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AASLD 2016: Non-Adherence Is Most Important Risk Factor for Sofosbuvir/Ledipasvir Failure


Research carried out by researchers at Mount Sinai Medical Center in New York found that non-adherence was the strongest risk factor for treatment failure in people taking sofosbuvir/ledipasvir (Harvoni) to treat hepatitis C. The main reasons cited for non-adherence were failing to take medication as prescribed and hospitalization, according to a report at the 2016 AASLD Liver Meeting in Boston earlier this month.

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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 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 medication refill, 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.

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

Researchers identified 43 people who experienced post-treatment viral relapse. A sample of 101 patients treated at the same clinic who achieved sustained virological response at 24 weeks post-treatment (SVR24) was compared with the relapse group to identify risk factors for treatment failure.

The 43 people who experienced treatment failure had an average age of 59 years, 54% were African American, 26% were Hispanic, and 20% were white. 18 had prior hepatitis C treatment experience (4 with direct-acting antivirals, the rest with interferon) and 21 had liver cirrhosis (17 with Child-Pugh A, 4 with Child-Pugh B). The predominant hepatitis C virus (HCV) genotypes were 1a (26) and 1b (12); none had genotype 3 infection.

Among the patients with treatment failure, 5 people received an 8-week course of treatment, 33 received a 12-week course, and 5 received a 24-week course. Most (38 people) achieved undetectable HCV RNA during treatment and none experienced subsequent viral breakthrough while on treatment.

Viral relapse had occurred in 37 of these 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.

A majority (33) of the 43 people who experienced treatment failure reported to their physician that they had been adherent. Non-adherence was defined as missing at least 7 doses of sofosbuvir/ledipasvir. Reasons for non-adherence were not taking medication as prescribed (5 patients), hospitalization (3), loss of medication (1), failure to refill medication (1), and side effects (1).

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

  • Black race: odds ratio (OR) 3.84 (p=0.001);
  • Male sex: OR 3.86 (p=0.007);
  • Non-adherence: OR 16.3 (p<0.0001).

The only significant difference between people who adhered well to treatment 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 counseling and a pill bottle monitoring system may also improve SVR rates.

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

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 frequently cited as a reason for missing doses in the same study (Petersen, CROI 2014, abstract #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 treatment to ensure that it will be successful.

Patients can also assess their own readiness for treatment 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 about treatment adherence, side effects, and lab test results.



D Sarpel, I Wasserman, AL Trochtenberg, et al. Non-adherence is the most important risk factor for ledipasvir/sofosbuvir HCV treatment failure in the real world. AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract 1978.