| CROI 2022 - Day One Summaries
|
|
|
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 those presented from investigators from UCSF and our CFAR affiliates. Thanks to Akanksha Vaidya. MD for assisting with the Monday summaries!
Thank you!
CFAR Leadership
|
|
|
Basic Science Plenary
HIV Nonhuman Primate Models for Studies of Virus Pathogenesis, Persistence, and Cure
In this plenary session, Dr. Michaela Muller-Trutwin described the importance of non-human primate (NHP) models in ongoing studies of viral pathogenesis and cure. Asian macaques are a useful animal model given that infection with SIV in these animals leads to disease progression, which can be studied further. The natural hosts of SIV are African non-human primates, but infection with the virus in these animals does not progress to AIDS and they do not display signs of chronic inflammation. Studying these models can help with understanding features giving rise to pathogenic HIV-1 infection in humans.
Insights into disease pathogenesis from NHP studies
Studies in (NHP) so far have provided information that chronic inflammation is the primary driving force for disease and that the gut is a major site of viral replication. Studies in African NHPs, which are natural hosts of SIV in which disease progression does not occur, have shown that while CD4 T cells are depleted in the gut mucosa, the mucosal barrier remains intact. These studies have also shown that Th17 cells, which secrete IL-17, remain intact in the gut of these NHPs, and may be important in maintaining the mucosal barrier. Macrophage associated wound healing -along with CD8 T cells that express NK cell receptors -may also play a role in controlling the virus. Lymph nodes of these NHPs also have an expansion of these immunoregulatory cells that may play a role in controlling disease.
Insights into HIV cure research and viral reservoir from NHP studies
Studies have shown that events occur early on in the course of infection that impact the ultimate outcome. Viral escape from cytotoxic T cells has been shown to occur within 7 days post infection. Furthermore, studies have also shown that tissue damage and immune dysregulation occur early on in infection. These studies suggest that intervention very early on after viral transmission is necessary to prevent immune dysregulation. With regards to the viral reservoir, studies in NHPs have shown that nearly all organs can harbor infected cells. The gut has a very high viral reservoir and the lymph nodes also harbor a significant amount of viral burden. During the first week of infection, viral replication takes place in the T zones of lymph nodes. If ART is started early, studies have shown that there is a lower viral reservoir in the lymph nodes, however, this is not sufficient to avoid establishment of a viral reservoir. Of particular interest in cure research are NK cells given their ability to destroy virus-infected cells. A study by Reeves et. al. (Reeves et. al. Nature Immunology 2015), showed that antigen specific NK cell memory can be induced in NHPs and this has potential implications for vaccine and cure research. In one of the study’s by Dr. Muller-Trutwin’s group, they aimed to study how NK cells mediate viral control in the lymph nodes of NHPs. These studies showed that NK cells acquire CXCR5 to enter follicles and IL-6 induces CXCR5 expression on NK cells in African NHPs. Furthermore, SIV infection in African NHPs was found to induce terminally differentiated NK cells in lymph nodes via increased MHC-E restricted cytotoxicity, a process that was not seen in SIV-macaques. NK cell maturation was also thought to be influenced by the microenvironments in the African NHPs, which differs from that of other NHPs.
Future directions
NHP models remain good models to study immune responses within tissues. Host immune responses within tissues will need to be understood in more detail to help with a better understanding of the viral reservoir and help develop cure strategies.
|
|
|
Clinical Plenary
Children Exposed to HIV, But Uninfected: Evidence for Action
In this plenary session, Dr. Andrew Prendergast discussed health outcomes among children who were HIV exposed but uninfected (HEU). In the pre-ART era, survival rates among infants born with HIV were less than 50%. However, even among children HEU, mortality rates and number of clinic visits were higher compared to children who were HIV-unexposed. In the ART era, there has been a decline in children born with HIV globally, but over 15 million children globally are HIV exposed and uninfected. Understanding health outcomes in this group is therefore important.
Mortality and Morbidity in children HEU
In a metaanalysis (Brennan et. al., AIDS 2016), 22 cohorts of children born in different countries in Africa between 1994-2016 were studied. More than 29,000 children were included and there was a 60-70% increased risk of death at every age stratum in children HEU. The overall RR was 1.70 (95 % CI 1.30-2.22) and even after scale-up of maternal ART in 2002, the RR remained high at 1.46 (95% CI 1.14-1.87.)
In another study conducted in South Africa (Le Roux SM, Lancet Child adolescent health 2020), there were more infection-related hospitalizations in children HEU between 8 days and 3 months of age compared to HIV unexposed children. This study also showed that admission rates were highest in those children born to mothers with advanced HIV. Even in a multistate study conducted in the US (Labuda et. al. CID 2020) over 11 years, there was a 2 fold higher hospitalization rate in the first 2 years of life. This study also found that maternal CD4 counts influenced infant outcomes.
Neurological and growth outcomes among children HEU
Children HEU have also been shown to have higher rates of stunting compared to those who were HIV unexposed (Ntozini et. al. JIAIDS 2020, SHINE trial) and to have impairments in gross motor and expressive language development (Wedderburn C et al, submitted.)
Etiologies of poor health outcomes in children HEU
It is thought that HIV exposure leaves an immune footprint on the fetus and may modify the child’s immune response to infections early in life. These immune changes could include increased B cells, reduced NK cells and neutrophils, and reduced transplacental antibodies.
Areas to intervene on to improve health outcomes
In a study conducted in 21 cohorts in Africa and Asia (Arikawa S et. al. CID 2017), four major factors explained 66% of deaths by 6 months of age in children HEU. These four factors included never initiating breastfeeding, mother not receiving ART for life, mother not being alive, and low birth weight of the infant. Socioeconomic factors also appear to play a major role with studies showing that wealth decreases mortality and stunting.
Based on the available data, strategies such as early HIV diagnosis and support with maternal ART adherence, early breastfeeding, and HIV prevention programs are important. Early ART, in particular, ART initiated before pregnancy, has been shown to be associated with fewer hospitalization rates in children (Goetghebuer T et. al. CID 2018).
Future directions
Addressing multiple factors simultaneously (“packaged interventions”) are likely needed to improve health outcomes in this group. UNICEF’s holistic approach of addressing health, nutrition, caregiving, safety, and learning in children is one potential approach to address these issues. Ultimately, we need to broaden the focus beyond just preventing vertical transmission and focus on improving outcomes in children who are exposed to HIV and uninfected.
|
|
|
Highlights from Session 4: Evolving epidemiology of HIV and SARS-CoV2
OA43: ESTIMATING THE LIFETIME RISK OF A DIAGNOSIS OF HIV INFECTION IN THE UNITED STATES
Sonia Singh of the CDC presented a model to estimate the lifetime risk of HIV in the US. To create this model, data from the National HIV Surveillance System (data through December 2020) and census data (data 2017-2019) was used to obtain mortality estimates. Probabilities estimated from this data were then applied to a hypothetical cohort to estimate lifetime risks of HIV acquisition. For men, it was estimated that the lifetime risk of HIV acquisition is 1 in 76 overall. Highlighting the disparities, inn Black men, it is 1 in 27 and it is 1 in 50 in Hispanic men. In females, the overall lifetime risk is 1 in 309. In females, again, the risk is higher in black women (1 in 75) and in Hispanic women (1 in 287.) In terms of lifetime risk of HIV by US state, 9 out of 10 states with the highest lifetime risk of HIV were located in the south. This shows that lifetime risk has decreased compared to an earlier 2010-2014 analysis, but disparities by race, sex, and location persist.
OA45: HIV-1 DIAGNOSES IN NORTH CAROLINA, 2018-21: INCIDENT INFECTIONS AND DRUG RESISTANCE
In this oral abstract presented by Shuntai Zhou from the University of North Carolina at Chapel Hill, a new tool to identify HIV transmission, active transmission clusters, and resistance was discussed. A phylodynamics platform was used for all new HIV-1 diagnoses at the North Carolina State Lab of Public Health. This platform used primer ID next generation sequencing to assess viral diversity (which correlates well with recent infection) and multiplex PCR to identify drug resistance mutations and transmission clusters. From 2018-2021, 814 new HIV diagnoses were identified. Eighty-four percent of these occurred in men, with 66% in black men, 17% in white men, and 12% in Hispanic men. Forty percent of these infections were found to be recently transmitted (within 9 months). A multivariable analysis of factors associated with diagnosis at recent infection vs at chronic infection, showed that early diagnosis was associated with Caucasian race, younger age, tests in the year 2020, and testing site. Hispanic ethnicity was associated with diagnosis of HIV at a later, chronic stage. With regards to mutations, K103N mutations were found to be the most abundant mutations, but the rates of this mutation declined over time.
OA47: SAFETY AND EFFECTIVENESS OF THE Ad26.COV2.S VACCINE IN SOUTH AFRICA
Glenda E Gray discussed the results of the SISONKE 1 and SISONKE 2 studies in South Africa, where healthcare workers who received one dose (SISONKE 1) of the Ad26.COV2.S (J&J vaccine) and a booster 4-6 months later (SISONKE 2) were followed. 496,424 health care workers were enrolled in the studies. The overall vaccine effectiveness for SISONKE 1 was noted to be 67% at preventing hospitalizations, 75% at preventing ICU admissions, and 83% at preventing death. For SISONKE 2, vaccine effectiveness for preventing COVID-19 admissions was 85% 1-2 months after the second dose, and 84% 14-27 days after the second dose. Adverse effects were low, although 4 cases of Guillan Barre syndrome and 2 cases of Thrombosis with thrombocytopenia were seen in SISONKE 1. When SISONKE 1 vaccine efficacy was compared between the delta and beta variants, while efficacy at preventing hospital admissions and death did not differ based on the variant, efficacy at preventing ICU admissions was reduced for the beta variant compared to delta (49% vs 78%.) Lastly, with regards to comorbidities, in SISONKE 1, vaccine efficacy at preventing hospitalizations was 73% in those with HIV compared to 63% in those with other comorbidities, efficacy at preventing ICU admissions was 79% in those with HIV vs 71% in those with other comorbidities, and 65% efficacy at preventing death in those with HIV compared to 78% in those with other comorbidities.
OA48: COVID-19 BOOSTER VACCINE EFFECTIVENESS IN PEOPLE WITH AND WITHOUT IMMUNE DYSFUNCTION
Jing Sun from Johns Hopkins University discussed covid booster effectiveness. For this study, data from N3c, which is a NIH funded resource with medical records along with lab testing data was used. Participants who received a full series of vaccination by August 1 2021 were included. Using propensity score matching, comparable groups with and without a booster were compared. 784,555 participants were included. There were a total of 48,893 breakthrough infection cases recorded. Weekly breakthrough infection cases increased after Delta and Omicron strains became the dominant strains of infection. Among those without immune dysfunction, booster vaccine efficacy was highest at 7 months since full vaccination (77.4%), after which efficacy decreased (52.1% at 9 months since full vaccination.) Among those with immune dysfunction, booster vaccine efficacy was highest again at 7 months since full vaccination (60.2%), after which it decreased (39.5% at 9 months since full vaccination.) Overall, more breakthrough infections were seen in the group with immune dysfunction, even following boosters, although the protection against severe outcomes was durable.
OA49: INFECTIOUSNESS OF BREAKTHROUGH INFECTIONS AFTER VACCINATION AND NATURAL INFECTION
In this talk by Laith J Abu-Raddad of Weill Cornell Medicine-Qatar, breakthrough infections and infectiousness after vaccination and natural infection was discussed. Qatar’s national database was reviewed for PCR testing between Feb 2020 to July 2021. Pairwise comparisions of RT PCR cycle threshold values were compared in matched cohorts of primary infections in unvaccinated people, reinfections in unvaccinated people, breakthrough infections in those vaccinated with Pfizer and Moderna vaccines. Cycle threshold values were lowest in unvaccinated people. Those with breakthrough infections after the Pfizer vaccine had CT values 1 cycle higher than unvaccinated people. Those with breakthrough infections after Moderna vaccination had CT values 3 cycles higher than unvaccinated people, and those with reinfections had CT values 4 cycles higher than unvaccinated people. The results were similar when analysis was stratified by symptomatic and asymptomatic people and after multivariable regression analysis controlling for gender and age among other factors. Of note, CT values were noted to be higher in younger people, indicating that there was faster clearance of virus in younger people compared to older people.
OA50: COVID-19 VACCINATION RATES IN A GLOBAL HIV COHORT
In this oral abstract presented by Evelynne Fulda of the Massachusetts General Hospital, COVID-19 vaccination rates among people with HIV were presented. The data was obtained from the REPRIEVE trial with enrollment of people with HIV aged 40-75 between 2015 and 2019. 7770 participants were followed and vaccination data was collected every 4 months beginning December 4th 2020. The cumulative vaccination rate in the cohort was 55%. The rates of vaccination were comparable to the general population in most regions where the study was conducted. With regards to those who were more likely to be vaccinated in the cohort, white race, male sex, older age, higher BMI, and longer duration on ART were associated with higher vaccination rates.
|
|
|
Interactive session: COVID-19 Treatments Consensus and Controversies
In this interactive, case-based session moderated by UCSF’s Dr. Annie Luetkemeyer and Dr. Rajesh Gandhi from MGH, different scenarios for COVID-19 therapeutics were discussed.
Comparison of available therapies for COVID-19
The antiviral therapies in use that were discussed were Nirmatrelvir/ritonavir (Paxlovid), sotrovimab, remdesivir, and molnupiravir. The slide below depicts comparisons between the different treatment. Notable features are that the relative risk reduction for prevention of hospitalization or death is 85-88% for remdesivir, sotrovimab, and paxlovid, but is only 30% for molnupiravir in the clinical trials. Molnupiravir is also not recommended in pregnancy due to possible teratogenicity. Paxlovid has multiple DDIs because of its ritonavir component. Of note, however, is that guidelines state that for patients with HIV, ARVs (including PI based regimens) do not need to be changed while on Paxlovid given the very short (5 day) course.
|
|
|
Other investigational therapies, including fluvoxamine and budesonide, were also discussed. While one RCT has shown that fluvoxamine has a 32% relative risk reduction in hospitalization, larger studies are needed to determine efficacy. Similarly, the PRINCIPLE trial, which studied budesonide, found a decreased rate of hospitalization and death (6.8% vs 8.8%) and a decreased time to recovery (OR 0.75, CI 0.55-1.03) with budesonide use, however, larger studies are needed.
COVID-19 therapeutics in immunocompromised hosts
In immunocompromised hosts, it is known that there is prolonged viremia and thus concern for the emergence of variants. Molnupiravir is not favored in such hosts because of its decreased efficacy. Paxlovid and sotrovimab are both good treatment options in immunocompromised hosts. It was also discussed that if resources are available, dual antiviral treatment with both Paxlovid and sotrovimab may be the best treatment for severely immunocompromised hosts. However, regardless of which agent is used for treatment, it is possible that in immunocompromised hosts, viral replication may not be terminated and this remains a concern.
COVID-19 therapeutics in pregnancy
Pregnancy is a risk factor for severe COVID-19 with an increased risk of hospitalization (aRR 5.4 (5.1-5.6), ICU admission aRR 1.5(1.2-1.8), and ventilation aRR 1.7(1.2-2.4) (Ellington CDC MMWR 2020.) Unvaccinated pregnant women also have worse outcomes compared to vaccinated women (Morgan et. al. Obstetric gynecology 2022.) Treatment for COVID-19 in pregnancy, especially in unvaccinated women, is therefore warranted. Molnupiravir is not recommended in pregnancy, hence the available options for treatment in pregnancy include remdesivir, paxlovid, and sotrovimab. Although there are more data on remdesivir compared to Paxlovid, preliminary data has not suggested any adverse effects related to Paxlovid use in pregnancy. The slide below summarizes the available therapies in pregnancy.
|
|
|
Pre-exposure prophylaxis for COVID 19 in immunocompromised hosts
Tixagevimab/cilgavimab has an EUA for pre-exposure prophylaxis in people with moderate to severe immune compromise. This approval is based on the PROVENT study where a 77% reduction in symptomatic COVID-19 was found in unvaccinated people (of note only 3.8% were immunocompromised in this study.) The role of checking a SARS COV-2 spike antibody prior to administering this was discussed, but there are complications with this including deciding what threshold of antibodies will adequately prevent infection. Checking antibodies prior to administering this prophylaxis is therefore not recommended by the FDA. Lastly, it is unclear how well this performs against Omicron, however, preliminary studies suggest efficacy, although there is a right shift in the neutralization curve against omicron (see slide below.)
|
|
|
Highlights from Session 3: Malignancies And Comorbidities: An Increasing Burden
OA34: GEOGRAPHICAL DIFFERENCES IN FUNCTIONAL IMPAIRMENT OF PEOPLE WITH HIV
Kristine Erlandson presented perhaps the largest assessment of functional impairment in people with HIV to date using baseline data from 7736 REPRIEVE trial participants (trial of pitavastatin in middle-aged and older adults with treated HIV). Nearly 1/3 of participants had some functional impairment and while there were differences by geographic region, female sex, black race, obesity, and smoking emerged as important risk factors for functional impairment. Interestingly, NNRTI-based regimens were associated with less functional impairment than all other classes, with NRTI-sparing regimens associated with the worst functional status. Whether these regimen differences in functional status are mediated by differences in weight gain or other factors remains to be elucidated.
OA36: INFLAMMATION AND KYNURENINE PATHWAY LINKED TO TYPE 2 DIABETES AND FAT FIBROSIS IN HIV
Presenter: Diana Alba, UCSF*
UCSF’s own Diana Alba presented a study characterizing the immunologic predictors of Type 2 diabetes in treated HIV infection using a cohort study within the CNICS network as well as an intensive adipose tissue sampling study (SCOPE-IDEO). She found that several inflammatory pathways predicted incident diabetes in CNICS. In the local cohort, compared to an HIV-negative control group, inflammation was a much more consistent predictor of insulin resistance and visceral adiposity in people with HIV, suggesting that the inflammatory state is playing a more important role in T2DM risk in the setting of HIV. She also found that adipose tissue fibrosis was abnormally high in people with HIV even at low BMI, and while related to some inflammatory pathways (including the kynurenine pathway of tryptophan catabolism), adipose tissue fibrosis seemed to be less consistently associated with inflammation, visceral adiposity and insulin resistance in people with HIV than in those without HIV. Whether HIV medications like INSTIs (which nearly all participants were taking) might be directly contributing to adipose tissue fibrosis in the absence of inflammation or insulin resistance remains to be seen.
OA39: TRENDS IN MYOCARDIAL INFARCTION RISK BY HIV STATUS IN TWO US HEALTHCARE SYSTEMS
Our CFAR’s own Mike Silverberg presented fascinating data from two independent cohorts in the Northern CA Kaiser network and the Partners health system in Boston suggesting that the relative risk of myocardial infarction in people with HIV compared to the general population has actually been increasing in recent years. As of 2010, the relative risk of MI in people with HIV was very similar to the general population, but by 2017, was 70-80% higher. The difference appeared to be explained by continued declines in MI risk in the general population, which were not apparent in those with HIV. Why MI risk has increased in people with HIV recently remains unclear, but could be linked to metabolic effects of modern ART regimens (compared to older regimens). Much of the increase in relative MI risk occurred prior to the approval of TAF in 2016. Whatever the mechanism responsible, cardiovascular complications appear to be an increasingly important morbidity in PWH, raising the importance of primary prevention efforts as we await REPRIEVE trial results as well as the development of novel interventions.
|
|
|
Highlights from Session 2: Maternal And Child Health: New Insights Into Hepatitis, SARS-CoV-2, and HIV
GROWTH OF INFANTS WITH PERINATAL EXPOSURE TO MATERNAL DTG VS EFV AND TDF VS TAF (Abstract 30)
|
|
|
IMPAACT 2010 compared virologic and other outcomes in HIV-positive mothers randomized to one of three regimens starting 12 to 26 weeks before delivery: DTG + emtricitabine (FTC)/TAF, DTG + FTC/TDF, or EFV/FTC/TDF. In the primary analysis, the DTG regimens controlled HIV better at delivery than the EFV combination, A high proportions of infants in a 9-country 617-infant trial had stunting 26 and 50 weeks after birth, but growth was slower in infants of mothers taking efavirenz (EFV) than in those whose mothers took dolutegravir (DTG).
|
| |
|
Poster Highlights
Poster 429: IV PUSH ADMINISTRATION OF IBALIZUMAB: PHARMACOKINETICS, SAFETY, AND EFFICACY
|
|
|
Ibaluzimab (for MDR HIV) is given as an intravenous infusion every 2 weeks. This study examined whether this can be done more quickly via IV push over 30 seconds instead of a long infusion. The methods are shown here and groups were compared in terms of PK, safety and efficacy.
|
| |
|
The main finding was that whether ibaluzimab is infused slowly or quickly, the pharmacokinetics show concentrations above the desired threshold level throughout the 2 week period. There was therefore bioequivalence between the IV infusion and IV push administration strategies for this difficult-to-give drug. The push method was safe and well tolerated and remained effective among people living with HIV. This suggests an easier to give strategy for the drug.
|
|
|
Poster 552: DISTINCT CANCERS HAVE DISTINCT INFLAMMATORY PREDICTORS IN TREATED HIV
A poster by Sam Schnittman (formerly at UCSF, now at Harvard) and Peter Hunt identified several novel inflammatory predictors of anal cancer, lung cancer, and non-Hodgkin lymphoma among people with HIV in the CNICS cohort, potentially explaining why these cancers continue to be increased in treated HIV infection. Interestingly inflammatory markers (other than CMV IgG titer) tended not to predict prostate cancer, a malignancy that is actually decreased in HIV infection. In fact, higher LPS binding protein actually predicted a decreased risk of prostate cancer, which may provide a mechanistic clue as to why HIV decreases the risk of prostate cancer since LPS is known to suppress testosterone levels in men.
Poster 631: NEUROLOGIC AND IMMUNOLOGIC BIOMARKERS ASSOCIATED WITH POST-COVID NEUROLOGIC SYMPTOMS
UCSF’s own Michael Peluso identified several novel immunologic and neurologic predictors of post-COVID neurologic symptoms in the LIINC cohort including IL-6, TNFa, and GFAP, providing some of the first data linking persistent inflammation to neurologic post-acute sequelae of COVID-19 (PASC) symptoms, which are quite common among COVID-19 survivors.
Poster 523: HIGH INCIDENCE RATE OF CT-MEASURED NAFLD IN MEN WITH AND WITHOUT HIV INFECTION
UCSF’s Jennifer Price presented a poster from the MACS/WIHS CCS showing that while NAFLD by CT was common (2.5/100 PY) in men both with and without HIV, and predicted by higher BMI and visceral adiposity, there was no differences by HIV status. This is a relatively surprising finding given the increased insulin resistance and metabolic abnormalities in PWH compared to those without HIV, but nevertheless suggests that NAFLD is a very common cause of liver disease in treated HIV.
|
|
|
Also make sure to check out the abstracts from these other presentations from UCSF-Bay Area CFAR- affiliated investigators:
|
|
|
Manage your preferences | Opt Out using TrueRemove™
Got this as a forward? Sign up to receive our future emails.
View this email online.
|
1700 Owens Street | San Francisco, CA 94158 US
|
|
|
This email was sent to .
To continue receiving our emails, add us to your address book.
|
| |
|
|
