Is HCV the new HIV? Health Activists Meet to Develop Strategies to Improve Access to HCV Treatment

Sean Flynn
March 31, 2009 

Another lifesaving treatment is being denied to the world’s poor through global pricing that provides access only to the nation’s wealthy. A biologic drug called pegylated interferon can cure Hepatitis C (HCV) in over half of the patients that take it. But at a global price of over $20,000 a year, only a small portion of the world’s 150 million people living with HCV can afford access.

The situation is reminiscent of the late 1990s when breakthrough triple drug HIV therapies were priced throughout the world at over $12,000 a year, excluding the majority of the affected population from access. Will the same strategies that pressed the lowest global price for an effective AIDS treatment to under $100 a year today be effective at improving access to affordable HCV treatment? That question lied at the heart of a meeting in Kiev last week of public health advocates, academics, lawyers, drug manufacturers and representatives of the Open Society Institute.

This note provides some background information on the problems being faced in promoting access to HCV treatment. The information is derived from presentations at the meeting and in the background documents, particularly from the draft background report circulated to meeting participants by Jeff Hoover, titled: “Shining a Light on a Hidden Epidemic: Why and How Civil Society Advocates Can Support the Expansion of Hepatitis C Treatment in Eastern Europe and Central Asia.” 

Following the background information, I provide some preliminary thoughts on next steps for public health advocates researching strategies to address IP barriers to HCV treatment access.

HCV Prevalence

Hepatitis is an inflammation of the liver that reduces the liver’s ability to filter bodily waste and regulate a wide range of essential biological functions. Hepatitis C (HCV) was identified as a distinct strain in the 1980s. There are three main genotypes of HCV, of which genotype 1 is the most common. It accounts for 60 percent of HCV infections, including the majority in Eastern Europe and Central Asia (EECA). It is also the hardest to treat.

Symptoms from chronic HCV disease vary widely by patient and often include fatigue, depression, aches and pains, and forgetfulness. The lack of clear symptoms makes HCV difficult to diagnose. There are several tests for HCV, the best of which is a PCR viral load test that is relatively expensive and lacks robust generic competition in most countries.

In Russia, Georgia and Ukraine, official statistics suggest that 2-5 percent of the general population is affected with HCV. About half of people living with HIV are co-infected and up to 90 percent of IDUs are infected. Similar levels of prevalence are reported in India and Thailand.

Globally, there are about 150 million people living with HCV. There are 3-4 million new infections a year. HCV is the world’s number one cause of liver disease.

The highest prevalence of HCV in the world is in Egypt, where it is estimated that up to a fifth of the population is infected. Widespread transmission in Egypt has been traced to a botched immunization program that for decades used improperly sterilized needles to infect millions of people. Importantly, there is now a generic version of peg-interferon in use in Egypt, as discussed below.

Treatment

The best available treatment for HCV is a combination therapy including a widely available generic drug, ribavirin, and a widely patented biologic treatment called pegylated interferon (peg interferon). Use of the combination therapy including pegylated interferon was approved by the U.S. FDA in 2001 and has been international best practice for over a decade.

Interferon is a naturally occurring protein that helps boost the immune system and combat the HCV virus. Treatment of patients with non-pegylated interferon combined with ribavirin is effective at suppressing, but not curing, HCV.

Pegylation, which refers to the linking of a peg molecule (which is similar to a long sugar molecule) to interferon provides two major benefits. First, it allows more time between injections of interferon, thus reducing side effects and increasing adherence. More importantly, in about 50-60 percent of patients, peg interferon completely cures the virus, which non-peg interferon combination therapy cannot achieve.  

Side effects from peg interferon combination therapy are relatively severe. Side effects include fairly common flu-like symptoms following the weekly injections. More severe depression, anxiety and anemia occur in about a quarter of patients.

The efficacy of the treatment varies depending on the genotype of HCV that a person has. The treatment is about 50 percent effective for Genotype 1 HCV, which is the most common type in many countries. Treatment is more effective in genotype 2 or 3 patients.

Access barriers

The brand name product, which is the only product available in many countries of the region, is provided from two multinational companies -- Roche and Schering-Plough. It is thought that each company has a separate patent on different versions of the drug that share similar properties.

Hoover explains:

“Generic versions of ribavirin are available, but for years pegylated interferon has been available only in two brand-name versions: Pegasys, made by Roche, and Schering-Plough’s PegIntron. The lack of generic alternatives means that a standard 48-week course of treatment for HCV infection can cost more than $20,000 even in resource-constrained countries such as those in Eastern Europe and Central Asia. As a result, most health systems either cannot or refuse to pay for the highest-quality HCV treatment for the majority of patients in need.”

There are no global price discrimination policies by the multinational companies to lower prices for poorer countries or public programs, as is now widespread for AIDS medications. It appears that every country in the world is being required to pay essentially the same price for access to the drug. This pricing strategy is not surprising – monopoly economic models suggest that the most profitable pricing behavior for a provider of an essential product will be to price to the global top income earners, which may justify a set price for the globe regardless of median income levels (see Flynn, Hollis, Palmedo 2009).

Russia may soon lack any access to peg interferon because of a recent law banning the importation of medicines into the country. According to two people at the meeting, about 6 months ago Russia passed a law banning the marketing of any medicine in Russia that was not locally manufactured. There is no peg interferon manufactured in Russia.

A representative of a Russian pharmaceutical company described the new requirements and explained the main treatment response in Russia is to promote non-peg interferon treatments. As discussed above, non-peg interferon is a dramatically inferior treatment because it cannot cure the disease, as peg interferon can in 50 percent of patients.    

Patents and competition

Pegylated interferon is widely patented in the region, including in Russia and Ukraine – the two countries in the region with the largest populations. The patents cover a combination of two non-patentable inventions. Neither peg nor interferon is patentable when used alone.

Two presenters at the meeting referred to an understanding that Chiron holds a patent on the DNA or gene sequencing of HCV that restricts other companies from creating competing diagnostic tests. It seems unlikely, however, that there exist such patents widely outside of the U.S.  

Generic peg interferon

In the absence of patent barriers to entry, there would likely be a robust generic market for non-pegylated interferon. 

The potential suppliers of peg interferon are quite numerous. A medical researcher at the meeting reported that once a firm has the capacity to make interferon itself, attaching the peg is a relatively simple step that any supplier of non-peg interferon could master. It is estimated that there are at least 20 companies around the world making high quality non-peg interferon presently.

There is a generic version of peg interferon currently available from Egyptian manufacturer Minapharm. The drug, known as “Relferon,” has been in use in Egypt since 2006 and is currently sold at about 25 percent of the branded price (approximately $4,000 /year). The patent and licensing status of Relferon is unclear. There have been suggestions that the product may be produced under a patent or know how license from Schering Plough. Hoover’s paper reports being told in an interview that a German firm extended a license (presumably a know how license) to it. Minapharm has not responded to inquiries and this information is largely conjecture.

There are reportedly several Chinese companies that currently make peg interferon. There have been unconfirmed rumors of quality problems with these products.

Peg Interferon is patented in India. It is unkown the extent to which it is patented in other possible producing countries such as Thailand, India and South Africa.

Indian pharmaceutical firm Wockhardt challenged a patent granted to Roche in India for Pegasys. That challenge, filed in 2007, was later joined by Indian NGO Sankalp, which works with intravenous drug users and was represented by the Lawyer’s Collective. The briefing in the post-grant challenges has been completed and the parties are now awaiting a decision. A key argument in the cases is that peg interferon is a combination of two known substances – peg and interferon – neither of which is itself patentable.

There are other Indian biotech firms, including Shantha Biotech and Bharath Biotech, thought to be interested in peg interferon production should the patent barrier in India be eased.

Downstream innovations

There are companies developing new methods of altering interferon to achieve pegylation in ways that do not violate the Schering and Roche patents and therefore may not need compulsory licenses to supply the world market.

In the U.S., Human Genome Sciences and Novartis are developing “Albuferon.” The treatment will presumably be patented and targeted at wealthy countries.

Poly Therics invented (and has patented in four countries) a new pegylated interferon placing a peg in a different part of the interferon molecule. The inventors have licensed Shantha Biotech in India to take the medicine through the final clinical trials and produce and market the product. The drug will go into clinical trials in India in end of 2009. French biotech firm Biomerieux has bought Shantha and is continuing development of the drug. The goal of the firm is to focus initial product marketing in the developing world for approximately $2,000 per course of treatment.

Competition problems in supply of peg raw material

There may be immediate supply problems with obtaining pharmaceutical quality peg to link to interferon. High quality peg is relatively difficult to produce, contrasted with the process of linking the peg to interferon which is reportedly relatively simple.

There is one main supply of peg currently – Nektar in Japan – which supplies Roche and Schering Plough. Nektar has reportedly been very unresponsive to requests to purchase small amounts of peg for developing competing products.

There is one known alternative supplier of peg. Biovectra of Canada was established at a university with government support and now provides peg to Shantha.

Pipeline for new HCV treatments

There are other drugs in R&D pipelines that are attempting to improve the efficacy of the peg interferon treatment by adding a third drug to the treatment cocktail. Any of these drugs appear to be at least two years away from marketing. 

Thoughts on the way forward

It appears from the information shared at the meeting that a compulsory licensing or other strategy to bring down patent barriers to the marketing of generic forms of pegylated interferon could be effective at improving access to affordable treatment for HCV. The current global price for pegylated interferon is incredibly high – reminiscent of AIDS drugs in the 1990s before campaigns to shame companies and support generic production began. If there were no patent or registration barriers to marketing generic peg interferon, it seems likely that a large number of generic producers (e.g. those currently making non-peg interferon) would compete in supply markets and force prices down to much more affordable levels. Immediate savings of 75-80% appear likely. Longer term, prices may be pushed much lower.

Patent pools may help promote further downstream innovation, particularly for firms that are seeking to develop new versions of HCV combination therapy that add a third drug to the existing two-drug treatment.

There should be further investigation into the patent and licensing status of Relferon in Egypt. If the product is being produced under license from Schering Plough, could parallel importation be used to access the drug in other countries i.e. does the license exhaust Schering’s rights in countries with international exhaustion rules?)? Is the drug one of high quality? Are their licensing or other conditions that would prevent export of the drug to other countries? If so, could those provisions be challenged under patent, completion or human rights law provisions?

India is likely to be a key site of advocacy. If the current challenge to peg interferon patents fail, research into other licensing strategies will become necessary. Given the likely need to establish export capacities in India, these strategies will likely need to include either use of competition grounds for licenses (thus allowing unlimited exports under TRIPS article 31(k)) or utilization of India’s “paragraph 6” implementing language.

More research should be conducted on best practices for biologic product registration for implementation in developing countries. Biologic drugs are a new technology, and most countries lack a specifically defined avenue for registering generic versions of biologic treatments. The U.S. is currently developing legislation to open a registration pathway for generic drugs and the EU has had such a regulatory pathway for several years. The issue is unlikely to be addressed in developing country legislation, however. Research should be conducted on best practices for altering or interpreting registration procedures in developing countries to permit registration of quality generic biologic drugs.  

On June 3, PIJIP and OSI will convene an expert meeting of IP specialists in Kiev to further discuss possible licensing and other solutions to the IP barriers to HCV treatment.

In September 2009, PIJIP and OSI plan to organize a training on intellectual property and access to medicines for health activists in the EECA.

 

 

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