The race to find a tolerable cure for hepatitis C virus (HCV) is queueing up again. Barely two years after researchers and clinicians hailed the “disease-changing” protease-inhibitor drugs boceprevir (Victrelis) and telaprevir (Incivek), two more drugs have been approved, and several others are in late-stage development.
“The story in HCV is a remarkable triumph of science and it is playing out in dramatic fashion as we speak,’” said Michael S. Saag MD, who directs the Center for AIDS Research at the University of Alabama at Birmingham.
So why are clinicians turning their backs on the latest “miracle cures” and counseling their patients to wait for next wave of therapies?
Cost and complexity.
$1,000 a Pill
We find ourselves in the gratifying position to offer almost all patients a future without HCV infection. Our challenges continue to be identifying patients through screening so we can offer these curative therapies. These exciting potent therapies are important tools for the public health campaign to eradicate HCV.”
--- Muir AJ. The Rapid Evolution of Treatment Strategies for Hepatitis C. Am J Gastroenterol (2014) Published online 4/15/2014.
The Food and Drug Administration (FDA) approved the new drugs in December 2013. The nucleotide polymerase inhibitor sofosbuvir (Solvadi) is approved to treat patients with HCV genotypes 1 and 4 in combination with interferon and ribavarin, and as therapy used in combination with ribavirin in patients with genotypes 2 and 3. The protease inhibitor simeprevir (Olysio) was approved in combination with ribavirin and interferon in patients with genotype 1.
Both are oral and taken once daily for 12 to 24 weeks, depending on the type of infection. That compares to the 24 to 48 weeks required with an interferon-based regimen, which has significant side effects that limit patient eligibility, and a cure rate of 30%- 80% depending on the patient and HCV genotype. In clinical trials, patients experienced cure rates as high as 95% on the new drugs, even those with late-stage disease.1
The medications come with their own drawbacks, however, not the least of which is the cost. Gilead Sciences, the maker of sofosbuvir, priced a 12-week course at $84,000, or about $1,000 a pill, while Janssen Therapeutics, the maker of simeprevir, priced a 12-week course at $66,360. With an estimated 3.2 million Americans infected with HCV—at least half of whom do not know they are infected—private and public insurers fear the astronomical costs could overwhelm already tight budgets.2
In April, the Department of Veterans Affairs and the California Technology Assessment Forum recommended that doctors use the new drugs only in patients with advanced liver disease, and wait for additional drugs expected on the market later this year.3 Meanwhile, an editorial in the New England Journal of Medicine called the cost of the drugs a major barrier to their use, noting that “costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a safe and effective therapy for hepatitis C.”2 In addition, the House Energy and Commerce Committee has asked Gilead officials to testify and explain the high cost.4
As more drugs are approved, said Dr. Saag, he and others hope the economics of the market will drive prices down. “Certainly the third-party payers are going to look at that, and the providers,” he said. After all, a copayment of 20% on a drug that costs $84,000 means a nearly $17,000 out-of-pocket cost for patients, most of whom are low-income.
Nonetheless, he said, he is able to get insurance approval to use the expensive new drugs “if I give them a good rationale.”
Another drawback of the new drugs is that they are approved only for use with interferon in patients with genotype 1, the most common form of the virus. “No one wants to use interferon,” said Dr. Saag. So some doctors are using the drugs ‘off label,’ particularly in interferon-intolerant patients, combining the two for 12 or 24 weeks.
Indeed, a phase IIb open-label, 12-week clinical trial of the combination with or without ribavarin found similar cure rates to the triple regimen, with similar side effects. Ninety-three percent of patients with early disease who previously did not respond to interferon treatment experienced a sustained virological response (SVR) as early as four weeks, as did 100% of treatment-naïve patients and non-responders with advanced disease.5 Getting approval for the off-label use of two such expensive drugs from insurers, however, is difficult.
So for now most clinicians are adopting a “treat-or-wait” approach, delaying treatment for patients with early-stage disease and type 1 genotype until the interferon-free drugs hit the market later this year.1
The next three expected are the NS-5A inhibitors ledipasvir, daclatasvir, and ombitasvir, which interfere with viral replication and assembly.
Clinical studies find SVR rates of more than 90% with a 12-week course of ledipasvir, and rates of 100% when it is combined with sofosbuvir and ribavirin.6,7
The combination of ombitasvir, ritonavir, and the still-investigational non-nucleoside polymerase inhibitor ABT-333 also resulted in SVR rates greater than 90%.8
Daclatasvir, studied in combination with a non-nucleoside protease inhibitor, and the protease inhibitor asunaprevir, studied in combination with sofosbuvir, also demonstrated a better than 90% SVR rate.1,9
Of course, it is ultimately the patient’s decision whether to wait and treat, or to treat now, said Dr. Saag. “It’s all in how you explain it. I put it in the context of the fact that they’ve been living with the virus for 20 or more years; so what’s another four to six months?”
The Hepatitis C Epidemic Unfolds
In 2012, the Centers for Disease Control and Prevention (CDC) recommended screening all adults born between 1946 and 1965 for hepatitis C. This cohort accounts for approximately 75% of HCV infections in the United States, with more than half unaware that they are infected.10,11
The majority of people with HCV are on Medicaid, non-white, and uninsured, according to one large study, with many receiving the bulk of their medical care in the emergency department.12 Thus, researchers at the University of Alabama-Birmingham decided to test all adults seen in the emergency room who were born between 1945 and 1965, about 18% of patients.
In two weeks, they screened 565 patients, 75% of whom did not know their HCV status. Of those, 12% were antibody positive, 71% with a confirmed chronic infection. About 43% of those infected were either uninsured or covered by Medicare or Medicaid.13
“This study confirms there is a large number of people who have hepatitis C and don’t know it,” said Michael S. Saag, MD, who directs the Center for AIDS Research at the University of Alabama at Birmingham. “With all of the new treatments coming out, most of which have cure rates over 95%, it is important for everyone to know their HCV status, especially if they were born between 1945 and 1965.”
1. Muir AJ. The Rapid Evolution of Treatment Strategies for Hepatitis C. Am J Gastroenterol. (2014) Published online ahead of print 4/15/2014
2. Hoofnagle JH, Sherker AH. Therapy for hepatitis C--the costs of success. N Engl J Med. (2014) 370:1552-1553.
3. Appleby J. VA, California Panels Urge Costly Hepatitis C Drugs For Sickest Patients. Kaiser Health News. April 17, 2014.
4. Pollack A. Lawmakers Attack Cost of New Hepatitis Drug. The New York Times. March 21, 2014.
5. Jacobson IM, et al. VR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington DC; 2013.
6. Gane EI, Stedman CA, Hyland RH, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON trial. Hepatology (2013) 58(Suppl 1):243A.
7. Lawitz E, Poordad F, Hyland RH, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin resulted in ≥ 95% sustained virologic response in patients with HCV genotype 1, including patients with cirrhosis: the LONESTAR trial. Hepatology (2013) 58(Supp 1):315A-316A.
8. Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon free regimens of ABT-450/r, ABT-267, ABT-333 +/ ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatology (2013) 58(Suppl 1):S2.
9. Everson Gt, Sims KD, Thuluvath PJ, et al. Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naive patients with chronic HCV genotype 1 infection. The 64th Annual Meeting of the American Association for the Study of Liver Diseases. Washington DC; 2013.
10. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR (2012) 61(RR-4):1-32.
11. Denniston MM, Klevens RM, McQuillan GM, et al. Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001-2008. Hepatology (2012) 55:1652-1661.
12. Tsui JI, Maselli J, Gonzales R. Sociodemographic trends in national ambulatory care visits for hepatitis C virus infection. Dig Dis Sci. (2009) 54:2694-2698.
13. Galbraith JW, et al. Screening in the Emergency Department Identifies a Large Cohort of Unrecognized Chronic HCV Infection Among Baby Boomers. The 64th Annual Meeting of the American Association for the Study of Liver Diseases. Washington DC; 2013