Hepatitis C guidance: AASLD-IDSA recommendations for testing,
managing, and treating adults infected with hepatitis C virus Aug 4 2015
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Article first published online: 4 AUG 2015
Not mentioned in this document is that Daclatasvir was just approved by the FDA for GT3:
FDA Approves Daklinza (daclatasvir) for the Treatment of Patients with Chronic Hepatitis C Genotype 3 - (07/28/15) PI attached
ALSO last week
the FDA approved:
TECHNIVIE™ (ombitasvir, paritaprevir, and ritonavir tablets) Receives FDA Approval as the First and Only All-Oral, Interferon-Free Treatment for Genotype 4 Chronic Hepatitis C in the U.S. - (07/28/15) PI attached
"........Evidence clearly supports treatment for all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non-liver-related comorbid conditions. Although treatment is best administered early in the course of the disease before fibrosis progression and the development of complications, the most immediate benefits of treatment will be realized by populations at highest risk for liver-related complications. Thus, where resources limit the ability to treat all infected patients immediately as recommended, it is most appropriate to treat first those at greatest risk of disease complications and those at risk for transmitting HCV or in whom treatment may reduce transmission risk. Where such limitations exist, prioritization of immediate treatment for those listed in Tables 3 and 4 is recommended, including patients with progressive liver disease (Metavir stage F3 or F4), transplant recipients, or those with severe extrahepatic manifestations."
"Recent reports suggest that initiating therapy in patients with lower-stage fibrosis may extend the benefits of an SVR. In a long-term follow-up study, 820 patients with Metavir stage F0 or F1 fibrosis confirmed by biopsy were followed for more than 20 years. The 15-year survival rate was significantly better in those who experienced an SVR than in those whose treatment had failed or those who were untreated (93%, 82%, and 88%, respectively; P = 0.003) and argues for consideration of earlier initiation of treatment. Several other modeling studies suggest greater mortality benefit if treatment is initiated at stages prior to F3.[56-58]"
When and in Whom to Initiate HCV Therapy
Successful hepatitis C treatment is achievable in nearly all infected patients and is reflected by a sustained virological response (SVR), defined as the continued absence of detectable HCV RNA for 12 or more weeks after completion of therapy. SVR is a marker for virological cure of HCV infection and has been shown to be durable in large prospective studies in more than 99% of patients followed up for at least 5 years.[39, 40] Patients who are cured of their HCV infection experience numerous health benefits, including a decrease in liver inflammation, regression of fibrosis in most cases, and resolution of cirrhosis in half. Among the latter group, portal hypertension, splenomegaly, and other clinical manifestations of advanced liver disease also improve. An SVR is associated with a more than 70% reduction in the risk of liver cancer (HCC) and a 90% reduction in the risk of liver-related mortality and liver transplantation.[42-44]
Cure of HCV infection may also reduce symptoms and mortality from severe extrahepatic manifestations, including cryoglobulinemic vasculitis, a condition affecting up to 15% of HCV-infected individuals.[45, 46] Persons infected with HCV with non-Hodgkin lymphoma and other lymphoproliferative disorders achieve complete or partial remission in up to 75% of cases following successful HCV treatment.[47-51] These reductions in disease severity contribute to dramatic reductions in all-cause mortality.[43, 52] Lastly, patients achieving an SVR have substantially improved quality of life, including physical, emotional, and social health.[53, 54]
Evidence clearly supports treatment for all HCV-infected persons, except those with limited life expectancy (less than 12 months) due to non-liver-related comorbid conditions. Although treatment is best administered early in the course of the disease before fibrosis progression and the development of complications, the most immediate benefits of treatment will be realized by populations at highest risk for liver-related complications. Thus, where resources limit the ability to treat all infected patients immediately as recommended, it is most appropriate to treat first those at greatest risk of disease complications and those at risk for transmitting HCV or in whom treatment may reduce transmission risk. Where such limitations exist, prioritization of immediate treatment for those listed in Tables 3 and 4 is recommended, including patients with progressive liver disease (Metavir stage F3 or F4), transplant recipients, or those with severe extrahepatic manifestations.
Initial Treatment of HCV Infection
This section addresses treatment of patients with chronic hepatitis C who are naive to any type of therapy. Although regimens containing peginterferon (PEG-IFN) and ribavirin (RBV) plus direct-acting antiviral (DAA) drugs are approved by the FDA for many HCV genotypes, the initial regimen for patients who are treatment-naive with HCV genotype 1 generally has been superseded by treatments incorporating regimens using only DAAs. Recommended treatments are viewed as equivalent, and the decision of which to use may involve consideration of drug interactions between the DAAs and concomitant medications (see http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection#drug-interactions). For example, the daily fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (hereafter ledipasvir/sofosbuvir) has a potential interaction with proton pump inhibitors. Similarly, the daily fixed-dose combination of paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) (hereafter paritaprevir/ritonavir/ombitasvir plus dasabuvir [PrOD]) has a substantial interaction with the long-acting inhaled beta-adrenoceptor agonist salmeterol and other drugs that interface with the cytochrome P450 3A4 isoenzyme.
Patients with HCV genotype 1a tend to have higher relapse rates than patients with HCV genotype 1b with certain regimens. Genotype 1 HCV infection that cannot be subtyped should be treated as genotype 1a infection.
For HCV genotype 1a-infected, treatment-naive patients, there are three regimens of comparable efficacy: ledipasvir/sofosbuvir,[68, 69] PrOD and weight-based RBV,[70, 71] and sofosbuvir plus simeprevir. For PrOD, the use of RBV and the length of therapy differ for those with compensated cirrhosis versus those who do not have cirrhosis. The standard weight-based dosing of RBV is 1000 mg for individuals who weigh less than 75 kg to 1200 mg for those who weigh 75 kg or more. The known safety profiles of each of these recommended regimens are excellent. Across numerous phase 3 studies, fewer than 1% of patients without cirrhosis discontinued treatment early and adverse events were mild. Most adverse events occurred in RBV-containing arms. Patients with cirrhosis and HCV genotype 1a who were harboring the nonstructural protein 3 (NS3) Q80K polymorphism had lower SVR rates after treatment with sofosbuvir and simeprevir than those who did not harbor the Q80K polymorphism;73 in these patients, one of the other recommended regimens for cirrhosis should be used.
· 9. Treatment options for treatment-naive patients with HCV genotype 1a who are initiating therapy (regimens are listed in alphabetical order):
Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (I-A)
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis). (I-A)
Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) for patients with a negative test result for the Q80K variant using commercially available resistance assays. In patients with HCV genotype 1a and cirrhosis who have the Q80K variant, one of the other regimens for cirrhosis detailed above is recommended. (IIa-B)
For HCV genotype 1b-infected, treatment-naive patients, there are three regimens of comparable efficacy: ledipasvir/sofosbuvir for 12 weeks, PrOD for 12 weeks[70, 71] and sofosbuvir plus simeprevir with or without weight-based RBV for 12 weeks (or 24 weeks for patients with cirrhosis).[72, 74, 75]
· 10. Treatment options for treatment-naive patients with HCV genotype 1b who are initiating therapy (regimens are listed in alphabetical order):
Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (I-A)
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks. (I-A)
Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis). (IIa-B)
Sofosbuvir plus weight-based RBV is the recommended therapy for treatment-naive patients with HCV genotype 2 infection.[75-78] Until more data are available, extending treatment to 16 weeks in HCV genotype 2-infected patients with cirrhosis is recommended.
· 11. Regimen for treatment-naive patients with HCV genotype 2 infection:
Daily sofosbuvir (400 mg) and weight-based RBV for 12 weeks. (I-A)
Extending treatment to 16 weeks is recommended for patients with cirrhosis.
Genotype 3 is the most difficult genotype to treat with available DAAs. Sofosbuvir plus weight-based RBV for 24 weeks is the recommended DAA-only regimen in the United States.[76, 79] Based on recent data from a randomized trial demonstrating higher SVR rates than those seen with sofosbuvir and RBV for 24 weeks, the combination of sofosbuvir plus PEG-IFN and RBV for 12 weeks is recommended for interferon (IFN)-eligible patients, although the adverse effects and increased monitoring requirements of PEG-IFN may make this a less attractive therapeutic option. Daclatasvir plus sofosbuvir for 12 weeks has been studied, but daclatasvir is not FDA-approved. [FROM JULES: Daclatasvir+Sof for GT3 was just approved last week by the FDA....so was Abbvie 2D for GT4]
· 12. Treatment for treatment-naive patients with HCV genotype 3 infection:
Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN for 12 weeks for IFN-eligible patients. (I-A)
Daily sofosbuvir (400 mg) and weight-based RBV for 24 weeks for IFN-ineligible patients. (I-B)
For the treatment of therapy-naive patients with HCV genotype 4, three therapeutic options are recommended: daily combination of paritaprevir/ritonavir/ombitasvir with weight-based RBV, ledipasvir/sofosbuvir,[83, 84] or sofosbuvir plus weight-based RBV.[85-87] Given the demonstrated activity in vitro and in vivo of simeprevir against HCV genotype 4, simeprevir plus sofosbuvir may be considered; but supportive clinical data are limited.
· 13. Treatment options for treatment-naive patients with HCV genotype 4 infection (listed in alphabetical order):
Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (IIb-B)
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 weeks. (I-B)
Daily sofosbuvir (400 mg) and weight-based RBV for 24 weeks.
Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN for 12 weeks. (II-B)
Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV for 12 weeks. (IIb-B)
Genotype 5 or 6
Few data are available to help guide decision making for patients infected with HCV genotype 5 or 6. Nonetheless, based on emerging data, sofosbuvir plus ledipasvir is recommended.,,
HCV Testing and Linkage to Care
Of the estimated 2.2 million to 3.2 million persons chronically infected with HCV in the United States, half are unaware that they are infected.
Identification of those with active infection is the first step toward improving health outcomes and preventing transmission.[5-7] Accordingly, HCV testing is recommended in select populations based on demography, prior exposures, risk behaviors, and medical conditions (Table 2). In 2012, the CDC expanded its risk-based HCV testing guidelines originally issued in 19987 with a recommendation to offer a one-time HCV test to all persons born from 1945 through 1965, regardless of whether HCV risk factors have been identified. This recommendation was supported by the failure of the risk-based screening strategy to identify more than 50% of HCV infections. Furthermore, persons in the 1945 to 1965 birth cohort accounted for nearly three-fourths of all HCV infections, with a five times higher prevalence (3.25%) than other cohorts. A retrospective review showed that 68% of persons with HCV infection would have been identified through a birth cohort testing strategy, whereas only 27% would have been screened with the risk-based approach. The cost-effectiveness of one-time birth cohort testing is comparable to that of current risk-based screening strategies.
· 1. Consistent with the CDC and the US Preventive Services Task Force, a one-time HCV test is recommended in asymptomatic persons in the 1945-1965 birth cohort and other persons based on exposures, behaviors, and conditions that increase risk for HCV infection. (I-B)
Testing for HCV antibody (anti-HCV) should be performed using FDA-approved methods such as testing for anti-HCV9, with laboratory-based assays or a point-of-care assay. A positive anti-HCV test result indicates current (active) HCV infection (acute or chronic), past infection that has resolved, or a false-positive test result. Therefore, FDA-approved quantitative or qualitative nucleic acid testing with a detection level of 25 IU/mL or lower should be used to detect HCV RNA to confirm active HCV infection and guide clinical management. Testing for HCV RNA should also be performed in persons with a negative anti-HCV test who are immunocompromised (e.g., persons receiving chronic hemodialysis) or who might have been exposed to HCV in the prior 6 months because these persons may be anti-HCV-negative. An HCV RNA test is also needed to detect reinfection in anti-HCV-positive persons after previous spontaneous or treatment-related viral clearance. Further details for interpreting results of different antibody and nucleic acid testing can be found in the CDC testing algorithm at www.hcvguidelines.org.
· 2. All persons recommended for HCV testing should first be tested for anti-HCV using an FDA-approved test. Positive results should be confirmed by nucleic acid testing for HCV RNA. (I-A)
Evidence regarding the optimal frequency of testing in persons at risk for ongoing exposure to HCV is lacking; therefore, clinicians should determine the periodicity of testing based on the risk of reinfection. Because of the high incidence of HCV infection among persons who inject drugs and among HIV-infected men who have sex with men who have unprotected sex,[14-19] at least annual HCV testing is recommended in these subgroups.
· 3. Annual HCV testing is recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men. Periodic testing should be offered to other persons at ongoing risk of HCV exposure. (IIa-C)
Persons infected with HCV should be educated about preventing further damage to their liver. Most important is prevention of the potential deleterious effect of alcohol, which may lead to more rapid progression of liver fibrosis and the development of hepatocellular carcinoma (HCC).[20-26] Persons with HCV should be tested for HIV antibody and hepatitis B surface antigen as coinfection with hepatitis B virus or HIV has been associated with poorer prognosis of HCV,[27, 28] they share overlapping risk factors, and additional benefits accrue from their diagnosis and treatment[29, 30] (http://www.aafp.org/afp/200/0315/p819.html and http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm).
Patients with obesity and metabolic syndrome who have underlying insulin resistance are more prone to have nonalcoholic fatty liver disease, which may accelerate fibrosis progression in HCV-infected persons.[31, 32] Therefore, HCV-infected persons who are overweight or obese (defined by a body mass index of 25 kg/m2 or higher or 30 kg/m2 or higher, respectively) should be counseled regarding strategies to reduce weight and improve insulin resistance through diet, exercise, and medical therapies.[33, 34]
· 4. Persons infected with HCV should be educated about their disease and how to prevent further damage to their liver. (IIa-B)
Improvements in identification of current hepatitis C and advances in treatment will have limited impact on HCV-related morbidity and mortality unless patients have access to appropriate medical care. In the United States, it is estimated that only 13%-18% of persons with chronic HCV infection receive treatment. Indeed, in many cases referral to practitioners who are able and willing to evaluate such patients and provide treatment is delayed or never occurs.[36-38] Thus, it is crucial that all patients with current hepatitis C and a positive HCV RNA test result be referred to and evaluated by a practitioner with expertise in the assessment of liver disease severity and HCV treatment.
Further, those with advanced fibrosis or cirrhosis require specialized management, including consideration of liver transplantation as indicated.
5. Evaluation by a practitioner who is prepared to provide comprehensive management, including consideration of antiviral therapy, is recommended for all persons with current (active) HCV infection. (IIa-C)