The forecasted prevalence of comorbidities and multimorbidity in people with HIV in the United States through the year 2030: A modeling study.

BACKGROUND: Estimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030. METHODS AND FINDINGS: Using the PEARL model-an agent-based simulation of PWH who have initiated ART in the US-the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART-reaching 908,000 individuals by 2030-PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts. CONCLUSIONS: The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV.

The changing landscape of both causes and locations of death in a regional HIV population 2010-2021.

BACKGROUND: Although HIV-related deaths among people with HIV have dramatically decreased, deaths from other medical conditions and non-medical events have increased. The location of death among people with HIV remains underreported. OBJECTIVES: We reviewed the deaths, causes of death, and reported location of death (i.e. within or outside of medical settings) of all people with HIV with the Southern Alberta Cohort, Calgary, Canada, between 1 January 2010 and 1 January 2022. METHODS: This was a retrospective longitudinal cohort study reviewing all deaths within a comprehensive geographically defined HIV cohort over 11 years. RESULTS: Deaths from HIV-related causes decreased from 52% of all deaths in 2010 to 14% in 2021. In 2021, non-HIV medical deaths increased from 38% to 44%, and non-medical deaths (e.g. violence, suicide, drug overdose) increased from 0.5% to 39%. Of non-medical deaths, 67% resulted from substance use/overdose. Overall, deaths in any medical setting decreased from 91% in 2010 to 39% in 2021; 61% of all deaths occurred in a medical setting (e.g. hospital/emergency department or supported/long-term/hospice care), 27% in a residence, and 9% in the community. CONCLUSION: The shifting causes of death (i.e. fewer HIV-related deaths, more overdose deaths) and location of death (i.e. fewer in medical settings, more at home/in the community) requires close monitoring so future resources can be matched to predicted patient needs.

Colloidal Inorganic Ligand-Capped Nanocrystals: Fundamentals, Status, and Insights into Advanced Functional Nanodevices.

Colloidal nanocrystals (NCs) are intriguing building blocks for assembling various functional thin films and devices. The electronic, optoelectronic, and thermoelectric applications of solution-processed, inorganic ligand (IL)-capped colloidal NCs are especially promising as the performance of related devices can substantially outperform their organic ligand-capped counterparts. This in turn highlights the significance of preparing IL-capped NC dispersions. The replacement of initial bulky and insulating ligands capped on NCs with short and conductive inorganic ones is a critical step in solution-phase ligand exchange for preparing IL-capped NCs. Solution-phase ligand exchange is extremely appealing due to the highly concentrated NC inks with completed ligand exchange and homogeneous ligand coverage on the NC surface. In this review, the state-of-the-art of IL-capped NCs derived from solution-phase inorganic ligand exchange (SPILE) reactions are comprehensively reviewed. First, a general overview of the development and recent advancements of the synthesis of IL-capped colloidal NCs, mechanisms of SPILE, elementary reaction principles, surface chemistry, and advanced characterizations is provided. Second, a series of important factors in the SPILE process are offered, followed by an illustration of how properties of NC dispersions evolve after ILE. Third, surface modifications of perovskite NCs with use of inorganic reagents are overviewed. They are necessary because perovskite NCs cannot withstand polar solvents or undergo SPILE due to their soft ionic nature. Fourth, an overview of the research progresses in utilizing IL-capped NCs for a wide range of applications is presented, including NC synthesis, NC solid and film fabrication techniques, field effect transistors, photodetectors, photovoltaic devices, thermoelectric, and photoelectrocatalytic materials. Finally, the review concludes by outlining the remaining challenges in this field and proposing promising directions to further promote the development of IL-capped NCs in practical application in the future.

Recent advances in conductive hydrogels: classifications, properties, and applications.

Hydrogel-based conductive materials for smart wearable devices have attracted increasing attention due to their excellent flexibility, versatility, and outstanding biocompatibility. This review presents the recent advances in multifunctional conductive hydrogels for electronic devices. First, conductive hydrogels with different components are discussed, including pure single network hydrogels based on conductive polymers, single network hydrogels with additional conductive additives (i.e., nanoparticles, nanowires, and nanosheets), double network hydrogels based on conductive polymers, and double network hydrogels with additional conductive additives. Second, conductive hydrogels with a variety of functionalities, including self-healing, super toughness, self-growing, adhesive, anti-swelling, antibacterial, structural color, hydrophobic, anti-freezing, shape memory and external stimulus responsiveness are introduced in detail. Third, the applications of hydrogels in flexible devices are illustrated (i.e., strain sensors, supercapacitors, touch panels, triboelectric nanogenerator, bioelectronic devices, and robot). Next, the current challenges facing hydrogels are summarized. Finally, an imaginative but reasonable outlook is given, which aims to drive further development in the future.

Evaluating Clinic-Based Interventions to Reduce Racial Differences in Mortality Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Mortality remains elevated among Black versus White adults receiving human immunodeficiency virus (HIV) care in the United States. We evaluated the effects of hypothetical clinic-based interventions on this mortality gap. METHODS: We computed 3-year mortality under observed treatment patterns among >40 000 Black and >30 000 White adults entering HIV care in the United States from 1996 to 2019. We then used inverse probability weights to impose hypothetical interventions, including immediate treatment and guideline-based follow-up. We considered 2 scenarios: "universal" delivery of interventions to all patients and "focused" delivery of interventions to Black patients while White patients continued to follow observed treatment patterns. RESULTS: Under observed treatment patterns, 3-year mortality was 8% among White patients and 9% among Black patients, for a difference of 1 percentage point (95% confidence interval [CI], .5-1.4). The difference was reduced to 0.5% under universal immediate treatment (95% CI, -.4% to 1.3%) and to 0.2% under universal immediate treatment combined with guideline-based follow-up (95% CI, -1.0% to 1.4%). Under the focused delivery of both interventions to Black patients, the Black-White difference in 3-year mortality was -1.4% (95% CI, -2.3% to -.4%). CONCLUSIONS: Clinical interventions, particularly those focused on enhancing the care of Black patients, could have significantly reduced the mortality gap between Black and White patients entering HIV care from 1996 to 2019.

Hospital Readmissions Among Persons With Human Immunodeficiency Virus in the United States and Canada, 2005-2018: A Collaboration of Cohort Studies.

BACKGROUND: Hospital readmission trends for persons with human immunodeficiency virus (PWH) in North America in the context of policy changes, improved antiretroviral therapy (ART), and aging are not well-known. We examined readmissions during 2005-2018 among adult PWH in NA-ACCORD. METHODS: Linear risk regression estimated calendar trends in 30-day readmissions, adjusted for demographics, CD4 count, AIDS history, virologic suppression (<400 copies/mL), and cohort. RESULTS: We examined 20 189 hospitalizations among 8823 PWH (73% cisgender men, 38% White, 38% Black). PWH hospitalized in 2018 versus 2005 had higher median age (54 vs 44 years), CD4 count (469 vs 274 cells/µL), and virologic suppression (83% vs 49%). Unadjusted 30-day readmissions decreased from 20.1% (95% confidence interval [CI], 17.9%-22.3%) in 2005 to 16.3% (95% CI, 14.1%-18.5%) in 2018. Absolute annual trends were -0.34% (95% CI, -.48% to -.19%) in unadjusted and -0.19% (95% CI, -.35% to -.02%) in adjusted analyses. By index hospitalization reason, there were significant adjusted decreases only for cardiovascular and psychiatric hospitalizations. Readmission reason was most frequently in the same diagnostic category as the index hospitalization. CONCLUSIONS: Readmissions decreased over 2005-2018 but remained higher than the general population's. Significant decreases after adjusting for CD4 count and virologic suppression suggest that factors alongside improved ART contributed to lower readmissions. Efforts are needed to further prevent readmissions in PWH.

Cryptococcal Meningitis and Clinical Outcomes in Persons With Human Immunodeficiency Virus: A Global View.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of morbidity and mortality in persons with human immunodeficiency virus (HIV; PWH). Little is known about CM outcomes and availability of diagnostic and treatment modalities globally. METHODS: In this retrospective cohort study, we investigated CM incidence and all-cause mortality in PWH in the International Epidemiology Databases to Evaluate AIDS cohort from 1996 to 2017. We estimated incidence using quasi-Poisson models adjusted for sex, age, calendar year, CD4 cell count (CD4), and antiretroviral therapy (ART) status. Mortality after CM diagnosis was examined using multivariable Cox models. A site survey from 2017 assessed availability of CM diagnostic and treatment modalities. RESULTS: Among 518 852 PWH, there were 3857 cases of CM with an estimated incidence of 1.54 per 1000 person-years. Mortality over a median of 2.6 years of post-CM diagnosis follow-up was 31.6%, with 29% lost to follow-up. In total, 2478 (64%) were diagnosed with CM after ART start with a median of 253 days from ART start to CM diagnosis. Older age (hazard [HR], 1.31 for 50 vs 35 years), lower CD4 (HR, 1.15 for 200 vs 350 cells/mm3), and earlier year of CM diagnosis (HR, 0.51 for 2015 vs 2000) were associated with higher mortality. Of 89 sites, 34% reported access to amphotericin B; 12% had access to flucytosine. CONCLUSIONS: Mortality after CM diagnosis was high. A substantial portion of CM cases occurred after ART start, though incidence and mortality may be higher than reported due to ascertainment bias. Many sites lacked access to recommended CM treatment.

Effect of Adopting the New Race-Free 2021 Chronic Kidney Disease Epidemiology Collaboration Estimated Glomerular Filtration Rate Creatinine Equation on Racial Differences in Kidney Disease Progression Among People With Human Immunodeficiency Virus: An Observational Study.

BACKGROUND: The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. METHODS: We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. RESULTS: With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73-.82), an equal risk of progressing from stage 2 to 3 (1.00; .92-.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60-3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. CONCLUSIONS: The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.

Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

BACKGROUND: Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. METHODS: Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. RESULTS: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/µL (10-56/µL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively. CONCLUSIONS: We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

Optimizing Treatment for Human Immunodeficiency Virus to Improve Clinical Outcomes Using Precision Medicine.

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009-2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen.

Contribution of alcohol use in HIV/hepatitis C virus co-infection to all-cause and cause-specific mortality: A collaboration of cohort studies.

Among persons with HIV (PWH), higher alcohol use and having hepatitis C virus (HCV) are separately associated with increased morbidity and mortality. We investigated whether the association between alcohol use and mortality among PWH is modified by HCV. Data were combined from European and North American cohorts of adult PWH who started antiretroviral therapy (ART). Self-reported alcohol use data, collected in diverse ways between cohorts, were converted to grams/day. Eligible PWH started ART during 2001-2017 and were followed from ART initiation for mortality. Interactions between the associations of baseline alcohol use (0, 0.1-20.0, >20.0 g/day) and HCV status were assessed using multivariable Cox models. Of 58,769 PWH, 29,711 (51%), 23,974 (41%) and 5084 (9%) self-reported alcohol use of 0 g/day, 0.1-20.0 g/day, and > 20.0 g/day, respectively, and 4799 (8%) had HCV at baseline. There were 844 deaths in 37,729 person-years and 2755 deaths in 443,121 person-years among those with and without HCV, respectively. Among PWH without HCV, adjusted hazard ratios (aHRs) for mortality were 1.18 (95% CI: 1.08-1.29) for 0.0 g/day and 1.84 (1.62-2.09) for >20.0 g/day compared with 0.1-20.0 g/day. This J-shaped pattern was absent among those with HCV: aHRs were 1.00 (0.86-1.17) for 0.0 g/day and 1.64 (1.33-2.02) for >20.0 g/day compared with 0.1-20.0 g/day (interaction p < .001). Among PWH without HCV, mortality was higher in both non-drinkers and heavy drinkers compared with moderate alcohol drinkers. Among those with HCV, mortality was higher in heavy drinkers but not non-drinkers, potentially due to differing reasons for not drinking (e.g. illness) between those with and without HCV.

Verbal Memory Performance and Depressive Symptoms in Persons with Treated HIV.

The link between memory and comorbid depression in persons with HIV (PWH) is unclear based on evidence from published cohorts. We compared verbal memory in the HVLT-R in a well-characterized HIV cohort (n = 354) with (n = 102) or without (n = 252) comorbid depressive symptoms, and examined memory correlates in both scenarios. Memory fell within unimpaired ranges, but was lower in depressed than non-depressed PWH. Memory was related to quality of life, sociodemographic, and mental health factors, but not to assessed HIV-related or antiretroviral factors. However, longitudinally (n = 52) memory declined with presence and severity of depressive symptoms. In this treated cohort, verbal memory was unrelated to HIV-related variables but to quality of life and depressive symptoms. Greater performance decline over time also related to acute or ongoing depressive symptoms. These findings highlight the importance of addressing comorbid depressive symptoms to improve quality of life in persons with treated HIV.

Association of Race and Ethnicity With Initial Prescription of Antiretroviral Therapy Among People With HIV in the US.

Importance: Integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) is currently the guideline-recommended first-line treatment for HIV. Delayed prescription of INSTI-containing ART may amplify differences and inequities in health outcomes. Objectives: To estimate racial and ethnic differences in the prescription of INSTI-containing ART among adults newly entering HIV care in the US and to examine variation in these differences over time in relation to changes in treatment guidelines. Design, Setting, and Participants: Retrospective observational study of 42 841 adults entering HIV care from October 12, 2007, when the first INSTI was approved by the US Food and Drug Administration, to April 30, 2019, at more than 200 clinical sites contributing to the North American AIDS Cohort Collaboration on Research and Design. Exposures: Combined race and ethnicity as reported in patient medical records. Main Outcomes and Measures: Probability of initial prescription of ART within 1 month of care entry and probability of being prescribed INSTI-containing ART. Differences among non-Hispanic Black and Hispanic patients compared with non-Hispanic White patients were estimated by calendar year and time period in relation to changes in national guidelines on the timing of treatment initiation and recommended initial treatment regimens. Results: Of 41 263 patients with information on race and ethnicity, 19 378 (47%) as non-Hispanic Black, 6798 (16%) identified as Hispanic, and 13 539 (33%) as non-Hispanic White; 36 394 patients (85%) were male, and the median age was 42 years (IQR, 30 to 51). From 2007-2015, when guidelines recommended treatment initiation based on CD4+ cell count, the probability of ART initiation within 1 month of care entry was 45% among White patients, 45% among Black patients (difference, 0% [95% CI, -1% to 1%]), and 51% among Hispanic patients (difference, 5% [95% CI, 4% to 7%]). From 2016-2019, when guidelines strongly recommended treating all patients regardless of CD4+ cell count, this probability increased to 66% among White patients, 68% among Black patients (difference, 2% [95% CI, -1% to 5%]), and 71% among Hispanic patients (difference, 5% [95% CI, 1% to 9%]). INSTIs were prescribed to 22% of White patients and only 17% of Black patients (difference, -5% [95% CI, -7% to -4%]) and 17% of Hispanic patients (difference, -5% [95% CI, -7% to -3%]) from 2009-2014, when INSTIs were approved as initial therapy but were not yet guideline recommended. Significant differences persisted for Black patients (difference, -6% [95% CI, -8% to -4%]) but not for Hispanic patients (difference, -1% [95% CI, -4% to 2%]) compared with White patients from 2014-2017, when INSTI-containing ART was a guideline-recommended option for initial therapy; differences by race and ethnicity were not statistically significant from 2017-2019, when INSTI-containing ART was the single recommended initial therapy for most people with HIV. Conclusions and Relevance: Among adults entering HIV care within a large US research consortium from 2007-2019, the 1-month probability of ART prescription was not significantly different across most races and ethnicities, although Black and Hispanic patients were significantly less likely than White patients to receive INSTI-containing ART in earlier time periods but not after INSTIs became guideline-recommended initial therapy for most people with HIV. Additional research is needed to understand the underlying racial and ethnic differences and whether the differences in prescribing were associated with clinical outcomes.

Five-Year Mortality for Adults Entering Human Immunodeficiency Virus Care Under Universal Early Treatment Compared With the General US Population.

BACKGROUND: Mortality among adults with human immunodeficiency virus (HIV) remains elevated over those in the US general population, even in the years after entry into HIV care. We explore whether the elevation in 5-year mortality would have persisted if all adults with HIV had initiated antiretroviral therapy within 3 months of entering care. METHODS: Among 82 766 adults entering HIV care at North American AIDS Cohort Collaboration clinical sites in the United States, we computed mortality over 5 years since entry into HIV care under observed treatment patterns. We then used inverse probability weights to estimate mortality under universal early treatment. To compare mortality with those for similar individuals in the general population, we used National Center for Health Statistics data to construct a cohort representing the subset of the US population matched to study participants on key characteristics. RESULTS: For the entire study period (1999-2017), the 5-year mortality among adults with HIV was 7.9% (95% confidence interval [CI]: 7.6%-8.2%) higher than expected based on the US general population. Under universal early treatment, the elevation in mortality for people with HIV would have been 7.2% (95% CI: 5.8%-8.6%). In the most recent calendar period examined (2011-2017), the elevation in mortality for people with HIV was 2.6% (95% CI: 2.0%-3.3%) under observed treatment patterns and 2.1% (.0%-4.2%) under universal early treatment. CONCLUSIONS: Expanding early treatment may modestly reduce, but not eliminate, the elevation in mortality for people with HIV.

Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.

BACKGROUND AND AIMS: Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV. APPROACH AND RESULTS: We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995-2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non-White), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5-2.1] events/1,000 person-years). Risk factors for HCC included age 40-49 years (aHR, 1.97 [1.22-3.17]), age ≥50 years (aHR, 2.55 [1.49-4.35]), HCV coinfection (aHR, 1.61 [1.07-2.40]), and heavy alcohol use (aHR, 1.52 [1.04-2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56-1.43]) and time-updated CD4+ percentage <14% (aHR, 1.03 [0.56-1.90]) were not. The risk of HCC was increased with time-updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42-3.47]) and was higher with each 1.0 log10 IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05-1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24-0.73]). CONCLUSION: Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.

Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1 (LPA1) antagonists.

BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA1) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA1 antagonism, two structurally distinct LPA1 antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma BAs in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA1.

Do contemporary antiretrovirals increase the risk of end-stage liver disease? Signals from patients starting therapy in the North American AIDS Cohort Collaboration on Research and Design.

PURPOSE: Despite effective antiretroviral therapy, rates of end-stage liver disease (ESLD) remain high. It is not clear whether contemporary antiretrovirals contribute to the risk of ESLD. METHODS: We included patients from cohorts with validated ESLD data in the North American AIDS Cohort Collaboration on Research and Design. Patients had to initiate antiretroviral therapy after 1 January 2004 with a nucleos(t)ide backbone of either abacavir/lamivudine or tenofovir/emtricitabine and a contemporary third (anchor) drug. Patients were followed until a first ESLD event, death, end of a cohort's ESLD validation period, loss to follow-up or 31 December 2015. We estimated associations between cumulative exposure to each drug and ESLD using a hierarchical Bayesian survival model with weakly informative prior distributions. RESULTS: Among 10 564 patients included from 12 cohorts, 62 had an ESLD event. Of the nine anchor drugs, boosted protease inhibitors atazanavir and darunavir had the strongest signals for ESLD, with increasing hazard ratios (HR) and narrowing credible intervals (CrI), from a prior HR of 1.5 (95% CrI 0.32-7.1) per 5 year's exposure to posterior HRs respectively of 1.8 (95% CrI 0.82-3.9) and 2.0 (95% CrI 0.86-4.7). Both backbones and efavirenz showed no signal. Hepatitis C coinfection was the most important covariate risk factor (HR 4.4, 95% CrI 2.6-7.0). CONCLUSIONS: While contemporary antiretrovirals pose less risk for ESLD than hepatitis coinfection, atazanavir and darunavir had a toxicity signal. We show how hierarchical Bayesian modelling can be used to detect toxicity signals in cohort event monitoring data even with complex treatments and few events.

In Vivo reflectance confocal microscopy of cutaneous acute graft-versus-host disease: concordance with histopathology and interobserver reproducibility of a glossary with representative images.

BACKGROUND: The reliability to non-invasively identify features of inflammatory dermatoses by reflectance confocal microscopy (RCM) remains unknown. Lack of formal training among RCM readers can result in inconsistent assessments, limiting clinical utility. Specific consensus terminology with representative images is necessary to ensure consistent feature-level interpretation among RCM readers. OBJECTIVES: (1) Develop a glossary with representative images of RCM features of cutaneous acute graft-versus-host disease (aGVHD) for consistent interpretation among observers, (2) assess the interobserver reproducibility among RCM readers using the glossary, and (3) determine the concordance between RCM and histopathology for aGVHD features. METHODS: Through an iterative process of refinement and discussion among five international RCM experts, we developed a glossary with representative images of RCM features of aGVHD. From April to November 2018, patients suspected of aGVHD were imaged with RCM and subsequently biopsied. 17 lesions from 12 patients had clinically and pathologically confirmed cutaneous aGVHD. For each of these lesions, four dermatopathologists and four RCM readers independently evaluated the presence of aGVHD features in scanned histopathology slides and 1.5 × 1.5 mm RCM submosaics at 4 depths (blockstacks) respectively. RCM cases were adjudicated by a fifth RCM expert. Interobserver reproducibility was calculated by mean pairwise difference (U statistic). Concordance between modalities was determined by fraction of assignments with agreement. RESULTS: We present a glossary with representative images of 18 aGVHD features by RCM. The average interobserver reproducibility among RCM readers (75%, confidence interval, CI: 71-79%) did not differ significantly from dermatopathologists (80%, 76-85%). The concordance between RCM and histopathology was 59%. CONCLUSIONS: By using the glossary, the interobserver reproducibility among RCM readers was similar to the interobserver reproducibility among dermatopathologists. There was reasonable concordance between RCM and histopathology to visualize aGVHD features. The implementation of RCM can now be advanced in a variety of inflammatory conditions with a validated glossary and representative image set.

Mortality Among Persons Entering HIV Care Compared With the General U.S. Population : An Observational Study.

BACKGROUND: Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population. OBJECTIVE: To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time. DESIGN: Observational cohort study. SETTING: Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design. PARTICIPANTS: 82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics. MEASUREMENTS: Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function. RESULTS: Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017. LIMITATION: Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors. CONCLUSION: Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. PRIMARY FUNDING SOURCE: National Institutes of Health.

A multifunctional 2D black phosphorene-based platform for improved photovoltaics.

As one of the latest additions to the 2D nanomaterials family, black phosphorene (BP, monolayer or few-layer black phosphorus) has gained much attention in various forms of solar cells. This is due largely to its intriguing semiconducting properties such as tunable direct bandgap (from 0.3 eV in the bulk to 2.0 eV in the monolayer), extremely high ambipolar carrier mobility, broad visible to infrared light absorption, etc. These appealing optoelectronic attributes make BP a multifunctional nanomaterial for use in solar cells via tailoring carrier dynamics, band energy alignment, and light harvesting, thereby promoting the rapid development of third-generation solar cells. Notably, in sharp contrast to the copious work on revealing the fundamental properties of BP, investigation into the utility of BP is comparatively less, particularly in the area of photovoltaics. Herein, we first identify and summarize an array of unique characteristics of BP that underpin its application in photovoltaics, aiming at providing inspiration to develop new designs and device architectures of photovoltaics. Subsequently, state-of-the-art synthetic routes (i.e., top-down and bottom-up) to scalable BP production that facilitates its applications in optoelectronic materials and devices are outlined. Afterward, recent advances in a diverse set of BP-incorporated solar cells, where BP may impart electron and/or hole extraction and transport, function as a light absorber, provide dielectric screening for enhancing exciton dissociation, and modify the morphology of photoabsorbers, are discussed, including organic solar cells, dye-sensitized solar cells, heterojunction solar cells and perovskite solar cells. Finally, the challenges and opportunities in this rapidly evolving field are presented.