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EASL 2016: How Generic Direct-Acting Antivirals Are Changing the Hepatitis C Treatment Landscape

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

[Produced in collaboration with infohep.org]

Generic drugs are versions of branded pharmaceutical products manufactured either under voluntary license or by companies which have worked out the production process for themselves. Gilead Sciences has issued voluntary licenses to 11 companies in India and to Pharco in Egypt to manufacture sofosbuvir (brand name Sovaldi), while Bristol-Myers Squibb has assigned the voluntary licensing rights for daclatasvir (brand name Daklinza) to the Medicines Patent Pool, at least for lower-income countries. Any company can apply to the Medicines Patent Pool for a license to produce daclatasvir, as long as it is sold only in those countries covered by the 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.

Egypt

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 branded sofosbuvir and sofosbuvir/ledipasvir (Harvoni), followed by generic versions from India as well as licensed manufacturing of generic versions by 2 Egyptian companies.

Egypt has the highest prevalence of hepatitis C in the world and the largest government-funded treatment program for the disease. The national treatment program aims to treat 200,000 people each year, rising to 400,000 per year in 2017, Ayman Yosry of Cairo University told a workshop organized by the World Hepatitis Alliance and the European Association for Study of the Liver (EASL).

Preliminary results suggest that treatment organized through a network of 51 liver centers, 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 onward. If this level of treatment can be sustained up to 2030, Egyptian modeling 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.

Pakistan

In Pakistan, the launch of generic versions of sofosbuvir in early 2016 led to an enormous increase in the number of people starting treatment. Saeed Hamid, president of the Pakistan Society for the Study of Liver Disease, told a symposium organized by the World Health Organization (WHO) that nearly 10,000 people started hepatitis C treatment in 2 weeks during February 2016 alone.

Pakistan treated around 257,000 people for hepatitis C between 2011 and 2015 using pegylated or conventional interferon and ribavirin, and was able to achieve relatively high cure rates in its predominantly genotype 3 population, with sustained response rates as high as 80% in people under age 30.

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 -- Hamid revealed that the government of the state of Punjab has just finalized 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 Hamid.

India

In India, the availability of generic DAAs produced by more than 15 companies at a cost of between $177 and $300 for a 3-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 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 4 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, 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 Sarin.

A potential short-term solution for many countries in Asia and sub-Saharan Africa may lie in partnering with national tuberculosis (TB) programs. 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 Program to catalyze 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 HCV infection and staging of liver disease.

Barriers to Generic Access for Millions with Hepatitis C

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 trade agreement 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 $7000 for sofosbuvir, though the country’s [gross national income] per capita is $961 per month."

Access to generic sofosbuvir produced under voluntary license 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 program covers 101 countries, Gilead has registered sofosbuvir in only 9 of these countries to date.

4/22/16

Sources

EASL-WHA Joint Workshop. Barcelona, April 14, 2016.

S Hamid. The promise and the challenge of generic direct- acting antivirals for the treatment of hepatitis C infection: The Pakistan experience. Launch of updated WHO guidelines for the screening,
care and treatment of persons with hepatitis C infection. EASL International Liver Congress 2016. Barcelona, April 15, 2016.