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Supplements Battling a Stormy C: Addressing Managed Care Challenges and Opportunities in Management of Hepatitis

A Review of Standard and Newer Treatment Strategies in Hepatitis C

Tram T. Tran, MD
Chronic infection with hepatitis C virus (HCV) is common, but underdiagnosed and undertreated worldwide. The most important treatment outcome in HCV is sustained virological response (SVR), due to its impact on reducing the risks of liver-related mortality, hepatocellular carcinoma, and hepatic decompensation. The degree of baseline liver disease, IL28B genotype, and HCV genotype are important determinants of response to treatment, and SVR rates less than 50% can be expected for persons with genotype 1 receiving standard peginterferon with ribavirin. The rates are even lower when cirrhosis is present. There is little evidence supporting improved outcomes with peginterferon and ribavirin retreatment, and escalation of ribavirin dosage leads to an increased risk of adverse events. Introduction of the protease inhibitors, boceprevir and telaprevir, has resulted in SVR rates between 67% and 79% when used as part of a triple therapy regimen, which has become the standard of care for those with genotype 1 HCV. More work is needed to develop strategies to further improve treatment outcomes, and ideally to develop a vaccine to prevent the development of chronic HCV.

(Am J Manag Care. 2012;18:S340-S349)
Estimates suggest that if 1998 treatment practices were in place from 2005 to 2025, then 196,000 (confidence interval [CI], 178,000-214,000) hepatitis C virus (HCV)-related deaths would occur during this period in the United States. If 15% of patients were treated and sustained virological response (SVR) were achieved in 80%, then 182,000 (CI, 165,000-198,000) HCV-related deaths would occur during that period. If 50% of patients were treated and 60% SVR were achieved, the death rate would be decreased to 160,000 (CI, 145,000-175,000). If 100% of patients were treated and 60% SVR were achieved, the mortality would be decreased to 124,000 (CI, 111,000-136,000).1 In a recent meta-analysis, SVR was associated with a 77% reduction in liver-related mortality, a 79% reduction in hepatocellular carcinoma (HCC), and an 84% reduction in hepatic decompensation, compared with treatment failure.2 These data highlight the importance of HCV treatment from a patient and public health perspective. This article, the second in a series of 3 articles focused on hepatitis C, will highlight the standard and newer treatment options in the context of guidelines and provide suggestions for incorporating newer options into treatment algorithms.

Rationale for Early and Effective Treatment

The goals of treatment are to prevent complications and death related to HCV. Since these outcomes are not easily measured due to the insidious progression of HCV complications over decades, the treatment of HCV centers around improving virological outcomes associated with quantitative polymerase chain reaction (PCR) HCV assays.3 The most important outcome is SVR, because it has been linked to a reduction in mortality.2,3 SVR is defined as a negative HCV ribonucleic acid (RNA) test 24 weeks after cessation of treatment, and is generally referred to as a virological cure. A rapid virological response (RVR) is defined as the clearance of HCV from serum by week 4 using a sensitive PCR-based assay with a lower limit of detection of 50 international units (IUs)/mL, although this may change with increased sensitivity of newer assays. Achieving an RVR is a strong predictor of achieving an SVR with therapy. An early virological response (EVR) is defined as a reduction of 2 log or more in HCV RNA level compared with baseline HCV RNA level or negative HCV RNA at treatment week 12. Failure to achieve an EVR is a powerful predictor of failure to achieve an SVR. If an EVR or RVR is achieved, an end-of-treatment response (ETR) refers to undetectable virus at the end of a 24- or 48-week course. ETR does not predict SVR, but is a necessary predecessor. A relapse is said to occur when there is a reappearance of HCV RNA in serum after therapy is discontinued, but after an ETR is documented.3

When patients are still receiving treatment, several virological outcomes suggest poor response to treatment. A nonresponder refers to a patient who fails to clear HCV RNA from serum after 24 weeks of therapy, while a partial nonresponder exhibits a decrease of 2 log or less in HCV RNA, but a positive HCV RNA test result at week 24. A null nonresponder demonstrates failure to decrease HCV RNA by 2 logs or more after 24 week of therapy. A virological breakthrough occurs when there is reappearance of HCV RNA while still on therapy.3 These adverse virological events while on therapy are associated with a need for treatment regimen discontinuation or modification to optimize outcomes.

Historical Standard of Care Treatment Options

Historically, interferon-based therapies were the standard antiviral strategy for the initial management of HCV. The addition of ribavirin to interferon alfa-2b was found to be effective in improving SVR at 24 to 48 weeks of treatment compared with placebo (31%-38% vs 6%-13%; P <.001, respectively).4 Ribavirin plus interferon alfa-2b also improved SVR relative to interferon alfa-2b alone in relapsed patients (49% vs 5%, P <.001).5 Meta-analyses demonstrated that ribavirin plus interferon also improved SVR in patients who were non-responsive to initial interferon monotherapy, but this older regimen was only associated with a 14% to 15% success rate.6,7

As peginterferon was introduced, it was compared with interferon-based treatment.8,9 Peginterferon has a polyethylene glycol molecule added to the interferon, which increases the half-life of the interferon molecule and allows for convenient dosing.8 Peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b for the initial treatment of HCV,8 with the dosing regimen being subcutaneous peginterferon 1.5 mcg/kg each week plus oral ribavirin 800 mg per day for 48 weeks, or peginterferon 1.5 mcg/kg each week subcutaneously for 4 weeks followed by 0.5 mcg/kg per week for 44 weeks plus ribavirin 1000 to 1200 mg per day. Interferon was dosed as 3 million units subcutaneously 3 times per week plus ribavirin 1000 to 1200 mg per day for 48 weeks. Ribavirin was dosed based on weight and the total daily dose was divided into 2 doses per day. In that trial, the SVR for the high-dose peginterferon alfa-2b regimen was 54%, which was higher than the rate for the low-dose peginterferon (47%, P = .01) or interferon (47%, P = .01) regimens. Among patients with genotype 1, the respective SVR rates were 42%, 34%, and 33%, while in patients with genotypes 2 and 3, SVR was achieved in approximately 80% of patients in all 3 treatment groups. In multivariate modeling, SVR was independently associated with non-genotype 1 patients, lower baseline viral load, lighter patient weight, and younger age. Presence or absence of cirrhosis in association with SVR could not be adequately assessed due to its low prevalence (5% to 7%) in the baseline population. Adverse effect profiles were similar among groups.8 Another study compared subcutaneous peginterferon alfa-2a 180 mcg once weekly plus ribavirin 1000 to 1200 mg daily, subcutaneous peginterferon alfa-2a 180 mcg once weekly plus placebo, and interferon alfa-2b 3 times weekly plus ribavirin 1000 to 1200 mg daily for 48 weeks. The rate of SVR was greater with peginterferon alfa-2a plus ribavirin (56%) than interferon alfa-2b plus ribavirin (44%, P <.001) or peginterferon alfa-2a alone (29%, P <.001). Among patients with genotype 1, the respective SVR rates were 46%, 36%, and 21%. The incidence of influenza-like symptoms (P = .02) and depression (P = .01) was lower in the peginterferon groups.9 These studies indirectly suggested similar efficacy of the peginterferon products when combined with ribavirin, and improvement in SVR relative to interferon with ribavirin.8,9

A head-to-head study of the peginterferon products was conducted to determine the therapy of choice for HCV.10 In the study, patients with HCV genotype 1 who were previously untreated were randomized to undergo 48 weeks of peginterferon alfa-2b 1.5 mcg/kg per week plus ribavirin 800 to 1400 mg per day, or a low dose of 1 mcg/kg per week plus ribavirin 800 to 1400 mg per day, or peginterferon alfa-2a 180 mcg per week plus ribavirin 1000 to 1200 mg per day. SVR was achieved in 39.8% of the standard-dose peginterferon alfa-2b group, 38% of the low-dose peginterferon alfa-2b group, and 40.9% of the peginterferon alfa-2a group (P = NS for all comparisons). Relapse occurred in 23.5%, 20%, and 31.5% of patients, respectively (P value not assessed). However, when HCV RNA was undetectable at week 4, 86.2% achieved an SVR, and when the virus was undetected at week 12, SVR was achieved in 78.7% of patients. The adverse effect profile was similar among all 3 regimens, with more serious adverse events occurring among patients in the peginterferon alfa-2a group (11.7%) than among patients in the standard dose peginterferon alfa-2b group (8.6%, P = .02). Common adverse effects included discontinuation for any reason (low-dose peginterferon alfa-2b, 51.5%; standard-dose peginterferon alfa- 2b, 47%; peginterferon alfa-2a, 40%), discontinuation for virological non-response (low-dose peginterferon alfa-2b, 35.1%; standard-dose peginterferon alfa-2b, 25.7%; peginterferon alfa-2a, 20.4%), neutrophil count less than 750 per mm3 (14.6%-27%), hemoglobin less than 10 g/dL (25.3%- 30.7%), use of an erythrocyte-stimulating agent (14.2%- 16.6%), fatigue (64.4%-66.5%), headache (42.3%-49.9%), nausea (36.4%-42.5%), insomnia (38.3%-41.4%), pyrexia (22.9%-34.9%), anemia (28.8%-33.9%), myalgia (22.5%- 26.9%), neutropenia (18.5%-31.5%), depression (19.4%- 25.5%), irritability (25.1%-25.8%), and rash (21.9%-28%). Dose modification was necessary in 33.3% of patients in the low-dose peginterferon alfa-2b group, 43.3% of patients in the standard-dose peginterferon alfa-2b group, and 42.9% of patients in the peginterferon alfa-2a group; the majority of these involved modification of the ribavirin component of the regimen.10

Peginterferon and ribavirin regimens have also been utilized for other clinical scenarios, including patients with hepatitis C and cirrhosis, patients experiencing treatment failure, and patients co-infected with HIV.11-16 Studies have demonstrated that higher-risk patients had lower SVR rates, ranging from 18% to 35%, and that high-dose ribavirin increased efficacy, but also increased adverse effects, such as anemia. The studies also demonstrated that non-Hispanic white patients had a higher rate of SVR with peginterferon alfa plus ribavirin (52%) than black patients (19%, P <.001), primarily in patients with genotype 1 (98%).16 The results highlight the differential response to treatment based on patient demographic characteristics, and suggest that in most situations, an SVR rate of less than 50% may be expected with standard doses of peginterferon with ribavirin.

Evidence-Based Treatment Guidelines and Limitations of Current Treatment Options

Treatment guidelines focused on standard therapies suggest that treatment decisions should be based on the severity of liver disease, potential for serious adverse effects, likelihood of treatment response, presence of comorbid conditions, and patient acceptance of treatment.3 Although treatment with peginterferon with ribavirin is no longer the standard of care for genotype 1 HCV, it is the foundational regimen for current triple drug regimens, so clinicians should understand the standard approach to treatment.

For patients with genotype 1 and 4, historical guidelines suggested that peginterferon plus ribavirin should be planned for 48 weeks, using peginterferon alfa-2a 180 mcg subcutaneously per week with oral ribavirin 1000 mg for patients weighing 75 kg or less, and ribavirin 1200 mg for patients over 75 kg, or peginterferon alfa-2b 1.5 mcg/kg subcutaneously per week with ribavirin 800 mg for patients up to 65 kg, 1000 mg for patients 65 kg to 85 kg, 1200 mg for patients 85 kg to 105 kg, and 1400 mg for patients over 105 kg. Follow-up HCV RNA testing should occur at week 12 for assessment of EVR, and treatment should be discontinued in patients who do not achieve an EVR. If a complete EVR is obtained, treatment may continue for a total of 48 weeks. For patients with a partial EVR, a 24-week HCV RNA assessment should be conducted, and if negative, treatment should be continued to 48 weeks, and if positive, therapy should be discontinued. In patients with genotype 1 who have delayed virus clearance, therapy may be extended to 72 weeks. Patients who achieve negative HCV RNA should be assessed 24 weeks after treatment for SVR. In patients with genotype 2 or 3, treatment with standard dose peginterferon and ribavirin 800 mg for 24 weeks is recommended. Genotype 2 or 3 patients who achieve negative HCV RNA at 24 weeks should be assessed 24 weeks after treatment for SVR.

 
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