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Direct-acting antivirals: The treatment paradigm for hepatitis C virus

Upon its discovery in 1989, the only treatment for hepatitis C was interferon. Later, ribavirin was added, and patients received interferon and ribavirin for 24 to 48 weeks depending on their viral genotype.

This regimen resulted in a sustained virologic response of:

• 40% to 50% in patients with genotype 1;
• approximately 80% in patients with genotypes 2, 3, 5 and 6; and
• between 40% and 80% for those with genotype 4.

Once HCV was cultured in the laboratory, researchers achieved a greater understanding of the virus and in 2011, a real breakthrough in the treatment of HCV occurred, changing the way we think about the virus. Direct-acting antiviral medication was developed to target vital steps in the replication of the virus and have revolutionized the treatment of HCV in much the same way as antiretroviral therapy has for HIV.

2011: The first DAAs receive FDA approval

Telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck) each received FDA approval in 2011 for the treatment of chronic HCV in patients with genotype 1; both DAAs are protease inhibitors, targeting the NS3/4A pathway. Following the approval of these first-generation agents were the second-generation protease inhibitors, including simeprevir (Olysio, Janssen Pharmaceuticals) and paritaprevir (AbbVie), and the NS5A inhibitors, including daclatasvir (Daklinza, Bristol-Myers Squibb), velpatasvir (Gilead Sciences) and ombitasvir (AbbVie). The second-generation protease inhibitors have fewer drug interactions and fewer severe adverse effects compared with their first-generation counterparts, and they also have higher antiviral activity, especially against genotype 1.

Although DAAs have transformed the treatment of chronic HCV, this new standard of care also presented new challenges. It is important to know certain aspects about these drugs and how they work, as well as how the virus itself works. The hepatitis C virus is a single-stranded RNA virus that lacks a so-called “proofreading” function, resulting in a high number of errors during replication. This in turn leads to a variable viral population with multiple genotypes and many mutations that can exist within a single infected individual. DAAs themselves vary in antiviral potency, especially between genotypes, and may have low barriers to viral resistance.

With the variability of DAAs and the high error rate in viral replication, monotherapy with DAAs is currently not an option, as this would lead to the development of drug-resistant variants of the virus. As such, a patient with HCV will receive two or more DAAs, depending on his or her genotype, and some patients may still receive one or more DAAs in addition to interferon and/or ribavirin. Because of the possibility of resistance, it is important that patients be monitored for virologic response during treatment to avoid treatment failure. This response-guided therapy was used to monitor patients during the interferon/ribavirin era but is especially vital now.

Success in previously hard-to-treat populations

The main goal of HCV treatment is total elimination of the virus, or SVR. With interferon-based regimens, SVR could be achieved, especially in those with genotypes 2, 3, 5 and 6, though treatment was arduous and could last up to a year. For a patient with genotype 1, the typical treatment regimen consisted of a weekly interferon injection for 1 year along with daily tablets, and a hospital visit every 4 weeks; after all this, the potential for a cure was a dismal 35% to 40%.2 DAAs, however, have been curative in 94% to 98% of patients across all genotypes, and 96% of those who fail first-line treatment can expect to be cured using second-line therapy. Additionally, more than 99% of patients who achieve SVR on DAAs remain HCV negative for 4 to 5 years after completion of treatment, with late occurrences being extremely rare.1,5 DAAs are also much easier to take, as they come in oral tablets and do not require injections.

Direct-acting antivirals have also proven to be highly successful in patients coinfected with HCV and HIV. Coinfected patients, historically, have had lower SVR rates than those without HIV; this was especially true of patients with genotype 1. These patients also experienced accelerated disease progression, with higher rates of liver fibrosis, cirrhosis and hepatocellular carcinoma. With DAAs, coinfected patients can achieve SVR in more than 95% of cases, even in patients who have failed prior treatments. In one study, 93.8% of patients with HCV and HIV coinfection and cirrhosis achieved SVR without a regimen containing interferon. It should be noted that of particular concern in coinfected patients is the likelihood of drug-drug interactions between antiviral and ART regimens; in the previously mentioned study, almost one-third of coinfected patients treated with DAAs had to make changes to their ART regimen because of a drug interaction.

Looking forward: Safe, effective treatment with fewer adverse effects

DAAs are preferable to interferon-based regimens not just for their ability to achieve high rates of cure. Patients treated with DAAs report:

• improved quality of life;
• lower rates of depression; and
• increased productivity.

Patients with chronic HCV infection experience not only hepatic complications but also symptoms caused by involvement of the central nervous system, including mental fog and depression. In one study, QOL data from patients receiving DAAs was compared with similar data from those who received interferon-based therapy. Patients who received and responded to interferon-based treatment reported similar QOL improvements to those who received interferon-free treatment in posttreatment assessments; however, these patients reported a significant worsening of QOL during treatment, while patients receiving interferon-free treatment reported improved QOL early in the treatment process. This improved QOL continued to improve as treatment progressed and remained high in the posttreatment period.

In another study, patient-reported outcomes were gathered from patients who participated in two clinical trials. Together, the trials included 1,160 patients representing all HCV genotypes; none of the participants had received prior treatment with any DAA. About half of these patients received Epclusa (Gilead Sciences), which is a combination of sofosbuvir (an NS5B inhibitor) and velpatasvir (an HS5A inhibitor), and the others were treated with Vosevi (Gilead Sciences), which is a combination of sofosbuvir, velpatasvir and voxilaprevir (an NS3/4A protease inhibitor). Nearly all patients reported significant improvements in patient-reported outcome measures, including physical functioning, bodily pain, general health, social functioning, mental health, emotional well-being, fatigue and systemic symptoms. These improvements were noted soon after the initiation of treatment and coincided with early virologic response, which was seen as a reduction in viral load, and the improvements continued as treatment progressed.

Overall, DAAs are safer and better tolerated than interferon-based treatment regimens. A review of available safety data from clinical trials found that the most commonly reported adverse effects associated with DAAs include:

• fatigue;
• headache;
• pruritus;
• nausea;
• diarrhea; and
• insomnia.

Most of these were reported as mild or moderate. Hyperbilirubinemia and increased alanine aminotransferase and aspartate aminotransferase were reported with simeprevir, dasabuvir (Exviera, AbbVie) and paritaprevir-containing regimens; although these increases were generally transient, these drugs are contraindicated in patients with Child-Pugh B and C cirrhosis. Photosensitivity has been reported in patients treated with simeprevir and may lead to discontinuation of treatment. In general, the NS5A and NS5B inhibitors are very well tolerated, and have no contraindications (aside from potential drug interactions).

One area in which direct-acting antivirals have received particular attention is in relation to HCC. Hepatocellular carcinoma is a potential complication of chronic HCV infection, as the greatest risk factor for HCC is advanced liver disease; the annual incidence rate of HCC is about 4%. In the interferon era, treatment was associated with a decrease in reported cases of HCC in patients who had achieved SVR. Early case reports suggested an increased risk of HCC associated with DAA treatment, though the mechanism was unclear.

Further data support that, in patients with HCV cirrhosis who are treated with DAAs and achieve SVR, there is a lower rate of incident HCC, disputing the idea that direct-acting antivirals may cause liver cancer. However, patients who go on to develop hepatocellular carcinoma after DAA therapy have been found to have more aggressive tumors. Research suggests that DAAs may reduce the body’s tumor-specific immune response, allowing tumor cells to escape detection by the immune system. This phenomenon may also be the reason that patients treated with DAAs are at greater risk for hepatitis B virus reactivation. DAA use is safe in patients who do not have HCC and should not be withheld in this population. In patients with HCC, direct-acting antivirals should not be given for 3 to 6 months after a complete response to HCC treatment.

The value of a cure

One of the most common criticisms of DAAs is price. The high cost of these drugs remains a significant barrier to their widespread use, even with the data supporting their curative ability and the treatment guidelines that recommend their use. This has sparked a debate in the U.S. regarding the value of treatment.

When sofosbuvir (Sovaldi, Gilead Sciences) was approved in 2013, the list price for the drug was $84,000 for a 12-week treatment course, which is the equivalent of about $1,000 per pill. Because of market competition, the prices of most DAAs have fallen since 2013, with the regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak, AbbVie) running about $50,000 for a course of treatment. Although this seems exorbitant, the cost of a cure with DAA regimens is similar to the cost of a cure using interferon-based therapies, considering the length of treatment. Indirect costs must be considered as well, including the costs associated with the systemic complications of chronic HCV infection, lost work productivity and the mental health impact and social stigma of the disease. The cost-effectiveness of DAA therapy is especially remarkable in patients with advanced disease and in younger patients.

Compared with the previous standard of care for the treatment of HCV, direct-acting antivirals are significantly more effective, safer and better tolerated, and are associated with an increased QOL both during and after treatment. Some of these drugs can even be used to clear HCV infection in patients with advanced liver disease and in those who have failed other treatments. Although the cost of these drugs is high, the cost-effectiveness is clear when considering the potential for a cure in much less time and with fewer adverse effects in more than 95% of those receiving the treatment.

References

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