How generic direct-acting antivirals are changing the landscape for hepatitis C treatment

The arrival of generic versions of direct-acting antivirals is transforming the global hepatitis C treatment landscape and highlighting the overlooked importance of the cost of monitoring technologies, delegates at the 2016 International Liver Congress heard last week in Barcelona.

Generic drugs are versions of branded pharmaceuticals manufactured either under voluntary licence or by companies which have worked out the production process for themselves. Gilead Sciences has issued voluntary licences to eleven companies in India and to Pharco in Egypt to manufacture sofosbuvir, while Bristol-Myers Squibb has assigned the voluntary licensing rights for daclatasvir to the Medicines Patent Pool, at least for lower-income countries. Any company can apply to the Medicines Patent Pool for a licence to produce daclatasvir, as long as it is sold only in those countries covered by the licence agreement.

Generic production reduces prices through market competition, even where originators have previously negotiated lower prices with governments. Affordable generic direct-acting antivirals have allowed some countries to begin scaling up treatment, and access to these products would permit more countries to do so if they can overcome patent and registration barriers.

Nowhere has the arrival of affordable generics had a greater impact than in Egypt, where negotiations between government and pharmaceutical companies has permitted the importation of Gilead’s sofosbuvir (Sovaldi) and sofosbuvir/ledipasvir (Harvoni), followed by generic versions from India as well as licensed manufacturing of generic versions by two Egyptian companies. Egypt has the highest prevalence of hepatitis C in the world, and the largest government-funded treatment programme for the disease. The national treatment programme aims to treat 200,000 people each year, rising to 400,000 per year in 2017, Professor Ayman Yosry of Cairo University told a workshop organised by the World Hepatitis Alliance and the European Association for Study of the Liver (EASL).

Preliminary results suggest that treatment organised through a network of 51 liver centres, provided free of charge to 83% of the population who do not have private health insurance, is achieving results similar to those observed in clinical trials, with cure rates above 90%. For Egypt, the big challenge will be increasing the rate of diagnosis in order to raise the number of people treated and achieve elimination of hepatitis C by 2030. The number of new diagnoses needs to increase from 150,000 per year in 2015 to 340,000 per year in 2018 in order to achieve a target of treating 325,000 people per year from 2018. If this level of treatment can be sustained up to 2030, Egyptian modelling estimates that the prevalence of hepatitis C could be reduced by 95% and deaths due to hepatitis C by 77%.

Disease elimination in Egypt will be critically dependent on the prevention of new infections, not just by treatment but by the adoption of universal infection control precautions at all levels of the health system. Without this focus on prevention the prevalence of hepatitis C might remain above 1.25 million in 2030 despite a massive treatment campaign, underlining the importance of a comprehensive national plan for prevention and for investment in the health system.

In Pakistan, the launch of generic versions of sofosbuvir in early 2016 led to an enormous increase in the number of people starting treatment. Professor Saeed Hamid, President of the Pakistan Society for the Study of Liver Disease told a symposium organised by the World Health Organization (WHO) that nearly 10,000 people started hepatitis C treatment in two weeks during February 2016 alone. Pakistan treated around 257,000 people for hepatitis C between 2011 and 2015 using pegylated interferon or interferon and ribavirin, and was able to achieve relatively high cure rates in its predominantly genotype 3-infected population, with cure rates as high as 80% in under-30s. The arrival of sofosbuvir supplied by Chinese generic manufacturers is set to drive down the cost of treatment from approximately US$300 per month of treatment to $252 per treatment course. The cost could fall further – Prof. Hamid revealed that the government of the state of Punjab has just finalised a tender for 2016-2017 that will permit people to be treated with sofosbuvir and ribavirin for $80 per treatment course – less than the estimated cost of the active pharmaceutical ingredients.

The arrival of generic products has thrown up problems too. Counterfeit products and poor quality products have already been detected, including pills that fail to dissolve when tested. Unregulated prescribing also risks misuse of direct-acting antivirals. “I’ve had patients come in whose cardiologist has prescribed sofosbuvir,” said Professor Hamid.

In India, the availability of generic direct-acting antivirals produced by more than 15 companies at a cost of between $177 and $300 for a three-month course of treatment – has permitted around 42,000 people to be treated with products manufactured by one company alone. A comprehensive national picture of how many people are being treated is lacking and, outside a few states, treatment is dependent on private means. India lacks a national strategy for hepatitis C treatment and prevention. To eliminate hepatitis C as a public health problem in India by 2030, the country would need to treat 10 million people by 2020.

“To treat 10 million people by 2020 we need to treat over 5500 patients a day,” said Professor Shiv Sarin, Director of New Delhi’s Institute of Liver and Biliary Science. This implies that at least 10,000 doctors will each need to treat at least 180 patients with hepatitis C a year, he went on. India currently has around 2500 liver specialists, so the only way to achieve this big increase in capacity is to train primary care physicians to manage hepatitis C treatment.

Another barrier to treatment in India is the high cost of viral monitoring tests. At the very least, viral load (HCV RNA) should be measured four weeks after starting treatment to check response, again at the end of treatment and 12 weeks after completion of treatment, but with each test costing around $30, the cost of testing is equivalent to the cost of one month of treatment in India, Prof. Sarin said. Furthermore, testing needs to be carried out in laboratories equipped to conduct PCR testing. “We need a global strategy for affordable, point-of-care diagnostic and monitoring tests for hepatitis B and C,” said Prof. Sarin.

A potential short-term solution for many countries in Asia and sub-Saharan Africa may lie in partnering with national tuberculosis (TB) programmes. Recent investment in the GeneXpert molecular diagnostic platform has provided access to fast-throughput diagnostic testing for TB and drug-resistant TB. Manufacturer Cepheid recently launched an HCV Xpert test that can be used on the platform to provide an HCV RNA test result within 2 hours, on a machine that can be located in a primary health clinic or a small hospital rather than a large central laboratory.

In the longer term, FIND is working with the WHO Global Hepatitis Programme to catalyse the development an array of diagnostic and monitoring tests (see its strategy document here), in particular affordable point-of-care molecular diagnostics and a core antigen assay for monitoring hepatitis C treatment, as well as improved tests for diagnosing hepatitis C infection and staging of liver disease.

For middle-income countries such as Argentina, Brazil, Russia, Ukraine and China, each of which have large populations with hepatitis C, use of generic versions of drugs patented by Gilead and Bristol-Myers Squibb is not an option, unless patent oppositions are successful, or governments invoke TRIPS flexibilities that allow compulsory licensing on public health grounds. Patent oppositions against Gilead’s patent on sofosbuvir have already been filed in these countries; success could lead to further oppositions, and to wider access.

“Without access to generic sofosbuvir, countries are left at Gilead’s mercy for drug pricing,” said Tracy Swan of Treatment Action Group. “In Brazil, Gilead charges more than US$7000 for sofosbuvir, though the country’s GNI per capita is US$961 per month”.

Access to generic sofosbuvir produced under voluntary licence is also restricted by a clause in the licensing agreements which prevents licensees from selling to countries where Gilead has not registered the product. Although the company says that its voluntary licensing programme covers 101 countries, Gilead has registered sofosbuvir in only nine of these countries to date.