Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?
Dr. Rosen: Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.
For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.
Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.
Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.
Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.
When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.
The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.
Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.
Are there any other unmet needs that still exist in treating any of these special patient populations?
Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.
Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.
You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.
In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.
I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand.
What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?
Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.
We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.
COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.
We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.
The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.
