Description of the condition
Hepatitis C is an enveloped ribonucleic acid (RNA) virus. It is divided into 11 major genotypes, with six of the genotypes occurring more frequently (Foster 2009). An estimated 130 to 170 million people worldwide are infected with hepatitis C, and four million of them are in the United States (WHO 2011). Around 75% to 85% of patients who become infected with hepatitis C fail to clear the virus and become chronic carriers (Ghany 2009). Among these individuals, 5% to 20% are reported to develop cirrhosis over a period of approximately 20 to 25 years (Seeff 2002; Seeff 2009). Annually, approximately 2% to 4% of patients with advanced fibrosis or cirrhosis develop liver complications such as liver failure, portal hypertension, and hepatocellular carcinoma (Benvegnu 2001; Fattovich 2002). Chronic hepatitis C is the single most common indication for liver transplantation (OPTN 2005).
Description of the intervention
The goal of therapy in chronic hepatitis C is to prevent liver-related morbidity and mortality from the virus infection (Ghany 2009). The commonly used outcome for hepatitis C virus treatment is sustained virologic response (SVR) (Strader 2004). SVR is used as a surrogate measure for patient-relevant outcomes such as mortality, morbidity, and quality of life. A recent systemic review revealed that treatment-related SVR was associated with a substantially reduced risk of hepatocellular carcinoma (Morgan 2013). However, it has not been established whether achieving a SVR in chronic hepatitis C patients will have an impact on other final health outcomes, including mortality (Gluud 2007; Brok 2010; Koretz 2013).
Currently, the standard of care for patients with chronic hepatitis C is a 24 to 48-week course of pegylated interferon-alpha-2a (PEG-IFN-α2a) or pegylated interferon-alpha-2b (PEG-IFN-α2b) in combination with ribavirin. This therapy leads to a SVR in 42% to 52% of individuals infected with hepatitis C virus genotype 1, 65% to 85% in virus genotypes 4, 5, or 6, and 76% to 82% in virus genotypes 2 or 3 (Hoofnagle 2006).
The duration of therapy depends on the virologic response. The rapidity of virologic response appears to be an important predictor for a SVR. Multiple trials have attempted to shorten the duration of hepatitis C therapy based upon the patient's virologic response (Fried 2002). A shorter course of therapy is optimal, to decrease the cost of therapy and the associated adverse effects.
How the intervention might work
During the past 10 years, intensive efforts have been made to develop different compounds with antiviral activities against the hepatitis C virus, which are referred to as direct-acting antiviral agents. These antiviral agents are inhibitors of NS3 protein/NS4A cofactor complex which plays an important role in the final stages of the hepatitis C virus replication cycle (Simmonds 1993). Adding one of these direct-acting antiviral agents to standard treatment can increase the frequency of achieving SVR and may permit a shorter duration of therapy to achieve it (McGovern 2008).
The clinical development programme for the two hepatitis C virus nonstructural (NS) 3/4A protease inhibitors boceprevir and telaprevir has now been completed. A few reviews, including narrative reviews, and randomised clinical trials have been published so far (Hofmann 2011).
Why it is important to do this review
We aim to identify all randomised clinical trials to strengthen inferences about the benefits and harms of adding one of the protease inhibitors to the current standard treatment of pegylated interferon and ribavirin for adult patients with chronic hepatitis C.