use of statins in patients with hepatitis??? looks like a "yes"

one question that comes up a lot in patient care is whether it is safe to use statins in patients with ongoing hepatic inflammation. a new retrospective VA study of hepatitis C (HCV) patients found an actual  benefit for statins, as has been found in some other studies (see hep c statin hepatol2016​ in dropbox, or DOI 10.1002/hep.28506). details:

--from the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, they looked at subjects initiated on anti-HCV therapy from 2001 to 2014, as well as all incident cases of cirrhosis and hepatocellular carcinoma (HCC). those coinfected with HIV or hepatitis B were excluded, as well as those with baseline cirrhosis

--mean age 53, 65% white/18% black/6% Hispanic, 95% male, ALT 75, AST 53, FIB-4 score 1.7 (see below), median length of follow-up was 7-8 years. more statin users were diabetic (24% vs 9%), on metformin, other lipid-lowering agents, ACE-I, and they had a higher baseline LDL , triglycerides, and lower HDL). 90% were treated with PEG/RBV, 10% with PEG/RBV/telaprevir (ie, the old drugs)

--9135 eligible people, of whom 1,649 developed cirrhosis, and 239 developed incident HCC [cirrhosis was defined by a FIB-4 score of >3.5, where the FIB-4 score is a mathematical calculation based on age, AST, platelet count, ALT]

--results:

    --Statin use was associated with 

            --higher likelihood of sustained viral response (55.1% vs 47.5%, p<0.0001)

            --a 36% reduction in development of cirrhosis, adjusted HR: 0.64 (0.53-0.68), p<0.0001. 

            --lower fibrosis progression, with a dose-response curve revealing progressively decreasing risk

    --of the statins used, the highest decrease in FIB-4 score was with atorvastatin and fluvastatin (though only 34 patients were on fluvastatin): those without statin had FIB-4 increase of 0.26, those on simvastatin had increase of 0.11, but those on atorvastatin had decrease (-0.17), p=0.04, after adjustment for baseline FIB-4 score and established predictors of cirrhosis. 

    --Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed. [interestingly, the decrease in HCC was independent of changes in the FIB-4 score. though with hep C, the progression to HCC is tied in with presence of fibrosis].

so, does this make sense?

    --there are several mechanisms by which statins could decrease progression of liver fibrosis:

        ​--they have lots of "pleiotrophic" (non-lipid ) effects: anti-inflammatory, antiproliferative, anitangiogenic, pro-apoptotic, immunomodulatory. and there are data suggesting they can inhibit cell growth, decrease proteolysis, block tumor spread, and may be chemoprotective against such malignancies as HCC.

        ​--hepatitis C virus depends on cholesterol to replicate, so interference by statins might well help control hep C (statins do inhibit hep C in vitro; and people with hep C have lower LDL levels, which increase after the virus is cleared)

        --statins also decrease components of the metabolic syndrome, and there are several studies suggesting that the combination of hep C infection and metabolic syndrome, present in about 20-25% of people with hep C, leads to a higher incidence of HCC

        --humans studies (including another one from the above VA database: Butt AA. Hepatology 2015; 62: 365) have found decreased risk of hepatic fibrosis progression and development of cirrhosis by 43%; a Taiwanese study found that just using statins in patient with hep C infection found a reduced risk of cirrhosis in a dose-dependent fashion, also found in the HALT-C study. another VA study of patients with compensated cirrhosis found a 45% decreased risk of decompensation and a similar mortality benefit

--for patients currently on DAAs (direct-acting antiretrovirals) for hepatitis C, i found the following drug-drug interactions:

        --ledipasvir/sofosbuvir possibly increases the levels of the statins (i checked atorvastatin, pravastatin, rosuvastatin, and simvastatin), though the warning for atorvastatin seems the most benign

        --elbasvir/grazoprevir increases atorvastatin dose by 94%, rosuvastatin by 126%, simvastatin has likely interaction but not studied, no interaction with pravastatin

        --daclatasvir expected increases in levels of atorvastatin, pravastatin, simvastatin -- not studied, and 58% increase in rosuvastatin

        --ombitasvir/paritaprevir/ritonavir increases levels of rosuvastatin 1-2 fold and pravastatin by about 33%. do not use with atorvastatin or simvastatin

        --and, none of the statins seemed to affect the levels of the DAAs​

Effects of statins on other hepatitides:

    --NAFLD: statins have been shown also to decrease liver inflammation in those with NAFLD

        ​--one of my favorite studies, because of its name, was the GREASE study, which in fact was a study of Greek people with high lipids!! (Athyros VG. Lancet 2010; 376: 1916). they looked at 437 patients with baseline elevated ALT (but < 3x the upper limit of normal), 90% with metabolic syndrome, and all with LDL>100 and documented CAD, finding that atorvastatin for 3 years led to 1/3 the rate of recurrent CAD events (30% in placebo and 10% with atorvastatin), but 89% had normalization of their LFTs on the statin (although a simultaneous increase in ALT in those on placebo)

    --Hepatitis B: data on hepatitis B is somewhat mixed:

        ​--there are case reports of asymptomatic hepatitis B reactivation in a patient on atorvastatin, which resolved with discontinuation of the atorvastatin (see Wu DC. Intl J Infect Dis; 2013:e1069). though, i should add that i had a patient with chronic hepatitis B, who was asymptomatic but developed a dramatic increase in his ALT to 450 on routine check after being on atorvastatin for 8 years, and the hepatic inflammation spontaneously resolved within weeks even while continuing the atorvastatin. so, it seems that even if statins did cause the hep B reactivation, there are not necessarily bad outcomes (perhaps my patient had HBV reactivation related to the statin, but then enough of an immunologic response to contain it).

        ​--on the other hand, a recent 2-year Chinese study (Hsiang JC. J Hepatol 2015; 63: 1190) in patients with chronic HBV infection found a 32% decreased risk of HCC in those on statins, and on subgroup analysis, those on a statin and nucleos(t)ide analog had a 59% risk reduction compared to those on a nucleos(t)ide analog alone (ie, the combo might even be better: which may be really significant for HBV, since unlike hep c, the development of HCC is not so dependent on having baseline cirrhosis)

--in general, it is pretty well accepted that there is no significant relationship between statin use and liver disease. in most large trials, there is no increase in statin-induced liver disease. as a result, the FDA changed their recommendations in 2012: check LFTs prior to starting statins, then only if clinically indicated

so, what does this all mean in the era of the potent new hepatitis C drugs?

    --my guess is that it is very unlikely that a statin will improve the efficacy of these new hep C drugs, since they are so powerful on their own

    --the issue of statin effect on decreasing the progression of fibrosis/cirrhosis is interesting, as well as the decreased likelihood of developing HCC. Unclear exactly why: it may well be that the effect of statins is not a direct effect on the development of these conditions, but simply its anti-inflammatory effect (though that is still welcome, and still  could have long-term effects in preventing cirrhosis). and this could also be different in the current era of hep C treatment

    --if someone is on a statin prior to starting hep C DAA therapy, it makes sense to check the most up to date drug interactions (eg at http://www.hep-druginteractions.org/checker ) and likely decrease the dose of the statin, stop or change the statin, as indicated

    --for someone with hepatitis C who is not currently on treatment, it looks to me like there are good reasons to use a statin, probably best for atorvastatin (in part for its role in preventing CAD in those with this chronic inflammatory state -- though it would be important to have confirmatory RCTs; and in part based on the above studies of its anti-hep C potential)

    ​--and, overall, it seems very likely than statins may be useful for those more generally with inflammatory liver disease, with reasonably impressive data for NAFLD and probably as well for hepatitis B. it would be really great to have more long-term data, preferably based on RCTs, which looked at real clinical outcomes and not just changes in ALT as with the NAFLD data (though i should add that the dramatic decrease in CAD events seems to justify the use of statins independent of their hepatic effects. and there are some data suggesting that simvastatin is less effective in decreasing biopsy-proved hepatic inflammation than atorvastatin). so, i have been using atorvastatin in particular in my patients with NAFLD and both hepatitis B and C, but following their LFTs more regularly, even in asymptomatic patients.