Table of Contents
Special thanks to Juliana Chan and Polly Clayden
Dedicated to Luis Mendão: brilliant activist and delightful human being.
In May of 2011, a long-awaited improvement in the standard of care for hepatitis C virus (HCV) became reality: the US Food and Drug Administration (FDA) approved the first direct-acting antivirals (DAAs), Merck's boceprevir (Victrelis) and Vertex's telaprevir (Incivek). But excitement about these new drugs has already been overshadowed by a triple-whammy: the first proof-of-concept that hepatitis C can be cured without peginterferon (PEG-IFN) and ribavirin (RBV); reports of better drugs on the horizon; and challenges in clinical care, including the complexity and cost of new HCV regimens, a critical shortage of specialists to administer HCV treatment, and lack of infrastructure for treatment delivery.
In April 2011, groundbreaking results from a 21-person pilot study were announced: after only 24 weeks of treatment with two oral DAAs, a protease inhibitor and an NS5a inhibitor from Bristol-Myers Squibb, four of ten people were cured. Quad therapy (with peginterferon and ribavirin added) was even more effective, curing nine of ten people.1 For now, the success of HCV treatment rests largely upon response to peginterferon. Hopefully, peginterferon will become a therapeutic relic as the standard of care for HCV continues to evolve. The next batch of DAAs may cure more people in less time than triple therapy with peginterferon, ribavirin, and boceprevir or telaprevir. Trials are exploring DAA combinations without peginterferon; some are using it only when DAAs do not fully suppress HCV. Although ribavirin plays an essential role at present, there may be equally effective and more tolerable replacements in the future.
"The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. ... The influx of patients requesting HCV therapy will present a significant problem. ... On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity ... we anticipate at least 500 requests for evaluation for HCV therapy within the first few weeks of DAA availability, [so] current staffing will be unable to meet the demands of all patients with HCV."
-- Andrew Aronsohn and Donald Jensen,"Distributive Justice and the Arrival of Direct-Acting Antivirals: Who Should Be First in Line?"
The current challenge -- to fully realize the benefits of boceprevir and telaprevir by avoiding drug resistance and treatment failure -- is immediately ahead of us. In the United States, there are not enough specialists to meet current demand for HCV treatment. Many have "warehoused" patients in anticipation of better treatment, and are not seeing any new patients. At the same time, patient management is becoming more complex, involving response-guided therapy and drug-specific treatment algorithms. We are not prepared for the anticipated surge in HCV treatment uptake triggered by more effective treatment.
"... And, please, let me talk about money. In Spain, we received the news about the price of boceprevir and telaprevir in the US with incredulity. We are indignant, and we do not understand how pharmaceutical companies can justify these outrageous prices. Western society has given the private sector the opportunity to research and develop treatment, but this doesn't entitle you to charge disproportionate prices. At a time when cuts are causing the closure of entire hospital units, emergency rooms and a variety of medical services in this country, how do you expect us to be able to advocate for your new drugs?"
-- Xavi Franquet, European Community Advisory Board and Grupo de Trabajo sobre Tratamientos del VIH, Sitges IV Meeting, June 2011
Most of the 130 to 170 million people who are living with chronic hepatitis C will not be cured, because HCV treatment is too expensive. Many high-burden countries cannot afford to offer hepatitis C testing, let alone treatment. Although efforts to produce generic peginterferon are underway, access to HCV treatment remains limited or nonexistent.
In the United States, 48 weeks of peginterferon and ribavirin costs more than $30,000. Boceprevir-and telaprevir-based regimens halved treatment duration for 44% (boceprevir) to 58% (telaprevir) of study participants.2-4 But any possible savings on peginterferon and ribavirin are offset by the cost of HCV protease inhibitors (see Table 1. Cost of HCV Treatment with a Protease Inhibitor in the United States).
Unfortunately, the boom in drug development has not been accompanied by innovative and affordable diagnostics for HCV, and point-of-care viral load testing for monitoring response to treatment. There is no single test for acute-stage HCV, and diagnosis of chronic hepatitis C remains an expensive two-step process. In many parts of the world, people do not have access to HCV testing. Even when HCV RNA testing is accessible, the process can be overly cumbersome, since people have to return for a second testing visit without being given a diagnosis. Research to streamline HCV diagnostics with a single inexpensive test should proceed in tandem with drug development.
|Table 1. Cost of HCV Treatment With a Protease Inhibitor in the United States|
(Does not include: HCV RNA testing and other labs, medical visits, and additional medications for side effects)
|Drug, Duration, Price Range||Early Response||Slow Response||Responder/Relapser||Partial and Null Responders*||People With Cirrhosis|
Total duration: 28-48 weeks $45,227 to $80,675 (with PegIntron)
|24 weeks of boceprevir $26,400 (+PEG/RBV for 28 weeks at $18,827)||32 weeks of boceprevir $35,200 (+PEG/RBV for 48 weeks at $32,275)||32 weeks of boceprevir $35,200 (+ PEG/RBV for 36-48 weeks at $24,206-$32,275)||32 weeks of boceprevir $35,200 (+ PEG/RBV for 36-48 weeks at $24,206-$32,275)||44 weeks of boceprevir $48,400 (+PEG/RBV for 48 weeks at $32,275)|
Total duration: 24-48 weeks $65,322 to $81,445 (with Pegasys)
|12 weeks of telaprevir $49,200 (+ PEG/RBV for 24 weeks at $16,122)||12 weeks of telaprevir $49,200 (+ PEG/RBV for 48 weeks at $32,245)||12 weeks of telaprevir $49,200 (+ PEG/RBV for 24-48 weeks at $16,122-$32,245)||12 weeks of telaprevir $49,200 (+PEG/RBV for 48 weeks at $32,245)||12 weeks of telaprevir $49,200 (+PEG/RBV for 48 weeks at $32,245)|
* Boceprevir labeling suggests that people with <0.5 log10 drop in HCV RNA at week 4 are likely to be null responders; they were not included in the phase III trial for treatment-experienced people.
Public and private payers are sure to balk at the cost of DAAs, and are likely to impose restrictive treatment eligibility criteria and other barriers, such as prior authorization and top-tier pricing, making access difficult. It is unfortunate that payers are the strongest recourse for price controls.
HCV clinical trials are going to become even more complex, with the advent of triple therapy (peginterferon and ribavirin plus boceprevir or telaprevir). Different dosing schedules will make it difficult to assess efficacy of a single drug and to compare regimens. Boceprevir and telaprevir need to be taken every eight hours, while most second-generation DAAs are once-a-day drugs. Blinded trials will require twice-daily placebo with once-daily drugs. People who are taking a once-daily drug plus placebo may skip their only dose of active drug, placing them at higher risk for treatment failure and drug resistance, since adherence is known to worsen with more frequent dosing requirements. The advantages of a once-daily drug may be obscured by placebo.
HCV clinical trials must incorporate drug- and patient-specific considerations. Treatment algorithms and stopping rules differ for each drug and according to the population it is studied in. Host and viral factors, such as IL28B genotype, stage of liver disease, race/ethnicity, age, HCV subtype (1a versus 1b), and prior response to HCV treatment must also be taken into account. Designing clinical trials and interpreting their results will become more and more of a challenge.
Cure rates with telaprevir- and boceprevir-based regimens are high, making it more difficult for other DAAs to demonstrate superiority. Non-inferiority trials will be needed for the next generation of drugs. These agents are likely to offer other advantages, such as shortened treatment duration, simpler regimens, and more convenient and tolerable drugs. Hopefully regulators and sponsors will consider non-traditional endpoints, such as treatment duration and discontinuations for adverse events, and type, incidence and severity of side effects, along with efficacy. Tolerability and convenience are also extremely important to people who will be taking these drugs.
Interpreting data from complex clinical trials and translating them directly into clinical practice is difficult, particularly in the absence of a standing, multidisciplinary treatment guidelines panel, an approach that has optimized HIV treatment outcomes and facilitated reimbursement by public and private payers. Simplicity should become a major focus of HCV drug development.
Merck and Vertex chose not to conduct early access trials in people with urgent need, who were ineligible for their clinical trials. Early access trials could have saved lives, and allowed physicians to gather information about if and how HCV protease inhibitors could be used in patients who need them most. It is likely that boceprevir and telaprevir will be used in desperate patients, regardless of the lack of information about their safety and efficacy. It is time for the pharmaceutical industry to work with regulators, physicians, and activists to launch early access trials.
Unfortunately, boceprevir and telaprevir are not going to be able to get the job done for people with poor prognostic factors, urgent need, and peginterferon intolerance. Prior null responders with cirrhosis did not reap much benefit; adding telaprevir to peginterferon and ribavirin increased the cure rate from 10% to only 14%, and there are limited data on boceprevir in this population.5
Safety and efficacy of boceprevir and telaprevir are not yet known in HIV/HCV coinfected people (although pilot studies are ongoing, and larger ones planned). No studies have been initiated in children, the elderly, people with renal insufficiency, or liver transplant candidates and recipients (although there have been no pharmacokinetic studies of boceprevir and telaprevir is not recommended for people with hepatic impairment).
Despite low enrollment of African Americans in registration trials for boceprevir and telaprevir, it is clear that adding one of these drugs significantly increased rates of sustained virological response (SVR; meaning no hepatitis C can be detected six months after treatment completion; regarded as a cure) over PEG-IFN/RBV (see Table 2. Translating Trial Results into Clinical Practice: Boceprevir and Telaprevir in Treatment-Naive Persons). But there are lingering questions about the optimal duration of boceprevir-based therapy in African Americans, since the SVR among African Americans was 11% lower for response-guided therapy versus 48 weeks of treatment.3
Unfortunately, data on SVR among Latinos/Latinas are scarce. Latinos and Latinas comprised less than 10% of treatment-naive study participants in telaprevir phase III trials Nonetheless, telaprevir did boost SVR among treatment naive Latinos/Latinas; SVR rates ranged from to 70% to 94%, a significant improvement over peginterferon and ribavirin.2,4 Merck did not provide any data on boceprevir in Latinos and Latinas.
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