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Protective effect of coffee consumption on all-cause mortality of French HIV-HCV co-infected patients

  • Author Footnotes
    † These authors contributed equally to this work.
    Maria Patrizia Carrieri
    Correspondence
    Corresponding author. Address: Aix Marseille Univ, INSERM, IRD, SESSTIM, Faculté de Médecine, 27 Bd. Jean Moulin, 13385 Marseille Cedex 5, France. Tel.: +33 4 91 32 47 59; fax: +33 4 84 25 61 72.
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France

    ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
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  • Author Footnotes
    † These authors contributed equally to this work.
    Camelia Protopopescu
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France

    ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
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  • Fabienne Marcellin
    Affiliations
    Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France

    ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
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  • Silvia Rosellini
    Affiliations
    Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France

    ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
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  • Linda Wittkop
    Affiliations
    Univ. Bordeaux, ISPED, Centre INSERM U1219-Bordeaux Population Health, Bordeaux, France

    INSERM, ISPED, Centre INSERM U1219-Bordeaux Population Health, Bordeaux, France

    CHU de Bordeaux, Pole de santé publique, Bordeaux, France
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  • Laure Esterle
    Affiliations
    Univ. Bordeaux, ISPED, Centre INSERM U1219-Bordeaux Population Health, Bordeaux, France

    INSERM, ISPED, Centre INSERM U1219-Bordeaux Population Health, Bordeaux, France
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  • David Zucman
    Affiliations
    Service de Médecine Interne, Hôpital Foch, Suresnes, France
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  • François Raffi
    Affiliations
    Infectious and Tropical Diseases Department, Nantes University Hospital, Nantes, France
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  • Eric Rosenthal
    Affiliations
    Nice Sophia-Antipolis University, Nice, France

    Department of Internal Medicine, L’Archet Hospital, Nice, France
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  • Isabelle Poizot-Martin
    Affiliations
    Aix Marseille Univ, APHM Sainte‐Marguerite, Service d’Immunohématologie clinique, Marseille, France
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  • Dominique Salmon-Ceron
    Affiliations
    Service des Maladies Infectieuses et Tropicales, Hôpital Cochin, AP-HP, Paris, France

    Université Paris Descartes, Paris, France
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  • François Dabis
    Affiliations
    Univ. Bordeaux, ISPED, Centre INSERM U1219-Bordeaux Population Health, Bordeaux, France

    INSERM, ISPED, Centre INSERM U1219-Bordeaux Population Health, Bordeaux, France

    CHU de Bordeaux, Pole de santé publique, Bordeaux, France
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  • Bruno Spire
    Affiliations
    Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France

    ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
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  • theANRS CO13 HEPAVIH Study Group
    Author Footnotes
    ‡ See Acknowledgement section for list of Study Group Members.
  • Author Footnotes
    † These authors contributed equally to this work.
    ‡ See Acknowledgement section for list of Study Group Members.
Published:September 21, 2017DOI:https://doi.org/10.1016/j.jhep.2017.08.005

      Highlights

      • Coffee has anti-inflammatory and hepato-protective properties.
      • Drinking three or more cups/day halves mortality risk in HIV-HCV co-infected patients.
      • While curing HCV is fundamental, not smoking further improves survival in this group.
      • Healthy behavior change should also be promoted after HCV clearance.

      Background & Aims

      Coffee has anti-inflammatory and hepato-protective properties. In the general population, drinking ≥3 cups of coffee/day has been associated with a 14% reduction in the risk of all-cause mortality. The aim of this study was to investigate the relationship between coffee consumption and the risk of all-cause mortality in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV).

      Methods

      ANRS CO13 HEPAVIH is an ongoing French nationwide prospective cohort of patients co-infected with HIV-HCV collecting both medical and psychosocial/behavioural data (annual self-administered questionnaires). We used a Cox proportional hazards model to estimate the effect of elevated coffee consumption (≥3 cups/day) at baseline on all-cause mortality during the cohort’s five-year follow-up.

      Results

      Over a median [interquartile range] follow-up of 5.0 [3.9–5.9] years, 77 deaths occurred among 1,028 eligible patients (mortality rate 1.64/100 person-years; 95% confidence interval [CI] 1.31–2.05). Leading causes of death were HCV-related diseases (n = 33, 43%), cancers unrelated to AIDS/HCV (n = 9, 12%), and AIDS (n = 8, 10%). At the first available visit, 26.6% of patients reported elevated coffee consumption. Elevated coffee consumption at baseline was associated with a 50% reduced risk of all-cause mortality (hazard ratio 0.5; CI 0.3–0.9; p = 0.032), after adjustment for gender and psychosocial, behavioral and clinical time-varying factors.

      Conclusions

      Drinking three or more cups of coffee per day halves all-cause mortality risk in patients co-infected with HIV-HCV. The benefits of coffee extracts and supplementing dietary intake with other anti-inflammatory compounds need to be evaluated in this population.

      Lay summary

      Coffee has anti-inflammatory and hepato-protective properties but its effect on mortality risk has never been investigated in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). This study shows that elevated coffee consumption (≥3 cups/day) halves all-cause mortality risk in patients co-infected with HIV-HCV. The benefits of coffee extracts and supplementing dietary intake with other anti-inflammatory compounds need to be evaluated in this population.

      Graphical abstract

      Keywords

      Introduction

      Patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are particularly vulnerable to developing liver disease due to immune activation/inflammation, exposure to antiretroviral therapy (ART) and evolution of HCV co-infection.
      • Körner C.
      • Tolksdorf F.
      • Riesner K.
      • Krämer B.
      • Schulte D.
      • Nattermann J.
      • et al.
      Hepatitis C coinfection enhances sensitization of CD4(+) T-cells towards Fas-induced apoptosis in viraemic and HAART-controlled HIV-1-positive patients.
      • Bourcier V.
      • Winnock M.
      • Ait Ahmed M.
      • Sogni P.
      • Pambrun E.
      • Poizot-Martin I.
      • et al.
      Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir).
      In addition, HIV infection modifies the natural course of chronic hepatitis C infection, resulting in a more rapid progression to fibrosis and development of cirrhosis and end-stage liver disease.
      • Poynard T.
      • Mathurin P.
      • Lai C.L.
      • Guyader D.
      • Poupon R.
      • Tainturier M.H.
      • et al.
      A comparison of fibrosis progression in chronic liver diseases.
      • Kramer J.R.
      • Kowalkowski M.A.
      • Duan Z.
      • Chiao E.Y.
      The Effect of HIV Viral Control on the Incidence of Hepatocellular Carcinoma in Veterans With Hepatitis C and HIV Coinfection.
      The impressive reduction in mortality rates since the introduction of ART has led to HCV-related causes of mortality, including end-stage liver disease, being more frequent than HIV-related causes in patients co-infected with HIV-HCV.
      • Greub G.
      • Ledergerber B.
      • Battegay M.
      • Grob P.
      • Perrin L.
      • Furrer H.
      • et al.
      Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study.
      • Tedaldi E.M.
      • Baker R.K.
      • Moorman A.C.
      • Alzola C.F.
      • Furhrer J.
      • McCabe R.E.
      • et al.
      Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy.
      Potent HCV therapeutic strategies based on direct-acting antiviral agents (DAAs) have been developed in recent years, making HCV clearance possible for nearly all treated patients.
      • Heim M.H.
      25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end.
      HCV clearance following successful HCV treatment is often accompanied by a regression of histologic lesions in co-infected patients – even with suboptimal interferon-based treatment
      • Cacoub P.
      • Halfon P.
      • Rosenthal E.
      • Pialoux G.
      • Benhamou Y.
      • Perronne C.
      • et al.
      Treatment of hepatitis C virus in human immunodeficiency virus infected patients in “real life”: modifications in two large surveys between 2004 and 2006.
      • Chung R.T.
      • Andersen J.
      • Volberding P.
      • Robbins G.K.
      • Liu T.
      • Sherman K.E.
      • et al.
      Peginterferon Alfa-2a plus ribavirin vs. interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.
      ANRS CO13 HEPAVIH Cohort. Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients.
      – and therefore reduces progression to end-stage liver disease. Accordingly, improving access to HCV treatment is crucial in reducing the burden of end-stage liver disease in patients co-infected with HIV-HCV.
      Nevertheless, this population, even when cured of HCV, remains at an increased risk of death because of an accelerated aging process, which may result in cardiovascular events, cancers, and complications related to diabetes and to liver disease, for example esophageal bleeding.
      • Operskalski E.A.
      • Kovacs A.
      HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies.
      Polyphenols and caffeine in coffee have several hepato-protective properties. In people at risk of liver disease, previous research has shown that coffee consumption is associated with better liver function,
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      and less fibrosis,
      • Modi A.A.
      • Feld J.J.
      • Park Y.
      • Kleiner D.E.
      • Everhart J.E.
      • Liang T.J.
      • et al.
      Increased caffeine consumption is associated with reduced hepatic fibrosis.
      cirrhosis and liver cancer.
      • Bravi F.
      • Tavani A.
      • Bosetti C.
      • Boffetta P.
      • La Vecchia C.
      Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies.
      In patients co-infected with HIV-HCV, individuals with elevated coffee consumption (defined as drinking three cups or more per day) have a reduced risk of insulin resistance and lower levels of liver enzymes.
      • Carrieri M.P.
      • Sogni P.
      • Cohen J.
      • Loko M.-A.
      • Winnock M.
      • Spire B.
      • et al.
      Elevated coffee consumption and reduced risk of insulin resistance in HIV-HCV coinfected patients (HEPAVIH ANRS CO-13).
      • Carrieri M.P.
      • Lions C.
      • Sogni P.
      • Winnock M.
      • Roux P.
      • Mora M.
      • et al.
      Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: Results from the ANRS CO13 HEPAVIH cohort study.
      In the general population, there is also strong evidence that coffee consumption is associated with a 13–14% risk reduction in all-cause mortality, as well as a reduced risk of cancer and diabetes.
      • Loftfield E.
      • Freedman N.D.
      • Graubard B.I.
      • Guertin K.A.
      • Black A.
      • Huang W.-Y.
      • et al.
      Association of coffee consumption with overall and cause-specific mortality in a large US prospective cohort study.
      • Ding M.
      • Satija A.
      • Bhupathiraju S.N.
      • Hu Y.
      • Sun Q.
      • Han J.
      • et al.
      Association of coffee consumption with total and cause-specific mortality in 3 large prospective cohorts.
      • Crippa A.
      • Discacciati A.
      • Larsson S.C.
      • Wolk A.
      • Orsini N.
      Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.
      • Je Y.
      • Giovannucci E.
      Coffee consumption and total mortality: a meta-analysis of twenty prospective cohort studies.
      • Kennedy O.J.
      • Roderick P.
      • Buchanan R.
      • Fallowfield J.A.
      • Hayes P.C.
      • Parkes J.
      Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis.
      • Setiawan V.W.
      • Wilkens L.R.
      • Lu S.C.
      • Hernandez B.Y.
      • Le Marchand L.
      • Henderson B.E.
      Association of coffee intake with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort.
      However, the extent to which coffee consumption may be associated with a reduced risk of all-cause mortality in patients co-infected with HIV-HCV, a population where liver-associated complications and alcohol use are often present,
      • Operskalski E.A.
      • Kovacs A.
      HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies.
      • Roux P.
      • Cohen J.
      • Lascoux-Combe C.
      • Sogni P.
      • Winnock M.
      • Salmon-Ceron D.
      • et al.
      Determinants of the underreporting of alcohol consumption by HIV/HCV co-infected patients during face-to-face medical interviews: the role of the physician.
      remains unknown.
      We used five-year follow-up data from the French ANRS CO13 HEPAVIH cohort to investigate the effect of coffee consumption on mortality risk in this population, after adjusting for clinical status (including HCV clearance) and psychosocial/behavioural factors.

      Materials and methods

       Study design

      ANRS CO13 HEPAVIH is a multicenter prospective cohort that started in 2005 and enrolled HIV-HCV co-infected adults from 21 centres throughout France, representative of the French population living with these two viruses and in care.
      • Loko M.-A.
      • Salmon D.
      • Carrieri P.
      • Winnock M.
      • Mora M.
      • Merchadou L.
      • et al.
      The French national prospective cohort of patients co-infected with HIV and HCV (ANRS CO13 HEPAVIH): early findings, 2006–2010.
      Inclusion criteria in the cohort were as follows: aged 18 years or more, HIV-1 infection and chronic HCV co-infection. Patients who had already cleared HCV i.e. those who had a sustained virological response (SVR) to previous HCV treatment and (in a second enrolment phase) those who had spontaneously cleared HCV could also be included if eligible. Clinical follow-up of patients was at enrolment (M0) and yearly thereafter (every six months for patients with cirrhosis) until the end of the study (60 months, M60). All patients provided written informed consent at enrolment. The study was designed and implemented in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics committee of the Cochin University Hospital in Paris.

       Data collection

       Medical data

      A standardized medical questionnaire, completed by physicians at each clinical visit, collected biological and clinical parameters related to HIV and HCV infection, including CD4 cell count, HIV plasma RNA level, HIV CDC clinical stage, HIV transmission category, ART use, HCV treatment status and virological response, HCV genotype, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and platelet counts. Any history of liver problems such as hepatocellular carcinoma, liver transplantation, or the presence of indirect clinical signs of cirrhosis (ascites, esophageal varices with or without bleeding, hepatic encephalopathy) was recorded at enrolment. Information about mortality and causes of death were recorded for the entire cohort and validated by an expert committee.
      Data concerning patients’ tobacco use were recorded at each visit during face-to-face medical interviews with physicians. Patients were asked about their experience of smoking (non-smoker, former smoker, or current smoker).

       Psychosocial/behavioural data

      Patients enrolled in the cohort answered a self-administered questionnaire at enrolment and yearly thereafter until M60. This questionnaire collected socio-demographic data including gender, age, having a steady partner (or not), having children (or not), employment status, and housing type. It also included behavioural characteristics such as adherence to ART and depressive symptoms, assessed using the Center for Epidemiological Studies Depression Scale (CES-D).
      • Furher R.
      • Rouillon F.
      La version française de l’échelle CES-D. Description and translation of the auto-evaluation.
      In addition, the questionnaire contained items on the occurrence of 39 self-reported symptoms over the previous four weeks. Alcohol consumption in the six months prior to the visit were assessed using the AUDIT-C questionnaire.
      • Bush K.
      • Kivlahan D.R.
      • McDonell M.B.
      • Fihn S.D.
      • Bradley K.A.
      The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.
      Coffee intake was investigated using a question referring to the six months prior to the visit, with the following five possible answers: never, occasionally, one cup/day, two cups/day, more than two cups/day (one cup corresponding to 150–200 ml).

       Statistical analyses

       Selection of the study population (patients and visits)

      We first selected all available annual follow-up visits between M0-M60 for patients with at least one completed self-administered questionnaire. Of these patients, those who had a latest news date (corresponding either to a follow-up visit or to death) after their entry date (i.e. having at least two time points with available information during the cohort follow-up) were selected for this study. Moreover, among these patients, only those who reported their coffee consumption at baseline (i.e. at the first visit with available data from a self-administered questionnaire) were considered eligible for this analysis. The follow-up period for each eligible patient was defined as follows: the duration between the first follow-up visit with an available self-administered questionnaire (entry date) and the latest news date (corresponding either to the last visit with an available self-administered questionnaire, or to a follow-up visit without a self-administered questionnaire, or to death) with censoring at 72 months after the M0 visit.

       Outcome

      The study outcome was deaths from all causes occurring between M0 and M72 among eligible patients.

       Explanatory variables

      The following explanatory variables were tested in the multivariable analysis to adjust for known predictors of mortality and possible confounders. The AUDIT-C questionnaire was used to calculate the number of alcohol units (AU) consumed per day for individuals who reported current alcohol consumption. One AU was defined as a standard drink, containing 11–14 g of alcohol and corresponding to one small bottle of beer, one medium glass of wine, or a shot of distilled spirits. We used the following categories for average daily alcohol consumption: no consumption, low consumption (≤1 AU/day), moderate consumption (1–3 AU/day for women and 1–4 AU/day for men), and elevated consumption (>3 AU/day for women and >4 AU/day for men).
      • Bissell D.
      • Paton A.
      • Ritson B.
      ABC of alcohol. Help: referral.
      Regular binge drinking was defined as drinking at least 5 AU on one occasion at least once a week. We defined the following categories for coffee consumption: low consumption (one cup/day of coffee or occasional consumption or no consumption), moderate consumption (two cups/day of coffee) and elevated consumption (at least three cups/day of coffee). Individuals with depressive symptoms were identified using gender-specific cut-off values for the CES-D score (17 for men and 23 for women).
      • Furher R.
      • Rouillon F.
      La version française de l’échelle CES-D. Description and translation of the auto-evaluation.
      A score above these cut-off values was taken to be indicative of having depressive symptoms. Patients who reported living in hotels, accommodation centers, on the street or in therapeutic apartments were considered to have unstable housing.
      Adherence to ART was assessed according to the methodology established by the AIDS Clinical Trial Group
      • Chesney M.A.
      • Ickovics J.R.
      • Chambers D.B.
      • Gifford A.L.
      • Neidig J.
      • Zwickl B.
      • et al.
      Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG).
      using a three-level score (high, moderate and low adherence) based on a validated algorithm using ART doses – both those prescribed and those actually taken – during the previous four days, as described elsewhere.
      • Roux P.
      • Lions C.
      • Cohen J.
      • Winnock M.
      • Salmon-Céron D.
      • Bani-Sadr F.
      • et al.
      Impact of HCV treatment and depressive symptoms on adherence to HAART among HIV-HCV-coinfected patients: results from the ANRS-CO13-HEPAVIH cohort.
      The fibrosis-4 (FIB-4) index, which is calculated by age, AST, ALT and platelet count, was used as a non-invasive marker of liver fibrosis, using the intervals defined by the cut-off values 1.45 and 3.25 which corresponding to F0-F1, F2 and F3-F4 Metavir stages, respectively.
      • Sterling R.K.
      • Lissen E.
      • Clumeck N.
      • Sola R.
      • Correa M.C.
      • Montaner J.
      • et al.
      Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
      Except for gender, HCV genotype, HIV transmission category, smoking status, coffee and alcohol consumption (which were measured at baseline), all the other explanatory variables were evaluated at each visit and used as time-varying covariates in the statistical analyses.

       Statistical methods

      The all-cause mortality rate was computed as the number of deaths occurring between M0 and M72 divided by the number of person-years during the study period (computed as the sum, for all patients, of the number of years between entry date and latest news date, i.e., death, latest news visit or censoring). The ‘last observation carried forward’ method was used to impute the values for the explanatory variables when they were missing (i.e., at clinical visits without self-administered questionnaires).
      The association between baseline coffee consumption and mortality was assessed after adjustment for potential predictors and confounding factors, using a Cox proportional hazards model with robust standard errors. Potential adjustment variables with a p value <0.20 (Wald test) in the univariate analyses were considered eligible for inclusion in the multivariable analysis. A backward selection procedure, based on the Wald test, was then used to identify the adjustment variables in the final multivariable model (variables were considered significantly associated with the outcome if the p value ≤0.05). The final multivariable model was adjusted for gender and age, irrespective of their p values. The presence of confounding factors was evaluated by removing each non-significant variable, one at a time, and noting the effect on the coefficients for the remaining variables (the eliminated variable was considered to be a confounder and included in the final model if at least one of the coefficients for the remaining variables changed by more than 25%). The proportional hazards assumption was tested in the final multivariable Cox model by examining the rescaled Schoenfeld residuals.
      • Grambsch P.M.
      • Therneau T.M.
      Proportional hazards tests and diagnostics based on weighted residuals.
      In order to verify whether different follow-up durations could have an impact on our results, we identified two subgroups of patients with different follow-up durations (last follow-up visit <48 months vs. last follow-up visit ≥48 months) and performed a secondary analysis using a shared-frailty Cox model, each subgroup having a specific baseline hazard ratio (HR). Further details about the shared-frailty Cox model are provided elsewhere.
      • Protopopescu C.
      • Raffi F.
      • Spire B.
      • Hardel L.
      • Michelet C.
      • Cheneau C.
      • et al.
      Twelve-year mortality in HIV-infected patients receiving antiretroviral therapy: the role of social vulnerability. The ANRS CO8 APROCO-COPILOTE cohort.
      Stata/SE 12.1 software (StataCorp LP, College Station, USA) was used for all the analyses.
      For further details regarding the materials used, please refer to the CTAT table.

      Results

       Study population

      The selection of the study population (patients and visits) is presented in the flow chart in Fig. 1. Among the 1,246 patients included in the cohort between 2005 and November 2014, 1,051 completed at least one self-administered questionnaire during follow-up. Of these, 1,028 had both a latest news date after their entry date and available coffee consumption data at baseline, and were thus eligible for analyses (study population).
      Figure thumbnail gr1
      Fig. 1Flow chart of the study population (ANRS CO13 HEPAVIH patients enrolled between 2005 and November 2014).

       Causes of death

      In the 72 months from enrolment, a total of 97 deaths were notified in the cohort, 77 of these occurring in the 1,028 patients of the present study. The distribution of causes of death was similar between patients in the study and all the patients included in the cohort (Table 1). Median (interquartile range [IQR]) follow-up duration for study patients was 5.0 (3.9–5.9) years, representing 4,700 person-years. The mortality rate was 1.64/100 person-years (95% confidence interval [CI] 1.31–2.05).
      Table 1Causes of deaths (ANRS CO13-HEPAVIH patients enrolled between 2005 and November 2014).
      Causes of deathsEligible patients
      Eligible patients comprised all individuals who completed at least one self-administered questionnaire, reported coffee consumption at baseline and had a latest news date posterior to their first available questionnaire (i.e., latest news date after entry date). AIDS, acquired immune deficiency syndrome; HCV, hepatitis C virus.
      (N = 1,028)

      n (%)
      All patients (N = 1,246)

      n (%)
      HCV-related cause

      (including hepatocellular carcinoma)


      33 (42.8)


      40 (41.2)
      Unknown11 (14.3)13 (13.4)
      Non AIDS/HCV-related cancer9 (11.7)12 (12.4)
      AIDS-related cause8 (10.4)13 (13.4)
      Cardiovascular disease3 (3.9)5 (5.2)
      Overdose3 (3.9)3 (3.1)
      Suicide3 (3.9)3 (3.1)
      Respiratory diseases2 (2.6)3 (3.1)
      Unexplained sudden death2 (2.6)2 (2.1)
      Infectious and parasitic diseases1 (1.3)1 (1.0)
      Digestive diseases1 (1.3)1 (1.0)
      Endocrine, nutritional and metabolic diseases1 (1.3)1 (1.0)
      Total77 (100)97 (100)
      * Eligible patients comprised all individuals who completed at least one self-administered questionnaire, reported coffee consumption at baseline and had a latest news date posterior to their first available questionnaire (i.e., latest news date after entry date).AIDS, acquired immune deficiency syndrome; HCV, hepatitis C virus.
      Among patients with documented causes of death, the main underlying causes were (Table 1): HCV-related (42.8%, n = 33, including hepatocellular carcinoma: 14.3%, n = 11), cancer not related to AIDS or hepatitis (11.7%, n = 9), AIDS-related (10.4%, n = 8), cardiovascular disease (3.9%, n = 3), overdose (3.9%, n = 3), suicide (3.9%, n = 3), and respiratory diseases (2.6%, n = 2). The cause of death was unknown in 14.3% (n = 11) of the notified cases among the study patients.

       Characteristics of the study patients

      The study patients’ main characteristics at their last available follow-up visit are presented in Table 2. The median age of participants was 49 years (IQR: 46–52 years) and most were males (70.2%). The main HIV transmission category was intravenous drug use (63.2%) and HCV genotype 1 was predominant (53.4%). At the end of follow-up, more than half of the study patients had not yet started HCV treatment (53.3%), a minority (7%) were on treatment, while the remaining patients had completed treatment (15.7% were not cured and 24% were sustained responders). Seventeen percent had a F3-F4 fibrosis stage according to the FIB-4 index. At enrolment, 1.3% of the patients had experienced hepatocellular carcinoma and/or liver transplantation, and 2.9% had experienced indirect clinical signs of cirrhosis. With respect to HIV-related characteristics, 94.5% were receiving ART and most (82.5%) had an undetectable HIV RNA plasma viral load. Elevated coffee consumption was reported by 26.6% of the study patients at baseline, half of them (51.3%) reported low coffee consumption, and 48.8%, 17.8%, 5.9% and 24.9% reported low, moderate, elevated, and no alcohol consumption at baseline, respectively. The prevalence of regular binge drinking was 13.9%. Twelve percent of the patients had never smoked and more than a third (36.5%) reported depressive symptoms.
      Table 2Characteristics of the study population at last available follow-up visit and factors associated with mortality (Cox proportional hazards models, the ANRS CO13 HEPAVIH cohort, n = 1,028).
      n (%)No. of deathsUnivariate analyses
      With robust standard errors.
      Multivariable analysis
      With robust standard errors.
      HR [95% CI]p valueAHR [95% CI]p value
      Coffee consumption at baseline
      We used the following categories for average daily coffee consumption: low consumption (≤1cups/day), moderate consumption (2cups/day), and elevated consumption (≥3cups/day).
      ,
      Fixed variable, measured at baseline (i.e. at the first available visit of each patient).
       Low527 (51.3)451
       Moderate227 (22.1)211.1 [0.6–1.9]0.650
       Elevated274 (26.6)110.5 [0.2–0.9]0.022
      Coffee consumption at baseline
      We used the following categories for average daily coffee consumption: low consumption (≤1cups/day), moderate consumption (2cups/day), and elevated consumption (≥3cups/day).
      ,
      Fixed variable, measured at baseline (i.e. at the first available visit of each patient).
       Low/moderate754 (73.3)6611
       Elevated274 (26.6)110.4 [0.2–0.8]0.0130.5 [0.3–0.9]0.032
      Gender
       Male722 (70.2)6111
       Female306 (29.8)160.6 [0.3–1.0]0.0770.7 [0.4–1.2]0.226
      Age (years)
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       18-3950 (4.9)20.3 [0.1–1.4]0.1300.6 [0.1–2.7]0.544
       40-49531 (51.6)4811
       50+447 (43.5)271.0 [0.6–1.6]0.9980.8 [0.5–1.3]0.371
      Having a steady partner
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No395 (38.4)4011
       Yes628 (61.1)370.5 [0.3–0.8]0.0070.5 [0.3–0.9]0.012
      Having children
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No715 (69.5)601
       Yes310 (30.2)160.5 [0.3–0.9]0.034
      Being employed
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No536 (52.1)541
       Yes487 (47.4)230.4 [0.3–0.7]0.001
      Unstable housing
      Patients who reported living in hotels, accommodation centres, on the street or in therapeutic apartments were considered to have unstable housing.
      ,
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No1,006 (97.9)711
       Yes18 (1.7)64.9 [2.2–10.7]<10−3
      HCV genotype
       1549 (53.4)421
       241 (4.0)51.5 [0.6–4.0]0.359
       3219 (21.3)110.6 [0.3–1.3]0.220
       4206 (20.0)191.2 [0.7–2.0]0.527
      HCV treatment status
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       Not yet treated/on treatment620 (60.3)6511
       Treated but not cured161 (15.7)80.6 [0.3–1.3]0.1910.4 [0.2–0.9]0.036
       Treated and cured247 (24.0)40.2 [0.1–0.5]0.0010.2 [0.1–0.7]0.011
      FIB-4 index (correspondence with Metavir score)
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       ≤3.25 (F0-F2)848 (82.5)4011
       >3.25 (F3-F4)179 (17.4)374.9 [3.1–7.5]<10−32.3 [1.3–3.9]0.002
      History of hepatocellular carcinoma and/or liver transplantation at enrolment0.005
       No1,015 (98.7)6711
       Yes13 (1.3)1013.5 [7.1–25.9]<10−34.4 [1.9–9.9]<10−3
      History of indirect clinical signs of cirrhosis at enrolment
      The presence of indirect clinical signs of cirrhosis was defined by one of the following: ascites, esophageal varices with or without bleeding, hepatic encephalopathy. (A)HR, (adjusted) hazard ratio; AU, alcohol units; CI, confidence interval; IDU, intravenous drug use; IQR, interquartile range.
       No998 (97.1)6411
       Yes30 (2.9)138.4 [4.7–15.1]<10−33.3 [1.7–6.2]<10−3
      HIV transmission category
       IDU650 (63.2)551
       Homosexual/bisexual117 (11.4)50.5 [0.2–1.2]0.142
       Heterosexual144 (14.0)100.8 [0.4–1.6]0.509
       Other114 (11.1)70.7 [0.3–1.5]0.340
      HIV clinical stage
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       A/B728 (70.8)3911
       C297 (29.0)372.5 [1.6–3.9]<10−32.2 [1.4–3.5]<10−3
      ART-treated
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No52 (5.1)61
       Yes972 (94.5)710.7 [0.3–1.7]0.480
      Adherence to ART
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       Low140 (13.6)91
       Moderate175 (17.0)120.7 [0.3–1.8]0.521
       High652 (63.4)500.9 [0.4–1.8]0.768
       Not treated52 (5.1)61.2 [0.4–3.3]0.741
      Undetectable plasma HIV RNA level
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No180 (17.5)251
       Yes848 (82.5)520.5 [0.3–0.8]0.005
      CD4 count ≤200 cells/mm3,
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No944 (91.8)5811
       Yes84 (8.2)193.9 [2.3–6.4]<10−31.8 [1.1–2.9]0.021
      Depressive symptoms
      Patients with a CES-D25 score ≥17(23) for men (women) were considered to have depressive symptoms.
      ,
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
       No612 (59.5)381
       Yes375 (36.5)331.4 [0.9–2.2]0.171
      Smoking status at baseline
      Fixed variable, measured at baseline (i.e. at the first available visit of each patient).
       Past/current900 (87.5)7311
       Never120 (11.7)30.3 [0.1–0.9]0.0280.3 [0.1–1.0]0.051
      Alcohol consumption at baseline
      We used the following categories for average daily alcohol consumption: no consumption, low consumption (≤1AU/day), moderate consumption (1–3AU/day for women and 1–4AU/day for men), and elevated consumption (>3AU/day for women and >4AU/day for men).27
      ,
      Fixed variable, measured at baseline (i.e. at the first available visit of each patient).
       No consumption256 (24.9)241
       Low502 (48.8)280.6 [0.3–1.0]0.056
       Moderate183 (17.8)130.7 [0.4–1.5]0.395
       Elevated61 (5.9)101.8 [0.9–3.8]0.110
      Regular binge drinking at baseline
      Regular binge drinking was defined as drinking at least 5AU on one occasion at least once a week.
      ,
      Fixed variable, measured at baseline (i.e. at the first available visit of each patient).
       No842 (81.9)551
       Yes143 (13.9)181.9 [1.1–3.3]0.014
      Number of self-reported symptoms (excluding lipodystrophy), median [IQR]
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
      8 [4–14]1.0 [1.0–1.1]0.105
      Number of self-reported lipodystrophy symptoms, median [IQR]
      Time-varying variable, descriptive statistics are given at last available visit of each patient.
      2 [0–5]1.0 [0.9–1.1]0.729
      § Time-varying variable, descriptive statistics are given at last available visit of each patient.
      §§ Fixed variable, measured at baseline (i.e. at the first available visit of each patient).
      * With robust standard errors.
      1 We used the following categories for average daily coffee consumption: low consumption (≤1 cups/day), moderate consumption (2 cups/day), and elevated consumption (≥3 cups/day).
      2 Patients who reported living in hotels, accommodation centres, on the street or in therapeutic apartments were considered to have unstable housing.
      3 Patients with a CES-D
      • Furher R.
      • Rouillon F.
      La version française de l’échelle CES-D. Description and translation of the auto-evaluation.
      score ≥17(23) for men (women) were considered to have depressive symptoms.
      4 We used the following categories for average daily alcohol consumption: no consumption, low consumption (≤1 AU/day), moderate consumption (1–3 AU/day for women and 1–4 AU/day for men), and elevated consumption (>3 AU/day for women and >4 AU/day for men).
      • Bissell D.
      • Paton A.
      • Ritson B.
      ABC of alcohol. Help: referral.
      5 Regular binge drinking was defined as drinking at least 5 AU on one occasion at least once a week.
      6 The presence of indirect clinical signs of cirrhosis was defined by one of the following: ascites, esophageal varices with or without bleeding, hepatic encephalopathy.(A)HR, (adjusted) hazard ratio; AU, alcohol units; CI, confidence interval; IDU, intravenous drug use; IQR, interquartile range.
      The characteristics of the study population according to the three categories of coffee consumption at first available patient follow-up visit are presented in Table 3.
      Table 3Characteristics of the study population according to coffee consumption at first available patients’ follow-up visit (baseline) (the ANRS CO13 HEPAVIH cohort, n = 1,028).
      Coffee consumption at baseline
      We used the following categories for average daily coffee consumption: low consumption (≤1cups/day), moderate consumption (2cups/day), and elevated consumption (≥3cups/day).
      Variable, % or median (IQR)Low (n = 527)Moderate (n = 227)Elevated (n = 274)p value
      Fisher’s exact test or Kruskal-Wallis rank test; IQR, interquartile range.
      Gender
       Male66.272.276.30.010
       Female33.827.723.7
      Age (years)
       18-3915.711.412.00.014
       40-4964.770.575.9
       50+19.518.112.0
      Having a steady partner
       No38.837.338.20.934
       Yes61.262.761.8
      Having children
       No67.470.063.50.292
       Yes32.630.036.5
      Being employed
       No53.348.048.70.283
       Yes46.752.051.3
      Unstable housing
      Patients who reported living in hotels, accommodation centres, on the street or in therapeutic apartments were considered to have unstable housing.
       No96.698.298.50.234
       Yes3.41.81.5
      HCV genotype
       152.656.055.30.948
       24.04.53.7
       321.920.222.1
       421.519.318.8
      FIB-4 index (correspondence with Metavir score)
       <1.45 (F0-F1)41.843.754.40.002
       1.45–3.25 (F2)38.542.034.8
       >3.25 (F3-F4)19.714.310.7
      History of hepatocellular carcinoma and/or liver transplantation at enrolment§§
       No95.398.798.90.005
       Yes4.71.31.1
      History of indirect clinical signs of cirrhosis at enrolment
      The presence of indirect clinical signs of cirrhosis was defined by one of the following: ascites, esophageal varices with or without bleeding, hepatic encephalopathy. ART, antiretroviral therapy; FIB-4, fibrosis-4; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, intravenous drug use; IQR, interquartile range.
      ,§§
       No95.697.899.30.008
       Yes4.42.20.73
      HIV transmission category
       IDU57.665.572.90.027
       Homosexual/bisexual12.012.49.5
       Heterosexual16.012.411.7
       Other14.49.75.9
      HIV clinical stage
       A45.345.850.90.270
       B25.125.326.7
       C29.628.922.3
      ART-treated
       No8.58.98.70.977
       Yes91.591.191.3
      Adherence to ART
       Low6.08.57.20.870
       Moderate21.923.321.2
       High63.659.262.9
       Not treated8.59.08.7
      Undetectable plasma HIV RNA level
       No26.733.327.40.177
       Yes73.366.772.6
      CD4 count ≤200 cells/mm3
       No88.690.291.50.427
       Yes11.49.88.5
      Depressive symptoms
      Patients with a CES-D25 score ≥17(23) for men (women) were considered to have depressive symptoms.
       No59.265.356.10.128
       Yes40.834.743.9
      Smoking status
       Past/current19.16.24.0<10−3
       Never80.993.796.0
      Alcohol consumption
      We used the following categories for average daily alcohol consumption: no consumption, low consumption (≤1AU/day), moderate consumption (1–3AU/day for women and 1–4AU/day for men), and elevated consumption (>3AU/day for women and >4AU/day for men).27
       No consumption27.319.627.10.348
       Low50.052.248.4
       Moderate17.321.017.8
       Elevated5.47.16.6
      Regular binge drinking
      Regular binge drinking was defined as drinking at least 5AU on one occasion, at least once a week.
       No86.285.584.10.727
       Yes13.814.515.9
      Number of self-reported symptoms (excluding lipodystrophy)9 (4–14)8 (4–13)8.5 (3–14)0.781
      Number of self-reported lipodystrophy symptoms2 (0–5)2 (0–5)2 (0–5)0.497
      * Fisher’s exact test or Kruskal-Wallis rank test; IQR, interquartile range.
      1 We used the following categories for average daily coffee consumption: low consumption (≤1 cups/day), moderate consumption (2 cups/day), and elevated consumption (≥3 cups/day).
      2 Patients who reported living in hotels, accommodation centres, on the street or in therapeutic apartments were considered to have unstable housing.
      3 Patients with a CES-D
      • Furher R.
      • Rouillon F.
      La version française de l’échelle CES-D. Description and translation of the auto-evaluation.
      score ≥17(23) for men (women) were considered to have depressive symptoms.
      4 We used the following categories for average daily alcohol consumption: no consumption, low consumption (≤1 AU/day), moderate consumption (1–3 AU/day for women and 1–4 AU/day for men), and elevated consumption (>3 AU/day for women and >4 AU/day for men).
      • Bissell D.
      • Paton A.
      • Ritson B.
      ABC of alcohol. Help: referral.
      5 Regular binge drinking was defined as drinking at least 5 AU on one occasion, at least once a week.
      6 The presence of indirect clinical signs of cirrhosis was defined by one of the following: ascites, esophageal varices with or without bleeding, hepatic encephalopathy.ART, antiretroviral therapy; FIB-4, fibrosis-4; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, intravenous drug use; IQR, interquartile range.

       Factors associated with mortality

      The crude and adjusted HR for the factors associated with mortality are reported in Table 2.
      In the multivariable model adjusted for socio-demographic, behavioural and clinical factors (including severe fibrosis and HCV treatment status), elevated coffee consumption at baseline (≥3 cups/day) (HR 0.5; CI 0.3–0.9; p = 0.032) was associated with a lower mortality risk, along with reporting never smoking (HR 0.3; CI 0.1–1.0; p = 0.051). After multivariable adjustment, an 80% and 60% reduction in mortality risk was observed, respectively, in individuals who cleared HCV post-treatment (HR 0.2; CI 0.1–0.7; p = 0.011) and individuals treated but not cured (HR 0.4; CI 0.2–0.9; p = 0.036), compared with those not yet treated and those on treatment. The other factors independently associated with higher mortality risk were: not having a steady partner, severe fibrosis (FIB-4 >3.25), HIV clinical stage C, and CD4 cell count ≤200 cells/mm3, a history of hepatocellular carcinoma and/or liver transplantation at enrolment, and a history of indirect clinical signs of cirrhosis at enrolment.
      In the secondary analysis using the shared-frailty Cox model with different baseline HR according to follow-up duration, we found similar results concerning the association between elevated coffee consumption and reduced mortality risk (data not shown).

      Discussion

      In this large prospective nationwide cohort of patients co-infected with HIV-HCV followed-up in French hospital departments, we found that elevated coffee consumption had an independent protective effect on all-cause mortality risk. This is the first time that such an association has been found in a population at high risk of death because of the double burden of two concomitant diseases and associated conditions. It is worth noting that HCV-related mortality was four times higher than HIV-related mortality in the study population, and that AIDS was the third largest cause of mortality in this population after non-HIV- and non-HCV-related cancer. One additional key result of our study is that an 80% reduction in mortality risk was observed in individuals who cleared HCV post-treatment compared with those not yet treated.

       Coffee and mortality

      In recent years, the number of experimental and clinical research studies exploring the association between coffee consumption and clinical conditions has increased exponentially. The effect of coffee or coffee compounds has been studied on a series of pathologies, including Alzheimer’s disease,
      • Liu Q.-P.
      • Wu Y.-F.
      • Cheng H.-Y.
      • Xia T.
      • Ding H.
      • Wang H.
      • et al.
      Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies.
      inflammatory-related diseases including cancer, cardiovascular diseases, and metabolic and liver-related diseases
      • Setiawan V.W.
      • Wilkens L.R.
      • Lu S.C.
      • Hernandez B.Y.
      • Le Marchand L.
      • Henderson B.E.
      Association of coffee intake with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort.
      • Pereira M.A.
      • Parker E.D.
      • Folsom A.R.
      Coffee consumption and risk of type 2 diabetes mellitus: an 11-year prospective study of 28 812 postmenopausal women.
      • Zelber-Sagi S.
      • Salomone F.
      • Webb M.
      • Lotan R.
      • Yeshua H.
      • Halpern Z.
      • et al.
      Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.
      • Ding M.
      • Bhupathiraju S.N.
      • Satija A.
      • van Dam R.M.
      • Hu F.B.
      Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.
      and also on total and cause-specific mortality.
      • Loftfield E.
      • Freedman N.D.
      • Graubard B.I.
      • Guertin K.A.
      • Black A.
      • Huang W.-Y.
      • et al.
      Association of coffee consumption with overall and cause-specific mortality in a large US prospective cohort study.
      • Ding M.
      • Satija A.
      • Bhupathiraju S.N.
      • Hu Y.
      • Sun Q.
      • Han J.
      • et al.
      Association of coffee consumption with total and cause-specific mortality in 3 large prospective cohorts.
      • Crippa A.
      • Discacciati A.
      • Larsson S.C.
      • Wolk A.
      • Orsini N.
      Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.
      • Je Y.
      • Giovannucci E.
      Coffee consumption and total mortality: a meta-analysis of twenty prospective cohort studies.
      • Kennedy O.J.
      • Roderick P.
      • Buchanan R.
      • Fallowfield J.A.
      • Hayes P.C.
      • Parkes J.
      Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis.
      • Setiawan V.W.
      • Wilkens L.R.
      • Lu S.C.
      • Hernandez B.Y.
      • Le Marchand L.
      • Henderson B.E.
      Association of coffee intake with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort.
      Three or more cups of coffee per day was the threshold for coffee consumption most often associated with a lower morbidity and mortality. Although a recent meta-analysis did not show any association between coffee consumption and cancer mortality, its findings did suggest an inverse relationship between coffee consumption and all-cause mortality, as well as mortality from cardiovascular diseases.
      • Crippa A.
      • Discacciati A.
      • Larsson S.C.
      • Wolk A.
      • Orsini N.
      Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.
      Cardiovascular diseases were the second largest non-HIV/non-HCV-related causes of mortality after cancer in our population. One meta-analysis showed a non-linear association between coffee consumption and the risk of cardiovascular diseases, with the lowest risk being observed in the second highest category of coffee consumption (median: 3.5 cups per day), and no association between elevated risk of cardiovascular diseases and the highest consumption category (median: 5 cups per day).
      • Ding M.
      • Bhupathiraju S.N.
      • Satija A.
      • van Dam R.M.
      • Hu F.B.
      Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.
      Previous research using data from long-term follow-up prospective cohort studies showed no significant association between daily coffee consumption and coronary heart disease.
      • Sofi F.
      • Conti A.A.
      • Gori A.M.
      • Eliana Luisi M.L.
      • Casini A.
      • Abbate R.
      • et al.
      Coffee consumption and risk of coronary heart disease: a meta-analysis.
      In another meta-analysis, moderate coffee consumption was inversely associated with the risk of heart failure, the largest inverse association being observed for consumption of four servings per day.
      • Mostofsky E.
      • Rice M.S.
      • Levitan E.B.
      • Mittleman M.A.
      Habitual coffee consumption and risk of heart failure: a dose-response meta-analysis.
      Moderate coffee consumption has also been shown to be weakly inversely associated with the risk of stroke.
      • Larsson S.C.
      • Orsini N.
      Coffee consumption and risk of stroke: a dose-response meta-analysis of prospective studies.
      In addition, there is growing evidence for the hepato-protective role of coffee intake in patients with liver disease, including patients co-infected with HIV-HCV. It has already been shown that coffee consumption is associated with a reduced risk of elevated serum ALT activity
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      and with a dose-dependent improvement in serum gamma glutamyltransferase and AST values, in populations at risk of liver disease.
      • Saab S.
      • Mallam D.
      • Cox G.A.
      • Tong M.J.
      Impact of coffee on liver diseases: a systematic review.
      Coffee intake has been associated with a reduced risk of fibrosis and cirrhosis
      • Kennedy O.J.
      • Roderick P.
      • Buchanan R.
      • Fallowfield J.A.
      • Hayes P.C.
      • Parkes J.
      Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis.
      • Liu F.
      • Wang X.
      • Wu G.
      • Chen L.
      • Hu P.
      • Ren H.
      • et al.
      Coffee consumption decreases risks for hepatic fibrosis and cirrhosis: a meta-analysis.
      • Khalaf N.
      • White D.
      • Kanwal F.
      • Ramsey D.
      • Mittal S.
      • Tavakoli-Tabasi S.
      • et al.
      Coffee and caffeine are associated with decreased risk of advanced hepatic fibrosis among patients with hepatitis C.
      and with a reduced risk of death in patients with cirrhosis,
      • Tverdal A.
      • Skurtveit S.
      Coffee intake and mortality from liver cirrhosis.
      even after transplantation.
      • Friedrich K.
      • Smit M.
      • Wannhoff A.
      • Rupp C.
      • Scholl S.G.
      • Antoni C.
      • et al.
      Coffee consumption protects against progression in liver cirrhosis and increases long-term survival after liver transplantation.
      Meta-analyses also suggest a protective effect of coffee intake on the risk of hepatocellular carcinoma in different populations, with a reduction in the risk by approximately 40%.
      • Bravi F.
      • Tavani A.
      • Bosetti C.
      • Boffetta P.
      • La Vecchia C.
      Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies.
      It has also been hypothesized that polyphenols contained in coffee
      • Carrieri M.P.
      • Sogni P.
      • Cohen J.
      • Loko M.-A.
      • Winnock M.
      • Spire B.
      • et al.
      Elevated coffee consumption and reduced risk of insulin resistance in HIV-HCV coinfected patients (HEPAVIH ANRS CO-13).
      and chocolate
      • Almoosawi S.
      • Tsang C.
      • Ostertag L.M.
      • Fyfe L.
      • Al-Dujaili E.A.
      Differential effect of polyphenol-rich dark chocolate on biomarkers of glucose metabolism and cardiovascular risk factors in healthy, overweight and obese subjects: a randomized clinical trial.
      may play a protective role in liver injury through a reduced risk of insulin resistance and reduced inflammation.
      • Aleksandrova K.
      • Bamia C.
      • Drogan D.
      • Lagiou P.
      • Trichopoulou A.
      • Jenab M.
      • et al.
      The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.
      Coffee consumption has also been shown to be inversely associated with the risk of type 2 diabetes in a dose-response meta-analysis.
      • Ding M.
      • Bhupathiraju S.N.
      • Chen M.
      • van Dam R.M.
      • Hu F.B.
      Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: a systematic review and a dose-response meta-analysis.
      Several studies have identified preventive effects of coffee and caffeine extracts on hepatic fibrosis in standard rodent models and on the development of hepatic cirrhosis,
      • Moreno M.G.
      • Chávez E.
      • Aldaba-Muruato L.R.
      • Segovia J.
      • Vergara P.
      • Tsutsumi V.
      • et al.
      Coffee prevents CCl(4)-induced liver cirrhosis in the rat.
      • Chan E.S.L.
      • Montesinos M.C.
      • Fernandez P.
      • Desai A.
      • Delano D.L.
      • Yee H.
      • et al.
      Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis.
      for example through the inhibition of hepatic stellate cell activation.
      • Wang H.
      • Guan W.
      • Yang W.
      • Wang Q.
      • Zhao H.
      • Yang F.
      • et al.
      Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.
      • Shi H.
      • Dong L.
      • Zhang Y.
      • Bai Y.
      • Zhao J.
      • Zhang L.
      Protective effect of a coffee preparation (Nescafe pure) against carbon tetrachloride-induced liver fibrosis in rats.
      Caffeinated and decaffeinated coffee are similarly associated with improved liver function indicators, irrespective of the underlying disease.
      • Xiao Q.
      • Sinha R.
      • Graubard B.I.
      • Freedman N.D.
      Inverse associations of total and decaffeinated coffee with liver enzyme levels in National Health and Nutrition Examination Survey 1999–2010.
      Moreover, recent reports have indicated that pure caffeine at non-toxic concentrations
      • Batista M.N.
      • Carneiro B.M.
      • Braga A.C.S.
      • Rahal P.
      Caffeine inhibits hepatitis C virus replication in vitro.
      and caffeic acid
      • Tanida I.
      • Shirasago Y.
      • Suzuki R.
      • Abe R.
      • Wakita T.
      • Hanada K.
      • et al.
      Inhibitory effects of caffeic acid, a coffee-related organic acid, on the propagation of hepatitis C virus.
      can inhibit HCV replication in vitro.
      Although HCV infection remained the most prevalent cause of death in our study population, cancer and cardiovascular diseases are becoming increasingly common causes of deaths in patients co-infected with HIV-HCV. This underlines the need to implement specific measures for the screening and management of cancer and cardiovascular diseases in this population.

       HCV clearance and mortality

      The effectiveness of HCV clearance on reducing mortality risk, found in this study, is consistent with results from previous research in patients with HCV and HIV-HCV co-infection. It is important to note that exposure to HCV treatment without achieving HCV clearance has also been significantly associated with reduced mortality risk, but that the reduction observed was not as great as for HCV clearers. In a multicenter cohort of 920 Italian patients with HCV-related cirrhosis, a significant reduction in the rates of liver-related complications, hepatocellular carcinoma, and liver-related mortality was found in those who achieved SVR compared with those who did not.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • Bollani S.
      • Benvegnù L.
      • Mazzella G.
      • et al.
      Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: A retrospective study.
      A recent study including 2,743 patients with chronic HCV infection identified a significant reduction of all-cause mortality in patients who achieved HCV clearance as a result of successful treatment.
      • Tada T.
      • Kumada T.
      • Toyoda H.
      • Kiriyama S.
      • Tanikawa M.
      • Hisanaga Y.
      • et al.
      Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis.
      In HIV-HCV co-infected patients, a previous study using data from the ANRS CO13 HEPAVIH cohort showed a significant association between HCV clearance and a reduction in liver stiffness, a marker of liver fibrosis.
      ANRS CO13 HEPAVIH Cohort. Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients.
      This result may partially explain the decrease in HCV-related mortality observed in HCV clearers. In addition, elevated coffee consumption has already been shown to increase adherence to HCV treatment and to reduce side effects
      • Freedman N.D.
      • Curto T.M.
      • Lindsay K.L.
      • Wright E.C.
      • Sinha R.
      • Everhart J.E.
      • et al.
      Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C.
      but also to reduce self-reported symptoms.
      • Carrieri M.P.
      • Cohen J.
      • Salmon-Ceron D.
      • Winnock M.
      Coffee consumption and reduced self-reported side effects in HIV-HCV co-infected patients during PEG-IFN and ribavirin treatment: results from ANRS CO13 HEPAVIH.
      It is worth noting that when analysing HCV-related mortality as an outcome using a competing risk model which took into account causes of death other than HCV, elevated coffee consumption remained significantly associated with a reduced risk of HCV-related mortality (subHR 0.27; CI 0.08–0.89; p = 0.031).

       Study limitations

      One limitation of the present study was the difficulty of standardizing self-reported coffee intake and the lack of data about other caffeine sources and/or polyphenols. Nevertheless, our results are consistent with those obtained in the general population, which suggest a lower mortality risk from all causes in coffee drinkers compared with non-consumers.
      Another limitation of the study is that the questionnaire only explored coffee intake and consequently we were not able to address the impact of individual genetic diversity on the metabolism of coffee and related ingredients,
      • Yang A.
      • Palmer A.A.
      • de Wit H.
      Genetics of caffeine consumption and responses to caffeine.
      • Higdon J.V.
      • Frei B.
      Coffee and health: a review of recent human research.
      or the effect of other caffeine sources and polyphenols.
      Finally, it is important to note that this study is observational in nature and the associations found cannot be interpreted in terms of causality.

      Conclusions

      Our findings indicate that elevated coffee consumption (≥3 cups/day) has a protective effect on all-cause mortality in patients co-infected with HIV-HCV, a population at specific risk of end-stage liver disease and greater risk of cardiovascular diseases and cancer. This would also suggest that the benefits of elevated coffee are more relevant in patients with HIV-HCV than in the general population. The benefits of coffee extracts and supplementing dietary intake with other anti-inflammatory compounds need to be evaluated in this population. Further research will help to better elucidate the causal mechanisms of this relationship and reveal whether polyphenols contained in coffee are also implicated.

      Financial support

      This work was supported by the French National Agency for Research on Aids and Viral Hepatitis (ANRS), with the participation of Abbott France; Glaxo-Smith-Kline; Roche; Schering-Plough; and INSERM’s ‘Programme Cohortes TGIR’. The funding source was not involved in the study’s design or in the data analysis. Neither was it involved in the writing and submission of this manuscript.

      Conflict of interest

      With respect to the main results of the study (coffee effects), the authors have no conflicts of interests to declare. However some of the authors report to have been in advisory board of trials conducted by the firms producing treatments for hepatitis C. These authors who have taken part in this study have declared a relationship with the manufacturers of the drugs involved.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      Study concept and design: MPC, CP, DZ, FR, ER, IPM, DSC, FD, BS.
      Acquisition of data: LW, LE, DZ, FR, ER, IPM, DSC, FD.
      Analysis and interpretation of data: MPC, CP, SR.
      Drafting of the manuscript: MPC, CP, FM.
      Critical revision of the manuscript for important intellectual content: MPC, FM, LW, LE, DZ, FR, ER, IPM, DSC, FD, BS.
      Statistical analysis: CP, SR.
      Obtained funding: FD, LW, MPC.
      Administrative, technical, or material support: FM, SR, LE.
      Study supervision: MPC, LW, BS.
      All authors have approved the final revised version of the manuscript.

      Acknowledgements

      We thank all members of the ANRS CO13-HEPAVIH Study Group∗. We especially thank all the physicians and nurses involved in the follow-up of the cohort and all the patients who took part in this study. Finally, we thank Jude Sweeney for the English revision and editing of our manuscript.

      ‡The ANRS CO13 HEPAVIH Study Group

      Scientific Committee: Scientific Committee of the ANRS CO13 HEPAVIH Study Group: D. Salmon, F. Dabis, L. Wittkop, L. Esterle, P. Sogni, P. Trimoulet, J. Izopet, L. Serfaty, V. Paradis, B. Spire, P. Carrieri, M.A. Valantin, G. Pialoux, J. Chas, I. Poizot-Martin, K. Barange, A. Naqvi, E. Rosenthal, A. Bicart-See, O. Bouchaud, A. Gervais, C. Lascoux-Combe, C. Goujard, K. Lacombe, C. Duvivier, D. Vittecoq, D. Neau, P. Morlat, F. Bani-Sadr, L. Meyer, F. Boufassa, S. Dominguez, B. Autran, A.M. Roque, C. Solas, H. Fontaine, D. Costagliola, L. Piroth, A. Simon, D. Zucman, F. Boué, P. Miailhes, E. Billaud, H. Aumaître, D. Rey, S. Couffin-Cadiergues, L. Marchand.
      Clinical Centres (ward/participating physicians): APHP Cochin, Paris (Médecine Interne et Maladies Infectieuses: D. Salmon, L. Alagna; Hépato-gastro-entérologie: P. Sogni; Anatomo-pathologie: B. Terris; Virologie: A. Krivine); APHP Pitié-Salpétrière, Paris (Maladies Infectieuses et Tropicales: C. Katlama, M.A. Valantin, H. Stitou; Hépato-gastro-entérologie: Y. Benhamou; Anatomo-pathologie: F. Charlotte; Virologie: S. Fourati); APHP Pitié-Salpétrière, Paris (Médecine Interne: A. Simon, P. Cacoub, S. Nafissa); APHM Sainte-Marguerite, Marseille (Service d'Immuno-Hématologie Clinique – CISIH: I. Poizot-Martin, O. Zaegel, M. Porcher; Virologie: C. Tamalet); APHP Tenon, Paris (Maladies Infectieuses et Tropicales: G. Pialoux, J. Chas, L. Slama; Anatomo-pathologie: P. Callard, F. Bendjaballah; Virologie: C. Le Pendeven); CHU Purpan, Toulouse (Maladies Infectieuses et Tropicales: B. Marchou; Hépato-gastro-entérologie: L. Alric, K. Barange, S. Metivier; Anatomo-pathologie: J. Selves; Virologie: F. Larroquette); CHU Archet, Nice (Médecine Interne: E. Rosenthal; Infectiologie: Alissa Naqvi; Anatomo-pathologie: J. Haudebourg, M.C. Saint-Paul; Virologie: C. Partouche); APHP Avicenne, Bobigny (Médecine Interne – Unité VIH: O. Bouchaud; Anatomo-pathologie: M. Ziol; Virologie: Y. Baazia); Hôpital Joseph Ducuing, Toulouse (Médecine Interne: M. Uzan, A. Bicart-See, D. Garipuy, M.J. Ferro-Collados; Anatomo-pathologie: J. Selves; Virologie: F. Nicot); APHP Bichat – Claude-Bernard, Paris (Maladies Infectieuses:, A. Gervais, Y. Yazdanpanah; Anatomo-pathologie: H. Adle-Biassette; Virologie: G. Alexandre); APHP Saint-Louis, Paris (Maladies infectieuses: C. Lascoux-Combe, J.M. Molina,; Anatomo-pathologie: P. Bertheau, J. Duclos; Virologie: P. Palmer); APHP Saint-Antoine (Maladies Infectieuses et Tropicales:, K. Lacombe, P. Campa; P.M. Girard, Anatomo-pathologie: D. Wendum, P. Cervera, J. Adam; Virologie: C. Viala); APHP Bicêtre, Paris (Médecine Interne: C. Goujard, Elina Teicher; Virologie: C. Pallier; Maladies Infectieuses: D. Vittecoq); APHP Necker, Paris (Maladies Infectieuses et Tropicales: O. Lortholary, C. Duvivier, M. Shoai-Tehrani: Virologie: A. Mélard); CHU Pellegrin, Bordeaux (Maladies Infectieuses et Tropicales: D. Neau, A. Ochoa, E. Blanchard, S. Castet-Lafarie, C. Cazanave, D. Malvy, M. Dupon, H. Dutronc, F. Dauchy, L. Lacaze-Buzy; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet, S. Reigadas); Hôpital Saint-André, Bordeaux (Médecine Interne et Maladies Infectieuses: P. Morlat, D. Lacoste, F. Bonnet, N. Bernard, M. Bonarek Hessamfar, J. Roger-Schmeltz, P. Gellie, P. Thibaut, F. Paccalin, C. Martell, M. Carmen Pertusa, M. Vandenhende, P. Mercier, D. Malvy, T. Pistone, M.C. Receveur, S. Caldato; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet, S. Reigadas); Hôpital du Haut-Levêque, Bordeaux (Médecine Interne: J.L. Pellegrin, J.F. Viallard, E. Lazzaro, C. Greib; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet, S. Reigadas); Hôpital FOCH, Suresnes (Médecine Interne: D. Zucman, C. Majerholc; Virologie: F. Guitard); APHP Antoine Béclère, Clamart (Médecine Interne: F. Boué, J. Polo Devoto, I. Kansau, V. Chambrin, C. Pignon, L. Berroukeche, R. Fior, V. Martinez; Virologie: C. Deback); CHU Henri Mondor, Créteil (Immunologie Clinique: Y. Lévy, S. Dominguez, J.D. Lelièvre, A.S. Lascaux, G. Melica); CHU Hôtel Dieu, Nantes (Maladies Infectieuses et Tropicales: E. Billaud, F. Raffi, C. Alavena; Virologie: A. Rodallec); Hôpital de la Croix Rousse, Lyon (Maladies Infectieuses et Tropicales: P. Miailhes, D. Peyramond, C. Chidiac, F. Ader, F. Biron, A. Boibieux, L. Cotte, T. Ferry, T. Perpoint, J. Koffi, F. Zoulim, F. Bailly, P. Lack, M. Maynard, S. Radenne, M. Amiri; Virologie: T.T. Le-Thi); CHU Dijon, Dijon (Département d'infectiologie:, L. Piroth, P. Chavanet M. Duong Van Huyen, M. Buisson, A. Waldner-Combernoux, S. Mahy, R. Binois, A.L. Simonet-Lann, D. Croisier-Bertin); CHU Perpignan, Perpignan (Maladies infectieuses et tropicales: H. Aumaître); CHU Robert Debré, Reims (Médecine interne, maladies infectieuses et immunologie clinique: F. Bani-Sadr, D. Lambert, Y Nguen, C. Rouger, J.L. Berger); CHU Strasbourg (CISIH: D. Rey, M. Partrisiani, P. Gautner, M.L. Batard).
      Data collection: D Beniken, C. Lupin, C. Lions, A.-S. Ritleng, P. Honoré, V. Payssan, S. Breau, A. Joulie, M. Mole, C. Bolliot, F. Touam, F. André, H. Hue, L. Larmet, C. Brochier, V. Thoirain, M. Raho-Moussa, S Ogoudjobi, M Azar, D. Bornarel, S. Gohier, C. Chesnel, G. Maradan, P. Kurkdji, S. Hadjoudj, M. Malet, I. Kmiec, P. Fischer, A. Palacin, M.P. Pietri, V. Le Baut, P. Guet, S. Le Puil, M. Mebarki, A. Fior, A. Adda-Lievin.
      Management, statistical analyses: V Conte, J. Delaune, L. Dequae Merchadou, N. Douiri, S. Gillet, C. Gilbert, A. Jacquet, R. Kherraz, P. Lagorse, F. Marcellin, M. Mora, C. Protopopescu.

      Supplementary data

      References

        • Körner C.
        • Tolksdorf F.
        • Riesner K.
        • Krämer B.
        • Schulte D.
        • Nattermann J.
        • et al.
        Hepatitis C coinfection enhances sensitization of CD4(+) T-cells towards Fas-induced apoptosis in viraemic and HAART-controlled HIV-1-positive patients.
        Antivir Ther. 2011; 16: 1047-1055
        • Bourcier V.
        • Winnock M.
        • Ait Ahmed M.
        • Sogni P.
        • Pambrun E.
        • Poizot-Martin I.
        • et al.
        Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir).
        Clin Res Hepatol Gastroenterol. 2012; 36: 214-221
        • Poynard T.
        • Mathurin P.
        • Lai C.L.
        • Guyader D.
        • Poupon R.
        • Tainturier M.H.
        • et al.
        A comparison of fibrosis progression in chronic liver diseases.
        J Hepatol. 2003; 38: 257-265
        • Kramer J.R.
        • Kowalkowski M.A.
        • Duan Z.
        • Chiao E.Y.
        The Effect of HIV Viral Control on the Incidence of Hepatocellular Carcinoma in Veterans With Hepatitis C and HIV Coinfection.
        J Acquir Immune Defic Syndr. 1999; 2015: 456-462
        • Greub G.
        • Ledergerber B.
        • Battegay M.
        • Grob P.
        • Perrin L.
        • Furrer H.
        • et al.
        Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study.
        Lancet. 2000; 356: 1800-1805
        • Tedaldi E.M.
        • Baker R.K.
        • Moorman A.C.
        • Alzola C.F.
        • Furhrer J.
        • McCabe R.E.
        • et al.
        Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy.
        Clin Infect Dis. 2003; 36: 363-367
        • Heim M.H.
        25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end.
        Nat Rev Immunol. 2013; 13: 535-542
        • Cacoub P.
        • Halfon P.
        • Rosenthal E.
        • Pialoux G.
        • Benhamou Y.
        • Perronne C.
        • et al.
        Treatment of hepatitis C virus in human immunodeficiency virus infected patients in “real life”: modifications in two large surveys between 2004 and 2006.
        J Hepatol. 2008; 48: 35-42
        • Chung R.T.
        • Andersen J.
        • Volberding P.
        • Robbins G.K.
        • Liu T.
        • Sherman K.E.
        • et al.
        Peginterferon Alfa-2a plus ribavirin vs. interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.
        N Engl J Med. 2004; 351: 451-459
      1. ANRS CO13 HEPAVIH Cohort. Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients.
        AIDS Lond Engl. 2015; 29: 1821-1830
        • Operskalski E.A.
        • Kovacs A.
        HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies.
        Curr HIV/AIDS Rep. 2011; 8: 12-22
        • Ruhl C.E.
        • Everhart J.E.
        Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
        Gastroenterology. 2005; 128: 24-32
        • Modi A.A.
        • Feld J.J.
        • Park Y.
        • Kleiner D.E.
        • Everhart J.E.
        • Liang T.J.
        • et al.
        Increased caffeine consumption is associated with reduced hepatic fibrosis.
        Hepatology. 2010; 51: 201-209
        • Bravi F.
        • Tavani A.
        • Bosetti C.
        • Boffetta P.
        • La Vecchia C.
        Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies.
        Eur J Cancer Prev. 2016; https://doi.org/10.1097/CEJ.0000000000000252
        • Carrieri M.P.
        • Sogni P.
        • Cohen J.
        • Loko M.-A.
        • Winnock M.
        • Spire B.
        • et al.
        Elevated coffee consumption and reduced risk of insulin resistance in HIV-HCV coinfected patients (HEPAVIH ANRS CO-13).
        Hepatology. 2012; 56: 2010
        • Carrieri M.P.
        • Lions C.
        • Sogni P.
        • Winnock M.
        • Roux P.
        • Mora M.
        • et al.
        Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: Results from the ANRS CO13 HEPAVIH cohort study.
        J Hepatol. 2014; 60: 46-53
        • Loftfield E.
        • Freedman N.D.
        • Graubard B.I.
        • Guertin K.A.
        • Black A.
        • Huang W.-Y.
        • et al.
        Association of coffee consumption with overall and cause-specific mortality in a large US prospective cohort study.
        Am J Epidemiol. 2015; 182: 1010-1022
        • Ding M.
        • Satija A.
        • Bhupathiraju S.N.
        • Hu Y.
        • Sun Q.
        • Han J.
        • et al.
        Association of coffee consumption with total and cause-specific mortality in 3 large prospective cohorts.
        Circulation. 2015; 132: 2305-2315
        • Crippa A.
        • Discacciati A.
        • Larsson S.C.
        • Wolk A.
        • Orsini N.
        Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.
        Am J Epidemiol. 2014; 180: 763-775
        • Je Y.
        • Giovannucci E.
        Coffee consumption and total mortality: a meta-analysis of twenty prospective cohort studies.
        Br J Nutr. 2014; 111: 1162-1173
        • Kennedy O.J.
        • Roderick P.
        • Buchanan R.
        • Fallowfield J.A.
        • Hayes P.C.
        • Parkes J.
        Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis.
        Aliment Pharmacol Ther. 2016; 43: 562-574
        • Setiawan V.W.
        • Wilkens L.R.
        • Lu S.C.
        • Hernandez B.Y.
        • Le Marchand L.
        • Henderson B.E.
        Association of coffee intake with reduced incidence of liver cancer and death from chronic liver disease in the US multiethnic cohort.
        Gastroenterology. 2015; 148: 118-125
        • Roux P.
        • Cohen J.
        • Lascoux-Combe C.
        • Sogni P.
        • Winnock M.
        • Salmon-Ceron D.
        • et al.
        Determinants of the underreporting of alcohol consumption by HIV/HCV co-infected patients during face-to-face medical interviews: the role of the physician.
        Drug Alcohol Depend. 2011; 116: 228-232
        • Loko M.-A.
        • Salmon D.
        • Carrieri P.
        • Winnock M.
        • Mora M.
        • Merchadou L.
        • et al.
        The French national prospective cohort of patients co-infected with HIV and HCV (ANRS CO13 HEPAVIH): early findings, 2006–2010.
        BMC Infect Dis. 2010; 10: 303
        • Furher R.
        • Rouillon F.
        La version française de l’échelle CES-D. Description and translation of the auto-evaluation.
        Psychiatr Psychobiol. 1989; 4: 163-166
        • Bush K.
        • Kivlahan D.R.
        • McDonell M.B.
        • Fihn S.D.
        • Bradley K.A.
        The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.
        Arch Intern Med. 1998; 158: 1789-1795
        • Bissell D.
        • Paton A.
        • Ritson B.
        ABC of alcohol. Help: referral.
        Br Med J Clin Res Ed. 1982; 284: 495-497
        • Chesney M.A.
        • Ickovics J.R.
        • Chambers D.B.
        • Gifford A.L.
        • Neidig J.
        • Zwickl B.
        • et al.
        Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient Care Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG).
        AIDS Care. 2000; 12: 255-266
        • Roux P.
        • Lions C.
        • Cohen J.
        • Winnock M.
        • Salmon-Céron D.
        • Bani-Sadr F.
        • et al.
        Impact of HCV treatment and depressive symptoms on adherence to HAART among HIV-HCV-coinfected patients: results from the ANRS-CO13-HEPAVIH cohort.
        Antivir Ther. 2014; 19: 171-178
        • Sterling R.K.
        • Lissen E.
        • Clumeck N.
        • Sola R.
        • Correa M.C.
        • Montaner J.
        • et al.
        Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
        Hepatology. 2006; 43: 1317-1325
        • Grambsch P.M.
        • Therneau T.M.
        Proportional hazards tests and diagnostics based on weighted residuals.
        Biometrika. 1994; 81: 515-526
        • Protopopescu C.
        • Raffi F.
        • Spire B.
        • Hardel L.
        • Michelet C.
        • Cheneau C.
        • et al.
        Twelve-year mortality in HIV-infected patients receiving antiretroviral therapy: the role of social vulnerability. The ANRS CO8 APROCO-COPILOTE cohort.
        Antivir Ther. 2015; 20: 763-772
        • Liu Q.-P.
        • Wu Y.-F.
        • Cheng H.-Y.
        • Xia T.
        • Ding H.
        • Wang H.
        • et al.
        Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies.
        Nutrition. 2015; https://doi.org/10.1016/j.nut.2015.11.015
        • Pereira M.A.
        • Parker E.D.
        • Folsom A.R.
        Coffee consumption and risk of type 2 diabetes mellitus: an 11-year prospective study of 28 812 postmenopausal women.
        Arch Intern Med. 2006; 166: 1311-1316
        • Zelber-Sagi S.
        • Salomone F.
        • Webb M.
        • Lotan R.
        • Yeshua H.
        • Halpern Z.
        • et al.
        Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.
        Transl Res J Lab Clin Med. 2015; 165: 428-436
        • Ding M.
        • Bhupathiraju S.N.
        • Satija A.
        • van Dam R.M.
        • Hu F.B.
        Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.
        Circulation. 2014; 129: 643-659
        • Sofi F.
        • Conti A.A.
        • Gori A.M.
        • Eliana Luisi M.L.
        • Casini A.
        • Abbate R.
        • et al.
        Coffee consumption and risk of coronary heart disease: a meta-analysis.
        Nutr Metab Cardiovasc Dis. 2007; 17: 209-223
        • Mostofsky E.
        • Rice M.S.
        • Levitan E.B.
        • Mittleman M.A.
        Habitual coffee consumption and risk of heart failure: a dose-response meta-analysis.
        Circ Heart Fail. 2012; 5: 401-405
        • Larsson S.C.
        • Orsini N.
        Coffee consumption and risk of stroke: a dose-response meta-analysis of prospective studies.
        Am J Epidemiol. 2011; 174: 993-1001
        • Saab S.
        • Mallam D.
        • Cox G.A.
        • Tong M.J.
        Impact of coffee on liver diseases: a systematic review.
        Liver Int. 2014; 34: 495-504
        • Liu F.
        • Wang X.
        • Wu G.
        • Chen L.
        • Hu P.
        • Ren H.
        • et al.
        Coffee consumption decreases risks for hepatic fibrosis and cirrhosis: a meta-analysis.
        PLoS One. 2015; 10: e0142457
        • Khalaf N.
        • White D.
        • Kanwal F.
        • Ramsey D.
        • Mittal S.
        • Tavakoli-Tabasi S.
        • et al.
        Coffee and caffeine are associated with decreased risk of advanced hepatic fibrosis among patients with hepatitis C.
        Clin Gastroenterol Hepatol. 2015; 13 (e3): 1521-1531
        • Tverdal A.
        • Skurtveit S.
        Coffee intake and mortality from liver cirrhosis.
        Ann Epidemiol. 2003; 13: 419-423
        • Friedrich K.
        • Smit M.
        • Wannhoff A.
        • Rupp C.
        • Scholl S.G.
        • Antoni C.
        • et al.
        Coffee consumption protects against progression in liver cirrhosis and increases long-term survival after liver transplantation.
        J Gastroenterol Hepatol. 2016; 31: 1470-1475
        • Almoosawi S.
        • Tsang C.
        • Ostertag L.M.
        • Fyfe L.
        • Al-Dujaili E.A.
        Differential effect of polyphenol-rich dark chocolate on biomarkers of glucose metabolism and cardiovascular risk factors in healthy, overweight and obese subjects: a randomized clinical trial.
        Food Funct. 2012; 3: 1035-1043
        • Aleksandrova K.
        • Bamia C.
        • Drogan D.
        • Lagiou P.
        • Trichopoulou A.
        • Jenab M.
        • et al.
        The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.
        Am J Clin Nutr. 2015; 102: 1498-1508
        • Ding M.
        • Bhupathiraju S.N.
        • Chen M.
        • van Dam R.M.
        • Hu F.B.
        Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: a systematic review and a dose-response meta-analysis.
        Diabetes Care. 2014; 37: 569-586
        • Moreno M.G.
        • Chávez E.
        • Aldaba-Muruato L.R.
        • Segovia J.
        • Vergara P.
        • Tsutsumi V.
        • et al.
        Coffee prevents CCl(4)-induced liver cirrhosis in the rat.
        Hepatol Int. 2011; 5: 857-863
        • Chan E.S.L.
        • Montesinos M.C.
        • Fernandez P.
        • Desai A.
        • Delano D.L.
        • Yee H.
        • et al.
        Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis.
        Br J Pharmacol. 2006; 148: 1144-1155
        • Wang H.
        • Guan W.
        • Yang W.
        • Wang Q.
        • Zhao H.
        • Yang F.
        • et al.
        Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.
        PLoS One. 2014; 9: e92482
        • Shi H.
        • Dong L.
        • Zhang Y.
        • Bai Y.
        • Zhao J.
        • Zhang L.
        Protective effect of a coffee preparation (Nescafe pure) against carbon tetrachloride-induced liver fibrosis in rats.
        Clin Nutr Edinb Scotl. 2010; 29: 399-405
        • Xiao Q.
        • Sinha R.
        • Graubard B.I.
        • Freedman N.D.
        Inverse associations of total and decaffeinated coffee with liver enzyme levels in National Health and Nutrition Examination Survey 1999–2010.
        Hepatology. 2014; 60: 2091-2098
        • Batista M.N.
        • Carneiro B.M.
        • Braga A.C.S.
        • Rahal P.
        Caffeine inhibits hepatitis C virus replication in vitro.
        Arch Virol. 2015; 160: 399-407
        • Tanida I.
        • Shirasago Y.
        • Suzuki R.
        • Abe R.
        • Wakita T.
        • Hanada K.
        • et al.
        Inhibitory effects of caffeic acid, a coffee-related organic acid, on the propagation of hepatitis C virus.
        Jpn J Infect Dis. 2015; 68: 268-275
        • Bruno S.
        • Stroffolini T.
        • Colombo M.
        • Bollani S.
        • Benvegnù L.
        • Mazzella G.
        • et al.
        Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: A retrospective study.
        Hepatology. 2007; 45: 579-587
        • Tada T.
        • Kumada T.
        • Toyoda H.
        • Kiriyama S.
        • Tanikawa M.
        • Hisanaga Y.
        • et al.
        Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis.
        Liver Int. 2016; https://doi.org/10.1111/liv.13071
        • Freedman N.D.
        • Curto T.M.
        • Lindsay K.L.
        • Wright E.C.
        • Sinha R.
        • Everhart J.E.
        • et al.
        Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C.
        Gastroenterology. 2011; 140: 1961-1969
        • Carrieri M.P.
        • Cohen J.
        • Salmon-Ceron D.
        • Winnock M.
        Coffee consumption and reduced self-reported side effects in HIV-HCV co-infected patients during PEG-IFN and ribavirin treatment: results from ANRS CO13 HEPAVIH.
        J Hepatol. 2012; 56: 745-747
        • Yang A.
        • Palmer A.A.
        • de Wit H.
        Genetics of caffeine consumption and responses to caffeine.
        Psychopharmacology. 2010; 211: 245-257
        • Higdon J.V.
        • Frei B.
        Coffee and health: a review of recent human research.
        Crit Rev Food Sci Nutr. 2006; 46: 101-123

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