Discussion Only
Discussion
The present retrospective analysis of two large registration trials indicates that adherence to duration of treatment with P plus R plus BOC is an important factor associated with achieving SVR in patients with chronic hepatitis C genotype 1 infection. In particular, adherence to treatment duration appeared to be more important than adherence to the dosing interval with BOC in achieving SVR in the overall, nonblack and black populations.
Patients who discontinued treatment due to meeting the futility rules would have been defined as having low adherence rates to the duration of treatment. Approximately 9% and 19% of the treatment-naïve patients and those who failed previous treatment met the futility rules, respectively. However, patients who discontinued treatment could still have been defined as having high adherence rates to the t.d.s. dosing interval with BOC. Therefore, protocol-defined discontinuations (or early discontinuations due to adverse events) may have influenced the adherence rates to the duration of treatment, but may not have had an effect on the adherence rates to the t.d.s. dosing interval with BOC.
These results indicate that higher SVR rates were achieved when patients adhered to ≥80% of the treatment duration when compared with <80% of the treatment duration. In SPRINT-2, previously untreated patients with treatment duration adherence of ≥80% and BOC dose adherence of <80% had high SVR rates (78–100%) and in RESPOND-2, SVR rates in patients who had failed previous therapy and had good adherence to the treatment duration of ≥80% were still high (83–100%) even with <80% adherence to the doses of BOC. In addition, black and nonblack patients who adhered to ≥80% of the assigned dosing interval achieved similar SVR rates. It is important to note that non-adherence to the assigned duration of treatment includes patients who met futility rules or discontinued due to adverse events or other reasons.
Although the approved dosing of BOC every 8 h was effective, the present analysis indicates that strict adherence to the 7- to 9-h BOC dosing interval had minimal impact on SVR among patients who were otherwise adherent to the assigned duration of therapy. Specifically, different rates of adherence to the t.d.s. dosing interval with BOC (<60% to >80%) did not impact the SVR rates except for patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC. Different rates of adherence before or after treatment week 8 did not differentially impact SVR rates or the emergence of resistance. Adherence rates above or below 80% did not impact the emergence of resistance.
In these Phase 3 registration trials, it is not surprising that patients had high rates of adherence to the study drug, BOC, and that patients who were adherent to BOC were likewise adherent to both P and R. Accordingly, it was not possible to discern whether adherence to an individual agent within this triple drug regimen, by itself, influenced overall response rates. These findings are consistent with the HCV anti-viral pivotal registration trials of a decade ago,[2] wherein most patients managed to achieve the goals of 80% adherence to their study medication doses of P and R and treatment durations. At that time, it was conjectured that such high patient motivation and careful management in the context of controlled trials at tertiary referral centres might not be representative of patients treated in the community. Subsequent studies over the past 10 years, however, have confirmed that patients who were treated with P and R in the community were, in fact, largely reflective of the patients treated within clinical trials.[8] In one small analysis, however, including 23% who were HIV co-infected, 7% of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of R in the last 7 days, with the authors noting that self-reported dose non-adherence to hepatitis C treatment occurs frequently.[9]
Moreover, often in the real world setting, patients who ordinarily would not be considered candidates for anti-viral therapy are treated with HCV anti-virals, including those with serious psychiatric disorders and those with recent injection drug use. Among a group of 109 Australian patients with recently acquired HCV infection, many of whom were recent injection drug users, an exceptionally high rate of adherence to therapy was observed with the interesting observation that patients with no 'tertiary education' were less likely to have '80/80' P adherence, whereas injection drug use prior to or during treatment, however, did not impact such adherence.[10] Regarding underlying depression and anxiety, at least two European studies[11, 12] confirmed that aggressive and pre-emptive therapy of such psychiatric conditions allows for the optimisation of adherence and virological efficacy to anti-viral treatment in hepatitis C. Such observations were corroborated by a recent report by Schaefer et al., [13] showing that prophylactic therapy with antidepressants may lessen the depression adverse events associated with interferon therapy in patients with hepatitis C infection.
The concept of anti-viral therapy adherence as it relates to efficacy became known in the HIV era, and it was recently emphasised that the term 'non-adherence' differs in how it is used in the HCV from the HIV literature. Weiss et al.[14] note that in HIV, non-adherence refers primarily to patient-missed doses, whereas in HCV, the term refers primarily to dose reductions by the clinician and early treatment discontinuations. The authors propose that investigators codify such terminology, noting correctly that such compliance measures will become increasingly important to future treatment given the potential for resistant mutations emerging in the HCV direct-acting anti-viral agents.
In a report by Lo Re et al., utilising an adherence calculation that assessed pharmacy refill data, the investigators found that adherence of ≥85% to pegylated interferon and ribavirin was associated with increased HCV suppression and early virological response during the initial phases of HCV anti-viral therapy during the period of rapid virological decay compared with <85% adherence.[15] Decreases in HCV viral load with adherence levels of 90–99% or 100–109% were similar to that with 85–89% adherence. This indicated that an adherence level of ≥85% achieved the maximal decrease in HCV viral load. Recently, Lo Re et al. reported that early virological response and SVR rates were increased with higher levels of adherence to P and R.[16]
Moving forward to a new generation of HCV therapy with agents that have specific actions on the replication cycle of the HCV RNA virus has mandated a re-evaluation of the role of patient adherence to such therapy. Using additional agents with defined half-lives reinforces the need for patient adherence to maximise the chance of sustained viral eradication and minimise the possibility of resistance. The present report is reassuring because it validates the continued inherent motivation of the HCV-infected patient to undergo an arduous and sometimes protracted course of therapy. In the absence of serological tags of seroconversion or other markers to denote the point at which no further virological suppression is required to achieve a cure from therapy, duration of on-treatment viral negativity remains a surrogate indicator. The current findings strengthen the need for patient adherence in the new anti-viral era, but distinguish the heightened importance of adherence to duration, with somewhat lesser importance of the need for adherence to the t.d.s. dosing interval with BOC. Future regimens involving therapy with once-daily agents should allow for improved patient compliance and potentially, improved anti-viral outcomes.
http://www.medscape.com/viewarticle/806314_4
No comments:
Post a Comment