Azathioprine-induced vanishing bile duct syndrome: The value of early thiopurine metabolism assessment.

About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine-induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34-year-old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6-MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 6-MMPN blood levels may help physicians to identify patients at risk of similar duct injury.

Cardiac toxicity associated with pharmacokinetic drug-drug interaction between crizotinib and sofosbuvir/velpatasvir: A case report.

This case report describes a pharmacokinetic drug-drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic nonsmall cell lung cancer with mesenchymal-epithelial transition exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb oedema and class III New York Heart Association dyspnoea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug-drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir, velpatasvir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

International survey among hepatologists and pulmonologists on the hepatic hydrothorax: plea for recommendations.

BACKGROUND: The Hepatic hydrothorax is a pleural effusion related to portal hypertension; its diagnosis and therapeutic management may be difficult. The aims of this article are which follows: To gather the practices of hepatogastroenterologists or pulmonologists practitioners regarding the diagnosis and management of the hepatic hydrothorax. METHODS: Practitioners from 13 French- speaking countries were invited to answer an online questionnaire on the hepatic hydrothorax diagnosis and its management. RESULTS: Five hundred twenty-eight practitioners (80% from France) responded to this survey. 75% were hepatogastroenterologists, 20% pulmonologists and the remaining 5% belonged to other specialities. The Hepatic hydrothorax can be located on the left lung for 64% of the responders (66% hepatogastroenterologists vs 57% pulmonologists; p = 0.25); The Hepatic hydrothorax can exist in the absence of clinical ascites for 91% of the responders (93% hepatogastroenterologists vs 88% pulmonologists; p = 0.27). An Ultrasound pleural scanning was systematically performed before a puncture for 43% of the responders (36% hepatogastroenterologists vs 70% pulmonologists; p < 0.001). A chest X-ray was performed before a puncture for 73% of the respondeurs (79% hepatogastroenterologists vs 54% pulmonologists; p < 0.001). In case of a spontaneous bacterial empyema, an albumin infusion was used by 73% hepatogastroenterologists and 20% pulmonologists (p < 0.001). A drain was used by 37% of the responders (37% hepatogastroenterologists vs 31% pulmonologists; p = 0.26).An Indwelling pleural catheter was used by 50% pulmonologists and 22% hepatogastroenterologists (p < 0.01). TIPS was recommended by 78% of the responders (85% hepatogastroenterologists vs 52% pulmonologists; p < 0.001) and a liver transplantation, by 76% of the responders (86% hepatogastroenterologists vs 44% pulmonologists; p < 0.001). CONCLUSIONS: The results of this large study provide important data on practices of French speaking hepatogastroenterologists and pulmonologists; it appears that recommendations are warranted.

Multicenter study on recent portal venous system thrombosis associated with cytomegalovirus disease.

BACKGROUND & AIMS: Recent non-malignant non-cirrhotic portal venous system thrombosis (PVT) is a rare condition. Among risk factors for PVT, cytomegalovirus (CMV) disease is usually listed based on a small number of reported cases. The aim of this study was to determine the characteristics and outcomes of PVT associated with CMV disease. METHODS: We conducted a French multicenter retrospective study comparing patients with recent PVT and CMV disease ("CMV positive"; n = 23) to patients with recent PVT for whom CMV testing was negative ("CMV negative"; n = 53) or unavailable ("CMV unknown"; n = 297). RESULTS: Compared to patients from the "CMV negative" and "CMV unknown" groups, patients from the "CMV positive" group were younger, more frequently had fever, and had higher heart rate, lymphocyte count and serum ALT levels (p ≤0.01 for all). The prevalence of immunosuppression did not differ between the 3 groups (4%, 4% and 6%, respectively). Extension of PVT was similar between the 3 groups. Thirteen out of 23 "CMV positive" patients had another risk factor for thrombosis. Besides CMV disease, the number of risk factors for thrombosis was similar between the 3 groups. Heterozygosity for the prothrombin G20210A gene variant was more frequent in "CMV positive" patients (22%) than in the "CMV negative" (4%, p = 0.01) and "CMV unknown" (8%, p = 0.03) groups. Recanalization rate was not influenced by CMV status. CONCLUSIONS: In patients with recent PVT, features of mononucleosis syndrome should raise suspicion of CMV disease. CMV disease does not influence thrombosis extension nor recanalization. More than half of "CMV positive" patients have another risk factor for thrombosis, with a particular link to the prothrombin G20210A gene variant. LAY SUMMARY: Patients with cytomegalovirus (CMV)-associated portal venous system thrombosis have similar thrombosis extension and evolution as patients without CMV disease. However, patients with CMV-associated portal venous system thrombosis more frequently have the prothrombin G20210A gene variant, suggesting that these entities act synergistically to promote thrombosis.

Burden of liver disease progression in hospitalized patients with type 2 diabetes mellitus.

BACKGROUND & AIMS: There are uncertainties regarding the burden of liver disease in patients with type 2 diabetes (T2D). Thus, we aimed to quantify the burden of liver disease, identify risk factors, and estimate attributable risks in patients with T2D. METHODS: We measured adjusted hazard ratios of liver disease progression to hepatocellular carcinoma and/or decompensated cirrhosis in a 2010-2020 retrospective, bicentric, longitudinal, cohort of 52,066 hospitalized patients with T2D. RESULTS: Mean age was 64±14 years and 58% were men. Alcohol use disorders accounted for 57% of liver-related complications and were associated with all liver-related risk factors. Non-metabolic liver-related risk factors accounted for 37% of the liver burden. T2D control was not associated with liver disease progression. The incidence (95% CI) of liver-related complications and of competing mortality were 3.9 (3.5-4.3) and 27.8 (26.7-28.9) per 1,000 person-years at risk, respectively. The cumulative incidence of liver disease progression exceeded the cumulative incidence of competing mortality only in the presence of well-identified risk factors of liver disease progression, including alcohol use. The incidence of hepatocellular carcinoma was 0.3 (95% CI 0.1-0.5) per 1,000 person-years in patients with obesity and it increased with age. The adjusted hazard ratios of liver disease progression were 55.7 (40.5-76.6), 3.5 (2.3-5.2), 8.9 (6.9-11.5), and 1.5 (1.1-2.1), for alcohol-related liver disease, alcohol use disorders without alcohol-related liver disease, non-metabolic liver-related risk factors, and obesity, respectively. The attributable fractions of alcohol use disorders, non-metabolic liver-related risk factors, and obesity to the liver burden were 55%, 14%, and 7%, respectively. CONCLUSIONS: In this analysis of data from 2 hospital-based cohorts of patients with T2D, alcohol use disorders, rather than obesity, contributed to most of the liver burden. These results suggest that patients with T2D should be advised to drink minimal amounts of alcohol. LAY SUMMARY: There is uncertainty on the burden of liver-related complications in patients with type 2 diabetes. We studied the risks of liver cancer and complications of liver disease in over 50,000 patients with type 2 diabetes. We found that alcohol was the main factor associated with complications of liver disease. This finding has major implications on the alcohol advice given to patients with type 2 diabetes.

HCV cure: an appropriate moment to reduce cannabis use in people living with HIV? (ANRS CO13 HEPAVIH data).

BACKGROUND: Thanks to direct-acting antivirals, hepatitis C virus (HCV) infection can be cured, with similar rates in HCV-infected and HIV-HCV co-infected patients. HCV cure is likely to foster behavioral changes in psychoactive substance use, which is highly prevalent in people living with HIV (PLWH). Cannabis is one substance that is very commonly used by PLWH, sometimes for therapeutic purposes. We aimed to identify correlates of cannabis use reduction following HCV cure in HIV-HCV co-infected cannabis users and to characterize persons who reduced their use. METHODS: We used data collected on HCV-cured cannabis users in a cross-sectional survey nested in the ANRS CO13 HEPAVIH cohort of HIV-HCV co-infected patients, to perform logistic regression, with post-HCV cure cannabis reduction as the outcome, and socio-behavioral characteristics as potential correlates. We also characterized the study sample by comparing post-cure substance use behaviors between those who reduced their cannabis use and those who did not. RESULTS: Among 140 HIV-infected cannabis users, 50 and 5 had reduced and increased their use, respectively, while 85 had not changed their use since HCV cure. Cannabis use reduction was significantly associated with tobacco use reduction, a decrease in fatigue level, paying more attention to one's dietary habits since HCV cure, and pre-HCV cure alcohol abstinence (p = 0.063 for alcohol use reduction). CONCLUSIONS: Among PLWH using cannabis, post-HCV cure cannabis reduction was associated with tobacco use reduction, improved well-being, and adoption of healthy behaviors. The management of addictive behaviors should therefore be encouraged during HCV treatment.

Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis (NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis ("Warburg effect") in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this "Gordian Knot" in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this "citrate strategy" could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness.

Atherosclerotic Cardiovascular Events in Patients Infected With Human Immunodeficiency Virus and Hepatitis C Virus.

BACKGROUND: An increased risk of cardiovascular disease (CVD) was reported in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), without identifying factors associated with atherosclerotic CVD (ASCVD) events. METHODS: HIV-HCV coinfected patients were enrolled in the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS) CO13 HEPAVIH nationwide cohort. Primary outcome was total ASCVD events. Secondary outcomes were coronary and/or cerebral ASCVD events, and peripheral artery disease (PAD) ASCVD events. Incidences were estimated using the Aalen-Johansen method. Factors associated with ASCVD were identified using cause-specific Cox proportional hazards models. RESULTS: At baseline, median age of the study population (N = 1213) was 45.4 (interquartile range [IQR] 42.1-49.0) years and 70.3% were men. After a median follow-up of 5.1 (IQR 3.9-7.0) years, the incidence was 6.98 (95% confidence interval [CI], 5.19-9.38) per 1000 person-years for total ASCVD events, 4.01 (2.78-6.00) for coronary and/or cerebral events, and 3.17 (2.05-4.92) for PAD ASCVD events. Aging (hazard ratio [HR] 1.06; 95% CI, 1.01-1.12), prior CVD (HR 8.48; 95% CI, 3.14-22.91), high total cholesterol (HR 1.43; 95% CI, 1.11-1.83), high-density lipoprotein cholesterol (HR 0.22; 95% CI, 0.08-0.63), statin use (HR 3.31; 95% CI, 1.31-8.38), and high alcohol intake (HR 3.18; 95% CI, 1.35-7.52) were independently associated with total ASCVD events, whereas undetectable baseline viral load (HR 0.41, 95% CI, 0.18-0.96) was associated with coronary and/or cerebral events. CONCLUSIONS: HIV-HCV coinfected patients experienced a high incidence of ASCVD events. Some traditional cardiovascular risk factors were the main determinants of ASCVD. Controlling cholesterol abnormalities and maintaining undetectable HIV RNA are essential to control cardiovascular risk.

Prognosis of French COVID-19 patients with chronic liver disease: A national retrospective cohort study for 2020.

BACKGROUND & AIMS: The impact of chronic liver disease on outcomes in patients with COVID-19 is uncertain. Hence, we aimed to explore this association. METHODS: We explored the outcomes of all adult inpatients with COVID-19 in France, in 2020. We computed adjusted odds ratios to measure the associations between chronic liver disease, alcohol use disorders, mechanical ventilation and day-30 in-hospital mortality. RESULTS: The sample comprised 259,110 patients (median [IQR] age 70 (54-83) years; 52% men), including 15,476 (6.0%) and 10,006 (3.9%) patients with chronic liver disease and alcohol use disorders, respectively. Death occurred in 38,203 (15%) patients, including 7,475 (28%) after mechanical ventilation, and 2,941 (19%) with chronic liver disease. The adjusted odds ratios for mechanical ventilation and day-30 mortality were 1.54 (95% CI 1.44-1.64, p <0.001) and 1.79 (1.71-1.87, p <0.001) for chronic liver disease; 0.55 (0.47-0.64, p <0.001) and 0.54 (0.48-0.61, p <0.001) for mild liver disease; 0.64 (0.53-0.76; p <0.001) and 0.71 (0.63-0.80, p <0.001) for compensated cirrhosis; 0.65 (0.52-0.81, p <0.001) and 2.21 (1.94-2.51, p <0.001) for decompensated cirrhosis; 0.34 (0.24-0.50; p <0.001) and 1.38 (1.17-1.62, p <0.001) for primary liver cancer; and 0.82 (0.76-0.89; p <0.001) and 1.11 (1.05-1.17; p <0.001) for alcohol use disorders. Chronic viral hepatitis; non-viral, non-alcoholic chronic hepatitis; organ, including liver, transplantation, and acquired immunodeficiency syndrome were not associated with COVID-19-related death. CONCLUSION: Chronic liver disease increased the risk of COVID-19-related death in France in 2020. Therapeutic effort limitation may have contributed to COVID-19-related death in French residents with a liver-related complication or an alcohol use disorder. LAY SUMMARY: We studied the outcomes, including mechanical ventilation and day-30 mortality, of all adults with COVID-19 who were discharged from acute and post-acute care in France in 2020 (N = 259,110). Patients with mild liver disease; compensated cirrhosis; organ, including liver, transplantation; or acquired immunodepression syndrome were not at increased risk of COVID-19-related mortality. Patients with alcohol use disorders, decompensated cirrhosis, or primary liver cancer were at increased risk of COVID-19-related mortality but were less likely to receive mechanical ventilation. Our results suggest that therapeutic effort limitation may have contributed to the excess mortality in French residents with a liver-related complication or an alcohol use disorder.

Increased mortality in HIV/HCV-coinfected compared to HCV-monoinfected patients in the DAA era due to non-liver-related death.

BACKGROUND & AIMS: Direct-acting antivirals (DAA) lead to high sustained virological response (SVR) rates and decrease the risk of disease progression. We compared SVR rates and all-cause, liver- and non-liver-related deaths, liver-related events, and non-liver-related cancers in HIV/HCV-coinfected and HCV-monoinfected participants from 2 French cohort studies after initiation of DAA treatment. METHODS: Up to 4 HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to each HIV/HCV-coinfected patient from the ANRS CO13 HEPAVIH cohort; both are nationwide, prospective, multicentre, and observational. Participants were initiated on DAAs between March 2014 and December 2017. Cox proportional hazards models adjusted by age, sex, duration since HCV diagnosis, HCV transmission routes, HCV genotypes, cirrhosis, tobacco, alcohol consumption, and SVR (time dependent) were used. RESULTS: A total of 592 HIV/HCV-coinfected and 2,049 HCV-monoinfected participants were included; median age was 53.3 years (inter-quartile range: 49.6-56.9) and 52.9 years (49.6; 56.7), 1,498 (73.1%) and 436 (73.6%) were men, and 159 (28.8%) and 793 (41.2%) had cirrhosis, respectively. SVR was observed in 92.9% and 94.6%, respectively. HIV coinfection was associated with higher risk of all-cause death (hazard ratio [HR] 1.93; 95% CI 1.01-3.69), non-liver-related death (HR 2.84; 95% CI 1.27-6.36), and non-liver-related cancer (HR 3.26; 95% CI 1.50-7.08), but not with liver-related-death (HR 1.04; 95% CI 0.34-3.15) or liver-related events (HR 0.66; 95% CI 0.31-1.44). CONCLUSIONS: After DAA treatment, HIV-coinfected individuals had similar SVR rates and risk of liver-related deaths and events compared with HCV-monoinfected individuals, but had a higher risk of all-cause and non-liver-related deaths and non-liver-related cancers. LAY SUMMARY: We compared the risk of several clinical events in participants infected by human immunodeficiency virus and hepatitis C virus with those infected with hepatitis C virus alone, matched on age and sex, after treatment with contemporary direct-acting antivirals. We found a higher risk of all-cause deaths, non-liver-related deaths, and non-liver-related cancers in participants coinfected with the human immunodeficiency virus and hepatitis C virus, and no differences for the risk of liver-related deaths or events.

Risk of severe clinical events after sustained virological response following direct-acting antiviral therapy in HIV and hepatitis C virus coinfected participants.

OBJECTIVES: Sustained virological response (SVR) decreases the risk of hepatitis C virus (HCV)-related events. Nevertheless, a substantial risk of events persists. We estimated incidences and identified factors associated with severe clinical events after SVR following treatment with a direct-acting antiviral (DAA) in HIV/HCV-coinfected patients. METHODS: Participants from the ANRS CO13 HEPAVIH were included if they reached SVR. Incidence rates of overall mortality, liver-related events, AIDS-defining events, ischaemic events and non-liver non-AIDS-defining cancers (NLNA) were estimated. Factors associated with the risk of those events were identified using Poisson models adjusted on age at SVR and sex. RESULTS: In all, 775 participants were included. Incidence rates (95% confidence interval) of liver-related events, overall mortality, AIDS-defining events, ischaemic events and NLNA cancers per 1000 person-years were 5.9 (3.3-10.3), 22.2 (16.8-29.5), 0.6 (0.1-4.5), 7.3 (4.4-12.2) and 13.7 (9.4-20.0), respectively. For all events, incidence rates were higher in cirrhotic than in non-cirrhotic participants. Cirrhosis, liver stiffness and CD4 count were associated with liver-related events. Factors associated with overall mortality were age, cirrhosis, liver stiffness and gamma-glutamyl transferase (GGT). For ischaemic events and NLNA cancers, associated factors were total cholesterol and CD4 count, respectively. CONCLUSIONS: After SVR following a DAA treatment, liver-related and AIDS-defining events were observed less frequently than NLNA cancers. Severity of liver disease was associated with the risk of liver-related events and of overall mortality but not with ischaemic events and NLNA cancers. Factors reflecting HIV infection were associated with NLNA cancers and liver-related events.

Direct, indirect and total effect of HIV coinfection on the risk of non-liver-related cancer in hepatitis C virus-infected patients treated by direct-acting antivirals: a mediation analysis.

OBJECTIVES: HIV-coinfected patients experience higher incidences of non-liver-related cancers than HCV-monoinfected patients. Chronic inflammation, immunosuppression, but also higher tobacco or alcohol consumption and metabolic dysregulation could explain this higher risk. We aimed to estimate the direct, indirect and total effects of HIV coinfection on the risk of non-liver-related cancers in HCV participants treated with direct-acting antivirals (DAAs). METHODS: Up to four HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to HIV/HCV-coinfected participants from the ANRS CO13 HEPAVIH cohort. Participants were followed from DAA initiation until the occurrence of a non-liver-related cancer. Counterfactual mediation analysis was carried out to estimate the direct (chronic inflammation and immunosuppression), indirect (tobacco and alcohol consumption and metabolic syndrome) and total effect of HIV coinfection on the risk of non-liver-related cancers. RESULTS: 548 HIV/HCV-coinfected and 2016 monoinfected participants were included. Overall, HIV coinfection was associated with a 3.7-fold [95% confidence interval (CI): 1.7-7.0] higher risk of non-liver-related cancers in HCV participants. This increased risk was explained by significant direct effect [hazard ratio (HR) = 3.4, 95% CI: 1.7-6.6] but not indirect effect (HR = 1.1, 95% CI: 0.8-1.5) of HIV coinfection. CONCLUSIONS: In HCV participants treated with DAAs, the direct effect of HIV coinfection, reflecting chronic inflammation and immunosuppression, was associated with a 3.7-fold higher risk of non-liver-related cancer. By contrast, the indirect effect of HIV coinfection, reflecting higher tobacco and alcohol consumption and metabolic dysregulation, was not significantly associated with the risk of non-liver-related cancers.

Elevated Fatty Liver Index as a Risk Factor for All-Cause Mortality in Human Immunodeficiency Virus-Hepatitis C Virus-Coinfected Patients (ANRS CO13 HEPAVIH Cohort Study).

BACKGROUND AND AIMS: Human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients are at high risk of metabolic complications and liver-related events, which are both associated with hepatic steatosis and its progressive form, nonalcoholic steatohepatitis, a known risk factor for mortality. The fatty liver index (FLI), a noninvasive steatosis biomarker, has recently drawn attention for its clinical prognostic value, although its capacity to predict mortality risk in HIV-HCV-coinfected patients has never been investigated. Using a Cox proportional hazards model for mortality from all causes, with data from the French National Agency for Research on Aids and Viral Hepatitis CO13 HEPAVIH cohort (983 patients, 4,432 visits), we tested whether elevated FLI (≥60) was associated with all-cause mortality. APPROACH AND RESULTS: After multiple adjustment, individuals with FLI ≥ 60 had almost double the risk of all-cause mortality (adjusted hazard ratio [95% confidence interval], 1.91 [1.17-3.12], P = 0.009), independently of the following factors: HCV cure (0.21 [0.07-0.61], P = 0.004), advanced fibrosis (1.77 [1.00-3.14], P = 0.05), history of hepatocellular carcinoma and/or liver transplantation (7.74 [3.82-15.69], P < 10-3 ), history of indirect clinical signs of cirrhosis (2.80 [1.22-6.41], P = 0.015), and HIV Centers for Disease Control and Prevention clinical stage C (2.88 [1.74-4.79], P < 10-3 ). CONCLUSIONS: An elevated FLI (≥60) is a risk factor for all-cause mortality in HIV-HCV-coinfected patients independently of liver fibrosis and HCV cure. In the present era of nearly 100% HCV cure rates thanks to direct-acting antivirals, these findings encourage the more systematic use of noninvasive steatosis biomarkers to help identify coinfected patients with higher mortality risk.

HCV Cure and Cannabis Abstinence Facilitate Tobacco Smoking Quit Attempts in HIV-HCV Co-Infected Patients (ANRS CO13 HEPAVIH Cohort Study).

In Western countries, tobacco smoking is highly prevalent among patients co-infected with HIV and hepatitis C virus (HCV). In the era of antiretrovirals and HCV cure, smoking-related health damages contribute greatly to morbidity and mortality in HIV-HCV co-infected patients. We used longitudinal data from the ANRS CO13 HEPAVIH cohort to identify the correlates of tobacco smoking quit attempts (TSQA) in HIV-HCV co-infected patients. TSQA were modelled using a multivariable discrete-time Cox proportional hazards model in 695 HIV-HCV co-infected tobacco smokers. HCV cure was associated with a 76% higher chance of TSQA (adjusted hazard ratio [95% confidence interval]: 1.76 [1.06-2.93], p = 0.029), and cannabis use with a 37% lower chance (0.63 [0.40-1.00], p = 0.049), independently of the mode of HIV transmission, other psychoactive substance use, and body mass index. Patients should be screened for tobacco and cannabis use at HCV treatment initiation and during follow-up. They should also be provided with comprehensive counselling and referral to addiction services. Non-smoking routes of cannabis administration should be promoted for cannabis users who wish to quit smoking tobacco.

Life after hepatitis C cure in HIV-infected people who inject drugs and men who have sex with men treated with direct-acting antivirals in France: Health perceptions and experiences from qualitative and quantitative findings (ANRS CO13 HEPAVIH).

There remains a substantial gap in our understandings of the life experiences of patients following HCV cure among HIV-HCV-co-infected people who inject drugs (PWID) and men who have sex with men (MSM), two key populations targeted for HCV elimination. We described the experiences and perspectives of HIV-positive PWID and MSM, HCV-cured following treatment with direct-acting antivirals (DAA). We used an exploratory sequential mixed approach using both qualitative data (semi-structured interviews with 27 PWID and 20 MSM) and quantitative data (self-administered questionnaires with 89 PWID) via the prospective ANRS CO13 HEPAVIH cohort. PWID reported improvements in physical health-related quality of life (HRQL) and self-reported symptoms following treatment, but no significant change in mental HRQL. During interviews, several MSM, more recently diagnosed with HCV, expressed less concern regarding HCV than HIV infection and interpreted improvements in their overall well-being after HCV cure to be more related to a closer connection with healthcare providers than with viral elimination. By contrast, PWID, particularly those previously exposed to interferon-based treatments, described major improvements in their physical HRQL. Both MSM and PWID reported improvements in cognitive or psychological wellbeing, and a majority of them reported some degree of concern over potential HCV reinfection. To conclude, though health benefits of HCV cure concern both groups, HIV-infected PWID and MSM may have different representations and experiences following DAA treatment, related to their history with HCV. They are thus likely to benefit from holistic, post-treatment follow-up care that is responsive to their evolving health and social contexts.

Human Immunodeficiency Virus/Hepatitis C Virus (HCV) Co-infected Patients With Cirrhosis Are No Longer at Higher Risk for Hepatocellular Carcinoma or End-Stage Liver Disease as Compared to HCV Mono-infected Patients.

It is widely accepted that human immunodeficiency virus (HIV) infection is a risk factor for increased severity of hepatitis C virus (HCV) liver disease. However, owing to better efficacy and safety of combination antiretroviral therapy (cART), and increased access to HCV therapy, whether this condition remains true is still unknown. Overall, 1,253 HCV mono-infected patients and 175 HIV/HCV co-infected patients with cirrhosis, included in two prospective French national cohorts (ANRS CO12 CirVir and CO13 HEPAVIH), were studied. Cirrhosis was compensated (Child-Pugh A), without past history of complication, and assessed on liver biopsy. Incidences of liver decompensation (LD), hepatocellular carcinoma (HCC), and death according to HIV status were calculated by a Fine-Gray model adjusted for age. Propensity score matching was also performed to minimize confounding by baseline characteristics. At baseline, HIV/HCV patients were younger (47.5 vs. 56.0 years; P < 0.001), more frequently males (77.1% vs. 62.3%; P < 0.001), and had at baseline and at end of follow-up similar rates of HCV eradication than HCV mono-infected patients. A total of 80.4% of HIV/HCV patients had an undetectable HIV viral load. After adjustment for age, 5-year cumulative incidences of HCC and decompensation were similar in HIV/HCV and HCV patients (8.5% vs. 13.2%, P = 0.12 and 12.8% vs. 15.6%, P = 0.40, respectively). Overall mortality adjusted for age was higher in HIV/HCV co-infected patients (subhazard ratio [SHR] = 1.88; 95% confidence interval [CI], 1.15-3.06; P = 0.011). Factors associated with LD and HCC were age, absence of sustained virological response, and severity of cirrhosis, but not HIV status. Using a propensity score matching 95 patients of each group according to baseline features, similar results were observed. Conclusion: In HCV-infected patients with cirrhosis, HIV co-infection was no longer associated with higher risks of HCC and hepatic decompensation. Increased mortality, however, persisted, attributed to extrahepatic conditions.

Can we differentiate HIV-associated obliterative portopathy from liver cirrhosis using MRI?

AIM: To describe the magnetic resonance imaging (MRI) features of HIV-associated obliterative portopathy (HIV-OP) and determine the most indicative appearance of this condition on MRI by using a retrospective case-control study. METHODS: MRI examinations of 24 patients with HIV-OP (16 men, 8 women; mean age = 48 ± 6.6 [SD] years; age range, 35-71 years) were analyzed by two blinded observers and compared with those obtained in 18 HIV-infected patients with hepatic cirrhosis (14 men, 4 women; mean age = 51 ± 3.4 [SD] years; age range, 35-60 years). Images were qualitatively and quantitatively analyzed with respect to imaging presentation. Comparisons were performed using uni- and multivariate analyses. RESULTS: Regular liver contours had the highest accuracy for the diagnosis of HIV-OP (83%, 35 of 42; 95% confidence interval [CI], 69-93%) and was the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio, 51; 95%CI, 4.96-1272%) (p < 0.0001). At multivariate analysis, the width of segment 4 in millimeters (OR = 1.23 [95%CI, 1.05-1.44%]; p = 0.011) and the presence of regular liver contours (OR = 7.69 [95%CI, 1.48-39.92%]; p = 0.015) were the variables independently associated with the diagnosis of HIV-OP. CONCLUSIONS: Regular liver contours are the most discriminating independent variable for the diagnosis of HIV-OP but have limited accuracy. Familiarity with this finding may help differentiate HIV-OP from cirrhosis in HIV-infected patients. KEY POINTS: • Regular liver contour is the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio = 51) with 83% accuracy. • At multivariate analysis, the width of segment 4 in millimeters and the presence of regular liver contours are the variables independently associated with the diagnosis of HIV-OP. • MRI helps diagnose HIV-OP in the presence of several categorical findings, which are more frequently observed in HIV-OP patients than in HIV patients with cirrhosis.

HCV-Related Mortality Among HIV/HCV Co-infected Patients: The Importance of Behaviors in the HCV Cure Era (ANRS CO13 HEPAVIH Cohort).

Mortality among individuals co-infected with HIV and hepatitis C virus (HCV) is relatively high. We evaluated the association between psychoactive substance use and both HCV and non-HCV mortality in HIV/HCV co-infected patients in France, using Fine and Gray's competing-risk model adjusted for socio-demographic, clinical predictors and confounding factors, while accounting for competing causes of death. Over a 5-year median follow-up period, 77 deaths occurred among 1028 patients. Regular/daily cannabis use, elevated coffee intake, and not currently smoking were independently associated with reduced HCV-mortality (adjusted sub-hazard ratio [95% CI] 0.28 [0.10-0.83], 0.38 [0.15-0.95], and 0.28 [0.10-0.79], respectively). Obesity and severe thinness were associated with increased HCV-mortality (2.44 [1.00-5.93] and 7.25 [2.22-23.6] versus normal weight, respectively). Regular binge drinking was associated with increased non-HCV-mortality (2.19 [1.10-4.37]). Further research is needed to understand the causal mechanisms involved. People living with HIV/HCV co-infection should be referred for tobacco, alcohol and weight control interventions and potential benefits of cannabis-based therapies investigated.

Geographical Disparities of Outcomes of Hepatocellular Carcinoma in France: The Heavier Burden of Alcohol Compared to Hepatitis C.

BACKGROUND: Data on alcohol-related HCC are limited. AIMS: Our aim was to describe the incidence, management, and prognosis of alcohol compared to Hepatitis C (HCV)-related HCC at a national level. METHODS: Incident cases of HCC were identified in French healthcare databases between 2009 and 2012 and analyzed retrospectively. Demographic data, type, location, and annual HCC-caseload of the hospitals where patients were first managed were retrieved. Survival of incident cases was computed from the time of diagnosis and adjusted for potential confounding variables. RESULTS: The study population included 14,060 incident cases of alcohol and 2581 HCV-related HCC. Alcohol-related HCC was more frequent than HCV-related HCC (29.37 and 5.39/100,000 adults/year, respectively) with an heterogeneous distribution on the French territory. The optimal treatment was less frequently curative (20.5% vs 35.9%; p < 0.001), and survival was significantly shorter (9.5 [9.0-10.0] versus 16.8 [15.5-18.7] months p < 0.001) in alcohol compared to HCV-related HCC, with marked variations between regions for a given risk factor. In multivariable analysis in the whole study population, curative treatment was a strong predictor of survival (adjusted HR 0.28 [0.27-0.30] months p < 0.001). Being managed at least once in a teaching hospital during follow-up was independently associated with receiving a curative treatment and survival. CONCLUSION: In France, incidence of alcohol-related HCC is high and prognosis is poor compared to HCV-related HCC, with marked variations between regions. These results should guide future health policy initiatives pertaining to HCC care. Importantly, increasing patient' referral in expert centers could increase chances to receive curative treatment and improve outcomes.

Contributing factors and outcomes of burn-associated cholestasis.

BACKGROUND & AIMS: Cholestasis often occurs after burn injuries. However, the prevalence of cholestasis and its effect on outcomes in patients with severe burn injuries are unknown. The aim of this study was to describe the course and the burden of cholestasis in a cohort of severely burned adult patients. METHODS: We investigated the relationship between burn-associated cholestasis (BAC) and clinical outcomes in a retrospective cohort of patients admitted to our unit for severe burn injuries between 2012 and 2015. BAC was defined as an increased level of serum alkaline phosphatase (ALP) ≥1.5x the upper limit of normal (ULN) with an increased level of gamma-glutamyltransferase (GGT) ≥3x ULN, or as an increased level of total bilirubin ≥2x ULN. RESULTS: A total of 214 patients were included: 111 (52%) patients developed BAC after a median (IQR) stay of 9 (5-16) days. At 90 days, the mortality rate was 20%, including 34 and 9 patients with and without BAC (p <0.001), respectively, which corresponded to a 2.5-fold higher (95% CI 1.2-5.2, p = 0.012) risk of 90-day mortality for patients with BAC. After being adjusted for severity of illness, patients with BAC, hyperbilirubinemia and without elevated ALP and GGT levels had a hazard ratio of 4.51 (95% CI 1.87-10.87) for 90-day mortality. BAC was associated with the severity of the burn injury, shock and bacteraemia. BAC was present in 38 (51%) patients at discharge, and 7 (18%) patients had secondary sclerosing cholangitis. These patients maintained elevated levels of ALP and GGT that were 5.8x (1.7-15) the ULN and 11x the ULN (4.5-22), respectively, 20 months (3.5-35) after discharge. CONCLUSION: BAC is prevalent among patients with severe burn injuries and is associated with worse short-term outcomes, especially when total bilirubin levels were increased without elevated ALP and GGT levels. BAC survivors are at risk of developing sclerosing cholangitis. LAY SUMMARY: Cholestasis is common after burn injuries and is associated with burn severity, sepsis, organ failure and mortality. Patients with hyperbilirubinemia without elevated alkaline phosphatase and gamma-glutamyltransferase levels after the burn injury have a poor prognosis. Patients with burn-associated cholestasis may develop sclerosing cholangitis and secondary biliary cirrhosis.