The Daniel K. Inouye College of Pharmacy Scripts

Background

Approximately 130 – 170 million people worldwide are infected with chronic hepatitis C virus (HCV).¹ Of those infected, 3.2 – 3.7 million reside in the United States, or approximately 1.3% of the population.^1,2 Furthermore, up to 75% of individuals who are infected with the virus are unaware of their infection.³ Hepatitis C virus is the most common blood-borne infection in the United States and will infect and kill more patients than those affected by the human immunodeficiency virus (HIV).⁴ Risk factors for transmission of HCV include previous injection drug use, receipt of blood transfusions or solid organ transplants before 1992 or clotting factors before 1987, hemodialysis, and being born to a HCV-positive mother. In 2012, the Centers for Disease Control and Prevention (CDC) recommended that all patients born from 1945 – 1965, regardless of risk factors, should receive a one-time screening for HCV. This specific birth cohort was selected because approximately 75% of all HCV-infected patients were born during those years.³ Currently, HCV is the leading cause of end-stage liver disease, liver-related death, and hepatocellular carcinoma in the United States. Unlike hepatitis A or B, there is no vaccination to protect against hepatitis C infection.⁵

Six genotypes of HCV have been identified, with genotype 1 (GT 1) accounting for approximately 75% of HCV infections in the United States, followed by genotypes 2 (GT 2) and 3 (GT 3), which represent about 20%.⁴ In Europe, genotypes 1 – 3 are also most common, while genotype 4 (GT4) is found primarily in the Middle East, genotype 5 (GT5) in South Africa, and genotype 6 (GT6) in Asia.

Within genotype 1, there are sub-genotypes 1a and 1b, with 1a being harder to treat, comparatively. Genotypes 2 and 3 are historically “easier-to-treat” than genotype 1, however studies have demonstrated that patients with GT3 may have lower response rates compared to patients with GT2.⁶ In addition to treatment response variability based on genotype, several other factors may increase the risk for treatment failure. Such characteristics include patients who have failed previous treatment attempts, those with advanced liver disease, and those with comorbidities, such as advanced kidney disease or co-infection with HIV. Patients with these characteristics have traditionally been classified as “harder-to-treat.”

Chronic HCV infection progresses slowly, with complications of the virus often taking several decades to be clinically manifest.⁵ Therefore, conducting clinical trials that identify disease-related morbidity and mortality as a primary outcome would be unrealistic given the time required to reach these outcomes. Instead, conducting efficacy and safety trials for HCV agents that achieve a sustained virologic response (SVR) is deemed acceptable by regulatory agencies that decide on approvals of upcoming therapies. Historically, SVR has been defined as the absence of HCV RNA in the blood 24 weeks after completion of therapy. Recently, however, there has been data to support measuring an SVR as early as 12 weeks after the completion of therapy. Reporting data on what is referred to as an “SVR12,” to indicate measurements recorded 12 weeks after the completion of therapy, is considered an appropriate primary endpoint for drug companies seeking regulatory approval for new HCV therapies.⁷ Achieving an SVR has demonstrated a reduction in mortality in those infected with HCV and is considered curative.^8,9

In the past several years, there has been an increasingly heightened focus on drug research and development for new HCV agents. This trend is prompted by the emerging liver-related complications of those who have now been infected with HCV for several years or even decades as well as the increasing need for treatment options that are effective with minimal adverse effects. This review article identifies the progress that has been made in hepatitis C treatment options and discusses the challenges that patients with HCV continue to face.

History of Treatment Options

Table 1 provides a synopsis of previously and currently approved HCV treatment options.

Table 1.

Characteristics of Previous and Current HCV Treatment Options

	Approved GT	Treatment Duration (weeks)	SVR (%)	Peginterferon-Free	Ribavirin-Free
1990s – 201l (“Dual-therapy”)
Peginterferon & ribavirin	1 – 6	24 – 48	40 – 50*	No	No
2011 – 2013 (“Triple-Therapy”)
Boceprevir or telaprevir, plus peginterferon & ribavirin	1	24 – 48	32 – 86	No	No
2013 Approvals
Simeprevir	1	24 – 48	53 – 80	No	No
Sofosbuvir	1 – 4	12 – 24	56 – 100	Depends on regimen	No
2014 Approvals
Ledipasvir/sofosbuvir combination tablet	1	12 – 24†	94 – 100	Yes	Yes
Ombitasvir/paritaprevir/ ritonavir combination tablet & dasabuvir	1	12 – 24	89 – 99	Yes	Depends on regimen
Simeprevir; to be used in combination with sofosbuvir	1	12 – 24	95 – 100	Yes	Yes
2015 Approvals
Daclatasvir; to be used in combination with sofosbuvir	3	12	58 – 98	Yes	Yes

^*= SVR rates with dual-therapy for genotype 1 (most common form of HCV in the United States); genotypes 2 and 3 experienced SVR rates of 80% or more with dual-therapy

^†= A shortened treatment duration of 8 weeks may be considered in treatment-naïve patients without cirrhosis who have a pre-treatment HCV RNA less than 6 million IU/mL

Prior to 2011, the first-line treatment of HCV was dual-therapy with ribavirin, an oral capsule dosed twice daily, and polyethylene glycol encapsulated interferon (peginterferon), a once weekly subcutaneous injection.⁵ Ribavirin works by inhibiting the replication of viral RNA and DNA and has also demonstrated efficacy against influenza and adenoviruses.¹⁰ Peginterferon has antiviral and immune-regulating activity and was historically also been used to treat hepatitis B infections in addition to HCV.^11,12

For the treatment of HCV, the duration of therapy with ribavirin and peginterferon was 24 or 48 weeks, depending on the genotype being treated.⁵ In addition to long treatment durations, a number of significant adverse events posed medication adherence challenges. Peginterferon has been associated with flu-like symptoms, depression, anxiety, alopecia, neutropenia, thrombocytopenia, and several other significant adverse reactions. Ribavirin frequently leads to the development of anemia, which may require treatment with an erythropoiesis stimulating agent when hemoglobin levels decrease below 10g/dL, despite dose reductions in ribavirin. In some instances, adverse events may become severe enough to warrant treatment discontinuation. Additionally, the SVR rates with this treatment were only 40%–50% in patients with HCV genotype 1.

In 2011, two novel first-generation NS3/4A protease inhibitors, boceprevir and telaprevir, received FDA approval for the treatment of HCV genotype 1 infections as a part of combination therapy with ribavirin and peginterferon.^{13, 14} Unlike ribavirin and peginterferon, these protease inhibitors specifically target the replication of the hepatitis C virus.^15,16 As a result, when combined with ribavirin and peginterferon, the replication of HCV and the host immune response to the virus were impacted through multiple mechanisms.

Treatment with ribavirin, peginterferon, and either boceprevir or telaprevir became known as “triple-therapy”. Compared to dual-therapy, triple-therapy revealed improved SVR rates ranging between 63–79% for treatment-naïve patients and 32–86% for treatment-experienced, depending on the type of previous treatment response.^17,18 Despite improvements in SVR rates, HCV treatment with triple therapy still presented a number of less than ideal characteristics, including continued lengthy treatment durations (24 – 48 weeks, based on initial response), extensive adverse events, high daily pill burdens with strict timing of administration given the incidence of resistance, and several drug-drug interactions with the protease inhibitors, both of which are strong inhibitors of cytochrome P450 (CYP450) enzymes.

In late 2013 two more agents, simeprevir and sofosbuvir, were approved for treatment of HCV.^{19, 20} Simeprevir, a second-generation NS3/4A protease inhibitor approved for use in HCV genotype 1, demonstrated similar SVR rates as boceprevir and telaprevir but offered the advantage of being administered once daily, compared to three times daily with the first-generation agents.²¹ Sofosbuvir, an NS5B polymerase inhibitor which acts similarly to the protease inhibitors to interrupt hepatitis C viral replication, was also approved for once daily administration and yielded improved SVR rates of 56–100%. In addition, sofosbuvir also offered several beneficial characteristics that included treating multiple HCV genotypes and patients co-infected with HIV, thereby increasing the treatment opportunities for a large group of patients who previously had limited options. Furthermore, sofosbuvir was approved for a shorter treatment duration (12 – 24 weeks based on treatment history), as well as the possibility of an all-oral/peginterferon-free regimen, which was a novel concept for chronic hepatitis C treatment.^21,22 As a result, the shortened treatment duration and elimination of peginterferon-related side effects allowed for the opportunity for improved adherence.

Recent Approvals

Since the Fall of 2014, the FDA approved three new HCV therapies and expanded the indication for the use of simeprevir in combination with sofosbuvir.^23–26 These recently approved agents work by distinct but related mechanisms, all of which target specific pathways within the HCV life cycle.

The first approved combination therapy, ledipasvir/sofosbuvir is a fixed-dose combination oral tablet that is dosed once daily and is approved for treatment of HCV genotype 1.²⁷ The approved treatment duration is 12 – 24 weeks, based on prior treatment experience as well as the degree of disease progression. A shortened treatment duration of 8 weeks may be considered in treatment-naïve patients without cirrhosis who have a pre-treatment HCV RNA less than 6 million IU/mL. Subjects in clinical trials, including traditionally harder-to-treat patients with advanced liver disease, experienced SVR rates of 94%–100%.

The second approval, which is marketed as Viekira Pak™ includes a combination tablet consisting of ombitasvir, paritaprevir, and ritonavir and an additional tablet consisting of dasabuvir.²⁸ The combination tablet is dosed once daily and dasabuvir is dosed twice daily. Viekira Pak™ is approved with or without ribavirin for the treatment of HCV genotype 1, including patients with compensated cirrhosis. The treatment duration is 12–24 weeks based on genotype subtype (1a versus 1b) and the presence of cirrhosis. Pre-marketing clinical trial data revealed SVR rates between 89%–99%.

The third and most recent approval, daclatasvir, is indicated for use with sofosbuvir for the treatment of chronic HCV GT3 infections.²⁹ It is the first drug approved for GT 3 infections that does not require co-administration of peginterferon or ribavirin, which is a considerable advance for the treatment options for this genotype. Daclatasvir is administered once daily for a treatment duration of 12 weeks. Clinical trial results evaluating the use of daclatasvir showed that patients without cirrhosis achieved SVR 92%–98% of the time, based on treatment history. This compares to SVR rates of 58%–69% in patients with cirrhosis, thus highlighting an area for future improvement.

The decision to approve the combined use of simeprevir and sofosbuvir was largely based on results of a study that demonstrated SVR rates of 95%–100% in patients, including those with cirrhosis. Like ledipasvir/sofosbuvir, the combined use of simeprevir and sofosbuvir is dosed once daily and is recommended for a treatment duration of 12 – 24 weeks.²¹

Compared to the adverse effects that frequently hindered previous treatments with peginterferon and ribavirin, the common side effects reported with the newer HCV agents include headache, fatigue, nausea and diarrhea.^{21–22, 27–29}

Implications and Economic Considerations

Hepatitis C virus was discovered less than three decades ago and during that time, an extraordinary amount of progress has been made, most of which has occurred in the last 24 months. Less than five years ago, the treatment for HCV warranted almost 12 months of therapy, intolerable adverse effects and was successful in fewer than 50% of cases. Since that time, recently approved therapies have allowed for improved SVR rates above 90% for a large majority of patients, a drastic reduction in treatment-related adverse effects, considerably shorter treatment durations, and improved ease of administration.

As a result of these advancements, the approach and attitude towards HCV from the medical community has also changed. Previously, only patients with advanced liver disease may have been considered for therapy when the potential benefits of the less than ideal treatment may have outweighed the likely risks of receiving no treatment. Currently, however, while the most recent guidance still recommends “urgent initiation of treatment” for patients with advanced liver disease, the general recommendations support treatment of all HCV-infected individuals, with the exception of those expected to live less than 12 months.³⁰

Despite vast amounts of clinical evidence supporting the benefits of treating all patients infected with HCV, therapy for many patients has been denied or delayed due to the high prices of recently approved treatment options.³¹ The wholesale acquisition costs, or “sticker prices” of these new drugs range from $1,000 USD per day for sofosbuvir to a staggering $1,750 USD per day for daclatasvir when prescribed concomitantly with sofosbuvir.³² Based on treatment history and genotype, total treatment costs may reach and exceed $150,000 USD for some patients.

The high costs of these therapies have come under high scrutiny from lawmakers, insurance companies, medical providers and patients. One argument in defense of these high prices is that treating HCV now will offset the economic burden of untreated disease and subsequent complications in the future. A recent economic analysis, however, found conflicting data.³³ The authors of this analysis found that treating eligible patients with HCV over the course of the next 5 years would cost the United States $65 billion USD, whereas the economic burden of not treating the same patients would be $16 billion USD.

Over the past several months, much action has been taken in order to examine the legality and ethics of such high prices as well as encourage improved access to care. Healthcare experts from the Public Health Service and the president's Advisory Council on HIV/AIDS have requested for Medicaid officials to widen access to new HCV agents by lessening current restrictions to treatment, citing that they “defy clinical guidelines and best practices.”³⁴ Members of the HCV Guidance Panel have even weighed in on the issue, recognizing that access to care is as much of a challenge as developing effective therapies. In response to this challenge, a new section on cost, reimbursement, and cost-effectiveness was added to the clinical guidelines, which encourages insurers, government and pharmaceutical companies to work together in order to make HCV treatment affordable and accessible.³⁰

Focusing on Chronic Hepatitis C in Hawai‘i

Hepatitis C is estimated to affect approximately 23,000 residents in Hawai‘i, or 1.6% of the population. The true prevalence, however, may be closer to 2.1% of the population as the survey used to estimate disease prevalence does not include prisoners, illegal immigrants, homeless or institutionalized patients (N. Tsai, personal communication, June 29, 2015).

Currently, the State of Hawai‘i Department of Health (DOH) and Hep Free Hawai‘i, a local coalition of over 80 partner agencies, have been making strides to increase awareness and screening efforts for hepatitis C from both the patient and provider perspective (H. Lusk, personal communication, July 10, 2015). The DOH established 16 free testing sites, the majority of which are located in community health centers or non-profit organizations, where patients can be screened. The DOH also sent letters to all licensed providers encouraging them to screen their patients for hepatitis C, along with hepatitis B and HIV (T. Pham, personal communication, July 13, 2015).

Additionally, Hep Free Hawai‘i provides downloadable forms on its website that patients can bring to their healthcare providers (H. Lusk, personal communication, July 10, 2015). These forms provide information about who should be screened and billing codes for various screening procedures. This is especially helpful for those providers who may not be as familiar with the screening recommendations or how to implement them into their individual practices.

The efforts of the Department of Health and Hep Free Hawai‘i have largely contributed to increasing awareness and screening for hepatitis C for both patients and providers. This progress, however, is still limited by the challenges surrounding the approval process for patients to receive recently approved treatment options, as described previously.

Conclusion

As treatment options for chronic hepatitis C virus emerge, the approach to this disease continues to develop. Recent and upcoming treatments focus on improving SVR rates for “harder-to-treat” patients and decreasing the duration of therapy. Despite this clinical progress, the high price of new therapies poses an unfortunate treatment barrier that greatly limits access to care.

List and Definitions of Abbreviations

HCV	Hepatitis C virus
HIV	Human immunodeficiency virus
GT	Genotype
SVR	Sustained virologic response
CYP450	Cytochrome P450 enzymes
NS3/4A protease	Protease required for hepatitis C viral replication
NS5B polymerase	Polymerase required for hepatitis C viral replication