In the early 1960s, when only hepatitis types A and B were recognized, treatment was focused on the acute illness and consisted of strict bed rest, a nutritious diet, and the judicious use of medications.1, 2 Corticosteroid treatment was attempted and reduced serum bilirubin levels, but it probably promoted the evolution of acute hepatitis B to chronic hepatitis B.3, 4 The search for drugs was impelled by the discovery of hepatitis B virus, which permitted the accurate identification of chronic hepatitis B.5 Numerous drugs were evaluated, but many had little positive effect or actually caused harm.4, 6 Among them, interferon (IFN) appeared to be the most effective.7
In the mid-1970s, after hepatitis A virus had been identified, non-A, non-B (NANB) hepatitis was recognized8; it was originally believed to be inconsequential but was later documented to be a mostly progressive disease that often advanced silently to cirrhosis and even cancer.9 Thus, together with efforts to identify the causative agent, attention was turned to seeking drug treatments that might impede this inexorable advance.
Acyclovir, one of the first antiviral agents to be evaluated, failed to show a positive effect.10 The apparent success of IFN for hepatitis B, however, encouraged a pilot study at the National Institutes of Health in 1986: recombinant IFNα was used to treat patients with NANB hepatitis even before hepatitis C virus (HCV) was identified as the cause of the disease.11 Encouraging results from this study prompted several mid-sized controlled trials with IFN for NANB hepatitis,12, 13 and its partial effectiveness was confirmed. IFNα alone, dosed at 3 MU 3 times a week (tiw) for 24 weeks, induced an end-of-treatment response in approximately one-third of patients; most, however, relapsed, and this left a sustained virological response (SVR) rate of approximately 6% (Fig. 1).12, 13 Several studies followed in the 1990s with the aim of establishing the appropriate dose and the necessary treatment length. Increasing the treatment length to 48 weeks raised SVR rates to approximately 16%. Meanwhile, ribavirin (RBV), when it was evaluated as monotherapy, was found to lower alanine aminotransferase levels but not HCV RNA levels.14 However, when it was added to IFNα, RBV raised SVR rates to approximately 34% after 24 weeks of treatment and to approximately 42% after 48 weeks.15, 16 The achievement of SVR was later regarded as a virological cure because almost all who achieved SVR remained aviremic a decade or more later with an excellent long-term prognosis (Fig. 2).17–19 The next step was enhancing the half-life of IFN via pegylation, which improved the virological response rates and reduced the injection frequency. Trials using weekly injections of long-acting pegylated interferon (PEG) alone for 48 weeks induced a positive SVR rate of approximately 39%, and this rate increased to approximately 54% to 56% when PEG was coupled with RBV for 48 weeks (Fig. 1).20–22 Host factors that were associated with a good response were young age, female sex, non–African American heritage, and low fibrosis levels.23–25
On this background, 3 registration trials were conducted using 2 different products: peginterferon alfa-2a, which was given weekly in a fixed SQ dose of 180 μg and ribavirin tablets daily, the dose of which were adjusted for weight (1,000 mg for <75 kg; 1,200 mg for >75 kg given daily), and peginterferon alfa-2b, 1.5 μg/kg SQ given weekly with a fixed dose of ribavirin (800 mg daily) (Figures 3, 4, 5).26–28 Three important findings emerged from these trials:
- 1SVR rates were higher for patients infected with HCV genotype 2 or 3 (76%-82%) versus patients with genotype 1 (42%-46%; Figs. 3 and 4).
- 2SVR rates were higher (78%) when the baseline viral loads were lower (HCV RNA ≤ 2 × 106 IU/ml), and they were lower (42%) when the baseline viral loads were higher (HCV RNA > 2 × 106; Fig. 4).
- 3Genotype 2/3 patients could be treated for 24 weeks, whereas patients with genotype 1 infections required treatment for 48 weeks (Fig. 5).
Moreover, the improvement in the SVR rate with the addition of RBV was primarily the result of a reduced relapse rate; there was only a small direct antiviral effect (Fig. 6).
Subsequent efforts focused on improving response rates among patients naive to treatment through increases in the treatment dose or duration, and there was partial success.29–32 More useful was the creation of definitions for virological responses, including the end-of-treatment response, SVR, breakthrough, relapse, nonresponse, and null response. Definitions for predicting early virological responses were particularly useful for shortening or curtailing treatment. Negative HCV RNA results in treatment week 4 [i.e., a rapid virological response (RVR)] allowed the treatment to be shortened for patients with genotype 2/3 or genotype 1 with a low viral load33–35; negative HCV RNA results or reduced HCV RNA levels (at least 2-log) at week 12 (an early virological response) predicted the likelihood of SVR.36, 37
The treatment effectiveness varied in retreated partial responders and nonresponders and in difficult-to-treat groups and other originally untreated groups: children; patients with acute HCV, human immunodeficiency virus coinfections, or kidney disease; patients who received liver or solid organ transplants; patients with compensated or decompensated cirrhosis; patients with psychiatric disorders; African Americans; and active injection drug users.38–64 One large trial of nonresponders failed to show efficacy with the extension of PEG treatment to 3.5 years.41
As our knowledge of the structure, function, lifecycle, and pathogenesis of HCV increased, intense investigations were undertaken in the past decade to develop therapies directed at the virus itself because of lingering subpar response rates of HCV genotype 1 to PEG/RBV treatment.65 Protease inhibitors (PIs) are the first of these direct-acting antivirals (DAAs) to show promise: they inhibit the nonstructural 3/4A protease of HCV genotype 1 and dramatically decrease HCV RNA levels.66, 67 However, when they are used as monotherapy, resistance mutations develop rapidly; these mutations significantly decline when PIs are combined with PEG and RBV.68 International phase 2 and 3 trials of two PIs, telaprevir (TVR) and boceprevir (BOC), which were evaluated for their safety and efficacy in treating HCV genotype 1 disease, demonstrated the following69–75 (Figs. 7, 8, 9):
- 4Both led to rapid, sustained declines in HCV RNA in treatment-naive patients with HCV genotype 1.
- 5Both shortened the duration of therapy without sacrificing SVR in patients achieving RVR.
- 6Both led to minimal relapse and development of resistance mutations.
- 7Both had efficacy in prior relapsers and partial responders to PEG and RBV.
- 8Both had improved (albeit lesser) efficacy in patients with cirrhosis and in African Americans.
The PIs induced SVR rates in patients with genotype 1 infections similar to the rates achieved by patients with genotype 2/3 infections who were treated with PEG and RBV alone (Figs. 10 and 11). Triple therapy is now regarded as the standard of care for patients with HCV genotype 1 infections,76 although it is very likely that future DAAs will be effective and safe without the need for added PEG and RBV.