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Direct-Acting Antiviral Sustained Virologic Response: Impact on Mortality in Patients without Advanced Liver Disease
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Hepatology Jan 29 2018 - Lisa I. Backus MD PhD,Pamela S. Belperio PharmD,Troy A. Shahoumian PhD, Larry A. Mole PharmD, Department of Veterans Affairs, Population Health Services, PaloAlto Health Care System, Palo Alto, CA, USA.
"Specifically, successful interferon-freeDAA treatment was associated with an unadjusted 69% reduction in all-cause mortality compared to untreatedpatients and a 59% reduction in all-cause mortality compared to DAA-treated patients who did not achieve SVRin this large cohort of patients without clinically apparent advanced liver disease cared for in routine medicalpractice......80% reduction observed in similar analyses of DAA-treated patients with advanced liverdisease, but remains clinically significant.30While the mortality benefit for those in the lowest FIB-4 strata(<1.45) is less than those with FIB-4 in a higher strata (1.45-3.25), indicating that risk of death indeed increaseswith worsening liver disease, substantial mortality benefit was observed even in those with milder disease"

The impact of sustained virologic response (SVR) on mortality after direct-acting antiviral (DAA) treatment is not well documented in patients without advanced liver disease and affects access to treatment. This study evaluated the impact of SVR achieved with interferon-free DAA treatment on all-cause mortality in hepatitis C (HCV) infected patients without advanced liver disease. This observational cohort analysis was comprised of 103,346 genotype 1, 2 and 3, HCV-monoinfected patients without advanced liver disease, defined by FIB-4 ≤3.25 and no diagnosis of cirrhosis, hepatic decompensation, hepatocellular carcinoma or history of liver transplantation, identified from the Veterans Affairs Hepatitis C Clinical Case Registry.
Among 40,664 patients treated with interferon-free DAA regimens, 39,374 (96.8%) achieved SVR and 1,290 (3.2%) patients were No SVR; 62,682 patients constituted the untreated cohort. The mortality rate for SVR patients of 1.18 deaths/100 patient years was significantly lower than both the rate for No SVR patients (2.84 deaths/100 patient years)(p<0.001) and untreated patients (3.84 deaths/100 patient years)(p<0.001). SVR patients with FIB-4 <1.45 and 1.45-3.25 had a 46.0% (p=0.036) and 63.2% (p<0.001) reduction in mortality rates, respectively, compared to No SVR patients and a 66.7% (p<0.001) and 70.6% (p<0.001) reduction in mortality rates, respectively, compared to untreated patients. In multivariate Cox proportional hazard models controlling for baseline demographics, clinical characteristics and comorbidities, SVR was independently associated with reduced risk of death compared to No SVR (hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.32-0.59, p<0.001) and compared to untreated patients (HR 0.32, 95%CI 0.29-0.36, p<0.001).
Conclusion: Successfully treating HCV with DAAs in patients without clinically apparent advanced liver disease translates into a significant mortality benefit. This article is protected by copyright. All rights reserved.


from Jules: these studies were presented at AASLD:
SVR Reduced HCC by 71%- (12/22/17) -published in Jan 2018
AASLD:Impact of Sustained Virologic Response with Direct-Acting Antiviral Treatment on Mortality and Hepatocellular Carcinoma - significantly lower mortality, HCC 60% to 84%- (10/24/17)
AASLD:Real life clinical outcomes in DAA-treated and untreated patients with HCV advanced liver disease. Interim one year data from the ongoing PITER cohort- (11/17/17)
AASLD:Survival Benefit of Direct-Acting Antiviral Therapy in Patients with Decompensated Cirrhosis- (11/29/17)
AASLD:Treatment of HCV-induced cryoglobulinemic vasculitis with new direct acting antiviral (DAA) regimens- (11/20/17)
AASLD:Long-term Follow-Up of Patients With Chronic HCV and No or Minimal Fibrosis Shows Low Risk for Liver-Related Morbidity and Mortality After Achieving SVR With DAA-Based Therapy: Results From the Gilead SVR Registry- (11/16/17)
AASLD:Treatment of Hepatitis C Virus (HCV) Leads to Economic Gains Related to Reduction in Cases of Hepatocellular Carcinoma (HCC) and Decompensated Cirrhosis (DCC) in Japan- (11/13/17)
AASLD:Improved Short-term Survival among HCV Patients following Liver Transplantation in the Era of Direct Acting Antiviral Agents- (11/13/17)
AASLD:The Declining Burden of HCV on the Liver Transplant Waitlist associated with the DAA era- (11/13/17)
AASLD:Treatment of HCV with Direct Acting Antivirals Significantly Reduces Liver-Related Hospitalizations in Patients with Cirrhosis- (11/13/17)
AASLD:Regression of liver stiffness (LS) after direct acting anti-viral (DAA) therapy for hepatitis C in the country of Georgia- (11/06/17)
AASLD:Significant and Sustained Improvement of Health-Related Quality of Life Scores in Patients with Hepatitis C and Sustained Virologic Response- (10/29/17)
AASLD:Hepatitis C in Patients Without Fibrosis or with Minimal Fibrosis: The Impact of Treatment and Sustained Virologic Response on Patient-Reported Outcomes- (10/29/17)
AASLD:Economic Burden of Chronic Hepatitis C (CHC) in Medicaid and Commercially Insured Patients in the United States- (10/23/17)
Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD- (12/29/17)

This study provides the strongest and most direct evidence yet that treatment of HCV infection in patientswithout advanced liver disease results in significant clinical benefit. Specifically, successful interferon-freeDAA treatment was associated with an unadjusted 69% reduction in all-cause mortality compared to untreatedpatients and a 59% reduction in all-cause mortality compared to DAA-treated patients who did not achieve SVRin this large cohort of patients without clinically apparent advanced liver disease cared for in routine medical practice. In multivariate models controlling for numerous clinical characteristics and co-morbidities, SVR wasassociated with a 68% reduction in the risk of death compared to untreated patients and a 56% reduction in therisk of death compared to treated patients who did not achieve SVR. Even when limited to patients with the least evidence of liver disease - FIB-4 <1.45 - SVR was still associated with a 67% reduction in the risk ofdeath compared to untreated patients and a 43% reduction in the risk of death compared to treated patients whodid not achieve SVR. As such, this data provides strong support for initiation of DAA-based therapies inpatients without advanced liver disease and helps to validate decisions to treat all patients with HCV regardlessof the stage of liver disease, as has been done in VA. We provide impetus to lift existing restrictions imposedby private and other public payers that restrict treatment to those with more advanced liver disease.
All oral DAA regimens only became widely available after 2014 and there has been no long-term data on thebenefit of achieving SVR with interferon-free DAA regimens in those with mild liver disease. While it isspeculated that clinical benefits seen with HCV cures obtained with interferon-free DAAs would be similar tothose observed with SVR after prior interferon-based regimens, we provide direct evidence to support this.12,13The considerable number of HCV patients that have received DAA treatment in VA provided the powernecessary to assess mortality that is not possible in smaller healthcare systems or in smaller clinical trials withlimited follow-up. The present work demonstrates a substantial all-cause mortality benefit in patients withoutadvanced liver disease – a population where demonstration of clinical benefit has been sparse, sparkingcontroversy regarding the clinical urgency in treating this population.2,11,16-17,20-22,28-29
The observed 56% reduction in the risk of mortality in well-controlled multivariate models in patients withoutclinically apparent advanced liver disease when comparing SVR patients to treated patients who did not achieveSVR is less than the 80% reduction observed in similar analyses of DAA-treated patients with advanced liver disease, but remains clinically significant.30 While the mortality benefit for those in the lowest FIB-4 strata(<1.45) is less than those with FIB-4 in a higher strata (1.45-3.25), indicating that risk of death indeed increaseswith worsening liver disease, substantial mortality benefit was observed even in those with milder disease. Asidentified in other studies, albumin level, even at near normal levels, influenced mortality in this evaluationindependently of SVR status.31 This suggests that the mortality benefits of SVR in patients with syntheticdysfunction may be slightly lessened and serves as additional leverage for treating patients earlier in their HCVinfection, prior to development of more advanced liver disease. From a population standpoint, in addition to thereduction in mortality, treating all patients with HCV regardless of stage of disease would also further reduceHCV transmission.18,20,22,28,32
In this cohort, we compared patients who achieved SVR to both untreated patients and patients who weretreated but did not achieve SVR, though the latter comparison between patients who achieved SVR and thosewho were treated and did not achieve SVR is the more relevant comparison to assess the mortality benefit ofSVR with DAA treatment. Unlike many other healthcare providers and systems, in VA there were minimaltreatment restrictions, all patients were considered for treatment, and extensive outreach occurred to bringpatients in for treatment. Thus, those patients who did not receive treatment in this aggressive treatmentenvironment likely represent a fundamentally different population than those who did receive HCV antiviraltreatment. This may help explain why, in the multivariate models, the risk for death for the No SVR patientswas generally lower than the risk for death for untreated patients despite the finding that untreated patientsappeared generally healthier at baseline. Perhaps a somewhat surprising finding in our analysis was that thenumber of primary care visits was the same for all three groups in the year prior to evaluation and the number ofoutpatient visits overall was similar between the untreated and those with SVR and higher in those treated withNo SVR. This suggests that the observed difference in mortality did not arise from a difference in medical care.Some VA data suggest that compared with patients engaged in care, non-engaged patients were significantlymore likely to have unstable housing or active substance use.33 Considering the data we present, it is possiblethat the untreated patients have other social or behavioral priorities which are being addressed prior to receipt ofHCV treatment, or are engaged in care but are uninterested or have made a personal decision not to receiveHCV treatment. These scenarios cannot be identified from the electronic data. Regardless, outreach to HCV-infectedindividuals and, ideally, initiation of HCV treatment may provide a good opportunity for patients toengage in the health care system and improve overall outcomes. Nevertheless, for the purposes of assessing theimpact of SVR on mortality, the most appropriate comparison is the comparison between SVR patients and NoSVR patients as these patients are already engaged in HCV treatment.
Information about reported cause of death was unavailable, thus we were unable to determine liver-relatedmortality. As such, the mechanism of the observed reduction in all-cause mortality associated with SVR cannotbe elucidated with the present research but is likely multifactorial. Chronic HCV infection is known to lead to amultifaceted systemic disease whereby some extrahepatic manifestations are immune mediated and othersdriven by chronic inflammation.34 A growing body of evidence supports the essential role of chronic HCV-relatedinflammation in the pathogenesis of hepatic and extrahepatic HCV-related disease,35 and increasingevidence links chronic inflammatory states with all-cause mortality.36-39 The relatively early appearance of aneffect on mortality which occurred in patients who were treated with DAA's compared to untreated patients,suggests that any exposure to DAAs may reduce chronic inflammation and SVR may eliminate chronicinflammation from HCV contributing to reduced all-cause mortality through mechanisms still being defined.Patients and their families remain concerned with death from any cause, not necessarily disease-specificmortality, making all-cause mortality a relevant outcome and the observed effect meaningful.
There are several other study limitations. Since the determination of SVR requires testing at least 12 weeks afterEOT, we excluded patients who died before 12 weeks of follow up which may underestimate the death rate.Our categorization of patients as without advanced liver disease relied on FIB-4 score ≤3.25, no clinicaldiagnosis of cirrhosis, decompensation or HCC and no history of liver transplant. Thus, it is important to notethat our cohort may still include some patients who have occult advanced liver disease, although that diagnosisdid not seem clinically apparent. Many of our measures of comorbidities rely on ICD-9/10 coding and requireda code within 1 year of DAA treatment, thus some diagnoses may be underreported in both the treated anduntreated groups though the rate of underreporting is likely similar. The follow-up time is limited given therelatively recent introduction of interferon-free DAA regimens. The observed differences in risk of death maychange over time as more time from treatment elapses, however, longer term benefits in survival rate are likelyto be realized given the substantial benefits already observed in the short term and as shown in the Kaplan-Meier survival curves. Despite controlling for multiple factors in multivariable analysis, it is possible that NoSVR, SVR, and untreated patients differ on unmeasured or unmeasurable factors that might account for the observed differences in SVR benefit and mortality.
Successfully treating HCV before the development of clinically apparent advanced liver disease translates into asignificant mortality benefit. These data strongly support a clinically significant benefit of DAA treatment inpatients without clinically apparent advanced liver disease and establishes SVR as a pivotal outcome post DAAtreatment specifically in relation to mortality. Increasing access to DAAs for all HCV-infected individualsshould result in fewer deaths.

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