Cover Story

Understanding the Role of Statins in the DAA Era

Most cardiologists use statins with few concerns or reservations. They are safe and effective in their primary role of lowering lipids, and they have demonstrated the capacity to improve a cross-section of cardiovascular outcomes. Similarly, direct-acting antiviral drugs are used safely and to great effect without major drawbacks. So it may be unsurprising that the labels of most approved direct-acting antiviral therapies contain few warnings about using the classes of drugs together.

But there are warnings. Allen J. Taylor, MD, chief of cardiology at MedStar Heart & Vascular Institute, weighed in. “Statins are very safe drugs, first and foremost,” he said. “There are slight differences in how they are metabolized and how they change cholesterol, but, virtually across the board, they are highly safe, uniformly effective, without major problems. The only major problems with DAAs are idiosyncratic, such as the incidence of rhabdomyolysis.”

Most experts in the HCV community agree. However, the safety and efficacy of using these classes of drugs together is not the only issue for debate. One concerns whether statins are associated with liver damage. Another concerns whether statins alone have an antiviral effect in HCV. Historically, there has been a perception that statins cause liver damage, but many — including Taylor — believe that this is not the case. “Statins, in my view, are virtually innocuous when it comes to harming the liver,” he said. “There is no credible evidence of toxicity.”

The antiviral effect of statins is a slightly different story, according to Esperance A. Schaefer, MD, an instructor at Harvard Medical School. “At this point, given the lack of firm data to prescribe statins outside of currently recommended guidelines for hypercholesterolemia, there is not likely to be a dramatic shift in the use of statins in HCV patients,” she said.

Allen J. Taylor

Many clinicians outside of the HCV community, including cardiologists, know very little about DAA therapies, according to Taylor. “There is a gap in cardiologists’ understanding of the new hepatitis C drugs. More education is needed,” he said. “The perception is that they are expensive, complicated to use, and that the prescriptions are restricted.”

With this in mind, HCV Next explored the association between the drugs more thoroughly, since there may be knowledge gaps in the hepatology and gastroenterology communities surrounding statins as well.

Understanding Interactions

Schaefer broke down the association during an interview. “The hepatitis C virus depends on cholesterol to propagate itself,” she said. “Statins, or HMG co-A reductase inhibitors, were found in in vitro studies to have a potent anti-HCV effect. The mechanism of their viral inhibition involves depletion of metabolites of the mevalonate pathway of cholesterol biosynthesis, which HCV requires for replication. Statins that were shown to inhibit HCV in vitro included lovastatin, atorvastatin and simvastatin. However, when examined as therapies against HCV, there was only modest effect in humans at conventional clinically utilized doses.”

Schaefer said early results indicated that the effect of statins on pegylated interferon plus ribavirin showed promise. “In studies examining patients receiving [pegylated interferon plus ribavirin], those who were also receiving statins had higher rates of [sustained virologic response] than those who were not,” she said. “Whether there is any additional benefit from combining statins with current highly effective direct-acting antiviral therapies remains to be determined, but is unlikely.”

She cited findings from Atsukawa and colleagues indicating that fluvastatin failed to improve SVR rates when combined with telaprevir-based triple therapy.

“A separate consideration from the direct antiviral effect of statins is the more global metabolic perturbations seen in patients with HCV,” Schaefer said. “It has been well described that patients with HCV have lower circulating LDL levels following infection, and that the LDL level increases once the virus is cleared. However, despite this lower LDL level, patients with chronic HCV are not protected from cardiovascular events. Thus, statin therapy may be important for patients with chronic HCV outside of its antiviral impact.”

Delang and colleagues wrote that statins have demonstrated in vitro replication of HCV, but that the mechanism by which this occurs remains unexplained. They passaged hematoma cells carrying an HCV replicon into increasing concentrations of fluvastatin. The researchers were able to reproduce fluvastatin-resistant cells containing the replicon. These cells were more than eight times less susceptible to the statin than wild-type cells. Comparable growth efficiency was reported for the resistant replicon cells and wild-type cells, according to the findings. “The fluvastatin-resistant phenotype was not conferred by mutations in the viral genome but is caused by cellular changes,” the researchers wrote. “The resistant cell line had a markedly increased HMG-CoA reductase expression upon statin treatment. Furthermore, the expression of the efflux transporter P-gp was increased in fluvastatin-resistant replicon cells (determined by [quantitative real-time polymerase chain reaction] and flow cytometry). This increased expression resulted also in an increased functional transport activity as measured by the P-gp mediated efflux of calcein AM.”

Drug–Drug Interactions in the DAA Era

Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, Va., encouraged clinicians to look at the warning labels of DAA drugs to stay up to date on drug-drug interactions. As the new regimens are being developed, these drug-drug interactions have to be assessed. Several approved therapies, including sofosbuvir/ledipasvir (Harvoni, Gilead Sciences), ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak, AbbVie), daclatasvir (Daklinza, Bristol-Myers Squibb), elbasvir/grazoprevir (Zepatier, Merck), ombitasvir/paritaprevir and ritonavir (Technivie, AbbVie) and simeprevir (Olysio, Janssen), contain information about statins.

“Co-administration of Harvoni with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis,” according to the FDA label. “Co-administration of Harvoni with rosuvastatin is not recommended.” However, the drug has shown no clinically significant drug interactions with pravastatin, according to the label.

Prashant K. Pandya

The potential for myopathy, including rhabdomyolysis, is also associated with Viekira Pak when used with lovastatin and simvastatin, according to the FDA. “When Viekira Pak is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day,” according to the label. “When Viekira Pak is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.”

Prashant K. Pandya, DO, associate professor of medicine in the division of gastroenterology and hepatology at the Kansas University School of Medicine and director of hepatology at the Kansas City VA Medical Center, put these findings in perspective. “The compounds of Viekira Pak are either metabolized by or inhibit CYP3A and CYP2(C,D) and are transported by P-gp and also inhibit OATP1B (1 and 3),” he said. “With co-administration, pravastatin Cmax was increased 37%, [area under the curve] was increased 82% and the pharmacokinetics of the 3D regimen were unchanged. The pravastatin dose should be reduced by 50% (maximum dose of 40 mg daily) with the 3D regimen. When rosuvastatin was co-administered with the 3D regimen, rosuvastatin Cmax increased sevenfold and AUC increased 2.6-fold, while paritaprevir Cmax increased 59% and AUC increased 52% and dasabuvir and ombitasvir pharmacokinetics were unchanged.”

For daclatasvir, the FDA noted that atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin use should be monitored for HMG-CoA reductase inhibitor-associated adverse events such as myopathy. Daclatasvir also demonstrated inhibitory effects on rosuvastatin (an OATP1B1, OATP1B3, and BCRP substrate) in drug-drug interaction trials, according to the label.

“Daclatasvir is metabolized by CYP3A4, is transported by P-gp and inhibits OATP1B1,” Pandya said. “Use this combination with caution.”

The grazoprevir/elbasvir label notes that co-administration of elbasvir and grazoprevir with atorvastatin increases the concentrations of atorvastatin. “The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with Zepatier,” according to the label. “Co-administration of elbasvir and grazoprevir with rosuvastatin increases the concentrations of rosuvastatin. The dose of rosuvastatin should not exceed a daily dose of 10 mg when co-administered with Zepatier.”

The FDA also wrote that co-administration of elbasvir/grazoprevir with fluvastatin, lovastatin and simvastatin has not been studied but may increase the concentrations. Myopathy should be monitored, and the lowest necessary dose should be used when these statins are co-administered with elbasvir/grazoprevir, according to the label. It is also written that no dose adjustments are required when elbasvir/grazoprevir is co-administered with pitavastatin or pravastatin.

“Zepatier is metabolized by CYP3A4 and inhibits CYP3A4 and CYP2C8,” Pandya said. “They are transported by P-gp and OATP1B1 and inhibit BCRP.”

For ombitasvir/paritaprevir and ritonavir , when that drug is co-administered with pravastatin, the statin dose should not be higher than 40 mg per day, according to the label. Rosuvastatin has shown no interaction with ombitasvir/paritaprevir and ritonavir. However, the FDA warns that ombitasvir/paritaprevir and ritonavir should not be taken by patients treated with lovastatin or simvastatin due to possible myopathy, including rhabdomyolysis, risk.

The simeprevir label is the most comprehensive in terms of information about statins. “Concomitant use of Olysio with rosuvastatin resulted in increased plasma concentrations of rosuvastatin due to inhibition of OATP1B1 by simeprevir,” the FDA wrote. “Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co-administered with Olysio.”

Concomitant use of simeprevir and both atorvastatin and simvastatin yielded increased plasma concentrations of the statin from inhibition of OATP1B1 and/or CYP3A4 by simeprevir, according to the FDA. The lowest necessary dose of atorvastatin is recommended. The daily dose of atorvastatin should not exceed 40 mg when used with simeprevir. For simvastatin, careful titration is recommended, and the lowest necessary dose should also be used.

Zobair M. Younossi

Researchers have yet to study pitava-statin, pravastatin or lovastatin with simeprevir, according to the label. “The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co-administered with Olysio,” the FDA wrote in the label.

No clinically relevant drug-drug interaction is likely to occur between simeprevir and fluvastatin, according to the label.

“Simeprevir is an inhibitor of CYP3A, OATP1B1/3 and P-gp,” Pandya said. “Simvastatin doses should be kept lowest as needed. No data are noted with pitava-statin, lovastatin or simvastatin and doses should also be kept as low as possible.”

“There are a number of important drug-drug interactions between statins and DAAs,” Schaefer said. “Both Daklinza and Harvoni have been shown to increase serum levels of rosuvastatin, and co-administration of these medications should be avoided. Levels of rosuvastatin and pravastatin are both increased with administration of Viekira Pak. Olysio has interactions with a number of statins, including rosuvastatin, atorvastatin, simvastatin, and possibly pitavastatin, pravastatin and lovastatin. Similar drug-drug interactions have been described with the newly approved Zepatier.

Younossi said there are some adverse effects with drugs like sofosbuvir and ledispasvir/sofosbuvir, and underscored some of the concerns in the labels that Schaefer addressed. “But these are not really a problem,” he said. “There were some concerns with the first generation of DAA therapies, but in the second generation, there is very little to be concerned about. Nevertheless, the interaction may depend on the regimen. Just be sure to look at the label and check for the specific statin you’re using with the HCV drug.”

Pandya tells a slightly different story. “The complexity ... should raise extreme caution when considering co-administration of statins with HCV antivirals,” he said. “Whether this activity is clinically significant in special populations needs to be addressed in well-conceived prospective clinical trials.”

Younossi summed up the findings on these labels. “Statins, generally speaking, are pretty safe,” he said. “Millions of individuals use them every day. They show strong cardiovascular effects but also some positive impact on liver disease.”

Associations with Cirrhosis

Mohanty and colleagues conducted a retrospective cohort study of VA data to determine whether long-term statin use would have a beneficial or detrimental effect on cirrhotics. Patients with compensated cirrhosis from January 1996 to December 2009 were included in the analysis. Data for 40,512 patients with HCV compensated cirrhosis were reviewed. The researchers identified 2,802 statin users. They developed a propensity score associated with statin prescription and paired new statin users with as many as five individuals who did not use statins for an analysis composed of 685 statin users and 2,062 nonusers. Decompensation was lower among statin users compared with nonusers (HR = 0.55; 95% CI, 0.39-0.77). Mortality was also lower in the statin group (HR = 0.56; 95% CI, 0.46-0.69). Both of these findings persisted when the researchers adjusted for age, Fibrosis-4 index (FIB-4) score, serum level of albumin, MELD and Child-Turcotte-Pugh scores (HR for decompensation = 0.55; 95% CI, 0.39-0.78) and mortality (HR = 0.55; 95% CI, 0.45-0.68).

“Based on data from the Veteran Affairs Clinical Case Registry, statin use among patients with HCV and compensated cirrhosis is associated with a more than 40% lower risk of cirrhosis decompensation and death,” the researchers concluded. “Although statins cannot yet be recommended widely for these patients, their use should not be avoided.”

“Compelling evidence is emerging that statins protect against cirrhosis,” Schaefer said, and added that there is an emerging body of evidence to support this claim. “However, in these studies, it is challenging to tease out how much of the protection was related to statin-dependent viral suppression vs. direct antifibrotic effect of the drugs. Additionally, these studies are limited by their cohort and retrospective design, and thus it would be challenging at this point to routinely recommend statin therapy as an antifibrotic in HCV.”

Pandya said these findings appear to support the safety of statins in chronic liver disease. “While these studies suggest a protective impact of statins for HCV-related liver complications, prospective trials are needed to assess whether all statins confer the protection, determine optimal dosing and timing of initiation of therapy, as well as information regarding duration of therapy with attention to safety,” he said.

Data from Yang and colleagues indicate that despite prior evidence demonstrating that statins can prevent the progression of fibrosis in patients with HCV advanced fibrosis, there are few data on patients who have not yet progressed to cirrhosis. They conducted a population-based cohort study that included 226,856 patients with HCV culled from the Taiwan National Health Insurance Research Database. Patients were followed from 1997 to 2010. During a follow-up period of 2,874,031.7 person-years, they identified 34,273 cases of cirrhosis, which amounted to an incidence rate of 445.5 cases of cirrhosis per 100,000 person-years (95% CI, 423.3-465.7) for statin users, which the researchers defined as patients treated with more than 28 cumulative defined daily doses. For nonstatin users, the cirrhosis rate was 1,311.2 cases per 100,000 person-years (95% CI, 1,297.1-1,325.6). Further evidence showed a dose–response relationship between statin use and cirrhosis risk. For patients who used statins from 28 to 83 cumulative defined daily doses, the adjusted HR for cirrhosis risk was 0.33 (95% CI, 0.31-0.36) compared with nonstatin use. The HR for cirrhosis risk was 0.24 (95% CI, 0.22-0.25) for 84 to 365 cumulative defined daily doses and 0.13 (95% CI, 0.12-0.15) for more than 365 doses compared with no statin use.

“Among the patients with HCV infection, statin use was associated with a reduced risk of cirrhosis development in a dose-dependent manner,” the researchers concluded.

“I don’t think statins cause cirrhosis of the liver at all,” Younossi said. “Statins can have two kinds of toxicity: in the liver and in muscle. In liver toxicity, liver enzymes may become elevated, but typically will not result in adverse long-term outcomes. If you look at the literature, although the rate of elevated liver enzymes [alanine aminotransferase and aspartate aminotransferase] may be frequent, the possibility of severe liver damage is extremely small, so the benefit far outweighs the risk.”

Younossi suggested clinicians closely monitor liver enzymes in this patient group. “This side effect is not going to result in cirrhosis,” he said. “The side effects are likely to just show up as elevated enzymes. In that case, I would recommend that you just change to another statin.”

Having said that, there is still a belief in the clinical community that statins are associated with increased liver disease. Younossi addressed this issue. “A lot of patients who are taking statins probably have underlying [nonalcoholic steatohepatitis] or [nonalcoholic fatty liver disease]. In this context, their risk is for cirrhosis is nonalcoholic steatohepatitis rather than statins,” he said. “These are confounding diseases associated with statin use which can lead to cirrhosis.”

He added that NASH and NAFLD may continue to confound results even after successful treatment of other liver diseases such as HCV. “Even if you cure a patient’s HCV, about 20% or 25% of those patients will have NASH or NAFLD,” he said. “You can get rid of the virus and they still have fatty liver disease, so if you have fatty liver and HCV, it could accelerate both diseases. Curing the HCV will potentially reduce the risk for cirrhosis but will not completely eliminate it because you still have another disease (non-alcoholic fatty liver disease). In that context, it is better to clear the virus, but they will still have the NASH or NAFLD that needs to be managed, and so the cirrhosis risk will persist.”

Treatment Outcomes Impact

Butt and colleagues explored variability in the data regarding the effect of statins on HCV treatment response, fibrosis progression and HCC incidence. They suggested that some statins have a more pronounced impact than others. They aimed to evaluate some of these outcomes using longitudinal data from the Electronically Retrieved Cohort of HCV Infected Veterans. Patients who were treated for HCV with at least 24 weeks of follow-up data were included, whereas those with HIV, hepatitis B surface antigen positivity, cirrhosis and HCC were excluded. Fibrosis as assessed by FIB-4 score served as the primary outcome measure, along with SVR and incidence of HCC. The study included 7,248 patients, of whom 46% had been treated with a statin. A significant association was reported between statin use and SVR (39.2% vs. 33.3%; P < .01). Statins also were associated with a decrease in the development of cirrhosis (17.3% vs. 25.2%; P < .001) and incident HCC (1.2% vs. 2.6%; P < .01). Multivariate analysis results showed that the significant association between statins and increased odds of SVR persisted (OR = 1.44; 95% CI, 1.29-1.61). In addition, statins yielded a lower risk for progression to cirrhosis (HR = 0.56; 95% CI, –0.5 to 0.63) and incident HCC (HR = 0.51; 95% CI, 0.34-0.76) in this analysis.

“Additional data on the potential benefit of statin treatment following viral clearance would be of great interest,” Schaefer said.

Esperance A. Schaefer

Pandya and colleagues investigated the impact of statin use on SVR in a cohort of 37,611 VA patients with genotypes 1 to 3 disease. The study was conducted in patients treated between 2001 and 2011 with pegylated interferon plus ribavirin.

“The intricate relationship between the HCV replication cycle and host lipid metabolism encompasses a wide range of interactions ranging from viral entry to virion export,” Pandya said in an interview. “We also know that the histopathologic demonstration of hepatic steatosis is genotype dependent. Therefore, we set out to evaluate whether perturbations of lipid metabolism by commonly prescribed antihyperlipidemic agents, statins, demonstrated variable impact when used as adjunctive therapy in different genotypes.”

The final analysis included 236 patients with genotype 1 disease, 78 with genotype 2, and 3 with genotype 3. Outcome measures included SVR in statin users and non-users along with changes in serum ALT. For patients with genotype 1 disease, the SVR rate was 26.3% for statin users and 19.5% for non-users (P < .01; OR = 1.49; 95% CI, 1.06-2.08). Statins failed to have a significant impact on SVR in patients with genotypes 2 or 3 disease. There was a positive association between higher baseline LDL and SVR. Other findings indicated that statins reduced ALT in genotype 1 patients. “In view of additional benefits of statins, and the prohibitive cost of newer HCV therapies, statins could be a potential assist for hard-to-treat [genotype 1] patients, especially in resource-poor settings,” the researchers concluded.

“Although the exact mechanism by which statins inhibit viral replication is not clear, several authors have suggested that inhibition of mevalonate synthesis results in reduction of downstream prenyl precursors such as geranylgeranyl pyrophosphatase, which are required for optimal HCV replication,” Pandya said. “The resultant decrease in efficiency of HCV replication can enhance the antiviral activity of HCV- directed therapy. This modest increase in antiviral response is easier to demonstrate in populations that are less responsive to antiviral therapy — such as those with genotype 1 infection — but would require a large number of enrolled patients among populations that are much more responsive to similar antiviral therapy — such as those with genotype 2 and 3 infection.”

“Our results reveal that statin therapy modestly improved antiviral response when used as adjunctive therapy with pegylated interferon and ribavirin in genotype 1 infection but had no significant impact on similar response to genotype 2 and 3 infection,” he said.

For Younossi, there is still much research to be done in terms of studying statins with newer DAA therapies. “There is some theoretical interaction between the virus itself and lipids,” he said. “The virus can theoretically use the lipid particles to get access to liver cells. So, theoretically, if you have hyperlipidemia, you may actually get rid of that reservoir. But I haven’t seen a great deal of evidence to support that as yet.”

Moreover, it may be nearly impossible to demonstrate that effect, given that many DAAs show SVR rates above 95%, according to Younossi. “I don’t know how you can improve on that,” he said.

Cardiologist’s Perspective

Taylor admitted that he was not incredibly familiar with what is happening in HCV before reviewing relevant data for the interview with HCV Next. “The medical public in general should know that statins may be useful in the treatment of HCV in terms of viral replication, reduction in cirrhosis and augmenting standard viral drugs,” he said. “These are really exciting developments.”

Generally speaking, cardiologists do not spend much time reading literature outside of their speciality, according to Taylor. “You can find these data sets in gastroenterology and hepatology journals, but it hasn’t made it into the mainstream or cardiology journals,” he said. “Most cardiologists, if you gave them the option of statin or no statin in combination with HCV drugs, they wouldn’t even blink. They would say, ‘no statins.’ But that is no longer true. Given how common HCV is, and how these patients are seen so frequently not just by hepatologists and gastroenterologists but by internists and cardiologists, we are missing opportunities.”

Taylor said that what is commonly thought among most non-HCV specialists is that statins and liver disease do not mix. “This is a complete myth,” he said. “Dispelling the myth that statins are dangerous for the liver is really important. [They are] not only not harmful, but also useful in the liver.”

“If there are important drug interactions with statins and these new drugs, the orientation to that is really important so that cardiologists can begin to understand what’s out there,” he added.

Younossi offered the hepatology perspective on statins. “The general view of statins by hepatologists is very favorable, that they are safe,” he said. “Once their HCV is cured, it may be necessary to treat patients with statins. It is helpful to know that we may easily monitor these patients for toxicity.”

Statins and Mortality

Younoszai and colleagues investigated whether statins were associated with liver failure and mortality in a cohort of more than 20,000 patients culled from the NHANES III database between 1988 and 1994. After excluding individuals who were HCV RNA-positive or HBsAg-positive, had NAFLD by hepatic ultrasound, or had iron overload or excessive alcohol use of greater than 20 g of alcohol per day with elevated liver enzymes, they ended up with a cohort of 9,207 individuals. The group was about three-quarters men, with an average BMI of 26.39 ± 0.38. About 17% had diabetes or insulin resistance, 17% had hypertension and 65% had dyslipidemia. Ninety patients were being treated with statins at the time of the interview. The mortality rate among patients treated with statins was 40.15% (37 deaths) after a median follow-up duration of 143.35 months. Multivariate analysis results indicated that statin use carried no association with CV death in men (HR = 0.79; 95% CI, 0.3-2.13). However, statins did increase mortality in women (OR = 2.32; 95% CI, 1.58-3.4). Statin users experienced significantly lower liver-related mortality rates than nonusers (P = .0035). “After a decade of follow-up, there was no association between statin use and liver-related mortality,” the researchers concluded.

“There are data to suggest that statins may protect against both cirrhosis and hepatocellular carcinoma,” Schaefer said.

Despite some of his reservations, and despite the lack of evidence, Pandya ultimately acknowledged that statins can be used with DAA therapies. “Clinicians should not withhold statin therapy among patients with HCV-related chronic liver disease who need statin therapy for cardiovascular protection,” he said. “This needs particular attention based on the evidence that suggests that HCV-infected individuals are at a higher risk for coronary artery disease and that LDL levels have been shown to increase after SVR as viral replication is no longer present and thus, the host lipid metabolism is no longer co-opted by the virus.”

For Taylor, the issue is much simpler. “Just the notion that there is no longer a dispute that statins are safe with these drugs is big,” he said. When asked whether the clinical community should stop there, satisfied with this positive association, he raised the stakes. “If there is the possibility that statins can have antiviral activity in HCV, we should explore it. We shouldn’t just settle. We should be greedy.” – by Rob Volansky

Disclosures: Pandya and Schaefer report no relevant financial disclosures. Taylor reports financial relationships with Amgen, Lily and Sanofi. Younossi reports financial relationships with AbbVie, Bristol-Myers Squibb, Conatus, Gilead Sciences, Intercept, Janssen Therapeutics, Merck and Salix.

Most cardiologists use statins with few concerns or reservations. They are safe and effective in their primary role of lowering lipids, and they have demonstrated the capacity to improve a cross-section of cardiovascular outcomes. Similarly, direct-acting antiviral drugs are used safely and to great effect without major drawbacks. So it may be unsurprising that the labels of most approved direct-acting antiviral therapies contain few warnings about using the classes of drugs together.

But there are warnings. Allen J. Taylor, MD, chief of cardiology at MedStar Heart & Vascular Institute, weighed in. “Statins are very safe drugs, first and foremost,” he said. “There are slight differences in how they are metabolized and how they change cholesterol, but, virtually across the board, they are highly safe, uniformly effective, without major problems. The only major problems with DAAs are idiosyncratic, such as the incidence of rhabdomyolysis.”

Most experts in the HCV community agree. However, the safety and efficacy of using these classes of drugs together is not the only issue for debate. One concerns whether statins are associated with liver damage. Another concerns whether statins alone have an antiviral effect in HCV. Historically, there has been a perception that statins cause liver damage, but many — including Taylor — believe that this is not the case. “Statins, in my view, are virtually innocuous when it comes to harming the liver,” he said. “There is no credible evidence of toxicity.”

The antiviral effect of statins is a slightly different story, according to Esperance A. Schaefer, MD, an instructor at Harvard Medical School. “At this point, given the lack of firm data to prescribe statins outside of currently recommended guidelines for hypercholesterolemia, there is not likely to be a dramatic shift in the use of statins in HCV patients,” she said.

Allen J. Taylor

Many clinicians outside of the HCV community, including cardiologists, know very little about DAA therapies, according to Taylor. “There is a gap in cardiologists’ understanding of the new hepatitis C drugs. More education is needed,” he said. “The perception is that they are expensive, complicated to use, and that the prescriptions are restricted.”

With this in mind, HCV Next explored the association between the drugs more thoroughly, since there may be knowledge gaps in the hepatology and gastroenterology communities surrounding statins as well.

Understanding Interactions

Schaefer broke down the association during an interview. “The hepatitis C virus depends on cholesterol to propagate itself,” she said. “Statins, or HMG co-A reductase inhibitors, were found in in vitro studies to have a potent anti-HCV effect. The mechanism of their viral inhibition involves depletion of metabolites of the mevalonate pathway of cholesterol biosynthesis, which HCV requires for replication. Statins that were shown to inhibit HCV in vitro included lovastatin, atorvastatin and simvastatin. However, when examined as therapies against HCV, there was only modest effect in humans at conventional clinically utilized doses.”

Schaefer said early results indicated that the effect of statins on pegylated interferon plus ribavirin showed promise. “In studies examining patients receiving [pegylated interferon plus ribavirin], those who were also receiving statins had higher rates of [sustained virologic response] than those who were not,” she said. “Whether there is any additional benefit from combining statins with current highly effective direct-acting antiviral therapies remains to be determined, but is unlikely.”

She cited findings from Atsukawa and colleagues indicating that fluvastatin failed to improve SVR rates when combined with telaprevir-based triple therapy.

“A separate consideration from the direct antiviral effect of statins is the more global metabolic perturbations seen in patients with HCV,” Schaefer said. “It has been well described that patients with HCV have lower circulating LDL levels following infection, and that the LDL level increases once the virus is cleared. However, despite this lower LDL level, patients with chronic HCV are not protected from cardiovascular events. Thus, statin therapy may be important for patients with chronic HCV outside of its antiviral impact.”

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Delang and colleagues wrote that statins have demonstrated in vitro replication of HCV, but that the mechanism by which this occurs remains unexplained. They passaged hematoma cells carrying an HCV replicon into increasing concentrations of fluvastatin. The researchers were able to reproduce fluvastatin-resistant cells containing the replicon. These cells were more than eight times less susceptible to the statin than wild-type cells. Comparable growth efficiency was reported for the resistant replicon cells and wild-type cells, according to the findings. “The fluvastatin-resistant phenotype was not conferred by mutations in the viral genome but is caused by cellular changes,” the researchers wrote. “The resistant cell line had a markedly increased HMG-CoA reductase expression upon statin treatment. Furthermore, the expression of the efflux transporter P-gp was increased in fluvastatin-resistant replicon cells (determined by [quantitative real-time polymerase chain reaction] and flow cytometry). This increased expression resulted also in an increased functional transport activity as measured by the P-gp mediated efflux of calcein AM.”

Drug–Drug Interactions in the DAA Era

Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, Va., encouraged clinicians to look at the warning labels of DAA drugs to stay up to date on drug-drug interactions. As the new regimens are being developed, these drug-drug interactions have to be assessed. Several approved therapies, including sofosbuvir/ledipasvir (Harvoni, Gilead Sciences), ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak, AbbVie), daclatasvir (Daklinza, Bristol-Myers Squibb), elbasvir/grazoprevir (Zepatier, Merck), ombitasvir/paritaprevir and ritonavir (Technivie, AbbVie) and simeprevir (Olysio, Janssen), contain information about statins.

“Co-administration of Harvoni with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis,” according to the FDA label. “Co-administration of Harvoni with rosuvastatin is not recommended.” However, the drug has shown no clinically significant drug interactions with pravastatin, according to the label.

Prashant K. Pandya

The potential for myopathy, including rhabdomyolysis, is also associated with Viekira Pak when used with lovastatin and simvastatin, according to the FDA. “When Viekira Pak is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day,” according to the label. “When Viekira Pak is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.”

Prashant K. Pandya, DO, associate professor of medicine in the division of gastroenterology and hepatology at the Kansas University School of Medicine and director of hepatology at the Kansas City VA Medical Center, put these findings in perspective. “The compounds of Viekira Pak are either metabolized by or inhibit CYP3A and CYP2(C,D) and are transported by P-gp and also inhibit OATP1B (1 and 3),” he said. “With co-administration, pravastatin Cmax was increased 37%, [area under the curve] was increased 82% and the pharmacokinetics of the 3D regimen were unchanged. The pravastatin dose should be reduced by 50% (maximum dose of 40 mg daily) with the 3D regimen. When rosuvastatin was co-administered with the 3D regimen, rosuvastatin Cmax increased sevenfold and AUC increased 2.6-fold, while paritaprevir Cmax increased 59% and AUC increased 52% and dasabuvir and ombitasvir pharmacokinetics were unchanged.”

For daclatasvir, the FDA noted that atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin use should be monitored for HMG-CoA reductase inhibitor-associated adverse events such as myopathy. Daclatasvir also demonstrated inhibitory effects on rosuvastatin (an OATP1B1, OATP1B3, and BCRP substrate) in drug-drug interaction trials, according to the label.

“Daclatasvir is metabolized by CYP3A4, is transported by P-gp and inhibits OATP1B1,” Pandya said. “Use this combination with caution.”

The grazoprevir/elbasvir label notes that co-administration of elbasvir and grazoprevir with atorvastatin increases the concentrations of atorvastatin. “The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with Zepatier,” according to the label. “Co-administration of elbasvir and grazoprevir with rosuvastatin increases the concentrations of rosuvastatin. The dose of rosuvastatin should not exceed a daily dose of 10 mg when co-administered with Zepatier.”

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The FDA also wrote that co-administration of elbasvir/grazoprevir with fluvastatin, lovastatin and simvastatin has not been studied but may increase the concentrations. Myopathy should be monitored, and the lowest necessary dose should be used when these statins are co-administered with elbasvir/grazoprevir, according to the label. It is also written that no dose adjustments are required when elbasvir/grazoprevir is co-administered with pitavastatin or pravastatin.

“Zepatier is metabolized by CYP3A4 and inhibits CYP3A4 and CYP2C8,” Pandya said. “They are transported by P-gp and OATP1B1 and inhibit BCRP.”

For ombitasvir/paritaprevir and ritonavir , when that drug is co-administered with pravastatin, the statin dose should not be higher than 40 mg per day, according to the label. Rosuvastatin has shown no interaction with ombitasvir/paritaprevir and ritonavir. However, the FDA warns that ombitasvir/paritaprevir and ritonavir should not be taken by patients treated with lovastatin or simvastatin due to possible myopathy, including rhabdomyolysis, risk.

The simeprevir label is the most comprehensive in terms of information about statins. “Concomitant use of Olysio with rosuvastatin resulted in increased plasma concentrations of rosuvastatin due to inhibition of OATP1B1 by simeprevir,” the FDA wrote. “Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co-administered with Olysio.”

Concomitant use of simeprevir and both atorvastatin and simvastatin yielded increased plasma concentrations of the statin from inhibition of OATP1B1 and/or CYP3A4 by simeprevir, according to the FDA. The lowest necessary dose of atorvastatin is recommended. The daily dose of atorvastatin should not exceed 40 mg when used with simeprevir. For simvastatin, careful titration is recommended, and the lowest necessary dose should also be used.

Zobair M. Younossi

Researchers have yet to study pitava-statin, pravastatin or lovastatin with simeprevir, according to the label. “The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co-administered with Olysio,” the FDA wrote in the label.

No clinically relevant drug-drug interaction is likely to occur between simeprevir and fluvastatin, according to the label.

“Simeprevir is an inhibitor of CYP3A, OATP1B1/3 and P-gp,” Pandya said. “Simvastatin doses should be kept lowest as needed. No data are noted with pitava-statin, lovastatin or simvastatin and doses should also be kept as low as possible.”

“There are a number of important drug-drug interactions between statins and DAAs,” Schaefer said. “Both Daklinza and Harvoni have been shown to increase serum levels of rosuvastatin, and co-administration of these medications should be avoided. Levels of rosuvastatin and pravastatin are both increased with administration of Viekira Pak. Olysio has interactions with a number of statins, including rosuvastatin, atorvastatin, simvastatin, and possibly pitavastatin, pravastatin and lovastatin. Similar drug-drug interactions have been described with the newly approved Zepatier.

Younossi said there are some adverse effects with drugs like sofosbuvir and ledispasvir/sofosbuvir, and underscored some of the concerns in the labels that Schaefer addressed. “But these are not really a problem,” he said. “There were some concerns with the first generation of DAA therapies, but in the second generation, there is very little to be concerned about. Nevertheless, the interaction may depend on the regimen. Just be sure to look at the label and check for the specific statin you’re using with the HCV drug.”

Pandya tells a slightly different story. “The complexity ... should raise extreme caution when considering co-administration of statins with HCV antivirals,” he said. “Whether this activity is clinically significant in special populations needs to be addressed in well-conceived prospective clinical trials.”

Younossi summed up the findings on these labels. “Statins, generally speaking, are pretty safe,” he said. “Millions of individuals use them every day. They show strong cardiovascular effects but also some positive impact on liver disease.”

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Associations with Cirrhosis

Mohanty and colleagues conducted a retrospective cohort study of VA data to determine whether long-term statin use would have a beneficial or detrimental effect on cirrhotics. Patients with compensated cirrhosis from January 1996 to December 2009 were included in the analysis. Data for 40,512 patients with HCV compensated cirrhosis were reviewed. The researchers identified 2,802 statin users. They developed a propensity score associated with statin prescription and paired new statin users with as many as five individuals who did not use statins for an analysis composed of 685 statin users and 2,062 nonusers. Decompensation was lower among statin users compared with nonusers (HR = 0.55; 95% CI, 0.39-0.77). Mortality was also lower in the statin group (HR = 0.56; 95% CI, 0.46-0.69). Both of these findings persisted when the researchers adjusted for age, Fibrosis-4 index (FIB-4) score, serum level of albumin, MELD and Child-Turcotte-Pugh scores (HR for decompensation = 0.55; 95% CI, 0.39-0.78) and mortality (HR = 0.55; 95% CI, 0.45-0.68).

“Based on data from the Veteran Affairs Clinical Case Registry, statin use among patients with HCV and compensated cirrhosis is associated with a more than 40% lower risk of cirrhosis decompensation and death,” the researchers concluded. “Although statins cannot yet be recommended widely for these patients, their use should not be avoided.”

“Compelling evidence is emerging that statins protect against cirrhosis,” Schaefer said, and added that there is an emerging body of evidence to support this claim. “However, in these studies, it is challenging to tease out how much of the protection was related to statin-dependent viral suppression vs. direct antifibrotic effect of the drugs. Additionally, these studies are limited by their cohort and retrospective design, and thus it would be challenging at this point to routinely recommend statin therapy as an antifibrotic in HCV.”

Pandya said these findings appear to support the safety of statins in chronic liver disease. “While these studies suggest a protective impact of statins for HCV-related liver complications, prospective trials are needed to assess whether all statins confer the protection, determine optimal dosing and timing of initiation of therapy, as well as information regarding duration of therapy with attention to safety,” he said.

Data from Yang and colleagues indicate that despite prior evidence demonstrating that statins can prevent the progression of fibrosis in patients with HCV advanced fibrosis, there are few data on patients who have not yet progressed to cirrhosis. They conducted a population-based cohort study that included 226,856 patients with HCV culled from the Taiwan National Health Insurance Research Database. Patients were followed from 1997 to 2010. During a follow-up period of 2,874,031.7 person-years, they identified 34,273 cases of cirrhosis, which amounted to an incidence rate of 445.5 cases of cirrhosis per 100,000 person-years (95% CI, 423.3-465.7) for statin users, which the researchers defined as patients treated with more than 28 cumulative defined daily doses. For nonstatin users, the cirrhosis rate was 1,311.2 cases per 100,000 person-years (95% CI, 1,297.1-1,325.6). Further evidence showed a dose–response relationship between statin use and cirrhosis risk. For patients who used statins from 28 to 83 cumulative defined daily doses, the adjusted HR for cirrhosis risk was 0.33 (95% CI, 0.31-0.36) compared with nonstatin use. The HR for cirrhosis risk was 0.24 (95% CI, 0.22-0.25) for 84 to 365 cumulative defined daily doses and 0.13 (95% CI, 0.12-0.15) for more than 365 doses compared with no statin use.

“Among the patients with HCV infection, statin use was associated with a reduced risk of cirrhosis development in a dose-dependent manner,” the researchers concluded.

“I don’t think statins cause cirrhosis of the liver at all,” Younossi said. “Statins can have two kinds of toxicity: in the liver and in muscle. In liver toxicity, liver enzymes may become elevated, but typically will not result in adverse long-term outcomes. If you look at the literature, although the rate of elevated liver enzymes [alanine aminotransferase and aspartate aminotransferase] may be frequent, the possibility of severe liver damage is extremely small, so the benefit far outweighs the risk.”

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Younossi suggested clinicians closely monitor liver enzymes in this patient group. “This side effect is not going to result in cirrhosis,” he said. “The side effects are likely to just show up as elevated enzymes. In that case, I would recommend that you just change to another statin.”

Having said that, there is still a belief in the clinical community that statins are associated with increased liver disease. Younossi addressed this issue. “A lot of patients who are taking statins probably have underlying [nonalcoholic steatohepatitis] or [nonalcoholic fatty liver disease]. In this context, their risk is for cirrhosis is nonalcoholic steatohepatitis rather than statins,” he said. “These are confounding diseases associated with statin use which can lead to cirrhosis.”

He added that NASH and NAFLD may continue to confound results even after successful treatment of other liver diseases such as HCV. “Even if you cure a patient’s HCV, about 20% or 25% of those patients will have NASH or NAFLD,” he said. “You can get rid of the virus and they still have fatty liver disease, so if you have fatty liver and HCV, it could accelerate both diseases. Curing the HCV will potentially reduce the risk for cirrhosis but will not completely eliminate it because you still have another disease (non-alcoholic fatty liver disease). In that context, it is better to clear the virus, but they will still have the NASH or NAFLD that needs to be managed, and so the cirrhosis risk will persist.”

Treatment Outcomes Impact

Butt and colleagues explored variability in the data regarding the effect of statins on HCV treatment response, fibrosis progression and HCC incidence. They suggested that some statins have a more pronounced impact than others. They aimed to evaluate some of these outcomes using longitudinal data from the Electronically Retrieved Cohort of HCV Infected Veterans. Patients who were treated for HCV with at least 24 weeks of follow-up data were included, whereas those with HIV, hepatitis B surface antigen positivity, cirrhosis and HCC were excluded. Fibrosis as assessed by FIB-4 score served as the primary outcome measure, along with SVR and incidence of HCC. The study included 7,248 patients, of whom 46% had been treated with a statin. A significant association was reported between statin use and SVR (39.2% vs. 33.3%; P < .01). Statins also were associated with a decrease in the development of cirrhosis (17.3% vs. 25.2%; P < .001) and incident HCC (1.2% vs. 2.6%; P < .01). Multivariate analysis results showed that the significant association between statins and increased odds of SVR persisted (OR = 1.44; 95% CI, 1.29-1.61). In addition, statins yielded a lower risk for progression to cirrhosis (HR = 0.56; 95% CI, –0.5 to 0.63) and incident HCC (HR = 0.51; 95% CI, 0.34-0.76) in this analysis.

“Additional data on the potential benefit of statin treatment following viral clearance would be of great interest,” Schaefer said.

Esperance A. Schaefer

Pandya and colleagues investigated the impact of statin use on SVR in a cohort of 37,611 VA patients with genotypes 1 to 3 disease. The study was conducted in patients treated between 2001 and 2011 with pegylated interferon plus ribavirin.

“The intricate relationship between the HCV replication cycle and host lipid metabolism encompasses a wide range of interactions ranging from viral entry to virion export,” Pandya said in an interview. “We also know that the histopathologic demonstration of hepatic steatosis is genotype dependent. Therefore, we set out to evaluate whether perturbations of lipid metabolism by commonly prescribed antihyperlipidemic agents, statins, demonstrated variable impact when used as adjunctive therapy in different genotypes.”

The final analysis included 236 patients with genotype 1 disease, 78 with genotype 2, and 3 with genotype 3. Outcome measures included SVR in statin users and non-users along with changes in serum ALT. For patients with genotype 1 disease, the SVR rate was 26.3% for statin users and 19.5% for non-users (P < .01; OR = 1.49; 95% CI, 1.06-2.08). Statins failed to have a significant impact on SVR in patients with genotypes 2 or 3 disease. There was a positive association between higher baseline LDL and SVR. Other findings indicated that statins reduced ALT in genotype 1 patients. “In view of additional benefits of statins, and the prohibitive cost of newer HCV therapies, statins could be a potential assist for hard-to-treat [genotype 1] patients, especially in resource-poor settings,” the researchers concluded.

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“Although the exact mechanism by which statins inhibit viral replication is not clear, several authors have suggested that inhibition of mevalonate synthesis results in reduction of downstream prenyl precursors such as geranylgeranyl pyrophosphatase, which are required for optimal HCV replication,” Pandya said. “The resultant decrease in efficiency of HCV replication can enhance the antiviral activity of HCV- directed therapy. This modest increase in antiviral response is easier to demonstrate in populations that are less responsive to antiviral therapy — such as those with genotype 1 infection — but would require a large number of enrolled patients among populations that are much more responsive to similar antiviral therapy — such as those with genotype 2 and 3 infection.”

“Our results reveal that statin therapy modestly improved antiviral response when used as adjunctive therapy with pegylated interferon and ribavirin in genotype 1 infection but had no significant impact on similar response to genotype 2 and 3 infection,” he said.

For Younossi, there is still much research to be done in terms of studying statins with newer DAA therapies. “There is some theoretical interaction between the virus itself and lipids,” he said. “The virus can theoretically use the lipid particles to get access to liver cells. So, theoretically, if you have hyperlipidemia, you may actually get rid of that reservoir. But I haven’t seen a great deal of evidence to support that as yet.”

Moreover, it may be nearly impossible to demonstrate that effect, given that many DAAs show SVR rates above 95%, according to Younossi. “I don’t know how you can improve on that,” he said.

Cardiologist’s Perspective

Taylor admitted that he was not incredibly familiar with what is happening in HCV before reviewing relevant data for the interview with HCV Next. “The medical public in general should know that statins may be useful in the treatment of HCV in terms of viral replication, reduction in cirrhosis and augmenting standard viral drugs,” he said. “These are really exciting developments.”

Generally speaking, cardiologists do not spend much time reading literature outside of their speciality, according to Taylor. “You can find these data sets in gastroenterology and hepatology journals, but it hasn’t made it into the mainstream or cardiology journals,” he said. “Most cardiologists, if you gave them the option of statin or no statin in combination with HCV drugs, they wouldn’t even blink. They would say, ‘no statins.’ But that is no longer true. Given how common HCV is, and how these patients are seen so frequently not just by hepatologists and gastroenterologists but by internists and cardiologists, we are missing opportunities.”

Taylor said that what is commonly thought among most non-HCV specialists is that statins and liver disease do not mix. “This is a complete myth,” he said. “Dispelling the myth that statins are dangerous for the liver is really important. [They are] not only not harmful, but also useful in the liver.”

“If there are important drug interactions with statins and these new drugs, the orientation to that is really important so that cardiologists can begin to understand what’s out there,” he added.

Younossi offered the hepatology perspective on statins. “The general view of statins by hepatologists is very favorable, that they are safe,” he said. “Once their HCV is cured, it may be necessary to treat patients with statins. It is helpful to know that we may easily monitor these patients for toxicity.”

Statins and Mortality

Younoszai and colleagues investigated whether statins were associated with liver failure and mortality in a cohort of more than 20,000 patients culled from the NHANES III database between 1988 and 1994. After excluding individuals who were HCV RNA-positive or HBsAg-positive, had NAFLD by hepatic ultrasound, or had iron overload or excessive alcohol use of greater than 20 g of alcohol per day with elevated liver enzymes, they ended up with a cohort of 9,207 individuals. The group was about three-quarters men, with an average BMI of 26.39 ± 0.38. About 17% had diabetes or insulin resistance, 17% had hypertension and 65% had dyslipidemia. Ninety patients were being treated with statins at the time of the interview. The mortality rate among patients treated with statins was 40.15% (37 deaths) after a median follow-up duration of 143.35 months. Multivariate analysis results indicated that statin use carried no association with CV death in men (HR = 0.79; 95% CI, 0.3-2.13). However, statins did increase mortality in women (OR = 2.32; 95% CI, 1.58-3.4). Statin users experienced significantly lower liver-related mortality rates than nonusers (P = .0035). “After a decade of follow-up, there was no association between statin use and liver-related mortality,” the researchers concluded.

“There are data to suggest that statins may protect against both cirrhosis and hepatocellular carcinoma,” Schaefer said.

Despite some of his reservations, and despite the lack of evidence, Pandya ultimately acknowledged that statins can be used with DAA therapies. “Clinicians should not withhold statin therapy among patients with HCV-related chronic liver disease who need statin therapy for cardiovascular protection,” he said. “This needs particular attention based on the evidence that suggests that HCV-infected individuals are at a higher risk for coronary artery disease and that LDL levels have been shown to increase after SVR as viral replication is no longer present and thus, the host lipid metabolism is no longer co-opted by the virus.”

For Taylor, the issue is much simpler. “Just the notion that there is no longer a dispute that statins are safe with these drugs is big,” he said. When asked whether the clinical community should stop there, satisfied with this positive association, he raised the stakes. “If there is the possibility that statins can have antiviral activity in HCV, we should explore it. We shouldn’t just settle. We should be greedy.” – by Rob Volansky

Disclosures: Pandya and Schaefer report no relevant financial disclosures. Taylor reports financial relationships with Amgen, Lily and Sanofi. Younossi reports financial relationships with AbbVie, Bristol-Myers Squibb, Conatus, Gilead Sciences, Intercept, Janssen Therapeutics, Merck and Salix.