New Drugs, New Strategies: Conquering Hepatitis C with Direct-Acting Antivirals
By Tracy Swan
Hepatitis C has to be one of the most grossly miscalculated diseases by
governments on the planet.
—Michel Kazatchkine, UN secretary general’s special envoy on HIV/AIDS in Eastern Europe and Central Asia and commissioner, Global Commission on Drug Policy
The evolution of hepatitis C virus (HCV) treatment has been swift, dazzling, and unprecedented. In only five years, proof of concept for oral, interferon-free treatment has been established, nine direct-acting antivirals (DAAs) have been approved, treatment duration has been shortened to 12 weeks, and cure rates have been nearly 100% in clinical trials.1,2,3,4
Scaling up access to these wonder drugs – and primary prevention – could eliminate HCV, even without a vaccine. Unfortunately, sky-high DAA prices have created a paradox: the more treatment improves, the fewer people have access to it.
A public health approach will be needed to select, procure, and deliver HCV treatment. It is time to pick a first-line regimen, consider options for second-line treatment, and turn up the pressure for universal access to HCV treatment.
HCV Treatment Rationing
What is a cynic? A man who knows the price of everything and the value of nothing.
Worldwide, 185 million people have been infected with hepatitis C; 73% of them live in middle-income countries (MICs).5 Pharmaceutical companies see MICs as emerging markets, even though they are home to the “bottom billion” – 73% of the world’s poorest people.6 MIC governments cannot afford DAAs for everyone who needs them.
The price of DAAs in the United States should not be the benchmark anywhere – even in the United States. In high-income countries (HICs), payers have been withholding treatment for hepatitis C, citing sofosbuvir’s scandalous launch price (US$1,000 per pill). People who drink alcohol or who use and inject drugs are often ineligible for treatment.
HCV guidelines have been deliberately misinterpreted to justify withholding treatment. DAAs are given only to people with advanced liver disease, to stave off liver cancer, liver failure, transplantation, and death. Limiting HCV treatment access to people with advanced liver damage will stem liver-related mortality, but not epidemics.
HCV Disease Burden and Treatment Access in Egypt
Egypt has the world’s highest HCV prevalence: more than 7%.7,8 In 2006, the country instituted a national hepatitis C program. Since 2008, it has provided treatment for nearly 200,000 people. In 2014, Egypt’s government negotiated with Gilead and Janssen to obtain volume-based discounts on their DAAs. Companies can charge higher prices on the private market, where uninsured Egyptians buy their own medicine. In Egypt, 85% of drugs are paid for out of pocket.9
Most Egyptians cannot afford HCV treatment. It is a middle-income country where the per capita gross national income (GNI) is US$3,140 – but more than 25% of Egyptians live on less than US$600 a year.10,11 On the private market, a month of sofosbuvir (Sovaldi) costs EGP2,670 (US$350); simeprevir costs EGP3,166 (US$414).12,13,14 Government prices are much lower: sofosbuvir costs EGP1,400 (US$184) per month; simeprevir costs EGP1,900 (US$248).12,13
The government provides free treatment to people who are unable to afford it, but it cannot do so for millions of people. In 2015, Egypt plans to treat 100,000 people through the national program.15,16
Rationing HCV treatment is a stopgap, not a solution – for several reasons:
- If HCV treatment is withheld for too long, it is less effective, and adverse events are worsened.17,18
- People with HCV-related cirrhosis remain at risk for liver cancer – even after being cured – and must undergo lifelong monitoring. Earlier treatment removes this risk.19,20
- HCV lowers quality of life and might cause or worsen many systemic health problems, even in the absence of serious liver disease.21,22,23,24,25,26,27,28
- HCV increases health care costs and hospitalization rates, even in people with mild-to-moderate liver disease.29,30,31,32
- Chronic HCV infection is associated with a higher incidence of non-liver-related comorbidities (alcohol and substance use disorders, mental illness, chronic kidney disease, obesity, metabolic disorders, pneumonia, and HIV) in people who are 45 to 64 years old.33
- People with HCV are dying two decades earlier from non-liver-related causes (including cardiovascular disease and respiratory failure) than people without HCV.34
- Many state-funded programs in the United States withhold HCV treatment from people who use alcohol. Withholding treatment based on alcohol use or dependence is harmful because alcohol accelerates HCV liver damage.34
- There is no evidence that alcohol use during DAA treatment impairs efficacy (or safety).
- People who inject drugs are often ineligible for HCV treatment, although they are the highest-prevalence population. Worldwide, HCV prevalence among people who inject drugs is estimated at 67%; anywhere from 6 million to 15 million of them have chronic HCV.35
- Likelihood of HCV reinfection is often a rationale for withholding treatment, although actual reinfection rates are low.36
- People who inject drugs are often ineligible for HCV treatment because of concerns about poor adherence and treatment outcomes. But cure rates in injection drug users are similar to those in nonusers.37,38
- Withholding treatment allows HCV to keep spreading, especially among people who inject drugs (since access to injection equipment, methadone, and buprenorphine are woefully inadequate).
- Larger volume and competition between originators and generic drug producers can be leveraged to reduce prices. DAA prices have rapidly dropped by over 40% in some countries.39,40,41,42 Still, these prices are unsustainable, even for HICs.
Competition, negotiations, and volume-based discounts have begun to bring down originator DAA prices in HICs. Gilead is expected to drop U.S. DAA prices by 46% or more in 2015.41 Financial analysts estimate that DAA prices will drop to US$45,000 per treatment course in the United States and US$35,000 in HICs elsewhere.41
In France and Germany, sofosbuvir alone costs €488 per pill (US$550), or €41,000 (US$46,248) for a 12-week treatment course.39,42 In Spain, sofosbuvir costs €297 (US$335) per pill, or €25,000 (US$28,200) for a 12-week treatment course.40 No information about E.U. prices for simeprevir and daclatasvir (DAAs often used with sofosbuvir) is publicly available.
In 2012, worldwide sales of hepatitis C treatment reached US$4.4 billion and were projected to reach US$10.8 billion by 2022.43 In just one year, sofosbuvir sales have reached US$10.8 billion.44 Lack of access to these lifesaving medicines has sparked outrage. Since sofosbuvir was approved, patent challenges, government inquiries, lawsuits, sit-in protests at hospitals, and massive demonstrations have sprung up worldwide.
The right to health and clinical evidence should inform access to HCV treatment. Withholding treatment for a curable infectious disease is not justifiable, particularly for one that is often chronic, known to worsen overall health, and potentially life-threatening.
HCV Treatment Strategies: Less Knowledge, More Options
We can’t make perfectovir the enemy of goodovir.
—Jennifer Cohn, medical director, Médicines Sans Frontières/Doctors Without Borders Access Campaign
Three decades of antiretroviral drug development for HIV have been augmented by research from publicly funded networks, public-private partnerships, postmarketing trials, registries, and other sources. This robust evidence base informs treatment strategies and guidelines. But HCV DAAs are coming in a very short time frame; there are many choices – but far less knowledge about them. Although real-life data are emerging from registries, compassionate use/early access programs, and postmarketing studies, most of what we know about HCV DAAs comes from registration trials in HICs.
For now, optimizing DAA treatment means selecting the best available regimen and devising a follow-up strategy for new DAAs – or treatment failure (see figure 1).
Goodovir: Sofosbuvir and Daclatasvir
HCV “perfectovir” does not exist – yet.45 But hepatitis C treatment is already “goodovir” – and it is not likely to improve enough to justify waiting for perfectovir.
Sofosbuvir and daclatasvir together constitute a once-daily, multigenotypic regimen. These DAAs have been effective, safe, and tolerable for thousands of people (including in liver transplant candidates and recipients or HIV/HCV coinfection) (see table 1).46,47,48
There is no reason to delay HCV treatment scale-up. A first-line regimen of sofosbuvir and daclatasvir (possibly plus ribavirin [RBV] for people with cirrhosis) will simplify procurement and delivery of HCV treatment. It can be profitably mass-produced for less than US$175.49
Table 1. Goodovir and the Future Perfectovir 1,2,3,4,46,47,48,50,51,52,53,54,55,56,57,58,59,60,61,62
REGIMEN, STATUS, MANUFACTURER
Used in HIV
YES (laboratory data only for
Possibly, with RBV in cirrhosis (especially G3)
YES, except in
RBV may be needed to boost cure rate in cirrhosis (especially for genotype 3)
YES, except in G2 and
Longer treatment needed in cirrhosis; RBV needed for G3
NO (unless sofosbuvir is added)
NO; less effective in G2; high failure rate in G3; indication sought for G1, G4, and G6
Adding sofosbuvir significantly increased efficacy in G3
Depends on duration of treatment, genotype, cirrhosis
Phase II data only
Phase II data only
BMS: Bristol-Myers Squibb
FDC: fixed-dose combination
G: genotype (as in G1, G2, G3, G4, G5, G6)
SVR: sustained virologic response; undetectable HCV RNA 12 or 24 weeks after finishing treatment, equivalent to cure
QD: once daily
HCV Drug Resistance
Resistance-associated variants (RAVs) occur naturally in people who have never been treated for hepatitis C. During DAA treatment, RAVs can persist or emerge. In clinical trials, most people with pretreatment RAVs were cured – but RAVs are found in most people who were not cured. The prevalence, longevity, and impact of RAVs differ. Some RAVs have greater impact on drug potency than others.
Baseline resistance testing is not done outside of HCV clinical trials since it is expensive and not always predictive of treatment outcomes.
The barrier to resistance varies by class and individual DAA. NS5A inhibitors, although potent, have a low resistance barrier. Many people with pretreatment NS5A RAVs have been cured by an NS5A-containing regimen – but people who are not cured are likely to have NS5A RAVs. In the C-EDGE, ION-1, ION-2, and ION-3 trials of NS5A-containing regimens, most people who were not cured had NS5A RAVS before and after treatment.1,2,3,53,62 In these trials, treatment failure occurred only in people with an HCV RNA >800,000 IU/mL, suggesting that NS5A RAVs are more likely with a high viral load.
Treatment-emergent NS5A RAVs are persistent for 96–170 weeks after treatment failure.63,64,65,66
Second-generation NS5A inhibitors might be able to overcome resistance.67
NS3 resistance (protease inhibitors)
With HCV protease inhibitors, treatment-emergent RAVs tend to wane within months.63 People who were not cured by a protease inhibitor–based regimen can be successfully re-treated with DAAs from different classes or with a regimen including a second-generation HCV protease inhibitor with a different resistance profile.2,68,69
NS5B resistance (sofosbuvir)
Sofosbuvir has a high resistance barrier and can be recycled in re-treatment regimens. In one trial, 98% (44/45) of sofosbuvir-experienced people were cured by a sofosbuvir-based re-treatment regimen.70 Although rare, sofosbuvir treatment failure with baseline or emergent RAVs has been documented (especially in genotype 1b).71,72,73,74
HCV Treatment in HIV/HCV Coinfection
With DAAs, cure rates do not differ by HIV status, although drug-drug interactions between antiretroviral therapy and HCV treatment need to be avoided or managed.
New HCV Treatment Strategies
Approximately 90% of people are cured by sofosbuvir and daclatasvir (with or without ribavirin); the remaining 10% will need a second-line regimen. There is still a robust HCV pipeline to pluck for second-line DAAs.
Although HCV treatment is moving toward pangenotypic regimens, current strategies are still based on genotype (and sometimes subtype), treatment history, and extent of liver damage. Re-treatment options are limited, especially in genotypes 2 and 3. If pipeline DAAs live up to expectations, it will be possible to select interferon-free first- and second-line regimens.
Figure 1. Current and Proposed Interferon-Free HCV DAA Treatment Strategies
Current first-line strategies for HCV genotype 1
- Nucleotide + NS5A inhibitor, with or without RBV
- Protease inhibitor + NS5A inhibitor + non-nucleoside inhibitor, with or without RBV (complexity, subgenotyping, drug interactions, and RBV use may limit this approach)
- Nucleotide + protease inhibitor (also HCV genotype 4; high DAA prices may limit use of this combination)
Current first-line strategies for HCV non-1 genotypes
- Nucleotide + RBV (suboptimal efficacy in G3/cirrhosis)
- Nucleotide + NS5A inhibitor, with or without RBV (RBV may increase efficacy in G3/cirrhosis)
- For G4, protease inhibitor + NS5A inhibitor, with or without RBV
Next-generation, first-line strategies for all HCV genotypes
- Nucleotide + NS5A inhibitor, with or without RBV (NS5A resistance may limit efficacy)
- 12 weeks (or less) of a pangenotypic, triple-class regimen (NS5A inhibitor + protease inhibitor + nucleotide polymerase inhibitor).
The drawback: this strategy limits options for second-line treatment unless second-generation NS5A and protease inhibitors are effective against RAVs
Future retreatment strategies for all HCV genotypes
- Pangenotypic protease inhibitor (preferably active against RAVs) + nucleotide (for people with NS5A RAVs)
- Pangenotypic protease inhibitor + pangenotypic NS5A inhibitor; both must be effective against NS3 and NS5A RAVs; these could be paired with a nucleotide
DAAs and Diagnostic Simplification
Costly, complex diagnostic and monitoring requirements are also barriers to HCV treatment, particularly in resource-limited settings. DAAs and innovative diagnostics will make it simpler to identify people with chronic HCV, treat them, and cure them (see figure 2).
- Pre- and posttreatment HCV core-antigen tests could replace anti-HCV and HCV RNA tests.75
- Safety monitoring can be less intensive, since adverse event rates are lower and duration of treatment is shorter with DAAs versus interferon.49
- Routine blood tests can be used for pretreatment assessment, identifying people with advanced liver damage (such as APRI or FIB-4), and safety monitoring during treatment.76
- Pangenotypic regimens will eliminate the need for pretreatment HCV genotyping and subtyping.
Figure 2. HCV Diagnostics, Assessment for Treatment, and Efficacy Monitoring:*
High-Income Country Recommendations versus a Streamlined Process for
High-Income Country Recommendations
HCV antibody testing (to screen)
HCV RNA (to diagnose; with some regimens, may determine duration of treatment and, possibly, whether to add another DAA)
Genotyping/subtyping (to select regimen and duration)
Assess liver damage (to inform duration of treatment)
Assess overall health* (for safety)
HCV RNA testing during and after treatment (to monitor treatment adherence, efficacy, and outcome)
Streamlined Process for Resource-Limited Settings
Core antigen (to diagnose HCV)
Assess overall health* and liver damage with routine blood tests (to inform regimen selection and safety monitoring)
Select pangenotypic DAA regimen with fixed duration of treatment (and potential for re-treatment, with longer duration or second-line regimen)
Monitor according to DAA safety profile and patient health
Adherence education, support, counseling
Core-antigen testing 12 or 24 weeks after EOT (to check treatment outcome)
*Additional pretreatment testing is recommended (including pregnancy testing; complete blood count; international normalized ratio; renal function; and levels of albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase).
EOT: end of treatment
HCV Drug Development and Pipeline Strategies
HIV treatment strategies are based on data from industry-sponsored clinical trials, cohort studies, government-funded research networks, public-private partnerships, and investigator-initiated trials. For decades, drugs from different companies have been combined in trials, clinical practice, and fixed-dose combinations (FDCs) from generic and originator companies.
Pharmaceutical companies mastermind DAA development. Clinical collaborations are rare. Incestuous DAA combinations are usually co-formulated to prevent use with a competitor’s drug. Other market-driven strategies have delayed or prevented research into and development of optimal DAA combinations.
HCV drug development continues at breakneck speed. DAAs in early development promise to be pangenotypic and active against common RAVs. There is a trend to shorten treatment with multiclass DAA regimens. Several companies are developing – or buying – nucleotide polymerase inhibitors. In the meantime, they are doing “proxy” trials, using sofosbuvir as a placeholder for their own DAAs.
Table 2. Shortening Treatment58,61,69,79,80,81
TRIAL, POPULATION, AND MANUFACTURER
REGIMEN, POPULATION, AND DURATION
G1, TX-naive (N = 30)
ACH-3102 50 mg + sofosbuvir 400 mg
Achillion used sofosbuvir as a placeholder for its own nucleotide polymerase inhibitor, ACH-3422 (currently in phase I)
G3, TX-naive (N = 104)
sofosbuvir 400 mg
+ GS-5186 25 mg or 100 mg
+/– weight-based RBV
+ 25 mg
This regimen has been studied in other populations. Gilead selected the 100 mg dose of GS-5816 for co-formulation with sofosbuvir; the FDC is currently in phase III
+ 25 mg & RBV
+ 100 mg
+ 100 mg & RBV
G1 and G2
noncirrhotic (N = 223)
sofosbuvir 400 mg
+ GS-5186 25 mg or 100 mg
+/– weight-based RBV
G1 + 25 mg
Longer duration of treatment with this regimen may increase efficacy
G1 + 25 mg & RBV
G1 + 100 mg
G1 + 100 mg & RBV
G2 + 25 mg
G2 + 25 mg & RBV
G2 + 100 mg
G2 + 100 mg & RBV
G1, TX-naive or
+ GS-9857 100 mg
Longer treatment and RBV might be needed in cirrhosis, especially in people who are treatment-experienced
TX-naive + cirrhosis
DAA-experienced + cirrhosis
G1 and G3, TX-naive Noncirrhotic and cirrhotic (N = 143)
+ sofosbuvir 400 mg
Merck is using sofosbuvir as a placeholder for MK-3682 (currently in phase II)
This regimen was less effective for HCV RNA >2,000,000 IU/mL (85% vs. 100%)
G1 + cirrhosis
G1 + cirrhosis
G3 + cirrhosis
G1, TX-naive (N = 60)
sofosbuvir/ledipasvir 400 mg/90 mg FDC
SYNERGY led the way for trials of shorter, multiclass regimens
Gilead has not used GS-9669 or GS-9451 in other trials
sofosbuvir/ledipasvir 400 mg/90 mg FDC
sofosbuvir/ledipasvir 400 mg/90 mg FDC
*modified intent-to-treat analysis; 5 people excluded for nonvirological failure
ACH-3102 (NS5A inhibitor); elbasvir (NS5A inhibitor); grazoprevir (protease inhibitor); GS-5186 (NS5A inhibitor); GS-9451 (protease inhibitor); GS-9669 (non-nucleoside polymerase inhibitor); GS-9857 (protease inhibitor); ledipasvir (NS5A inhibitor); sofosbuvir (nucleotide polymerase inhibitor)
FDC: fixed-dose combination
QD: once daily
SVR: sustained virological response
Company-Specific Strategies for DAA Development
AbbVie is developing ABT-530 (an NS5A inhibitor) and ABT-493 (a protease inhibitor). In preclinical studies, ABT-530 was active against many NS5A RAVs and pangenotypic; ABT-493 was active against HCV genotypes 1, 2, 3 (especially 3a), 4, and 6 – and common NS3 RAVs.82,83 These drugs are being studied with or without RBV in phase II trials of all HCV genotypes. An April 8 press release announced a 99% sustained virological response four weeks after treatment (SVR-4) from a phase II trial combining these DAAs.84
If AbbVie’s pipeline DAAs live up to their pangenotypic, resistance-proof promise, they could be part of second-line treatment. ABT-493 could be paired with sofosbuvir for a pangenotypic re-treatment regimen; if ABT-530 is effective against RAVs, it could be used with sofosbuvir or ABT-493.
Bristol-Myers Squibb (BMS)
Data from thousands of people have supported the safety, tolerability, and efficacy of daclatasvir. Hopefully, it will be available – and affordable – worldwide; it is urgently needed for a pangenotypic first-line regimen.
Daclatasvir’s approval – and BMS’s overall HCV drug development program – has been stymied by bad luck, inopportune timing, and bold decisions that should have been cautious (and vice versa). The future of the BMS HCV program and its twice-daily, RBV-free TRIO regimen is uncertain. Although SVR in genotype 1b is 98%, TRIO is less effective for genotype 1a than other RBV-free treatment options (SVR: 89% in noncirrhotic; 88% in cirrhotic).85,86
Gilead’s drug development program has been swift, flexible, efficient – and ruthless. The company is seeking to shorten treatment with once-daily, multiclass, pangenotypic FDCs. Gilead’s FDC of sofosbuvir and GS-5816 (an NS5A inhibitor) is in phase III. It remains to be seen whether GS-5816 has advantages over daclatasvir (aside from being owned by Gilead). The company is also developing a triple-class combination with the sofosbuvir/GS-5816 FDC and GS-9857 (a protease inhibitor), currently in phase II.
Sofosbuvir has been the backbone of short-course regimens (with grazoprevir/elbasvir; Achillion’s NS5A inhibitor, ACH-3102; and Gilead’s own drugs, ledipasvir, GS-9669 [a non-nucleoside polymerase inhibitor], or GS-9451 [a protease inhibitor]) (see table 2). Coming up with a short, cure-all regimen has proved to be tricky: six weeks of Gilead’s triple-class regimen cured 93% (14/15) of treatment-naive people with HCV genotype 1, but only 68% (17/25) of DAA-experienced people.69
At the end of 2013, results from the phase II COSMOS trial were used to recommend off-label use of simeprevir with sofosbuvir for genotype 1.87 Since then, simeprevir has been used in HIV/HCV, cirrhosis, after liver or kidney transplantation, in HCV genotype 4, and with daclatasvir.88,89,90,91,92,93,94,95
Janssen will continue to develop DAAs, with a focus on nucleotides. The company has an NS5A inhibitor, JNJ-56914845, in phase II. In November 2014, it purchased Alios BioPharma and acquired two nucleotides: AL-335 (currently in phase I) and AL-516 (currently in preclinical development). In May 2015, Janssen announced a licensing agreement with Achillion, which is developing ACH-3102 (an NA5A inhibitor in phase II) and ACH-3422 (a nucleotide in phase I). Medivir, a past development partner of Janssen’s, has a nucleotide (MIV-802) in preclinical development.
Merck’s nautically themed development program for the grazoprevir/elbasvir FDC was bedeviled by dosing problems with grazoprevir and loss of “breakthrough therapy” designation from the U.S. Food and Drug Administration (although Merck subsequently regained it).
It was nearly impossible to figure out the combined impact of host and viral factors, regimen, and duration on SVR in Merck’s phase II, multiarm C-WORTHY trial. In phase III trials, a fuller picture of the strengths and vulnerabilities of the FDC emerged. Cure rates in genotype 1b and genotype 4 have been >90%, regardless of HIV status, treatment experience, or cirrhosis.53,59,62,68 In the oddly named C-SURFER trial, 12 weeks of grazoprevir/elbasvir cured 94% (115/122) of people with HCV genotype 1 and end-stage renal disease, a population with few options and urgent need for HCV treatment.96 The FDC was less effective against genotype 1a – especially for people with baseline NS5A RAVs known to lower elbasvir potency more than fivefold.53,62,68 In the C-EDGE treatment-naive trial, overall SVR in HCV genotype 1a was 92% (144/157). It dropped to 58% (11/19) among people with baseline NS5A RAVs and was even lower in people with RAVs associated with lower elbasvir potency (22%; 2/9).62 In the C-EDGE treatment-experienced trial, SVR dropped from >90% in genotype 1a to 52% (11/21) in people with baseline NS5A RAVs that lower the potency of elbasvir more than fivefold.53
On May 28, Merck announced submission of a new drug application for the FDC in genotypes 1, 4, and 6 (the FDC underperformed in genotypes 2, 3, and 5).51,97,98
Merck has a strategy beyond launching the FDC: to shorten treatment, with a multiclass regimen. In C-SWIFT, sofosbuvir was added to the FDC for four to 12 weeks of treatment. SVR topped 90% in people with genotype 1 and cirrhosis after only eight weeks of treatment; in people with genotype 3 and cirrhosis, SVR was >90% after 12 weeks of treatment (see table 2).58
Merck has DAAs to advance this strategy: MK-8408, a second-generation NS5A that was pangenotypic and active against drug resistance in laboratory studies, and MK-3682, a nucleotide polymerase inhibitor Merck acquired with its 2014 purchase of Idenix.99 Based on proof of concept from phase I and C-SWIFT, Merck’s trials are combining grazoprevir and MK-3682 with elbasvir or MK-8408 for six to eight weeks in ongoing phase II studies in HCV and HIV/HCV, genotypes 1, 2, 3, 4, and 6.58,100
Company-Specific Access Strategies for Low- and Middle-Income Countries
World CAB Meeting
In February 2014, the first WORLD CAB meeting was held in Bangkok, Thailand, where activists from low- and middle-income countries (LMICs) met with representatives from AbbVie, BMS, Gilead, Janssen, Merck, and Roche to discuss HCV treatment access. During the meeting, company representatives insisted that access in LMICs would not be possible without a global funding mechanism (such as the U.S. President’s Emergency Plan for AIDS Relief or the Global Fund to Fight AIDS, Tuberculosis and Malaria) and that governments needed to “show commitment by scaling up HCV treatment programs before obtaining price reduction.”101
AbbVie has not disclosed access plans for LMICs. According to a statement on its website from Richard A. Gonzalez, AbbVie’s chairman and CEO, the company is “committed to improving lives, and we pledge to go about it in a transparent and sustainable way.”102
A corporate responsibility brochure describes AbbVie’s philanthropic initiatives, including a US$100 million investment in “state-of-the art manufacturing facilities to ensure patients receive a consistent supply of our HIV products”; the “Week of Possibilities” (an adult volunteer program to “transform educational spaces” and “support patients”); and AbbVie Foundation grants for pediatric AIDS, Buruli ulcer detection programs, and disaster relief, but it says nothing about hepatitis C.103
In November 2014, BMS announced its plans for a “Hepatitis C (HCV) Developing World Strategy.” The company plans to offer tiered pricing and grant voluntary licenses (VLs) to 90 LMICs – including places where the drug is not patented.104 Médicines Sans Frontières/Doctors Without Borders (MSF) has described the BMS plan as “a restrictive commercial strategy for sales of its new direct-acting antiviral (DAA) hepatitis C drug daclatasvir in developing countries.”105
Notably, BMS has not offered VLs to high-burden MICs such as China, Brazil, Egypt, Thailand, and Ukraine. In fact, 50 million people with HCV live in countries where BMS is not offering VLs.5 Although the country has “initiated discussions with government health authorities and other stakeholders,” there is no additional information on plans to license, register, and price daclatasvir.
Gilead has not offered VLs to certain high-burden MICs where there are over 50 million people with HCV.5,106 This means that generic DAAs cannot be sold in these countries. Gilead has blocked other pathways by limiting access to the raw ingredients for its drugs. Gilead’s licensees must purchase them from certain suppliers, who are not allowed to sell them to unlicensed generic drug producers. Gilead’s extortionate pricing in HICs, unwillingness to provide HCV treatment access to millions of people in MICs, and unethical antidiversion measures (which would not be necessary if its drugs were affordable) are unacceptable.
Janssen’s website features a global public health section that does not mention hepatitis C.107 Johnson & Johnson’s “Strategic Framework” does not mention HCV. Another part of the company’s website (“Pricing Strategies and Programs”) describes “strategic, innovative and equitable pricing strategies for a wide variety of diseases” and the access strategy of “a tiered pricing model based on a combination of a country’s economic conditions and public health situation.”108,109
Merck’s website does not provide any HCV-specific access information.
The company’s “Statement of Guiding Principles” cites Merck’s commitments to research and development, manufacturing and supply, registration, and community investment. Expectations are managed: “While we cannot address complex public health challenges on our own, we will engage in community investment to address the barriers to access where we believe we can make the strongest contributions.”110
The Medicines Patent Pool and HCV
The Medicines Patent Pool (MPP) is considering expanding its mandate to include negotiating VLs for tuberculosis and hepatitis C. But the MPP has not announced a strategy, goal, or vision for increasing access to DAAs.
MSF has released a statement of support for the MPP’s entry into HCV, contingent on consideration of “key issues.”111
Activists have expressed deep concerns about the MPP entering the “HCV space”:
- The MPP’s VLs for HIV treatment have excluded most MICs, where access to HCV treatment is needed most. The MPP has not disclosed plans to increase access to HCV treatment in MICs, including countries that have been excluded from the Gilead HCV licensing agreements.
- Unless the MPP can significantly broaden the geographic scope of the HCV VLs, it will have limited impact on access to HCV treatment.
- The MPP does not directly support other means to increasing access, including patent oppositions and TRIPS flexibilities (allowing countries to produce affordable medicines through a compulsory license, or to import medicines from countries where prices are lower). In fact, some MPP licenses may actually undermine legal TRIPS flexibilities.112
- The MPP’s existing HIV licensing agreements with Gilead have the same clauses as Gilead’s own HCV licenses; this lowers confidence that the MPP will be able to improve the terms of existing HCV VLs.110
- The MPP’s entry into HCV may discourage other community-led approaches, such as pushing governments to issue compulsory licenses. Brazil’s compulsory license for efavirenz saved US$100 million, which the country used to provide universal HIV treatment.113
- The MPP VLs will attract more generic drug producers. This will limit the remaining sources from which excluded countries can obtain generic DAAs and their raw ingredients.110
- The MPP has not made a public statement about the antidiversion measures initially included in Gilead’s HCV VLs. These included requiring proof of identity, residence, and citizenship; issuing a one-month supply of medicine in a smartphone-enabled, coded pill bottle that tracks patients by name, address, and adherence; and refusing to refill medication until empty pill bottles were returned to the local distributor. MSF has issued a briefing document that calls on Gilead to remove these measures.114
- VLs are not needed in countries where drugs are not patented. If the MPP offers them, ongoing patent oppositions in LMICs may be undermined.
- DAAs are covered under patents for years to come: daclatasvir until 2027, sofosbuvir until 2029.115 Each year, 700,000 people die from HCV-related liver disease.116 Delaying access to DAAs in LMICs until patent expiry will cost millions of lives.
The same strategies that have led to dramatic price reductions for HIV treatment must be used to provide a cure for millions of people with hepatitis C in LMICs. Generic DAAs can be profitably – and affordably – mass-produced for less than US$200 per treatment course.49,117
Curing hepatitis C with safe and effective oral drugs is now possible. The challenge is to secure universal access to HCV treatment and deliver DAAs to the millions of people who need them.
Thanks to Jules Levin and NATAP.
AASLD: American Association for the Study of Liver Diseases
CROI: Conference on Retroviruses and Opportunistic Infections
EASL: European Association for the Study of the Liver
Unless noted otherwise, all links were accessed in May 2015.
- Afdhal N, Zeuzem S, Kwo P, et al.; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889–98. doi: 10.1056/NEJMoa1402454.
- Afdhal N, Reddy KR, Nelson DR, et al.; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
N Engl J Med. 2014 Apr 17;370(16):1483–93. doi: 10.1056/NEJMoa1316366.
- Kowdley KV, Gordon SC, Reddy KR, et al.; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
N Engl J Med. 2014 May 15;370(20):1879–88. doi: 10.1056/NEJMoa1402355.
- Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014 Jan 16;370(3):211–21. doi: 10.1056/NEJMoa1306218.
- Mohd Hanafiah K, Groeger J, Flaxman AD, et al. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013 Apr;57(4):1333–42. doi: 10.1002/hep.26141.
- Sumner A. Global poverty and the new bottom billion: what if three-quarters of the world’s poor live in middle-income countries? Brighton (U.K.): Institute of Development Studies; 2010 November. http://www.ids.ac.uk/files/dmfile/Wp349.pdf.
- Dore GJ, Ward J, Thursz M. Hepatitis C disease burden and strategies to manage the burden. J Viral Hepat. 2014 May;21 Suppl 1:1–4.
- Doss W, Shiha G, Hassany M, et al. Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4. J Hepatol. 2015 Apr 30. doi: 10.1016/j.jhep.2015.04.023.
- World Health Organization. Egypt: country cooperation strategy at a glance. Geneva: World Health Organization; 2013.
- CAPMAS. Egypt’s poverty rate rises to 26% in 2012/2013. Ahram Online [Internet]. 2013 November 28.
- World Bank. Data: Egypt, Arab Republic.
- Currency conversions throughout this report were made with the converter at using the June 5, 2015, currency exchange rates.
- Al-Youm A. Health ministry: Sovaldi to be available in May at LE2,670 [Internet]. Egypt Independent. 2015 March 2.
- Al-Youm A. Hepatitis C drug ‘Olysio’ in Qalyubia as of Sunday [Internet]. Egypt Independent. 2015 May 22.
- Mada Masr. More than 100,000 Egyptians applied for ‘miracle’ hepatitis C drug [Internet]. Mada Masr. 2014 September 19.
- Wanis H. HCV treatment in Egypt: why cost remains a challenge? Egyptian initiative for personal rights. Cairo: Egyptian Initiative for Personal Rights; 2014 November.
- Pol S, Bourlière M, Lucier S, et al. Safety and efficacy of the combination daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients from the French observational cohort ANRS CO22 HEPATHER (Abstract LB3). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Saxena V, Nyberg L, Pauly M, et al. Safety and efficacy of simeprevir/sofosbuvir in hepatitis C infected patients with compensated and decompensated cirrhosis. Hepatology. 2015 Jun 1. doi: 10.1002/hep.27922. [Epub ahead of print]
- Aleman S, Rahbin N, Weiland O, et al. A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis. Clin Infect Dis. 2013 Jul;57(2):230–6. doi: 10.1093/cid/cit234.
- Lee YA, Friedman SL. Reversal, maintenance or progression: what happens to the liver after a virologic cure of hepatitis C? Antiviral Res. 2014 Jul;107:23–30. doi: 10.1016/j.antiviral.2014.03.012.
- 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):2269–80. doi: 10.3748/wjg.v21.i8.2269.
- Cacoub P, Gragnani L, Comarmond C, et 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.
- Ferri C, Sebastiani M, Giuggioli D, et al. Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin’s lymphoma, and cancer. World J Hepatol. 2015 Mar 27;7(3):327–43. doi: 10.4254/wjh.v7.i3.327.
- Grasso A, Malfatti F, Andraghetti G, et al. HOMA, BMI, and serum leptin levels variations during antiviral treatment suggest virus-related insulin resistance in noncirrhotic, nonobese, and nondiabetic chronic hepatitis C genotype 1 patients. Gastroenterol Res Pract. 2015;2015:975695. doi: 10.1155/2015/975695.
- Lai JC, Shoback DM, Zipperstein J. Bone mineral density, bone turnover, and systemic Inflammation in non-cirrhotics with chronic hepatitis C.
Dig Dis Sci. 2015 Jun;60(6):1813–9. doi: 10.1007/s10620-014-3507-6.
- Olubamwo OO, Onyeka IN, Miettola J, et al. Hepatitis C as a risk factor for carotid atherosclerosis – a systematic review. Clin Physiol Funct Imaging. 2015 Jan 26. doi: 10.1111/cpf.12229. [Epub ahead of print]
- Park H, Adeyemi A, Henry L, et al. A meta-analytic assessment of the risk of chronic kidney disease in patients with chronic hepatitis C virus infection. J Viral Hepat. 2015 Apr 22. doi: 10.1111/jvh.12413. [Epub ahead of print]
- 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.
- Grant WC, Jhaveri RR, McHutchison JG, et al. Trends in health care resource use for hepatitis C virus infection in the United States. Hepatology. 2005 Dec;42(6):1406–3.
- McCombs JS, Yuan Y, Shin J, et al. Economic burden associated with patients diagnosed with hepatitis C. Clin Ther. 2011 Sep;33(9):1268–80. doi: 10.1016/j.clinthera.2011.07.008.
- Myers RP, Liu M, Shaheen AA. The burden of hepatitis C virus infection is growing: a Canadian population-based study of hospitalizations from 1994 to 2004. Can J Gastroenterol. 2008 Apr;22(4):381–7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662896/.
- Oramasionwu CU, Toliver JC, Johnson TL, et al. National trends in hospitalization and mortality rates for patients with HIV, HCV, or HIV/HCV coinfection from 1996–2010 in the United States: a cross-sectional study. BMC Infect Dis. 2014 Oct 10;14:536. doi: 10.1186/1471-2334-14-536.
- Tong X, Spradling PR. Increase in nonhepatic diagnoses among persons with hepatitis C hospitalized for any cause, United States, 2004–2011.
J Viral Hepat. 2015 Apr 20. doi: 10.1111/jvh.12414. [Epub ahead of print]
- Ly KN, Xing J, Klevens RM, et al. Causes of death and characteristics of decedents with viral hepatitis, United States, 2010. Clin Infect Dis. 2014 Jan;58(1):40–9. doi: 10.1093/cid/cit642.
- Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet. 2011 Aug 13;378(9791):571–83. doi: 10.1016/S0140-6736(11)61097-0.
- Grebely J, Knight E, Ngai T, et al. Reinfection with hepatitis C virus following sustained virological response in injection drug users. J Gastroenterol Hepatol. 2010 Jul;25(7):1281–4. doi: 10.1111/j.1440-1746.2010.06238.x.
- Aspinall EJ, Corson S, Doyle JS, et al. Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis. Clin Infect Dis. 2013 Aug;57 Suppl 2:S80–9. doi: 10.1093/cid/cit30.
- Hellard M, Sacks-Davis R, Gold J. Hepatitis C treatment for injection drug users: a review of the available evidence. Clin Infect Dis. 2009 Aug 15;49(4):561–73. doi: 10.1086/600304.
- Palmer E. Gilead strikes sovaldi deal in Germany as it picks up speed in EU [Internet]. Fierce Pharma. 2015 February 13.
- Sevillano EG. “Spanish hepatitis C patients to march for access to expensive new drugs.” El Pais [Internet]. 2015 January 6.
- Silverman E. What the “shocking” Gilead discounts on its hepatitis C drugs will mean. Pharmalot (blog). 2015 February 4.
- Taylor P. France agrees lowest sovaldi pricing in EU [Internet]. 2014 November 21. PMLiVe. .
- Gohil K. Huge growth seen in hepatitis C market. P T. 2014 Jul;39(7):517.
- Gilead Sciences (Press Release). Gilead Sciences announces fourth quarter and full year 2014 financial results. 2015 February 4.
- Dore GJ, Feld JJ. Hepatitis C virus therapeutic development: in pursuit of “perfectovir.” Clin Infect Dis. 2015 Jun 15;60(12):1829–36.
- Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir, sofosbuvir and ribavirin combination for HCV patients with advanced cirrhosis or post-transplant recurrence: ALLY-1 phase 3 study (Abstract L08). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Wyles D, Ruane P, Sulkowski MS, et al. Daclatasvir in combination with sofosbuvir for HIV/HCV coinfection: ALLY-2 study (Abstract 151LB). Paper presented at: 22nd CROI; 2015 February 23–24; Seattle, WA.
- Wyles DL, Ruane P, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for treatment of HCV genotypes 1-4 in HIV-HCV coinfection: the ALLY-2 study (Abstract LP01). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- van de Ven N, Fortunak J, Simmons B, et al. Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus. Hepatology. 2015 Apr;61(4):1174–82. doi: 10.1002/hep.27641.
- Abergel A, Loustaud-Ratti V, Metivier S, et al. Ledipasvir/sofosbuvir for the treatment of patients with chronic genotype 4 or 5 HCV infection (Abstract 0056). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Brown A, Hézode C, Zuckerman E, et al. C-SCAPE: efficacy and safety of 12 weeks of grazoprevir ± elbasvir ± ribavirin in patients with HCV G2, 4, 5 or 6 infection (Abstract PO771). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. .
- Gane EJ, Hyland RH, An D, et al. Ledipasvir/sofosbuvir fixed-dose combination is safe and effective in difficult-to-treat populations including GT 3 patients, decompensated GT 1 patients, and GT 1 patients with prior sofosbuvir experience (Abstract O6). Paper presented at: 49th EASL; 2014 April 9–13; London, England.
- Kwo P, Gane E, Pang C-Y, et al. Efficacy and safety of grazoprevir/elbasvir +/-RBV for 12 or 16 weeks in patients with HCV G1, G4 or G6 infection who previously failed peginterferon/RBV: C-EDGE treatment-experienced (Abstract PO886). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. .
- Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015 Mar 21;385(9973):1075–86. doi: 10.1016/S0140-6736(14)61795-5.
- Naggie S, Cooper C, Saag MS, et al. Ledipasvir/sofosbuvir for 12 weeks in patients coinfected with HCV and HIV-1 (Abstract 152LB). Paper presented at: 22nd CROI; 2015 February 23–24; Seattle, WA.
- Nelson DR, Cooper JN, Lalezari JP, et al.; ALLY-3 Study Team. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015 Apr;61(4):1127–35. doi: 10.1002/hep.27726.
- Pianko S, Flamm SL, Shiffman ML, et al. High efficacy of treatment with sofosbuvir + GS-5816 ± RBV for 12 weeks in treatment-experienced patients with genotype 1 or 3 HCV infection (Abstract 197). Paper presented at: 65th AASLD; 2014 November 7–11; Boston, MA.
- Poordad F, Lawitz E, Gutierrez J, et al. C-SWIFT: grazoprevir/elbasvir + sofosbuvir in cirrhotic and noncirrhotic, treatment naive patients with hepatitis C genotype 1 infection for durations of 4, 6 or 8 weeks and genotype 3 infection for durations of 8 or 12 weeks (Abstract O006). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Rockstroh JK, Nelson M, Katlama C, et al. C-EDGE coinfection: phase 3 study of grazoprevir/elbasvir in patients with HCV/HIV (Abstract P0887). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Sulkowski M, Hézode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015 Mar 21;385(9973):1087–97. doi: 10.1016/S0140-6736(14)61793-1.
- Tran TT, Morgan TR, Thuluvath PJ, et al. Safety and efficacy of treatment with sofosbuvir + GS-5816 ± ribavirin for 8 or 12 weeks in treatment-naive patients with genotype 1-6 infection (Abstract 80). Paper presented at: 65th AASLD; 2014 November 7–11; Boston, MA.
- Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med. 2015 Apr 24. doi: 10.7326/M15-0785. [Epub ahead of print]
- Krishnan P, Tripathi R, Schnell G, et al. Long-term follow-up of treatment-emergent resistance-associated variants in NS3, NS5A and NS5B with paritaprevir/r-obmitasvir- and dasabuvir-based regimens (Abstract 0057). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. http://www.natap.org/2015/EASL/EASL_38.htm.
- McPhee F, Hernandez D, Yu F, et al. Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir. Hepatology. 2013 Sep;58(3):902–11. doi: 10.1002/hep.26388.
- Yoshimi S, Imamura M, Murakami E, et al. Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J Med Virol. 2015 May 8. doi: 10.1002/jmv.24255. [Epub ahead of print]
- Wyles D, Mangia A, Cheng W, et al. Long-term persistence of HCV NS5A variants after treatment with NS5A inhibitor ledipasvir (Abstract 0059). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Patel D, Zhao Y, Fabryck J et al. Achievement of SVR24 despite the presence of HCV variants resistant to first-generation NS5A inhibitors in genotype-1 hepatitis C patients after 8-week therapy of ACH-3102 in combination with sofosbuvir (Abstract PO805). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Forns X, Gordon SC, Zuckerman, E et al. Grazoprevir/elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. J Hepatol. 2015 Apr 17. doi: 10.1016/j.jhep.2015.04.009. [Epub ahead of print]
- Gane EJ, Hyland RH, Yang Y, et al. Safety and efficacy of short-duration treatment with GS-9857 combined with sofosbuvir/GS-5816 in treatment-naïve and DAA-experienced patients with and without cirrhosis (Abstract LPO3). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. http://www.natap.org/2015/EASL/EASL_37.htm.
- Wyles D, Pockros P, Morelli G, et al. Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens. Hepatology. 2015 Jun;61(6):1793–7. doi: 10.1002/hep.27814.
- 50th EASL; 2015 April 22–26; Vienna, Austria.
- Svarovskaia ES, Dvory-Sobol H, Parkin N, et al. Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis. 2014 Dec 15;59(12):1666–74. doi: 10.1093/cid/ciu697.
- Svarovskaia ES, Zeuzem S, Hedskog C, et al. Prevalence of pretreatment NS5A and NS5B resistance-associated variants and genetic variations within HCV subtypes across different countries (Abstract PO894). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Wilson EP, Kattakuzhy S, Sims Z, et al. High efficacy of retreatment with ledipasvir and sofosbuvir in HCV patients who failed initial short course therapy with combination DAA regimens (NIH SYNERGY Trial) (Abstract LP09). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. http://www.natap.org/2015/EASL/EASL_69.htm.
- Cooke GS, Hill AM. Diagnostics for resource-limited settings in the era of interferon-free HCV therapy. J Viral Hepat. 2015 May;22(5):459–60. doi: 10.1111/jvh.12401.
- World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. Geneva: World Health Organization; 2014 April.
- European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2015 [Internet]. 2015 April.
- American Association for the Study of Liver Diseases, Infectious Diseases Society of America, International Antiviral Society–USA. Recommendations for testing, managing, and treating hepatitis C [Internet]. 2014 April 24 (updated 2014 December 19).
- Gane E, Schwabe C, Mader M, et al. Sustained virologic response after ACH-3102 and sofosbuvir treatment for 8 or 6 weeks: a phase 2 “proxy” study (Abstract PO17). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Gane EJ, Hyland RH, An D, et al. Once-daily sofosbuvir with GS-5816 with or without ribavirin in patients with HCV genotype 3 without cirrhosis result in high rates of SVR-12: the ELECTRON-2 study (Abstract 79). Paper presented at: 65th AASLD; 2014 November 7–11; Boston, MA.
- Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet. 2015 Mar 21;385(9973):1107–13. doi: 10.1016/S0140-6736(14)61228-9.
- Ng T, Krishnan P, Kati W, et al. ABT-530, an NS5A inhibitor with potent pangenotypic activity and a high barrier to resistance (Abstract 639). Paper presented at: 21st CROI; 2014 March 3–6; Boston, MA. http://www.natap.org/2014/CROI/croi_11.htm.
- Ng T, Reisch T, Middleton T, et al. ABT-493, a potent NS3/4A protease inhibitor with broad genotype coverage (Abstract 636). Paper presented at: 21st CROI; 2014 March 3–6; Boston, MA.
- AbbVie (Press Release). AbbVie to present new data from hepatitis C clinical development program at the International Liver Congress™ 2015. 2015 April 8. .
- Hézode C, Herring Jr R, Pockros P, et al. Effect of baseline factors on the response to the fixed-dose combination of daclatasvir, asunaprevir and beclabuvir, with or without ribavirin, in patients with HCV genotype 1 and cirrhosis (Abstract PO888). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Reddy KR, Beavers KL, Gordon S, et al. Effect of baseline factors on the response to the fixed-dose combination of daclatasvir, asunaprevir and beclabuvir in non-cirrhotic patients with HCV genotype 1 infection (Abstract P0889). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. http://www.natap.org/2015/EASL/EASL_119.htm.
- Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014 Nov 15;384(9956):1756–65. doi: 10.1016/S0140-6736(14)61036-9.
- Bhamidimarri K, Carrion AF, Peyton A, et al. Safety and efficacy of sofosbuvir and simeprevir treatment for hepatitis C genotype 1 in liver transplant recipients with advanced fibrosis and cirrhosis (Abstract PO042). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Brown RS, Reddy KR, O’Leary JG, et al. Safety and efficacy of new DAA-based therapy for hepatitis C post-transplant: interval results from the HCV TARGET longitudinal, observational study (Abstract LB-4). Paper presented at: 65th AASLD; 2014 November 7–11; Boston, MA.
- Fontaine H, Hézode C, Zoulim F, et al. Efficacy of the oral sofosbuvir-based combination in HCV genotype 4-monoinfected patients from the French observational cohort ANRS CO22 HEPATHER (Abstract LP28). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Kwo P, Gitlin N, Nahass R, et al. A phase 3, randomized, open-label study to evaluate the efficacy and safety of 12 weeks of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-naïve and -experienced patients with chronic HCV genotype 1 infection without cirrhosis: OPTIMIST-1 (Abstract LP14). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria. http://www.natap.org/2015/EASL/EASL_72.htm.
- Lawitz E, Matusow G, De Jesus E, et al. A phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-naïve or -experienced patients with chronic HCV genotype 1 infection and cirrhosis: OPTIMIST-2 (Abstract LP04). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- n treatment-naïve and treatment-experienced patients with chronic hepatitis C virus genotype 1 or 4 infection and decompensated liver disease: interim results from the phase II IMPACT study (Abstract LP07). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Lin M, Sise ME, Pavlakis M, et al. Safety and efficacy of novel antivirals in kidney transplant recipients with chronic hepatitis C virus (HCV) infection (Abstract LP42). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Mauss S, Inglitz P, Christiensen S, et al. German multicenter cohort on sofosbuvir-based treatment in HCV-mono and HIV/HCV co-infected patients (GECOSO) (Abstract P0835). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Roth D, Nelson D, Bruchfeld A, et al. C-SURFER: grazoprevir plus elbasvir in treatment-naïve and treatment-experienced patients with hepatitis C virus genotype 1 infection and chronic kidney disease (Abstract LP02). 50th EASL; 2015 April 22–26; Vienna, Austria.
- Merck (Press Release). Merck submits U.S. new drug application for grazoprevir/elbasvir, an investigational once-daily, single tablet combination therapy, for treatment of chronic hepatitis C genotypes 1, 4, and 6 infection. 2015 May 28.
- Gane EJ, Nahass R, Luketic V, et al. Efficacy of 12 or 18 weeks of grazoprevir plus elbasvir with ribavirin in treatment-naïve, noncirrhotic HCV genotype 3-infected patients (Abstract PO776). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Asante-Appiah E, Liu R, Curry S, et al. MK-8408, a potent and selective NS5A inhibitor with a high genetic barrier to resistance and activity against HCV genotypes 1-6 (Abstract 1979). Paper presented at: 65th AASLD; 2014 November 7–11; Boston, MA.
- Zhou X-J, Sicard E, Chen J, et al. A phase 1 study to evaluate the interaction of HCV NS5B inhibitor MK-3682 with HCV NS3/4A protease inhibitor MK-5172 and HCV NS5A inhibitor MK-8408 in healthy subjects (Abstract P0824). Paper presented at: 50th EASL; 2015 April 22–26; Vienna, Austria.
- Cousin O, Kaplan K. Pills cost pennies, greed costs lives. New York: Treatment Action Group; 2015 February. http://www.treatmentactiongroup.org/sites/g/files/g450272/f/201407/1st%20HCV%20World%20CAB%20Report.pdf.
- AbbVie. Responsibility: letter from the chairman and CEO. (date unknown). http://www.abbvie.com/responsibility/home.html.
- AbbVie. Corporate responsibility. North Chicago: AbbVie; 2014. http://www.abbvie.com/content/dam/abbviecorp/us/desktop/responsibility/AbbVie_CorpResp_Brochure_121014.pdf.
- Bristol-Myers Squibb. HCV developing world strategy. 2015.
- Médecins Sans Frontières Access Campaign. MSF responds to BMS commercial strategy for hepatitis C drug daclatasvir in developing countries [Internet]. 2014 November.
- Gilead Sciences. Hepatitis C generic licensing fact sheet. 2015. http://www.gilead.com/~/media/Files/pdfs/other/HCV%20Generic%20Agreement%20Fast%20Facts%203215.pdf.
- Janssen Research and Development. Global health. (date unknown).
- Johnson & Johnson. Our strategic framework. Pricing strategies and programs. (date unknown). http://www.jnj.com/caring/citizenship-sustainability/strategic-framework/pricing-strategies-and-programs.
- Johnson & Johnson. Access strategies and programs. (date unknown). http://www.jnj.com/caring/citizenship-sustainability/strategic-framework/access-strategies-and-programs.
- Merck. Access to health: statement of guiding principles. Kenilworth (NJ): Merck; 2014. http://merckresponsibility.com/wp-content/uploads/2014/07/Merck-Access-to-Health-Statement-of-Guiding-Principles-2014.pdf?2cc4ef.
- Médecins Sans Frontières Access Campaign. Médecins Sans Frontières policy position on expansion of the Médecins Patent Pool mandate to cover hepatitis C and tuberculosis. Geneva: Médecins Sans Frontières; 2015 May 8.
- Amin T, Radhakrishnan P. Letter to UNITAID about MPP entry into HCV. Lewes (DE): Initiative for Medicines Access and Knowledge; 2015 April 22.
- Working Group on Intellectual Property of the Brazilian Network for the Integration of the Peoples. Letter to UNITAID about MPP entry into HCV. Brazil: Working Group on Intellectual Property of the Brazilian Network for the Integration of the Peoples; 2015 April 23. http://www.hepcoalition.org/IMG/pdf/gtpi_letter_utd.pdf.
- Médecins Sans Frontières Access Campaign. Barriers to access and scale up of hepatitis C (HCV) treatment: Gilead’s anti-diversion program. Geneva: Médecins Sans Frontières Access Campaign; 2015 March. http://www.msfaccess.org/sites/default/files/HepC_Gilead_anti-diversion_FINAL_updated%20clean_0.pdf.
- Hill A, Khoo S, Simmons B, et al. Minimum costs to produce hepatitis C direct-acting antivirals (Abstract 1097). Paper presented at: 64th AASLD; 2013 November 1–5; Washington, D.C.
- Global Burden of Disease 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 Jan 10;385(9963):117–71. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340604/.
- Hill A, Khoo S, Fortunak J, et al. Minimum costs for producing hepatitis C direct-acting antivirals for use in large-scale treatment access programs in developing countries. Clin Infect Dis. 2014 Apr;58(7):928–36. doi: 10.1093/cid/ciu012.