Hepatitis C Treatment in 2016: Reasons to Be an OPTIMIST
Authors: Hugo E. Vargas
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Vargas received grants from AbbVie, Merck, Gilead, and Bristol‐Myers Squibb. See Article on page 360 and 370 The rapid translation of hepatitis C virus (HCV) direct antiviral agent (DAA) development into clinical regimens that began in 2011 with the introduction of the first‐generation protease inhibitors (PIs), telaprevir and boceprevir, has transformed the field. The difficult road to an interferon (IFN)‐free regimen has been fraught with dead ends as promising compounds were abandoned in search of the optimal antiviral. Even on introduction of the first wave of agents, still requiring the use of IFN, clinicians were frustrated by results that were inferior to those of the studies that led to U.S. Food and Drug Administration (FDA) approval for those compounds.1 In late 2013, sofosbuvir (SOF) became the first FDA‐approved regimen that eliminated IFN, if only for viral genotypes 2 and 3. But it was the results of two progressive, small, phase 2 clinical trials that set the stage for an approach to patient management that is at the root of the optimism that enshrouds the field. In the first trial, the nonstructural protein 5A (NS5A) inhibitor, daclatasvir (then in phase 2 clinical trials), was used in combination with SOF to treat patients who were treatment inexperienced (genotypes 2, 3, and 1) and previous PI‐based treatment failures (genotype 1; G1) with 12‐week sustained virological response (SVR12) rates that were above 93%.2 In the second, the COSMOS trial, patients infected with G1 HCV with previous nonresponse (cohort 1) and later naïve to therapy and nonresponders (cohort 2) were treated with a combination of SOF and the second wave, first‐generation PI, simeprevir (SMV), with or without ribavirin for 12 or 24 weeks. The excellent results (SVR12 rates of 90% and 94% for cohorts 1 and 2, respectively) with no apparent need for the use of ribavirin and excellent safety profile were widely presented and eventually published.3 The creation of a program called OPTIMIST to further explore the findings of COSMOS was promptly announced (J&J press release, April 4, 2014). The FDA approval of SMV (which shortly preceded that of SOF) led the treating community to quickly embrace the COSMOS results. The IFN‐free era for patients with G1 infection using the agents in combination (with and without ribavirin) in off‐label fashion had thus begun. The impact of this practice was rapidly reflected in the medical literature, with large numbers of early reports of safe and effective treatment outside of registration clinical trials, including real‐world data from the TARGET consortium.4 It was not until the registration of the coformulated SOF and ledipasvir (LDV) almost a year later, shortly followed by formal endorsement of SMV/SOF and that of the so‐called 3D regimen (paritaprevir/ritonavir, ombitasvir, and dasabuvir), that the FDA formally approved all oral HCV treatment options for G1 patients. In this issue of Hepatology, two phase 3 studies, the results of the OPTIMIST program, are published.9 In OPTIMIST‐1, Kwo et al. report on a randomized, open‐label study that addressed the efficacy of SOF combined with SMV in 310 patients without cirrhosis who were treatment naïve and treatment‐experienced G1 patients.9 Subjects were randomized to receive 8 or 12 weeks of treatment and were stratified according to infecting viral subtype, presence or absence of Q80K polymorphism in G1a (a resistance‐associated mutation known to decrease the effectiveness of SMV), interleukin 28B (IL28B) genotype, and past treatment history (both host factors known to influence treatment response in the IFN era). The investigators compared efficacy of both regimens against a composite historical control of DAA‐based regimens available at the time of study launch and aimed to demonstrate noninferiority of both regimens. Care was taken to evaluate the impact of baseline viral loads and preexisting resistance‐associated variants (RAVs). Safety reports were excellent, with mild symptoms that did not lead to treatment discontinuation. The overall SVR12 was 97% for the 12‐week regimen, which was superior to the historical rate of 87%. The 8‐week regimen at 83% SVR12 was lower than the historical rates observed with SOF/LDV (94%) and thus was found to be inferior. A key finding was that Q80K polymorphism in the G1a patients rendered the 8‐week regimen less effective, whereas these variants did not impact the results of the 12‐week regimen. Ultimately, the number of patients who relapse on this shorter regimen without emergent resistant variants highlights the need for longer treatment with this combination. In OPTIMIST‐2, Lawitz et al.10 report the results of a treatment protocol, with the same regimen, targeted toward the same genotypes, but who had well‐compensated cirrhosis. They treated 103 patients diagnosed with cirrhosis by liver biopsy or indirect methods for 12 weeks with SOF and SMV in open‐label fashion. Once again, a predetermined noninferiority threshold based on expected SVR with available DAA regimens was used as comparator. For this group, the historical control index was 76%. In this very difficult‐to‐treat group, the overall SVR was 83%, with a very respectable 92% SVR in those patients who did not have Q80K variants. Emergent RAVs were more important in this population, as evidenced by on‐treatment breakthroughs that were confirmed to be attributable to NS3/4a region mutation. In this patient population, IL28B genotype had an impact on SVR, as did the degree of hepatic decompensation as measured indirectly by the serum albumin level at start of treatment. Although the regimen was superior to historical controls, its performance in patients with G1a was lackluster in those who harbored RAVs. So, why the OPTIMISM? These studies clearly had limitations. Based on the promise of the small COSMOS study, this program did not study the performance of SOF/SMV with ribavirin in patients with cirrhosis, nor did it consider the potential benefit of a 24‐week regimen. In view of better results with other DAA combinations of similar duration, SOF/SMV may not be the regimen of choice for a large swath of the population. The limited size of the studies also curtails the extrapolations that can be made from subgroup analyses. However, SMV/SOF can, in the right setting, be a very good choice for a population of patients that cannot or will not tolerate IFN or ribavirin. Because it does not contain NS5A complex blockers and is not impacted by NS5A RAVs, it may be a very good choice for patients who failed a regimen that included such an agent. The safety and efficacy of this regimen remains well established, even in difficult‐to‐treat patients.11 The publication of these phase 3 studies are an important milestone in the development of a sound HCV treatment strategy. Whereas the dawn of IFN‐free treatment is a very important event on its own merit, the manner in which this era arrived is also remarkable. The dynamic state of HCV treatment has seen rapid adoption of regimens based on initial positive reports, followed by reporting of efficacy and safety that beat even the forward‐looking FDA streamlining of the drug approval process. It is a testament to the dedication of investigators, clinicians, patients, and their advocates that regimens such as SOF/SMV have been deployed and cured hundreds of patients before the results of the phase 3 trials are published. We have overcome the most difficult barrier to HCV treatment: the length, complexity, and side‐effect profile of IFN‐containing regimens. We can and must overcome the financial barriers that currently limit wide access worldwide to these new drugs, which is a human and not a viral challenge. This is why we should rejoice and remain OPTIMISTic about the future for our HCV patients.