Current Therapies for Chronic Hepatitis C

McKenzie C. Ferguson, Pharm.D.

Pharmacotherapy. 2011;31(1):92-111.

Conclusion

Treatment of patients with chronic HCV should be individualized, with consideration given to prevention of transmission, risk factor modification as appropriate, adverse events and tolerability, adherence, and avoidance of complications. Current practice guidelines published by the AASLD represent the evidence-based standard for management of HCV. Currently, peginterferon and ribavirin represent the standard of care for treatment of chronic HCV. A surrogate marker for clinical outcomes in HCV is SVR. Of the two available pegylated interferons, both are equally efficacious in attaining SVR. Duration of therapy is guided by HCV genotype and virologic response. Because of the high rates of RVR and SVR, patients with genotype 2 or 3 can be treated for 24 weeks. Those with genotype 1 or 4 require 48 weeks' duration of treatment. In all patients undergoing treatment, appropriate monitoring for serious treatment-related adverse effects must be conducted. Hematologic abnormalities, including anemia and neutropenia, may require a reduction in dosage or withdrawal from treatment. New therapies in development for treatment of HCV have the potential to reduce adverse effects and improve outcomes. Special populations, including patients coinfected with HIV, patients with severe chronic kidney disease, injection drug users, pregnant women, and pediatric patients should be closely monitored to prevent HCV-related morbidity and mortality.

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Table 1. Selected American Association for the Study of Liver Diseases Guideline Recommendations for Management of Hepatitis C Infection⁷
Recommendation	Class^a	Level of Evidence^b
All patients with HCV infection
Treatment decisions should be individualized based on the severity of liver disease, the potential for serious adverse effects, the likelihood of treatment response, the presence of comorbid conditions, and patients' willingness to undergo treatment.	IIa	C
Optimal therapy for chronic HCV infection is the combination of peginterferon alfa + ribavirin.	I	A
Hepatitis C RNA should be tested at the start of or shortly before treatment and at week 12 of therapy.	I	A
Patients with genotype 1 or 4 HCV infection
Peginterferon + ribavirin should be administered for 48 wks; the dosage of peginterferon alfa-2a should be 180 μg/wk s.c. + ribavirin 1000 mg/day if weight ≤ 75 kg and 1200 mg/day if > 75 kg; the dosage for peginterferon alfa-2b should be 1.5 μg/kg/wk s.c. + ribavirin 800 mg/day if weight < 65 kg, 1000 mg/day if > 65 but ≤ 85 kg, 1200 mg/day if > 85 but ≤ 105 kg, and 1400 mg/day if > 105 kg.	I	A
Treatment may be discontinued in patients who do not achieve an early virologic response.	I	A
Patients who do not achieve a complete early virologic response should be retested at week 24, and if HCV RNA remains positive, treatment should be discontinued.	I	A
Patients with genotype 1 infection who receive treatment for 48–72 wks and whose HCV measurement is negative at the end of treatment should be retested for HCV RNA 24 wks later to evaluate for sustained virologic response.	I	A
Patients with genotype 2 or 3 HCV infection
Treatment with peginterferon + ribavirin should be administered for 24 wks, using ribavirin 800 mg/day.	I	A
Patients whose treatment continues through 24 wks and whose measurement of HCV RNA is negative should be retested for HCV RNA 24 wks later to evaluate for sustained virologic response.	I	A
Retreatment with peginterferon + ribavirin can be considered for nonresponders or those who relapse and had been treated with nonpegylated interferon ± ribavirin, or with peginterferon monotherapy, particularly if they have bridging fibrosis or cirrhosis.	IIa	B
Retreatment with peginterferon + ribavirin in patients who did not achieve sustained virologic response after a previous full course of peginterferon + ribavirin is not recommended, even if a different type of peginterferon is administered.
Patients who relapse	III	C
Nonresponders	III	B
Patients with HIV and HCV infection
Initial treatment of HCV in most HIV-infected patients should be peginterferon + ribavirin for 48 wks at doses recommended for HCV-monoinfected patients.	I	A
Children with HCV infection
Children aged 2–17 yrs who are infected with HCV should be considered appropriate candidates for treatment using the same criteria as those used for adults.	IIa	B

HCV = hepatitis C virus; HIV = human immunodeficiency virus.
^aThe American Association for the Study of Liver Diseases classifications of recommendations are as follows: class I = conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective; class II = conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness or efficacy of a diagnostic evaluation, procedure, or treatment; class IIa = weight of evidence or opinion is in favor of usefulness or efficacy; class IIb = usefulness or efficacy is less well established by evidence or opinion; class III = conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful or effective and in some cases may be harmful.
^bThe American Association for the Study of Liver Diseases levels of evidence are as follows: level A = data derived from multiple randomized clinical trials or meta-analyses; level B = data derived from a single randomized trial, or nonrandomized studies; level C = only consensus opinion of experts, case studies, or standard of care.

Table 2. Risk Factors for Hepatitis C Virus^{1–3, 7, 9, 10}
Risk Factor	Explanation	Recommendation
Injection drug use	Most common route of exposure	Screen for HCV
Receipt of blood or blood component before 1992	Routine blood screening implemented in 1992	Screen for HCV
Health care exposure	After needle-stick injury or mucosal exposure of HCV-positive blood	Screen for HCV
Receipt of long-term hemodialysis	Higher prevalence of HCV infection	Screen for HCV
Human immunodeficiency virus infection	Higher prevalence of HCV infection	Screen for HCV
Children of HCV-infected mothers	< 5% of children acquire infection; not linked to breastfeeding	Screen for HCV
Current partners of HCV-infected persons	Risk with monogamous sexual partners is < 1%	Screen for reassurance
Multiple sexual partners	Higher prevalence of HCV infection	Practice safe sex

HCV = hepatitis C virus.

Table 3. Diagnosis of Hepatitis C Virus^{3, 7}
Anti-RNAa	HCV RNA	Interpretation	Follow-up
Positive	Positive	Acute or chronic infection	Assess for therapy
Positive	Negative	Acute infection with low-level viremia or resolution of infection	Consider repeat testing in 4–6 mo, evaluate signs and symptoms
Negative	Positive	Possible false-positive HCV RNA, acute infection, or inadequate immune response	Consider repeat testing in 4–6 mo
Negative	Negative	Absence of infection	Assess for at-risk behaviors and development of signs or symptoms

HCV = hepatitis C virus.
^aConfirmed by enzyme immunoassay.

Table 4. Definitions of Treatment Responses for Hepatitis C Virus Infection⁷
Response	Definition
Rapid virologic response	Undetectable HCV RNA at week 4 of therapy
Early virologic response	At least a 2-log reduction in HCV RNA by 12 wks of therapy
End-of-treatment response	No detectable HCV RNA at the end of therapy
Sustained virologic response	No detectable HCV RNA at the conclusion of treatment and 24 wks after discontinuation of therapy
Breakthrough	Reappearance of HCV RNA while still receiving therapy
Relapse	Reappearance of HCV RNA after discontinuation of therapy
Nonresponder	Failure to achieve undetectable HCV RNA after 24 wks of therapy
Partial responder	At least a 2-log reduction in HCV RNA but never reaches undetectable HCV RNA

HCV = hepatitis C virus.

Table 5. Summary of Clinical Trials of Treatment of Hepatitis C Infection^23–33
Treatment Group^a	HCV Genotype	Treatment Duration (wks)	Virologic Response (%)	Relapse Rate (%)	Discontinuation Rate (%)
Comparative efficacy of pegylated interferons
Peg-IFN alfa-2a + ribavirin	1	12	66 EVR		1
Peg-IFN alfa-2b + ribavirin (n=380)²³			63 EVR		6
Peg-IFN alfa-2a + ribavirin	1–4	24 and 48	66 SVR
Peg-IFN alfa-2b + ribavirin (n=183)²⁴			62 SVR
Standard-dose Peg-IFN alfa-2b + ribavirin	1	48	40 SVR
Low-dose Peg-IFN alfa-2b + ribavirin			38 SVR
Standard-dose Peg-IFN alfa-2a + ribavirin (n=3070)²⁵			41 SVR
Duration of therapy according to genotype
Peg-IFN alfa-2a + ribavirin (n=455)²⁶	1	48 72	53 SVR (17 SVR^b) 54 SVR (29 SVR^b)	29 21	24 41
Peg-IFN alfa-2b + ribavirin (n=101)²⁷	1	48 72	18 SVR^c 38 SVR^c	59 20	14 15
Peg-IFN alfa-2a or Peg-IFN alfa-2b + ribavirin (n=696)²⁸	1	24 48 72	87 vs 77 SVR^d 70 vs 72 SVR^d 38 vs 63 SVR^d	19^e 19f	10^e 13f
Peg-IFN alfa-2a + ribavirin (n=516)²⁹	1 or 4	24	29 RVR, 77 SVR	11	1
Peg-IFN alfa-2a + ribavirin (n=1469)³⁰	2 or 3	16 24	67 RVR, 89 EVR,65 SVR 64 RVR, 89 EVR, 76 SVR	31 18	4 5
Peg-IFN alfa-2a + ribavirin (n=382)³¹	2 or 3	12 24	59 SVR 78 SVR	33 12	1 10
Peg-IFN alfa-2b + ribavirin (n=428)³²	2 or 3	14 24	71 RVR,^g 81 SVR^h 91 SVR^h	11 5	6 21
Peg-IFN + ribavirin (n=35)³³	6	24 48	39 SVR 75 SVR

HCV = hepatitis C virus; Peg-IFN = peginterferon; EVR = early virologic response; SVR = sustained virologic response; RVR = rapid virologic response.
^aComplete treatment regimens with dosing are provided in text.
^bSlow responders: HCV RNA positive at 12 wks.
^cSlow responders: 2-log reduction in HCV RNA and undetectable levels at wk 24.
^dFor standard duration (48 wks) vs individualized durations (24, 48, and 72 wks) based on achievement of RVR. Rapid virologic response was at 4 wks, 8 wks, and 12 wks for the three individualized durations, respectively.
^eAt standard duration (48 wks).
^fAt variable duration (24, 48, and 72 wks).
^gOverall RVR occurred in 302 of 428 patients before randomization.
^hThe SVR is only for those who achieved RVR.

Table 6. Summary of Clinical Trials of Alternative and Investigational Therapies for Hepatitis C Infection^34–38
Population	Study Treatment^a	Treatment Duration (wks)	Sustained Virologic Response (%)	Relapse Rate (%)	Discontinuation Rate (%)
Treatment naïve, HCV genotype 1 (n=458)³⁴	Albinterferon alfa-2b 900 μg q 2 wks	48	59	29	19
	Albinterferon alfa-2b 1200 μg q 2 wks		56	31	29
	Albinterferon alfa-2b 1200 μg q 4 wks		51	28	17
	Peg-IFN alfa-2a (+ ribavirin for all treatments)		58	29	13
Treatment naïve, HCV genotype 2 or 3 (n=43)³⁵	Albinterferon alfa-2b q 2 wks	24	62	28	38
	Albinterferon alfa-2b q 4 wks (+ ribavirin for both treatments		77	19	14
Treatment naïve (n=180)³⁶	Taribavirin 1200 mg/day	24 or 48^c	37	42	25
	Taribavirin 800 mg/day		23	64	24
	Taribavirin 1600 mg/day		29	57	30
	Ribavirin (+ Peg-IFN alfa-2a for all treatments)		44	41	21
Treatment naïve (n=962)³⁷	Taribavirin	24 or 48^b	40	35	26
	Ribavirin (+ Peg-IFN alfa-2a for both treatments)		55	18	26
Previously treated, HCV genotype 1 (n=453)³⁸	Telaprevir + Peg-IFN ± ribavirin regimens:
	T12PR24	Varied	51	30	25^c
	T24PR48		53	13	51^c
	T24P24		24	53	48^c
			14	53	68^c

HCV = hepatitis C virus; Peg-IFN = peginterferon.
^aComplete treatment regimens with dosing are provided in text.
^bDependent on HCV genotype (genotype 2 or 3: duration 24 wks; non–genotype 2 or 3: duration 48 wks).
^cMost patients discontinued as a result of meeting a stopping rule, including virologic breakthrough, nonresponse at week 4, 12, or 24.

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