The goals for treating persons with chronic hepatitis C virus (HCV) are threefold: (1) eradicate HCV, (2) improve HCV-related health outcomes and survival in all populations, and (3) reduce transmission of HCV to others. For clinicians, the primary and immediate goal is to treat the individual with a regimen that has a very high likelihood of curing the individual of their HCV infection. With the current armamentarium of highly effective and safe direct-acting antiviral (DAA) medications, cure of chronic HCV is expected in more than 95% of persons receiving HCV treatment, regardless of HCV genotype, baseline HCV RNA levels, race, HIV status, or severity of hepatic fibrosis.[1,2] The health outcome benefits following successful treatment of persons with chronic HCV infection are multiple and include reduced prevalence of hepatic fibrosis, lower risk of developing hepatic failure, decreased occurrence of hepatocellular carcinoma (HCC), improved survival, and amelioration of some extrahepatic HCV-related manifestations.[3,4,5,6] With widespread treatment of HCV, the number of persons capable of transmitting HCV would decline dramatically, which could have a major impact on HCV incidence and the overall HCV epidemic.
- Module 4 Overview
Evaluation and Preparation for Hepatitis C Treatment - 0%Lesson 1
Goals and Benefits with HCV TreatmentLesson 3. Addressing Structural Barriers to HCV Treatment
Module Core Competency
Provide Evidence-Based Evaluation and Preparation for Treatment of Persons with Hepatitis C Infection
Target Audience
For clinicians evaluating persons with chronic HCV infection for hepatitis C treatment, including clinicians who will independently assess treatment candidacy and clinicians who will provide treatment candidacy with assistance from a hepatitis C expert.Editors
John D. Scott, MD,John D. Scott, MD
Assistant Director Hepatitis and Liver Clinic
Harborview Medical Center
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: Consulting: Gilead SciencesDavid H. Spach, MDDavid H. Spach, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: NoneFree CE CNE/CME
Module Lessons
1Lesson 1 Goals and Benefits with HCV Treatment
- Learning Objectives
- Summarize the goals and rationale for HCV therapy in persons with chronic HCV
- Discuss the long-term impact of HCV treatment in persons with chronic HCV
- List several factors that potentially impact response to HCV treatment with direct-acting antiviral therapy
- Goals and Benefits with HCV Treatment
- Background
- Virologic Cure and Sustained Virologic Response
- Impact of HCV Treatment on Clinical Outcomes
- Viral Factors that May Impact Response to Therapy
- Host Factors that May Impact Response to Therapy
- Prior Treatment
- Summary Points
- Citations
- Additional References
- Figures
- Quick ReferenceGoals and Benefits with HCV Treatment Core Concepts
- Background
- Virologic Cure and Sustained Virologic Response
- In a pooled analysis of adults who had paired liver biopsies before and 1 month to 6 years after treatment with interferon-based therapies, individuals who achieved an SVR were twice as likely to have lower necroinflammatory scores after treatment, compared to those with virologic relapse (67% versus 32%) and some patients with an SVR had complete regression of liver fibrosis.[20]
- In a meta-analysis, investigators evaluated the impact of HCV treatment on liver stiffness, as measured by vibration-controlled transient elastography.[17] Individuals who achieved an SVR12 had a significantly greater decrease in liver stiffness at the end of treatment and after treatment than patients who failed to achieve an SVR12 (Figure 2).[17] In addition, the decline in liver stiffness among those who achieved an SVR12 was greater with DAA treatment than with interferon-based therapy (decrease of 5.1 kPa versus decrease of 2.8 kPa).[17]
- In a recent study, investigators performed liver stiffness measurements in 70 patients treated with DAA therapy, among whom 95.7% achieved an SVR.[18] Treatment of HCV with DAA therapy resulted in a significant decrease in liver stiffness at the end of treatment and at 12 months posttreatment when compared with baseline measurements (Figure 3).[18]
- In a multi-center, prospective cohort study that enrolled 71 Danish adults with advanced fibrosis, investigators found that liver stiffness decreased by an average of 20% at the end of sofosbuvir-based direct-acting antiviral therapy, and by an additional 15% 1 year after treatment, a finding that was suggestive of fibrosis regression.[21]
- Multiple large, controlled studies have clearly shown a reduction in the risk of HCC occurrence after achievement of SVR with HCV therapy; in these studies, control groups consisted of persons with HCV who were treated but did not achieve an SVR.[4,22,23,24] Several of the more recent studies exclusively involved persons treated with DAA therapy.[23,25,26]
- Although HCV eradication with HCV therapy reduces the risk of HCC occurrence, the risk of developing HCC remains substantial for persons who, prior to treatment, had advanced fibrosis or cirrhosis.[26] Accordingly, individuals who met HCC surveillance criteria prior to HCV treatment should continue to receive HCC surveillance every 6 months after achieving an SVR with HCV treatment.[8,26,27]
- It is important to note posttreatment transient elastography often overestimates the regression in fibrosis, probably because of reduced hepatic inflammation and congestion. Thus, persons with F3-4 fibrosis prior to HCV treatment should continue to have regular hepatocellular carcinoma surveillance, even if testing shows a reduction in liver stiffness or improvement in other non-invasive fibrosis measures.
- Among persons with a history of successfully treated HCC, there are conflicting data regarding the impact of DAA therapy on the risk of HCC recurrence; most studies report no difference in the risk of recurrent HCC among DAA-treated and untreated persons. As such, DAA-treated individuals with a history of HCC require close ongoing HCC surveillance.[27,28,29,30,31]
- In a retrospective cohort study, investigators examined the impact of HCV treatment during the years 1990 and 2003 in 5 hepatology units in Europe and Canada.[36] Individuals with advanced fibrosis who underwent antiviral therapy and achieved an SVR had reduced overall mortality, liver-related death, liver failure, and hepatocellular carcinoma compared with those who did not achieve an SVR (Figure 4).[36]
- In a meta-analysis of 35 studies that included 33,360 persons with chronic HCV infection, investigators showed a clear benefit in 5-year overall survival in persons who achieved an SVR with treatment when compared with those who had not achieved an SVR; all the studies analyzed all involved interferon-based therapies, and some included individuals with cirrhosis or persons with HIV coinfection (Figure 5).[37]
- In an observational cohort analysis of 103,346 persons with chronic HCV (genotype 1, 2, or 3) in the Veterans Affairs Hepatitis C Clinical Case Registry, investigators examined the impact of achieving SVR with DAA treatment on mortality.[34] Among the 40,664 persons treated with a DAA regimen, 39,374 (96.8%) achieved an SVR. The mortality rate in persons who achieved an SVR was significantly lower than in those who did not achieve an SVR with treatment, after adjusting for baseline demographics, clinical characteristics, and comorbidity (Figure 6).[34] The reduction in mortality was 69.3% among those who achieved an SVR compared to persons who did not receive HCV treatment.[34]
- Recent cohort studies of persons with HCV and successfully treated HCC have found a significantly lower overall risk of death among persons who receive DAA therapy when compared to those who do not, suggesting that patients with a history of HCC should receive HCV DAA treatment due to multiple treatment-related benefits, including overall improved survival.[38,39]
- A few studies evaluating contemporary trends have suggested an early signal of benefit since the introduction of DAA therapy with decreased mortality and liver transplantation rates in patients with advanced HCV liver disease.[40,41]
- Impact of HCV Treatment on Clinical Outcomes
- Viral Factors that May Impact Response to Therapy
- Host Factors that May Impact Response to Therapy
- Prior Treatment
- There are multiple goals with antiviral therapy for hepatitis C, including (1) eradicate HCV, (2) improve HCV-related health outcomes and survival in all populations, and (3) reduce transmission of HCV to others.
- A sustained virologic response is defined as an undetectable HCV RNA level 12 weeks after stopping antivirals; this is referred to as the SVR12, and the SVR12 has a high correlation with SVR24. An SVR is durable and indicates HCV cure.
- Achieving an SVR following HCV treatment results in improvement of hepatic fibrosis, decreased development of HCC, improvement in survival, and reduction in extrahepatic manifestations associated with chronic HCV.
- In the DAA treatment era, HCV genotype has a reduced role in predicting treatment response given the availability of a variety of DAA combinations with high efficacy across genotypes.
- Older patients, including those 70 years of age and older have comparable responses to DAA therapy when compared with younger patients.
- With newer DAA therapies, individuals with more advanced fibrosis and compensated cirrhosis typically have HCV treatment SVR rates greater than 95% with 12-week treatment regimens. Persons with decompensated cirrhosis are more difficult to treat and often have reduced response rates.
- Summary Points
Background
Virologic Cure and Sustained Virologic Response
HCV Eradication and Sustained Virologic Response (SVR)
The gold standard for determining cure of HCV is the demonstration of sustained undetectable HCV RNA levels after treatment.[7] A sustained virologic response (SVR) is an undetectable HCV RNA level using a sensitive assay (typically with a lower limit of 25 IU/mL) at least 12 weeks after completing HCV therapy (Figure 1).[8] In the current era, most expert guidelines recommend measuring an HCV RNA level 12 weeks after therapy to evaluate for SVR; individuals with an undetectable HCV RNA level at 12-week posttreatment, also known as an SVR12, are considered to have achieved a virologic cure.[7] Among persons who achieve an SVR12 with direct-acting antiviral (DAA) HCV therapy, greater than 99% go on to achieve a durable response and ongoing absence of detectable viremia.[9,10] Trial outcomes with SVR time frames of shorter duration (SVR8 and SVR4) have been presented in an effort to expedite conclusions from these trials, but SVR4 and SVR8 are not the standard time frame used in clinical practice to determine cure.
Durability of SVR
Long-term follow-up of persons who achieve an SVR12 or SVR24 has shown that nearly 100% remain HCV RNA negative years after therapy.[11,12,13] Several large studies have shown a minimal relapse rate, between 0 to 1% at 5 years.[14,15] Thus, an undetectable HCV RNA 12 or 24 weeks after antiviral therapy can be considered a virologic cure. It is important to note that persons cured of HCV can become reinfected with HCV.[15,16]
Impact of HCV Treatment on Clinical Outcomes
Impact of HCV Treatment on Hepatic Fibrosis
Individuals who achieve an SVR are more likely to have an improvement in liver inflammation and fibrosis than those who do not achieve an SVR.[17,18,19,20] The following studies highlight data related to the impact of HCV eradication on hepatic fibrosis.
Impact of HCV Treatment on Hepatocellular Carcinoma
Considering that achievement of SVR reduces liver fibrosis, one might expect that successful treatment of HCV would lead to a reduced risk of HCC. The following provides a summary of the impact of HCV DAA-based therapy on HCC occurrence and reoccurrence.
Impact of HCV Treatment on Survival
In persons with chronic HCV infection, treatment with achievement of SVR12 or SVR24 has been shown to markedly reduce the risk of death, including liver-related and non-liver-related deaths.[6,14,32,33] Recently, multiple studies have shown major survival benefit in persons with chronic HCV who achieve SVR with DAA therapy.[34,35] The following summarizes key data related to the impact of DAA therapy on survival after achieving an SVR.
Impact of HCV Treatment on Extrahepatic Manifestations
Infection with HCV can cause a myriad of extrahepatic complications, including cryoglobulinemia, membranoproliferative glomerulonephritis, dermatologic disorders, insulin resistance and diabetes mellitus, and B-cell non-Hodgkin's lymphoma.[42,43,44] There is growing evidence that most HCV-related extrahepatic manifestations improve after eradication of HCV, particularly in females.[45,46] Most notably, a retrospective cohort study that involved 160,875 United States veterans with chronic HCV, patients who achieved an SVR12 with interferon-based therapy had substantial reductions in HCV-related extrahepatic manifestations when compared with individuals who did not achieve an SVR with HCV treatment or were not treated at all (Figure 7).[47] In some patients, successful treatment of hepatitis C is associated with improvement or remission of these underlying conditions.[48,49] In addition, achieving an SVR has been shown to reduce the chance of impaired fasting glucose and diabetes development by 50%, an effect that is independent of other established risk factors for diabetes, such as age and body mass index. A recent meta-analysis of 48 studies showed that an SVR reduced extrahepatic mortality by 56%, improved response to malignant B-cell lymphoproliferative therapy, and vastly improved the chances of a complete resolution of cryoglobulinemic vasculitis.[3]
Viral Factors that May Impact Response to Therapy
HCV Genotype
Hepatitis C is classified into 6 major genotypes, numbered 1 through 6. In the prior interferon era of treatment, genotype was the strongest predictor of obtaining an SVR.[50,51,52] In the current direct-acting antiviral (DAA) era, particularly with the approval os pangenotypic regimens, the role of HCV genotype in predicting treatment response has decreased significantly given the high efficacy of different DAA combinations across all genotypes and the introduction of pangenotypic agents. Overall, with a preferred regimen, the SVR12 rate is greater than 95%, regardless of HCV genotype.[53,54,55,56,57]
HCV RNA Level
In the registration clinical trials of peginterferon and ribavirin, a baseline HCV RNA level over 2 million IU/mL was associated with a 9% lower chance of cure.[50] Subsequent studies found that patients with high HCV RNA levels and genotype 1 infection had a 16 to 27% lower chance of achieving an SVR depending on the cutoff used.[58] In the current DAA era, the baseline HCV RNA usually has little impact on the likelihood of achieving an SVR. One exception to this is when considering whether to use 8 or 12 weeks of ledipasvir-sofosbuvir in treatment-naïve persons. A post hoc analysis from the ION-3 trial in treatment-naïve patients without cirrhosis noted that participants with a baseline HCV RNA level less than 6 million IU/mL had similar relapse rates using 8 or 12 weeks of therapy.[59] Subsequent studies have also shown comparable SVR rates for treatment-naïve individuals without cirrhosis who received either 8 or 12 weeks of ledipasvir-sofosbuvir (if the baseline HCV RNA level was less than 6 million IU/mL).[60] Baseline HCV RNA levels have not been associated with likelihood of SVR with the more recently approved pangenotypic DAA regimens.
Host Factors that May Impact Response to Therapy
Race
Several clinical trials involving DAA therapy did not demonstrate significant differences in SVR by race, although these trials may not have been sufficiently powered to detect a difference if one existed.[61,62,63] Several observational studies of DAA effectiveness in the United States Veterans Administration have suggested a slightly reduced likelihood of SVR among Black individuals after adjusting for baseline characteristics.[64,65,66] The largest of these observational studies analyzed 2014-2015 DAA HCV treatment data by race and found similar overall SVR rates (Figure 8), but after adjusting for baseline characteristics, the odds of achieving an SVR were slightly lower in Black or Hispanic individuals, when compared with White persons (Figure 9).[66] It is important to note that the absolute difference in SVR rates were small (1 to 4 percentage points) and these findings have not been reproduced in settings outside the Veterans Administration. One analysis using nationwide observational data from the Veterans Administration facilities found that among persons with chronic HCV, Black individuals were less likely to receive DAA therapy than White persons.[67] Overall, when taken together, these data show that SVR12 rates with DAA therapy are excellent across all racial groups, and that while subtle differences might exist, they do not in any way preclude the use of these DAA in Black of Hispanic persons.[68]
Age
In multiple studies with interferon-based therapy, increasing age was significantly associated with poor tolerance and a lower chance of cure.[69,70] In contrast, HCV treatment with DAA therapy in the elderly is well tolerated and SVR rates are similar to those seen in younger patients.[69,71,72] The excellent response in elderly patients has included data in septuagenarians and octogenarians.[73] In a retrospective analysis of 17,487 patients with chronic HCV infection in the Department of Veterans Affairs healthcare system, age did not significantly impact the SVR rates, even when analyzed using multivariate models (Figure 10).[72]
Degree of Hepatic Fibrosis
Advanced fibrosis is typically defined as F3 (pre-cirrhosis or bridging fibrosis) and F4 (cirrhosis) on liver biopsy. In earlier DAA trials, lower SVR rates were observed among persons with compensated cirrhosis.[64,74] In subsequent trials, newer medication, longer duration of treatment, and modified therapy (with the addition of ribavirin) have all contributed to improved responses in patients with compensated cirrhosis.[63,75,76,77] The one exception to this has been treatment of persons with genotype 3 HCV and cirrhosis, a group that has emerged as the hardest to treat in the DAA era. Nevertheless, two regimens— glecaprevir-pibrentasvir and sofosbuvir-velpatasvir have been shown to achieve high SVR rates in persons with genotype 3 HCV and compensated cirrhosis.[56,57] Similarly, when using currently recommended DAA regimens for persons with compensated cirrhosis, studies show SVR12 rates are greater than 90% across all genotypes.[78] Individuals with decompensated cirrhosis (Child-Turcotte-Pugh class B or C) treated with 12 weeks of ledipasvir-sofosbuvir have lower SVR rates (86 to 87%) compared with SVR rates of 95% or greater in similarly treated persons without cirrhosis.[79] In a similar study, SVR12 rates of 94% were observed in persons with decompensated cirrhosis when treated with a 12-week regimen of sofosbuvir-velpatasvir plus ribavirin.[80]
Prior Treatment
Type of Treatment Response with Prior Failure
Prior treatment failure with interferon-based therapy does not significantly impact treatment response to DAA therapy. In general, when using DAA therapy for persons previously treated with an interferon-based regimen, more than 95% should achieve an SVR with retreatment. In contrast, prior treatment failure with a regimen that consisted of or included DAA therapy can impact retreatment response rates, especially if certain HCV resistance-associated substitutions developed during treatment.[81,82] Nevertheless, with the multiple DAA options now available, most persons with prior DAA treatment failure have very good options available.[83] The addition of ribavirin or extension of therapy duration may be required with some regimens to overcome the treatment refractory aspect of persons who previously experienced treatment failure.[83,84]
Summary Points
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- 6.van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584-93.[PubMed Abstract] -
- 7.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. When and in whom to initiate HCV therapy.
- 8.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. Monitoring patients who are starting HCV treatment, are on treatment, or have completed therapy.
- 9.Burgess SV, Hussaini T, Yoshida EM. Concordance of sustained virologic response at weeks 4, 12 and 24 post-treatment of hepatitis c in the era of new oral direct-acting antivirals: A concise review. Ann Hepatol. 2016;15:154-9.[PubMed Abstract] -
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- 12.Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology. 2008;135:821-9.[PubMed Abstract] -
- 13.Morisco F, Granata R, Stroffolini T, et al. Sustained virological response: a milestone in the treatment of chronic hepatitis C. World J Gastroenterol. 2013;19:2793-8.[PubMed Abstract] -
- 14.Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis. 2011;52:889-900.[PubMed Abstract] -
- 15.Simmons B, Saleem J, Hill A, Riley RD, Cooke GS. Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis. 2016;62:683-694.[PubMed Abstract] -
- 16.Page K, Hahn JA, Evans J, et al. Acute hepatitis C virus infection in young adult injection drug users: a prospective study of incident infection, resolution, and reinfection. J Infect Dis. 2009;200:1216-26.[PubMed Abstract] -
- 17.Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16:27-38.e4.[PubMed Abstract] -
- 18.Chan J, Gogela N, Zheng H, et al. Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12 Months Post-treatment. Dig Dis Sci. 2018;63:486-492.[PubMed Abstract] -
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- 20.Pockros PJ, Hamzeh FM, Martin P, et al. Histologic outcomes in hepatitis C-infected patients with varying degrees of virologic response to interferon-based treatments. Hepatology. 2010;52:1193-200.[PubMed Abstract] -
- 21.Laursen TL, Siggaard CB, Kazankov K, et al. Time-dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct-acting antiviral therapy of chronic hepatitis C. J Viral Hepat. 2020;27:28-35.[PubMed Abstract] -
- 22.Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2017. pii: S0168-8278(17)32273-0.[PubMed Abstract] -
- 23.Calvaruso V, Cabibbo G, Cacciola I, et al. Incidence of Hepatocellular Carcinoma in Patients With HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2018;155:411-21.e4.[PubMed Abstract] -
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- 25.Konjeti VR, John BV. Interaction Between Hepatocellular Carcinoma and Hepatitis C Eradication With Direct-acting Antiviral Therapy. Curr Treat Options Gastroenterol. 2018;16:203-214.[PubMed Abstract] -
- 26.Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2017;153:996-1005.e1.[PubMed Abstract] -
- 27.Singal AG, Lim JK, Kanwal F. AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review. Gastroenterology. 2019;156:2149-57.[PubMed Abstract] -
- 28.ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). . Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol. 2016;65:734-40.[PubMed Abstract] -
- 29.Cabibbo G, Petta S, Calvaruso V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther. 2017;46:688-695.[PubMed Abstract] -
- 30.Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther. 2018;48:127-37.[PubMed Abstract] -
- 31.Singal AG, Rich NE, Mehta N, et al. Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. Gastroenterology. 2019;156:1683-92.e1.[PubMed Abstract] -
- 32.Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol. 2011;9:509-516.e1.[PubMed Abstract] -
- 33.Berenguer J, Rodríguez E, Miralles P, et al. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus. Clin Infect Dis. 2012;55:728-36.[PubMed Abstract] -
- 34.Backus LI, Belperio PS, Shahoumian TA, Mole LA. Direct-acting antiviral sustained virologic response: Impact on mortality in patients without advanced liver disease. Hepatology. 2018;68:827-38.[PubMed Abstract] -
- 35.Backus LI, Belperio PS, Shahoumian TA, Mole LA. Impact of Sustained Virologic Response with Direct-Acting Antiviral Treatment on Mortality in Patients with Advanced Liver Disease. Hepatology. 2019;69:487-97.[PubMed Abstract] -
- 36.Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677-84.[PubMed Abstract] -
- 37.Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin Infect Dis. 2015;61:730-40.[PubMed Abstract] -
- 38.Cabibbo G, Celsa C, Calvaruso V, et al. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol. 2019;71:265-73.[PubMed Abstract] -
- 39.Singal AG, Rich NE, Mehta N, et al. Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma. Gastroenterology. 2019;157:1253-63.e2.[PubMed Abstract] -
- 40.Arora SS, Axley P, Ahmed Z, et al. Decreasing frequency and improved outcomes of hepatitis C-related liver transplantation in the era of direct-acting antivirals - a retrospective cohort study. Transpl Int. 2019;32:854-64.[PubMed Abstract] -
- 41.Kim D, Li AA, Perumpail BJ, et al. Changing Trends in Etiology-Based and Ethnicity-Based Annual Mortality Rates of Cirrhosis and Hepatocellular Carcinoma in the United States. Hepatology. 2019;69:1064-74.[PubMed Abstract] -
- 42.El-Serag HB, Hampel H, Yeh C, Rabeneck L. Extrahepatic manifestations of hepatitis C among United States male veterans. Hepatology. 2002;36:1439-45.[PubMed Abstract] -
- 43.Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol. 2010;8:1017-29.[PubMed Abstract] -
- 44.Tang L, Marcell L, Kottilil S. Systemic manifestations of hepatitis C infection. Infect Agent Cancer. 2016;11:29.[PubMed Abstract] -
- 45.Ioannou GN, Feld JJ. What Are the Benefits of a Sustained Virologic Response to Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection? Gastroenterology. 2019;156:446-460.e2.[PubMed Abstract] -
- 46.Li J, Gordon SC, Zhou Y, et al. Sex Differences in Extrahepatic Outcomes After Antiviral Treatment for Hepatitis C. Am J Gastroenterol. 2021;116:576-83.[PubMed Abstract] -
- 47.Mahale P, Engels EA, Li R, et al. The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection. Gut. 2018;67:553-561.[PubMed Abstract] -
- 48.Arase Y, Suzuki F, Suzuki Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49:739-44.[PubMed Abstract] -
- 49.Conjeevaram HS, Wahed AS, Afdhal N, Howell CD, Everhart JE, Hoofnagle JH. Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology. 2010;140:469-77.[PubMed Abstract] -
- 50.Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82.[PubMed Abstract] -
- 51.Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alfa2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55.[PubMed Abstract] -
- 52.Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-65.[PubMed Abstract] -
- 53.Zeuzem S, Foster GR, Wang S, et al. Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection. N Engl J Med. 2018;378:354-369.[PubMed Abstract] -
- 54.Feld JJ, Foster GR. Second generation direct-acting antivirals - Do we expect major improvements? J Hepatol. 2016;65:S130-S142.[PubMed Abstract] -
- 55.Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review. Ann Intern Med. 2017;166:637-48.[PubMed Abstract] -
- 56.Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373:2608-17.[PubMed Abstract] -
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- 76.Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis. 2017;17:1062-1068.[PubMed Abstract] -
- 77.Asselah T, Bourgeois S, Pianko S, et al. Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1-6 and compensated cirrhosis or advanced fibrosis. Liver Int. 2018;38:443-450.[PubMed Abstract] -
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- 79.Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology. 2015;149:649-59.[PubMed Abstract] -
- 80.Curry MP, O'Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373:2618-28.[PubMed Abstract] -
- 81.Kwo PY, Badshah MB. Treatment of HCV in Patients who Failed First-Generation PI Therapy: a Review of Current Literature. Curr Gastroenterol Rep. 2015;17:462.[PubMed Abstract] -
- 82.Wyles DL. Resistance to DAAs: When to Look and When It Matters. Curr HIV/AIDS Rep. 2017;14:229-237.[PubMed Abstract] -
- 83.Zuckerman A, Chastain CA, Naggie S. Retreatment Options Following HCV Direct Acting Antiviral Failure. Curr Treat Options Infect Dis. 2017;9:389-402.[PubMed Abstract] -
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- Andersen ES, Moessner BK, Christensen PB, et al. Lower liver stiffness in patients with sustained virological response 4 years after treatment for chronic hepatitis C. Eur J Gastroenterol Hepatol. 2011;23:41-4.[PubMed Abstract] -
- Butt AA, Wang X, Moore CG. Effect of hepatitis C virus and its treatment on survival. Hepatology. 2009;50:387-92.[PubMed Abstract] -
- Cabibbo G, Petta S, Calvaruso V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther. 2017;46:688-95.[PubMed Abstract] -
- Campos-Varela I, Castells L, Esteban JI, et al. Twelve-week posttreatment follow-up to predict sustained virologic response for recurrent hepatitis C infection in liver recipients. Transplantation. 2012;93:450-3.[PubMed Abstract] -
- Chang CY, Nguyen P, Le A, et al. Real-world experience with interferon-free, direct acting antiviral therapies in Asian Americans with chronic hepatitis C and advanced liver disease. Medicine (Baltimore). 2017;96:e6128.[PubMed Abstract] -
- Cheung MCM, Walker AJ, Hudson BE, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016;65:741-747.[PubMed Abstract] -
- Dieperink E, Pocha C, Thuras P, Knott A, Colton S, Ho SB. All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C. Dig Dis Sci. 2014;59:872-80.[PubMed Abstract] -
- El-Sherif O, Jiang ZG, Tapper EB, et al. Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection. Gastroenterology. 2018;154:2111-2121.e8.[PubMed Abstract] -
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Last Updated: April 9th, 2021Authors:John D. Scott, MD,John D. Scott, MD
Assistant Director Hepatitis and Liver Clinic
Harborview Medical Center
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: Consulting: Gilead SciencesH. Nina Kim, MDH. Nina Kim, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: Grant to institution: Gilead SciencesReviewer:Maria A. Corcorran, MD, MPHMaria A. Corcorran, MD, MPH
Acting Assistant Professor
Division of Allergy & Infectious Diseases
University of WashingtonTable of ContentsCitations
Additional References
Figures
Figure 1. Sustained Virologic Response 12 (SVR 12)This graphic shows an example of an SVR12 in a person who received 12 weeks of HCV treatment. The SVR12 is shown by the undetectable HCV RNA 12 weeks after treatment was stopped.Source: illustration by David H. Spach, MDFigure 2. Liver Stiffness in Persons With or Without SVR12In this review and meta-analysis, investigators compared liver stiffness measured by vibration-controlled transient elastography (VCTE) before and after treatment. This graph compares liver stiffness before and after treatment in adults who attained SVR12 with those who do not achieve SVR12. The decline in liver stiffness among persons who achieved an SVR12 was greater when treated with direct-acting antiviral therapy than with interferon-based therapy (decrease of 5.1 kPa versus decrease of 2.8kPa).Source: Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16:27-38.e4.Figure 3. Liver Stiffness Treatments in Persons Treated with Direct-Acting Antiviral TherapyThis study enrolled 70 persons who received direct-acting antiviral therapy for chronic HCV infection. This graphic shows liver stiffness measurement at baseline, end-of-treatment, and 12-month posttreatment. Overall, 48.6% of the participants had a 30% or greater improvement in the liver stiffness measurement (at end of follow-up compared with baseline).Source: Chan J, Gogela N, Zheng H, et al. Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12 Months Post-treatment. Dig Dis Sci. 2018;63:486-92.Figure 4. Clinical Outcome by Response to Treatment in Patients with Chronic Hepatitis C and Advanced FibrosisThis retrospective study was performed in Europe and Canada and examined whether sustained virologic response following hepatitis C treatment correlated with clinical outcomes. The major finding was that treatment was associated with improved clinical outcomes, primarily because of lower rates of liver failure.Source: Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677-84.Figure 5. 5-Year Survival Rate following HCV Treatment Based on SVR ResponseThis graphic is based on data from 31 studies published from 2000 to 2014 that included 33,360 participants. The 5-year mortality rates shown are based on whether the patient achieved an SVR.Source: Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin Infect Dis. 2015;61:730-40.Figure 6. Impact of SVR on Mortality Rates with DAA TherapySource: Backus LI, Belperio PS, Shahoumian TA, Mole LA. Direct-Acting Antiviral Sustained Virologic Response: Impact on Mortality in Patients without Advanced Liver Disease. Hepatology. 2018 Jan 29. [Epub ahead of print]Figure 7. HCV Treatment and Outcome of Extrahepatic ManifestationsSource: Mahale P, Engels EA, Li R, et al. The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection. Gut. 2018;67:553-61.Figure 8. Sustained Virologic Response Rates (Unadjusted), by RaceThis graphic shows unadjusted sustained virologic response rates with DAA therapy among persons who are White, Black, Hispanic, and persons of another race.Source: Su F, Green PK, Berry K, Ioannou GN. The association between race/ethnicity and the effectiveness of direct antiviral agents for hepatitis C virus infection. Hepatology. 2017;65:426-38.Figure 9. Sustained Virologic Response Rates (Adjusted Odds Ratio), by RaceThis graphic shows adjusted odds ratio sustained virologic response rates with DAA therapy among persons who are White, Black, Hispanic, and persons of another race. This model includes the following baseline characteristics: age, genotype/subgenotype, regimen, gender, HCV viral load, platelet count, serum bilirubin level, serum albumin level, alcohol use disorder, diabetes, cirrhosis, decompensated cirrhosis, HCC, liver transplantation, and prior treatment.Source: Su F, Green PK, Berry K, Ioannou GN. The association between race/ethnicity and the effectiveness of direct antiviral agents for hepatitis C virus infection. Hepatology. 2017;65:426-38.Figure 10. Sustained Virologic Response, by Age GroupIn this retrospective analysis of DAA treatment of HCV in the Department of Veterans Affairs health care system, investigators analyzed treatment response based on age. As shown in this graph, excellent SVR rates occurred across all age groups, including those 75 years of age and older.Source: Su F, Beste LA, Green PK, Berry K, Ioannou GN. Direct-acting antivirals are effective for chronic hepatitis C treatment in elderly patients: a real-world study of 17 487 patients. Eur J Gastroenterol Hepatol. 2017;29:686-93.2Lesson 2 Making a Decision on When to Initiate HCV Therapy
- Learning Objectives
- Summarize current recommendations for HCV treatment indications in persons with chronic HCV
- Discuss relative and absolute contradictions for HCV treatment with direct-acting antiviral therapy
- List specific monitoring studies when HCV treatment is deferred
- Quick ReferenceMaking a Decision on When to Initiate HCV Therapy Core Concepts
- Persons with HCV and HIV coinfection
- Persons with HCV who have decompensated cirrhosis
- Persons who develop HCV post-liver transplantation
- Persons with HCV and renal impairment
- Persons with HCV who are post-renal transplantation
- Persons with acute HCV infection
- Pregnant women with HCV
- Children with HCV
- Indications for Treatment
- Contraindications for Treatment
- Treatment Readiness
- Timing of Initiation of Treatment
- Monitoring and Follow-Up if Not Treated
- The availability of highly effective, convenient, safe, well-tolerated therapy has changed the landscape for HCV treatment.
- Nearly all persons with chronic HCV will benefit from therapy; persons with a severely limited lifespan (less than 12 months) are the exception.
- For nearly all persons with chronic HCV, DAAs should be initiated and not deferred due to ongoing substance use or fibrosis requirements.
- In situations when HCV treatment is deferred (for whatever reason), the individual should periodically undergo reevaluation for disease progression and reconsideration of treatment, with the frequency of reevaluation individualized based on the person’s current fibrosis stage, likely fibrosis progression rate, and other factors that may influence treatment readiness.
- Summary Points
Indications for Treatment
Background
Multiple studies have shown that successful antiviral therapy of chronic hepatitis C virus (HCV) infection dramatically reduces both liver-related morbidity (including rates of end-stage liver disease and hepatocellular carcinoma) and mortality, as well as all-cause mortality.[1,2,3,4] Direct-acting antiviral (DAA) treatment for HCV has proven to be much safer, better tolerated, and more effective than treatments used in the interferon era, now rendering the decision to initiate therapy much easier. The AASLD-IDSA HCV Guidance notes that evidence clearly supports treatment of nearly all persons with chronic HCV infection.[5] Decisions regarding initiating therapy will naturally be influenced by the individual’s willingness and readiness to undertake treatment.
Generally Accepted Indicators for Treatment
The AASLD-IDSA HCV Guidance previously provided a priority ranking for treatment based on clinical factors and public health considerations.[5] This priority ranking arose, in part, due to the relatively limited infrastructure capable of treating the surge of persons with chronic HCV infection who had been waiting to receive treatment with new DAA therapy.[5] This treatment priority ranking is no longer used in the AASLD-IDSA HCV Guidance; instead, the current guidance emphasizes that all persons, except for those with a short (i.e. less than 12 months) life expectancy, should receive treatment for chronic HCV infection.[5] The recommendation to treat virtually all persons with chronic HCV infection stems from multiple factors, including the very high sustained virologic response (SVR) rates with current DAA therapy, the safety and tolerability of DAA therapy, and the preponderance of data demonstrating benefit across a spectrum of clinical outcomes with achievement of SVR.[5,6] The AASLD-IDSA HCV Guidance also addresses the following unique populations that may require special considerations when weighing treatment decisions:[5]
Contraindications for Treatment
Absolute Contraindications
In the DAA era, there are relatively few absolute contraindications to HCV treatment with DAAs. The AASLD-IDSA HCV Guidance recommends against treating persons with a short life expectancy that cannot be improved by HCV treatment, liver transplantation, or another directed therapy.[5] Available data from animal studies indicate that ribavirin has significant teratogenic and embryocidal adverse effects.[7] Accordingly, the use of ribavirin is contraindicated in women who are pregnant, women who may become pregnant, or men whose female partners are pregnant or trying to conceive.[8,9] Persons with chronic HCV who are of reproductive age and are to receive a regimen that includes ribavirin should be advised to use two forms of contraception during treatment and for at least 6 months following the end of treatment.[10] With DAA therapy, decompensated cirrhosis, renal failure, and recent or active substance use (e.g. drugs and alcohol) are not contraindications to treatment.[11,12,13] Indeed, multiple studies involving persons with past or current injection-drug use have shown very good adherence and excellent SVR rates with HCV DAA therapy.[14,15,16,17]
Relative Contraindications
In addition to some absolute contraindications, there are several situations in which the clinician should exert careful consideration before starting HCV treatment: active severe substance use disorder that would interfere with making follow-up appointments; psychiatric issues that are not well controlled; and social issues that may negatively impact an individual’s ability to adhere with therapy, to make visits for monitoring treatment safety, or to show up for scheduled office visits.[18,19] Since there are no large-scale studies on the use of pangenotypic DAA regimens during pregnancy, the AASLD-IDSA HCV Guidance recommends initiation of HCV therapy before trying to conceive.[5] For children with HCV, DAA therapy should be deferred until at least 3 years of age, as there are no approved DAA regimens for children younger than 3 years of age.[5] Ledipasvir-sofosbuvir is approved for the treatment of HCV genotypes 1, 4, 5, or 6 starting at 3 years of age, with the pangenotypic regimens sofosbuvir-velpatasvir and glecaprevir-pibrentasvir approved starting at ages 6 and 12 years, respectively.[5]
Treatment Readiness
Assessing Readiness
An individual’s readiness to start therapy can be difficult to assess, but a checklist can be used as a general guide (Figure 1). It is important to have a frank discussion with each person considering HCV treatment about the chance of cure, the potential side effects of therapy, the cost of treatment, and, if using a regimen that includes ribavirin, the impact of treatment on their quality of life, including deferring pregnancy.
Pretreatment Counseling
In addition, the HCV pretreatment discussion should cover counseling on adherence, drug interactions, potential side effects, contact numbers for after-hour questions or issues, and specific information on follow-up visits. Given the high cost of DAAs and the potential for drug resistance, it is very important that persons considering HCV treatment understand fully the importance of remaining 100% adherent with the treatment regimen.
Timing of Initiation of Treatment
The availability of DAAs has provided tremendous opportunities for highly effective, convenient, well-tolerated therapy. Although the high cost of these medications remains a concern, the cost of DAA therapy has significantly decreased over the past several years, and many states are now covering DAA therapy for all Medicaid and Medicare patients without restriction. Nevertheless, some state Medicaid plans continue to have fibrosis, sobriety, and prescriber restrictions for DAA therapy.[20] These restrictions are not in step with AASLD-IDSA HCV Guidance and represent a suboptimal and short-sighted approach to care.[5,21,22,23] If possible, DAA therapy should be initiated in all persons with chronic HCV and not deferred due to ongoing substance use or fibrosis requirements.
Advanced Age and Comorbid Conditions
Many persons living with chronic HCV infection in the United States are over 50 years of age. With the availability of new, highly effective, safe, well-tolerated regimens, it is likely that more interest and experience will accumulate in treating persons with advanced age. Notably, some clinical trials with newer direct-acting antivirals have enrolled persons older than 70 years of age, but overall relatively little experience exists with treatment of HCV in elderly populations. In some circumstances, individuals with chronic HCV may have advanced age and minimal HCV-related fibrosis, and thus HCV-related liver disease may not be expected to play a major role in shortening their lifespan. In addition, some individuals may have limited life expectancy due to other comorbid conditions, and as such, HCV treatment would not be expected to alter their quality of life or life expectancy. Thus, in some situations involving persons with advanced age or significant medical comorbidities associated with an expected short lifespan (less than 12 months), it may be sensible to withhold therapy.
Obtaining Authorization and Payment for Medications
If an individual with chronic HCV has been deemed an appropriate candidate for antiviral therapy, the medical provider should begin investigating payment for the HCV treatment. Because these antiviral agents are quite costly, they typically need to be preapproved. The authorization process may take several weeks, with the exact time dependent on the insurance coverage and state of residence. Restrictions vary by state and insurer as to who can prescribe DAAs, as well as the level of fibrosis and sobriety. In addition, individuals with HCV waiting to start treatment should be warned in advance that the DAA medication approval process may be drawn out.
Monitoring and Follow-Up if Not Treated
General Recommendations for Monitoring and Follow-Up
There may be various reasons for deferring HCV treatment, including specific barriers that are present for the individual considering treatment, such as active psychosocial instability, a competing severe illness, or insurance denial. At least annual follow-up is recommended for these individuals. During these follow-up visits, counseling should occur regarding behaviors that will optimize liver health, including avoiding a diet high in saturated fat, achieving an optimal body weight, limiting intake of hepatotoxic medications, and abstaining from or limiting alcohol intake. Medical providers should be aware of indicators associated with accelerated hepatic fibrosis progression, such as older age at the time of HCV infection, male sex, alcohol consumption, nonalcoholic steatohepatitis (NASH), genotype 3 HCV, and coinfection with HIV and/or hepatitis B virus (HBV) (Figure 2).[24,25,26] Individuals who have indicators associated with accelerated hepatic fibrosis should receive counseling regarding the risk and impact of accelerated hepatic fibrosis progression; in this setting, clinicians should attempt to promptly initiate HCV treatment. These individuals also should receive information and education on the warning signs and symptoms of liver dysfunction, including jaundice, melena, clay-colored stools, confusion, abdominal distention, and lower extremity edema.[27,28] Finally, persons with chronic HCV should receive counseling on the HCV transmission and strategies on how to prevent transmission of HCV to others.
Reassessing Hepatic Fibrosis
For individuals with chronic HCV and mild to moderate fibrosis (F0 to F2), progression of liver fibrosis can occur. As such, they should undergo annual monitoring with laboratory studies that include aspartate aminotransferase (AST), alanine aminotransferase (ALT), complete blood cell count (CBC), and platelet count. From these basic laboratory tests, an AST to Platelet Ratio Index (APRI) and/or a FIB-4 index can be calculated.[29,30] In addition, subsequent noninvasive testing to reevaluate hepatic fibrosis, such as FibroSure, FibroTest, ActiTest, or transient elastography, is recommended.[31,32] The optimal interval for reevaluating hepatic fibrosis may depend on clinical factors and the stage of liver disease. For individuals with cirrhosis, hepatocellular carcinoma (HCC) surveillance with a liver ultrasound, with or without alpha-fetoprotein (AFP), is recommended every 6 months.[33,34]
Monitoring and Assistance with an Unstable Psychosocial Situation
Individuals living with chronic HCV who have an unstable psychosocial situation should have these issues addressed by referring to appropriate resources, such as a mental health professional or a substance use disorder counselor. Ongoing alcohol use disorder is a high priority to address since it can markedly accelerate hepatic fibrosis; for this reason, persons with chronic HCV should receive a clear and strong counseling message to completely abstain from alcohol intake.[31,35] Special effort should be made to address psychosocial issues in persons with advanced fibrosis (F3 or F4), since they have a more immediate need for HCV treatment.
Summary Points
- 1.Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158:329-37.[PubMed Abstract] -
- 2.Tada T, Kumada T, Toyoda H, et al. Viral eradication reduces all-cause mortality, including non-liver-related disease, in patients with progressive hepatitis C virus-related fibrosis. J Gastroenterol Hepatol. 2017;32:687-694.[PubMed Abstract] -
- 3.van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012 ;308:2584-93.[PubMed Abstract] -
- 4.Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677-84.[PubMed Abstract] -
- 5.AASLD-IDSA. HCV Guidance: Recommendations for testing, management, and treating hepatitis C. When and in whom to initiate HCV therapy.
- 6.Marcellin F, Roux P, Protopopescu C, Duracinsky M, Spire B, Carrieri MP. Patient-reported outcomes with direct-acting antivirals for the treatment of chronic hepatitis C: current knowledge and outstanding issues. Expert Rev Gastroenterol Hepatol. 2017;11:259-268.[PubMed Abstract] -
- 7.Ferm VH, Willhite C, Kilham L. Teratogenic effects of ribavirin on hamster and rat embryos. Teratology. 1978;17:93-101.[PubMed Abstract] -
- 8.Feld JJ, Jacobson IM, Sulkowski MS, Poordad F, Tatsch F, Pawlotsky JM. Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection. Liver Int. 2017;37:5-18.[PubMed Abstract] -
- 9.Roberts SS, Miller RK, Jones JK, et al. The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003-2009. Birth Defects Res A Clin Mol Teratol. 2010;88:551-9.[PubMed Abstract] -
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- 16.Grebely J, Dore GJ, Zeuzem S, et al. Efficacy and Safety of Sofosbuvir/Velpatasvir in Patients With Chronic Hepatitis C Virus Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ASTRAL Trials. Clin Infect Dis. 2016;63:1479-1481.[PubMed Abstract] -
- 17.Grebely J, Hajarizadeh B, Dore GJ. Direct-acting antiviral agents for HCV infection affecting people who inject drugs. Nat Rev Gastroenterol Hepatol. 2017;14:641-651.[PubMed Abstract] -
- 18.Grebely J, Oser M, Taylor LE, Dore GJ. Breaking down the barriers to hepatitis C virus (HCV) treatment among individuals with HCV/HIV coinfection: action required at the system, provider, and patient levels. J Infect Dis. 2013;207 Suppl 1:S19-25.[PubMed Abstract] -
- 19.Meyer JP, Moghimi Y, Marcus R, Lim JK, Litwin AH, Altice FL. Evidence-based interventions to enhance assessment, treatment, and adherence in the chronic Hepatitis C care continuum. Int J Drug Policy. 2015;26:922-35.[PubMed Abstract] -
- 20.Hepatitis C. State of Medicaid Access. Center for Health Law and Policy Innovation of Harvard Law School (CHLPI) and the National Viral Hepatitis Roundtable (NVHR).[CHLPI and NVHR] -
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- 22.Butt AA, Yan P. Natural history of hepatitis C virus infection in a large national seroconversion cohort in the direct-acting antiviral agent era: Results from ERCHIVES. J Viral Hepat. 2021 Mar 24. Online ahead of print.[PubMed Abstract] -
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[PubMed Abstract] -
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- 30.Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53:726-36.[PubMed Abstract] -
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- 34.Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358-80.[PubMed Abstract] -
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- Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054-8.
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- Fartoux L, Chazouillères O, Wendum D, Poupon R, Serfaty L. Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. Hepatology. 2005;41:82-7.[PubMed Abstract] -
- Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562-9.[PubMed Abstract] -
- Hellard ME, Jenkinson R, Higgs P, et al. Modelling antiviral treatment to prevent hepatitis C infection among people who inject drugs in Victoria, Australia. Med J Aust. 2012;196:638-41.[PubMed Abstract] -
- Martin NK, Hickman M, Hutchinson SJ, Goldberg DJ, Vickerman P. Combination interventions to prevent HCV transmission among people who inject drugs: modeling the impact of antiviral treatment, needle and syringe programs, and opiate substitution therapy. Clin Infect Dis. 2013;57 Suppl 2:S39-45.[PubMed Abstract] -
- Martin NK, Vickerman P, Grebely J, et al. Hepatitis C virus treatment for prevention among people who inject drugs: Modeling treatment scale-up in the age of direct-acting antivirals. Hepatology. 2013;58:1598-609.[PubMed Abstract] -
- Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology. 2008;134;1699-714.[PubMed Abstract] -
- Poynard T, Bedossa P, Opolon P. Lancet. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-32.[PubMed Abstract] -
- Schmid P, Bregenzer A, Huber M, et al. Progression of Liver Fibrosis in HIV/HCV Co-Infection: A Comparison between Non-Invasive Assessment Methods and Liver Biopsy. PLoS One. 2015;10:e0138838.[PubMed Abstract] -
- Thomas DL, Villano SA, Riester KA, et al. Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected mothers. Women and Infants Transmission Study. J Infect Dis. 1998;177:1480-8.[PubMed Abstract] -
Last Updated: April 19th, 2021Author:Maria A. Corcorran, MD, MPHMaria A. Corcorran, MD, MPH
Acting Assistant Professor
Division of Allergy & Infectious Diseases
University of WashingtonReviewer:David H. Spach, MDDavid H. Spach, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: NoneTable of ContentsCitations
Additional References
Figures
Figure 2. Factors Associated with Accelerated Hepatic FibrosisSource: American Association for the Study of Liver Disease, the Infectious Diseases Society of America. When and in whom to initiate HCV therapy. Recommendations for testing, management, and treating hepatitis C.3Lesson 3 Addressing Structural Barriers to HCV Treatment
- Learning Objectives
- Summarize the key steps in hepatitis C care continuum
- List major barriers to hepatitis C testing
- Describe approaches for improving linkage to hepatitis C care services
- Discuss strategies for expanding hepatitis C medical provider capacity
- Addressing Structural Barriers to HCV Treatment
- Background
- The Path to HCV Cure: HCV Care Continuum
- HCV Testing: Access, Efficiency, and Reimbursement
- Improving Services for Linkage-to-Care
- Expanding Medical Provider Capacity
- Expanding Settings for HCV Clinical Care and Treatment
- Insurance and Medicaid Restrictions to HCV Treatment Access
- Summary Points
- Citations
- Additional References
- Figures
- Tables
- Quick ReferenceAddressing Structural Barriers to HCV Treatment Core Concepts
- Decrease new HCV infections by 20% for 2025 and by 90% for 2030
- Reduce HCV-related death rate by 25% for 2025 and by 65% for 2030
- Reduce rate of new HCV infections in persons who inject drugs by 25% for 2025 and by 90% for 2030
- Increase proportion of persons with HCV viral clearance by 35% for 2025 and by 85% for 2030
- Background
- The Path to HCV Cure: HCV Care Continuum
- HCV Testing: Access, Efficiency, and Reimbursement
- Improving Services for Linkage-to-Care
- Project ECHO: The Extension for Community Healthcare Outcomes (ECHO) model was developed at the University of New Mexico Health Sciences Center as an innovative strategy to improve access to treatment for underserved populations who have complex medical problems, including hepatitis C. In this model, providers comanage their initial patient cohort via a confidential teleconferencing platform with input from experts and their community of peers.[41] Further, the ECHO program is constructed such that in addition to providing direct consultation, subject-matter experts provide didactic training and facilitate collaborative learning for medical providers to gain competence and confidence in providing HCV treatment. This program has shown that hepatitis C treatment outcome (sustained virologic response rates) was comparable for patients treated at ECHO sites throughout New Mexico and patients treated at the University of New Mexico viral hepatitis clinic.[41] A follow-up study that involved the New Mexico Veterans Affairs (VA) hepatitis C ECHO program demonstrated that the 6,431 patients who had a primary care provider who attended at least one ECHO session had higher HCV treatment rates compared to the 32,322 VA primary care providers who did not participate in ECHO, but SVR rates were the same in the two groups.[42] Other adaptations of the ECHO model have been shown to similarly increase the number of medical provider trained to provide HCV treatment in non-specialist settings.[43,44]
- Electronic and Remote Consultation: Less intensive models such as electronic/remote consult services with a team-based approach to HCV treatment in primary care settings have also been associated with increased rates of HCV treatment. For example, an initiative was implemented in a safety net health system in California in which primary care providers were offered a 4-hour HCV treatment overview and ongoing support for providing HCV treatment through an electronic consultation system.[45] As a result, there was a 3-fold increase in HCV treatment in the post-implementation period compared to the pre-implementation period.[45]. The National Clinician’s Consultation Center, based at the University of California at San Francisco, provides clinician-to-clinician advice on HCV monoinfection and HCV-HIV coinfection management; this service provides the option to submit a clinical case online or to call for a phone consultation (844) 437-4636, available Monday-Friday 9 a.m. to 8 p.m. EST.
- Expanding Medical Provider Capacity
- Expanding Settings for HCV Clinical Care and Treatment
- State of Medicaid Access The National Viral Hepatitis Roundtable and Harvard Center for Health Law and Policy Innovation provide an online, state-by-state assessment of DAA access through Medicaid programs (see Hepatitis C: State of Medicaid Access).[57]
- Patient Advocate Foundation: The Patient Advocate Foundation's Hepatitis C CareLine is a hotline (800-532-5274) for both patients and medical providers: this is a nonprofit organization that provides assistance, including case management services, to persons living with chronic HCV infection. The Hepatitis C CareLine has case managers that will assist patients in efforts to try and access new medications to treat hepatitis C.
- Patient Assistance Programs: The Target HIV Site has a Patient Assistance Program for Hepatitis C Medications Costs online resource for patient assistance programs, including programs accessed through foundations and from the pharmaceutical companies that manufacture the medications.
- Insurance and Medicaid Restrictions to HCV Treatment Access
- There is a real opportunity to achieve HCV elimination by reducing the HCV viral burden on a population-based level through large-scale treatment as prevention with DAAs. There are, however, a number of structural barriers and gaps in the HCV care cascade that pose challenges to this goal.
- Identifying persons with HCV through widespread screening has been hampered by limited testing access to testing and an inefficient testing algorithm that still relies on a blood draw and laboratory-based assessment of HCV RNA to confirm chronic infection. Reliable point-of-care RNA testing is needed to facilitate diagnosis and linkage.
- Linkage to care is another area in need of improvement in the care cascade. Strategies such as navigation services or contingency management have proven successful but are resource-intensive to sustain.
- In order to expand HCV treatment, more medical providers and heath care settings must be called upon to deliver HCV care, which has historically been the purview of specialists and hospital-based settings. Non-traditional care settings and nonspecialist providers have been shown to deliver HCV treatment with comparable success rates.
- Insurance-mandated prerequisites and prior authorization remain among the major structural barriers to more equitable and expansive HCV care. Exclusions based on disease severity or substance use continue to restrict access to key populations despite recommendations against such exclusions and emphasizing the importance of treating all individuals with chronic or acute HCV infection.
- Summary Points
Background
Overview
There are an estimated 4.1 million Americans infected with hepatitis C virus (HCV) infection, making hepatitis C the most common blood-borne infectious disease in the United States.[1] It is also associated with significant morbidity and mortality, driven largely by progression to liver cirrhosis, liver cancer and death. Hepatitis C infection is often associated with substance use, mental health disorders and poverty, all of which contribute to the stigma and discrimination associated with this infection. Since 2014, hepatitis C has become one of the few chronic viral infections that can be cured through the use of safe, well-tolerated, oral direct-acting antiviral (DAA) medications. Current recommended DAA therapy cures HCV infection in 95% or greater of treated persons.[2] The availability of DAA therapy has revolutionized the management of hepatitis C and provides an opportunity not only to prevent the negative health consequences of hepatitis C at the individual level but also to prevent new infections by reducing the reservoir of people infected with HCV who can, in turn, transmit HCV to others. This concept of treatment as prevention is supported by modeling data and more recent real-world data suggesting that treating a significant proportion of people infected with hepatitis C can over time lead to reductions in both incident and prevalent infections over time.[3,4,5]
CDC 2025 and 2030 HCV Elimination Goals
The Division of Viral Hepatitis at the Centers for Disease Control and Prevention has issued a 2025 strategic plan for HCV elimination that outlines the following goals for 2025 and 2030 when compared to a baseline in 2017 (Figure 1).[6]
These HCV elimination goals have proved challenging in the midst of the ongoing opioid epidemic in the United States.[7,8,9] Indeed, in 2019, there was a 70% increase in incident HCV infection compared to new infections in 2015.[10] Multilevel barriers at the patient, provider, and system levels contribute to difficulties with access to HCV testing and treatment, substance use treatment and harm reduction services required to achieve HCV elimination goals. This topic review will identify and discuss the major structural barriers to HCV treatment in the United States.
The Path to HCV Cure: HCV Care Continuum
The “care continuum” or the “cascade of care” is a public health framework that outlines the benchmarks a society needs to track in order to optimize care for their population and was first introduced in the HIV arena (Figure 2).[11,12] The steps in the HCV care cascade include diagnosis of HCV infection, linkage to HCV care, evaluation for HCV treatment, prescription of HCV treatment, initiation of treatment, completion of treatment, and measurement of HCV RNA level at 12 weeks after the end of treatment to evaluate response. An undetectable HCV RNA 12 weeks after the end of treatment is considered a sustained virologic response (SVR 12) and is equivalent to HCV cure. Prior to the availability of oral DAAs, estimates of progress along the HCV care continuum suggested that approximately 50% of individuals chronically infected with HCV were aware of their HCV infection, 16% were prescribed HCV treatment, and 9% were cured (Figure 3).[13] In addition, a study conducted in 2018 estimated that only 52% of individuals with chronic HCV were aware of their infection and 37% were cured (Figure 4).[14] The investigators projected that with the current gaps in the cascade, only marginal improvement would be expected to occur by 2030, with 62% aware and 49% cured by 2030.[14] In a more recent cross-sectional study of the National Health and Nutrition Examination Survey (NHANES), among individuals followed from 1999-2016, only 49.8 % of the participants were aware of their HCV infection.[15]
HCV Testing: Access, Efficiency, and Reimbursement
Limited Testing and Awareness of Infection
Many persons with chronic HCV infection do not have symptoms and only present with symptoms decades after infection when the disease has advanced to liver cirrhosis or hepatocellular cancer. Diagnosis of HCV infection requires specific tests and is often carried out as a 2-step process. The first test is an HCV antibody which is a marker of exposure to HCV in the past. A reactive antibody test must then be confirmed with HCV RNA testing to assess for viremia. Detection of HCV RNA is consistent with ongoing infection and should be followed immediately by evaluation for antiviral therapy. Historically, there has been confusion about this algorithm and limited infrastructure for HCV testing.[16]
Expanding Access to HCV Testing
It is critical that HCV testing is made available in a wide range of settings and also provided in a non-stigmatizing manner. Based on 2020 recommendations from the Centers for Disease Control and Prevention (CDC), testing for HCV is currently recommended at least once in a lifetime for all adults 18 years of age or older and for all pregnant persons during each pregnancy; one-time HCV screening is also recommended, regardless of age, for persons with recognized conditions or exposures (Table 1).[17] Further, routine periodic HCV testing is recommended at least annually for populations with ongoing risk of incident HCV infection, such as people who use drugs and men with HIV who have sex with men[17]. These recommendations are also endorsed in the AASLD-IDSA HCV Guidance and by the U.S. Preventive Services Task Force (USPSTF).[18,19] To increase access to HCV testing, it should be provided in a broad range of settings, including primary care clinics, obstetric offices, emergency departments, public health clinics, substance use disorder treatment programs, syringe service programs, jails and prisons, and other community-based settings. Multiple studies have demonstrated the feasibility and effectiveness of these approaches to increasing access to HCV testing.[20,21]
Improving HCV Testing Efficiency
Consideration will need to be given to the needs of the populations being tested in these settings to ensure awareness of infection and subsequent linkage to treatment for those who are found to have ongoing HCV infection. Implementation strategies that simplify the 2-step HCV testing algorithm are needed. For individuals being tested in settings where they routinely receive care such as primary care settings, reflex antibody to HCV RNA testing (where remaining serum from a person with a positive antibody sample is tested for HCV RNA) is preferred so that chronic HCV, if present, can be diagnosed with one blood draw.[17,18] In other settings, such as community-based and drop-in testing centers, emphasis may need to be placed on the use of the point-of-care, rapid HCV antibody testing (OraSure Technologies), whereby samples for testing can be collected by fingerstick with results available in 20 minutes. Since there are no FDA-approved point-of-care rapid HCV RNA tests, persons with a positive rapid HCV antibody test require additional testing with laboratory-based HCV RNA testing. Strategies that utilize point-of-care testing may be particularly impactful for reducing disparities in HCV status awareness as identified in the National Viral Hepatitis Strategic Plan.[6] A rapid HCV testing program implemented in a public health clinic increased the proportion of people who were made aware of their positive test result from 65.7% (90 of 137) when only traditional laboratory-based technologies were available for HCV testing to 97.9% (138 of 141) after availability of rapid HCV testing.[22]
Reimbursement for HCV Testing
Policy changes such as the Affordable Care Act which has expanded access to insurance for a large proportion of the US population and coverage of HCV testing without cost sharing provide financial support for these services. To maximize the benefits of the expanded HCV testing recommendations and coverage for this testing, efforts are required to increase awareness and support for providers to implement non-stigmatizing universal HCV testing. Other implementation strategies with the potential to facilitate increased HCV testing include electronic medical record prompts and reminders.[23,24]
Improving Services for Linkage-to-Care
Linkage to care is a key step in the pathway to effective HCV treatment. Multiple studies have shown a major drop-off in the HCV care continuum at this step.[25] Thus, consideration will need to be given to the needs of persons undergoing HCV testing to ensure those with positive HCV RNA test results become aware of their infection and are subsequently linked to HCV care and treatment. Several care continua have shown a steep drop off from awareness of HCV infection to attendance at an appointment for an initial HCV evaluation.[26,27]
Patient Navigation Services
One approach to increase linkage to care for HCV treatment evaluation is the provision of patient navigation services. Lack of these services has been reported as a significant barrier to HCV treatment.[28] Patient navigators can play varied roles including evaluating for insurance needs and assisting with insurance applications, appointment scheduling, facilitating appropriate referrals, and providing appointment reminders and linkage to community resources for transportation, assisting with food security or substance use treatment. An urban safety-net health system that screened 21,018 people for HCV over a 2-year period between 1017 and 2019 identified 878 individuals with positive HCV RNA tests. Of 562 patients with chronic HCV who were eligible for navigation services, 50% (281 of 562) were successfully linked to imaging services and among those who completed imaging, 72% (203 of 281) attended their first HCV medical evaluation appointment.[29] Another study evaluating outcomes of an HCV testing and linkage-to-care program in Baltimore demonstrated that patient navigation services resulted in 52% (81/155) of persons who tested positive for HCV RNA being successfully linked to an offsite HCV specialist appointment.[30] These patient navigation services may be especially important for patients with limited financial resources and comorbid medical conditions such as substance use and mental health disorders or complex social circumstances such as homelessness or previous incarceration. These populations also are more likely to be infected with HCV.[1] Using an embedded nurse navigator model at the University of Virginia infectious diseases HCV clinic, 76% (624 of 824) of persons referred for HCV care were successfully linked to care.[31]
Peer Navigation
Peer navigation, the involvement of a person with a lived experience of HCV to support another in HCV linkage to care and treatment, is an approach to patient navigation that has been most studied in populations of people who use drugs.[32] Peer support has been associated with a higher rate of HCV linkage: in a trial that recruited participants from outreach services who had problematic drug use and housing instability, 37% (23 of 63) people randomized to the peer support group had successful HCV linkage to care compared with only 18% (7 of 38) of those persons in the control group.[33]
Contingency Management
Another approach that has been evaluated to improve linkage to care is contingency management, a type of behavioral therapy where positive behavior change is reinforced, incentivized, or rewarded. This was shown in a small pilot study to examine contingency management as a strategy to improve HCV linkage to care rates among people who use drugs: participants were recruited through accessing a syringe service program in New York City and were enrolled in a contingency management arm or an enhanced standard of care arm.[34] Participants in the contingency management arm received an expedited appointment, transportation assistance, and $25 for up to 10 appointments, and $10 for each returned weekly medication blister pack; participants in the enhanced standard of care arm received only an expedited linked and expedited appointment and transportation assistance.[34] In this study, 74% (14 of 19) in the contingency management arm were successfully linked to HCV care compared to 6 of 20 (30%) in the enhanced standard of care arm, demonstrating that contingency management can be an effective strategy for linkage to care.[34]
Limitations for Implementation of Services
Programmatic efforts and interventions outlined above are largely driven by time-constrained grant funding with limited opportunities for widespread implementation and sustainability. Efforts are needed to identify funding sources to support the implementation and sustainability of these strategies for HCV treatment linkage.
Expanding Medical Provider Capacity
HCV treatment has traditionally been provided in gastroenterology and infectious diseases specialty settings. This is a major structural barrier to HCV treatment, since a limited number of specialists available to provide treatment can result in restricted access to treatment, long wait times for appointment scheduling, or, at times, lengthy travel to reach such settings, and ultimately attrition and loss to follow-up. The availability of pangenotypic oral DAAs that are highly effective, well tolerated, and safe has made the treatment of chronic HCV infection feasible for many primary care clinicians. The management of persons with chronic HCV by a specialist is now only required in select cases, such as for patients with decompensated cirrhosis or who have had liver transplantation. Streamlined HCV evaluation and simplified treatment algorithms for treatment-naïve persons with chronic HCV have been generated in the AASLD-IDSA HCV Guidance to promote HCV treatment by non-expert primary care clinicians.[35,36,37] Several studies have demonstrated the effectiveness of HCV treatment by primary care providers, substance use disorder treatment specialists, nurse practitioners, physician assistants and pharmacists.[38,39] Nurse-led models of HCV treatment delivery have also proven effective.[40] A critical step to increasing the number of HCV treatment locations is establishing training and support for various types of medical providers in these settings. A number of models and programs are available that can increase medical provider capacity and skill for providing HCV treatment.
Expanding Settings for HCV Clinical Care and Treatment
Other factors such as mistrust of the health system, perceived and enacted stigma and competing priorities may negatively impact the willingness or ability of some individuals to link to HCV care in specialist settings.[46] To increase access to HCV treatment for the broad range of populations who require HCV treatment, treatment needs to be made available in a wide range of settings where individuals feel safe and comfortable accessing care or services. These settings include primary care, substance use disorder treatment programs, public health clinics, needle and syringe service programs, jails and prisons and other community-based settings. Policies that incentivize health systems to screen for and treat hepatitis C may be beneficial in expanding HCV testing and treatment to a broader range of settings, such as primary care, corrections or substance use disorder care settings.
Insurance and Medicaid Restrictions to HCV Treatment Access
Requirement for Prior Authorization for HCV Treatment Coverage
Except for a limited number of jurisdictions, a prior authorization process is required for insurance coverage of HCV treatment. This process requires that medical care providers complete and submit documentation to insurance companies or payers to get advance approval for medications to be covered by the payer. These processes vary by payer/insurance plan, require the completion of various forms, are generally time-consuming and can delay HCV treatment. Some studies have reported that pre-authorization requirements significantly increase medical provider work load, and, in many cases, remain a significant obstacle to HCV care delivery.[47] Prior authorizations can also request additional information that should not impact coverage of HCV treatment, such as substance use status. This information is then used as justification to deny coverage of treatment. For medical providers and health care settings willing to take on HCV treatment, the additional work load and time required for prior authorization requests may serve as a deterrent to providing HCV treatment. Prior authorizations also have the potential to widen disparities in access to HCV treatment.[47]
Restricted Access to HCV Treatment Medications
Oral DAAs are significantly less expensive compared to when they were initially approved in 2014. Many payers, however, continue to restrict access to treatment due to cost. In particular, restrictions based on fibrosis stage and sobriety continue to pose a significant barrier to accessing HCV treatment.[48,49,50] The AASLD-IDSA HCV Guidance recommends HCV treatment for all persons with acute or chronic HCV infection, except those with a short life expectancy that cannot be remediated by HCV therapy, liver transplantation, or another directed therapy.[35] In contrast with these recommendations, many states have restrictions on Medicaid programs that restrict access to HCV treatment medications.
Restrictions Based on Fibrosis Stage
Multiple studies have shown an association with fibrosis stage and HCV treatment initiation, including a recent analysis of the HCV care continuum among 560 individuals treated for HCV at a public health clinic.[51] In this analysis of data collected at a time when the state Medicaid program had restrictions limiting HCV treatment coverage to Metavir stage F2 or greater, it was telling that of 227 patients with stage F2 or greater fibrosis, 205 (90%) initiated HCV treatment, compared to only 61 (51%) of patients with stage F0-F1 liver disease.[51] The logical assumption that HCV treatment uptake will increase if restrictions are removed is supported by data, including a recent study showing a 1.8-fold increase in HCV treatment initiation after HCV restrictions were removed for persons with HIV coinfection.[52] The gains in HCV treatment uptake were even more marked among people who inject drugs, a population that frequently suffers from disparities in access to HCV treatment; this group had a 3.6-fold increase in HCV treatment uptake after removal of fibrosis stage restrictions.[52] Fibrosis restrictions potentially may have a major impact on the role of HCV treatment as prevention: young people who inject drugs or men who have sex with men are more likely to have recently acquired HCV, and by extension have lower fibrosis scores, which may result in denial of treatment. These individuals are also more likely to transmit HCV to others and thus should be a priority population for HCV treatment. The AASLD-IDSA HCV Guidance recommends against excluding persons with low fibrosis scores from receiving HCV therapy.[35]
Restrictions Based on Substance Use
Sobriety restrictions, which require patients to be abstinent of alcohol or other drug use for varying periods of time prior to payer approval of HCV treatment, are also a major barrier to HCV treatment. Multiple studies have demonstrated high HCV cure rates regardless of ongoing substance use.[53,54] In addition, modeling and real-world data have demonstrated that increases in HCV treatment uptake in persons who inject drugs are needed to significantly reduce the reservoir of HCV-viremic individuals who can subsequently transmit HCV to others.[4,5,55] In addition, these restrictions further widen treatment disparities for people who use drugs and send the message that this group is not deserving of HCV treatment. The AASLD-IDSA HCV Guidance recommends against any mandatory pretreatment screening for alcohol or injection drug use.[35] In addition, the AASLD-IDSA HCV Guidance states that HCV treatment should not be restricted among persons with alcohol or injection drug use by requiring sobriety or abstinence, noting these types of prerequisites create a major barrier to HCV treatment, thereby potentially excluding populations that would likely derive clinical and prevention benefits from therapy.[35]
Large-Scale Discounted Purchasing of Medication
Instead of restricting HCV treatment access, state Medicaid programs and other jurisdictions could explore innovative models such as the “Netflix” subscription payment model adopted by the state of Louisiana in which a lump sum was agreed upon and paid to a pharmaceutical company in exchange for an unlimited number of treatment courses to treat all Medicaid beneficiaries and individuals in correctional facilities in the state over a 5-year period.[56] With a standard model that does not include lump-sum payments, pharmaceutical companies will make the greatest profit by increasing the price per treatment, a process that inherently restricts access to medications. The lump-sum payment strategy allows pharmaceutical companies to increase their profit and guarantee revenue without limiting access to medications. Other strategies, such as the Australian national DAA model, in which unrestricted access to oral DAA treatment is provided with an annual cap of expenditure for HCV treatment, may also be worth exploring.
Resources for Medication Access
Summary Points
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- Hepatitis C screening at least once in a lifetime for all adults aged ≥18 years, except in settings where the prevalence of HCV infection (HCV RNA-positivity) is <0.1%
- Hepatitis C screening for all pregnant women during each pregnancy, except in settings where the prevalence of HCV infection (HCV RNA-positivity) is <0.1%
- Persons with HIV
- Persons who ever injected drugs and shared needles, syringes, or other drug preparation equipment, including those who injected once or a few times many years ago
- Persons with selected medical conditions, including persons who ever received maintenance hemodialysis and persons with persistently abnormal alanine aminotransferase (ALT) levels
- Prior recipients of transfusions or organ transplants, including persons who received clotting factor concentrates produced before 1987, persons who received a transfusion of blood or blood components before July 1992, persons who received an organ transplant before July 1992, and persons who were notified that they received blood from a donor who later tested positive for HCV infection
- Health care, emergency medical, and public safety personnel after needle sticks, sharps, or mucosal exposures to HCV-positive blood
- Children born to mothers with HCV infection
- Persons who currently inject drugs and share needles, syringes, or other drug preparation equipment
- Persons with selected medical conditions, including persons who ever received maintenance hemodialysis
- Schillie S, Wester C, Osborne M, Wesolowski L, Ryerson AB. CDC Recommendations for Hepatitis C Screening Among Adults - United States, 2020. MMWR Recomm Rep. 2020;69:1-17. [PubMed Abstract]
Last Updated: January 28th, 2022Authors:Oluwaseun Falade-Nwulia, MBBS, MPH,Oluwaseun Falade-Nwulia, MBBS
Associate Professor of Medicine
Division of Infectious Diseases
Johns Hopkins University School of MedicineDisclosures: Grants to institution: Abbvie
Consulting fee: GileadH. Nina Kim, MDH. Nina Kim, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: Grant to institution: Gilead SciencesReviewer:David H. Spach, MDDavid H. Spach, MD
Professor of Medicine
Division of Allergy & Infectious Diseases
University of WashingtonDisclosures: NoneTable of ContentsCitations
Additional References
Figures
Figure 1. CDC Division of Viral Hepatitis 2025 Strategic Plan for Hepatitis CAbbreviations: HCV = hepatitis C virus; PWID = persons who inject drugsSource: Centers for Disease Control and Prevention (CDC). Division of Viral Hepatitis 2025 Strategic Plan, CDC; 2020:1-22.Figure 2. HCV Care ContinuumThis figure shows the five major stages of the HCV care continuum (colored circles), and the specific actions involved (arrows) to move individuals along the continuum.Illustration: David H. Spach, MDFigure 3. Treatment Cascade for People with Chronic Hepatitis C Virus in United States in the Pre-DAA EraThis treatment cascade is modeled based on studies from 2003-2013 and therefore represents a treatment cascade in the era prior to the widespread use of direct-acting antiviral (DAA) medications.Source: Yehia BR, Schranz AJ, Umscheid CA, Lo Re V 3rd. The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One. 2014;9:e101554.Figure 4. Treatment Cascade for People with Chronic Hepatitis C Virus in United States, 2018Source: Chhatwal J, Chen Q, Bethea ED, Hur C, Spaulding AC, Kanwal F. The impact of direct-acting anti-virals on the hepatitis C care cascade: identifying progress and gaps towards hepatitis C elimination in the United States. Aliment Pharmacol Ther. 2019;50:66-74.Tables
Table 1. CDC Recommendations for Hepatitis C Screening Among Adults — United States
Persons Recommended for Screening Universal hepatitis C screening:
One-time hepatitis C testing regardless of age or setting prevalence among persons with recognized risk factors or exposures:
Routine periodic testing for persons with ongoing risk factors, while risk factors persist:
Any person who requests hepatitis C testing should receive it, regardless of disclosure of risk, because many persons might be reluctant to disclose stigmatizing risks Source: - Learning Objectives
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