Primary Care Corner with Geoffrey Modest MD: Hepatitis C Treatment Leads to Lower Complication Rate in Prospective Study

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By Dr. Geoffrey Modest

A large prospective cohort study confirmed that successful treatment of hepatitis C infection led to many benefits, including decreased hepatocellular carcinoma (HCC) and hepatic decompensation, but also lower cardiovascular risk, bacterial infections and both liver- and nonliver-related overall mortality (see doi:10.1053/j.gastro.2016.09.009, though at this point the paper was an accepted manuscript and not formally published).

Details:

  • 1323 patients from the prospective CirVir cohort from 335 centers in France recruited from 2006-2012 with biopsy-proven cirrhosis, Child Pugh class A, and no prior liver complications. All patients received anti-HCV with interferon, and then direct antiviral agents (DAAs) starting in February 2014, had ultrasound every six months and endoscopic evaluation. Analysis of data was done January 2016.
  • 63% male, mean age 55, AST 58, ALT 63, normal serum albumin/bilirubin/prothrombin time, 31% with esophageal varices, 68% genotype 1, 16% genotype 3, 5% HIV co-infected, 32% excessive alcohol consumption and 25% ongoing alcohol consumption, 38% current smokers, 31% past substance abuse, BMI 26, 90% diabetes, 9% past CV event
  • Follow-up average of 58.2 months.
  • 94% of the patients had undergone antiretroviral therapy at the time of inclusion, of whom 20% had SVR. During follow-up, 1183 treatments were recorded in 793 patients, 287 had first-generation anti-protease agents in genotype 1 infections and 328 had DAA regimens.
  • Propensity match scoring was used to control for morbidities, etc by multivariate analysis, to decrease confounding by indication of treatment or capacity to achieve sustained viral response (SVR)

Results:

  • Overall 215 patients (16%) had at least one episode of liver decompensation or GI bleeding; 422 patients (32%) developed a first hepatic focal lesion of which 55% were considered indeterminate or benign. A total of 1550 extrahepatic events occurred in 697 patients (140 vascular events, with 33 having heart failure, 30 ischemic heart disease), 204 patients had a bacterial infection (27% UTI, 25% pulmonary infections, 11% spontaneous bacterial peritonitis, 12% skin infections). 83 patients had extrahepatic cancers (lymphomas 15, gynecologic 15, colorectal 12, lung 12, oral 12)
  • Factors related to complications:
    • HCC: age, low platelet count, high GGT levels, past excessive alcohol consumption. In those with SVR, risk factors included low PT, low platelet count, high GGT, high AST, and some metabolic syndrome features (BMI >25 and or diabetes and/or dyslipidemia; overall found in 60% of the population).
    • Bacterial infection: age, low albumin, low GFR
    • Cardiovascular events: low albumin, smoking, past history of CV events, hypertension
    • Hepatic decompensation: age, low platelet count, high GGT levels, low albumin, esophageal varices.
    • Overall death: age, low platelet count, high GGT, low albumin, past excessive alcohol consumption, past history CV events, tobacco, hypertension. In those with SVR, only 18 patients died but these patients had low platelet count, diabetes, a past history of cardiovascular events, or a past history of malignancy
    • Extrahepatic cancer: age
  • 668 patients (50.5%) achieved an SVR, associated with (vs. those not achieving SVR):
    • 71% decrease in HCC, HR 0.29 (0.19 – 0.43), p<0.001
    • 74% decrease in hepatic decompensation, HR 0.26 (0.17 – 0.39), p<0.001
    • 58% decrease in cardiovascular events, HR 0.42 (0.25 – 0.69), p=0.001
    • 56% decrease in bacterial infections, HR 0.44 (0.29 – 0.68), p<0.001
    • 73% decrease in total mortality, HR 0.27 (0.18 – 0.42), p<0.001
    • There was no effects of SVR on extrahepatic cancers
  • Similar results to the above were obtained through propensity score-matched population.
  • The curves for HCC, hepatic decompensation, and bacterial infections continued to increase in those without SVR over 108 months of follow-up, but were basically flat in those with SVR. The curves for major adverse cardiac events continued relatively parallel after about five years, and overall survival diverged till about 84 months, then curves were parallel.
  • Overall, there was no difference in outcome in SVR patients whether they achieved their SVR through interferon-based regimens or DAAs, though the follow-up in the latter group was too short to be definitive.

Commentary:

  • This large study adds to prior studies finding that those who achieved SVR had improvement in liver-related complications: including fibrosis and necrosis, portal hypertension and splenomegaly, HCC, risk for liver-related mortality and transplantation; as well as some non-liver related ones: non-Hodgkin’s lymphoma and other lymphoproliferative disorders, and all-cause mortality (see http://www.hcvguidelines.org/full-report-view , which has a regularly updated review of hepatitis C overall, with emphasis on therapy). This new study basically confirms the liver-related benefits but also includes non-liver benefits in cardiovascular and infectious diseases.
  • One important feature of this study is that this one involved a more inclusive prospective cohort study of HCV-treated cirrhotic patients, with most of the prior studies being retrospective cohorts and observational. This was also a rigorous study which required biopsy-proven cirrhosis.
  • There were a few findings of potential concern: in those who developed SVR, the incidence of hepatic decompensation seemed to be lower in those who were on interferon-based regimens. Those who had a protease inhibitor-based regimen had a higher risk of bacterial infections. But overall, there were no clear differences based on the regimens to achieve SVR.
  • The increase in cardiovascular events could be related to several conditions, including adverse cardiac effects from the metabolic syndrome, and the chronic inflammation associated with ongoing hepatitis C infection. There even is argument for a direct effect of HCV itself on cardiovascular disease (e.g. there seems to be a correlation between higher HCV viral loads and cardiovascular morbidity)
  • Of note, there was a recent FDA alert about DAAs (see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.htm ), where they note that there were 24 cases of patients dually-infected with hepatitis B and C who had reactivation of their hepatitis B.
  • So, this current study brings up  several points regarding successful treatment of hepatitis C:
    • It reinforces the remarkable decrease in many adverse hepatic and extra-hepatic outcomes of hepatitis C infection in those with cirrhosis
    • It tangentially raises the likely utility of treating chronic hepatitis C infections earlier, in the pre-cirrhotic and even pre-fibrotic stages, since many patients with SVR still have complications (though much less than without SVR). Also, from other studies, those with fibrosis often do not get significant reversal of their fibrosis with SVR and are therefore still potentially at risk for HCC and subject to on-going HCC surveillance
    • Unfortunately, this study looked only at hard endpoints: other studies have found important improvements in quality of life, including physical, emotional and social health.
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