In the United States Hepatitis C recently passed HIV as a cause of death. The USPSTF has recommended screening all baby boomers for Hepatitis C, i.e. those born between 1945 and 1965, with a category B strength of recommendation. This makes Hepatitis C screening a preventative service that is covered by all insurance policies without cost to the patient directly. The April 12, 2014 online edition of the NEJM has three studies of new multiple oral drug regimens. Each of these report on studies of Hepatitis C therapy using only oral medications, with minimal side effects, and of only 12 weeks duration (or maybe only 8 weeks) can result in viral eradication rates of 95% or higher. If these drugs hold up through phase 3 clinical trials they will be dramatic improvements over current therapy which requires a 6-9 month course of IV therapy regimens using interferon and that have been less effective and much more difficult to tolerate. Interferon often causes such challenging side effects that patients are unable to complete the recommended course of therapy. In the same article of NEJM are two perspective/editorial articles that bring into focus both the incredible scientific advances that led to these new treatments, and the financial implications of use of extraordinarily costly drugs to treat a common disease.
The perspective article is by Dr. Raymond Chung, Curing Hepatitis C- The Arc of a Medical Triumph. It is an article remarkable in that it clearly and understandably discusses the past 25 years of remarkable progress with this virus from its discovery through interferon based therapy and more recently to cocktails of antiviral therapy analogous to HIV therapy.
After reading the article by Dr. Chung, I was pleased to more clearly understand some of the key features of the Hepatitis C virus and the development of therapies, and want to share some of them with readers.
- The hepatitis C virus, unlike the HIV virus or the Hepatitis B virus, is a positive-stranded RNA virus. This means that it replicates its genetic material (genome) directly into RNA, without using a DNA phase. Without a DNA intermediary the Hepatitis C virus lacks a latent form, so it relies on continuous replication for its existence. This means that unlike in treatment of HIV and Hepatitis B if Hepatitis C therapy can stop replication, it can eradicate the virus. There is no latent virus remaining to recur.
- The bench science breakthroughs that have identified specific genotypes of Hepatitis C have led to understanding key differences in the epidemiology and prognosis of the different strains, allowing therapy to be more specific to the genotype a patient carries.
- The replication of Hepatitis C depends on an RNA-polymerase (enzyme that hooks together the building blocks of RNA in the viral genetic code) that is very prone to errors, which allows the virus to quickly develop resistance to the early HCV protease inhibitors as single drug therapy. Fortunately interferon works in a different fashion that is less susceptible to the development of resistance, so when interferon is added to the therapy cure rates were much higher. Still the toxicity of interferon made therapy difficult. The development of multiple direct acting anti-Hepatitis C agents acting at different viral replication steps made using anti-HIV type cocktails of relatively non-toxic drugs an option. This promises to be a great leap forward in terms of both cure rates and patient tolerability.
- The FDA allowed phase 2 clinical trials using anti-HIV like cocktails of new and potent direct antiviral agents without first requiring standard-of-care comparators as an exception to the normal process of drug development. This was key because being randomized to a cocktail of oral direct antiviral drugs expected to be more effective and less toxic vs. the standard of care including IV interferon with its expected side toxicity was expected to be a hard sell to prospective study participants. This has allowed expedited movement through the approval process of these new drugs.
- This rapid progression through the clinical trial process is expected to lead to FDA approval of these drugs by late 2014.
Another editorial in the same edition of the NEJM, Therapy for Hepatitis C- The Cost of Success, addresses the almost as remarkable cost of the new proposed therapies. A 12 week course of just one of the two new drugs, sofosbuvir, is expected to cost $84,000 ($1000/pill). When the cost of the second drug ledipasvir is added the cost of a course of oral therapy is likely to exceed $100,000 for just the drugs. Sofosbuvir is promising to be such a profitable drug for Gilead that other drug companies have filed suit for a share of the revenue. An estimated 1/33 American baby boomers are estimated to have chronic Hepatitis C, or 3.2 million total. If only 25% got this treatment, at this price the cost of the drugs might be $67 billion.
For all Americans with Hepatitis C to get this treatment the cost of drugs alone would approach $270 billion. For perspective the gross personal health care spending in the US in 2009 was about $1.37 trillion. This would mean that approaching 20% of U.S. health care dollars might be spent on the cost of drugs for Hepatitis C therapy. Admittedly in theory this would be a one-time expense, and there would be expectation of reduced future costs of treatment of the complications of chronic hepatitis C, but I expect this new therapy to lead to a lot of anguish among government officials, physicians, patients and their families as we face the decisions of cost vs. benefit of these new therapies. We live in interesting times.