Adherence to hepatitis C treatment: unravelling the complexities

Successful adherence to hepatitis C treatment may require physicians and care teams to address a wide range of factors, according to research from the United States and Germany presented at The Liver Meeting 2012, the 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston last month.

Hepatitis C treatment presents a number of adherence challenges that are distinct from other disease areas, due to the use of pegylated interferon, which causes both physical and psychological side-effects that affect numerous areas of a patient’s life during a treatment course that may last up to 48 weeks, and which may be undergone several times if the first course is unsuccessful.

Non-adherence to pegylated interferon and ribavirin often consists of non-completion of the treatment course, but a large cohort study of US veterans has also observed that adherence to ribavirin (as measured by prescription refills) declined after the first 12 weeks of therapy, even if the treatment course was completed, and that sustained virologic response was associated with higher levels of ribavirin adherence throughout the 48-week treatment course.

New direct-acting antivirals (DAAs) also present adherence challenges, because they must be taken up to three times a day for 12 to 24 weeks in most cases, and can cause side-effects that also interfere with daily functioning.

In addition to non-completion of the treatment course, missing doses of antivirals is a problematic form of non-adherence to DAA treatment, because it presents a risk of loss of virological control, resulting either in failure to achieve a rapid virologic response during the first four weeks of treatment (RVR), or in viral breakthrough after initial suppression has been achieved. This may lead to drug resistance to the antiviral agent.

Maximising people’s ability to adhere to treatment requires an understanding of behavioural as well as biological factors, including socioeconomic status, access to treatment, the disease stage, a patient’s individual ability to adapt and moderate behaviour, the treatment itself, its side-effects and cost.

Lauren Rover of George Mason University, Virginia, and Inova Health Systems, a large non-profit healthcare provider in northern Virginia, told a conference session that, for short-term treatment regimens, adherence rates of 70 to 80% are often achieved. For longer-term treatments, adherence rates drop to 40 to 50%, while adherence rates for therapies that also include an element of behaviour change are stuck at around 20 to 30%.

It is worth noting, however, that in one disease area – HIV infection – long-term adherence rates are closer to those for short-term medication courses than for chronic medication, due in part to the simplification of therapy and the provision of intensive adherence support.

Rover and colleagues carried out a study to examine the correlation between a range of psycho-behavioural measures and adherence to pegylated interferon and ribavirin in 63 people. Sociodemographic information included sex, race, substance use history, state of marriage and employment. Economic status and education were not measured.

Adherence scores were based on:

• showing up to appointments 

• “adherence to doctor’s orders” and

• filling out forms correctly.

Standardised patient-reported outcomes were assessed at baseline: expressing anger verbally or physically, level of angry reactions, anger as part of personality (“trait anger”), and expression of anger, all of which were higher in those who were already taking antidepressants at baseline; higher levels of emotions and worry were expressed by the same group all the way through the study. Of those patients (84%) who completed all patient reports, 45 individuals (71%) adhered to treatment (as defined) and 18 (29%) did not. Adherence was significantly lower in those who reported more frequently that they felt like expressing anger verbally (p < 0.01), and patients who reported more anger and worry at baseline were less likely to adhere to the course of treatment.

The research group concluded that it may be helpful to assess levels of anger and worry before treatment, and to use psycho-behavioural measures as a tool for monitoring people during treatment and to address need for specific interventions.

One issue not reported on was how many people started antidepressants during the study (a not-uncommon occurrence with pegylated interferon) and if that changed outcomes within that group.

In the two groups measured (those who were adherent to treatment and those who were not), age (47 vs 46 years old), marriage, substance-use history and employment were all similar, and therefore not considered predictive factors in adherence. Men had better adherence scores, as did Caucasians.

In discussions after the presentation, the session moderator and audience members suggested that lower adherence in women may be explained by women putting their roles as caregivers above their own health needs, and by possible gender differences in adverse events that affect treatment adherence. Both areas require further research.

Similarly, lower adherence in non-Caucasians may be a consequence of poorer early virological outcomes due to an unfavourable IL28B (non-CC) genotype, rather than a determinant of virologic response, since poor early response may act as a disincentive to subsequent adherence. Once again, further research would be useful.

What non-virological factors are important for successful therapy in a real-world setting?

Thomas Witthoeft from Stade, Germany, and 12 other authors from practices around Germany, looked at how to improve patient adherence, noting that there are few data on adherence to pegylated interferon and ribavirin in real life (non-clinical study settings).

In a prospective observational multicentre study, 746 treatment-naive patients with chronic hepatitis C infection were treated with pegylated interferon alfa-2b 1.5 µg/kg/wk and weight-based ribavirin (800 to 1200 mg/day) for up to 48 weeks at 42 German sites.

People who received at least 80% of each of the medications for at least 80% of the expected duration of therapy were considered adherent. The research group investigated which factors would predict adherence to treatment.

The median age of participants was 43 years, 40% were female, 3% were also had HIV and 65% of patients had HCV genotypes 1 or 4, with the remainder having genotype 2 or 3.

Sustained virological response (SVR₁₂ and SVR₂₄), defined as undetectable serum HCV RNA at 12 and 24 weeks after the end of treatment, was the goal of treatment. Overall SVR rates were 47.1% for genotype 1/4 and 59.9% for genotype 2/3 infection. The adherence numbers were much starker: whereas 75% of adherent patients (who took 80% of their medications at least 80% of the time) achieved success at both 12 and 24 weeks, only 25% of those who were non-adherent (below the threshold of 80%) achieved success at 12 and 24 weeks post-treatment. 

Trying to determine the non-virological factors associated with adherence, they saw that people were twice as likely to be non-adherent if they suffered adverse events, and twice as likely to be adherent if they had supportive psychotherapy. Presence of a psychiatric diagnosis lowers adherence, affecting treatment response, but this was modifiable via psychotherapy and/or antidepressants. “Psychiatric coaching and co-medication for treating the psychiatric issues help greatly regarding therapeutic adherence and results”, according to the author.

Factors such as a detailed demonstration of the pegylated interferon pen injection device before therapy, consumption of “soft” drugs (beer, wine, marijuana) or any alcohol (spirits) and the experience of the physician based on the number of HCV patients treated per year were not significantly associated with adherence. That is, they neither helped nor hindered adherence to the study regimen.

Although the number of telephone contacts with a trained nurse or technician in the office was not statistically important, it was almost as good as personal contact, which was considered highly important. According to Witthoeft, “Every contact to address problems or concerns may help the patient adhere to therapy; more often is even better.”