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
Authors: M. Patrizia Carrieri, Julien Cohen, Dominique Salmon-Ceron, Maria Winnock
Journal: Journal of Hepatology (2011)

Association of caffeine intake and histological features of chronic hepatitis CJournal of HepatologyVol. 54Issue 6PreviewThe severity of chronic hepatitis C (CHC) is modulated by host and environmental factors. Several reports suggest that caffeine intake exerts hepatoprotective effects in patients with chronic liver disease. The aim of this study was to evaluate the impact of caffeine consumption on activity grade and fibrosis stage in patients with CHC. Full-Text PDF Constentin and colleagues [[1]Costentin C.E. Roudot-Thoraval F. Zafrani E.S. Medkour F. Pawlotsky J.M. Mallat A. et al.Association of caffeine intake and histological features of chronic hepatitis C.J Hepatol. 2011; 54: 1123-1129Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] reported key results about the protective effect of elevated coffee consumption (three or more cups/day) on histological activity in patients with chronic hepatitis C. These findings bring additional evidence to the potential hepatoprotective properties of coffee in chronic liver diseases, as already suggested in studies showing its beneficial effects on liver cancer [[2]Bravi F. Bosetti C. Tavani A. Bagnardi V. Gallus S. Negri E. et al.Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.Hepatology. 2007; 46: 430-435Crossref PubMed Scopus (206) Google Scholar].More recently, Freedman and colleagues [[3]Freedman N. Curto T. Lindsay K. Wright E. Sinha R. Everhart J. et al.Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C.Gastroenterology. 2011; 140: 1961-1969Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar] showed associations between elevated coffee consumption (three or more cups/day) and early, week-20 and sustained virological response (SVR) during re-treatment with peginterferon alfa-2a (180 μg/wk) and ribavirin (1000–1200 mg/day) in the HALT trial. The study also highlighted that the proportion of individuals tolerating the full dose of treatment was significantly higher in those patients drinking more than three cups of coffee/day. In addition, during treatment, coffee drinkers were significantly less likely to have a dose reduction due to either low neutrophils or platelets.These results provide important insights into the double role that coffee consumption may play in slowing HCV progression, reducing medical side effects and improving response to HCV treatment. However, whether and to what extent elevated coffee consumption may also reduce the burden of patients' "personal experience" with HCV disease and/or HCV treatment, as expressed by self-reported symptoms/side effects, has not yet been documented.Individuals receiving HCV treatment experience a considerable range of symptoms/side effects [[4]Marcellin F. Preau M. Dellamonica P. Ravaux I. Kurkdji P. Protopopescu C. et al.Adding HCV treatment to HIV treatment in HIV-HCV coinfected patients: the impact on the different dimensions of fatigue and self-reported side effects.J Pain Symptom Manage. 2007; 34: 413-421Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], in particular fatigue, neurocognitive symptoms, depression, and problems of anger control which can seriously compromise their quality of life [[5]Marcellin F. Preau M. Ravaux I. Dellamonica P. Spire B. Carrieri M.P. Self-reported fatigue and depressive symptoms as main indicators of the quality of life (QOL) of patients living with HIV and Hepatitis C: implications for clinical management and future research.HIV Clin Trials. 2007; 8: 320-327Crossref PubMed Scopus (68) Google Scholar] and undermine adherence and continuity of treatment [[6]Weiss J.J. Brau N. Stivala A. Swan T. Fishbein D. Review article: adherence to medication for chronic hepatitis C – building on the model of human immunodeficiency virus antiretroviral adherence research.Aliment Pharmacol Ther. 2009; 30: 14-27Crossref PubMed Scopus (45) Google Scholar]. On the other hand, several performance benefits are attributed to coffee consumption including physical endurance, fatigue reduction, and improvements in mental concentration and alertness [[7]Heckman M.A. Weil J. Gonzalez de Mejia E. Caffeine (1,3,7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters.J Food Sci. 2010; 75: R77-R87Crossref PubMed Scopus (478) Google Scholar].Medically reported side effects document major toxicity events during HCV treatment, whereas self-reported discomforting symptoms are known to express perceived toxicity and disease burden on patients' daily life more accurately.To test whether elevated coffee consumption can indeed relieve the discomfort caused by side effects, we used data from the HEPAVIH ANRS CO13 cohort of HIV-HCV-infected patients [[8]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. 2011; 10: 303Crossref Scopus (80) Google Scholar]. Selection criteria for this analysis targeted patients receiving antiretroviral therapy (ART) who started peginterferon alfa-2a and ribavirin during follow-up and who had both complete data about coffee consumption before starting treatment and self-reported discomforting side effects during treatment at 3 months and before the end of treatment, collected through self-administered questionnaires (N = 106, 138 visits). A five-category variable measured coffee consumption on a five-point scale: "no consumption", "occasional consumption", "one cup per day", "two cups per day", "three or more cups of coffee per day". Self-reported symptoms [[9]Justice A.C. Holmes W. Gifford A.L. Rabeneck L. Zackin R. Sinclair G. et al.Development and validation of a self-completed HIV symptom index.J Clin Epidemiol. 2001; 54: S77-S90Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar] detailed 30 treatment-related symptoms (defined here as "self-reported side effects") over the previous 4 weeks and the discomfort they caused. This scale has already been shown to capture HCV-treatment toxicity in HIV-HCV infected patients [[4]Marcellin F. Preau M. Dellamonica P. Ravaux I. Kurkdji P. Protopopescu C. et al.Adding HCV treatment to HIV treatment in HIV-HCV coinfected patients: the impact on the different dimensions of fatigue and self-reported side effects.J Pain Symptom Manage. 2007; 34: 413-421Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar].Among the 106 selected patients, median [IQR] age was 44 [41–46] years, men accounted for 71% and most of the participants (80%) were HIV-infected through injecting drug use (IDU). At enrollment, 86% of the patients had undetectable plasma HIV RNA, 52% presented with severe fibrosis (F3–4) and 13% had a CD4 count <200/mm3. The median [IQR] number of self-reported side effects causing discomfort was 3 [0–8] and 31% did not report any discomforting side effects. A mixed model confirmed that individuals drinking more than three cups a day did not significantly change their consumption over time. A logistic regression model based on Generalized Estimating Equations was used to study the relationship between coffee consumption before starting treatment and the presence of discomforting side effects at 3 months and before the end of treatment.Patients drinking ⩾3 cups of coffee per day were less likely to report discomforting side effects than non-drinkers of coffee (OR [95% CI] = 0.19 [0.05–0.78], p = 0.02). The association between drinking three or more cups and self-reported side effects remained significant (AOR [95% CI]: 0.17 [0.03–0.96], p = 0.04) even after multiple adjustments for gender, age, history of opioid use, and liver fibrosis (F3–F4 vs. F0–F1–F2) which are known correlates of reporting a higher number of discomforting side effects [[10]Carrieri M.P. Villes V. Raffi F. Protopopescu C. Preau M. Salmon D. et al.Self-reported side-effects of anti-retroviral treatment among IDUs: a 7-year longitudinal study (APROCO-COPILOTE COHORT ANRS CO-8).Int J Drug Policy. 2007; 18: 288-295Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. In addition, the likelihood of reporting discomforting side effects during HCV treatment linearly decreased across the five categories of coffee consumption (OR [95% CI] = 0.67 [0.49–0.90], p = 0.008) and remained significant after multiple adjustment for age, gender, liver fibrosis, and history of opioid use (AOR [95% CI] = 0.62 [0.43–0.90], p = 0.01).These results outline an association between elevated coffee consumption and reduced perceived toxicity during HCV treatment, which needs confirmation in future studies.Although the study population may be particularly vulnerable to treatment toxicity and more prone to reporting discomforting side effects because of their double viral infection, our findings suggest the additional potential benefits of coffee consumption in patients receiving PEG-IFN + ribavirin therapy. While newer treatment options will soon become available, this combination will remain the only one available in resource-limited settings where treatment success is still greatly subordinate to patient readiness to start, strict adherence, and receipt of adequate side effects management and counseling. In the meantime, Constentin's and Freedman's results, together with our own, may provide an inexpensive and simple suggestion to lower necroinflammatory injury and potentially reduce the progression of liver fibrosis, improve response to HCV treatment as well as alleviating treatment-related toxicity once patients engage in HCV treatment.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding of conflict of interest with respect to this manuscript.Financial supportThis research was supported by the French National Agency for Research on AIDS and Hepatitis (ANRS) with the participation of Abbott France, GlaxoSmithKline, Roche and Schering-Plough. Constentin and colleagues [[1]Costentin C.E. Roudot-Thoraval F. Zafrani E.S. Medkour F. Pawlotsky J.M. Mallat A. et al.Association of caffeine intake and histological features of chronic hepatitis C.J Hepatol. 2011; 54: 1123-1129Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] reported key results about the protective effect of elevated coffee consumption (three or more cups/day) on histological activity in patients with chronic hepatitis C. These findings bring additional evidence to the potential hepatoprotective properties of coffee in chronic liver diseases, as already suggested in studies showing its beneficial effects on liver cancer [[2]Bravi F. Bosetti C. Tavani A. Bagnardi V. Gallus S. Negri E. et al.Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.Hepatology. 2007; 46: 430-435Crossref PubMed Scopus (206) Google Scholar]. More recently, Freedman and colleagues [[3]Freedman N. Curto T. Lindsay K. Wright E. Sinha R. Everhart J. et al.Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C.Gastroenterology. 2011; 140: 1961-1969Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar] showed associations between elevated coffee consumption (three or more cups/day) and early, week-20 and sustained virological response (SVR) during re-treatment with peginterferon alfa-2a (180 μg/wk) and ribavirin (1000–1200 mg/day) in the HALT trial. The study also highlighted that the proportion of individuals tolerating the full dose of treatment was significantly higher in those patients drinking more than three cups of coffee/day. In addition, during treatment, coffee drinkers were significantly less likely to have a dose reduction due to either low neutrophils or platelets. These results provide important insights into the double role that coffee consumption may play in slowing HCV progression, reducing medical side effects and improving response to HCV treatment. However, whether and to what extent elevated coffee consumption may also reduce the burden of patients' "personal experience" with HCV disease and/or HCV treatment, as expressed by self-reported symptoms/side effects, has not yet been documented. Individuals receiving HCV treatment experience a considerable range of symptoms/side effects [[4]Marcellin F. Preau M. Dellamonica P. Ravaux I. Kurkdji P. Protopopescu C. et al.Adding HCV treatment to HIV treatment in HIV-HCV coinfected patients: the impact on the different dimensions of fatigue and self-reported side effects.J Pain Symptom Manage. 2007; 34: 413-421Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], in particular fatigue, neurocognitive symptoms, depression, and problems of anger control which can seriously compromise their quality of life [[5]Marcellin F. Preau M. Ravaux I. Dellamonica P. Spire B. Carrieri M.P. Self-reported fatigue and depressive symptoms as main indicators of the quality of life (QOL) of patients living with HIV and Hepatitis C: implications for clinical management and future research.HIV Clin Trials. 2007; 8: 320-327Crossref PubMed Scopus (68) Google Scholar] and undermine adherence and continuity of treatment [[6]Weiss J.J. Brau N. Stivala A. Swan T. Fishbein D. Review article: adherence to medication for chronic hepatitis C – building on the model of human immunodeficiency virus antiretroviral adherence research.Aliment Pharmacol Ther. 2009; 30: 14-27Crossref PubMed Scopus (45) Google Scholar]. On the other hand, several performance benefits are attributed to coffee consumption including physical endurance, fatigue reduction, and improvements in mental concentration and alertness [[7]Heckman M.A. Weil J. Gonzalez de Mejia E. Caffeine (1,3,7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters.J Food Sci. 2010; 75: R77-R87Crossref PubMed Scopus (478) Google Scholar]. Medically reported side effects document major toxicity events during HCV treatment, whereas self-reported discomforting symptoms are known to express perceived toxicity and disease burden on patients' daily life more accurately. To test whether elevated coffee consumption can indeed relieve the discomfort caused by side effects, we used data from the HEPAVIH ANRS CO13 cohort of HIV-HCV-infected patients [[8]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. 2011; 10: 303Crossref Scopus (80) Google Scholar]. Selection criteria for this analysis targeted patients receiving antiretroviral therapy (ART) who started peginterferon alfa-2a and ribavirin during follow-up and who had both complete data about coffee consumption before starting treatment and self-reported discomforting side effects during treatment at 3 months and before the end of treatment, collected through self-administered questionnaires (N = 106, 138 visits). A five-category variable measured coffee consumption on a five-point scale: "no consumption", "occasional consumption", "one cup per day", "two cups per day", "three or more cups of coffee per day". Self-reported symptoms [[9]Justice A.C. Holmes W. Gifford A.L. Rabeneck L. Zackin R. Sinclair G. et al.Development and validation of a self-completed HIV symptom index.J Clin Epidemiol. 2001; 54: S77-S90Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar] detailed 30 treatment-related symptoms (defined here as "self-reported side effects") over the previous 4 weeks and the discomfort they caused. This scale has already been shown to capture HCV-treatment toxicity in HIV-HCV infected patients [[4]Marcellin F. Preau M. Dellamonica P. Ravaux I. Kurkdji P. Protopopescu C. et al.Adding HCV treatment to HIV treatment in HIV-HCV coinfected patients: the impact on the different dimensions of fatigue and self-reported side effects.J Pain Symptom Manage. 2007; 34: 413-421Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Among the 106 selected patients, median [IQR] age was 44 [41–46] years, men accounted for 71% and most of the participants (80%) were HIV-infected through injecting drug use (IDU). At enrollment, 86% of the patients had undetectable plasma HIV RNA, 52% presented with severe fibrosis (F3–4) and 13% had a CD4 count <200/mm3. The median [IQR] number of self-reported side effects causing discomfort was 3 [0–8] and 31% did not report any discomforting side effects. A mixed model confirmed that individuals drinking more than three cups a day did not significantly change their consumption over time. A logistic regression model based on Generalized Estimating Equations was used to study the relationship between coffee consumption before starting treatment and the presence of discomforting side effects at 3 months and before the end of treatment. Patients drinking ⩾3 cups of coffee per day were less likely to report discomforting side effects than non-drinkers of coffee (OR [95% CI] = 0.19 [0.05–0.78], p = 0.02). The association between drinking three or more cups and self-reported side effects remained significant (AOR [95% CI]: 0.17 [0.03–0.96], p = 0.04) even after multiple adjustments for gender, age, history of opioid use, and liver fibrosis (F3–F4 vs. F0–F1–F2) which are known correlates of reporting a higher number of discomforting side effects [[10]Carrieri M.P. Villes V. Raffi F. Protopopescu C. Preau M. Salmon D. et al.Self-reported side-effects of anti-retroviral treatment among IDUs: a 7-year longitudinal study (APROCO-COPILOTE COHORT ANRS CO-8).Int J Drug Policy. 2007; 18: 288-295Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. In addition, the likelihood of reporting discomforting side effects during HCV treatment linearly decreased across the five categories of coffee consumption (OR [95% CI] = 0.67 [0.49–0.90], p = 0.008) and remained significant after multiple adjustment for age, gender, liver fibrosis, and history of opioid use (AOR [95% CI] = 0.62 [0.43–0.90], p = 0.01). These results outline an association between elevated coffee consumption and reduced perceived toxicity during HCV treatment, which needs confirmation in future studies. Although the study population may be particularly vulnerable to treatment toxicity and more prone to reporting discomforting side effects because of their double viral infection, our findings suggest the additional potential benefits of coffee consumption in patients receiving PEG-IFN + ribavirin therapy. While newer treatment options will soon become available, this combination will remain the only one available in resource-limited settings where treatment success is still greatly subordinate to patient readiness to start, strict adherence, and receipt of adequate side effects management and counseling. In the meantime, Constentin's and Freedman's results, together with our own, may provide an inexpensive and simple suggestion to lower necroinflammatory injury and potentially reduce the progression of liver fibrosis, improve response to HCV treatment as well as alleviating treatment-related toxicity once patients engage in HCV treatment. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding of conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding of conflict of interest with respect to this manuscript. Financial supportThis research was supported by the French National Agency for Research on AIDS and Hepatitis (ANRS) with the participation of Abbott France, GlaxoSmithKline, Roche and Schering-Plough. This research was supported by the French National Agency for Research on AIDS and Hepatitis (ANRS) with the participation of Abbott France, GlaxoSmithKline, Roche and Schering-Plough. Principal investigators: D. Salmon-Ceron, F. Dabis Methodology: F. Dabis, M. Winnock Management Center: M. Winnock, M.A. Loko, L. Dequae Merchadou, S. Gillet Hepatology: Y. Benhamou, P. Sogni Virology: J. Izopet, M.-E. Lafon Social Sciences: B. Spire, M.P. Carrieri, P. Roux, L. Michel, J. Cohen, M. Mora, C. Taieb. Financial Support: French National Agency for Research on AIDS and hepatitis. List of participating groups: (ANRS CO13 HEPAVIH) AC7 cohorts: AQUITAINE (F. Dabis), RIBAVIC (F. BaniSadr), SEROCO/HEMOCO (L. Meyer) Clinical Centers: Paris: Hôpital Cochin – Service de Médecine Interne 2, Hôpital Tenon – Service des Maladies Infectieuses, Hôpital Pitié-Salpêtrière – Service des Maladies Infectieuses, Hôpital Avicenne – Service de Médecine Interne, Hôpital Bichat-Claude Bernard – Service des Maladies Infectieuses A, Hôpital de Bicêtre – Service de Médecine Interne, Hôpital Necker-Enfants Malades – Service des Maladies Infectieuses, Hôpital Saint Antoine – Service des Maladies Infectieuses, Hôpital Saint Louis – Service de Médecine Interne, Hôpital Paul Brousse – Service des Maladies Infectieuses; Marseille: Hôpital Sainte Marguerite – Service Hématologie et VIH; Nice: Hôpital de l'Archet – Services des Maladies Infectieuses et de Médecine Interne; Toulouse: Hôpital Purpan – Services des Maladies Infectieuses et de Médecine Interne, Hôpital Joseph Ducuing – Service de Médecine Interne; Bordeaux: Hôpital Pellegrin – Services des Maladies Infectieuses A et B, Hôpital Saint André Service de Médecine Interne, Hôpital Haut Lévêque Service de Médecine Interne Associated team: UMR912 INSERM-IRD-Université de la Méditerranée. We thank Jude Sweeney for the English revision of the manuscript. A special thank to all those people living with HIV and HCV who accepted to participate in the study.