overview of new treatments for hepatitis c virus: moving towards
TRANSCRIPT
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Overview of New Treatments for Hepatitis C Virus: Moving Towards a Public Health Agenda
Tracy Swan Hepatitis/HIV Project Director, Treatment Action Group
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Table of Contents
1. Hepatitis C: Natural History 2. Hepatitis C: Genotypes and Global Distribution 3. HCV Treatment: Goals and Evolution
3.1 HCV Protease Inhibitors 3.2 HCV Non‐nucleoside Polymerase Inhibitors 3.3 HCV Nucleoside/tide Polymerase Inhibitors 3.4 HCV NS5A Inhibitors
4. HCV Target Product/Regimen Profile 5. HCV Treatment Criteria and Strategies 5.1 DAA Pricing and Access 5.2. DAA implementation
6. State of the Field: HCV Drug Development and Research Gaps 6.1 Role of Ribavirin in DAA Regimens
6.2 Excluded and Under‐Represented Populations: Pregnancy, Nursing, Paediatrics, Comorbidities, People Who Inject Drugs, the Elderly 6.3 DAAs and Pharmacogenomics 6. 4 HCV Genotypes 5 and 6 6.5 HCV Drug Resistance and Treatment Sequencing 6.6 Research Coordination and Opportunities
7. The HCV Treatment Pipeline 7.1 Sofosbuvir‐based FDCs 2.2 Grazoprevir/Elbasvir‐Based Regimens
8. Conclusion
9. References
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Figure 1. Global Distribution of HCV Genotypes
Figure 2. Evolution of HCV Treatment
Figure 3: The First Generic DAAs Figure 4. Minimum Cost for HCV Treatment, Diagnostics, Genotyping and Monitoring
Table 1. Global Distribution of HCV Genotypes, By Income Classification Table 2. DAAs: Regulatory Approval in the European Union and the United States
Table 3. Target Product Profile: Viekira Pak, Daklinza, Sovaldi, Harvoni and Olysio
Table 4. Current HCV Treatment Criteria
Table 5. Sofosbuvir + GS‐5816* With or Without RBV in Phase 2 Table 6. SVR among Cirrhotic Participants in C‐WORTHY
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AIDS acquired immune deficiency syndrome ART antiretroviral therapy ARVs antiretrovirals DAAs direct‐acting antivirals DCV daclatasvir EMA European Medicines Agency EU European Union FDA Food and Drug Administration FDC fixed‐dose combination G genotype; as in genotype 1 (G1), genotype 2 (G2), and genotypes 3, 4, 5 and 6 HCC hepatocellular carcinoma HCV hepatitis C virus HIC high‐income country HIV human immunodeficiency virus LIC low‐income country LMIC low‐and middle‐Income countries MIC middle‐income country MSM men who have sex with men NSP needle syringe programme OST opioid substitution PEG‐IFN pegylated interferon PK pharmacokinetic PWID people who inject drugs RAVs resistance‐associated variants RBV ribavirin RLS resource limited setting SOF sofosbuvir SVR sustained virologic response SVR‐12 sustained virologic response, 12 weeks after treatment completion; equivalent to cure US United States WHO World Health Organization
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Hepatitis C may contribute to non‐liver related mortality. People with hepatitis C are dying two decades earlier from non‐liver related illness (such as cardiovascular disease, respiratory failure, hypertension and diabetes) than their uninfected peers.8 Spontaneous viral clearance occurs in 20% of children with HCV infection.9,10 Chronic hepatitis C is usually asymptomatic in children. During the first decade of infection, progression to cirrhosis and end‐stage liver disease is rare among otherwise healthy children.11,12,13 Over time, chronic hepatitis C causes liver scarring. The progression of liver damage is not linear, and it varies, by host and viral factors that include male sex, HIV status, coinfection with hepatitis B virus, alcohol intake, obesity, type 2 diabetes, steatosis (fatty liver) and aging.Error! Bookmark not defined. Duration of infection accelerates liver damage: after 20 years of HCV infection, the estimated prevalence of cirrhosis is 16%; at 30 years, it increases to 40%.14 People with cirrhosis are at risk for hepatocellular carcinoma (HCC) at the rate of 1% to 5% per year, and liver failure at the rate of 3% to 6% per year.Error! Bookmark not defined. Each year, 700,000 people die from these HCV complications.15 As of 2012, cirrhosis of the liver was the tenth leading cause of death in lower‐middle‐income countries, and liver cancer was the ninth leading cause of death in upper‐middle‐income countries.16,17 In certain high‐income countries, where access to antiretroviral therapy (ART) for HIV is widespread, more people are now dying from HCV complications than AIDS.18,19,20
2. Hepatitis C Genotypes and Their Global Distribution There are seven known HCV genotypes—each with dozens of subtypes.21,22 The high genetic variability of hepatitis C virus (>30% nucleotide difference between genotypes, 15% to 30% nucleotide difference among subtypes) has made it difficult to develop universally effective vaccines and treatment.22 In fact, the type, duration and outcome of HCV treatment may vary according to genotype—and sometimes subtype. Globally, genotype 1 predominates (46.2%, or 83.4 million cases), followed by genotype 3 (30.1%, or 54.3 million cases), genotype 2 (9.1%, or 16.5 million cases), genotype 4, (8.3%, or 15 million cases), genotype 6 (5.4%, or 9.8 million cases), and genotype 5 (<1%, or 1.4 million cases); there is a single known case of genotype 7.21 Mixed infections, with more than one hepatitis C genotype or subtype have been reported in people with multiple exposures, such as transfusion and blood product recipients, dialysis patients and people who inject drugs (PWID).23,24
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Source: http://pennstatehersheygireport.org/2013/06/27/new‐developments‐in‐the‐rapidly‐evolving‐landscape‐of‐hepatitis‐c‐therapy/ (did not request/obtain permission since I found it while searching for copyright‐free images)
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Table 2. DAAs: Regulatory Approval in the European Union and the United States
DAA or Regimen Class, formulation
Genotypes Approval
Sofosbuvir Used with PEG‐IFN and RBV or RBV alone; simeprevir or daclatasvir, with or without RBV, for 12 or 24 weeks
Nucleotide polymerase inhibitor
1,2,3,4(less data in genotypes 5 and 6)
2013 (EU and US)
Simeprevir Used with: PEG‐IFN and RBV, or sofosbuvir, with or without RBV, for 12 or 24 weeks
Protease inhibitor 1 and 4 2013 (US) 2014 (EU)
Daclatasvir Used with PEG‐IFN and RBV orsofosbuvir, with or without RBV, for 12 or 24 weeks
NS5A inhibitor 1,2,3,4 (no data in genotypes 5 and 6)
2014 (EU) Submitted in 2015 (US)
Sofosbuvir/ledipasvir Used with or without RBV, for 8, 12 or 24 weeks
FDC: nucleotide polymerase inhibitor and NS5A inhibitor
1,3,4 and 6 2014 (EU and US)
Ombitasvir/paritaprevir/ritonavir plus dasabuvir Used with or without RBV, for 12 or 24 weeks
FDC: NS5A inhibitor, ritonavir‐boosted HCV protease inhibitor used with a non‐nucleoside polymerase inhibitor
1 and 4 2014
DAA regimens are shorter, safer, better tolerated and significantly more effective across host and viral factors than PEG‐IFN and RBV. These regimens require minimal monitoring during and after treatment, so they are far simpler to administer and undergo than interferon‐based treatment. Although other approaches to treating hepatitis C virus—such as micro‐RNA and host‐targeting agents—are under study, none have been approved. There are four classes of
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DAAs: protease inhibitors, non‐nucleoside polymerase inhibitors, nucleoside/tide polymerase inhibitors and NS5A inhibitors.
3.1 HCV Protease Inhibitors
In 2002, BILN‐2061, the first HCV protease inhibitor entered human trials; it was discontinued for cardiotoxicity shortly thereafter.38 The first approved DAAs were HCV protease inhibitors (boceprevir and telaprevir). These drugs were used as part of response‐guided therapy with PEG‐IFN and RBV. Although they increased SVR (from approximately 45% to approximately 70%) in genotype 1, boceprevir and telaprevir were associated with serious adverse events and added to cost and complexity of treatment.
Now, once‐daily HCV protease inhibitors (simeprevir and paritaprevir/ritonavir) are part of all‐oral DAA combinations for HCV genotypes 1 and 4. HCV protease inhibitors are less effective for genotype 1a, due to a lower resistance barrier. Some protease inhibitor‐based regimens require ribavirin for genotype 1a, or are used only for genotype 1b.
Most HCV protease inhibitors are not pan‐genotypic—they are not sufficiently effective against genotype 3. But it may be possible to overcome this Achilles heel by combining them with other DAAs . Merck is exploring this strategy by adding sofosbuvir to their grazoprevir/elbasvir (HCV protease inhibitor and NS5A inhibitor fixed‐dose combination (FDC).
HCV protease inhibitors have a propensity for drug‐drug interactions and cannot be co‐administered with several commonly used medications, including some HIV antiretrovirals (ARVs).
Newer protease inhibitors may be more potent overall, have a higher genetic barrier to drug resistance, and activity against drug‐resistant strains of hepatitis C. The protease inhibitors currently in phase 2, ABT‐493 (under study as an FDC with ABT‐530, AbbVie’s NS5A inhibitor) and Gilead’s GS 9857 (under study sofosbuvir/velpatasvir [nucleotide polymerase inhibitor/ NS5A inhibitor] FDC), may be more effective against genotype 3.
3.2 HCV Non‐Nucleoside Polymerase Inhibitors
The potency and resistance barrier of drugs in this class range from low to moderate; many have been discontinued for toxicity or lack of efficacy. Most non‐nucleoside polymerase inhibitors are twice‐daily drugs, primarily active against genotype 1. Although non‐nucleosides contribute to regimen efficacy for HCV genotype 1, the need for, and future of drugs from this class is unclear.39,40
3.3 HCV Nucleoside/tide Polymerase Inhibitors
Sofosbuvir, the only approved nucleotide polymerase inhibitor, has the best features of this class: multi or pan genotypic activity, potency and high resistance barrier, low propensity
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for treating HCV genotype 1 is using DAAs from multiple classes, to shorten treatment and increase cure rates. Although cure rates in trials combining DAAs from 3 classes have topped 95%, those who are not cured may be left with few options.
Pan genotypic strategies are becoming more desirable, due to the global focus on HCV. Currently, sofosbuvir is the optimal backbone for a first‐line regimen, since it is pan‐genotypic, can be used in cirrhosis, has a low propensity for drug‐drug interactions, and a high resistance barrier. Pairing it with a pan‐genotypic NS5A inhibitor obviates pre‐treatment genotypic testing, and will minimize safety and efficacy monitoring during and after treatment. But the weakness of NS5A inhibitors is baseline or emergent drug resistance that may limit their effectiveness.41,42,43,44,45 Candidates in phase II development (AbbVie’s ABT‐530, Achillion’s ACH‐3102, and Merck’s MK‐8408) are purported to be more potent, and active against drug resistant virus.
The ideal DAA regimen for HCV treatment scale up does not exist—yet (especially in regard to affordability an use in pregnancy, nursing and paediatrics). These characteristics are: Safe and Tolerable; preferably ribavirin‐free; minimal pre‐treatment assessment or safety/efficacy monitoring needed;
Effective and Durable: potent, with high genetic barrier and SVR ≥85%, regardless of age, treatment experience, HIV status, HCV genotype, liver disease severity, kidney disease;
Universal: pan‐genotypic; safe for use during pregnancy and nursing, and in pediatrics, HIV/HCV, and cirrhosis;
o In paediatrics, age appropriate formulation, scored, dispersible tablets, usable across broad weight bands
Simple and convenient: manageable drug‐drug interactions with ARVs, opioid substitution treatment (OST) and other commonly‐used medications; fixed duration (≤ 12 weeks); minimal requirements for pre‐treatment assessment and safety/efficacy monitoring during and after treatment; once‐daily (FDC preferred), without food requirement;
Stable at high and low temperatures
Affordable.
Table 3. Target Product Profile: Ombitasvir/paritaprevir/ritonavir plus dasabuvir, Daclatasvir, Sofosbuvir, Sofosbuvir/ledipasvir and Simeprevir Error! Bookmark not defined.,Error! Bookmark not defined.,Error! Bookmark not defined.,Error! Bookmark not
defined.,Error! Bookmark not defined.
14
REGIMEN, STATUS, SPONSOR (s)
UNIVERSAL and SAFE
Assumptions: DAAs or regimens are well tolerated, as evidenced by low discontinuation rates in clinical trials (<5%). They are safe‐‐but less effective‐‐ for people with compensated cirrhosis, especially in G3. No data during pregnancy and nursing, or pediatrics
SIMPLE
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SVR >85%
COMMENTS
Pan‐genotypic
Data in HIV/HCV
Hepatic impairment
Renal impairment
≤12 weeks for all
Propensity for DDIs
QD
Ombitasvir/ paritaprevir/ ritonavir and dasabuvir
APPROVED in EU and US
AbbVie
G1 and G4 only
SVR is comparable
Not recommended for Child‐Pugh B; contraindicated in Child‐Pugh C
No dose adjustment for mild, moderate or severe renal impairment
NO HIGH NO YES Complex, subtyping required, RBV needed in some populations
Daclatasvir
APPROVED in EU; submitted in US
BMS
Pan‐genotypic in vitro; studied in G1, G2, G3 and G4
SVR is comparable
No dose adjustment for mild, moderate or severe hepatic impairment
No dose adjustment for mild, moderate or severe renal impairment
? MODERATE YES YES, except in G3 and cirrhosis
Optimal duration with sofosbuvir unclear for G3 and cirrhosis; RBV may be needed; contraindicated in pregnancy; no in vivo data in G5 and G6
Sofosbuvir
Gilead Sciences
APPROVED in EU and US
YES YES, SVR is comparable
No dose adjustment for mild, moderate or severe hepatic impairment
No dose adjustment for mild or moderate renal impairment; no data or dose for severe renal impairment
Varies LOW YES YES, except in G3 and cirrhosis
Used with RBV in G2 and G3; very limited in vivo data in G5 and G6; duration depends on genotype and regimen
Sofosbuvir/ ledipasvir)
APPROVED in EU and US
Gilead Sciences
NO; G1,3, 4 and 6
YES, SVR is comparable
No dose adjustment for mild, moderate or severe hepatic impairment
No dose adjustment for mild or moderate renal impairment; no data or dose for severe renal
Varies MODERATE YES YES, except in G3
RBV required in G3; under study in G2; no in vivo data in G5; limited in vivo data in G6
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16
To stem an annual death toll of 700,000 people, global HCV treatment scale‐up must be prioritized.15 HCV treatment has the potential to provide vast individual and public health benefits. But high prices have limited access to HCV treatment‐‐even in high‐income countries‐‐to people with advanced liver disease (METAVIR F3 and F4). In the United States, public and private payers have imposed non‐evidence based restrictions (such as requiring 3 to 12 months of abstinence from drugs and alcohol), and forged exclusivity agreements with pharmaceutical companies that limit clinical decision‐making.46,47,48,49 In Europe, high DAA prices have led France to threaten taxation for costly HCV drugs, delayed their approval in the United Kingdom, or limited access in Spain.50,51,52 If DAAs are to stem HCV‐related morbidity and mortality in the coming years, and reduce the global burden of HCV infection, current HCV treatment rates of 1% to <5%‐‐ must increase.53,54,55 Treating people with fibrosis (METAVIR SCORE: >F2) will reduce HCV‐associated morbidity and mortality—but unless people with less liver damage (METAVIR SCORE: F0 and F1) are treated, the epidemic will continue to spread.56 Table 4. Current HCV Treatment Criteria57,58,59
Source Recommendation
Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection World Health Organization April 2014
All adults and children with chronic HCV infection, including PWID, should be assessed for antiviral treatment...patients with advanced fibrosis and cirrhosis (METAVIR stages F3 and F4) should be prioritized for treatment as they are at higher risk of developing cirrhosis and hepatocellular carcinoma. If resources permit, then persons with less advanced fibrosis (METAVIR stages F1 and F2) could also be considered for treatment.
EASL Recommendations on Treatment of Hepatitis C 2014 European Association for the Study of the Liver (EASL) April 2014
All treatment‐naïve and –experienced patients with compensated disease due to HCV should be considered for therapy. Treatment should be prioritized for patients with significant fibrosis (METAVIR Score F3 to F4). Treatment is justified in patients with moderate fibrosis (METAVIR Score F2). In patients with no or mild disease (METAVIR Score F0‐F1), the indication for, and timing of therapy can be individualized.
Recommendations for Testing, Managing and Treating Hepatitis C American Association for the Study of Liver Diseases/ Infectious Diseases Society of America (AASLD/IDSA) March 2015
Treatment is recommended for patients with chronic HCV infection. Immediate treatment is assigned the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C.
17
In Egypt, home of the world’s highest HCV prevalence (14.7%), modeling the impact of different eligibility criteria on life‐years saved found that limiting treatment to people with advanced liver disease (METAVIR SCORE: F3 and F4) was most effective—but the model did not consider the annual infection rate, or the impact of these restrictions on transmission.60 Affordable DAAs increase the appeal and feasibility of HCV treatment‐as‐prevention (TasP). Primary prevention measures must be scaled up in tandem with TasP if it is to be fully effective. In Egypt, HCV is still spreading despite a national treatment program; scaling up infection control to prevent healthcare‐ and household‐associated exposures is as important as providing widespread HCV treatment.61 For people who inject drugs—the highest‐prevalence population‐‐ DAAs and high coverage opioid substitution treatment (OST) and needle and syringe programmes (NSP) — are essential for reducing HCV prevalence (PWID).62 Scaling up HCV treatment access ‐‐and rates‐‐among PWID could dramatically reduce prevalence in this population (estimated at 67%, or at least 10 million people).63 Martin and colleagues modeled the impact of DAA treatment scale‐up, based on a 90% SVR rate, HCV prevalence and current treatment rates among people who inject drugs in three cities. In Edinburgh (where prevalence among PWID is currently 25%, and 7/1000 are treated annually) and Melbourne (where prevalence is 50%, and 3/1000 are treated annually). In just 15 years, prevalence among people who inject drugs could be halved, by scaling up the annual treatment rate in these cities to 22/1000. In Vancouver, where HCV prevalence among PWID is 65% and 5/1000 are treated annually; treating 98/1000 would halve it in 15 years. Prevalence could be reduced to 30% in Vancouver and less than 5% in Edinburgh and Melbourne by treating 80/1000 annually.64 5.1 DAA Pricing and Access Although there are several barriers to universal HCV treatment access, high DAA prices are the greatest obstacle. The same steps that have led to a 99% drop in the price of antiretroviral therapy for HIV‐demand creation, community mobilization, treatment literacy, generic competition, economies of scale, and improved procurement of raw materials manufacturing processes are possible for HCV treatment.65,66
18
Figure 3: The First Generic DAAs
Source: MSF Access Campaign, India. Used with permission.
DAAs that simplify diagnostics and limit monitoring requirements can be mass‐produced affordably, and sustainably, according to Hill and colleagues, who compared chemical structure and synthesis complexity, molecular weight and dosing between antiretroviral agents and certain DAAs, and added margins for formulation and profit. DAAs were prioritized by safety and efficacy; these were ribavirin, sofosbuvir (nucleotide polymerase inhibitor), the NS5A inhibitors daclatasvir, ledipasvir and elbasvir (formerly MK‐8742; currently in phase 3) and the protease inhibitor grazoprevir (formerly MK‐5172; currently in phase 3). Regimens were priced at: US $118 (12 weeks of grazoprevir/elbasvir); US $121 (12 weeks of sofosbuvir/daclatasvir); US $129 to $193 (8 or 12 weeks of sofosbuvir/ledipasvir), US$ 149 to $298 (12 or 24 weeks of sofosbuvir and ribavirin). 67,68 As a next step, the researchers determined need for, type, and frequency of monitoring based on safety data from clinical trials (a complete blood count and other routine clinical chemistry tests, such as liver enzyme and creatinine levels, once before and once during treatment). They selected an antigen test (used for diagnosing HCV infection and determining treatment outcome), and included genotyping (in the absence of a pan genotypic regimen). The cost of diagnostics and monitoring was estimated based, on pricing in developing countries. Thus, a “package” of HCV treatment and diagnostics could be available without genotyping for US $174 to $354; with genotyping, from US $264 to $444.67,68
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DAA mono therapy trials are short; for certain classes, regulatory agencies recommend limiting duration to three days, to forestall drug resistance.72 It is challenging to identify best‐in‐class drugs—or develop optimal regimens, since most regimens are comprised of drugs from one sponsor. As the market for DAAs becomes saturated pharmaceutical companies will move from HCV into new areas, abandoning trials in key populations, and development and assessment of new treatment strategies or exploration of the relevance of pharmacogenomics. 6.1 Role of Ribavirin in DAA Regimens The prevailing commercial strategies for DAA drug development are to shorten treatment, and remove ribavirin use. These may be at odds, since both longer treatment and ribavirin may be needed for people with the most advanced liver disease. Although ribavirin has significant limitations (teratogenicity, and side effects including anemia; insomnia; irritability; anxiety; depression; insomnia; nausea; and muscle and join pain), it is pan genotypic and it may bolster DAA treatment efficacy for certain regimens, genotypes and patient populations. In addition, it is no longer under patent protection and can be manufactured inexpensively. In the DAA era, the role of ribavirin remains unclear. Although RBV use has not increased SVR in several phase II trials, the number of participants has been too small to determine if, and which patients will benefit from it. Indeed, ribavirin remains a mainstay of many trials in “harder‐to‐treat” populations (compensated and more advanced‐stage cirrhosis, especially in genotype 3, and HIV/HCV). In particular, RBV may be needed to cure genotype 3, especially in people with cirrhosis. In the ALLY‐3 trial, 12 weeks of sofosbuvir and daclatasvir cured 96% of non‐cirrhotic participants‐‐‐but only 63% of cirrhotic participants.Error! Bookmark not defined. In the ELECTRON‐2 trial, adding RBV to 12 weeks of sofosbuvir/ledipasvir increased SVR from 64% to 100% among non‐cirrhotic, treatment‐naïve people with genotype 3; in treatment‐experienced cirrhotics, sofosbuvir/ledipasvir plus RBV cured 73%.73,74 6.2 Excluded and Under‐Represented Populations: Pregnancy, Nursing, Paediatrics, Comorbidities, People Who Use and Inject Drugs, the Elderly Despite the prevalence of HCV among women of childbearing age, there are not data on safety and efficacy of ribavirin‐free DAA regimens during pregnancy and nursing. Information on safety of HCV treatment during pregnancy and nursing is particularly important, given that drug‐drug interactions between DAAs and hormonal contraceptives may limit HCV treatment options or lead women to use less effective birth control during HCV treatment.
22
Paediatric trials (ages 3 to 17) of sofosbuvir and ribavirin and sofosbuvir/ledipasvir are underway. More research—especially of pan genotypic regimens—and optimal formulations are needed. People 65 and over are often excluded from DAA clinical trials. To date, safety, efficacy and tolerability of DAAs in elderly patients—albeit without common comorbidities—do not differ from younger people. More research is needed. Early stage or post‐transplant DAA clinical trials often limit enrollment to people with mild liver disease (METAVIR SCORE F0 to F2). DAAs are likely to be more effective in people with mild liver damage; exploration of shortened treatment duration in this population is needed. Although people with compensated cirrhosis are eligible for most DAA clinical trials, research in people with more advanced liver damage (Child Pugh stages B or C) is delayed until after approval. In the absence of compassionate use programmes (or those with limited eligibility), people with the most urgent need must wait until approval to gain access to potentially lifesaving DAAs in the absence of adequate safety and efficacy information. HCV treatment is a priority for people with hepatic or renal impairment, and people with other significant, common comorbidities (including cardiovascular disease, type 2 diabetes, HBV coinfection, COPD, and depression). Typically, small, often single‐dose pharmacokinetic (PK) studies are performed in people with renal or hepatic impairment before DAAs are approved, but actual trials do not occur until after approval. Often, people with other comorbidities are not eligible for clinical trials—and information on drug safety and efficacy in people with other illnesses does not emerge until drugs have been on the market for years. Failure to include people who inject drugs, the highest‐prevalence population, in clinical trials creates a vicious cycle, where treatment is withheld due to lack of evidence. After years of pressure from people who use and inject drugs and their advocates, people on opioid substitution treatment have not been completely excluded from clinical trials; a few HCV treatment trials are being conducted in active drug users. 6.3 DAAs and Pharmacogenomics Researchers finally identified part of the reason for poorer response to interferon among African Americans: the IL‐28B gene; this was only possible because of adequate representation in clinical trials. Some DAA regimens appear to be less effective in people with the IL28B TT genotype (most common among African Americans), especially when duration of treatment is shortened.75 With ombitasvir/paritaprevir/ritonavir and dasabuvir, ribavirin increased SVR in African Americans who had genotype 1a.76 Simeprevir dose may need to be adjusted in people of East Asian ancestry.Error! Bookmark not defined.
23
Other, unidentified pharmacogenomics factors may lessen or increase DAA treatment efficacy. 6.4 HCV Genotypes 5 and 6 DAAs are often characterized as pan genotypic, using data from in vitro studies. Safety and efficacy of HCV treatment across genotypes—and in people who are infected with multiple genotype (which occurs among people who inject drugs, dialysis recipients and others with multiple exposures to HCV) must be characterized in clinical trials.23,24 Data in genotypes 5 and 6 are limited. Although over a million people are infected with HCV genotype 5, only a handful them have been included in clinical trials of sofosbuvir‐based regimens.21,77,78,79 Although DAAs have demonstrated efficacy in a small group of people with G5 or G6, more data are needed to inform regimen selection and global treatment scale‐up. 6.5 HCV Drug Resistance and Treatment Sequencing Mutations that confer resistance to one or more DAA classes may be present at baseline or after treatment failure. The prevalence of baseline resistance‐associated variants (RAVs) varies by HCV genotype and subtype.80 For example, baseline RAVs associated with certain HCV protease inhibitors and non‐nucleoside polymerase inhibitors have been observed in genotype 3a.81 In genotype 1, baseline NS5A RAVS have been found in 6% to 12%, although these do not always preclude successful treatment.80 In clinical trials of sofosbuvir/ledipasvir, prevalence of baseline NS5A RAVs ranged from 14% to 18%; although 90% of people with these baseline RAVs achieved SVR, post‐treatment NS5A RAVs were found in most people who were not cured.33,82
Sofosbuvir has a high resistance barrier. Although the S282T mutation has been selected in all genotypes during in vitro studies, the clinical significance of this RAV is unclear; it has been found in in 1 of 1545 trial participants, who was not cured.83 Other mutations have been associated with reduced efficacy and sofosbuvir treatment failure. The L159F mutation has been found at baseline and post‐treatment in genotypes 1b and 3a; the V321A mutation has been detected after treatment failure in genotype 3a; C316N, and S282R may also reduce efficacy of sofosbuvir in genotype 1a.84,85
The selection of first‐line treatment will set the stage for a second‐line regimen. Until the longevity and significance of DAA drug resistance is well understood, avoiding retreatment with DAAs from the same class—unless they have demonstrated sufficient activity against drug‐resistant virus—is the preferred strategy. More information is needed on the relationship between baseline or post‐treatment RAVs and HCV treatment—or retreatment outcomes.
Yet successful re‐treatment with sofosbuvir may be possible, even for people who were not cured by a sofosbuvir‐containing regimen. Lengthening treatment duration, adding ribavirin or use of additional DAAs may do the trick.43,86 In ELECTRON‐2, 100% of 19 sofosbuvir‐experienced participants were cured by retreatment with 12 weeks of sofosbuvir/ledipasvir
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7.1 Sofosbuvir‐based FDCs Gilead’s sofosbuvir/velpatasvir (NS5A inhibitor; formerly GS‐5816) is a once‐daily FDC in phase 3. Phase 2 results are promising, but more data are needed, especially in genotype 3 and cirrhosis, and genotypes 4, 5 and 6. In phase 2, after 12 weeks of treatment, SVR in genotype 1 ranged from 96% to 100%, regardless of ribavirin use, treatment history and cirrhosis; shortening treatment to 8 weeks—albeit in non‐cirrhotic, treatment naïve study participants—did not appear to be a viable strategy for this regimen, even with ribavirin. In genotype 3, SVR in treatment‐experienced, cirrhotic study participants was 88%; adding RBV to the mix increased SVR to 96%.87 The sofosbuvir/velpatasvir FDC is currently being studied in people who are treatment‐naïve or treatment experienced (PEG‐IFN and ribavirin, with or without an HCV protease inhibitor) , in HCV genotypes 1,2,4,5 and 6. The FDC is also being compared to 12 weeks (in G2) or 24 weeks (in G3) of sofosbuvir + RBV, and being studied in advanced liver disease: with or without ribavirin, in Child‐Pugh Class B for 12 weeks, and for 24 weeks, without ribavirin, in Child‐Pugh class C. A phase 2 trial is assessing sofosbuvir, GS‐5816 and GS‐9857, a pan genotypic protease inhibitor in genotypes 1, 2, 3, 4, 5 and 6, treatment‐naïve or –experienced people, with or without cirrhosis, for 6, 8 or 12 weeks.
Table 5. Sofosbuvir + GS‐5816* With or Without RBV in Phase 279,87
Genotype Duration Treatment‐experienced
Cirrhosis SVR
1 8 weeks NO NO 81% + RBV (25/31) 90% no RBV (26/29)
12 weeks
NO NO 100% no RBV (28/28) 100% no RBV (28/28)
12 weeks YES YES: Some participants were cirrhotic; data not broken out by cirrhosis status
96% + RBV (27/28) relapse occurred in a cirrhotic participant 100% no RBV (27/27)
2 8 weeks NO NO 88% no RBV (23/26) 88% + RBV (23/26)
12 weeks NO NO 100% no RBV (10/10)
26
7.2 Grazoprevir/Elbasvir‐Based Regimens Merck’s grazoprevir/elbasvir FDC (formerly MK‐5172, an HCV protease inhibitor, and MK‐8742, an NS5A inhibitor) has entered phase 3. In the phase 2 C‐WORTHY trial of grazoprevir/elbasvir, with or without ribavirin, cure rates in genotype 1 ranged from 93% (with RBV) to 98% (no RBV) in HCV monoinfection, and 87% (no RBV) to 97% (with RBV) in HIV/HCV.88 Grazoprevir and elbasvir also performed well in another genotype 1 trial, in treatment naïve people with cirrhosis, and treatment ‐experienced people with or without cirrhosis. An 8‐arm trial compared 12 or 18 weeks of treatment, with or without RBV, in treatment‐naïve people with cirrhosis, and treatment‐experienced people (with and without cirrhosis). There were no significant differences in SVR by ribavirin use, subtype, cirrhosis, treatment duration or experience.89
Table 6. SVR among Cirrhotic Participants in C‐WORTHY89
Population SVR, 12 weeks, + RBV
SVR, 12 weeks, no RBV
SVR, 18 weeks, + RBV
SVR, 18 weeks, no RBV
Treatment‐naïve, cirrhosis
90% (28/31) (97%) 28/29 97% (31/32) 94% (29/31)
Treatment‐experienced, cirrhosis
92% (23/25) no significant difference for RBV vs. no RBV
100% (22/23)no significant difference for RBV vs. no RBV
Merck’s FDC may become the backbone of an abbreviated, pan genotypic regimen. It is currently being studied in HCV genotypes 1, 2, 4, and 6, and in C‐SWIFT, a phase 2 trial of the FDC and sofosbuvir, in genotypes 1 and 3. Interim data from C‐SWIFT are available in genotype 1. Although the 4‐week regimen yielded an SVR‐4 of only 38% in non‐cirrhotic
3 12 weeks
NO
NO
93% no RBV (23/27)
YES NO 100% ± RBV (53/53)
YES YES 88% no RBV (23/26) 96% + RBV (25/26)
4 12 weeks NO NO 86% no RBV (6/7)
5 (25 mg GS‐5816)
12 weeks
NO NO 100% no RBV (1/1)
6 12 weeks NO NO 100% no RBV (5/5)
27
study participants, extending treatment to 6 weeks increased SVR‐4 to 86% in non‐cirrhotic participants (vs. 80% in cirrhotics); and 8 weeks of treatment cured 94% of cirrhotic participants.90 Merck is developing MK‐3682, a nucleotide polymerase inhibitor and MK‐8408, a pan genotypic NS5A inhibitor with activity against common NS5A RAVs.91 With these DAAs, the company has the potential to construct pan genotypic, once daily regimens. They are studying MK‐3682 with the grazoprevir/elbasvir FDC, and comparing efficacy of MK‐8404 versus elbasvir with grazoprevir and MK‐3682 in phase 2 trials.
8. Conclusion
Perfectovir should not become the enemy of Goodovir. ‐Jennifer Cohn, Medical Director, MSF Access Campaign
Other promising DAA candidates are in early‐phase development. With such high cure rates, improvements in DAA regimens are likely to be incremental and do not warrant delaying access until “perfectovir” appears—instead, the focus should be directed towards working with affected communities, scaling up and linking prevention and treatment programmes, building capacity among non‐specialist providers to deliver these simplified regimens,92 The real challenge is no longer curing hepatitis C—it is getting treatment to the millions of people who need it, as soon as possible. References 1 Wang CC, Krantz E, Klarquist J, et al. Acute hepatitis C in a contemporary US cohort: modes of acquisition and factors influencing viral clearance. J Infect Dis. 2007 Nov 15;196(10):1474‐82. Skip to main content 2 Adinolfi LE, Nevola R, Lus G, et al. Chronic hepatitis C virus infection and neurological and psychiatric disorders: An overview. World J Gastroenterol. 2015 Feb 28;21(8):2269‐2280. 3 Bladowska J, Zimny A, Knysz B, et al. Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV‐positive patients: a pilot study. J Hepatol. 2013 Oct;59(4):651‐7. doi: 10.1016/j.jhep.2013.05.008. 4 Cacoub P, Gragnani L, Comarmond C, Zignego AL. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014 Dec 15;46 Suppl 5:S165‐73. doi: 10.1016/j.dld.2014.10.005. 5 Thames AD, Castellon SA, Singer EJ, et al. Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C. Neurol Neuroimmunol Neuroinflamm. 2015 Jan 14;2(1):e59. doi: 10.1212/NXI.0000000000000059.
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