Primary Care Corner with Geoffrey Modest MD: Hep C Treatment and Regression of Cirrhosis

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By Dr. Geoffrey Modest

A recent study provides up to 12-13 year follow-up showing long-term improvement in important clinical outcomes (liver cancer, decompensation and death) in patients treated successfully for hepatitis C (see doi.org/10.1053/j.gastro.2016.03.036). The value of this study, using PEG interferon/ribavirin, is that it has long-term results which I think are applicable to our newer and much better therapies.

Details:

  • 444 patients with hepatitis C (HCV) infection and compensated cirrhosis were treated with PEG interferon/ribavirin (PEG- IFN/RBV) in Italy, from 2001-2009, with mean of 7.6 years of follow-up
  • Mean age 58, 62% male, BMI 27, ALT 150, bili 1, albumin 4, 27% with diabetes, 83% genotype 1, 26% IL28B SNP CC/74% either CT or TT (those with the CC genotype have a stronger immune response to HCV than the non-CC genotypes and historically have been more likely to be cured of HCV infection)
  • They looked at 2 groups of cirrhotic patients: those without (n=218) and those with esophageal varices (EVs) (n=226) on baseline endoscopy
  • Routine ultrasounds were scheduled every 6 months, and EGD every 3 years for those without baseline EV and every 2 years in those with EV. Those who developed larger EVs were put on b-blockers or got banding
  • Results (and, feel free to skip over the mass of statistics):
    • SVR was achieved in 67 patients (30.7%) of those without EV and 41 (18.1%) in those with EV (p=0.003); and more often in those with higher ALT, albumin, non genotype 1, and those with IL28B  SNP CC polymorphism [all pretty much as expected with this therapy]
    • Risk of developing/progression of EV:
      • In those without baseline EV: those achieving SVR had 77% less likelihood of developing EV [HR 0.23 (0.11-0.48), p<0.001], and those developing EV had small ones. The rate was 2.1%/yr for those with SVR and 9.1% without. These curves continued to diverge over the 12-13 years of follow-up
      • In those with baseline EV: no significant difference in developing more EVs. 22% had varices regress, 44% were stable, and 34% had progression
    • SVR was associated with 75% lower risk of developing hepatocellular carcinoma (HCC): [HR 0.25 (0.12-0.55), p<0.001]. In those without EV the HCC rate was 0.7%/yr vs 2.9%/yr if no SVR; in those with EV, the respective rates were 0.9% vs 3.6%/yr. and the severity of the HCC was much less in those who developed SVR. The HCC incidence curves for those with and without EV diverged over time.
    • For liver decompensation (LD): those without EV who developed SVR, none developed LD, though 1.7%/yr did if no SVR. In those with EV with SVR, 2.3%/yr developed LD vs 4.9%/yr if no SVR.
    • For overall survival: 2 of 67 SVR patients without EV died (both from HCC), vs 27 of 151 without SVR (18 from HCC and 9 from LD): 0.4%/yr vs 2.1%/yr (p=0.0035).  in those with EV, 1.8%/yr died in the SVR group and 4.6%/yr without SVR (p=0.005)
  • For those with EV at baseline (vs those without), independent of SVR, were at higher risk for
    • Liver decompensation:  [HR 2.82 (1.73-4.59), p<0.001]
    • Death:  [HR 1.77 (1.12-2.80), p=0.015]
  • In those without baseline EV
    • HCC: 2.9% with SVR died from HCC vs 11.9% in those who did not develop SVR (p=0.03)
    • Liver decompensation: in none with SVR but 7.1% without (p=0.009)
  • In those with baseline EV:
    • HCC: 2% with SVR died from HCC vs 18.4% in those without (p=0.003)
    • Liver decompensation was not statistically significant, though trend to improvement with SVR (12.1% vs 25.4%,  p=0.15)

Commentary

  • There were some limits inherent in this study
    • They excluded patients with any history of decompensated cirrhosis, or those with more advanced EV (moderate to large varices) or on prophylactic b-blockers. Also those with co-infection with hepatitis B or HIV, or prior to getting cirrhosis.
    • They only looked at patients treated with PEG-IFN/RBV
    • There might be inherent biases in this outcome analysis of this prospective review, including a response  bias (i.e., did those patients with SVR by PEG-IFN/RBV differ from those who did not respond because of some unmeasured difference in the aggressiveness of the virus, comorbidities, or intrinsic issues of their immunologic response)
  • BUT, there are, I think, some reasonable and probably generalizable conclusions
    • This study offers us the ability to look at really long-term conclusions about important clinical events after SVR. Although possible, it seems likely that the meds used to achieve the SVR are not particularly important to outcomes years later (and, the effect of any selection bias introduced by those responding to the old meds is unlikely to be significant anyway with the new direct acting antivirals, DAAs, since they pretty uniformly lead to SVR). So, the application of these results to the new era of DAAs seems pretty reasonable
    • It is quite remarkable how well patients did who had initial cirrhosis without EV: basically they do not develop liver decompensation, and only rarely develop HCC. And, they have a very low risk of mortality from liver disease
    • And, for those with EV at the time of treatment, effective treatment significantly reduced the risk of HCC, liver decompensation, and mortality, though there was still a risk of EV progression (though the risk of progression from small EV is still less: those with SVR had progression at an annual rate of 5.9% vs 9.0% in those who did not achieve SVR)
    • But, even in those without SVR, the presence of EVs portended a poorer prognosis, also reinforcing the benefit of earlier treatment
    • For the future, it will be important in this era of DAA therapies that we look at the long-term efficacy of successful hep C treatment in those excluded in the above long-term study, including those with both less advanced liver disease, those with more advanced cirrhosis (e.g. with history of liver decompensation), and in those with co-infection with hep B and HIV

So, based on this:

  • It seems appropriate to aggressively pursue hep C treatment at an earlier stage, and specifically prior to developing significant portal hypertension/esophageal varices. And I would add that the continued risk of HCC in those with cirrhosis even without EVs and the need for future HCC monitoring supports treating HCV prior to developing cirrhosis (which some insurance companies seem reluctant to do).
  • But this study still confirms that even those with more severe cirrhosis/earlier stages of portal hypertension derive major benefit from effective HCV treatment (i.e., still important to treat HCV even in later stages of cirrhosis/portal hypertension)
  • It will be important to develop a granular database in this age of DAA to guide future monitoring. For example, in HCV infection, given the predictable progression of liver disease to fibrosis prior to HCC, are there clear markers where SVR will make it unnecessary to do continued routine surveillance for HCC? For example, is there a stage of liver disease, perhaps some degree of cirrhosis regression or other markers after SVR, when we do not have to continue doing serial RUQ ultrasounds? Or in the group with EVs, continuing to do follow-up EGDs?
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