It has been estimated that 2.2% of the world population that is 130 million individuals are infected with hepatitis C. It represents a viral pandemic, one that is five times as widespread as infection with the human immunodeficiency virus type-1 (HIV-1). Hepatitis C is now one of the most common liver disease, is having overtaken alcohol included liver disease in the past few years around the world.
Hepatitis C infection may cause a benign, a symptomatic disorder with an indolent course but it may also cause progressive liver disease, cirrhosis and primary liver cancer. The illness has a complex, natural course and the ultimate, long term prognosis for patients with chronic hepatitis is difficult to predict1.
Hepatitis C is a viral infection that causes liver inflammation, sometimes leading to serious liver damage. The hepatitis C virus (HCV) spreads through contaminated blood. The virus persists in the liver in about 75% to 85% of those initially infected. Early on chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop complications such as liver failure, liver cancer, or esophageal and gastric varices.
At least half of hepatitis C patients develop chronic hepatitis C infection. Diagnosis is made by blood test. Treatment and probably cure is via antiviral drugs and is effective in over 90% of patients. Chronic hepatitis C was frequently treated with injectable interferon, in combination with antiviral oral medications, but now is most often treated with oral antivirals alone. There is no vaccine for hepatitis C.2.
Figure 1: Hepatitis C virus
Although it is uncertain when HCV originated, it is thought that the six subtypes may have originated about 500 years ago in Africa. However, there are no known blood samples old enough to verify this theory. In 1989, Daniel W. Bradley and Michael Houghton were the first to identify HCV which led to the screening of blood that was being or had been donated. In 2007, it was determined that 15,106 people died due to HCV while 12,734 people died due to HIV.3
HCV :Hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family HYPERLINK “https://en.wikipedia.org/wiki/Flaviviridae” o “Flaviviridae” Flaviviridae. Hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer (hepatocellular carcinoma, abbreviated HCC) and lymphomas in humans.4
The hepatitis C virus belongs to the genus HYPERLINK “https://en.wikipedia.org/wiki/Hepacivirus” o “Hepacivirus” Hepacivirus, a member of the family HYPERLINK “https://en.wikipedia.org/wiki/Flaviviridae” o “Flaviviridae” Flaviviridae. Until recently it was considered to be the only member of this genus. However a member of this genus has been discovered in dogs: canine hepacivirus. There is also at least one virus in this genus that infects horses. Several additional viruses in the genus have been described in bats and rodents.5
VIRAL STRUCTURE AND REPLICATION
Hepatitis C virus has an outer envelope containing two viral envelope proteins: E1 and E2. Underneath the membrane is a layer of the viral core protein, which binds to the viral genome forming the nucleocapsid where the RNA is located. You can think of it like a capsule (‘-capsid’) that holds nucleic acid (‘nucleo-‘), in this case RNA. The viral genome of Hepatitis C virus is a single-stranded RNAthat encodes 11 proteins.
The primary cells infected by Hepatitis C virus are liver cells called hepatocytes. The viral envelope proteins recognize markers on the surfaces of these cells. This causes the cell to fold its membrane inward, taking the virus up into a small pocket known as an endosome. It’s a little like Pac-Man eating a dot, where the liver cell is Pac-Man, and the endosome is the mouth of Pac-Man, which eats the dot, the virus. Only this dot doesn’t disappear
Once inside the cell, the viral membrane fuses with the endosome membrane releasing the viral nucleocapsid into the cell cytoplasm. The viral RNA genome is similar to the cell’s messenger RNA (mRNA) so it can be translated by ribosomes in the cell’s endoplasmic reticulum. The long stretch of viral RNA is translated into one long protein, a polypeptide, with all the viral proteins strung together.6
Figure 11: Structure and Replication
Hepatitis C is found worldwide. The most affected regions are WHO Eastern Mediterranean and European Regions, with the prevalence of 2.3% and 1.5% respectively. Prevalence of HCV infection in other WHO regions varies from 0.5% to 1.0%. Depending on the country, hepatitis C virus infection can be concentrated in certain populations (for example, among people who inject drugs) and/or in general populations. There are multiple strains (or genotypes) of the HCV virus and their distribution varies by region7
Figure 111: Global Hepatitis C Prevalence
SEROEPIDEMIOLOGY OF HBV AND HCV IN BANGLADESH
Virus related liver diseases are important cause of morbidity and mortality in Bangladesh. HBV accounts for 35% acute viral hepatitis, 40.5% chronic liver disease, 36.5% HCC and 29.1% cases of post transfusion hepatitis. HCV accounts for 3.5% acute viral hepatitis, 24.1% chronic liver disease, 9.6% HCC and 6.8% cases of post transfusion hepatitis. 29% of professional blood donors and 2.4% of voluntary blood donors are HBsAg carriers. Anti-HCV was found in 1.2% of professional blood donors and in no voluntary donors. HBsAg is positive in 7.5% of healthy adult jobseekers. There was no history suggestive of parenteral route of infeciton in 60% cases of HBV and 54% cases of HCV. In another study during 1994-1996 43,213 Bangladesh job seekers were screened for HBsAg and serological tests showed that 1884 (4.4%) were positive for HBsAg.
In conclusion, HBV is as yet the major aetiological factor for chronic liver disease and HCC. Whereas, HCV is emerging as the second important aetiological factor for such disease in Bangladesh.8
MODE OF TRANSMISSION
The hepatitis C virus is a bloodborne virus. It is most commonly transmitted through:
injecting drug use through the sharing of injection equipment;
the reuse or inadequate sterilization of medical equipment, especially syringes and needles in healthcare settings; and
the transfusion of unscreened blood and blood products.
Figure IV : Mode of Transmission
HCV can also be transmitted sexually and can be passed from an infected mother to her baby; however these modes of transmission are much less common.
Hepatitis C is not spread through breast milk, food, water or by casual contact such as hugging, kissing and sharing food or drinks with an infected person.9
The incubation period for hepatitis C is 2 weeks to 6 months. Following initial infection, approximately 80% of people do not exhibit any symptoms. Those who are acutely symptomatic may exhibit fever, fatigue, decreased appetite, nausea, vomiting, abdominal pain, dark urine, grey-coloured faeces, joint pain and jaundice (yellowing of skin and the whites of the eyes).10
Figure V: Symptom
SCREENING AND DIAGNOSIS
Due to the fact that acute HCV infection is usually asymptomatic, few people are diagnosed during the acute phase. In those people who go on to develop chronic HCV infection, the infection is also often undiagnosed because the infection remains asymptomatic until decades after infection when symptoms develop secondary to serious liver damage.
HCV infection is diagnosed in 2 steps:
Screening for anti-HCV antibodies with a serological test identifies people who have been infected with the virus.
If the test is positive for anti-HCV antibodies, a nucleic acid test for HCV ribonucleic acid (RNA) is needed to confirm chronic infection because about 30% of people infected with HCV spontaneously clear the infection by a strong immune response without the need for treatment. Although no longer infected, they will still test positive for anti-HCV antibodies.
After a person has been diagnosed with chronic hepatitis C infection, they should have an assessment of the degree of liver damage (fibrosis and cirrhosis). This can be done by liver biopsy or through a variety of non-invasive tests.10
GROUPS FOR CONSIDERATION OF HCV TESTING
Persons with signs and symptoms of hepatitis.
Patients with chronic hepatitis, cirrhosis or hepatocellular carcinoma.
Persons with unexplained increase in serum ALT or AST.
Intravenous drug abusers, or those with a history of past drug abuse.
Transfusion recipients, patients with malignancies or thalassaemia.
Recipients of blood products; haemophilia, Von Willebrand’s disease, other coagulopathies.
Sexually promiscuous people and prostitutes.
Occupational exposure: Medical, dental and laboratory health care workers, those with needle stick injuries or those routinely exposed to blood products.
Spouse or sexual partner of HCV infected person.
Liver, bone marrow or kidney transplant recipients.
Inmates of custodial institutions.
Infants of anti-HCV positive mothers. 10
HEPATITIS C TREATMENT MOLECULE
Until quite recently, treatment for chronic hepatitis C usually involved taking:
Pegylated interferon – a medication that encourages the immune system to attack the virus
Ribavirin – an antiviral medication that stops the virus reproducing
Pegylated interferon and Ribavirin
Pegylated interferon is usually taken as a weekly injection. You can be trained to inject yourself at home. It usually needs to be taken for up to 48 weeks, depending on your circumstances.
Ribavirin is available as capsules, tablets or an oral solution. It’s normally taken twice a day with food. It needs to be taken alongside pegylated interferon for up to 48 weeks.
There are also a number of newer medicines now used to treat hepatitis C.Some of these are taken alongside pegylated interferon and ribavirin but, in most cases, they can be taken on their own or in combination with other new medicines.
These medications include:
SimeprevirSofosbuvirDaclatasvira combination of ledipasvir and sofosbuvira combination of ombitasvir, paritaprevir and ritonavir, taken with or without dasabuvira combination of sofosbuvir and velpatasvira combination of sofosbuvir, velpatasvir and voxilaprevira combination of glecaprevir and pibrentasvirThese medications are taken as tablets once or twice a day for between 8 and 48 weeks, depending on the medicine you’re taking, your hepatitis C genotype and the severity of your condition.11
Sofosvel (Sofosbuvir ;Velpatasvir)
A Gold Standard combined drug for the treatment of HepcA single treatment regimen for all genotype
Highly effective for and well tolerable
No need for expensive genotype testing
Ensure high cure rate to HCV genotype 1,2,3,4,5,6
Ensures sustained virologic response to HCV genotype 2 or 3 with or without previous treatment including with compensated cirrhosis
Provides superior sustained SVR12 among both experienced and untreated patients infected with HCV
Exhibits excellent safety profile
Sofosvel Tablet: Each film coated tablet contains Sofosbuvir INN 400 mg and Velpatasvir INN 100 mg.
Therapeutic class: Antiviral agent.
Mechanism of Action
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with an IC50 value ranging from 0.36 to 3.3 micromolar. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate Velpatasvir targets NS5A as its mode of action.12
The effect of Sofosbuvir 400 mg (recommended dosage) and 1200 mg (three times the recommended dosage) on QTc interval was evaluated in an active-controlled (Moxifloxacin 400 mg) thorough QT trial. At a dose three times the recommended dose, Sofosbuvir does not prolong QTc to any clinically relevant extent. The effect of Velpatasvir 500 mg (five times the recommended dosage) was evaluated in an active-controlled (Moxifloxacin 400 mg) thorough QT trial. At a dose five times the recommended dose, Velpatasvir does not prolong QTc interval to any clinically relevant extent12
The pharmacokinetic properties of the components of SOFOSVEL are provided in Table 3. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite, GS-331007, and velpatasvir are provided below:
Tmax (h) 0.5-1 3
Effect of moderate meal (relative to fasting) Î 60% Î34%
Effect of high fat meal (relative to fasting) Î 78% Î21%
% Bound to human plasma proteins 61-65
Blood-to-plasma ratio 0.7 0.52-0.67
Metabolism Cathepsin A CYP2B6
Major route of elimination SOF: metabolism Biliary excretion as parent
GS-331007b: glomerular -77%
filtration and active tubular secretion
t1/2 (h)c SOF: 0.5 15
% Of dose excreted in urined80e 0.4
% Of dose excreted in fecesd14 94
The pharmacokinetics of Sofosbuvir or Velpatasvir in pediatric patients has not been established.
Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 82 years) analyzed, age did not have a clinically relevant effect on the exposure to Sofosbuvir, GS-331007 or Velpatasvir. 12
Patients with Renal Impairment
The pharmacokinetics of Sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of Sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80mL/min/1.73 m2), the Sofosbuvir AUC0-inf was 61%,,107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, Sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when Sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when Sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose.
The pharmacokinetics of Velpatasvir were studied with a single dose of 100 mg Velpatasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in Velpatasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. 12
Patients with Hepatic Impairment
The pharmacokinetics of Sofosbuvir were studied following 7-day dosing of 400 mg Sofosbuvir in HCV-infected subjects with moderate and severe
hepatic impairment (Child-Pugh Class B and C, respectively). Relative to subjects with normal hepatic function, the Sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively.
Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of Sofosbuvir and GS-331007. The pharmacokinetics of Velpatasvir were studied with a single dose of 100 mg Velpatasvir in HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Velpatasvir plasma exposure (AUCinf ) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV- infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of Velpatasvir. 12
Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of Sofosbuvir, GS-331007 or Velpatasvir. 12
Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of Sofosbuvir, GS-331007 or Velpatasvir. 12
Drug Interaction Studies
After oral administration of Sofosbuvir/Velpatasvir, Sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction (hydrolysis followed by sequential phosphorylation) to form the pharmacologically active triphosphate. In clinical pharmacology studies, both Sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir and Velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Velpatasvir is also transported by OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of Velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., Rifampin, St. John’s wort, Carbamazepine) may decrease plasma concentrations of Sofosbuvir and/or Velpatasvir, leading to reduced therapeutic effect of Sofosbuvir/ Velpatasvir. Coadministration with drugs that inhibit P-gp and/or BCRP may increase Sofosbuvir and/or Velpatasvir plasma concentrations without increasing GS-331007 plasma concentration. Drugs that inhibit12
CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of Velpatasvir.
Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentration, Velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes. 12
Sofosvel is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection:
without cirrhosis or with compensated cirrhosis.
with decompensated cirrhosis for use in combination with Ribavirin. 12
DOSAGE AND ADMINISTRATION
The recommended dosage of Sofosvel is one tablet taken orally once daily with or without food.
The most common side effects observed with Sofosbuvir and Velpatasvir combination were Fatigue, Nausea, Headache, Anemia, Diarrhea, Insomnia, Pruritus, Muscle spasm, Dyspnea and Cough. There are some rare adverse events including reduced hemoglobin level, reduced lymphocyte count, reduced neutrophil count and reduced platelet count. Serious Symptomatic Bradycardia developed when Sofosbuvir is coadministered with Amiodarone and another HCV Direct Acting Antiviral.
Sofosvel and Ribavirin combination regimen is contraindicated in patients for whom Ribavirin is contraindicated. Refer to the Ribavirin prescribing information for a list of contraindications for Ribavirin.
Interaction with other medicinal products and other forms of interaction
As sofosvel contains sofosbuvir and velpatasvir, any interactions that have been identified with these active substances individually may occur with sofosvel.
Potential for sofosvel to affect other medicinal products
Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Sofosvel with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. See Table 3 for examples of interactions with sensitive substrates of P-gp (digoxin), BCRP (rosuvastatin), and OATP (pravastatin).
Potential for other medicinal products to affect sofosvelSofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. Velpatasvir is also a substrate of drug transporter OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8 and CYP3A4 was observed. Medicinal products that are potent inducers of P-gp or potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital and phenytoin) may decrease plasma concentrations of sofosbuvir or velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinal products with Sofosvel is contraindicated (see section 4.3). Medicinal products that are moderate P-gp inducers or moderate CYP inducers (e.g. oxcarbazepine, modafinil or efavirenz) may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of Sofosvel. Co-administration with such medicinal products is not recommended with Sofosvel (see section 4.4). Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir or velpatasvir plasma concentrations. Medicinal products that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Clinically significant medicinal product interactions with Sofosvel mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Sofosvel may be co-administered with P-gp, BCRP, OATP and CYP inhibitors.
Patients treated with vitamin K antagonists
As liver function may change during treatment with Sofosvel, a close monitoring of International Normalised Ratio (INR) values is recommended.
Interactions between Sofosvel and other medicinal products
Table 3 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval CI of the geometric least-squares mean GLSM ratio were within “?”, extended above “?”, or extended below “?” the predetermined interaction boundaries). The medicinal product interactions described are based on studies conducted with either sofosbuvir/velpatasvir or velpatasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with sofosbuvir/velpatasvir. The table is not all-inclusive.
Table 3: Interactions between Sofosvel and other medicinal products
Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels.
Mean ratio (90% confidence interval)a,bRecommendation concerning co-administration with SofosvelActive CmaxAUC CminACID REDUCING AGENTS
Velpatasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease the concentration of velpatasvir.
e.g. Aluminium or magnesium hydroxide; calcium carbonate
(Increase in gastric pH) Interaction not studied.
? Sofosbuvir? VelpatasvirIt is recommended to separate antacid and Sofosvel administration by 4 hours.
(40 mg single dose)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose)c
Famotidine dosed simultaneously with SofosveldCimetidineeNizatidineeRanitidinee(Increase in gastric pH) Sofosbuvir? ? H2-receptor antagonists may be administered simultaneously with or staggered from Sofosvel at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
0.80 (0.70, 0.91) ?
0.81 (0.71, 0.91) Famotidine
(40 mg single dose)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose)c
Famotidine dosed 12 hours prior to Sofosveld(Increase in gastric pH) Sofosbuvir?
0.77 (0.68, 0.87) ?
0.80 (0.73, 0.88) Velpatasvir? ? Proton pump inhibitors
(20 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose fasted)c
Omeprazole dosed simultaneously with SofosveldLansoprazoleeRabeprazoleePantoprazoleeEsomeprazolee(Increase in gastric pH) Sofosbuvir?
0.66 (0.55, 0.78) ?
0.71 (0.60, 0.83) Co-administration with proton pump inhibitors is not recommended. If it is considered necessary to co-administer, then Sofosvel should be administered with food and taken 4 hours before proton pump inhibitor at max doses comparable to omeprazole 20 mg.
0.63 (0.50, 0.78) ?
0.64 (0.52, 0.79) Omeprazole
(20 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose fed)c
Omeprazole dosed 4 hours after Sofosveld(Increase in gastric pH) Sofosbuvir?
0.79 (0.68, 0.92) ? Velpatasvir?
0.67 (0.58, 0.78) ?
0.74 (0.63, 0.86) ANTIARRHYTHMICS
Amiodarone Interaction not studied.
Effect on amiodarone, velpatasvir, and sofosbuvir concentrations unknown. Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Sofosvel (see sections 4.4 and 4.8).
Digoxin Interaction only studied with velpatasvir.
? SofosbuvirCo-administration of Sofosvel with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with Sofosvel.
Digoxin (0.25 mg single dose)f/ velpatasvir (100 mg single dose)
(Inhibition of P-gp) Effect on velpatasvir exposure not studied
1.9 (1.7, 2.1) ?
1.3 (1.1, 1.6) ANTICOAGULANTS
Dabigatran etexilate(Inhibition of P-gp) Interaction not studied.
? Sofosbuvir? VelpatasvirClinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Sofosvel. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.
Vitamin K antagonists Interaction not studied Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Sofosvel.
(Induction of P-gp and CYPs) Interaction not studied.
? Sofosbuvir? VelpatasvirSofosvel is contraindicated with carbamazepine, phenobarbital and phenytoin, potent P-gp and CYP inducers (see section 4.3).
(Induction of P-gp and CYPs) Interaction not studied.
? Sofosbuvir? VelpatasvirCo-administration of Sofosvel with oxcarbazepine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Sofosvel. Co-administration is not recommended (see section 4.4).
Ketoconazole Interaction only studied with velpatasvirExpected:
? SofosbuvirNo dose adjustment of Sofosvel or ketoconazole is required.
Ketoconazole (200 mg twice daily)/ velpatasvir (100 mg single dose)d
(Inhibition of P-gp and CYPs)
ItraconazoleeVoriconazoleePosaconazoleeIsavuconazoleeEffect on ketoconazole exposure not studied.
? Ketoconazole Observed:
1.3 (1.0, 1.6) ?
1.7 (1.4, 2.2) ANTIMYCOBACTERIALS
Rifampicin (600 mg once daily)/ sofosbuvir (400 mg single dose)d
(Induction of P-gp and CYPs) Effect on rifampicin exposure not studied.
? Rifampicin Sofosvel is contraindicated with rifampicin, a potent P-gp and CYP inducer (see section 4.3).
0.23 (0.19, 0.29) ?
0.28 (0.24, 0.32) Rifampicin (600 mg once daily)/ velpatasvir (100 mg single dose)
(Induction of P-gp and CYPs) Effect on rifampicin exposure not studied.
? Rifampicin Observed:
0.29 (0.23, 0.37) ?
0.18 (0.15, 0.22) RifabutinRifapentine(Induction of P-gp and CYPs) Interaction not studied.
? Sofosbuvir? VelpatasvirSofosvel is contraindicated with rifabutin, a potent P-gp and CYP inducer (see section 4.3).
Co-administration of Sofosvel with rifapentine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Sofosvel. Co-administration is not recommended (see section 4.4).
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Tenofovir disoproxil fumarate Sofosvel has been shown to increase tenofovir exposure (P-gp-inhibition). The increase in tenofovir exposure (AUC and Cmax) was around 40-80% during co-treatment with Sofosvel and tenofovir disoproxil fumarate/emtricitabine as part of various HIV regimens.
Patients receiving tenofovir disoproxil fumarate and Sofosvel concomitantly should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. Refer to the tenofovir disoproxil fumarate-containing product’s Summary of Product Characteristics for recommendations on renal monitoring (see section 4.4).
Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate
(600/ 200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Efavirenz? ? ? Co-administration of Sofosvel with efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is expected to decrease the concentration of velpatasvir. Co-administration of Sofosvel with efavirenz-containing regimens is not recommended (see section 4.4).
1.4 (1.1, 1.7) ? Velpatasvir?
0.53 (0.43, 0.64) ?
0.47 (0.39, 0.57) ?
0.43 (0.36, 0.52) Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate
(200/ 25/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Rilpivirine? ? ? No dose adjustment of Sofosvel or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required.
Sofosbuvir? ? Velpatasvir? ? ? HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with ritonavir (300/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 / 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Atazanavir? ? ?
1.4 (1.2, 1.6) No dose adjustment of Sofosvel, atazanavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required.
Ritonavir ? ?
1.3 (1.5, 1.4) Sofosbuvir? ? Velpatasvir?
1.6 (1.4, 1.7) ?
2.4 (2.2, 2.6) ?
4.0 (3.6, 4.5) Darunavir boosted with ritonavir (800 / 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Darunavir? ? ? No dose adjustment of Sofosvel, darunavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required.
Ritonavir ? ? ? Sofosbuvir?
0.62 (0.54, 0.71) ?
0.72 (0.66, 0.80) Velpatasvir?
0.76 (0.65, 0.89) ? ? Lopinavir boosted with ritonavir (4×200 mg/ 50 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Lopinavir? ? ? No dose adjustment of Sofosvel, lopinavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required.
Ritonavir ? ? ? Sofosbuvir?
0.59 (0.49 0.71) ?
0.7 (0.6, 0.8) Velpatasvir?
0.70 (0.59, 0.83) ? ?
1.6 (1.4, 1.9) HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir (400 mg twice daily)g + emtricitabine/ tenofovir disoproxil fumarate (200 / 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Raltegravir? ? ?
0.79 (0.42, 1.5) No dose adjustment of Sofosvel, raltegravir or emtricitabine/ tenofovir disoproxil fumarate is required.
Sofosbuvir? ? Velpatasvir? ? ? Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate
(150/ 150/ 200/ 10 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Elvitegravir? ? ? No dose adjustment of Sofosvel or elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate is required.
Cobicistat? ? ?
2.0 (1.7, 2.5) Tenofovir alafenamide? ? Sofosbuvir? ?
1.4 (1.2, 1.5) Velpatasvir?
1.3 (1.2, 1.5) ?
1.5 (1.4, 1.7) ?
1.6 (1.4, 1.8) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate
(150/ 150/ 200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d Elvitegravir? ? ? No dose adjustment of Sofosvel or elvitegravir/ cobicistat/emtricitabine/ tenofovir disoproxil fumarate is required.
Cobicistat? ? ?
1.7 (1.5, 1.9) Sofosbuvir? ? Velpatasvir? ? ?
1.4 (1.2, 1.5) Dolutegravir (50 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily) Dolutegravir? ? ? No dose adjustment of Sofosvel or dolutegravir is required.
Sofosbuvir? ? Velpatasvir? ? ? HERBAL SUPPLEMENTS
St. John’s wort
(Induction of P-gp and CYPs) Interaction not studied.
? Sofosbuvir? VelpatasvirSofosvel is contraindicated with St. John’s wort a potent P-gp and CYP inducer (see section 4.3).
HMG-CoA REDUCTASE INHIBITORS
RosuvastatinInteraction only studied with velpatasvirExpected:
? SofosbuvirCo-administration of Sofosvel with rosuvastatin increases the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin, at a dose that does not exceed 10 mg, may be administered with Sofosvel.
Rosuvastatin (10 mg single dose)/ velpatasvir (100 mg once daily)d
(Inhibition of OATP1B and BCRP) Observed:
2.6 (2.3, 2.9) ?
2.7 (2.5, 2.9) Effect on velpatasvir exposure not studied
? VelpatasvirPravastatin Interaction only studied with velpatasvirExpected:
? SofosbuvirNo dose adjustment of Sofosvel or pravastatin is required.
Pravastatin (40 mg single dose)/ velpatasvir (100 mg once daily)d
(Inhibition of OATP1B) Observed:
1.3 (1.1, 1.5) ?
1.4 (1.2, 1.5) Effect on velpatasvir exposure not studied
? VelpatasvirOther statins Expected:
? Statins Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Sofosvel, careful monitoring for statin adverse reactions should be undertaken and a reduced dose of statins should be considered if required.
(Methadone maintenance therapy 30 to 130 mg daily)/ sofosbuvir (400 mg once daily)d R-methadone ? ? ? No dose adjustment of Sofosvel or methadone is required.
S-methadone ? ? ? Sofosbuvir? ?
1.3 (1.0, 1.7) Methadone Interaction only studied with sofosbuvirExpected:
Ciclosporin(600 mg single dose)/ sofosbuvir (400 mg single dose)f Ciclosporin? ? No dose adjustment of Sofosvel or ciclosporin is required.
2.5 (1.9, 3.5) ?
4.5 (3.3, 6.3) Ciclosporin(600 mg single dose)f/ velpatasvir (100 mg single dose)d Ciclosporin? ?
0.88 (0.78, 1.0) Velpatasvir?
1.6 (1.2, 2.0) ?
2.0 (1.5, 2.7) Tacrolimus
(5 mg single dose)f/ sofosbuvir (400 mg single dose)d Tacrolimus ?
0.73 (0.59, 0.90) ?
1.1 (0.84, 1.4) No dose adjustment of Sofosvel or tacrolimus is required.
0.97 (0.65, 1.4) ?
1.1 (0.81, 1.6) Tacrolimus Effect on velpatasvir exposure not studied.
? VelpatasvirORAL CONTRACEPTIVES
Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ sofosbuvir (400 mg once daily)d Norelgestromin? ? ? No dose adjustment of oral contraceptives is required.
1.2 (0.98, 1.5) ?
1.2 (1.0, 1.5) Ethinyl estradiol ? ? ? Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ velpatasvir (100 mg once daily)d Norelgestromin? ? ? Norgestrel? ? ? Ethinyl estradiol ?
1.4 (1.2, 1.7) ? ?
0.83 (0.65, 1.1) a. Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00.
b. All interaction studies conducted in healthy volunteers.
c. Administered as Sofosvel.
d. Lack of pharmacokinetics interaction bounds 70-143%.
e. These are medicinal products within class where similar interactions could be predicted.
f. Bioequivalence/Equivalence boundary 80-125%.
g. Lack of pharmacokinetics interaction bounds 50-200%.12
WARNINGS AND PRECAUTIONS
Serious Symptomatic Bradycardia When Sofosbuvir Is Coadministered with Amiodarone and another HCV Direct Acting Antiviral Coadministration of Amiodarone with Sofosbuvir/Velpatasvir is not recommended. For patients taking Amiodarone who have no other alternative viable treatment options and who will be coadministered Sofosbuvir/Velpatasvir: 12
? Counsel patients about the risk of symptomatic bradycardia.
??Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Patients who are taking Sofosbuvir/Velpatasvir who need to start Amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above.
Due to Amiodarone’s long half-life, patients discontinuing Amiodarone just prior to starting Sofosbuvir/Velpatasvir should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems. Risk of Reduced Therapeutic Effect Due to Concomitant Use of Sofosbuvir/Velpatasvir with Inducers of P-gp and/or Moderate to Potent Inducers of CYP
Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., Rifampin, St. John’s wort, Carbamazepine) may significantly decrease plasma concentrations of Sofosbuvir and/or Velpatasvir, leading to potentially reduced therapeutic effect of Sofosbuvir/Velpatasvir. The use of these agents with Sofosbuvir/Velpatasvir is not recommended.
Risks Associated with Ribavirin and Sofosbuvir/Velpatasvir Combination Treatment
If Sofosbuvir/Velpatasvir is administered with Ribavirin, the warnings and precautions for Ribavirin apply to this combination regimen. Refer to the Ribavirin prescribing information for a full list of the warnings and precautions for Ribavirin12
No specific antidote is available for overdose with Sofosbuvir/Velpatasvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir/Velpatasvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of Sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of Velpatasvir since Velpatasvir is highly bound to plasma protein. 12
Chronic HCV infection is a major cause of chronic liver disease and HCC worldwide. The many sporadic cases that occur in patients with no identifiable risk factors, the propensity of the virus to cause subclinical chronic hepatic injury and the lack of definite therapy or prevention will probably result in many cases of advanced liver disease secondary to HCV infection well into future.
In conclusion, whereas public measures may be successful ‘in preventing new infections, treatment will continue to be an option for old infections. For HCV chronic carriers without symptoms, regular monitoring of liver functions and periodic measurement of HCV-RNA should suffice. No treatment is necessary in this group. For chronic HCV carriers with symptoms such as chronic active hepatitis and compensated liver cirrhosis, combination therapy must be considered. However, Sofosvel ( sofosbuvir+velpatasvir) is a single tablet regimen for all genotypes . It ensures high SVR12 for patient with child –Pugh B and higly effective and tolerable. No need for genotype testing.
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