[Mike Isbell, Renée Ridzon, and Karin Timmermans, UNITAID/WHO , Link ] Executive summary: Hepatitis C virus (HCV) is a major global health problem. With 80−150 million people worldwide chronically infected with the virus, the prevalence of HCV is higher than that of the human immunodeficiency virus (HIV). Worldwide, 4−5 million people are coinfected with HIV and HCV. Each year, 500,000−700,000 people die of HCV-related liver disease, and evidence indicates that the HCV burden is increasing. While the HCV epidemic is global in scope, the HCV burden varies considerably between regions. There are six major genotypes of HCV, with genotypes 1 and 3 together accounting for more than three quarters of HCV infections.
Efforts to treat HCV have historically been hampered by inadequate treatments. Until recently, the standard treatment for HCV involved a combination of pegylated interferon (Peg-IFN) and ribavirin (RBV), with regimens lasting 24−48 weeks depending on the genotype. Weaknesses of Peg-IFN + RBV include suboptimal efficacy, poorer efficacy among patients with certain genotypes, and common, often severe side-effects that make the treatment intolerable for many patients. Diagnosis of HCV and treatment monitoring are also costly and complex, requiring multiple different tests, though this is in part attributable to the limitations of treatment with Peg-IFN and RBV.
The development of direct-acting antivirals (DAAs) has dramatically improved HCV treatment prospects and altered the standard of care. New DAAs that do not require Peg-IFN are being developed, with several receiving their first regulatory approval in late 2013 and 2014. A number of other DAAs are in development. These new DAAs are to be used in combinations. As measured by sustained virological response (SVR), several DAA combinations appear to generate cure rates that approach or exceed 90%. Some of these combination regimens may have pan-genotypic efficacy, although the “ideal” regimen has not yet been established since data are currently not available for all genotypes and all patients groups (such as HIV/HCV coinfected patients or patients with cirrhosis). These DAAs can shorten treatment duration (in many instances to 12 weeks) and have fewer side-effects. They also have the potential to reduce the cost and complexity of diagnosing HCV.
Widespread scale-up of DAAs in low- and middle-income countries is not currently feasible due to their very high prices. The DAAs that have already received regulatory approval have exceptionally high prices, and even high-income countries struggle to cover treatment costs. Sofosbuvir has a commercial price of US$ 1000 per pill, or US$ 84 000 for a 12-week course of treatment in the USA. The prices of other DAAs are comparable. Some high-income countries have succeeded in negotiating price reductions, but these prices nevertheless remain far beyond those that would be affordable for widespread use in low- and middle-income countries. The Government of Egypt has negotiated a public-sector price of US$ 900 for a 12-week treatment course for sofosbuvir, but the number of doses available at this price is limited and it is unclear whether many other countries will be able to obtain similar prices. Virtually all sales of these medicines to date have occurred in high-income countries, with the USA and Europe together accounting for 98% of sales of sofosbuvir.
The high prices of DAAs are not related to the cost of production. Assuming sufficient volumes, a recent academic analysis estimated that minimum production costs for a 12-week treatment course of several leading DAA combinations range from US$ 118 to US$193 per person.
Patents pose a barrier to affordability and scale-up, although voluntary licences offer an avenue for generic production. Patents for DAAs are likely to remain in force until at least 2025 and possibly beyond. In 2014, Gilead signed voluntary licences for two DAAs with seven Indian generic manufacturers, and Bristol-Myers Squibb, maker of other DAAs, also announced plans to issue voluntary licences. The Gilead licence covers 91 low- and middle-income countries, and includes half of all middle-income countries. However, it excludes the other 50% of middle-income countries, such as China which has the largest HCV epidemic in the world. The licensed manufacturers in India are currently developing generic DAAs; it is expected that generic equivalents will become available in late 2015 or 2016.
Generic manufacturers will need substantial orders to achieve the economies of scale required to offer DAAs at affordable prices. It is too early to obtain a firm market entry price for generic products, but most producers have indicated they would be able to offer sofosbuvir for less than US$ 900 for 12 weeks treatment (Gilead’s price for sofosbuvir in Egypt). Prices of generic daclatasvir could be even lower. Achieving prices for generic versions of sofosbuvir and other DAAs that are sufficiently affordable to encourage scaleup of HCV treatment in low- and middle-income countries will, however, depend on volumes.
The demand for DAAs among international donors and national governments remains uncertain. No major international donor and few national governments have prioritized procurement of HCV medicines, in large part due to the high prices of DAAs. Sharp price declines – or the prospect thereof – will be needed to persuade donors and governments to make substantial purchases of DAAs.
Additional factors potentially impede scale-up of DAAs. Most people infected with HCV are undiagnosed, resulting in limited on-the-ground demand for HCV treatment. Capacity for diagnosis is limited in many low- and middle-income countries. Other factors that could hinder scale-up include possible regulatory delays, challenges associated with translating international recommendations into national treatment guidelines, and building capacity for HCV diagnosis and treatment.
Addressing market weaknesses in the HCV treatment arena will require a combination of approaches that generate strong demand and address systemic issues. Long-term investments in demand generation will be needed to improve diagnostic tools and strategies, enhance strategic data, advocate for robust funding by donors and national governments, and strengthen the ability of advocates to demand lower prices. Proof-of-concept studies will be required to demonstrate that HCV can be diagnosed and cured at minimal cost in low- and middle-income countries. At the same time that efforts focus on increasing demand, systemic issues (e.g. patent barriers, regulatory processes, timely generation of national treatment guidelines, health systems capacity) will need to be addressed. Once demand has been created, consideration should be given to bulk purchasing and other strategies to expedite uptake.
