Roughly 185 million people worldwide are infected with hepatitis C virus (HCV), which is associated with progression to end-stage liver disease and hepatocellular carcinoma.1, 2 HCV genotype 4 accounts for about 8–13% of these infections, mainly concentrated in sub-Saharan Africa, northern Africa, the Middle East, and southeast Asia.3, 4 Within Europe, HCV genotype 4 is present in a substantial proportion of patients with HCV infections in countries including Belgium, France, and Greece.5 In Egypt, genotype 4 HCV is particularly common, and about 15% of the Egyptian population is infected with this subtype.3
Although the development of ribavirin-free and interferon-free regimens for HCV genotype 1 has progressed rapidly, simple well tolerated treatments for HCV genotype 4 are particularly crucial in view of the high concentration of this genotype in low-income countries, where laboratory monitoring for adverse events might not be feasible.4 In 2014, the directly acting antivirals sofosbuvir and simeprevir were introduced. Sofosbuvir or simeprevir in combination with pegylated interferon and ribavirin for 12 weeks substantially improved the proportion of patients with HCV genotype 4 achieving a sustained viral response (SVR).6 For patients who were ineligible for interferon treatment, sofosbuvir and ribavirin for 24 weeks was also recommended.6 Although these regimens are associated with high 59–100% SVR for patients who are treatment naive or treatment experienced, they include multiple pills, injections, and long treatment durations.6 Additionally, both interferon and ribavirin need frequent laboratory monitoring and are associated with toxic effects, including fatigue, anaemia, and teratogenicity.6
Research in context
Systematic review
We searched PubMed on Feb 11, 2015, for articles published between Jan 1, 2000, and Feb 11, 2015, using a combination of the MeSH search terms “HCV treatment”, “antiviral agent”, and “genotype 4” and consulted the hepatitis C virus (HCV) treatment guidelines for phase 2 or 3 clinical trials of treatments for patients with HCV genotype 4. We also searched the reference lists of articles from our search for additional reports that met our inclusion criteria of phase 2 and phase 3 clinical trials of interferon-free regimens for treatment of HCV genotype 4.
Four clinical trials have been reported (one journal article and four in abstract form) for interferon-free regimens for patients with HCV genotype 4. The results of these trials have shown promising safety and efficacy (sustained viral response at 12 weeks, 84–100%) with combination direct-acting antiviral drugs, with or without ribavirin for 12–24 weeks. Few patients with cirrhosis or who have previously been treated with interferon-containing regimens have been included.
Added value of this study
Although our study is small, we showed high rates of sustained viral response at 12 weeks with use of sofosbuvir and ledipasvir for 12 weeks, which supports the possibility that this simple regimen might be effective for some patients.
Implications of all the available evidence
Further development of this efficacious, simple, well tolerated regimen is warranted and studies in patients with cirrhosis and previously treated patients should be pursued.
Two directly acting antivirals, ledipasvir (an NS5A inhibitor) and sofosbuvir (a nucleotide polymerase inhibitor), have been approved in the USA for combination use for the treatment of HCV genotype 1. Results from studies of this combination, given as one pill per day for 12 weeks, have shown 91–100% SVR in patients with HCV genotype 1 who are treatment naive and treatment experienced, with few adverse events.7, 8 In vitro, both ledipasvir and sofosbuvir have anti-HCV activity against HCV genotype 4 that is similar to that noted against HCV genotype 1. However, the clinical efficacy of this regimen in vivo for HCV genotype 4 has not yet been established.
Historically, proportions of patients with HCV genotype 4 who achieve SVR when given interferon-containing treatments have been between those of patients with HCV genotype 1 and HCV genotypes 2 and 3.9, 10 Furthermore, the in-vitro efficacy of ledipasvir and sofosbuvir for HCV genotype 4 suggests that the combination of these potent directly acting antivirals without ribavirin for 12 weeks might be effective for the treatment of HCV genotype 4 in patients who are treatment naive or interferon treatment experienced. Therefore, we did a clinical trial to assess the two drug combination of ledipasvir and sofosbuvir for 12 weeks for the treatment of patients with HCV genotype 4.