treatment for hepatitis c virus infection in adults: comparative effectiveness prepared for: agency...

Treatment for Hepatitis C Virus Infection in Adults:

Comparative EffectivenessPrepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Introduction to hepatitis C virus (HCV) infection and the various therapies available for its treatment

Systematic review methods The clinical questions addressed by the comparative

effectiveness review Results of studies and evidence-based conclusions about the

relative benefits and adverse effects of currently available treatments for HCV infection

Gaps in knowledge and future research needs What to discuss with patients and their caregivers

Outline of Material

Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76.Available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.

Approximately 1.6 percent of adults in the United States over the age of 20 have antibodies to hepatitis C virus (HCV), indicating previous acute HCV infection.

About 70 to 85 percent of patients with acute HCV infection develop chronic HCV infection.

Among patients with chronic HCV infection, about 75 percent have genotype 1 HCV infection and about 20 percent have genotype 2 or 3 HCV infection.

The yearly incidence of chronic HCV infection has declined from more than 200,000 cases per year in the 1980s to around 16,000 cases in 2009.

An estimated 15,000 deaths and over 30 percent of cases of liver transplantation in the United States each year are related to chronic HCV infection.

Background: Hepatitis C Virus Infectionand Its Prevalence

Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76.Available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.Centers for Disease Control and Prevention. Hepatitis C Information for Professionals. Available at www.cdc.gov/hepatitis/HCV.Armstrong GL, Wasley A, Simard EP, et al. Ann Intern Med 2006;144(10):705-14. PMID: 16702586.Davis GL, Alter MJ, El-Serag H, et al. Gastroenterology 2010;138(2):513-21. PMID: 19861128.Ly KN, Xing J, Klevens RM, et al. Ann Intern Med 2012;156(4):271-8. PMID: 22351712.Nainan OV, Alter MJ, Kruszon-Moran D, et al. Gastroenterology 2006;131(2):478-84. PMID: 16890602.

Chronic hepatitis C virus (HCV) infection can lead to complications of the liver, including cirrhosis, liver failure, and hepatocellular cancer.

Chronic HCV infection has a variable course; in some patients disease progression to cirrhosis is slow, while in others, progression is more rapid. The risk of developing cirrhosis ranges from 5 to 25 percent over a

period of 25 to 30 years.

Identifying individuals at risk of progressive disease is challenging. Currently, the preferred strategy is to evaluate the degree of fibrosis

by liver biopsy; however, indications for liver biopsy continue to evolve.

Other modalities, including blood tests and indices, are available and have been evaluated as alternatives.

Background: Complications Associated With Chronic Hepatitis C Virus Infection

Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.Ghany MG, Strader DB, Thomas DL, et al. Hepatology 2009;49(4):1335-74. PMID: 19330875.

The goal of treating chronic hepatitis C virus (HCV) infection is to prevent long-term health complications and death.

The sustained virologic response (SVR) rate is a marker of successful treatment because it is strongly associated with the long-term absence of viremia.

Factors suggested to be associated with an increased likelihood of achieving an SVR include: Presence of HCV genotype 2 or 3 infection Pretreatment viral load <600,000 IU/mL Female sex Age <40 years Nonblack race (partly linked to polymorphisms in the interleukin-28B

gene) Absence of insulin resistance

Background: Hepatitis C Virus Treatment and Sustained Virologic Response

Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.Ge D, Fellay J, Thompson AJ, et al. Nature 2009;461(7262):399-401. PMID: 19684573.Kjaergard LL, Krogsgaard K, Gluud C. BMJ 2001;323(7322):1151-5. PMID: 11711405.Swain MG, Lai MY, Shiffman ML, et al. Gastroenterology 2010;139(5):1593- 601. PMID: 20637202.

In the early 2000s, the combination of ribavirin (a nucleoside analogue) with either pegylated interferon alfa-2a or alpha-2b became the standard treatment for hepatitis C virus (HCV) infection.

In 2011, the U.S. Food and Drug Administration approved the first direct-acting antiviral agents, boceprevir and telaprevir, for treating HCV genotype 1 infection. Each drug is administered in combination with pegylated

interferon (alfa-2a or alfa-2b) plus ribavirin.

Background: Currently Available Treatments for Chronic Hepatitis C Virus Infection in Adults

Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.FDA. Drugs@FDA: Boceprevir. Available at www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.FDA. Drugs@FDA: Telaprevir. Available at www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.Ghany MG, Strader DB, Thomas DL, et al. Hepatology 2009;49(4):1335-74. PMID:19330875.McHutchison JG, Lawitz EJ, Shiffman ML, et al. N Engl J Med. 2009;361(6):580-93. PMID:19625712.

Decisions about treatment strategies for patients with chronic hepatitis C virus (HCV) infection who are treatment naïve are based on various factors, including: Disease-related factors such as HCV genotype and severity of

liver disease Patient-related factors such as comorbidities and demographic

profile The continued development of new treatment strategies,

including the testing of the all-oral interferon-sparing therapies that may be available in the coming years

Knowledge of the comparative benefits and harms of dual and triple antiviral treatment regimens, which is particularly important, given the availability of new treatment options (telaprevir and boceprevir) for chronic HCV infections

Background: Uncertainties Related to the Treatment of Chronic Hepatitis C Virus Infection in Adults

Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.

Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.

A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.

The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/hepctreatment.cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development


Key Question 1: This question has two parts:a. What is the comparative effectiveness of antiviral

treatment in improving health outcomes in patients with hepatitis C virus (HCV) infection?

b. How does the comparative effectiveness of antiviral treatment for health outcomes vary according to patient subgroup characteristics including, but not limited to, HCV genotype, age, race, sex, stage of disease, or genetic markers?

Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 3)


Key Question 2: This question has two parts:a. What is the comparative effectiveness of antiviral

treatments on intermediate outcomes, such as the rate of sustained virologic response or histologic changes in the liver?

b. How does the comparative effectiveness of antiviral treatment for intermediate outcomes vary according to patient subgroup characteristics including, but not limited to, HCV genotype, age, race, sex, stage of disease, or genetic markers?



Key Question 3: This question has two parts:a. What are the comparative harms associated with antiviral

treatments?

b. Do these harms differ according to patient subgroup characteristics, including hepatitis C virus (HCV) genotype, age, race, sex, stage of disease, or genetic markers?

Key Question 4:Have improvements in intermediate outcomes (sustained virologic response; histologic changes) been shown to reduce the risk or rates of adverse health outcomes from HCV infection?



The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the Comparative Effectiveness Review


Triple therapy containing boceprevir was compared to dual therapy in patients with genotype 1 hepatitis C virus infection. The pooled relative risk was 1.8 (95-percent confidence interval, 1.6–2.1). Sustained virologic response (SVR) rates were 66–75 percent for triple

therapy versus 38 percent for dual therapy.

Strength of Evidence: Moderate In patients treated with 48 weeks of triple therapy containing

boceprevir, absolute SVR rates were lower in patients of black race when compared with patients of nonblack race; no clear differences in relative risk estimates for SVR were found.

Strength of Evidence: Moderate

Triple Therapy Containing Boceprevir Versus Dual Therapy for Patients With Hepatitis C Virus Genotype 1 Infection


Dual therapy = pegylated interferon alfa-2b + ribavirinTriple therapy = pegylated interferon alfa (2a or 2b) + ribavirin + boceprevir

The likelihood of achieving a sustained virologic response (SVR) was higher with 24 weeks of triple therapy containing telaprevir versus 48 weeks of dual therapy. Absolute increase in the SVR rate = 22 percent Pooled relative risk (RR) = 1.5 (95-percent confidence interval [95% CI],

1.3–1.8). SVR rates: 60–73 percent for triple therapy versus 41–49 percent for dual

therapy

Strength of Evidence: Moderate The likelihood of achieving an SVR was higher with response-guided

triple therapy containing telaprevir versus 48 weeks of dual therapy. Treatment regimen: initial triple therapy for 8–12 weeks followed by dual

therapy Pooled RR = 1.6 (95% CI, 1.4–1.9) SVR rates = 69–75 percent for triple therapy versus 44 percent for dual

therapy

Strength of Evidence: Low

Triple Therapy Containing Telaprevir Versus Dual Therapy for Patients With HCV Genotype 1 Infection (1 of 2)


Dual therapy = pegylated interferon alfa-2b + ribavirinTriple therapy = pegylated interferon alfa (2a or 2b) + ribavirin + telaprevir

In patients treated with response-guided triple therapy containing telaprevir (12 weeks) plus response-guided dual therapy (the next 12–36 weeks) versus dual therapy (48 weeks) alone, the characteristics associated with lower sustained virologic response rates were: Older age or black race

Strength of Evidence: Moderate Advanced fibrosis or cirrhosis and higher body mass

index; evidence for this finding was limited



Triple Therapy Containing Telaprevir Versus Dual Therapy for Patients With HCV Genotype 1 Infection (2 of 2)


The populations included in these studies had HCV genotype 1, 2, 3 or 4 infection.

The likelihood of achieving an SVR was similar for dual therapy with ribavirin plus pegylated interferon alfa-2b and ribavirin plus pegylated interferon alfa-2a (although the likelihood appeared to be slightly lower for dual therapy with ribavirin + pegylated interferon alfa 2b). Pooled relative risk = 0.87 (95-percent confidence interval, 0.80–

0.95) SVR rates = 38–62 percent for dual therapy with pegylated

interferon alfa-2b versus 41–71 percent for dual therapy with pegylated interferon alfa-2a


Dual Therapy Containing Pegylated Interferon Alfa-2a Versus Dual Therapy Containing Pegylated Interferon Alfa-2b (1 of 2)


When comparing dual therapy regimens containing pegylated interferon alfa-2a or alfa-2b, the sustained virologic response rates were lower by 24–42 percent in patients who had hepatitis C virus (HCV) genotype 1 infection when compared with those who had HCV genotype 2 or 3 infection; however, no clear differences in relative risk estimates were found.

Strength of Evidence: Moderate In patients treated with dual therapy regimens, the absolute

SVR rates were lower in those who were older, were black, had advanced fibrosis or cirrhosis, and had a high baseline viral load.


Dual Therapy Containing Pegylated Interferon Alfa-2a Versus Dual Therapy Containing Pegylated Interferon Alfa-2b (2 of 2)


The likelihood of achieving a sustained virologic response (SVR) was higher with dual therapy lasting 24 weeks when compared with dual therapy lasting 12–16 weeks. Pooled relative risk = 1.2 (95-percent confidence interval, 1.0–1.3) SVR rates = 67–78 percent for therapy lasting 24 weeks versus

57–62 percent for therapy lasting 12–16 weeks

Strength of Evidence: Moderate In patients with rapid virologic response,* the SVR rates did

not differ between 24 weeks and 12–16 weeks of therapy.


Response Rates in Patients With HCV Genotype 2 or 3 Infection According to Duration of Dual Therapy


*Hepatitis C virus (HCV) RNA was undetectable by 4 weeks.

Dual therapy = ribavirin + pegylated interferon alfa (2a or 2b)

Lower doses (0.75–1.0 mcg/kg or 50 mcg) of pegylated interferon alfa-2b were less effective than standard doses (1.5 mcg/kg or 100–150 mcg) in dual therapy regimens.

Strength of Evidence: Moderate No difference in the likelihood of achieving a sustained

virologic response was observed with lower doses (a 400–800 mg/day flat dose or a 600–800 mg/day weight-based dose) versus higher doses (a 800–1,200 mg/day flat dose or a 800–1,400 mg/day weight-based dose) of ribavirin.



Response Rates in Patients With HCV Genotype 2 or 3 Infection According to Dosage of Dual Therapy

Dual therapy = ribavirin + pegylated interferon alfa-2b

Achieving a sustained virologic response (SVR) after antiviral therapy for chronic hepatitis C virus (HCV) infection appeared to be associated with a lower risk of all-cause mortality when compared with not achieving an SVR. A large, good-quality Veterans Affairs cohort study found that an

SVR after antiviral therapy was associated with lower risk of all-cause mortality versus no SVR.

Eighteen other cohort studies found that an SVR after antiviral therapy was associated with a decreased risk of all-cause mortality versus no SVR. However, the smaller supporting studies had some methodological shortcomings.


SVR After Antiviral Therapy and Clinical Outcomes in Patients With Chronic HCV Infection


Triple therapy with boceprevir lasting 48 weeks was associated with increased risk of neutropenia, anemia, dysgeusia, and thrombocytopenia when compared with dual therapy; there was no difference in risk of withdrawal due to adverse events between the two treatment groups. Pooled relative risks: 1.8 for neutropenia (95-percent confidence

interval [95% CI], 1.5–2.3); 2.0 for anemia (95% CI, 1.4–2.8); 2.5 for dysgeusia (95% CI, 2.0–3.2); and 3.3 for thrombocytopenia (95% CI, 1.3–8.6)

In patients on triple therapy, the incidence of anemia was 50 percent, the incidence of neutropenia was 25 percent, the incidence of severe neutropenia was 8–15 percent, and the incidence of severe anemia was 4–5 percent.


Triple Therapy With Boceprevir Versus Dual Therapy in Patients With HCV Genotype 1 Infection: Adverse Effects


Dual therapy = pegylated interferon alfa-2b + ribavirinTriple therapy = pegylated interferon alfa (2a or 2b) + ribavirin + boceprevir

Triple therapy with telaprevir for 24 weeks was associated with an increased risk of anemia and rash when compared with dual therapy; there was no difference in the risk of withdrawal due to adverse events between the two treatment groups. Pooled relative risks: 1.3 for anemia (95-percent confidence

interval [95% CI], 1.1–1.5) and 1.4 for rash (95% CI, 1.1–1.7). In patients on triple therapy, the incidence of anemia was 27–91

percent, and the incidence of rash was 33–66 percent.



Triple Therapy With Telaprevir Versus Dual Therapy in Patients With HCV Genotype 1 Infection: Adverse Effects


Withdrawals due to adverse events did not differ between dual therapy containing pegylated interferon alfa-2a and dual therapy containing pegylated interferon alfa-2b.

Strength of Evidence: Moderate Dual therapy with ribavirin and pegylated interferon alfa-2b

was associated with a lower risk of neutropenia, rash, and serious adverse events* when compared with dual therapy with ribavirin and pegylated interferon alfa-2a.


Dual Therapy Containing Pegylated Interferon Alfa-2a Versus Dual Therapy Containing Pegylated Interferon Alfa-2b: Adverse Effects


*Serious adverse events included gastrointestinal disorders, cardiovascular disorders, infections, neoplasms, and psychiatric disorders.

No randomized trial or observational study evaluated the relative effectiveness of antiviral therapies for chronic HCV infection on: Long-term clinical outcomes Clinical outcomes in patients stratified by HCV genotype, age, race, sex, stage of

disease, genetic markers, or other factors

Strength of evidence: Insufficient

Limited evidence suggested a lack of difference in the risk of short-term mortality with current antiviral regimens; however, estimates were imprecise due to the small number of events reported.

Strength of evidence: Low

Limited evidence suggested that achieving an SVR, when compared with no SVR, was associated with greater improvement in measures of quality of life 24 weeks after antiviral therapy.

Strength of evidence: Low

Other Key Findings of This Review


Key U.S. Food and Drug Administration-Issued Information on Medications Used To Treat Hepatitis C Virus Infection (1 of 2)

U.S. Food and Drug Administration Web site. Drug Information. Available at www.fda.gov/Drugs/default.htm.

Key U.S. Food and Drug Administration-Issued Information on Medications Used To Treat Hepatitis C Virus Infection (2 of 2)

U.S. Food and Drug Administration Web site. Drug Information. Available at www.fda.gov/Drugs/default.htm.

Both dual and triple therapies in treatment-naive patients with hepatitis C virus (HCV) infection were found to produce sustained viral responses (SVRs). Triple therapy with pegylated interferon, ribavirin, and either

boceprevir or telaprevir induced substantially higher responses in patients with HCV genotype 1 when compared with dual therapy with pegylated interferon plus ribavirin.

The likelihood of achieving an SVR was similar with dual therapy of pegylated interferon alfa-2a and ribavirin and dual therapy with pegylated interferon alfa-2b and ribavirin; however, there appeared to be a slightly higher likelihood of achieving an SVR with dual therapy containing pegylated interferon alfa-2a.

For HCV genotype 2 or 3 infections, standard doses and duration of pegylated interferon as part of dual therapy were more effective than shorter regimens or lower doses.

Conclusions (1 of 2)


Triple-therapy regimens were associated with an increased risk of harms including anemia (both boceprevir and telaprevir) and rash (telaprevir).

Recent cohort studies provided moderate strength of evidence that achieving an SVR is associated with a decreased risk of all-cause mortality.

Conclusions (2 of 2)


The findings of the comparative effectiveness review (CER) are also relevant to recommendations for hepatitis C virus (HCV) screening. Important new evidence that may affect assessments of the potential benefits of screening includes: Stronger evidence of the link between achieving a

sustained virologic response (SVR) and improvement in clinical outcomes.

Evidence showing substantially higher SVR rates with newer triple-therapy regimens with boceprevir or telaprevir in patients with HCV genotype 1 infection.

Additional Information: Relevance of Findings of the CER to Screening for Hepatitis C Virus Infection


The applicability of the findings of this comparative effectiveness review are limited by the following factors:All studies included in this review were conducted only in treatment-naïve patients.The trials included in this review generally met criteria for efficacy studies, based on the exclusion of patients with common comorbidities such as serious psychiatric conditions or recent or ongoing substance abuse.Patients with HIV coinfection, those who were transplant recipients, and those who routinely undergo hemodialysis were excluded from this review.

Limitations in the Applicability of theFindings of This Review


No trials of patients with hepatitis C virus (HCV) infection directly compared antiviral regimens containing boceprevir with regimens containing telaprevir.

Few trials have evaluated the drug regimens approved by the U.S. Food and Drug Administration for use in clinical practice, thereby limiting confidence in conclusions about estimates of their benefits and adverse effects.

Few methodologically rigorous studies conducted in settings applicable to U.S. populations evaluated the association between achieving a sustained virologic response and improvements in clinical outcomes for HCV-infected patients.

Gaps in Knowledge (1 of 2)


Randomized, controlled trials that enroll broader populations of patients infected with the hepatitis C virus and have medical and psychological comorbidities, as frequently encountered in clinical practice, and studies that reflect real-world effects are lacking.

The effects of achieving a sustained virologic response on long-term quality of life are not known and remain to be evaluated.

Gaps in Knowledge (2 of 2)


The disease management strategy (considering no treatment vs. immediate treatment) that would be most appropriate for the individual patient with hepatitis C virus (HCV) infection based on the severity of liver disease

The type of treatment regimen that might be most suitable for the patient given his or her HCV genotype, severity of disease, likelihood of treatment response, and presence of comorbid conditions

The different types of therapeutic regimens currently available for treating chronic HCV infection

What To Discuss With Your Patients andTheir Caregivers (1 of 2)


The available evidence for the effectiveness of the various regimens for treating chronic hepatitis C virus (HCV) infection

The available evidence for the adverse effects associated with the various regimens for treating chronic HCV infection and what should be done if adverse effects develop

The potential new therapies on the horizon and their possible impact on the treatment approach for the patient

The possibility that other specialists might be involved in the patient’s care during the treatment process

The potential out-of-pocket costs that the patient might incur for the various treatments based on his or her insurance coverage

What To Discuss With Your Patients andTheir Caregivers (2 of 2)


treatment for hepatitis c virus infection in adults: comparative effectiveness prepared for: agency...

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