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Adherence in HCV Therapy
  Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C
In the current issue if Gastroenterology John McHutchison and colleagues reported an analysis of a group of studies, and the primary aim of this analysis was to evaluate the effect of adherence on sustained response rates to combination therapy (interferon -2b or peginterferon -2b plus ribavirin) in patients with chronic hepatitis C. In short, the results showed that >80% adherence resulted in 25% better response rates for genotype 1, the hardest to treat patient group. For genotype 2 patients they did not see a significant improvement associated with better adherence. The message is that adherence in HCV therapy improves response rates just as in HIV. Below in this article there is a discussion of methods to improve adherence that may be useful in treating HCV. But unlike in HIV there are few programs in place to address these needs.
The main reasons for not achieving the adherence goals (80/80/80) were adverse events to therapy in >75% of the patients. In the remaining patients, failure to attend scheduled appointments, withdrawal of consent, and nonadherence in the absence of apparent side effects were the other reasons for not achieving adherence targets in this study.
A preliminary data analysis presented at hepatitis science conferences from Pegasys plus ribavirin studies also show appreciable improvements in response with >80% adherence. In genotype 1 patients who achieved a viral response by week 12, 65% who were >80% adherent achieved a sustained response vs a 46% sustained response for patients who were <80% adherent. The preliminary findings suggest patients in this study who had a viral response by week 12 and dose reduced still had a good sustained response rate. Further study is needed to confirm the effects of dose reduction, and if dose reduction during the first 12 weeks is more harmful than after 12 weeks. Here is link to full report of this study: http://www.natap.org/2001/aasld2/day6h.htm
In all, 1010 patients treated with interferon a-2b (Schering-Plough) and ribavirin and 511 patients treated with peginterferon a-2b (PEG-Intron; Schering) plus ribavirin were considered in this analysis. These subgroups of patients evaluated in the aforementioned studies had been randomized to receive either interferon a-2b 3 times a week (for 24 or 48 weeks) in combination with daily ribavirin or, alternatively, peginterferon a-2b at a dose of 1.5 g/kg per week subcutaneously as a single injection with ribavirin 800 mg daily for 48 weeks. These patient subgroups were selected because they were those that received the most effective regimens in these respective trials. Data from a separate monotherapy trial of 304 patients treated with peginterferon a-2b, 1.5 g/kg per week, and 303 patients who received interferon a-2b 3 times a week for 48 weeks were also analyzed to evaluate the effect of adherence on response in this trial.
For this analysis, the amount of each drug administered to a patient was obtained from drug dispensing/return records and patient dosing diaries. Patients receiving combination therapy were divided into 2 groups for analysis: (1) the 80/80/80 subgroup, comprising patients who were 80% adherent (i.e., received 80% of their total interferon dose and 80% of the ribavirin dose) and were treated for 80% of the expected duration of therapy; and (2) the <80/<80/80 subgroup, comprising patients who underwent dose reduction (<80% of 1 or both drugs for 80% expected duration). Patients who withdrew from the study prematurely were excluded from the analysis. The goal of 80% of the planned drug dosage for 80% of the assigned duration represents an adherence criterion that had been adopted previously in the assessment of the efficacy of other pharmaceutical agents, including HIV drug therapy, antihypertensive drug therapy, and orally administered cancer drug therapies.
In this analysis the observation of improved response was apparent only for genotype 1 infected patients, those most difficult to treat. The results tabulated in table format below show an increase in response by 25% for genotype 1, but there was no statistically significant improvement in response for genotype 2.
Most patients in these clinical trials were able to be adherent because of these patients' motivation and their management in controlled trials at tertiary referral centers, however, these findings may not be representative or applicable to the larger universe of patients managed in clinical practice. Thus patients treated in community practices or in centers with limited expertise in the management of chronic hepatitis C may have lower response rates than those observed in this study. Nevertheless, it seems reasonable that the concept of adherence to therapy should also apply to patients treated outside the realm of clinical trials. Further prospective studies are needed to address this issue.
Of the 1010 patients evaluated who received interferon -2b plus ribavirin, 218 were excluded from further analysis because the duration of therapy was <80% of the assigned treatment regimen. Most of the remaining patients who were treated for longer than 80% of the planned duration, 631 of 792 (80%), also received >80% of both their interferon -2b and ribavirin doses. Similarly, for the 511 patients receiving peginterferon -2b 1.5 g/kg per week plus ribavirin, 88 were excluded from the analysis, and of the remaining 423, 305 (72%) were adherent and received >80% of both medications as defined previously. Of the 304 patients who received peginterferon -2b 1.5 g/kg per week alone, 45 (15%) were excluded because they failed to achieve at least 80% of the assigned duration of therapy. Likewise, 56 (18%) individuals were excluded from the 303 patients who received interferon -2b alone. Most of the remaining patients in these monotherapy trials were adherent to therapy, with 236 of 259 (91%) and 242 of 247 (98%) receiving >80% of peginterferon -2b 1.5 g/kg per week and interferon -2b alone, respectively.
In HIV infection and other diseases, adherence to therapy is related to the number of medications taken per day, dietary restrictions required for these medications, side effects and complications of the medications, dosing frequency, pill size, and the drug combinations used. In addition, low literacy level, beliefs regarding therapy (whether erroneous or otherwise), lack of support, inconvenient appointments, and lack of transportation have all been associated with a lack of adherence to therapy in HIV-infected patients. In HIV infection, the most common reasons for lack of adherence or skipping doses are simply forgetting, being "too busy," side effects, and feeling ill, all of which would seem to apply to patients with chronic hepatitis C undergoing therapy. Demographic variables, such as gender, age, race, socioeconomic status, and history of prior substance abuse, generally do not predict poor adherence to HIV therapy.
Such variables associated with nonadherence notwithstanding, physicians are able to accurately predict adherence in only about 50% of patients. Thus methods to monitor and improve adherence may help improve the likelihood of successful outcome during and after treatment of any disease process. Although no gold standard exists for monitoring adherence in clinical trials or in practice, theoretically, directly observed therapy (as previously used for tuberculosis) may be impracticable in hepatitis C treatment regimens, but it could be made available to a limited number of patients considered to be at high risk for nonadherence. Although currently impractical in hepatitis C treatment regimens, directly observed therapy could be facilitated by once-weekly peginterferon dosing regimens. Patient self-reporting, as in our studies, is less accurate than other potential methods but is a common and convenient way of aiding adherence. A medication diary is also an important behavioral tool that may help reinforce adherence. Electronic monitoring devices, such as medication event monitoring systems, may also increase adherence, and future studies of hepatitis C therapy involving these microprocessor recorders could provide a better assessment of the effect of adherence. In HIV therapy, encouraging telephone calls and feedback about viral loads have proven to improve adherence, but evidence to support their approach in hepatitis C therapy is lacking. Still, these approaches merit consideration. A number of other factors may impair treatment adherence in hepatitis C, including language barriers, negative staff attitudes toward injecting drug users, and social circumstances, such as lack of family support. Strategies to improve adherence include encouraging "reasonable" adherence instead of demanding full adherence, involving family members or significant others in the treatment process, and anticipating presumptively and responding to adverse social situations that could reduce adherence. Although patients themselves are the primary determinants of adherence, the importance of the role of health care providers should not be overlooked.
It may be possible to use a similar adherence-efficacy model in future clinical trials to gauge the impact of patient adherence on therapeutic outcome, and potentially to determine ideal drug dosages for those most compliant to therapy.
The findings of this study indicate that adherence with prescribed medication regimens does improve sustained response rates in patients with chronic hepatitis C infection. Further research must now be conducted in prospective trials to determine factors associated with adherence or lack thereof and strategies for improving adherence, in an attempt to enhance sustained response rates. Theoretically, patient education about side effects, necessary lifestyle changes during therapy, treatment of depression, support groups, telephone and frequent clinic follow-up visits, printed materials, pill boxes, reminders, and self-monitoring devices, as well as simplification of treatment regimens, all have the potential to improve adherence. Certainly, the introduction of peginterferon, by reducing the number and frequency of injections, has also simplified the treatment regimen, which may facilitate adherence to therapy.
Although more work in improving adherence is necessary, our results suggest that adherence will enhance the likelihood of achieving a virologic response during the first 3-6 months of therapy, and that maintaining adherence in patients who have responded to treatment by week 12-24 will lead to an increase in sustained virologic response rates.
These patients (80/80/80) were patients who took 80% interferon -2b plus 80% ribavirin for more than 80% of the expected duration of therapy. Patients who did not complete 80% of the duration of the study and who took less than 80% of interferon and ribavirin did not respond nearly as well.
  The overall SVR for study patients was 54%, and 42% for patients with genotype 1. As you can see adherence increased response from 54% to 63% and 42% to 51%.
Adherence did not appear to enhance virologic response in patients with HCV-2 or -3 infection treated for either 24 or 48 weeks. 82% to 90% was not statistically significant but improvement in genotype 1 was significant.
Whereas most patients who reduced their dose within the first 12 weeks of therapy maintained a reduced dose during the remainder of therapy, few if any patients who were not adherent during the first 12 weeks became adherent thereafter. A trend was observed between early dose reductions and impaired sustained response rates; this trend was less apparent for those who required dose reductions late in the course of therapy. But the results of this analysis were not statistically significant. We attempted to analyze the effect of dose reduction of each drug on the sustained response rate; however, >80% of the patients who received >80% of either interferon -2b or peginterferon -2b also received >80% of the doses of ribavirin. Thus we were unable to distinguish which drug was more important in terms of the impact of adherence on sustained response.
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