A Review of Standard and Newer Treatment Strategies in Hepatitis C

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