Saturday, June 25, 2011

Coffee Consumption is Associated with Response to Peginterferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

In patients with advanced HCV-related chronic liver disease in the HALT-C trial receiving peginterferon plus ribavirin treatment, 3 or more cups per day coffee drinkers were 3 times more likely to have a virologic response than nondrinkers. Associations were attenuated but persisted after adjustment for a wide range of behavioral, clinical, and genetic features, suggesting an effect independent of other known risk factors. In contrast to results for coffee, no effect was observed for tea drinking.
Coffee intake has been associated with lower level of liver enzymes, reduced progression of chronic liver disease,[25] and reduced incidence of hepatocellular carcinoma.[26,27] Because few other data on the association of coffee drinking with virologic response are available, the association observed here needs replication in other studies.
A number of risk factors have previously been associated with virologic response in HALT-C and in other studies,[5,8,12,14,15,18,25] including African American race, presence of cirrhosis, AST/ALT ratio, serum HCV RNA level, particular genotypes near the IL28B gene, and ability to tolerate full doses of peginterferon during treatment. Intriguingly, coffee was modestly associated with nearly all of these factors. African Americans in our study tended to drink less coffee than white patients, and coffee drinking was associated with lower AST/ALT ratio, ability to tolerate full doses of peginterferon α-2a during treatment, and particular genotypes of single nucleotide polymorphisms near to the IL28B gene, which have recently been linked to virologic response.[11–15] Yet, the association for coffee persisted after adjustment for these and other potential confounders and was similar across stratums of each of these risk factors, eg, a similar effect for coffee on virologic response was observed for both those receiving a full dose of peginterferon and those having a dose reduction. These results suggest that coffee drinkers had a better response to treatment that was independent of other risk factors, including higher tolerance for peginterferon treatment.
Associations between coffee and features associated with virologic response raise the possibility of reverse causality, ie, sicker patients were less likely to drink coffee and, in this way, less likely to respond to treatment. But in HALT-C, patients drinking coffee reported a worse quality of life on the Short Form-36 quality of life questionnaire than nondrinkers. Quality of life was also not associated with virologic response. As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance.
Coffee has >1000 compounds, any one of which could be involved in virologic response. One major constituent of coffee is caffeine. Although we could not distinguish caffeinated from decaffeinated coffee in our study, we found no association with consumption of black or green tea. Fewer individuals consumed tea in our study and tea contains less caffeine than coffee. It is unlikely that coffee and its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption. In fact, baseline levels were actually higher with greater consumption (Table 2). More likely coffee would have a facilitating effect on response to peginterferon and ribavirin treatment by a mechanism yet to be understood. It is intriguing that the C allele of rs12979860 near the IL28B gene has been associated with higher baseline viral levels, lower levels of interferon-stimulated gene expression, and better treatment response.[14,36,37] The IL28B genotype effect on virologic response may be through the Janus kinasesignal transducer and activator of transcription pathway.[38] Recently published results potentially link kahweol, a diterpene in coffee, to Janus kinase-signal transducer and activator of transcription pathway,[39] suggesting one of many possible mechanisms for the observed association in our study.
A number of studies have linked high serum total and low-density lipoprotein (LDL) cholesterol with increased virologic response to peginterferon plus ribavirin therapy.[40–42] LDL has also been recently posited to mediate, at least partly, the effect of the rs12979860 C allele.[41,43] Coffee intake was associated with higher serum total cholesterol in our study and has also been linked to higher serum total cholesterol and LDL in past observational and interventional studies.[44] Adjustment for total cholesterol, however, did not affect risk estimates in the current analysis. We lacked assessment of LDL. Alternatively, insulin resistance has been associated with poor virologic response in a number of previous studies.[9,10] Consistent with previous studies of type 2 diabetes,[45,46] coffee intake was inversely associated with insulin resistance in HALT-C. Adjustment for HOMA2 score did not affect risk estimates for coffee with virologic response in the current analysis.
Our study has several advantages, including a large number of patients with histological staging of liver fibrosis, careful assessment of virologic response using a central virology laboratory, and comprehensive assessment of clinical and histologic features. Limitations include a lack of information on caffeine and coffee brewing methods and the assessment of coffee via self-report at a single time point. As such, we do not know patients' coffee intake at the time of initial treatment or whether coffee consumption was maintained during the course of the lead-in phase. However, for patients failing lead-in therapy subsequently randomized to half-dose peginterferon treatment or to no treatment, coffee consumption was similar at baseline and 18 months later (6 months after randomization). Because patients in HALT-C also had previously failed interferon therapy, it is not clear whether our results can be generalized to other patient populations, such as those with less advanced disease, those who are treatment-naïve to prior therapy, or who are being treated with newer antiviral agents.
In summary, we observed an independent association between coffee intake and virologic response to peginterferon plus ribavirin retreatment in the lead-in phase of the HALT-C trial. Future studies are needed to replicate this finding in other populations.

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