Prevalence and determinants of hepatitis delta virus infection among HIV/hepatitis B-coinfected adults in care in the United States.

Hepatitis delta virus (HDV) infection increases the risk of liver complications compared to hepatitis B virus (HBV) alone, particularly among persons with human immunodeficiency virus (HIV). However, no studies have evaluated the prevalence or determinants of HDV infection among people with HIV/HBV in the US. We performed a cross-sectional study among adults with HIV/HBV coinfection receiving care at eight sites within the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) between 1996 and 2019. Among patients with available serum/plasma specimens, we selected the first specimen on or after their initial HBV qualifying test. All samples were tested for HDV IgG antibody and HDV RNA. Multivariable log-binomial generalized linear models were used to estimate prevalence ratios (PRs) with 95% CIs of HDV IgG antibody-positivity associated with determinants of interest (age, injection drug use [IDU], high-risk sexual behaviour). Among 597 adults with HIV/HBV coinfection in CNICS and available serum/plasma samples (median age, 43 years; 89.9% male; 52.8% Black; 42.4% White), 24/597 (4.0%; 95% CI, 2.4%-5.6%) were HDV IgG antibody-positive, and 10/596 (1.7%; 95% CI, 0.6%-2.7%) had detectable HDV RNA. In multivariable analysis, IDU was associated with exposure to HDV infection (adjusted PR = 2.50; 95% CI, 1.09-5.74). In conclusion, among a sample of adults with HIV/HBV coinfection in care in the US, 4.0% were HDV IgG antibody-positive, among whom 41.7% had detectable HDV RNA. History of IDU was associated with exposure to HDV infection. These findings emphasize the importance of HDV testing among persons with HIV/HBV coinfection, especially those with a history of IDU.

Delirium among people aging with and without HIV: Role of alcohol and Neurocognitively active medications.

BACKGROUND: People aging with and without HIV (PWH and PWoH) want to avoid neurocognitive dysfunction, especially delirium. Continued use of alcohol in conjunction with neurocognitively active medications (NCAMs) may be a largely underappreciated cause, especially for PWH who experience polypharmacy a decade earlier than PWoH. We compare absolute and relative risk of delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs. METHODS: Using the VACS cohort, we compare absolute and relative risk of inpatient delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs between 2007 and 2019. We matched each case based on age, race/ethnicity, sex, HIV, baseline year, and observation time with up to 5 controls. The case/control date was defined as date of admission for cases and the date corresponding to the same length of time on study for controls. Level of alcohol use was defined using Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Medication exposure was measured from 45 to 3 days prior to index date; medications were classified as anticholinergic NCAM, non-anticholinergic NCAM, or non NCAM and counts generated. We used logistic regression to determine odds ratios (ORs) for delirium associated with medication counts stratified by HIV status and adjusted for demographics, severity of illness, and related diagnoses. RESULTS: PWH experienced a higher incidence of delirium (5.6, [95% CI 5.3-5.9/1000 PY]) than PWoH (5.0, [95% CI 4.8-5.1/1000 PY]). In multivariable analysis, anticholinergic and non-anticholinergic NCAM counts and level of alcohol use demonstrated strong independent dose-response associations with delirium. CONCLUSIONS: Decreasing alcohol use and limiting the use of neurocognitively active medications may help decrease excess rates of delirium, especially among PWH.

Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing antiretroviral therapy.

OBJECTIVE: Antiretroviral therapy (ART) extends the life of people with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATMs). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions. DESIGN: We examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART ( n  = 5) and uninfected persons ( n  = 9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression. METHODS: ATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR. RESULTS: Adipose tissue from PWH had reduced populations of metabolically activated CD9 + ATMs compared to that of uninfected controls ( P  < 0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls ( P  < 0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism ( P  < 0.001) and increased expression of the fatty acid beta-oxidation enzyme enoyl-CoA hydratase, short chain 1 ( P  < 0.05). CONCLUSIONS: We report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation.

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.

Polypharmacy-associated risk of hospitalisation among people ageing with and without HIV: an observational study.

BACKGROUND: Polypharmacy, defined as use of five or more medications concurrently, is associated with adverse health outcomes and people ageing with HIV might be at greater risk than similar uninfected individuals. We aimed to determine whether known pairwise drug interactions (KPDIs) were associated with risk of admission to hospital (hereafter referred to as hospitalisation) and medication count among people ageing with and without HIV after accounting for physiological frailty. METHODS: In this observational study, we collected individual-level data for participants of the Veterans Aging Cohort Study (VACS) with HIV on antiretroviral therapy (ART) and with supressed HIV-1 RNA and people without HIV who were receiving at least one prescription medication, based on active medications in the 2009 fiscal year (ie, Oct 1, 2008, to Sept 30, 2009). We identified KPDIs among these patients by linking prescription fill and refill data with data from DrugBank (version 5.0.11). We collected data on all-cause mortality and hospitalisations between Oct 1, 2009, and March 31, 2019. We compared KPDI counts using random selection and actual patterns of use across medication counts from two to 12. We created a weighted KPDI Index on the basis of the average association of each KPDI with mortality among people ageing without HIV and used nested Cox models stratified by HIV status to estimate the association between medication count and hospitalisation, with incremental adjustments for demographics, physiological frailty, and KPDI Index. FINDINGS: We collected data for 9186 people ageing with HIV and 37 930 individuals without HIV. 45 913 (97·4%) of 47 116 patients were men and the sample was predominantly aged 50-64 years (30 413 [64·6%]). Compared with a random sample of medications, real-world pattern of medication counts and combinations were associated with five-to-six times more KPDIs (eg, for a combination of six medications, KPDI count was 1·09 in the random sample, 5·49 in the HIV-negative population, and 7·13 in the HIV-positive population). For each additional observed medication, people ageing with HIV had approximately 2·94 additional KPDIs and comparators had approximately 2·67 additional KPDIs. Adjustment for demographics, physiological frailty, and KPDI Index reduced the association between medication count and risk of hospitalisation for people ageing with HIV (hazard ratio 1·08 [95% CI 1·07-1·09] reduced to 1·06 [1·05-1·07]) and those without HIV (1·08 [1·07-1·08] reduced to 1·04 [1·03-1·05]). INTERPRETATION: For each additional medication, people ageing with HIV have more drug-drug interactions than those without HIV. Adjusting for known non-ART drug-drug interactions, each additional non-ART medication confers excess risk of hospitalisation for people ageing with HIV. Randomised trials will be needed to determine whether reducing these interactions improves outcomes. FUNDING: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Department of Veterans Affairs Health Services Research & Development, and Office of Research and Development.

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.

The Impact of Direct-Acting Antiviral Therapy on End-Stage Liver Disease Among Individuals with Chronic Hepatitis C and Substance Use Disorders.

BACKGROUND AND AIMS: Our aim was to evaluate the impact of direct-acting antivirals (DAAs) on decompensated cirrhosis (DCC) and HCC in patients with chronic HCV and substance use disorder (SUD) compared with those without an SUD. APPROACH AND RESULTS: This retrospective cohort study used the MarketScan database (2013-2018) to identify 29,228 patients with chronic HCV, where 22% (n = 6,385) had ≥1 SUD diagnosis. The inverse probability of treatment weighted multivariable Cox proportional hazard models were used to compare the risk of developing DCC and HCC. Among the those who were noncirrhotic, treatment reduced the DCC risk among SUD (adjusted hazard ratio [aHR] 0.13; 95% CI, 0.06-0.30) and non-SUD (aHR 0.11; 95% CI, 0.07-0.18), whereas the risk for HCC was not reduced for the SUD group (aHR 0.91; 95% CI, 0.33-2.48). For those with cirrhosis, compared with patients who were untreated, treatment reduced the HCC risk among SUD (aHR, 0.33; 95% CI, 0.13-0.88) and non-SUD (aHR, 0.40; 95% CI, 0.25-0.65), whereas the risk for DCC was not reduced for the SUD group (aHR, 0.64; 95% CI, 0.37-1.13). Among patients with cirrhosis who were untreated, the SUD group had a higher risk of DCC (aHR, 1.52; 95% CI, 1.03-2.24) and HCC (aHR, 1.69; 95% CI, 1.05-2.72) compared with non-SUD group. CONCLUSIONS: Among the HCV SUD group, DAA treatment reduced the risk of DCC but not HCC for those who were noncirrhotic, whereas DAA treatment reduced the risk of HCC but not DCC for those with cirrhosis. Among the nontreated, patients with an SUD had a significantly higher risk of DCC and HCC compared with those without an SUD. Thus, DAA treatment should be considered for all patients with HCV and an SUD while also addressing the SUD.

Trends in Hepatocellular Carcinoma Incidence and Risk Among Persons With HIV in the US and Canada, 1996-2015.

Importance: People with HIV (PWH) are often coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), leading to increased risk of developing hepatocellular carcinoma (HCC), but few cohort studies have had sufficient power to describe the trends of HCC incidence and risk among PWH in the combination antiretroviral therapy (cART) era. Objective: To determine the temporal trends of HCC incidence rates (IRs) and to compare rates by risk factors among PWH in the cART era. Design, Setting, and Participants: This cohort study used data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study, which was conducted between 1996 and 2015. NA-ACCORD pooled individual-level data from 22 HIV clinical and interval cohorts of PWH in the US and Canada. PWH aged 18 years or older with available CD4 cell counts and HIV RNA data were enrolled. Data analyses were completed in March 2020. Exposures: HBV infection was defined as detection of either HBV surface antigen, HBV e antigen, or HBV DNA in serum or plasma any time during observation. HCV infection was defined by detection of anti-HCV seropositivity, HCV RNA, or detectable genotype in serum or plasma at any time under observation. Main Outcomes and Measures: HCC diagnoses were identified on the basis of review of medical records or cancer registry linkage. Results: Of 109 283 PWH with 723 441 person-years of follow-up, the median (interquartile range) age at baseline was 43 (36-51) years, 93 017 (85.1%) were male, 44 752 (40.9%) were White, 44 322 (40.6%) were Black, 21 343 (19.5%) had HCV coinfection, 6348 (5.8%) had HBV coinfection, and 2082 (1.9%) had triple infection; 451 individuals received a diagnosis of HCC by 2015. Between the early (1996-2000) and modern (2006-2015) cART eras, the crude HCC IR increased from 0.28 to 0.75 case per 1000 person-years. HCC IRs remained constant among HIV-monoinfected persons or those coinfected with HBV, but from 1996 to 2015, IRs increased among PWH coinfected with HCV (from 0.34 cases/1000 person-years in 1996 to 2.39 cases/1000 person-years in 2015) or those with triple infection (from 0.65 cases/1000 person-years in 1996 to 4.49 cases/1000 person-years in 2015). Recent HIV RNA levels greater than or equal to 500 copies/mL (IR ratio, 1.8; 95% CI, 1.4-2.4) and CD4 cell counts less than or equal to 500 cells/µL (IR ratio, 1.3; 95% CI, 1.0-1.6) were associated with higher HCC risk in the modern cART era. People who injected drugs had higher HCC risk compared with men who had sex with men (IR ratio, 2.0; 95% CI, 1.3-2.9), adjusted for HBV-HCV coinfection. Conclusions and Relevance: HCC rates among PWH increased significantly over time from 1996 to 2015. PWH coinfected with viral hepatitis, those with higher HIV RNA levels or lower CD4 cell counts, and those who inject drugs had higher HCC risk.

Brief Report: Accuracy of FIB-4 for Cirrhosis in People Living With HIV and Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) may develop in the absence of cirrhosis in HIV, and determining how often this occurs can provide insights into mechanisms of carcinogenesis. Studies evaluating the prevalence of cirrhosis in the setting of HCC among people living with HIV (PLWH) often rely on noninvasive markers, such as the Fibrosis-4 Index for Hepatic Fibrosis (FIB-4). However, the accuracy of FIB-4 for cirrhosis in the setting of HCC has not been determined among PLWH. METHODS: We conducted a cross-sectional study among PLWH in the Veterans Aging Cohort Study with VA cancer registry-confirmed HCC diagnosed between 1999 and 2015. FIB-4 was calculated using the age, alanine aminotransferase, aspartate aminotransferase, and platelet count obtained closest to, but within 1 year before, HCC diagnosis. Medical records were reviewed within 1 year before HCC diagnosis to determine the cirrhosis status. We evaluated the area under the receiver-operating characteristic curve and performance characteristics of FIB-4 for confirmed cirrhosis. RESULTS: Incident HCC was diagnosed in 302 PLWH. After medical record review, 203 (67.2%, 95% confidence interval: 61.6% to 72.5%) had evidence of cirrhosis. FIB-4 identified patients with cirrhosis with an area under the receiver-operating characteristic curve of 0.67 (95% confidence interval: 0.60 to 0.73). FIB-4 scores >5.0 had a positive predictive value >80% and specificity of >77%, negative predictive value of <41%, and sensitivity of <45%. CONCLUSION: The accuracy of FIB-4 for cirrhosis in the setting of HIV and HCC is modest and may result in misclassification of cirrhosis in this population.

Impact of hepatitis C virus treatment on the risk of non-hepatic cancers among hepatitis C virus-infected patients in the US.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with with an increased risk of non-hepatic cancers, but the impact of HCV treatment on non-hepatic cancer is unclear. AIMS: To assess if HCV treatment reduced the incidence of non-hepatic cancers among patients with chronic HCV infection in the US. METHODS: We conducted a retrospective cohort study in MarketScan Databases from January 2005 to December 2016. Multivariable, time-varying Cox proportional-hazards models were used to determine hazard ratios (HRs) of incident non-hepatic cancers in treated and untreated patients with HCV infection. We conduscted subgroup analyses for sex, age, and presence of cirrhosis or diabetes. RESULTS: Among 62 078 patients with newly diagnosed HCV infection, 17 302 (28%) initiated HCV treatment, among whom 15 322 completed 8-16 weeks treatment (minimally effective treatment). Patients who initiated HCV treatment had an 11% decreased risk of developing an incident non-hepatic cancer compared to untreated patients (HR = 0.89, 95% confidence interval (Cl) = 0.82-0.96). The reduction was slightly higher when patients completed a minimally effective treatment (HR = 0.87; 95% Cl = 0.80 - 0.95). This was observed in most subgroup analyses for those who had a minimally effective treatment including patients with cirrhosis. When we stratified cancer or therapy subtypes, the association remained consistent for pancreatic and lung cancers, and dual HCV therapy. CONCLUSIONS: HCV treatment led to a significantly reduced incidence of non-hepatic cancers among patients with HCV infection. Despite discrepancies between cancer or HCV therapy subtypes, our findings suggest that treating HCV infection can decrease the extrahepatic cancer burden associated with chronic HCV infection.

Epidemiology, Natural History, and Treatment of Hepatitis Delta Virus Infection in HIV/Hepatitis B Virus Coinfection.

PURPOSE OF REVIEW: Limited data exist on the prevalence, determinants, and outcomes of hepatitis delta virus (HDV) infection among HIV/hepatitis B virus (HBV)-coinfected persons. This review provides current evidence on the epidemiology, natural history, and treatment of HDV infection in patients with HIV/HBV coinfection and highlights future research needs. RECENT FINDINGS: Cross-sectional studies in Europe, Africa, South America, and Asia show that the prevalence of HDV among HIV/HBV-coinfected patients ranges from 1.2 to 25%. No studies have evaluated the prevalence of HDV infection among HIV/HBV-coinfected patients in the USA. HDV infection increases the risk of hepatic decompensation and hepatocellular carcinoma among HIV/HBV-coinfected patients. HDV treatment remains limited to pegylated interferon-alpha, which results in sustained virologic response in fewer than 25%. Data on the epidemiology, natural history, and treatment of HDV among HIV/HBV-coinfected persons remain limited. More research is needed to address these knowledge gaps in order to better manage HDV coinfection in HIV/HBV-coinfected patients.

Differences in Pathology, Staging, and Treatment between HIV+ and Uninfected Patients with Microscopically Confirmed Hepatocellular Carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is substantially higher among HIV-infected (HIV+) than uninfected persons. It remains unclear if HCC in the setting of HIV infection is morphologically distinct or more aggressive. METHODS: We evaluated differences in tumor pathology in a cohort of HIV+ and uninfected patients with microscopically confirmed HCC in the Veterans Aging Cohort Study from 2000 to 2015. We reviewed pathology reports and medical records to determine Barcelona Clinic Liver Cancer stage (BCLC), HCC treatment, and survival by HIV status. Multivariable Cox regression was used to determine the hazard ratio [HR; 95% confidence interval (CI)] of death associated with HIV infection after microscopic confirmation. RESULTS: Among 873 patients with HCC (399 HIV+), 140 HIV+ and 178 uninfected persons underwent liver tissue sampling and had microscopically confirmed HCC. There were no differences in histologic features of the tumor between HIV+ and uninfected patients, including tumor differentiation (well differentiated, 19% vs. 28%, P = 0.16) and lymphovascular invasion (6% vs. 7%, P = 0.17) or presence of advanced hepatic fibrosis (40% vs. 39%, P = 0.90). There were no differences in BCLC stage (P = 0.06) or treatment (P = 0.29) by HIV status. After adjustment for risk factors, risk of death was higher among HIV-infected than uninfected patients (HR = 1.37; 95% CI, 1.02-1.85). CONCLUSIONS: We found no differences in HCC tumor characteristics or background hepatic parenchyma by HIV status, yet HIV was associated with poorer survival. Of note, pathology reports often omitted these characteristics. IMPACT: Systematic evaluation of HCC pathology by HIV status is needed to understand tumor characteristics associated with improved survival.

HIV RNA, CD4+ Percentage, and Risk of Hepatocellular Carcinoma by Cirrhosis Status.

BACKGROUND: Despite increasing incidence of hepatocellular carcinoma (HCC) among HIV-infected patients, it remains unclear if HIV-related factors contribute to development of HCC. We examined if higher or prolonged HIV viremia and lower CD4+ cell percentage were associated with HCC. METHODS: We conducted a cohort study of HIV-infected individuals who had HIV RNA, CD4+, and CD8+ cell counts and percentages assessed in the Veterans Aging Cohort Study (1999-2015). HCC was ascertained using Veterans Health Administration cancer registries and electronic records. Cox regression was used to determine hazard ratios (HR, 95% confidence interval [CI]) of HCC associated with higher current HIV RNA, longer duration of detectable HIV viremia (≥500 copies/mL), and current CD4+ cell percentage less than 14%, adjusting for traditional HCC risk factors. Analyses were stratified by previously validated diagnoses of cirrhosis prior to start of follow-up. RESULTS: Among 35 659 HIV-infected patients, 302 (0.8%) developed HCC over 281 441 person-years (incidence rate = 107.3 per 100 000 person-years). Among patients without baseline cirrhosis, higher HIV RNA (HR = 1.25, 95% CI = 1.12 to 1.40, per 1.0 log10 copies/mL) and 12 or more months of detectable HIV (HR = 1.47, 95% CI = 1.02 to 2.11) were independently associated with higher risk of HCC. CD4+ percentage less than 14% was not associated with HCC in any model. Hepatitis C coinfection was a statistically significant predictor of HCC regardless of baseline cirrhosis status. CONCLUSION: Among HIV-infected patients without baseline cirrhosis, higher HIV RNA and longer duration of HIV viremia increased risk of HCC, independent of traditional HCC risk factors. This is the strongest evidence to date that HIV viremia contributes to risk of HCC in this group.

Determinants of Liver Complications Among HIV/Hepatitis B Virus-Coinfected Patients.

BACKGROUND: Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown. SETTING: North American AIDS Cohort Collaboration on Research and Design. METHODS: We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL). RESULTS: Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]. CONCLUSIONS: Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.

Mortality and Kidney Transplantation Outcomes Among Hepatitis C Virus-Seropositive Maintenance Dialysis Patients: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Hepatitis C virus (HCV) infection is common among maintenance dialysis patients. Few studies have examined both dialysis survival and transplantation outcomes for HCV-seropositive patients because registry data sets lack information for HCV serostatus. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult long-term dialysis patients treated by a US national dialysis provider between January 1, 2004, and December 31, 2014. EXPOSURE: HCV antibody serostatus obtained as part of clinical data from a national dialysis provider. OUTCOMES: Mortality on dialysis therapy, entry onto the kidney transplant waiting list, kidney transplantation, and estimated survival benefit from kidney transplantation versus remaining on the waitlist. ANALYTICAL APPROACH: After linking clinical data with data from the Organ Procurement and Transplantation Network, Cox and cause-specific hazards regression were implemented to estimate the associations between HCV seropositivity and mortality, as well as entry onto the kidney transplant waitlist. Cox regression was also used to estimate the survival benefit from transplantation versus dialysis among HCV-seropositive individuals. RESULTS: Among 442,171 dialysis patients, 31,624 (7.2%) were HCV seropositive. HCV seropositivity was associated with a small elevation in the rate of death (adjusted HR [aHR], 1.09; 95% CI, 1.07-1.11) and a substantially lower rate of entry onto the kidney transplant waitlist (subdistribution HR [sHR], 0.67; 95% CI, 0.61-0.74). Once wait-listed, the kidney transplantation rate was not different for HCV-seropositive (sHR 1.10; 95% CI, 0.96-1.27) versus HCV-seronegative patients. HCV-seropositive patients lived longer with transplantation (aHR at 3 years, 0.42; 95% CI, 0.27-0.63). Receiving an HCV-seropositive donor kidney provided a survival advantage at the 2-year posttransplantation time point compared to remaining on dialysis therapy waiting for an HCV-negative kidney. LIMITATIONS: No data for HCV viral load or liver biopsy. CONCLUSIONS: HCV-seropositive patients experience reduced access to the kidney transplantation waitlist despite deriving a substantial survival benefit from transplantation. HCV-seropositive patients should consider foregoing HCV treatment while accepting kidneys from HCV-infected donors to facilitate transplantation and prolong survival.

Contributions of traditional and HIV-related risk factors on non-AIDS-defining cancer, myocardial infarction, and end-stage liver and renal diseases in adults with HIV in the USA and Canada: a collaboration of cohort studies.

BACKGROUND: Adults with HIV have an increased burden of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease. The objective of this study was to estimate the population attributable fractions (PAFs) of preventable or modifiable HIV-related and traditional risk factors for non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes. METHODS: We included participants receiving care in academic and community-based outpatient HIV clinical cohorts in the USA and Canada from Jan 1, 2000, to Dec 31, 2014, who contributed to the North American AIDS Cohort Collaboration on Research and Design and who had validated non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, or end-stage renal disease outcomes. Traditional risk factors were tobacco smoking, hypertension, elevated total cholesterol, type 2 diabetes, renal impairment (stage 4 chronic kidney disease), and hepatitis C virus and hepatitis B virus infections. HIV-related risk factors were low CD4 count (<200 cells per µL), detectable plasma HIV RNA (>400 copies per mL), and history of a clinical AIDS diagnosis. PAFs and 95% CIs were estimated to quantify the proportion of outcomes that could be avoided if the risk factor was prevented. FINDINGS: In each of the study populations for the four outcomes (1405 of 61 500 had non-AIDS-defining cancer, 347 of 29 515 had myocardial infarctions, 387 of 35 044 had end-stage liver disease events, and 255 of 35 620 had end-stage renal disease events), about 17% were older than 50 years at study entry, about 50% were non-white, and about 80% were men. Preventing smoking would avoid 24% (95% CI 13-35) of these cancers and 37% (7-66) of the myocardial infarctions. Preventing elevated total cholesterol and hypertension would avoid the greatest proportion of myocardial infarctions: 44% (30-58) for cholesterol and 42% (28-56) for hypertension. For liver disease, the PAF was greatest for hepatitis C infection (33%; 95% CI 17-48). For renal disease, the PAF was greatest for hypertension (39%; 26-51) followed by elevated total cholesterol (22%; 13-31), detectable HIV RNA (19; 9-31), and low CD4 cell count (13%; 4-21). INTERPRETATION: The substantial proportion of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes that could be prevented with interventions on traditional risk factors elevates the importance of screening for these risk factors, improving the effectiveness of prevention (or modification) of these risk factors, and creating sustainable care models to implement such interventions during the decades of life of adults living with HIV who are receiving care. FUNDING: National Institutes of Health, US Centers for Disease Control and Prevention, the US Agency for Healthcare Research and Quality, the US Health Resources and Services Administration, the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long Term Care, and the Government of Alberta.

Nonantiretroviral polypharmacy and adverse health outcomes among HIV-infected and uninfected individuals.

BACKGROUND: HIV-positive individuals (HIV+) on antiretrovirals commonly take enough other medications to cross a threshold for polypharmacy but little is known about associated outcomes. We asked whether non-antiretroviral polypharmacy is associated with hospitalization and mortality and whether associations differ by HIV status. METHODS: Data on HIV+ and uninfected individuals in the US Veterans Affairs Healthcare System were analyzed. Eligible HIV+ were on antiretrovirals with suppressed HIV-1 RNA and uninfected individuals received at least one medication. We calculated average non-antiretroviral medication count for fiscal year 2009. As there is no established threshold for non-antiretroviral polypharmacy, we considered more than two and at least five medications. We followed for hospitalization and mortality (fiscal year 2010-2015), adjusting for age, sex, race/ethnicity and VACS Index. RESULTS: Among 9473 HIV+ and 39 812 uninfected individuals respectively, non-antiretroviral polypharmacy was common (>2: 67, 71%; ≥5: 34, 39%). VACS Index discriminated risk of hospitalization (c-statistic: 0.62, 0.60) and mortality (c-statistic: 0.72, 0.70) similarly in both groups. After adjustment, more than two (hazard ratio 1.51, 95% CI 1.46-1.55) and at least five non-antiretrovirals (hazard ratio 1.52, 95% CI 1.49-1.56) were associated with hospitalization with no interaction by HIV status. Risk of mortality associated with more than two non-antiretrovirals interacted with HIV status (P = 0.002), but not for at least five (adjusted hazard ratio 1.43, 95% CI 1.36-1.50). For both groups and both outcomes, average medication count demonstrated an independent, dose response, association. CONCLUSION: Neither severity of illness nor demographics explain a dose response, association of non-antiretroviral polypharmacy with adverse health outcomes among HIV+ and uninfected individuals.

The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study.

Recent studies have reported higher rates of hepatocellular carcinoma (HCC) in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging because of the heterogeneous populations and methodologies of these reports. We investigated whether DAA use is associated with higher rates of incident HCC compared to treatment with interferon (IFN)-based regimens. We performed a retrospective, population-based cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database. In a cohort of 17,836 persons, sustained virological response (SVR) was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. Among all treated persons, risk of HCC was not higher in the DAA group compared to the IFN group (hazard ratio, 1.07; 95% confidence interval, 0.55, 2.08). Among persons with cirrhosis who achieved SVR, neither the HCC incidence rate nor HCC-free survival were significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1,000 person-years; P = 0.78 and log-rank P = 0.17, respectively). Untreated persons with cirrhosis had a significantly higher HCC incidence rate (45.3 per 1,000 person-years) compared to those treated with either IFN or DAAs (P = 0.03). Both groups of treated persons had significantly lower probability of HCC development compared to untreated persons (log-rank, P = 0.0004). CONCLUSION: DAA treatment is not associated with a higher risk of HCC in persons with cirrhosis with chronic HCV infection in the short term. Previously reported higher rates of HCC associated with DAA treatment may be explained by both the presence of relatively fewer baseline HCC risk factors in persons treated with IFN as well as selection bias, given that DAA regimens were used to treat persons at higher risk for developing HCC. (Hepatology 2018;67:2244-2253).

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer.

OBJECTIVES: Obesity prevalence among people living with HIV (HIV+) is rising. HIV and obesity are proinflammatory states, but their combined effect on inflammation (measured by interleukin 6, IL-6), altered coagulation (D-dimer), and monocyte activation (soluble CD14, sCD14) is unknown. We hypothesized inflammation increases when obesity and HIV infection co-occur. METHODS: The Veterans Aging Cohort Study survey cohort is a prospective, observational study of predominantly male HIV+ veterans and veterans uninfected with HIV; a subset provided blood samples. Inclusion criteria for this analysis were body mass index ≥ 18.5 kg/m and biomarker measurement. Dependent variables were IL-6, sCD14, and D-dimer quartiles. Obesity/HIV status was the primary predictor. Unadjusted and adjusted logistic regression models were constructed. RESULTS: Data were analyzed for 1477 HIV+ and 823 uninfected participants. Unadjusted median IL-6 levels were significantly higher and sCD14 levels significantly lower in obese/HIV+ compared with nonobese/uninfected (P <0.01 for both). In adjusted analyses, the odds ratio for increased IL-6 in obese/HIV+ patients was 1.76 (95% confidence interval: 1.18 to 2.47) compared with nonobese/uninfected, and obesity/HIV+ remained associated with lower odds of elevated sCD14. We did not detect a synergistic association of co-occurring HIV and obesity on IL-6 or sCD14 elevation. D-dimer levels did not differ significantly between body mass index/HIV status groups. CONCLUSIONS: HIV-obesity comorbidity is associated with elevated IL-6, decreases in sCD14, and no significant difference in D-dimer. These findings are clinically significant, as previous studies associated these biomarkers with mortality. Future studies should assess whether other biomarkers show similar trends and potential mechanisms for unanticipated sCD14 and D-dimer findings.