When Hepatitis C Treatment Failure Occurs
In phase II and III clinical trials, high rates of cure (greater than 90%) have been reported with newer combinations of direct-acting antivirals (DAAs). However, as these drugs become more widely used, researchers are beginning to report occasional cases of treatment failure. In some cases treatment failure can occur because of relapse. That happens when HCV viral load first falls to an undetectable level during a course of treatment; later, once a course of treatment has ended, HCV subsequently becomes detectable. Overall, and particularly among people who have never been previously treated, cases of relapse with DAAs are uncommon.
Doctors in Madrid, Spain, have reviewed data from clinical trials as well as reports and analyses of treatment failure (due to relapse or other causes) when DAAs have been used. They noted that the following factors have been associated with treatment failure:
- the presence of symptoms linked to cirrhosis
- prior treatment failure
- very high levels of HCV in the blood
- being infected with HCV genotypes 1a or 3
- being male
Small Errors in Virus Production
As HCV-infected cells produce millions of copies of this virus, some copies have changes, or mutations, in their genetic information that occur by chance. Some of these mutations inadvertently allow HCV the ability to resist the effect of one or more DAAs. Thus it is possible that in a small proportion of people who have never been treated there might be low levels of HCV circulating that possess the ability to resist a DAA.
An Evolving Field
Mutations associated with HCV drug resistance are different compared to drug resistance mutations associated with another virus -- HIV. In the case of HIV, drug resistance mutations can last for many years, and the presence of just one major mutation can greatly impair the activity of an anti-HIV drug and sometimes related drugs within a class.
In the case of HCV, the situation is somewhat different. That is, some of these DAA mutations can disappear from circulation within days. This is the case with mutations to the drug sofosbuvir (Sovaldi). Mutations that affect NS3 inhibitors (protease inhibitors) can take several months to disappear from circulation. Mutations that affect another key HCV target called NS5B can persist in circulation for more than a year. Lastly, mutations that affect NS5A inhibitors persist in circulation for two years, perhaps longer.
Another aspect of HCV drug resistance mutations is the frequency with which they occur. For instance, some researchers say that in most cases unless a drug resistance mutation is found in more than 15% of circulating copies of HCV, they do not expect that this should decrease the chances of a person being cured with DAAs.
Thus, resistance testing may become an important part of HCV care, particularly in cases of treatment failure and re-treatment.
In cases of severe cirrhosis (graded as Child-Turcotte-Pugh C) rates of cure have been generally lower than in cases of less severe cirrhosis. This problem arises because in such advanced cirrhosis, blood circulation within the liver is reduced. As DAAs are transported by blood, sufficient concentrations of these drugs may not penetrate all parts of the liver that contain HCV-infected cells. Less-than-ideal levels of DAAs may allow the development of drug resistance, ultimately leading to treatment failure.
In cirrhosis, the liver is also dysfunctional and may not process or break down DAAs. This could lead to cases of subtle toxicity.
After Treatment Failure
There is no simple path forward after HCV treatment failure because the reasons for such an outcome can differ from one patient to another. The Spanish researchers suggest that the following issues be considered by physicians in cases of possible re-treatment:
- Are drug resistant mutations present?
- Was the patient's genotype correct?
- Was the patient re-infected with a different strain of HCV?
- Consider adding ribavirin to a future regimen
- Think about extending the duration of a future regimen (beyond 12 weeks)
Maximize drug benefit
- Avoid drug interactions
- Prevent and manage side effects
- Ensure adherence to treatment
More Powerful Drugs on the Way
Later in 2016 and in 2017 new combinations of DAAs that should be effective against many strains of drug-resistant HCV will likely become licensed by regulatory authorities in North America and Western Europe. Drugs in these combinations include the following:
- ABT-493 + ABT-530
- sofosbuvir + velpatasvir
- sofosbuvir + velpatasvir + GS-9857
- MK-8408 in combination with other drugs
Benítez-Gutiérrez L, Barreiro P, Labarga P, et al. Prevention and management of treatment failure to new oral hepatitis C drugs. Expert Opinion on Pharmacotherapy. 2016; in press.