Direct-Acting Antiviral Agents for HCV Infection

We have come a long way in the treatment of hepatitis C using the new direct-acting antiviral (DAAs). This issue of Journal of Clinical and Experimental Hepatology (JCEH) covers several new aspects of DAAs in hepatitis C virus (HCV) therapy. With the availability of safety data from pooled trials, pan-genotypic drugs, and availability of cost effective generic drugs, the elimination of HCV is a very real possibility.^{1, 2} There is increasing data on the safety of DAAs in niche groups like post-transplantation, thalassemia and other hematological disorders, co-infections with hepatitis B virus (HBV) / human immunodeficiency virus (HIV), patients on hemodialysis, and the pediatric population. In this issue, there are a number of papers from the world over which focus on these interesting aspects of HCV therapy in the DAAs era.

Mehta V, et al.³ have reported their real-life experience of 648 hepatitis C patients who have received DAAs therapy over a period of one year. Of these, 181 subjects received sofosbuvir (SOF) and ledipasvir (LDV) and 461 were on SOF and daclatasvir (DCV). On intention-to-treat (ITT) analysis overall sustained viral response (SVR)-12 was achieved in 88.1% patients. SVR-12 in genotypes 1, 3 and 4 on ITT analysis were 96.8%, 85.2% and 93.5%, respectively. The authors have observed a high SVR-12 rate irrespective of the genotype, presence of cirrhosis or prior treatment experience. This is much higher than the published western data. The ION -1 involving genotype (GT)-1 patients with and without cirrhosis had SVR rates of 97-99%. When ION-2 included patients with treatment experience, this SVR-12 reduced to 94-96%.⁴ In GT-3, the SVR rates in the ALLY-3 were 94% and 58% in treatment experienced non-cirrhotic and cirrhotic patients respectively.⁵ It appears that the real-life data from India and Egypt has shown better results than in the trial setting.^{1, 6, 7} This data highlights the efficacy and safety of DAAs. The availability of low-cost or free of cost therapy offered in the public health setting in the state of Punjab provides a roadmap for HCV elimination in India.¹

The article by Mehta R, et al.⁸ sheds new light on the hepatitis C treatment in patients with thalassemia. This is a unique patient population who have transfusion dependent anemia, making them ribavirin (RBV) intolerant. Hence treatment in the pegylated-interferon and RBV era was fraught with difficulties, as the patients would often require increased transfusion frequency, and this would often result in need for increased iron chelation therapy. Conversely, estimation of fibrosis in these patients is again difficult as the presence of hepatic iron interferes with the non-invasive assessment of liver fibrosis by transient elastography. The liver stiffness measurement (LSM) is often falsely high and the patients are misclassified as having advanced fibrosis. This can usually be resolved by performing a liver biopsy, which is however invasive. Nagral et al⁹ have previously demonstrated an SVR-12 rate of near 100% in 29 thalassemia patients. About 30% of their study population was treatment experienced, 20% had evidence of cirrhosis and 75% had significant fibrosis. Irrespective of the severity and previous therapy, they showed 100% efficacy with 100% attaining end of treatment response and SVR-12.⁹ Sinakos et al.¹⁰ reported an SVR-12 of 90% in 61 thalassemia patients with hepatitis C and advanced liver fibrosis treated with different interferon-free regimens in Greece. It would appear from all these trials, that the efficacy of DAAs, including generic DAAs, in the thalassemic population is as good as in the non-thalassemic population.¹¹

In a study from Egypt, Abdel-Aziz AM, et al.¹² have investigated the efficacy and safety of SOF/DCV, with or without RBV in treatment of HCV genotype 4, as well as their effect on the liver fibrosis. Additionally, the authors tried to assess the relationship between interleukin (IL)-18 polymorphism (rs1946518) at position-607 C/A and response to SOF/DCV with or without RBV therapy. In hepatitis C, IL-18 is a pivotal mediator of the Th1/Th2 driven immune response. Two IL-18 promoter polymorphisms (-607 C/A and -137 G/C) and their haplotypes have been described as affecting HCV expression. Ibrahim et al reported genotype C/C genotype was only present in responders (35.2%) while A/C genotype was present in responder cases (64.8) as well as in hepatitis C relapsers (100%). There was no significant association between IL-18 polymorphism (rs1946518) at position -607 and SVR12. Two prior trials have also substantiated this finding.^{13, 14}

Lastly, Bunchorntavakul C et al.¹⁵ review the association of HCV related mixed cryoglobulinemia (MC), which is an HCV antigen stimulated B-lymphocyte clonal proliferation driven vasculitic disorder. The role of DAAs therapy in MC has thrown open new vistas of treatment of this disorder. Rituximab is currently considered the best biological target option for patients with MC. DAAs may be used alone or in combination with rituximab. Bonacci et al.¹⁶ have used various SOF-based DAAs combinations in 35 patients of MC, while Saadoun et al.¹⁷ have reported success in about 41 patients using SOF/DCV therapy. More data is needed before the treatment regimens of administering DAAs concurrently or sequentially with rituximab can be recommended as standard of care in MC.

The recently published Cohrane meta-analysis reviewed the results of 130 clinical trials on the pooled data for 51 different DAAs. They concluded that the available evidence for long term clinical effects of DAAs therapy is limited as no long-term trials have assessed whether or not DAAs treatment improves morbidity and mortality.¹⁸ However, more data is available from India and other countries where public health programmes have generated a wealth of information about the reduction of disease burden, which is both cost effective and cost saving.¹⁹

In conclusion, DAA therapy offers safe efficacious treatment options in chronic hepatitis C, including difficult to treat populations, and other niche groups. The availability of cheap and effective generic drugs is expected to change the natural course of chronic hepatitis C and improve treatment outcomes.