The sustained virologic response rate of chronic hepatitis C in registration trials with currently approved interferon-α based antiviral therapy ranges from 44%-54%[15,16
], but varies widely by genotype, ethnicity and underlying histology. In practice, at centers similar to the study site, HCV treatment response rates range from 20% for genotype 1 to 43%-52% for genotypes 2-3[17
]. Suboptimal response and significant toxicity continue to spur the development of novel anti-HCV therapies.
The capacity of HMG-CoA reductase inhibitors to impede HCV replicon replication in vitro
in a dose-dependent fashion raised hope that this commonly prescribed and acceptably safe class of medications could serve as an adjunct to standard interferon-based therapy. Data from such in vitro
studies further demonstrated a hierarchy of statin-induced viral inhibition, with the greatest effect demonstrated with fluvastatin followed by atorvastatin, simvastatin, and lovastatin, respectively. These in vitro
findings prompted a pilot study in which 10 subjects with chronic hepatitis C and laboratory evidence of dyslipidemia were treated with atorvastatin 20 mg daily. However, no significant changes in HCV RNA titers were demonstrated at the atorvastatin dose administered though such subjects did have a significant lowering of LDL and total cholesterol[13
]. This first study did not examine the effect of fluvastatin, the most potent statin identified in in vitro
experiments. A more recent small, uncontrolled study of 22 patients given fluvastatin at doses ranging from 20-80 mg/d found transient, 0.5-log reductions in HCV RNA titers in 50% of treated subjects[14
], but did not correlate these responses with the lipid lowering therapeutic effect of statins or specifically explore viral genotypes and other medications used.
In order to validate the need for further prospective study of the effect of statins on HCV viral replication in clinical practice, we performed a cross-sectional study of a larger number of subjects and controlled for potential confounders such as viral genotype, cholesterol levels, triglyceride levels and exposure to other lipid lowering medications. We found exposure to different statin preparations, primarily simvastatin, during routine clinical use, was not associated with a change in HCV viral titers. In a limited number of subjects with longitudinal measures of HCV viral load pre- and post-initiation of statin therapy, our data suggested that there was no evidence of clinically significant change in HCV RNA titers. Specifically for simvastatin, the statin for which we had the most data, we were unable to show a dose-dependent association with reduced HCV titers, contrasting with in vitro
]. Given the small number of fluvastatin-exposed subjects at our institution (n
= 2), we were unfortunately not able to analyze the effect of exposure to the most potent in vitro
A plausible explanation for the discrepancy between our in vivo
and others’ in vitro
results may rest with the pharmacokinetic properties of statins. There is a significant first pass effect for all statins with the exception of pravastatin[18
]. Intrahepatic concentrations of statins with routine use, however, have not been to our knowledge well documented in the literature. Serum levels of such agents after prolonged therapy are significantly lower than the statin concentrations that were used in replicon systems. For example, the maximal serum concentration of fluvastatin dosed at 40 mg daily is approximately 0.589 μmol/L[19
], approximately 10-fold lower than effective statin concentrations for inducing viral inhibition in the replicon systems[10-12
Additionally, replicon-bearing cell lines are highly adapted and behave quite differently from in vivo
hepatocytes. For instance, Huh7 cells exposed to interferons are exquisitely responsive to the agent regardless of viral genotype[20
]. This is in direct contrast to the disparate rates of sustained virologic response observed clinically with interferon therapy. It is possible that the adaptations that confer interferon sensitivity also confer statin sensitivity, explaining the in vitro
results. Alternatively, the specific dependence on prenylation of nonstructural proteins for establishment of the viral replication complex might be a feature of cell-culture models for which alternative pathways may be present in vivo
. The HCV might also develop resistance mutations under selection pressure induced by statin therapy, an effect that could be demonstrated via
sampling at regular intervals early after initial statin exposure for early viral load changes and sequence evolution. Lastly, pro-viral effects of statins might occur via
induction of LDL-receptor expression which may paradoxically facilitate viral uptake into uninfected hepatocytes[21
Another possible explanation for the lack of difference between our study groups could be the presence of a significant confounding variable. For example, obesity, which is associated with non-response to interferon-based antiviral therapy[22
], and hypercholesterolemia, were significantly more prevalent in Groups A and B than C. We, however, did not find within any of the groups an association of HCV RNA titers with height, weight or body-mass index (data not shown) nor with total cholesterol; therefore we do not believe that differences in these variables could explain our negative findings. Since hypertriglyceridemia was directly associated with viral titer, the excess of hypertriglyceridemia cases in Group A could contribute to a type II error. However, when we controlled for triglycerides in the regression analysis, statin exposure remained insignificantly associated with HCV RNA titer.
While not powered for an analysis of non-statin lipid lowering medications and their effect on HCV viral load, our analysis unexpectedly identified a possible direct association of triglycerides and viremia and a suggestion that niacin may have antiviral properties in vivo
. Recent work with human serum[23
] and with primary hepatocytes[24
] suggests that HCV is co-secreted with VLDL, implicating triglyceride metabolism as an additional critical step in the viral lifecycle. Given these preliminary findings as well as a biologically plausible mechanism for the action of triglyceride lowering medications on HCV replication, these findings merit further investigation in a larger dataset and, if confirmed, in a prospective clinical trial.
There are several limitations of this analysis that we would like to acknowledge. First, the cross-sectional design inherently precludes determining causality and is inherently weaker than prospective evaluation. Further, given the limited number of subjects with measurements prior to and after the initiation of statin therapy, we cannot definitively rule out an association between statins and reduction in HCV viral replication. Secondly, the sample size remained relatively small after applying our exclusion criteria, raising the possibility of a type II error and specifically that of finding no association when one does indeed exist. Thirdly, there were no direct measurements of patient adherence with prescribed statin therapy, an important factor since poor adherence may make the medication in question appear to be less efficacious. Fourthly, the preferred statin agent on the formulary during the observation period was not the most highly active agent in vitro. Lastly, there is a small possibility that patients in Group B could have received a statin agent prescribed by a non-VA physician, which was not recorded in the VA electronic medical record. Since there is significant financial incentive for most veterans to obtain medications through the VA, we believe the impact of this factor is quite small.
In summary, in this single center, retrospective analysis, there was no evidence of an apparent effect of statins on HCV viral replication. Unexpectedly, we found that triglyceride lowering agents such as niacin may have HCV antiviral properties in vivo. Therefore, we suggest exploration of this result. Additionally, the potential antiviral efficacy of drugs such niacin in chronic hepatitis C as adjuncts to interferon-based therapies merit further investigation.