Scaling‐up HCV treatment to achieve WHO targets by 2030

WHO recently launched a new strategy for tackling viral hepatitis with ambitious goals for reducing both deaths and new infections by 2030 1. Antiviral therapy is only part of a multifaceted strategy needed to tackle viral hepatitis, but for hepatitis C (HCV), the absence of an effective vaccine means that achieving these targets is going to require substantial scale-up of HCV treatment. Reaching the target of treating 80% of those in need by 2030 will require reaching at least 70 million people. The revolution in treatment for HCV over the last four years has been dramatic, with several new interferon-free combination therapies now approved for use (Table 1). These advances have the potential to overcome many of the existing barriers to care in poorer countries. Historically, treatments based on interferon have required 24–48 weeks of therapy (with regular monitoring) were associated with significant side effects (not just from interferon, but also ribavirin) and were unable to cure a significant proportion of patients 2. In contrast, newer interferon-free tablet treatment combinations, with good adherence to 12 weeks of therapy, are able to cure more than 90% of patients and have far fewer side effects. Cure for HCV is durable and associated with substantial health benefits even in those with advanced liver disease, notably a reduction in the incidence of liver cancer 3. Problems of dependency, poverty and homelessness will mean that many patients infected with HCV will still struggle to take 12 weeks of therapy despite these advances. This issue will become increasingly important as patients who attend clinics are cured, and efforts turn to finding those not engaged in routine care with a view to disease elimination. But the biggest barrier to scaling-up treatment, with or without interferon, is the cost. At this point, the high price of treatment is limiting access even in the world's richest countries 4. In the USA, high prices have become a political issue discussed on the presidential campaign trail and the Senate conducted an investigation into pricing 5. In England, treatments are restricted (pending legal challenge) to a few centres with strictly enforced quotas for treatment each month. Advanced healthcare systems are used to paying high sums of money for certain treatments (e.g. cancer chemotherapy), many of which are less cost-effective than new HCV cures. However, what makes the challenge of hepatitis C greater is the number of patients who would benefit from treatment. The potential budgetary impact of treatment remains a problem to many health systems, rich or poor. Some governments have invested heavily in HCV treatment. National deals have been made with companies (behind confidentiality agreements). There are examples where, in return for commitments to high volumes of treatment, there is an agreed cap on total expenditure but not on the number who can be treated. Australia provides the best example 6, and others, France for example, which spent more than 1 billion euros on treatment in 2014-2015, are beginning to follow. But for many countries, particularly poorer or high-burden countries, these are not immediately viable options and other solutions need to be found. The production of treatments by generic manufacturers should be part of the answer, but there is a long way to go. Although receiving strong criticism domestically for their pricing policy, widely viewed as prioritising profit over patient access, Gilead (manufacturer of some of the better new therapies – sofosbuvir, ledipasvir and velpatasvir) has led other originators in trying to make its treatments accessible in low middle-income countries (LMICs). Learning from the lessons of HIV treatment scale-up with tenofovir, several Indian and Bangladeshi manufacturers have signed voluntary licensing agreements 8 (the templates for which are available 7, 8) that allow them to sell to LMICs. These agreements have drawn criticism, particularly from non-governmental organisations (NGOs) concerned about access in upper middle-income countries 9, 10. Nonetheless, it is reasonable to expect prices for these drugs in LMIC to approach the targets predicted by detailed analysis of the processes required for manufacture 11, 12. Twelve weeks of therapy already cost <$200 in Egypt, which treated more than 500 000 individuals between January and September 2016 4, more than any other country. These prices may still be far too high to make widespread scale-up possible in many poorer countries, but it will at least become possible to have a realistic conversation. If other originator companies were to follow suit, it should help to accelerate access to treatment. Merck and AbbVie both have excellent alternative treatments in late-stage development, but as yet there are no public plans to engage generic manufacturers to supply LMICs. The newest treatment from manufacturer AbbVie (a combination of an NS5A inhibitor pibrentasvir, and the NS3/4A protease glecaprevir) has the potential to be both pangenotypic (active against all major HCV genotypes; 1–6) and require shorter treatment duration (8 weeks) than the best current treatments. This could significantly simplify the package of care required for treatment, but progressive policies are needed from all originators to speed access. One of the main criticisms of these agreements is that achieving lower prices in LMICs will only partially help address the WHO's ambitious targets. A significant proportion of the burden of HCV is found in upper middle-income countries (Table 2) that will find it harder to access cheaper generic treatment, notably Thailand, China and Brazil. These countries are seen as important growth markets for global pharma companies and excluded from existing voluntary licensing agreements 9, 10. One response to this challenge has led the Drugs for Neglected Diseases Initiative (DNDi) to make its first move into hepatitis C, investing in the development of the combination of sofosbuvir with ravidasvir (formerly PPI-668, a pangenotypic NS5a inhibitor), particularly for high-burden countries of South-East Asia 16. It remains to be seen how far competition in these markets will be able to push down prices, but it has to be hoped too that a more enlightened approach to tiered pricing can be adopted, potentially requiring different voluntary agreements with generics manufacturers. Compulsory licences are another way forward but have yet to be issued by any country for hepatitis C treatments. Fears that widely available generic treatments (and their likely counterfeit companions) may lead to an increase in resistance have been voiced. Whilst the emergence of resistance in those failing treatment is common, there is still much to learn about that resistance. It is becoming clear that a high proportion of patients with resistant variants can still be cured, depending on the variant's precise nature 17. Also, for the majority of patients who do not have advanced fibrosis, there are less severe consequences to failing therapy (in contrast to malaria or tuberculosis, for example) if taking a drug without active ingredient. Thus, although scaling-up generic therapy deserves careful attention, it is a crucial step of achieving more widespread treatment access. The WHO targets are ambitious but feasible if matched by political ambition and financing. But even if prices for new HCV treatments come down substantially, achieving the goals set out is still going to require significantly increased. Some government programmes may be able to shoulder the burden and create the volumes of demand that will bring down prices, but a global fund akin to that for HIV, TB and malaria is desperately needed. In its absence, alternatives are being considered, such as the creation of an organisation for shared procurement that would allow countries to combine forces to achieve the best prices possible for both drugs and diagnostics.