New drugs, such as simeprevir, sofosbuvir and daclatasvir, have the advantage of once-daily dosing, fewer adverse effects and efficacy against multiple hepatitis C virus genotypes
Marta Gómez Pérez PharmD
Marta Hernández Segurado PharmD
Mª Ángeles Arias Moya PharmD
Eva Mª Martín Gozalo PharmD
F Javier Bécares Martínez PharmD MD
University Hospital Fundación Jiménez Díaz,
Pilar Modamio PharmD PhD
Eduardo L Mariño PharmD PhD
Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy,
University of Barcelona, Spain
According to recent estimates, more than 185 million people around the world have been infected with the hepatitis C virus (HCV), of which 350,000 die each year. One third of those who become chronically infected are predicted to develop liver cirrhosis or hepatocellular carcinoma.1
In the Western world, the rate of chronically infected patients, in most countries, is between 1.5 and 3%. Current treatment of infection with the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), cure about 50% of cases of patients infected with genotype 1, which is the most common form (75% of infected).2,3
Beginning with the introduction of first-generation protease inhibitors, the first direct-acting antivirals (DAAs) for HCV (telaprevir and boceprevir) in 2011, there was a significant change in the treatment of chronic HCV. Subsequently, simeprevir, sofosbuvir and daclatasvir have been approved at the beginning of 2014. These new drugs have the advantage of once-daily dosing and fewer adverse effects compared with telaprevir and boceprevir. In addition, these new antivirals are effective against multiple HCV genotypes unlike the first DAA.
However, triple therapy may be associated with some undesirable effects. For example, telaprevir has been associated with skin rash in which up to 5% of cases can become severe. Incidences of anaemia (telaprevir and boceprevir) and dysgeusia (boceprevir) have also been noted. Moreover, lack of response to therapy is associated with universal development of mutations that contribute to increased resistance of DAA. The effect of this new-found resistance is still undetermined. No study has evaluated the sensitivity of subsequent exposure in these patients while taking other antiviral drugs in the same family. Ultimately, triple therapy has superior efficacy over standard treatment, but causes more side effects (boceprevir and telaprevir) which also imply the need for further evaluation and more frequent monitoring of patients on triple therapy. Both events can have a significant impact on economic and healthcare centres caring for patients with HCV.2–4
It should also be noted that not all patients with chronic hepatitis C respond in the same way to treatment with triple therapy, as shown in clinical trials.5 Response to triple therapy is best predicted based on response to previous treatment:
- Treatment-naïve patients: patients without prior treatment for HCV.
- Null responders: patients that have no decrease from the initial viral load at 12 weeks of treatment, or who do not achieve undetectable viral load at 24 weeks.
- Relapsing patients: patients whose viral load is undetectable at end of treatment but become detectable at six months after completion of therapy.
- Partial responders: patients with a two-log decrease in viral load at week 12 of treatment but which remain detectable at week 12 and 24.
- Patients with unknown response: those patients in whom treatment was terminated at an early stage due to adverse effects, etc.
- Co-infected patients: patients co-infected with HCV and HIV.
The main characteristics of DAA are detailed below.
Telaprevir is an inhibitor of the NS3 serine protease of HCV4A, an essential enzyme for virus replication. In combination with PEG-IFN alpha and RBV, telaprevir is indicated for the treatment of adult patients with chronic hepatitis C (genotype 1) with compensated liver disease (including cirrhosis).
The dosage is 1125mg telaprevir (three 375mg film-coated tablets) orally twice daily with food. The duration of treatment is 12 weeks, followed by treatment with IFN and RBV. The duration of this treatment is determined based on to the type of patient and the viral load detected at weeks 4 and 12.
The most common side effects are anaemia, rash, pruritus, nausea and diarrhoea. In clinical studies, serious skin reactions (grade 2 or more) were recorded in almost 5% of patients treated.
Clinical trials show variable efficacy depending on the type of patient: null responders sustained viral response (SVR) rate in week 12 was 31%, in partial responders was 61%, 74% in co-infected patients, 84% in relapsing patients and 74% in treatment-naïve patients.4,6
Boceprevir is an inhibitor of the HCV NS3 protease. Boceprevir covalently binds the serine of the active site of the NS3 protease to inhibit virus replication. It is indicated for the treatment of chronic HCV genotype 1 infection, in combination with IFN and RBV, in adult patients with compensated liver disease who are previously untreated or who have failed previous treatment.
Boceprevir is dosed at 800mg orally three times daily, with the duration of treatment depending on the patient and the changes in viral load in weeks 4, 8, 12 and 24. Prior to starting treatment with boceprevir, a lead-in with IFN and RBV for four weeks should be administered.
The most common side effects are fatigue, anaemia, nausea, headache and dysgeusia.
Clinical trials show variable efficacy depending on the type of patient: the rate of SVR at week 12 in partial responders was 40–52%, in co-infected patients 62.5%, in relapsing patients 69–75% and 63–66% in treatment-naïve patients.7
Simeprevir is a specific inhibitor of the NS3/4A proteases. Given in combination with IFN and RBV, it is recommended for persons with HCV genotype 1b infection and for persons with HCV infection without the first genotype polymorphism Q80K. The recommended dosage is one 150mg capsule of simeprevir daily, taken with food.8
Simeprevir in combination with IFN/RBV for 12 weeks is followed by 12 additional weeks of IFN/RBV, for a full 24 weeks of treatment for all treatment- naïve and relapsed patients (including those with cirrhosis). Prior non-responder patients (including partial or null responders) should undergo an additional 36 weeks of IFN/RBV for a total of 48 weeks of treatment. HCV RNA should be monitored and treatment discontinued if >25IU/ml at weeks 4, 12, or 24.
The combined SVR rate for patients treated with simeprevir/RBV/IFN was 79.2%. Patients with the genotype 1 infection with the Q80K mutation (approximately 30% of patients in the included studies) were found to have similar SVR rates to those who received IFN/RBV only.1
The majority of the adverse reactions reported during 12 weeks of treatment with simeprevir were grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 3.1% of patients receiving simeprevir. Serious adverse reactions were reported in 0.3% of simeprevir-treated patients, with two events requiring hospitalisation for photosensitivity. The most frequently reported adverse reactions (incidence ≥5%) were nausea, rash, pruritus, dyspnoea, hyperbilirubinaemia and photosensitivity reaction. Discontinuation due to adverse reactions caused by simeprevir occurred in 0.9% of patients.4,8
Sofosbuvir is an HCV viral polymerase nucleotide inhibitor. When used in combination with RBV alone or RBV in combination with IFN, it is associated with high SVR rates in persons infected with HCV genotypes 1, 2, 3 and 4.
At present, treatment with sofosbuvir and RBV is the only all-oral, IFN-free regimen available for HCV infection.1
The recommended dose is one 400mg tablet orally once daily with food.8
For infection with HCV genotypes 1 and 4, sofosbuvir/RBV/IFN may be given for 12 weeks. In people with genotype 1 infection who are IFN-intolerant, sofosbuvir/RBV may be given for 24 weeks, but this regimen will result in substantially lower SVR rates than an IFN-containing regimen. For infection with HCV genotype 2, sofosbuvir/RBV may be given for 12 weeks. For infection with HCV genotype 3, sofosbuvir/RBV may be given for 24 weeks or PEG-IFN/RBV/sofosbuvir may be given for 12 weeks.9
For treatment-naïve patients infected with genotypes 1 and 4, the combined SVR rate among those treated with sofosbuvir/PEG-IFN/RBV was 90.3%.
No data were available regarding the use of sofosbuvir-based regimens among persons with genotype 1 infection who had been previously treated with PEG-IFN/RBV.
For people with genotype 2 and 3, the use of 12 weeks of sofosbuvir/RBV versus no treatment was assessed for treatment- naïve patients. This analysis included one study with a high prevalence of cirrhosis in the patients.1 During treatment with sofosbuvir in combination with RBV or with PEG-IFN alpha and RBV, the most frequently reported adverse drug reactions were consistent with the expected safety profile of RBV and IFN treatment, without increasing the frequency or severity of the expected adverse drug reactions.
Assessment of adverse reactions is based on pooled data from five Phase III clinical studies. The most common adverse drug reactions occurring in subjects receiving sofosbuvir/RBV or sofosbuvir/RBV/PEG-IFN alpha were fatigue, headache, nausea, insomnia, anaemia and hyperbilirubinaemia.4,9
Daclatasvir is an inhibitor of the non-structural 5A protein (NS5A) – a multifunctional protein complex that inhibits replication of HCV. It is indicated for genotypes 1 and 4 in combination with sofosbuvir with a duration of therapy between 12 and 24 weeks depending on whether the patient is cirrhotic, although the data for genotype 4 were extrapolated from genotype 1 data. Patients with genotype 3 treated with the combination of daclatasvir/sofosbuvir/RBV and patients with genotype 4 treated with daclatasvir/conventional combination therapy both have response guided therapy, while no virological discontinuation rules apply to the combination of daclatasvir/sofosbuvir.
As for its efficacy, SVR at week 12 was achieved in 99% of patients with HCV genotype 1, 96% with genotype 2 and 89% with genotype 3. The response was rapid (in week 4, with more than 97% of patients responding to treatment), and was not influenced by the HCV subtype (1a/1b), IL28B genotype or use of RBV. Patients included in the trials were both treatment-naïve and previously treated patients with DAA. The results for genotype 4 were obtained from the clinical trial in combination with daclastavir/IFN/RBV, although SVR rates were not as promising as the combination with sofosbuvir.
With regards to the safety profile, the combination with sofosbuvir showed no adverse events of grade 3 or 4, but did show incidences of degree 1 or 2 (headaches, fatigue, nausea). When combined with conventional dual therapy, safety profiles were similar to those observed with IFN and RBV alone.4,10
The current landscape of chronic HCV is rapidly changing, with the advent of new drugs curing up to 90% of patients, and a decrease in the healthcare burden associated with these patients (derived from hospitalisation, transplant, chemotherapy, etc). It should be borne in mind that these treatments increase the healthcare costs, not only because of the treatment, but also the expenditure involved in the treatment of adverse effects, additional tests, etc. That is why a multidisciplinary approach is essential to optimise available resources ensuring the utmost quality of life for patients.
- Telaprevir and boceprevir are both indicated for the treatment of chronic HCV genotype 1 infection, in combination with interferon/ribavirin (IFN/RBV) but are associated with undesirable effects (skin rash, anaemia, dysgeusia).
- The new medications have the advantage of once-daily dosing, fewer adverse effects and efficacy against multiple hepatitis C virus genotypes.
- Simeprevir, when given in combination with IFN/RBV, is recommended for persons with HCV genotype 1b infection as well as persons with HCV infection without the genotype 1 Q80K polymorphisms.
- Sofosbuvir used in combination with RBV alone or IFN/RBV is associated with high SVR rates in people infected with HCV genotypes 1, 2, 3 and 4. At the moment, treatment with sofosbuvir and RBV is the only all-oral interferon-free regimen available for HCV infection.
- Daclatasvir is indicated for genotypes 1, 3 and 4 in combination with sofosbuvir, although the data for genotype 4 was extrapolated from genotype 1 data. Also, genotype 4 can be treated with daclatasvir/conventional combination therapy.
- World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. July 2014. www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (accessed 5 October 2014).
- Spanish Agency for Medicines and Health Products. Criteria and recommendations for early access to treatment with protease inhibitors of hepatitis C virus. Panel C Chronic Hepatitis. Version July 26, 2012. www.aemps.gob.es/medicamentosUsoHumano/medSituacionesEspeciales/docs/criterios-VHC-off-label.pdf (accessed 5 October 2014).
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2014;60:392–420.
- Kohli A et al. Treatment of hepatitis C: a systematic review. JAMA 2014;312:631–40.
- Mathis AS. Economic burden and current managed care challenges associated with hepatitis C. Am J Manag Care 2012;18(14 Suppl):S350–9.
- European Medicine Agency. Incivo: EPAR – Product Information. EMA. 2011. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002313/WC500115529.pdf (accessed 15 January 2015).
- European Medicine Agency. Victrelis: EPAR – Product Information. EMA. 2011. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002332/WC500109786.pdf (accessed 15 January 2015).
- European Medicine Agency. Olysio: EPAR – Product Information. EMA. 2014. www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/002777/WC500167867.pdf (accessed 15 January 2015).
- European Medicine Agency. Sovaldi: EPAR – Product Information. EMA. 2014. www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/002798/WC500160597.pdf (accessed 15 January 2015).
- European Medicine Agency. Daklinza: EPAR – Product Information. EMA. 2014. www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/003768/WC500172848.pdf (accessed 15 January 2015).