Hepatitis C medical therapy: Difference between revisions
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* Liver biopsy showing chronic hepatitis with bridging fibrosis or higher | * Liver biopsy showing chronic hepatitis with bridging fibrosis or higher | ||
* Compensated liver disease: | * Compensated liver disease: | ||
** ''Total bilirubin'' = 1.5 g/dL | ** ''[[Total bilirubin]]'' = 1.5 g/dL | ||
** ''INR'' = 1.5 | ** ''[[INR]]'' = 1.5 | ||
** ''Serum albumin'' > 3.4 | ** ''[[Serum albumin]]'' > 3.4 | ||
** ''Platelet count'' = 75,000 mm | ** ''[[Platelet count]]'' = 75,000 mm | ||
** ''No evidence of hepatic decompensation'' (hepatic encephalopathy or ascites) | ** ''No evidence of hepatic decompensation'' (hepatic encephalopathy or ascites) | ||
* Acceptable hematological and biochemical profile: | * Acceptable hematological and biochemical profile: | ||
** ''Hemoglobin'' = 13 g/dL for men; 12 g/dL for women | ** ''[[Hemoglobin]]'' = 13 g/dL for men; 12 g/dL for women | ||
** ''Neutrophil count'' = 1500 /mm3 | ** ''[[Neutrophil count]]'' = 1500 /mm3 | ||
** ''Serum creatinine'' = 1.5 mg/dL | ** ''Serum [[creatinine]]'' = 1.5 mg/dL | ||
* Willing to adhere to therapy | * Willing to adhere to therapy | ||
* No contraindications to therapy | * No contraindications to therapy | ||
Revision as of 13:47, 28 July 2014
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Hepatitis C |
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Diagnosis |
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Treatment |
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Hepatitis C medical therapy On the Web |
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American Roentgen Ray Society Images of Hepatitis C medical therapy |
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Risk calculators and risk factors for Hepatitis C medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian
Overview
The treatment of hepatitis C has changed dramatically over the past decade. Whereas relatively new protease inhibitors telaprevir and boceprevir were added to the regular regimen of IFN and ribavirin in 2011 to treat patients with genotype 1 HCV, newer oral agents sofosbuvir and simeprevir have demonstrated greater efficacy in viral clearance along with a better safety profile. New guidelines from the AASLD and the IDSA have recommended the use of these oral agents (particularly sofosbuvir) as first line agents in the treatment of chronic HCV in both relapsers and treatment-naive patients.
Treatment
Acute Hepatitis C
Since the majority of patients with acute hepatitis C are asymptomatic, the infection often goes unnoticed until the effects of chronic hepatitis begin to manifest. It is usually rare to closely monitor patients at risk to detect the development of acute hepatitis C. In the majority of patients, the response rate to treatment is higher in the acute rather than the chronic phase of infection. Moreover, treating patients with acute hepatitis has consistently shown high rates of viral clearance and significantly lower rates of chronicity. However, the best treatment regimen, the time of initiation, and the duration of therapy is still debatable.[1] If a patient is identified as having an acute hepatitis C infection, the initial approach would include a period of monitoring of 8 - 20 weeks (often 8 - 12 weeks) to detect spontaneous viral clearance.[1][2] New data suggests higher rates of viral clearance in untreated patients with acute clinical hepatitis C than previously reported.[3][4]For patients who fail to clear the infection spontaneously, treatment should be initiated with Peg-IFN alfa ± ribavirin for 24 to 48 weeks, based on HCV genotype and response to therapy determined by HCV RNA measurement.[2] Revised AASLD guidelines for the management of acute hepatitis C are expected in the summer of 2014.
Chronic Hepatitis C
Approach & Pre-treatment Assessment
Several key points need to be addressed in patients with chronic Hepatitis C prior to the initiation of therapy. Every patient with documented infection requires evaluation to determine if he/she qualifies for medical therapy. Patients with clear indications for treatment require an extensive pre-treatment assessment. Important considerations include HCV genotype, extent of liver disease, concomitant alcohol abuse, psychiatric disorders, and pregnancy among others. With current regimens being physically and financially demanding, screening is essential to identify patients requiring therapy.
| Necessary |
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| Recommended |
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Treatment Indications & Contraindications
Treatment accepted for patients with following characteristics: (should fulfill all characteristics)[1]
- Age ≥ 18 years
- HCV RNA positive
- Liver biopsy showing chronic hepatitis with bridging fibrosis or higher
- Compensated liver disease:
- Total bilirubin = 1.5 g/dL
- INR = 1.5
- Serum albumin > 3.4
- Platelet count = 75,000 mm
- No evidence of hepatic decompensation (hepatic encephalopathy or ascites)
- Acceptable hematological and biochemical profile:
- Hemoglobin = 13 g/dL for men; 12 g/dL for women
- Neutrophil count = 1500 /mm3
- Serum creatinine = 1.5 mg/dL
- Willing to adhere to therapy
- No contraindications to therapy
Treatment contraindicated for patients with any of the following characteristics:[1]
- Age ≤ 2 years
- Uncontrolled major depressive disorder
- Any solid organ transplant
- Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peg-interferon and ribavirin
- Untreated thyroid disease
- Pregnant or unwilling to comply with adequate contraception
- Severe comorbidities such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease
- Known hypersensitivity to drugs used
Treatment should be individualized for patients with any of the following characteristics:[1]
- Age < 18 years of age
- Failed initial treatment (non-responder or relapser)
- Decompensated cirrhosis
- Liver transplant recipients
- Liver biopsy showing mild or no fibrosis
- Current illicit drug or alcohol abusers willing to enroll in a substance abuse program. Abstinence for a minimum of 6 months is required
- Chronic renal disease
- HIV co-infection
With the advent of newer therapies to treat hepatitis C, updated guidelines regarding when and in whom to initiate therapy are expected from the AASLD in the summer of 2014.
Antiviral Agents
| Agent | Recommended Dose | Adverse Effects |
|---|---|---|
| PegIFN alfa-2a (Pegasys™) |
180 mcg subcutaneously once weekly[2] |
Serious adverse events: <1%[5]
Common adverse events: 99% of patients experienced at least one[5] |
| PegIFN alfa-2b (PEG-Intron™) |
1.5 mc / kg SC once weekly[2] |
Serious adverse events: <1%[6]
Common adverse events: 50% of patients have at least one[6]
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| Ribavirin (Rebetol™, Ribasphere™, Copegus™, RibaPak™) |
Genotype 1
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Ribavirin is teratogenic and may cause birth defects and/or death of the exposed fetus. Serious adverse events:[7]
Common adverse events: [7]
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| Sofosbuvir (Sovaldi™) |
400 mg orally daily |
Common events: 20%[8] |
| Simeprevir (Olysio™) |
150 mg orally daily |
Common adverse events: 20%[9]
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| Boceprevir [BOC] (Victrelis™) |
800 mg (4 × 200 mg capsules) PO every 7 – 9h with food in combination with PegIFN – RBV following a 4-week lead-in with PegIFN – RBV [2] No longer recommended given the safer profile of newer protease inhibitors |
Serious adverse events:[10]
Common adverse events:[10]
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| Telaprevir [TVR] (Incivek™) |
750 mg (2 × 375 mg tablets) PO every 7 – 9 h with food (20 grams fat) for 12 weeks, plus PegIFN – RBV 24 or 48 weeks [2] No longer recommended given the safer profile of newer protease inhibitors |
Serious adverse events:[11]
Common adverse events: [11]
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Monitoring Response to Treatment
Following viral kinetics and assessing the rate of viral clearance is useful to predict response to therapy and to determine the best duration of therapy. The following definitions relate to viral kinetics and are important in the management of Hepatitis C.
Early Virologic Response (EVR):
Defined as the decrease in HCV RNA in the serum by at least 2 logs at week 12 of treatment.[2] Absence of EVR is the best means to identify non-responders to therapy. Almost all treatment-naive patients with HCV genotype 1 who do not have and EVR with not have a sustained virologic response. This may be used as an indication to discontinue treatment. EVR is not very useful in monitoring the treatment of other genotypes.[1]
Rapid Virologic Response (RVR):
It is defined as undetectable HCV RNA at week 4 of therapy.[2] RVR was investigated in order to limit useless exposure to therapy. RVR is a good prognostic sign with patients achieving an RVR usually going on to achieve a sustained virologic response regardless of the genotype or therapeutic regimen.[1]
Sustained Virologic Response (SVR):
Defined as undetectable HCV RNA at 24 weeks after treatment completion.[2]
Partial Response
Defined as greater than 2 log reduction from baseline HCV RNA at week 12, but virus remains detectable through week 24 or after the end of treatment.[2]
Relapse
Defined as undetectable viremia during treatment and/or at the end of treatment, but subsequent viremia after cessation of treatment.[2] In most cases, virological relapse occurs in the first 12 weeks after discontinuation of therapy. Late relapses, beyond 24 weeks are extremely uncommon.[1]
Non-response
Defined as detectable HCV RNA throughout treatment.[2]
Treatment Algorithm
The treatment of HCV has changes drastically in the past half-decade, and with more trials showing improved outcomes with newer therapies, treatment recommendations have shifted away from older generation protease inhibitors such as boceprevir and telaprevir given the safer profile and the higher effectiveness of simeprevir and sofosbuvir. The 2014 AASLD/IDSA recommendations for testing, managing, and treating Hepatitis C have made these new agents first line therapies in the management of both treatment naive and relapsing patients.[12] The guidelines do not yet address the monitoring of patients who are on or have completed therapy. An update is expected in the summer of 2014.
Genotype 1
Treatment Naive Patients[12]
- Eligible for IFN therapy:
- Daily sofosbuvir + ribavirin + weekly PEGIFN for 12 weeks (regardless of subtype), or
- Daily simeprevir for 12 weeks + ribavirin + weekly PEGIFN for 24 weeks (if HCV genotype 1b or HCV genotype 1a without Q80K polymorphism)
- Not eligible for IFN therapy:
- Daily sofosbuvir + simeprevir ± ribavirin for 12 weeks (regardless of subtype)
Non-responders or relapsers[12]
- Prior IFN/RBV:
- Daily sofosbuvir + simeprevir ± ribavirin for 12 weeks (regardless of subtype)
- Prior IFN/RBV + Protease inhibitor:
- Daily sofosbuvir for 12 weeks + ribavirin + weekly PEGIFN for 12 - 24 weeks
- Daily sofosbuvir for 12 weeks + ribavirin + weekly PEGIFN for 12 - 24 weeks
Genotype 2
Treatment Naive Patients[12]
- Daily sofosbuvir + ribavirin for 12 weeks
Non-responders or relapsers[12]
- Daily sofosbuvir + ribavirin for 12 weeks
Genotype 3
Treatment Naive Patients[12]
- Daily sofosbuvir + ribavirin for 24 weeks, or
- Daily sofosbuvir + ribavirin + weekly PEGIFN for 12 weeks
Non-responders or relapsers[12]
- Daily sofosbuvir + ribavirin for 24 weeks
Genotype 4
Treatment Naive Patients[12]
- Eligible for IFN therapy:
- Daily sofosbuvir + ribavirin + weekly PEGIFN for 12 weeks, or
- Daily simeprevir for 12 weeks + ribavirin + weekly PEGIFN for 24 - 48 weeks
- Not eligible for IFN therapy:
- Daily sofosbuvir + ribavirin for 24 weeks
Non-responders or relapsers[12]
- Daily sofosbuvir for 12 weeks + ribavirin + weekly PEGIFN for 12 weeks, or
- Daily sofosbuvir + ribavirin for 24 weeks
Future Therapies
Several investigational drugs are being tested for use in hepatitis C. These agents focus proteins essential for viral replication. The table below summarizes the agents currently being investigated.
| Name | Alternative | Mechanism of Action |
| Danoprevir | RG7227/ITMN-191 | Inhibitor of the HCV NS3/4A serine protease |
| Asunaprevir | BMS-650032 | Inhibitor of the HCV NS3/4A serine protease |
| Vaniprevir | MK-7009 | Inhibitor of the HCV NS3/4A serine protease |
| Daclatasvir | BMS-790052 | Inhibitor of the HCV NS5A polymerase |
| Mericitabine | RG7128 | Inhibitor of the HCV NS5B polymerase |
| Ledipasvir | GS-5885 | Inhibits the HCV nonstructural protein NS5A |
| Faldaprevir | BI-2010335 | Protease Inhibitor |
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases (2009). "Diagnosis, management, and treatment of hepatitis C: an update". Hepatology. 49 (4): 1335–74. doi:10.1002/hep.22759. PMID 19330875.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 Yee HS, Chang MF, Pocha C, Lim J, Ross D, Morgan TR; et al. (2012). "Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office". Am J Gastroenterol. 107 (5): 669–89, quiz 690. doi:10.1038/ajg.2012.48. PMID 22525303.
- ↑ Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A; et al. (2003). "Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance". Gastroenterology. 125 (1): 80–8. PMID 12851873.
- ↑ Micallef JM, Kaldor JM, Dore GJ (2006). "Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies". J Viral Hepat. 13 (1): 34–41. doi:10.1111/j.1365-2893.2005.00651.x. PMID 16364080.
- ↑ 5.0 5.1 [| PEGASYS Prescribing Information. Genentech, Inc. 2013.]
- ↑ 6.0 6.1 [| PEGINTRON Prescribing Information. Merck & Co., Inc. 2013.]
- ↑ 7.0 7.1 [| COPEGUS Prescribing Information. Genentech, Inc. 2013.]
- ↑ [| SOVALDI Prescribing Information. Gilead Sciences, Inc. 2013]
- ↑ [| OLYSIO Prescribing Information. Janssen Products, LP 2013.]
- ↑ 10.0 10.1 [| VICTRELIS Prescribing Information. Merck & Co., Inc. 2013.]
- ↑ 11.0 11.1 [| INCIVEK Prescribing Information. Vertex Pharmaceuticals Incorporated, 2013.]
- ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed July 27, 2014.