1.Introduction

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The Hepatitis C virus (HCV) is a small-enveloped virus of the Flaviridae family and genus Hepacivirus, [7] with a single-stranded positive RNA molecule of approximately 9.6 kb [8]. Prior to the discovery of the viral agent, HCV was mainly transmitted via blood products. Since then, injection drug use has arisen as the major mode of transmission in developed countries [2]

The main problem is that, following exposure to HCV, only a minority of patients clears the acute infection, whereas 80% persist with life-long chronic viremia[9] Chronic HCV infection is a serious, progressive, and potentially life-threatening disease [10,11] If left untreated, over time it can cause liver damage or failure due to the development of cirrhosis. This liver complication can lead patients at substantial risk of decompensated disease and hepatocellular carcinoma (HCC), [12] which impose a considerable burden on affected people, healthcare systems and society [13,14] Early diagnosis could help prevent these consequences, but HCV infection is often undiagnosed because it is usually asymptomatic during decades and so, the majority of HCV-infected individuals are unaware of their infection [15].

The goal of treatment in all infected individuals, regardless of which of the six major genotypes are present, remains the achievement of a sustained virologic response (SVR) in which circulating HCV RNA is undetectable (with the use of a highly sensitive assay) following treatment. When a SVR is achieved, there is a 99% chance that the hepatitis C infection is cured [13,16]. Historically, SVR was defined as HCV RNA levels below a designated threshold of quantification 24 weeks after completion of treatment (SVR24)[17]. However, more recent data shows that viral clearance 12 weeks post-treatment (and sometimes, even 8 weeks) correlates closely to SVR24[18]. Therefore, an undetectable HCV RNA at 12 weeks after treatment (SVR12) is considered an appropriate primary efficacy endpoint [19] and translates into “cure” for nearly all patients[13]

2. Direct-Acting Antiviral Agents Versus Interferon-Based Therapies

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The new regimens for HCV mean a breakthrough novelty in the history of anti-HCV treatment. Previous treatments for HCV were often long and difficult. Many lasted from 24 to 48 weeks and showed suboptimal efficacy in viral response with a range of commonly occurring significant side effects, which impaired therapeutic compliance[20]. Nowadays, HCV patients can benefit from a less complex administration schedule and expect interferon (IFN) and even ribavirin (RBV)-free combinations. This results in a reduction of the incidence and severity of adverse events, optimizing quality of life during therapy and improving adherence to direct-acting antiviral agents (DAAs).

3. Sofosbuvir-Velpatasvir

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Sofosbuvir-velpatasvir (EPCLUSA®) is a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with or without cirrhosis (compensated). In clinical studies, sofosbuvir-velpatasvir (SOF-VEL) had high overall cure rates. (Table 1) The most common side effects were headache and tiredness [21].

Table1

4. Sofosbuvir-Velpatasvir-Voxilaprevir

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Four Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluated a once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1,2,3,4,5 and 6 chronic HCV infection. (Table 3)

The most common adverse events among patients who received SOF-VEL-VOX were headache, fatigue, diarrhea and nausea. The overall incidence of adverse events was similar to placebo or SOF- VEL. Among the 1,056 patients who received SOF-VEL-VOX in the four studies, only a patient receiving SOF-VEL-VOX for 12 weeks discontinued due to an adverse event[26]. These results show that this new three-drug co-formulation with different mechanisms of action and high barrier to resistance can provide high cure rates for patients who had previously failed treatment with other DAAs.

Table2    Table3

5. Glecaprevir-Pibrentasvir

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Glecaprevir-pibrentasvir is an investigational, pan-genotypic regimen that is being evaluated (table 4) not only as a potential cure in 8 weeks for HCV patients without cirrhosis and who are new to treatment, but also in patients with specific treatment challenges, such as genotype 3, patients who were not cured with previous DAA treatment and those with chronic kidney disease, including patients on dialysis.

This investigational, pan-genotypic regimen of glecaprevir-pibrentasvir is showing to be well tolerated with a favorable safety profile in these difficult-to-treat populations. The most commonly reported adverse events included fatigue and nausea.

Table4

6. Discussion

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Although the post-marketing phase always requires a careful evaluation of data from the “everyday” clinical practice experience, clinical trials have showed that these new DAA combinations have resolved most issues related to HCV treatment compared with the past regimens. Despite the approval of the first DAAs which have provided high cure rates and simplified treatment for most HCV patients, HCV genotype 3-infected patients with cirrhosis, patients with chronic kidney disease and those who have failed previous treatment with DAAs continued to represent an unmet medical need. In the era of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir- pibrentasvir, DAA therapy provides a new way to manage these difficult-to-treat HCV-infected patients, who are at a high risk of serious conditions[30]. They are now contemplated and are therefore expected to have a much better prognosis than they have had until very recently. Perhaps, soon, we may no longer have difficult-to-treat populations.

The advent of new generation oral antiviral therapy has led to major improvements in efficacy and tolerability but has also resulted in an explosion of data with increased treatment choice complexity [31].

Thus, clinicians need more detailed, accurate and timely information in order to choose the right regimen for individual patients and educate them. When they counsel and guide their patients, these ones are less likely to be anxious or resistant about taking steps toward possible cure. However, cure does not prevent reinfection and so, it is crucial to advise patients on measures that will reduce their risk (avoid alcohol intake and sexual and injection risk behaviors, eat a balanced diet and take exercise are some examples).

7. Conclusion

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DAAs have shown that it is possible to minimize the spread of HCV and the morbidity and mortality associated with HCV infection[32].

Despite the financial controversy around their high costs, which have served as a major barrier for more widespread use, many stakeholders recognize now their long-term cost-benefits and the advantages of a future free from hepatitis C are manifest.

It is true that patients undergoing treatment need systematic monitoring before, during and after therapy, but these new treatment options have offered them hope and re-awakening. It is a clear evolution compared with the previous IFN-based therapies.

8. Future Directions

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At a future time, treatment failure and resistance can occur and become a clinical challenge to be solved[30,33].

However, before them, there are already some questions that should concern us. First one is why is the association of RBV with DAAs, in some cases, increasing the SVR12 rate and shortening the duration of treatment? Then, at what point is it no longer worth treating a patient? Will we have the financial capacity to treat reinfected-patients? Will this simplicity of therapeutic regimen encourage risk behaviors in the future?