|Year : 2017 | Volume
| Issue : 2 | Page : 77-85
Sofosbuvir: Arrival of a paradigm shift in the management of hepatitis C in India
KNM Singh1, SK Kamat1, A Shukla2
1 Department of Pharmacology and Therapeutics, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India
2 Department of Gastroenterology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||20-Apr-2017|
Pharmacology and Therapeutics, Seth G.S. Medical College and K.E.M. Hospital, 1st Floor, Acharya Donde Marg, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
More than 185 million people in the world are affected by hepatitis C, with India having a huge patient load of about 18 million cases. The association of various complications and hepatocellular carcinoma risk with hepatitis C makes it a dangerous health issue. In the early 90s, due to lack of choice for hepatitis C treatment, pegylated interferon (peg-IFN) and ribavirin (RBV) were the widely used agents, but they have low efficacy and multiple side effects. Last decade saw the development of direct-acting antiviral (DAA) agents, including the hepatitis C-specific drug sofosbuvir (SOF). Multiple clinical trials were carried out testing SOF which showed it has excellent efficacy and low side effects. This ultimately led to the approval of SOF in the USA for hepatitis C treatment, in combination with RBV and/or peg-IFN as well as with other newer DAAs. India considered the excellent efficacy and tolerability profile of SOF in the international trials and gave it a marketing approval in early 2015, with a waiver of the national clinical trial data. This has come as a major boost to the millions of hepatitis C patients in the country. However, the exorbitant cost remains a deterrent for its universal use, especially in developing countries like India. The literature search was performed across various databases such as PubMed, EMBASE, and Google Scholar for articles.
Keywords: Direct-acting antiviral agents, hepatitis C, sofosbuvirCare, caregivers, complexities, confidentiality, consent, cost, sexual assault
|How to cite this article:|
Singh K, Kamat S K, Shukla A. Sofosbuvir: Arrival of a paradigm shift in the management of hepatitis C in India. J Med Soc 2017;31:77-85
|How to cite this URL:|
Singh K, Kamat S K, Shukla A. Sofosbuvir: Arrival of a paradigm shift in the management of hepatitis C in India. J Med Soc [serial online] 2017 [cited 2017 Dec 18];31:77-85. Available from: http://www.jmedsoc.org/text.asp?2017/31/2/77/204827
| Introduction|| |
Hepatitis C is a major health problem worldwide, and it is estimated that globally, more than 185 million people are living with hepatitis C virus (HCV) infection. The global prevalence data of 2010 mention that India has a prevalence of 1.5% which means more than 18 million people in the country are affected with HCV. HCV infection is the leading cause of liver-related mortality and liver transplant across the world. About a quarter of the patients with chronic hepatitis C infection develop cirrhosis of the liver, and about 3%–4% of these cirrhotic patients develop hepatocellular carcinoma each year making it a serious health-care concern.,,,
HCV strains have been classified into seven major genotypes. The most common genotype responsible for hepatitis C infection across the world is genotype 1 (GT-1) with about 46.2% cases of hepatitis C caused by it. HCV GT-3 is responsible for the second-highest number of cases worldwide (30.1%), but it is associated with a higher number of cases (45%–79%) of hepatitis C in South and Southeast Asia. GT-3 is the most common genotype (54.4%) of hepatitis C infections in India, followed by GT-1., In India, 54.4% of the genotype is GT-3 while prevalence of GT-1 in India is 24%. GT-3 is associated with infections having worse prognosis and inability to treat easily as compared to the infections caused by GT-1.
In the early 90s, type II alpha-interferon (α IFN) was considered to be the agent of choice for treatment of chronic hepatitis C. Although the response rates to α IFN were as low as 20%, it was used against hepatitis C due to lack of options. Later, the National Institute of Health Consensus guidelines recommended the use of pegylated interferon α 2 (peg-IFNα 2) along with ribavirin (RBV) for the patients with chronic hepatitis C. The sustained virological response (SVR) with the combination of these two drugs was 40%–50% in GT-1 infection and 70%–80% in GT-2 and GT-3 infections. The combination therapy of peg-IFNα 2 and RBV is associated with numerous side effects which include bone marrow suppression, hemolysis, alopecia, anorexia, thyroid dysfunction, and neuropsychiatric depression among others. Peg-IFNα 2 is contraindicated in decompensated liver cirrhosis as it can cause worsening of liver function and therefore may precipitate liver failure. RBV is relatively contraindicated in patients suffering from renal failure.
| Literature Search|| |
We searched the databases of PubMed, EMBASE, and Google Scholar for articles using the following text terms: hepatitis C, HCV, direct acting antiviral, sofosbuvir. The various websites providing important updates on the recent guidelines of hepatitis C management as well as the regulatory information in relation to sofosbuvir (SOF) were also reviewed thoroughly.
| The Advent of Direct-acting Antiviral Agents for Hepatitis C|| |
The low efficacy and poor safety profile of the combination therapy of peg-IFNα 2 and RBV led to the development of multiple direct-acting antiviral (DAA) agents for hepatitis C infection. These DAA agents act against specific proteins as targets which are involved in the replication of HCV [Figure 1]. The various classes of DAA agents have been mentioned in [Table 1].,
|Figure 1: Representative diagram of the structure of hepatitis C virus-RNA|
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|Table 1: Classification of direct-acting antiviral agents for the treatment of hepatitis C|
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In the year 2011, two first-generation protease inhibitors boceprevir (BOC) and telaprevir (TVR) were approved by the United States Food and Drug Administration (US FDA) to be used in combination with peg-IFNα 2 and RBV for infection caused by GT-1. The SVR was 60%–75% in GT-1 treatment naïve (TN) patients with the combination. However, the SVR was suboptimal (30%–40%) in the population which was difficult to cure, like the people with liver cirrhosis or the null responders to the peg-IFNα 2 and RBV combination. BOC and TVR were also associated with additional side effects such as anemia, skin rashes, and dysgeusia. Moreover, compliance with the regimen was poor. The regimen was difficult to take due to the high pill burden and the multiple associated drug interactions.
In late 2013, simeprevir (SMV), a second-generation DAA agent, was approved to be used with peg-IFNα 2 and RBV for treatment of GT-1 infections. However, a major problem with the protease inhibitors, both first and second generations, was the development of cross-resistance. Further before starting SMV, patients needed to be tested for the Q80K mutation in the HCV GT-1 variants as these patients have less SVR as compared to the patients without the mutation. Thus, the need of better DAAs was obvious, which ultimately led to work on the NS5B polymerase inhibitors and thus the development of SOF.
| Sofosbuvir – pharmacodynamics and Pharmacokinetics|| |
SOF is a nucleotide inhibitor and its action is HCV-specific. Originally called as GS-7977, it acts specifically by inhibiting the HCV NS5B polymerase and thus terminates the chain elongation when it is taken up by RNA polymerase as a substrate in HCV-RNA genome. This leads to inhibition of the viral replication. SOF is a pro-drug having a chemical structure of 2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate. It enters the hepatocytes and is transformed there into the active form. The active form is a uridine triphosphate which ultimately leads to the inhibition of viral replication [Figure 2]., The active triphosphate form has a long intracellular half-life of more than 17.8 h (derived from canine data), and hence, the drug dosage is reduced to just once per day. SOF has action against all the various HCV genotypes and thus is said to be pan-genotypic in its activity.In vitro studies have suggested that HCV variants having a specific S282T mutation may have low susceptibility to SOF. However, only one patient on SOF monotherapy in a phase II trial developed relapse through S282T mutation and was treated successfully by SOF + RBV combination. The S282T resistance associated variant is unfit for viral replication and hence not associated with clinical resistance. Thus, it can be said that the resistance barrier of SOF is high. The active form of SOF is inactivated by dephosphorylation and forms the metabolite GS-331007 which has no activity against HCV. The median half-life of SOF is 0.4 h while that of the metabolite GS-331007 is 27 h. The pharmacokinetics of both SOF and GS-331007 does not seem to be affected by factors such as age, gender, race, body mass index, or cirrhosis status. The SOF metabolite is cleared from the body by the kidneys, and no dose adjustment is required if the glomerular filtration rate is >30 mL/min/1.7 m 2. No dose adjustment is needed in hepatic impairment although the metabolism of the drug occurs in the hepatocytes.
| Sofosbuvir – international Clinical Trials|| |
US FDA approved the use of SOF in December 2013 for the treatment of HCV infection. The approved regimen is either for 12 weeks or 24 weeks depending on the genotype of the HCV as shown in [Table 2].,
|Table 2: The early US-FDA approved regimens for hepatitis C containing sofosbuvir|
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The approval of SOF by the FDA was based on various phase II and phase III trials, mentioned in [Table 3]. The triple regimen, containing SOF along with peg-IFNα 2 and RBV, was approved by FDA based on results of phase II trials (ATOMIC, PROTON) and one phase III trial (NEUTRINO).
|Table 3: Clinical trials testing sofosbuvir + pegylated interferon α2 + ribavirin regimen for hepatitis C treatment|
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The ATOMIC trial was a phase II study conducted in 316 TN patients to check the efficacy of the three-drug regimen of SOF, peg-IFNα 2, and RBV against GT-1. The clinical trial showed a SVR of 89% in TN patients. The results also showed no added benefit of a 24-week regimen over the 12-week regimen.,
The PROTON trial was another phase II study which was carried out to test the efficacy of the triple regimen of SOF, peg-IFNα 2, and RBV in 146 TN patients with GT-1, GT-2, and GT-3 genotypes of HCV. The study showed that the SVR at the end of 12 weeks was more than 90% across all genotypes.,
The NEUTRINO study was a phase-III trial, wherein 327 TN patients of hepatitis C with predominantly GT-1 and GT-4 genotypes of HCV were administered a 12-week regimen of SOF along with peg-IFNα 2 and RBV. The patients in the study, 98% of which comprised GT-1 and GT-4 HCV genotypes, showed an SVR of 90% at the end of 12 weeks. The SVR in cirrhotics was 80% at the end of 12 weeks. Moreover, the treatment discontinuation rate in patients with compensated cirrhosis was only 2%, pointing to the fact that the combination was well tolerated.,
The interferon-based treatment regimens of hepatitis C are associated with multiple adverse effects. Hence, new trials with interferon-free regimens were designed with the aim of developing regimens which were well tolerated. The FDA-approved peg-IFN-free regimens containing SOF and RBV [Table 2] were based on the results of phase III trials, namely, FISSION, POSITRON, FUSION, and VALENCE trials [Table 4].
|Table 4: Phase III clinical trials testing sofosbuvir+ribavirin regimen for hepatitis C treatment|
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The FISSION study was a noninferiority trial which studied the effect of SOF and RBV combination compared to the peg-IFNα 2 plus RBV regimen in 253 TN patients with GT-2 and GT-3 genotypes of HCV. The overall SVR at 12 weeks was observed to be 67% for both treatment groups. In the SOF and RBV combination treatment group, response rates were lower for GT-3 patients compared to that in GT-2 patients (56% compared to 97%).
The POSITRON study was a placebo-controlled trial which involved patients infected with GT-2 and GT-3 of HCV and only those patients who did not have peg-IFN as a treatment option were included. The SVR at the end of 12 weeks in the SOF plus RBV treatment group was 78% compared to 0% in placebo group. The FUSION study also involved patients suffering from GT-2 and GT-3 genotypes; however, the patients included had a previous trial with peg-IFNα 2 therapy but were nonresponsive to it. The SVR was 50% at the end of 12 weeks while 73% at the end of 16 weeks in the FUSION trial. In both POSITRON and FUSION trials, the response was less in GT-3 infected patients as compared to the GT-2-infected patients. Furthermore, the response was less among patients with cirrhosis compared to those without it.
The VALENCE trial involved patients suffering from GT-2 and GT-3 HCV infections and they were a mix of both TN and treatment-experienced patients. The SVR of patients treated with SOF and RBV was found to be 93% in GT-2-infected patients at 12 weeks and 85% in GT-3-infected patients at the end of 24 weeks. Among the GT-3-infected group, the SVR was 91% in noncirrhotic while 68% for cirrhotic patients.
| Sofosbuvir in Combination With Other Direct-acting Antiviral Agents|| |
SOF has been approved by the US FDA for use with other DAA agents such as ledipasvir (LDP) and SMV. The LDP plus SOF combination (Harvoni) was approved by the US FDA for the use in patients with GT-1 infection of HCV in October 2014, while the SMV-SOF combination was approved by the FDA in November 2014 [Table 2].
ION trials [Table 5] that were carried out to check for efficacy of the LDP plus SOF combination with or without RBV clearly show the high sustained viral response at 12 weeks.,,
|Table 5: Sofosbuvir plus ledipasvir clinical trials for hepatitis C treatment|
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The Cosmos trial [Table 6] was carried out for testing the efficacy of SMV plus SOF regimen with or without RBV. METAVIR scores were used to classify the patients who were then divided into Cohort 1 (F0-F2) and Cohort 2 (F3-F4). The treatment groups showed good efficacy to the regimen with SVR-12 between 79% and 100%.,
| Sofosbuvir in Decompensated Liver Cirrhosis|| |
Decompensated liver cirrhosis, according to the American Association for the Study of Liver Diseases (AASLD), is moderate or severe hepatic impairment with Child Turcotte Pugh Class B or C who may or may not be candidates for liver transplantation, including the ones diagnosed with hepatocellular carcinoma. The management of decompensated cirrhosis is classified into two groups based on the genotype of the HCV in the patient.
- Decompensated cirrhosis with GT-1 and GT-4 HCV infection
- Decompensated cirrhosis with GT-2 and GT-3 HCV infection.
The management of patients with decompensated liver cirrhosis according to the AASLD guidelines is given in [Table 7].
|Table 7: Management of patients with decompensated liver cirrhosis (American Association for the Study of Liver Diseases guidelines)|
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| Sofosbuvir for Patients Awaiting Liver Transplantation|| |
Patients who are awaiting liver transplantation are prescribed antiviral therapy to prevent the occurrence of graft infection. In such patients, treatment should be initiated at the earliest so that they can complete the full course of the anti-viral therapy followed by the assessment of their liver function. The various treatment regimens containing SOF as a drug, according to the European Association for the Study of Liver guidelines, have been enlisted in [Table 8].
|Table 8: Sofosbuvir containing regimens for patients awaiting liver transplant (European Association for the Study of Liver guidelines)|
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| Reported Adverse Events|| |
The adverse events reported in SOF-based interferon-free regimens were much less compared to the interferon-including ones. The discontinuation of treatment in phase III trials was just 1%–2% in SOF plus RBV treated groups as compared to 11% among the ones who received peg-IFN plus RBV. The adverse events such as anemia, insomnia, and fatigue which are commonly known to be associated with RBV use were more commonly reported in the clinical trials. In the FISSION trial, neutropenia and thrombocytopenia and depression were more commonly observed in patients treated with peg-IFN as compared to those not treated with peg-IFN. No study or review yet gives the detail of the effects of its use in pregnancy or lactation. Phase IV trials in these vulnerable populations in the future should throw more light on its usage in them.
| Treatment Failure With Sofosbuvir Plus Ribavirin Regimen|| |
In case of failure of the combination regimen of SOF plus RBV with or without peg-IFN, the AASLD has recommended regimens based on the fact whether the patient is cirrhotic or not. The recommended regimens are mentioned in [Table 9].
|Table 9: Recommended regimens for failure with sofosbuvir + ribavirin + pegylated interferon regimen|
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| Drug Interactions Associated With Sofosbuvir|| |
SOF is a substrate of P-glycoprotein (P-gp). Thus, it is expected that SOF concentrations may be reduced when it is coadministered with potent intestinal P-gp inducers such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifampicin, or hypericum perforatum (St. John's wort). In addition, coadministration of SOF with rifabutin, rifampicin, rifapentine, and tipranavir/ritonavir is not recommended as they can reduce SOF concentrations and hence decrease its therapeutic effect. SOF should be administered cautiously with amiodarone, and whenever required with cardiac monitoring, as serious symptomatic bradycardia has been reported.,
| Clinical Trial and Approval of Sofosbuvir in India|| |
The clinical trial to evaluate the safety and efficacy of SOF plus RBV was registered in India on February 14, 2014 (Registration number: CTRI/2014/02/004403). The trial was a randomized, open-label study which was multicenter (16 sites in total). The study participants were 120 TN patients infected with either GT-1 or GT-3 HCV. These 120 patients were divided into four study groups of 30 patients each [Table 10]. All groups were given SOF 400 mg QD plus RBV (1000–1200 mg/day). The primary outcome was to check the efficacy of the SOF plus RBV by measuring the SVR after 12 weeks of discontinuation of therapy.
|Table 10: Study groups in the Indian Phase III clinical trial for testing sofosbuvir + ribavirin efficacy|
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However, before the clinical trial in India could be completed, the Union Health Ministry gave approval to the manufacture and marketing of SOF in a meeting held on December 24, 2014. The waiver of the clinical trial data was based on the recommendation of Prof. Ranjit Roy Chaudhury Committee report which states that such a waiver for approval of new drugs which have been approved outside India can be considered in situ ations of national emergency, extreme urgency, epidemic and for orphan drugs for rare diseases and drugs indicated for such conditions for which no therapy is there. The Apex Committee of the Union Health Ministry noted that SOF has high efficacy and low dosing along with avoidance of side effects associated with peg-IFNα 2. Thus, SOF was approved for manufacture and marketing in India officially on January 13, 2015. The approved indication is the treatment of chronic hepatitis C infection in adults only in combination with other medicinal products.
The Indian National Association for Study of Liver (INASL) has recommended the use of SOF in combination with peg-IFNα and RBV for 12 weeks, in patients infected with GT-1, GT-3, GT-4, GT-5, and GT-6 HCV strains as the optimal treatment regimen. On the other hand, for HCV-infected patients with GT-2, SOF plus RBV regimen has been recommended by INASL for 12 weeks for noncirrhotic patients and 16 or 24 weeks for cirrhotic patients.
| Treatment Costs in the Usa and in India|| |
Although multiple clinical trials have proven the fact that SOF has good efficacy and tolerability in patients with HCV infection, the treatment course comprising it is exorbitant in cost. One pill of SOF costs US$1000 and thus, a 12-week course of it costs a whopping $84,000 in the USA, which is approximately equal to a staggering 54 lakh Indian rupees. The cost factor is an important determinant for drugs to be marketed, especially in developing countries. Zhang et al. in their study on cost-effectiveness of SOF-based treatments for chronic hepatitis C in the US mention that SOF-based treatment regimens for GT-1 HCV infections are not cost-effective due to their high price, and in the current scenario, the price of SOF should be reduced by 30% for achievement of its cost-effectiveness. However, the analysis presented by Gilead Sciences, the producer of SOF, shows that although the treatment regimens containing it had higher cost, they were associated with higher gained quality-adjusted life years, better chances of cure, and lesser chances of end-stage liver disease and mortality.,,,
SOF is currently being used in India in combination with RBV alone or with both RBV and peg-IFN in a triple regimen. Under the license of the original producer of the drug (Gilead Sciences), multiple pharmaceutical companies in India have launched the generic form of SOF. The cost of the generics in India is between US$ 750–1000 (Indian Rupees 48,750–65,000 approximately) for a 12-week course, 99% lesser than what it is in the USA.
The fixed dose combination (FDC) of LDP (90 mg) + SOF (400 mg) has been recently approved in India on December 8, 2015. This FDC has been specifically approved for the treatment of GT-1 patients of chronic hepatitis C in adults. Daclatasvir (DCV) 30 mg/60 mg has also been approved in India on December 14, 2015, for use with SOF. The indication of the DCV-SOF combination is the treatment of GT-3 patients of chronic hepatitis C.
| Patent Issues Associated With Sofosbuvir|| |
The Indian patent office granted a patent for SOF to the US-based pharmaceutical firm Gilead on May 9, 2016. This was after an earlier decision, wherein the patent office had rejected an application after the civil society organizations as well as the generic manufacturing firms had filed a formal complaint against the patent application. However, this patent decision advocates the increasing concerns amid the public-health advocates.
According to the amendment of the Indian Patents Act of 2005, medicine product patents were introduced to comply with the intellectual property rules of World Trade Organization. Since then, all new medicines are subject to patents lasting for 20 years. When a patent is given to a company, other manufacturers cannot produce the generic form of that drug till the patent expires. However, the patent grant to Gilead does not mean that the cheaper generics of SOF will not come in the market. A voluntary license agreement was signed between 11 Indian generic companies and Gilead for the production of the essential HCV medicines SOF, LDP/SOF combination tablet, and the investigational combination tablet SOF/velpatasvir. This agreement will help the millions of Indians suffering with HCV infection to get the new effective medicines at an affordable cost. However, it is important that organizations continue to scrutinize such patent decisions so that the essential medicines are supplied smoothly to the poor population in developing countries.
| Future of Sofosbuvir|| |
WHO intends to satisfy the priority health-care needs of the population and has recently included SOF in their essential medicines list. The efficacy of the drug is unquestionable and various manufacturers are providing it at affordable costs. The Indian approval of SOF has given a ray of hope to the millions of hepatitis C affected patients in the country. The recent approval of the FDCs containing LDP plus SOF and DCV plus SOF has given more options for the hepatitis C infected patients in India. Nevertheless, as with SOF, the cost of the new DAA drugs is high, and thus, even though these new anti-hepatitis C combinations are available in India, their moderate cost may be prohibitively expensive to a majority of Indian patients who pay out of pocket toward health-care expenses.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]