**5. Direct acting antiviral therapy**

\$84,000 with other DAA sharing similar price tags. The endeavor of validating coverage depends upon the tangible and the intangible, the objective and subjective, the cold hard science, and the cold hard dollars. Like prior novel pharmaceuticals before them, DAAs will need full support from the respective government in which the regimen is being distributed, as it does in the United States. Governing medical councils such as the FDA, the Health Products and Food Branch (HPFB) of Health Canada, the State Food and Drug Administration (SFDA) in China, and so on, will need to first approve drug regimens and define which

It is difficult to estimate the exact savings per patient due to the multitude of confounding variables. All things considered, if a patient with HCV progresses naturally without treatment to the point of being considered to have end-stage liver disease. The equivalent of hundreds of thousands of medical dollars will have been spent in order to treat and care for these patients. In addition to the cost savings achieved by no longer needing to treat the manifestations of chronic hepatitis C, the cure of hepatitis C has been also been shown to provide benefits. Beside the improvement in psychological and social well-being, which accompanies cure of HCV, treatment has been shown to decrease and potentially reverse cirrhosis, esophageal varices,

Notably, incomplete treatment, unsuccessful treatment, and reinfection are always possible, particularly in patients with comorbid psychiatric illness, concomitant drug addiction, and poor social support, all known risks factors for contracting HCV [3]. In the long run, this issue should continue to fade in its controversy given that the minimum manufacturing costs for producing direct acting antivirals have been estimated at \$100-250 for a 12-week course of treatment once patent expires and production of generic versions are widely available [14]. Additionally, immediate treatment upon detection as opposed to delay in therapy has shown

Over the past several years, more so recently, treatment options for HCV have exponentially grown. Treatment for HCV began with the FDA approval of interferon (IFN) in 1991, followed by combined IFN and RBV in 1998, and later with peg-IFN in 2001. The regimen of peg-IFN and RBV once stood as the standard of care, and still does in many nations, until recently. DAAs, which target nonstructural proteins involved in replication and infection of HCV, were

Peg-IFN and RBV historically have been shown to result in SVR rates of 75% in patients with genotypes 2 or 3, but only of 40% in patients with genotype 1 [16]. The duration of therapy often depended on both patient's genotype and their response to therapy as measured by HCV RNA viral load following initiation of treatment [17]. In one-third of all patients being treated with peg-IFN and RBV, adverse side effects were noted. These ranged from an influenza-like illness, characterized by fatigue, headache, fever, and rigors as well as complaints of depres‐ sion, irritability, or insomnia. In addition to the side effects, therapy with peg-IFN was a tedious

and the risk for the development of hepatocellular carcinoma [11-13].

population is to receive them.

60 Recent Advances in Liver Diseases and Surgery

cost-effectiveness [15].

first approved in 2011.

**4. Past therapy**

As noted thus far, the groundbreaking development of DAAs has appeared to instantaneous change a bleak and dismal diagnosis to one filled with hope and promise. HCV seems to be paralleling HIV in that it was once considered a death sentence where treatment was harsh and limited but has now changed to something treatable with a pill. Additionally, one can now expect to live a near normal lifespan and be contributors to society.

The genome of HCV is now well understood, and because of this, scientists have been able create inhibitors against components of the genome integral to HCV replication and function. As it currently stands, four classes of DAAs exist and include the NS3/4 protease inhibitors, NS5A polymerase inhibitors, and the NS5B polymerases (nucleoside and nonnucleoside) inhibitors. Starting with protease inhibitors in 2011, BOC and TEL changed the game and raised SVR to impressive levels in treatment-naive patients. Shortly after, SOF, a nucleoside NS5B inhibitor, and SIM, another NS3/4 protease inhibitor, were approved and progress soared. It was not long before the old regimen of peg-IFN was being disposed of for more convenient and more tolerable agents. In the past months, additional agents have been approved and include LED, OMB, PARr, and DAS. Many more are under investigation and will likely be approved by the time of this publication.

The treatment of HCV centers on achieving SVR because if one can achieve this then life expectancy approaches near normal [18]. Without a detectable HCV viral load, cirrhosis is not expected to be occurring, and therefore neither are the complications thereof. Historically, achieving SVR in unique patient populations has proven difficult. Additionally, patients with certain factors often did not tolerate treatment well. In these populations, treatment was not approved, i.e., post liver transplant HCV patients. Genotypic analysis has also helped to identify unique populations. It has been established that some strains of HCV appear to possess an innate resistance to peg-IFN and RBV. Further exploration into genotypic and polymorphic variation and its effect on treatment response is needed, particularly now that these new agents with different mechanisms of action than peg-IFN and RBV are being utilized.

### **5.1. Genotype specific**

HCV is classified into 11 genotypes with the first 6 of these garnering the majority of attention. Interestingly, various genotypes possess a geographic predominance [19] (Table 2).


#### **Table 2.** HCV genotype geographic distribution

Genotype 1 is the most prevalent genotype in the world and until recently had been the most difficult genotype to treat due to its poor SVR rates in response to peg-IFN and RBV. Treatment over the years has evolved significantly and the newest available guidelines support the use of the SOF/LED combination or the OMB/PARr/DAS/RBV combination [20-27]. Alternatively, data also indicate that use of SOF, SIM with or without RBV, achieved acceptable rates of SVR and can also be considered for use [28]. In patients with genotype 1 HCV infection, new SVR targets are now at greater than 90%. Newer therapies will need to measure up to these results. New agents remain under study, but preliminary results have been as impressive as the above regimens, and thus the market for treatment of genotype 1 infection will be saturated before we know it [29, 30] (Table 3).

Genotype 2 is found in clusters in the Mediterranean region and has historically responded well to the previous standard of peg-IFN and RBV. Genotype 3, now becoming the most difficult genotype to treat, has the unique characteristic of being associated with intravenous drug use. Recent studies using the newer DAAs show increased rates of SVR. Current recommendations for treatment suggest ample success is possible by utilizing a SOF and RBV regimen [31-36]. Building on excellent results of a phase II trial, an ongoing phase III trial is pending and expected to show widespread success with the use of daclatasvir (DAC) in combination with SOF [37, 38]. DAC, an NS5A inhibitor, has shown similar promising results throughout all genotypes as expected given its pan-genotypic treatment effect. Other prom‐ ising regimens include SOF/LED combination, as well as GS-5816, a pan-genotypic NS5A inhibitor in combination with RBV [39, 40] (Table 4).

Genotype 4 is found mostly in Egypt, the Middle East, and northern Africa. Although rare in the United States, in Egypt, the prevalence of HCV is upwards of 15% and thus remains an important research focus. Similarly, genotypes 5 and 6 are rare in the United States and are more frequently found in southern Africa, Southeast Asia, China, and Korea. Given the geographic distribution, few genotype 4-6 patients have been enrolled in clinical trials. More research is needed, but SOF-based regimens are likely to be significantly effective in the meantime [31, 41-46] (Table 5).


Legend: Wks: week; GRZ: grazoprevir; ELB: elbasvir

**5.1. Genotype specific**

62 Recent Advances in Liver Diseases and Surgery

**Genotype Geographic distribution** 1 United States, Europe, Japan

5 South Africa

we know it [29, 30] (Table 3).

**Table 2.** HCV genotype geographic distribution

2 Mediterranean, Europe, Japan, North America

4 Egypt, North Africa, sub-Saharan Africa, Middle East

3 Southeast Asia, Europe, United States

6-11 China, Korea, Taiwan, Southeast Asia

inhibitor in combination with RBV [39, 40] (Table 4).

HCV is classified into 11 genotypes with the first 6 of these garnering the majority of attention.

Genotype 1 is the most prevalent genotype in the world and until recently had been the most difficult genotype to treat due to its poor SVR rates in response to peg-IFN and RBV. Treatment over the years has evolved significantly and the newest available guidelines support the use of the SOF/LED combination or the OMB/PARr/DAS/RBV combination [20-27]. Alternatively, data also indicate that use of SOF, SIM with or without RBV, achieved acceptable rates of SVR and can also be considered for use [28]. In patients with genotype 1 HCV infection, new SVR targets are now at greater than 90%. Newer therapies will need to measure up to these results. New agents remain under study, but preliminary results have been as impressive as the above regimens, and thus the market for treatment of genotype 1 infection will be saturated before

Genotype 2 is found in clusters in the Mediterranean region and has historically responded well to the previous standard of peg-IFN and RBV. Genotype 3, now becoming the most difficult genotype to treat, has the unique characteristic of being associated with intravenous drug use. Recent studies using the newer DAAs show increased rates of SVR. Current recommendations for treatment suggest ample success is possible by utilizing a SOF and RBV regimen [31-36]. Building on excellent results of a phase II trial, an ongoing phase III trial is pending and expected to show widespread success with the use of daclatasvir (DAC) in combination with SOF [37, 38]. DAC, an NS5A inhibitor, has shown similar promising results throughout all genotypes as expected given its pan-genotypic treatment effect. Other prom‐ ising regimens include SOF/LED combination, as well as GS-5816, a pan-genotypic NS5A

Genotype 4 is found mostly in Egypt, the Middle East, and northern Africa. Although rare in the United States, in Egypt, the prevalence of HCV is upwards of 15% and thus remains an important research focus. Similarly, genotypes 5 and 6 are rare in the United States and are more frequently found in southern Africa, Southeast Asia, China, and Korea. Given the geographic distribution, few genotype 4-6 patients have been enrolled in clinical trials. More

Interestingly, various genotypes possess a geographic predominance [19] (Table 2).

**Table 3.** Results of DAA treatment in genotype 1 patients



Legend: Wks: week; DAC: daclatasvir

**Table 4.** Results of DAA treatment in genotypes 2 and 3 patients



**Table 5.** Results of DAA treatment in genotype 4, 5 and 6 patients
