Non-adherence most important risk factor for sofosbuvir/ledipasvir failure

Keith Alcorn
25 November 2016

Research carried out by Mount Sinai Medical Center, New York, found that non-adherence was the strongest risk factor for treatment failure in people taking sofosbuvir/ledipasvir (Harvoni). The main reasons cited for non-adherence were failing to take medication as prescribed and hospitalisation.

The findings were presented at the 2016 AASLD Liver Meeting in Boston earlier this month.

Although hepatitis C treatment failure rates are low, the cost of re-treatment is a substantial barrier to cure in people with hepatitis C who do experience the failure of a direct-acting antiviral regimen. Non-adherence may result in drug resistance, potentially reducing the response to subsequent therapy.

Once treatment is prescribed and payment for treatment through insurance or Medicaid is approved, people may still face a number of structural barriers to adherence, such as prohibitive co-payments required for each refill of medication, homelessness, incarceration or shift work patterns.

Motivational and educational barriers to adherence, such as lack of knowledge about pill-taking or the need for adherence, have been less explored.

The study investigated the relationship between treatment failure and non-adherence at a Mount Sinai Medical Center outpatient clinic in people receiving sofosbuvir/ledipasvir for either 8 or 12 weeks.

Forty-three people experienced post-treatment viral relapse. A sample of 101 patients treated at the same clinic who achieved SVR24 was compared with the treatment failure group to identify risk factors for treatment failure.

The 43 people who experienced treatment failure had an average age of 59 years, 53.5% were African American, 25.6% Hispanic and 20% white. Eighteen of the 43 people had prior experience of hepatitis C treatment (four with direct-acting antivirals) and 21 had cirrhosis (17 Child-Pugh A, 4 Child-Pugh B). The predominant genotypes were 1a (26) and 1b (12). None had genotype 3 infection.

Five people received an 8-week course of treatment, 33 received a 12-week course of treatment and five received a 24-week course of treatment. Thirty-eight of 43 people achieved undetectable HCV RNA on treatment and none experienced subsequent viral breakthrough on treatment.

Viral relapse had occurred in 37 of 38 patients by the time of the first post-treatment visit (variable periods elapsed before the first post-treatment visit) and, in the remaining patient, by the time of the 24-week post-treatment visit.

Thirty-three of 43 people reported to their physician that they had been adherent. Non-adherence was defined as missing at least seven doses of sofosbuvir/ledipasvir. Reasons for non-adherence were not taking medication as prescribed (5 patients), hospitalisation (3), loss of medication (1), failure to refill medication (1) and side-effects (1).

Multivariate analysis found significant associations between treatment failure and the following factors:

  • Black race: odds ratio (OR) 3.84 (95% CI 1.67-8.86) (p = 0.001)
  • Male sex: OR 3.86 (95% CI 1.37-10.85) (p = 0.007)
  • Non-adherence: OR 16.3 (95% CI 3.26-81.92) (p < 0.0001)

The only significant difference between those who adhered and those who were non-adherent was a modest difference in the number of clinic visits during the treatment period; non-adherent people visited the clinic an average of 3.9 times, adherent people 2.6 times (P = 0.03).

The researchers concluded that their findings “underscore the need for providers to clearly communicate dosing information and to ensure that patients have access to an uninterrupted supply of medication.” They suggested that pre-treatment adherence counselling and a pill bottle monitoring system may also improve SVR rates.

The content of pre-treatment counselling needs to be tailored to patient characteristics and pre-existing beliefs about treatment, as well as addressing lifestyle factors that might affect adherence.

Previous research has shown that adherence to interferon-free hepatitis C treatment declines with time on treatment, with patients frequently citing the perception that treatment was working as a reason for missing doses. Lack of privacy was cited frequently as a reason for missing doses in the same study (Petersen, CROI 2014, poster #667). Greater pill burden was also associated with non-adherence, a problem encountered in other disease areas along with greater non-adherence with multiple daily doses. Psychiatric issues and substance use may also affect treatment adherence.

The Psychosocial Readiness Evaluation and Preparation for Hepatitis C Treatment (PREP-C) tool has been designed to allow healthcare providers to conduct a psychosocial evaluation of readiness to take hepatitis C treatment, and to identify areas of psychosocial functioning that can be improved before a patient begins HCV treatment to ensure that treatment will be successful.

Patients can also assess their own readiness for treatment by using the HepCure app, developed by the Mount Sinai hepatitis C team. The app can also be used to set adherence reminders and to communicate with healthcare providers on treatment adherence, side-effects and lab test results.


Sarpel D et al. Non-adherence is the most important risk factor for ledipasvir/sofosbuvir HCV treatment failure in the real world. Hepatology Special Issue, The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, abstract 1978, Boston, 2016.