In 1989, I was privileged to be part of a relatively small multicenter group that submitted a paper to The New England Journal of Medicine on non-A, non-B hepatitis. The paper focused on the use of interferon and, in the final stages of preparation of our study for publication, serum testing showed that almost all the study patients had the newly described hepatitis C virus.
Our paper, along with an NIH report on the same subject, became a landmark paper in the field and with the encouragement of The New England Journal of Medicine the title changed from a “non-A, non-B paper” to a “hepatitis C paper.”
Everyone knows how meager the results from interferon therapy were in those days (and we learned much later with PCR technology in the early 1990s that we were curing an even smaller percentage of patients than sustained response rates defined by ALT normalization suggested) but the knowledge of the new virus and a potential treatment held promise.
Differentiating a New Virus
In the avalanche of new knowledge about interferon treatment that followed the approval of interferon alfa-2b, we learned more about the differentiation of HCV by the genotypes, and the disparate rates of response among different HCV genotypes.
When we began to examine them differently, the recognition that genotype 1 is the hardest type to cure with interferon was recognized and later we realized that genotype 2 had the highest response rate and genotype 3 was somewhat lower. (That’s ironic historically because genotype 3 became the hardest of the strains to treat with direct-acting antivirals.)
We learned about predictors of response to interferon like high viral load or low viral load. We learned that – at least with standard interferon therapy – patients coinfected with HIV and HCV were harder to cure of HCV. We learned that African Americans were much harder to cure. What also became clear was that our neediest patients – the ones with cirrhosis – were the hardest to cure.
We did not necessarily understand the why for these associations.
Interferon alfa-2b was the first interferon to be approved followed several years later by interferon alfa-2a, which was an identical molecule except for one amino acid out of 166 amino acids in the interferon alpha protein. Yet another interferon, consensus interferon, representing a protein containing the most common amino acid residue at each of the 166 amino positions of the molecule, was also approved, including for prior nonresponders.
In 1998, ribavirin received approval to be used as an adjunct to interferon. Despite its weak antiviral effect as an independent agent, and the controversy that has persisted to this day about its mechanism of action, it more than doubled the sustained response rates to interferon, which for about 5 years had come to be assessed virologically rather than biochemically. That improvement in response applied across all genotypes, though still leaving genotype 1 patients behind the others in terms of the rates of cure. Next, the pegylation of interferon was introduced and allowed for once weekly dosing with more level exposure to the drug when injected subcutaneously. Sustained response rates with pegylated interferon monotherapy were somewhat higher than with standard alpha interferon by itself. More importantly, the papers in the early 2000s showed peginterferon and ribavirin would be the new standard of cure. The sustained response rates were 8% to 10% higher than with standard interferon and ribavirin. It was at this time that the principle of treating patients with genotype 1 for a longer time than patients with genotypes 2 or 3 became firmly entrenched.
We entered a prolonged era of “refinement” through 2011 where we published seemingly innumerable studies on the application of peginterferon and ribavirin in subpopulations of people – African Americans, cirrhosis, HIV coinfection, renal failure, and others – but there were the same gradients in response across the subpopulations that there had been with interferon before. Most notably, viral genotype and viral load still remained a factor. We learned about “stopping rules” for futility and about the concept of varying the duration of therapy with parameters of response. Some studies evaluated extension of treatment to an arduous 72 weeks for “slow responders.”
Many academic careers were augmented by studies of these and other themes related to interferon or pegylated interferon and ribavirin therapy in different HCV populations. From a market viewpoint, a keen competition emerged between the two pegylated interferons, culminating in a study called “IDEAL” published in 2009 that compared the two in patients with genotype 1 and showed similar rates of SVR; peginterferon alfa-2a (which was flat dosed, not weight-based dosed) yielded higher on-treatment response rates but also higher rates of relapse. Both peginterferons remained in common use, but peginterferon alfa-2a ultimately predominated especially when peginterferon began to be combined with investigational DAA agents.
The End of the Interferon Era
By 2010-11, it did not take special visionary powers to sense that the era of interferon was starting to draw to a close. Between 2005 and 2010, we saw studies mature on two early protease inhibitors, and the beginning of efforts to develop other DAAs both in this class and other classes. These protease inhibitors were very potent inhibitors of viral replication and phase 2 trials showed distinctly higher rates of sustained response in genotype 1, for which these protease inhibitors were developed, when combined with peginterferon and ribavirin.
In 2011, we hit a new milestone with approval, following phase 3 trials, for Incivek (telaprevir, Vertex Pharmaceuticals) and Victrelis (boceprevir, Merck) for use with peg-interferon and ribavirin. These approvals were understandably hailed as a great advance because of the incremental efficacy in genotype 1 patients. Unfortunately, they added to the already substantial toxicity of interferon and ribavirin in the form of greater decrements in hemoglobin with more pronounced anemia, already a problem with peg-interferon and ribavirin. Though we tried using erythropoietin, reports of thrombotic events in other patients such as those with kidney disease, eventually made us reluctant to use these agents.
We were still desperate to get away from interferon and our hopes were nurtured by presentations and publications in 2010 and 2011. One of these was the INFORM trial, which was the first study to use two oral direct-acting antiviral agents in different classes, namely a protease inhibitor, danoprevir, and a nucleotide polymerase inhibitor, mericitabine. The research clearly showed proof of concept for a very potent reduction in viral replication in the first 28 days, but when the drug was stopped, the virus would always return to baseline or similar to baseline levels.
A New Revolution in Therapy
We didn’t establish proof of concept for cure until the first trials, published in 2011 with prior presentations at meetings showed that one could indeed cure patients without interferon by using combinations of different classes of antiviral drugs.
The ELECTRON study evaluated a nucleotide polymerase inhibitor superior to earlier drugs in this class, sofosbuvir (Gilead Sciences), in combination with ribavirin. It was this study along with everything that followed that laid the groundwork for sofosbuvir becoming the single most recognizable HCV DAA in its own right, with its potency and high barrier to resistance. Even without either of the other two classes in combination, it cured 10 out of 10 genotype 2 and 3 patients in that study.
I vividly recall the presentation by the outstanding clinical investigator Ed Gane, MBChB, MD, FRACP, MNZM, that uniquely resulted in four overflow rooms at the AASLD Liver Meeting. Many people remember the struggle to find seats (those who tried to sit on the floor were ejected), and the hush that fell over the audience as people heard for the first time that patients were being cured permanently of this viral infection with oral antivirals that were easily tolerated.
At around the same time we saw the results of a study from Anna Lok et al, subsequently also published in The New England Journal of Medicine, showing that four patients with genotype 1 had been cured with a combination of asunaprevir, a protease inhibitor, and daclatasvir, the first-in-class NS5A inhibitor (BMS). We knew that we had entered a new era.
In rapid succession over the next couple of years, larger proof-of-concept studies emerged, including a much larger study with daclatasvir and sofosbuvir with very high percentages of people across genotypes 1 to 3 achieving sustained virologic response. Another program focusing on the combination of paritaprevir (protease inhibitor)/ritonavir, ombitasvir (NS5A inhibitor) and dasabuvir (a non-nucleotide polymerase inhibitor; AbbVie) also indicated that we were going to be making a quantum leap to SVR rates of 90% or more without the incremental steps in efficacy that many had predicted might take years to evolve.
In late 2013, we witnessed the approval of sofosbuvir with ribavirin for genotypes 2 and 3 and peg-interferon/ribavirin/sofosbuvir for all genotypes, including genotype 1. Ironically, this was the shortest duration, at 12 weeks, and most efficacious peg-interferon regimen (SVR 90%) ever devised, but short lived in clinical use. Nearly simultaneously, simeprevir, a protease inhibitor at least as effective as telaprevir and boceprevir, and better tolerated, was also approved with peginterferon and ribavirin for genotype 1. However, the major impact of simeprevir through most of 2014 was its off-label use, accessible with gratifying if surprising frequency, in combination with sofosbuvir for genotype 1 based on the phase 2 COSMOS trial showing SVR rates over 90%. In late 2014 we had the approvals of Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) and Viekira Pak (paritaprevir/ritonavir/ombitasvir/dasabuvir, AbbVie), followed in early 2016 by grazoprevir and elbasvir (Merck) for genotypes 1 and 4. By mid-2016, the first DAA regimen approved for all genotypes, sofosbuvir and the NS5A inhibitor velpatasvir (Gilead Sciences) was introduced, with demonstrated efficacy in decompensated cirrhotics and HIV-HCV coinfected patients as well as “standard populations”. The use of interferon rapidly became extinct, cementing the evolution of HCV therapy as one of the great therapeutic advances in medicine of recent times.
By mid-2017, less than years after the first approval of a DAA therapy in HCV, we had two more pan-genotypic regimens – glecaprevir/pibrentasvir (AbbVie) – and a regimen approved for DAA failures across all genotyopes – sofosbuvir/velpatasvir/voxilaprevir (Gilead Sciences).
The End of History?
Have we reached the “end of history” in terms of the evolution of HCV therapy now that we have regimens that are up to 99% effective and have a salvage regimen(s) that can cure 96% of failures to the DAA regimens?
Today, when we encounter a patient with HCV for the first time, there’s only about a one in 1,000 chance – when you combine all the options for treatment and retreatment – that this patient will fail to be cured by the totality of the regimens we now have available. Of course, we want to save every last patient from having chronic HCV, but what level of resource can we devote to development of new regimens?
Hepatologists debate amongst themselves whether shortening therapy for its own sake even without improved cure rates would be an important advance. Many people – including myself – feel that 8- to 12-week regimens such as we have now seldom result in compliance issues, at least in developed countries. Though strategies for making the full potential of DAA regimens a reality in developing nations may be necessary, many American and European hepatologists think that we have reached the goal. Nevertheless, as recently as the AASLD meeting in November 2018 we saw presentations of data with new viral protein inhibitors representing the same classes as those in use; the goal of these development programs centers largely on further shortening of the duration of therapy.
Such efforts notwithstanding, the major emphasis when you look at the abstracts at international and national meetings, and recent publications, has shifted to the “social science” and pharmacoeconomics of diagnosing and treating HCV.
Researchers are exploring improved identification of infected people, especially amidst the burgeoning HCV epidemic in young people now due to the tragic opioid epidemic. There’s also interest in shifting the recommendation to use birth cohort screening as the standard to universal screening in adults as Michael S. Saag, MD, addresses in his counterpart editorial.
That debate will go on, but we have already had a complete about-face philosophically and medically coming from an extreme reluctance among most treaters to treat active drug users in the interferon era to a general acceptance that even patients who are actively using drugs or getting substitution therapy should be treated, ideally in a setting involving collaboration with, or even the major role being played by, experts in addiction medicine. There are, to be sure, cases of reinfection in this population, but they are acceptably low. By treating these patients, we are not only helping the majority of people with active drug use problems be cured of this potentially lethal virus, but you’re also protecting all of those with whom they may come into contact in the future.
Finally, this article would be incomplete without mention of the extraordinary development in the transplantation field reflected by the widespread implementation of the once unthinkable practice of transplanting HCV-positive organs to HCV-negative recipients across many organs to improve access, including not just liver and kidney transplants but heart and lung transplants as well. The near universal capacity to cure patients’ post-transplantation, even in the face of immunosuppression, is profoundly eloquent testimony to the HCV therapeutic revolution.
By Ira M. Jacobson, MD
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