{"id":1051,"date":"2016-05-16T14:41:46","date_gmt":"2016-05-16T14:41:46","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=1051"},"modified":"2017-08-21T10:54:29","modified_gmt":"2017-08-21T10:54:29","slug":"primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2016\/05\/16\/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Use of Statins in Patients with Hepatitis? Looks Like a &#8220;Yes&#8221;"},"content":{"rendered":"<p><strong>By Dr. Geoffrey Modest<\/strong><\/p>\n<p>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\u00a0of hepatitis\u00a0C (HCV)\u00a0patients\u00a0found an actual<strong>\u00a0benefit for statins<\/strong>, as has been found in some other studies (see\u00a0DOI 10.1002\/hep.28506).<\/p>\n<p>Details:<\/p>\n<ul>\n<li>From\u00a0the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, they looked at\u00a0subjects initiated on anti-HCV\u00a0therapy from 2001 to 2014, as well as\u00a0all incident cases of cirrhosis and hepatocellular carcinoma (HCC). Those coinfected with\u00a0HIV or hepatitis B\u00a0were excluded, as well as those with baseline\u00a0cirrhosis<\/li>\n<li>Mean age 53, 65% white\/18% black\/6% Hispanic, 95% male, ALT\u00a075, AST 53, FIB-4 score 1.7\u00a0(see below), median length of follow-up was 7-8 years. More statin users were diabetic\u00a0(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 (i.e., the old drugs)<\/li>\n<li>9135 eligible people, of whom\u00a01,649 developed cirrhosis,\u00a0and 239 developed incident HCC [cirrhosis was defined by a FIB-4 score of &gt;3.5, where the FIB-4 score is a mathematical calculation\u00a0based on\u00a0age, AST, platelet count, ALT]<\/li>\n<\/ul>\n<p>Results:<\/p>\n<ul>\n<li>Statin use was associated with\n<ul>\n<li>Higher likelihood of sustained viral response (55.1% vs 47.5%, p&lt;0.0001)<\/li>\n<li>A<strong> 36% reduction in development of cirrhosis<\/strong>,\u00a0adjusted HR: 0.64 (0.53-0.68), p&lt;0.0001.<\/li>\n<li>Lower\u00a0\ufb01brosis progression, with a dose-response curve revealing\u00a0progressively decreasing risk<\/li>\n<\/ul>\n<\/li>\n<li>Of the statins used, the <strong>highest decrease in FIB-4 score was with atorvastatin<\/strong> 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),\u00a0p=0.04,after adjustment for baseline FIB-4 score and established predictors of cirrhosis.<\/li>\n<li>Statin use was also associated with <strong>a 49% reduction in incident HCC<\/strong> (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\u00a0with hep C, the progression to HCC is tied in with presence of fibrosis].<\/li>\n<\/ul>\n<p>So, does this make sense?<\/p>\n<ul>\n<li>There are several mechanisms by which statins could decrease progression of liver fibrosis:\n<ul>\n<li>They have lots of &#8220;pleiotrophic&#8221; (non-lipid)\u00a0effects: anti-inflammatory,\u00a0antiproliferative, 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.<\/li>\n<li>Hepatitis C virus depends on cholesterol to replicate, so interference by statins might well help control\u00a0hep C (statins do inhibit hep C in vitro; and people with hep C have lower LDL levels, which increase after the virus is cleared)<\/li>\n<li>Statins also decrease components of the metabolic syndrome, and there are several studies suggesting that the combination of hep C infection\u00a0and metabolic syndrome, present in about 20-25% of people with hep C,\u00a0leads to a higher incidence of HCC<\/li>\n<li>Humans studies\u00a0(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\u00a0study 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\u00a0cirrhosis found a\u00a045% decreased risk of decompensation and a similar mortality benefit<\/li>\n<\/ul>\n<\/li>\n<li>For patients currently on\u00a0DAAs (direct-acting antiretrovirals) for hepatitis C, I found the following\u00a0drug-drug interactions:\n<ul>\n<li>Ledipasvir\/sofosbuvir possibly increases the levels of the statins (I checked atorvastatin, pravastatin, rosuvastatin, and simvastatin), though the warning for\u00a0atorvastatin seems the most benign<\/li>\n<li>Elbasvir\/grazoprevir increases atorvastatin dose by 94%, rosuvastatin by 126%,\u00a0simvastatin has likely interaction but not studied,\u00a0no interaction with pravastatin<\/li>\n<li>Daclatasvir expected increases in levels of atorvastatin, pravastatin, simvastatin &#8212; not studied, and 58% increase in rosuvastatin<\/li>\n<li>Ombitasvir\/paritaprevir\/ritonavir increases levels of\u00a0rosuvastatin 1-2 fold and pravastatin by about 33%. do not use with atorvastatin or simvastatin<\/li>\n<li>And, none of the statins seemed to affect the levels of the DAAs<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>Effects of statins on other hepatitides:<\/p>\n<ul>\n<li><strong>NAFLD<\/strong>:\u00a0statins have been shown also to <strong>decrease liver inflammation in those with NAFLD<\/strong><\/li>\n<li>One of my favorite studies, because of its name, was the GREASE study, which in fact\u00a0was a study of Greek\u00a0people with high lipids!!\u00a0(Athyros VG.\u00a0Lancet 2010; 376: 1916). They\u00a0looked at 437 patients with baseline elevated ALT (but &lt;\u00a03x the upper limit of normal), 90% with metabolic syndrome, and all with LDL&gt;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<strong> 89% had normalization of their LFTs on the statin <\/strong>(although a simultaneous\u00a0increase in ALT in those on placebo)<\/li>\n<li><strong>Hepatitis B<\/strong>:\u00a0data on hepatitis B is somewhat mixed:\n<ul>\n<li>There are case reports of asymptomatic\u00a0hepatitis 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\u00a0developed a\u00a0dramatic increase in his ALT to 450 on routine check\u00a0after being on atorvastatin for 8 years, and the hepatic inflammation spontaneously\u00a0resolved 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\u00a0(perhaps my patient had HBV\u00a0reactivation related to the statin, but then enough of an immunologic response to contain it).<\/li>\n<li>On the other hand, a recent 2-year\u00a0Chinese 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\u00a0analog alone (i.e., 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)<\/li>\n<li>In general, it is pretty well accepted that there is no significant\u00a0relationship between statin use and liver disease.\u00a0In most large trials, there is no increase in\u00a0statin-induced liver disease. As a result,\u00a0the\u00a0FDA changed their recommendations in 2012: check LFTs prior to starting statins, then only if clinically indicated<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>So, what does this all mean in the era of the potent new hepatitis C drugs?<\/p>\n<ul>\n<li>My guess is that it is very unlikely that a statin will improved the efficacy of these new hep C\u00a0drugs, since they are so powerful on their own<\/li>\n<li>The issue of statin effect on decreasing the\u00a0progression of fibrosis\/cirrhosis is interesting, as well as the decreased\u00a0likelihood 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<\/li>\n<li>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 (e.g. at\u00a0<a href=\"http:\/\/www.hep-druginteractions.org\/checker\">http:\/\/www.hep-druginteractions.org\/checker<\/a> ) and likely decrease the dose of the statin, stop\u00a0or change\u00a0the statin, as indicated<\/li>\n<li>For someone with hepatitis C who is not currently on treatment, it\u00a0looks 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\u00a0chronic inflammatory state\u00a0&#8212;\u00a0though it would be important to have confirmatory RCTs; and in part based on the above studies of its anti-hep C potential)<\/li>\n<li>And, overall, it seems very likely than statins may be useful for those more generally with inflammatory liver disease,\u00a0with reasonably impressive data for\u00a0NAFLD 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\u00a0hepatic\u00a0inflammation than atorvastatin). So, I have been using atorvastatin in particular in my patients with NAFLD and both hepatitis B and C, but following their\u00a0LFTs more regularly, even in asymptomatic patients.<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Primary Care Corner with Geoffrey Modest MD: Use of Statins in Patients with Hepatitis? Looks Like a &#8220;Yes&#8221; [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2016\/05\/16\/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes\/\">Read More&#8230;<\/a><\/p>\n","protected":false},"author":148,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[14283],"tags":[],"class_list":["post-1051","post","type-post","status-publish","format-standard","hentry","category-archive"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/1051","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/users\/148"}],"replies":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/comments?post=1051"}],"version-history":[{"count":0,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/1051\/revisions"}],"wp:attachment":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/media?parent=1051"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/categories?post=1051"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/tags?post=1051"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}