS INTO HIV RNA BIOLOGY
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In his plenary, Michael Summers presented new insights into the HIV life cycle, essentially rewriting the textbooks. It was always assumed that the HIV capsid was dissembled in the cytoplasm of the infected cell before cDNAs were brought to the nucleus, but new insights have revealed that capsid disassembly happens only after transport to the nucleus, which protects HIV nucleic acids from host restriction factors in the cytoplasm. He also discussed new insights in mechanisms for alternative splicing and the interactions between packaging signals on viral RNA and capsid proteins that are essential for capsid assembly, which may lead to the identification of novel antiviral strategies.
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Other important abstracts
S8-OA89: TRENDS IN HIV TESTING AND LINKAGE TO HIV TREATMENT IN 41 COUNTRIES: 2016-2021
Bakary Drammeh1, Anindya K. De1, Amy Medley1, Randy Yee2, Shazad Ahmed3, Helen Dale1, Arielle Lasry1, Vincent J. Wong4, Michael Grillo5, Emanny Sanchez1, David A. Miller1, Tiffiany Aholou1, Shahul Ebrahim1, Stephanie Behel1
In this descriptive analysis of treatment outcomes from the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) in 41 countries (22 in sub-Saharan Africa, 6 in the Caribbean, 2 in Central and South America, 10 in Asia, and 1 in Europe) between 2016-2021, the authors found that 443 million HIV tests were conducted. Of these 443 million tests, 17.5 million were positive. The number of tests increased by 42% from 19 million in March 2016 to a peak of 27 million in September 2018. PEPFAR had a change in policy in 2019 from universal testing to testing those at highest risk for HIV, at which time HIV testing decreased by 45% to 15 million in June 2021. The number of HIV diagnoses commensurately decreased over this interval; the number of positive tests peaked in September 2017 at one million and subsequently decreased by 40% to 0.6 million in June 2021. The authors also looked at percent positivity of HIV tests, which decreased from 5% in 2016 to 4% in June 2021. Those newly initiated on ART increased by 60% from 0.5 million in March 2016 to 0.8 million in September 2017 before decreasing to 0.6 million in June 2021. However, the percent of newly diagnosed individuals started on ART had increased from 60% in March 2016 to approximately 90% to June 2021, which the authors postulated might partially be attributed to same-day ART initiation. These findings suggest that while the number of HIV tests conducted have decreased since 2018, the percent positivity has remained relatively stable. The percent of newly diagnosed individuals who initiated ART has increased due to significant improvement in linkage strategies.
S7-OA82: PHASE I PK, SAFETY, AND ACCEPTABILITY STUDY OF A 90-DAY TENOFOVIR VAGINAL RING
Albert Liu1, Holly Gundacker2, Barbra A. Richardson2, Beatrice Chen3, Craig Hoesley4, Ariane Van der Straten5, May Beamer3, Jennifer Robinson6, Cindy Jacobson3, Rachel Scheckter7, Katherine Bunge3, Andrea Thurman8, Gustavo Doncel8, Jeanna Piper9, Mark Marzinke6
The UCSF Bay Area CFAR’s own Albert Liu (at the SFDPH) presented the results from MTN-038, a Phase 1 randomized trial comparing a 90-day TFV vaginal ring as compared to a placebo vaginal ring. TFV concentrations were measured in the plasma, cervicovaginal fluid, rectal fluid, and cervical tissue and TFV-diphosphate levels were measured in cervical tissue. Retention was high (98%) with 84% fully adherent for ring use. There were no statistically significant differences in adverse events in the TFV arm as compared to the placebo arm. TFV levels exceeded target cervical tissue concentrations through day 56, but levels declined thereafter and fell markedly after day 91. Returned rings were analyzed for residual TFV and 13/32 had low or no residual TFV with no significant differences by sociodemographics or sexual activity. A majority of participants reported liking the ring with a median score of 8 on a 10-point Likert scale. These initial results suggest that TFV-containing vaginal rings may be an acceptable and well-tolerated method for HIV prevention in women with additional studies needed to assess optional duration of use.
S7-OA83: ISLATRAVIR DISTRIBUTION IN MUCOSAL TISSUES, PBMC, & PLASMA AFTER MONTHLY ORAL DOSING
Craig W. Hendrix1, Sharon L. Hillier2, Linda-Gail Bekker3, Sharlaa Badal-Faesen4, Sharon A. Riddler5, Edward J. Fuchs1, Pippa J. Macdonald3, Stacey Edick6, Rebeca M. Plank7, Cynthia M. Chavez-Eng7, Barbara Evans7, Xiaowei Zang7, Ryan Vargo7, Michael N. Robertson7, Munjal Patel7
In this Phase 2a, double-blind, randomized, placebo-controlled trial, adults deemed to be at low-risk for HIV were given 60 mg and 120 mg monthly oral Islatravir for PrEP and monitored over 24 weeks. Both male and female participants were included in the study. Drug penetration in rectal and vaginal mucosa were measured over the 24 weeks, with parallel declines and similar trough concentrations seen between Islatravir doses for both the 60 mg and 120 mg tablets. For both doses, all levels remained above the PK threshold. Drug concentrations were generally similar across tissue types in women and men in its active form. Plasma Islatravir concentrations were similar to other tissue concentrations, suggesting plasma Islatravir levels can be used as a surrogate for cervical and rectal tissue levels. Islatravir is currently on hold by the US FDA due to changes in lymphocytes and thus all clinical trials have stopped. Lymphocyte counts were not included in this analysis.
S7-OA84: THE BIDIRECTIONAL EFFECTS OF HORMONE THERAPY AND PrEP IN TRANSGENDER INDIVIDUALS
Jill Blumenthal, Ravi Goyal, Leah Burke, Michael Dubé, Martin Hoenigl, David J. Moore, Karen Chow, Jordan Silva, Katya Corado, Richard H. Haubrich, Peter Anderson, Robert Bolan, Sheldon Morris
This analysis is a sub-study of a larger RCT evaluating PrEP adherence in transgender individuals. Participants were all stably on hormonal therapy. Tenofovir diphosphate levels were measured in addition to sex hormone levels at weeks 0 and 12. At week 12, there was no difference in TFV-DP levels in either transgender women or transgender men, regardless of whether they were taking hormonal therapy. Estradiol and testosterone levels did not change significantly in transgender women and transgender men, respectively. There was significant attrition over the course of the study, but there were no changes in perceived effect of hormone therapy on those taking PrEP.
S7-OA85: PHASE IIA TRIAL OF ISLATRAVIR QM FOR HIV PrEP: WEEK 24 METABOLIC AND RENAL OUTCOMES
Pippa J. Macdonald, Sharon A. Riddler, Sharlaa Badal-Faesen, Howard Schwartz, Johannes Lombaard, Yoseph Caraco, Avivit Peer, Ciaran McMullan, Keith D. Kaufman, Brenda Homony, Katherine Nedrow, Valerie Teal, Michael N. Robertson, Rebeca M. Plank
This study was a randomized, double-blind, placebo-controlled multi-center trial evaluating the safety, tolerability, and pharmacokinetics of monthly oral Islatravir in adults at low-risk for HIV as PrEP. Participants received either 60 mg of Islatravir, 120 mg of Islatravir, or placebo over six months. Metabolic outcomes and renal outcomes were assessed through Week 24. In this analysis, 67% were female and 41.7% were Black or African American. Baseline metabolic and renal characteristics were comparable across groups. For weight, median percent changes in baseline weight were small and comparable between the 60 mg ISL and placebo groups with a slight increase in weight observed in the 120 mg ISL group (1.82% change, IQR -0.93, 4.40). Similar findings were seen in peripheral and trunk fat measurements with slight increases seen in the 120 mg ISL group. There were no changes in baseline eGFR observed across all treatment groups. Islatravir is currently on hold by the US FDA due to changes in lymphocytes and thus all clinical trials have stopped. Lymphocyte counts were not included in this analysis.
S8-OA96: UPDATED EFFICACY, SAFETY, AND CASE STUDIES IN HPTN 083: CAB-LA VS TDF/FTC FOR PrEP
Raphael J. Landovitz, Deborah Donnell, Ha Tran, Esper G. Kallas, Manya Magnus, Mark Marzinke, Susan Eshleman, Brett Hanscom, Adeola Adeyeye, James F. Rooney, Alex R. Rinehart, Myron S. Cohen, Marybeth McCauley, Beatriz Grinsztejn, for the HPTN 083 Study Team
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In this fascinating update to HPTN 083, an ongoing Phase 2b/3 randomized control trial evaluating long-acting injectable cabotegravir (CAB-LA) versus daily oral TDF/FTC, updated HIV incidence rates from the blinded phase of the trial and for one year of follow-up were presented. After the completion of the blinded portion of the study in May 2020, eligible participants were offered CAB-LA.
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In the blinded trial, 51 incident HIV infections were identified (12 CAB, 39 TDF/FTC). In this updated analysis, 46 additional incident HIV infections were identified in the pre-planned analysis period (13 CAB, 33 TDF/FTC), of which 4 occurred in the blinded phase (2 CAB, 2 TDF/FTC) and 42 after unblinding (11 CAB, 31 TDF/FTC).
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However, reduction in risk for CAB-LA versus TDF/FTC remained similar in blinded and unblinded phases (HR=0.33 95% CI (0.18-0.62) and HR=0.34 95% CI (0.17-0.67)) with higher HIV incidence in both arms in the unblinded phase, suggesting increased HIV incidence may be attributable to reduced adherence in both groups.
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The two newly identified blinded CAB arm infections were in the setting of on-time CAB injections. Of the 11 identified unblinded CAB incident infections, one had on-time injections, three had delayed injections, and seven occurred greater than six months after the last CAB exposure (2/7 never received a CAB injection). While CAB-LA remains an exciting and effective PrEP option, barriers to adherence are still a challenge, presenting an important area for development of novel strategies and implementation approaches. Of note, we do not know the resistance patterns of the new failures yet.
S8-OA95: CAB- LA PrEP: EARLY DETECTION OF HIV INFECTION MAY REDUCE InSTI RESISTANCE RISK Susan Eshleman, Jessica M. Fogel, Elias K. Halvas, John W. Mellors, Estelle M. Piwowar-Manning, Alex R. Rinehart, Marybeth McCauley, Adeola Adeyeye, Juan C. Hinojosa, Robinson Cabello, Keren Middelkoop, Myron S. Cohen, Beatriz Grinsztejn, Raphael J. Landovitz, for the HPTN 083 Study Team
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Susan Eshleman and her co-authors at HPTN 083 did an analysis of the seven breakthrough infections from HPTN 083 that demonstrated INSTI resistance-associated mutations (RAMs) after cabotegravir exposure.
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Of note, two of these participants did not have genotypes available as their VLs were <500 c/mL. All seven infections had delay ed antigen/antibody conversion (median 60 days). In this analysis, the authors used single-genome sequencing INSTI genotyping assay to assess whether earlier detection of these HIV infections could have prevented INSTI emergent resistance. The assay detected INSTI RAMs in 6/7 participants. Through this analysis, an RNA assay would have detected infection before a major INSTI RAM was detected for four cases or, in two cases, prevented accumulation of major INSTI RAMs. In the last case, this could not be assessed as single-genome sequencing was not successful before the first site-positive visit. Importantly, in 5/7 cases, major INSTI RAMs were first detected in samples with low viral loads. As CAB use for PrEP becomes more widespread, considerations regarding the use of HIV RNA testing for earlier detection of HIV become increasingly important.
S5-OA65: HIV-1 REMISSION WITH CCR5∆32∆32 HAPLO-CORD TRANSPLANT IN A US WOMAN: IMPAACT P1107
Dr. Bryson presented an important case of the likely third cure of HIV infection, this time in a woman (59 years old) of mixed race with HIV and leukemia so difficult to find a match with homozygous 32 base pair deletions in the CCR5 gene. However, the investigators used partially matched cord blood with a haplo-cord transplant with full engraftment, cure of the AML, and, eventually, cure of the HIV (14 months after stopping antiretroviral therapy). Very nice write-up in the New York Times about this case here.
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S12-OA138: LENACAPAVIR AS PART OF A COMBINATION REGIMEN IN TREATMENT NAIVE PWH: WEEK 54 RESULTS
Lenacapavir (LEN), a potent first-in-class inhibitor of capsid function, is in development for treatment and prevention of HIV-1. CALIBRATE is an ongoing, open-label, phase 2 study evaluating subcutaneous (SC) and oral LEN, in combination with other antiretrovirals, in treatment-naïve people with HIV-1 (PWH) and this study presented the 54 week results. Participants were randomized to 4 treatment groups as shown here and the efficacy results are shown as well.
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There were two participants out of 157 who developed lenacapavir resistance (who suppressed on other agents) – please note the resistance mutations below (look like TAMS but they are not!)
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It is already well known that treatment of cervical HSIL is proven to reduce the incidence of cervical cancer, but whether the same benefits in both screening and treatment of anal HSIL was unknown.
In this randomized control trial across fourteen clinical sites, participants with HIV over age 35 were screened for anal HSIL. If participants had known HSIL, they were eligible only if they had not received treatment for over six months. If HSIL was found, they were enrolled and randomized into the active monitoring arm or the treatment arm. This analysis was an event-driven analysis with the primary outcome being event to cancer. In those whom anal cancer was diagnosed, they were referred to treatment and they exited the study.
In the treatment arm, participants were treated with either hyfrecation, IRC, 5-FU, or imiquimod. Specific treatment plans were followed by clinicians for each of the four available treatments; participants were able to switch treatment arms later in the study if the first treatment was unsuccessful. They received phlebotomy, anal swabs, and HRA with biopsy every six months.
In the active monitoring arm, participants received anal cytology, swabs, HRA, and phlebotomy every six months and were biopsied yearly to confirm persistent HSIL, although they could be biopsied at any visit if there was concern for cancer.
For this study, 10,723 PLWH were screened from September 2014 to August 2021. Surprisingly, 52.2% had biopsy-proven anal HSIL, 53.3% of men and 45.8% of female participants. Sixty two percent of those who identified as transgender had HSIL. Seventeen (0.16%, 160/100,000) were diagnosed with anal cancer (for context, 8/100,000 is the prevalence of cervical cancer in the general population).
The demographics of those included in the study represented a racially diverse population, with around 32% non-Hispanic white, 42% African-American, 1.2% Asian, and 17.1% Hispanic (remainder other/unknown). The median age was 51. Of the participants, around 80.5% were male, 15.5% were female, and 3.9% identified as transgender or non-binary. In both groups, 78% identified as homosexual. Overall, HIV status was well-controlled, with 84% of participants being virally suppressed.
In the treatment arm, the majority (92.9%) received office-based electrocautery ablation, with 86% requiring only one therapeutic modality. Once 32 cancers were diagnosed, the Data Safety and Monitoring Board was notified and the study was ended early due to efficacy of the intervention. Nine participants were diagnosed with anal cancer in the treatment arm and 21 were diagnosed in the monitoring arm. All those who were diagnosed in the monitoring arm were then referred for treatment. The median follow-up was 25.8 months, with a 57% reduction in anal cancer (95% CI 6 to 80%, p=0.029). Cancer incidence in the treatment arm was 173/100,000 person-years of follow-up as compared to 402/100,000 person-years in the monitoring arm. Adverse events were low, with only seven treatment-related adverse events in the study. Important risk factors included older age, lower CD4 nadir, and size of the lesion.
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There are many important implications from this study. First, HSIL is highly prevalent in this population, including in women. Treatment of anal HSIL is effective in reducing the incidence of anal cancer, bringing up important questions on the need to develop screening algorithms and HRA training for providers. Further research is needed on optimal screening and treatment modalities.
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Also make sure to check out the abstracts from these other presentations from UCSF-Bay Area CFAR-affiliated investigators:
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