Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.
What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?
Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.
Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.
What is the current standard of care for patients who failed a first line DAA regimen ?
Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).
Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.
Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.
Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?
Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.
We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.
Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.
With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.
Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?
Dr. Lim : Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR. 1, 2 For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR. 3 As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.
How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?
Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.
In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.
It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.
