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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Background

Adherence to therapeutic regimens affects the efficacy of peginterferon alfa (P) and ribavirin (R) therapy in patients with chronic hepatitis C virus genotype 1.

Aim

To determine if medication adherence impacts efficacy [sustained virological response (SVR)] with triple therapy that includes boceprevir (BOC) plus P/R.

Methods

Adherence was determined in two Phase 3 clinical studies with BOC: SPRINT-2 (previously untreated patients) and RESPOND-2 (patients who failed previous therapy with P/R). Adherence to the assigned duration of the dosing regimen and adherence to the three times a day (t.d.s.) dosing interval of 7–9 h for BOC were assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned.

Results

Most patients (63–71%) adhered to ≥80% of their assigned treatment duration and achieved SVR rates of 86–90%. In contrast, patients who adhered to <80% of their assigned treatment duration achieved SVR rates of 8–32% (< 0.0001), particularly low in patients who failed previous therapy (SVR = 8–15%). Different rates of adherence (<60% to >80%) to the t.d.s. dosing interval (7–9 h) with BOC did not influence the SVR rates (SVR = 60–83%) with the exception of patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC (SVR = 48–50%; P = 0.005).

Conclusions

The achievement of an SVR is more dependent on adherence to the assigned duration of treatment than adherence to the t.d.s. dosing interval with boceprevir. Adherence to >60% of t.d.s. dosing with boceprevir is important in patients who failed previous therapy.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

The observation that adherence to a protracted course of anti-viral therapy significantly affects outcomes was first convincingly established for HIV therapy.[1] Shortly thereafter, with the development of more effective hepatitis C virus (HCV) anti-viral therapy and the realisation that sustained virological response (SVR) translated into cure,[2] reports emerged that HCV genotype 1 individuals, who can be maintained on >80% of their peginterferon (P) and ribavirin (R) dosing for the specified duration of therapy, exhibited heightened rates of response.[3]

The recent transition of standard of care from the dual P/R regimen to a triple therapy regimen that now includes an HCV NS3/4A protease inhibitor has once again changed the landscape of HCV anti-viral therapy, and has again incrementally increased the proportion of HCV-infected patients, both treatment-naïve and treatment experienced, who may achieve SVR.[4-7] Moreover, the newer regimens allow for individualised care, such that those patients exhibiting more rapid virological decline may truncate their course of therapy from 48 weeks to roughly half that duration, with similar SVR rates.

With the advent of the triple therapy regimens has come an increased pill burden, which can result in patients being required to take 15–19 pills daily [for boceprevir (BOC)-based treatment depending on the dose of R] in addition to weekly P injections. In addition, any pills required for adverse event management and other daily chronic medication requirements only make the pill burden higher. Given the pill burden and other challenges related to triple therapy, we analysed the impact of adherence on SVR. We attempted to ascertain whether adherence to BOC-based therapy influences anti-viral responsiveness in the context of the SPRINT-2 (previously untreated patients) and RESPOND-2 (patients who failed previous therapy with P/R) clinical trials.[4, 5]

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Clinical Trials

Adherence rates were determined in two clinical studies with BOC/P/R in previously untreated patients (SPRINT-2; ClinicalTrials.gov number: NCT00705432) and in patients who failed previous treatment (RESPOND-2; ClinicalTrials.gov number: NCT00708500). These studies have been described previously[4, 5] and included adult patients (≥18 years) infected with HCV genotype 1 and with compensated liver disease with all degrees of fibrosis. Patients in RESPOND-2 included previous relapsers (undetectable plasma HCV RNA at the end of previous treatment with PR without subsequent attainment of SVR) and previous partial responders (decrease in plasma HCV RNA of at least two log10 by week 12 during previous treatment with P/R, but never undetectable HCV RNA), but excluded historical null responders (<2 log10 decrease in plasma HCV RNA by week 12 of previous treatment with P/R). The studies were conducted primarily in North America and Western Europe. Patients co-infected with HIV or HBV were excluded. All patients received a 4-week lead-in of P/R prior to having BOC or placebo added to their regimen. Adherence rates were determined in two arms of the studies. One arm used response-guided therapy (BOC RGT) in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2). The other arm (BOC/PR48) received 4 weeks of P/R followed by 44 weeks of BOC + P/R. The primary endpoint in both studies was SVR, which was defined as undetectable serum HCV RNA 24 weeks after the end of treatment. HCV RNA was determined by the COBAS TaqMan 2.0 (Roche) HCV test, which has a lower limit of detection (LLOD) of 9.3 IU/mL and a lower limit of quantitation of 25 IU/mL. All clinical decisions were based on the LLOD.

Assessment of Adherence

Weekly doses of P and daily doses of R and BOC were collected by patients in electronic dosing diaries. Study site personnel assessed adherence by comparing the amount of study drugs taken by the patient as reflected in the electronic dosing diary to the amount of study drugs dispensed and returned by the patient. Adherence to the assigned duration of the dosing regimen was defined as the actual treatment duration received by the patient divided by the per-protocol assigned duration of treatment (28 or 48 weeks for treatment-naïve patients; 36 or 48 weeks for patients who failed previous treatment). Adherence to the t.d.s. dosing interval of 7–9 h for BOC was defined as the number of doses taken by the patients within the 7- to 9-h time interval divided by the total number of doses of BOC taken by the patients. For example, if a patient discontinued treatment due to the futility rule at treatment week 12 or an adverse event, but was adherent to the t.d.s. dosing interval with BOC until this time, the patient's adherence to the t.d.s. dosing interval of BOC would be high. However, adherence to treatment duration would be low for this patient because adherence to duration was based on the assigned per-protocol duration of treatment (28 or 48 weeks). Adherence to the amount of the dose for each drug (P, R and BOC) was defined as the total dose of drug received by the patient divided by the expected total drug dose where the expected total drug dose was based on the actual treatment duration.

Statistical Analyses

Sustained virological response rates were summarised for various subgroups using descriptive statistics (n/m; %) and exact 95% confidence intervals (CIs). Exploratory analyses included calculation of P-values using the Chi-squared test to compare SVR rates in some subgroups.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Baseline Characteristics

The baseline characteristics of the patients in the clinical trials (previously untreated patients and patients who failed previous therapy with P/R) are shown in Table 1. The patients in the two studies were 62% (924/1500) male, 14% (208/1500) Black, 72% (1086/1500) from North America, 25% (381/1500) from Europe, and had a mean age of 50 years. Most of the patients had high viral loads [86% (1288/1500) > 800,000 IU/mL] and more patients [62% (934/1500)] were infected with HCV genotype 1a than 1b.

Table 1. Baseline characteristics
CharacteristicPreviously untreated patientsa, n = 1097Patients who failed previous P/R therapyb, n = 403Total, n = 1500
  1. s.d., standard deviation; IU, international units; NA, not applicable; P, peginterferon; R, ribavirin.

  2. a

    SPRINT-2.[5]

  3. b

    RESPOND-2.[4]

  4. c

    Race was self-reported.

  5. d

    The body mass index is the weight in kilograms divided by the square of the height in metres.

  6. e

    The HCV subtype was ascertained by means of sequencing of the HCV nonstructural 5B (NS5B) region. Thirty seven and six patients with nongenotype 1 or missing data in previously untreated patients and patients who failed previous therapy, respectively.

  7. f

    METAVIR scores were determined on the basis of assessment of liver-biopsy specimens by a single pathologist who was unaware of the assignment to boceprevir or placebo. METAVIR F3 = numerous septa without cirrhosis; METAVIR F4 = cirrhosis.

  8. g

    Prior partial response was defined as a decrease in the HCV RNA level of at least 2 log 10 IU per millilitre by week 12 of prior therapy, but a detectable HCV RNA level throughout the course of prior therapy, without subsequent attainment of a sustained virological response (SVR). Prior relapse was defined as an undetectable HCV RNA level at the end of prior therapy, but without subsequent attainment of a SVR.

Male, n (%)656 (60)268 (67)924 (62)
Blackc, n (%)159 (14)49 (12)208 (14)
Region, n (%)
North America801 (73)285 (71)1086 (72)
Europe264 (24)117 (29)381 (25)
Latin America32 (3)1 (<1)33 (2)
Age (mean, years)495350
Body mass indexd [mean (s.d.)]27.7 (5.0)28.4 (4.6)27.9 (4.9)
HCV subtypee, n (%)
1a698 (64)236 (59)934 (62)
1b362 (33)161 (40)523 (35)
Viral load >800,000 IU/mL, n (%)935 (85)353 (88)1288 (86)
METAVIR F3/F4f, n (%)100 (9)78 (19)178 (12)
Previous partial response g, n (%)NA144 (36)144 (10)
Previous relapseg, n (%)NA259 (64)259 (17)

Adherence to Assigned Treatment Duration or Dosing Interval with Boceprevir

Most previously untreated patients and patients who failed previous P/R therapy (63–71%) adhered to ≥80% of their assigned treatment duration with BOC/P/R (Figure 1). The SVR rates ranged from 86% to 90% in previously untreated patients and patients who failed previous therapy who adhered to ≥80% of their assigned treatment duration (Figure 2). In contrast, the SVR rates were significantly lower (P < 0.0001) in previously untreated patients (SVR = 19–32%) and in patients who failed previous therapy (SVR = 8–15%) who adhered to <80% of their assigned treatment duration (Figure 2).

image

Figure 1. Per cent of patients who adhered to ≥80% or <80% of their assigned treatment duration. Adherence to the assigned duration of the dosing regimen was assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the assigned duration of the dosing regimen was defined as the actual treatment duration received by the patient divided by the per-protocol assigned duration of treatment (28 or 48 weeks for treatment-naïve patients; 36 or 48 weeks for patients who failed previous treatment). Previously untreated patients are those in the SPRINT-2 clinical trial. Patients who failed previous therapy are those from the RESPOND-2 clinical trial. BOC RGT arm: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2). BOC/PR48 arm: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin. BOC, boceprevir; RGT, response-guided therapy; P, peginterferon; R, ribavirin; No./Tot., number of patients/number of patients with the indicated characteristic.

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image

Figure 2. Sustained virological response (SVR) rates in patients who adhered to ≥80% or <80% of their assigned treatment duration. Adherence to the assigned duration of the dosing regimen was assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the assigned duration of the dosing regimen was defined as the actual treatment duration received by the patient divided by the per-protocol assigned duration of treatment (28 or 48 weeks for treatment-naïve patients; 36 or 48 weeks for patients who failed previous treatment). Previously untreated patients are those in the SPRINT-2 clinical trial. Patients who failed previous therapy are those from the RESPOND-2 clinical trial. BOC RGT arm: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2). BOC/PR48 arm: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin. SVR (defined as undetectable serum HCV RNA 24 weeks after the end of treatment) was determined by the COBAS TaqMan 2.0 (Roche) HCV Test. BOC, boceprevir; RGT, response-guided therapy; P, peginterferon; R, ribavirin; No./Tot., number of patients with SVR/number of patients with the indicated characteristic.

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Approximately half (42–52%) of previously untreated patients and those who failed previous therapy adhered to ≥80% of the t.d.s. dosing interval with BOC (Figure 3). The SVR rates ranged from 62% to 83% in previously untreated patients who adhered to <60% to ≥80% of the t.d.s. dosing interval with BOC (Figure 4). In previously untreated patients, there was no significant difference (P = 0.195) between the SVR rates with adherence to ≥60% of the t.d.s. dosing interval for BOC compared to <60% of the t.d.s. dosing interval for BOC. The SVR rates were 60–77% in patients who failed previous therapy and adhered to 60% to ≥80% of the t.d.s. dosing interval with BOC (Figure 4). In contrast, the SVR rates were significantly lower (P = 0.005; SVR = 48–50%) in patients who failed previous therapy and adhered to <60% of the t.d.s. dosing interval with BOC compared with adherence to ≥60% of the t.d.s. dosing interval for BOC (Figure 4). Adherence to duration of therapy and adherence to the t.d.s. dosing interval with BOC had similar importance in both previous relapsers and previous partial responders. In addition, our conclusion that adherence to the duration of assigned therapy is more important than adherence to the t.d.s. dosing interval with BOC was true in both previous relapsers and previous partial responders (Table S1). In patients who adhered to ≥80% of the t.d.s. dosing interval with BOC, the discontinuation rate due to futility was 20% (29/149) in patients who failed previous therapy and 17% (50/290) in previously untreated patients. The overall discontinuation rates due to futility were 21% (65/316) in patients who failed previous therapy and 15% (102/703) in previously untreated patients (Table S2).

image

Figure 3. Per cent of patients who adhered to the t.d.s. dosing interval with boceprevir. The percentage of patients with varying levels of adherence to the t.d.s. dosing interval with boceprevir was calculated for the BOC RGT arm (filled bars) and the BOC/PR48 arm (open bars). The results for previously untreated patients (SPRINT-2) are on the left side of the figure and the results for patients who failed previous therapy (RESPOND-2) are on the right side of the figure. BOC RGT arm: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2). BOC/PR48 arm: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin. Adherence to the t.d.s. dosing interval of 7–9 h for BOC was assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the t.d.s. dosing interval of 7–9 h for BOC was defined as the number of doses taken by the patients within the 7- to 9-h time interval divided by the total number of doses of BOC taken by the patients. BOC, boceprevir; RGT, response-guided therapy; P, peginterferon; R, ribavirin; No./Tot., number of patients with SVR/number of patients with the indicated characteristic.

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image

Figure 4. Sustained virological responses (SVR) in patients by adherence to the t.d.s. dosing interval with boceprevir. The SVR rates for patients with varying levels of adherence to the t.d.s. dosing interval with boceprevir were calculated for the BOC RGT arm (filled bars) and the BOC/PR48 arm (open bars). The results for previously untreated patients (SPRINT-2) are on the left side of the figure and the results for patients who failed previous therapy (RESPOND-2) are on the right side of the figure. BOC RGT arm: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2). BOC/PR48 arm: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin. Adherence to the t.d.s. dosing interval of 7 –9 h for BOC was assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the t.d.s. dosing interval of 7–9 h for BOC was defined as the number of doses taken by the patients within the 7- to 9-h time interval divided by the total number of doses of BOC taken by the patients. SVR (defined as undetectable serum HCV RNA 24 weeks after the end of treatment) was determined by the COBAS TaqMan 2.0 (Roche) HCV Test. BOC, boceprevir; RGT, response-guided therapy; P, peginterferon; R, ribavirin; No./Total, number of patients with SVR/number of patients with the indicated characteristic.

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Adherence to doses of peginterferon, ribavirin and boceprevir

A majority of patients reported taking ≥80% of their assigned doses of BOC, P and R. Most patients who adhered to ≥80% of the doses of BOC also adhered to ≥80% of the doses of P and R (Table 2). SVR rates were high (89–91%) in patients who adhered to ≥80% of the treatment duration and ≥80% of the doses of each drug (BOC, P and R). Patients with treatment duration adherence of ≥80% but <80% adherence to the doses of BOC/P/R also had high SVR rates that ranged from 78% to 100%. Compared with patients who received ≥80% of the assigned treatment duration, SVR rates were lower in patients receiving <80% of the assigned treatment duration (SVR = 0–50%), regardless of adherence to the doses of BOC/P/R.

Table 2. Adherence to peginterferon, ribavirin and boceprevir in previously untreated (SPRINT-2) and previous treatment failure patients (RESPOND-2)a
Adherenceb (%)SVRc, n/m (%)
Assigned treatment durationAmount of doses of peginterferonAmount of doses of ribavirinAmount of doses of boceprevirBOC RGTd, n = 368BOC/PR48e, n = 366Combined arms (BOC RGT + BOC/PR48), n = 734
  1. BOC, boceprevir; RGT, response-guided therapy; n/m, number of patients with SVR/number of patients with the indicated characteristic.

  2. a

    Includes patients who received at least one dose of boceprevir. Patients who discontinued during 4-week lead-in not included.

  3. b

    Adherence to the assigned duration of the dosing regimen and adherence to the amount of doses for each drug (peginterferon, ribavirin and boceprevir) were assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the assigned duration of the dosing regimen was defined as the actual treatment duration received by the patient divided by the per-protocol assigned duration of treatment (28 or 48 weeks for treatment-naïve patients; 36 or 48 weeks for patients who failed previous treatment). Adherence to the amount of doses for each drug (P, R and BOC) was defined as the total dose of drug received by the patient divided by the expected total drug dose where the expected total drug dose was based on the actual treatment duration.

  4. c

    SVR (defined as undetectable serum HCV RNA 24 weeks after the end of treatment) was determined by the COBAS TaqMan 2.0 (Roche) HCV test.

  5. d

    BOC RGT: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2).

  6. e

    BOC/PR48: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin.

Previously untreated patients (SPRINT-2)   
≥80≥80≥80≥80153/169 (91)139/155 (90)292/324 (90)
≥80<80<80<8014/14 (100)14/18 (78)28/32 (88)
<80≥80≥80≥8017/79 (22)22/79 (28)39/158 (25)
<80<80<80<800/9 (0)6/12 (50)6/21 (29)
Total≥80≥80≥80170/248 (69)161/234 (69)331/482 (69)
Total<80<80<8014/23 (61)20/30 (67)34/53 (64)
Patients who failed previous therapy (RESPOND-2)n = 162n = 161n = 323
≥80≥80≥80≥8076/85 (89)79/88 (90)155/173 (90)
≥80<80<80<805/6 (83)11/11 (100)16/17 (94)
<80≥80≥80≥804/42 (10)6/39 (15)10/81 (12)
<80<80<80<800/1 (0)0/0 (0)0/1 (0)
Total≥80≥80≥8080/127 (63)85/127 (67)165/254 (65)
Total<80<80<805/7 (71)11/11 (100)16/18 (89)

Adherence in Previously Untreated Nonblack and Black Patients

The SVR rates in blacks and nonblacks who adhered to ≥80% of the assigned treatment duration were similar (85% and 90%, respectively) (Table 3). The SVR rates in blacks and nonblacks who adhered to <80% of the assigned treatment duration were 12% and 29%, respectively.

Table 3. SVR by adherence to t.d.s. dosing with boceprevir and assigned treatment duration in previously untreated nonblack and black patientsa
Adherenceb (%)SVRc, n/m (%)
NonblackBlack
Assigned treatment durationDosing (t.d.s.) with BOCBOC RGTd, n = 303BOC/PR48e, n = 299Combined arms (BOC RGT + BOC/PR48), n = 602BOC RGT, n = 47BOC/PR48, n = 55Combined arms (BOC RGT + BOC/PR48), n = 102
  1. BOC, boceprevir; RGT, response-guided therapy; P, peginterferon; R, ribavirin; n/m, number of patients with SVR/number of patients with the indicated characteristic.

  2. a

    Includes patients who received at least one dose of BOC. Patients who discontinued during 4-week lead-in not included.

  3. b

    Adherence to the assigned duration of the dosing regimen and adherence to the t.d.s. dosing interval of 7–9 h for BOC were assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the assigned duration of the dosing regimen was defined as the actual treatment duration received by the patient divided by the per-protocol assigned duration of treatment (28 or 48 weeks for treatment-naïve patients; 36 or 48 weeks for patients who failed previous treatment). Adherence to the t.d.s. dosing interval of 7–9 h for BOC was defined as the number of doses taken by the patients within the 7- to 9-h time interval divided by the total number of doses of BOC taken by the patients.

  4. c

    SVR (defined as undetectable serum HCV RNA 24 weeks after the end of treatment) was determined by the COBAS TaqMan 2.0 (Roche) HCV test.

  5. d

    BOC RGT: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2).

  6. e

    BOC/PR48: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin.

≥80≥80171/189 (91)152/170 (89)323/359 (90)16/20 (80)24/24 (100)40/44 (91)
≥80<8021/23 (91)23/26 (89)44/49 (90)4/6 (67)1/3 (33)5/9 (56)
<80≥8016/71 (23)27/78 (35)43/149 (29)2/17 (12)3/20 (15)5/37 (14)
<80<803/20 (15)11/25 (44)14/45 (31)0/4 (0)1/8 (13)1/12 (8)
≥80Total192/212 (91)175/196 (89)367/408 (90)20/26 (77)25/27 (93)45/53 (85)
<80Total19/91 (21)38/103 (37)57/194 (29)2/21 (10)4/28 (14)6/49 (12)

SVR rates ranged from 50% to 58% in blacks and 66% to 85% in nonblacks with varying levels of adherence (<60% to ≥80%) to the t.d.s. dosing interval with BOC (Table 4). Approximately 49% (31/63) and 24% (100/418) of black and nonblack patients, respectively, adhered to <60% of the t.d.s. dosing interval for BOC. The SVR rates were 58% and 66% in black and nonblack patients, respectively, who adhered to <60% of the t.d.s. dosing interval for BOC (Table 4).

Table 4. SVR by adherence to t.d.s. dosing interval with boceprevir in previously untreated nonblack and black patientsa
Adherence to t.d.s. dosing interval with BOCb (%)SVRc, n/m (%)
NonblackBlack
BOC RGTd, n = 215BOC/PR48e, n = 203Combined arms (BOC RGT + BOC/PR48), n = 418BOC RGT, n = 33BOC/PR48, n = 30Combined arms (BOC RGT + BOC/PR48), n = 63
  1. BOC, boceprevir; RGT, response-guided therapy; P, peginterferon; R, ribavirin; n/m, number of patients with SVR/number of patients with the indicated characteristic.

  2. a

    All patients in this table adhered to ≥80% of the assigned treatment duration for BOC, P and R.

  3. b

    Adherence to the t.d.s. dosing interval of 7–9 h for BOC was assessed by the recording of data from patients’ dosing diaries and by the amount of study drug dispensed and returned. Adherence to the t.d.s. dosing interval of 7–9 h for BOC was defined as the number of doses taken by the patients within the 7- to 9-h time interval divided by the total number of doses of BOC taken by the patients.

  4. c

    SVR (defined as undetectable serum HCV RNA 24 weeks after the end of treatment) was determined by the COBAS TaqMan 2.0 (Roche) HCV test.

  5. d

    BOC RGT: all patients received a 4-week lead-in of peginterferon/ribavirin prior to having boceprevir added to their regimen. The BOC RGT arm used response-guided therapy in which the duration of therapy was based on the virological responses at treatment week 8 and 12 (RESPOND-2) or treatment week 8 through 24 (SPRINT-2).

  6. e

    BOC/PR48: all patients received a 4-week lead-in of peginterferon/ribavirin followed by 44 weeks of boceprevir + peginterferon/ribavirin.

<6038/56 (68)28/44 (64)66/100 (66)7/17 (41)11/14 (79)18/31 (58)
60 to <7020/26 (77)23/27 (85)43/53 (81)2/5 (40)2/3 (67)4/8 (50)
70 to <8023/36 (64)22/27 (82)45/63 (71)3/5 (60)1/3 (33)4/8 (50)
≥8073/97 (75)69/105 (66)142/202 (70)4/6 (67)4/10 (40)8/16 (50)

Impact of adherence before or after treatment week 8 on SVR rates and resistance

Varying rates of adherence to t.d.s. dosing with BOC before treatment week 8 did not impact SVR rates in patients who failed previous therapy or in previously untreated patients (Table S3). Based on the 95% CIs, there were no significant differences in the SVR rates in patients who failed previous therapy and who adhered to <60% of the t.d.s. dosing with BOC before treatment week 8 [48/84 (57%; 95% CI = 46, 68)] compared to 64% [43/67 (95% CI = 52, 76)] or 70% [99/141 (95% CI = 62, 78)] in those who adhered to 60% to <80% or ≥80%, respectively, of the t.d.s. dosing with BOC before treatment week 8. In previously untreated patients, the SVR rates were similar (70–75%) with rates of adherence to the t.d.s. dosing with BOC of ≥80%, 60% to <80% or <60% before treatment week 8.

Varying rates of adherence to t.d.s. dosing with BOC after treatment week 8 also did not impact the SVR rates in patients who failed previous therapy or in previously untreated patients (Table S3). The SVR rates ranged from 82% to 89% in both patients who failed previous therapy and previously untreated patients whose adherence rates to the t.d.s. dosing with BOC after treatment week 8 were ≥80%, 60% to <80% or <60%.

Impact of adherence on emergence of resistance-associated variants

The percentage of patients who had treatment-emergent post-baseline resistance-associated variants (RAVs) ranged from 46% to 65% in patients who did not achieve an SVR (Table S4). Based on the 95% CIs, there were no significant differences in the rates of RAVs in patients who adhered to ≥80% or <80% of the t.d.s. dosing interval with BOC before treatment week 8 vs. after treatment week 8.

Based on the 95% CIs, there were no significant differences in the emergence of treatment-emergent post-baseline RAVs in patients who failed previous therapy, adhered to ≥80% of the assigned duration of therapy and did not achieve SVR [15/23 (65%; 95% CI = 43, 84)] compared with those who adhered to <80% of the assigned duration of therapy [32/81 (40%; 95% CI = 29, 51)] (Table S5). Previously untreated patients who adhered to ≥80% or <80% of the assigned duration of therapy had similar rates of RAVs [23/48 (48%) or 88/172 (51%)] respectively.

Patients who failed previous therapy, adhered to ≥80% of the t.d.s. dosing interval with BOC and did not achieve SVR had similar rates of treatment-emergent post-baseline RAVs (20/41; 49%) compared with those who adhered to <80% of the t.d.s. dosing interval with BOC (26/58; 45%) (Table S6). Based on the 95% CIs, there were no significant differences in the emergence of RAVs in previously untreated patients who adhered to ≥80% of the t.d.s. dosing interval with BOC [49/77 (64%; 95% CI = 52, 74)] compared with those who adhered to <80% of the t.d.s. dosing interval with BOC [62/124 (50%; 95% CI = 41, 59)].

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

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.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Guarantor of the article: Stuart Gordon, MD.

Author contributions: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ sponsored these studies. Merck, in conjunction with the external academic investigators, designed, managed and analysed these studies. The academic authors collected the data, which were then analysed by the sponsor. The sponsor held the data and made them available to the academic authors. Stuart Gordon and Frank Dutko wrote the first draft of the manuscript. All authors were involved in the collection, analysis or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol. The views expressed herein are those of the authors and do not reflect the official policy or position of Merck Sharp & Dohme Corp. All authors approved the final version of the manuscript.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Declaration of personal interests: We thank all the patients, health care providers and investigators involved in the study.

Declaration of funding interests: The authors report the following: S. Gordon has received research support from Abbott, Bristol-Myers Squibb, Exalenz, Gilead, GlaxoSmithKline, Merck, Roche and Vertex. He has also received consulting fees from Bristol-Myers Squibb, Gilead, Merck, Achillion, Salix and CVS-Caremark, received lecture fees from Merck, Genentech, Vertex and Gilead, and served on the Data and Safety Monitoring Board for Janssen.

E. Yoshida has received grant support from Merck; has grants/grants pending from Merck, Gilead, Vertex, Hoffmann La Roche, Pfizer, Novartis, Astellas, Cangene, Boeringher Ingleheim and Abbott; and has received payment for lectures including service on speakers bureaus from Vertex, Gilead, Merck, Hoffmann LaRoche and Cangene.

E. Lawitz has received clinical research grants from the following companies: Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, Sanofi-Aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, ZymoGenetics; and payment for lectures including service on speakers bureaus for Merck.

B. Bacon has received consultancy fees from Gilead, Kadmon Pharmaceuticals, Valeant, Vertex and Human Genome Sciences; has grants and grants pending from Roche, Gilead, Bristol-Myers Squibb, Kadmon Pharmaceuticals, Valeant, Vertex, Human Genome Sciences, Wyeth and Romark Laboratories; payment for lectures including service on speakers bureaus for Kadmon Pharmaceuticals, Gilead and Merck; and served on Data and Safety Monitoring Boards for Novartis, ISIS, Vertex and Gilead.

M. Sulkowski has received consultancy fees and has grants/grants pending from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Novartis, Pfizer and Vertex.

M. Davis has received grants or has grants pending from Merck, Schering-Plough (now part of Merck), Gilead, Bristol-Myers Squibb, Pharmasset and Abbott; consultancy fees or honorarium and support for travel to meetings for the study or other purposes from Schering-Plough (now part of Merck); consultancy fees from Vertex; and payment for lectures including service on speakers bureaus from Genentech, Vertex, Bristol-Myers Squibb and Merck.

F. Poordad has received consultancy fees from Merck, Vertex, Abbott, Gilead, Achillion, Genentech and Tibotec; has grants/grants pending from Merck; and has received payment for development of educational presentations and speaker fees from Merck, Genentech, Salix and Gilead (now at Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, USA).

J.-P. Bronowicki has received consultancy fees from Schering-Plough (now part of Merck), Roche, Gilead, Bristol-Myers Squibb, Janssen, Boehringer Ingelheim, Novartis, and Bayer; payment for lectures including service on speakers bureaus for Schering-Plough (now part of Merck), Roche, Bayer and Bristol-Myers Squibb and travel/accommodations/meeting expenses unrelated to activities listed from Roche.

R. Esteban is a member of speaker′s bureau or advisor for Schering-Plough (now part of Merck), Gilead, Novartis, Bristol-Myers Squibb and GlaxoSmithKline.

F. Dutko, M. Burroughs and W. Deng are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ and hold stock and/or stock options.

V. Sniukiene is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ and holds stock and/or stock options. Now at Warner Chilcott.

C. Brass is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ and holds stock and/or stock options. Now at Novartis.

J. Albrecht is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ and holds stock and/or stock options. Now at jkalbrecht1308@gmail.com.

K. R. Reddy has received consultancy fees from Genentech-Roche, Merck, Salix, Vertex, Tibotec and Human Genome Science; has grants/grants pending from Roche, Vertex, Tibotec, Bristol-Myers Squibb and Gilead; and payment for development of educational presentations from ViralEd.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  10. Supporting Information
FilenameFormatSizeDescription
apt12342-sup-0001-TableS1-S6.docxWord document24K

Table S1. SVR rates with varying adherence rates in previous relapsers or previous partial responders.

Table S2. Discontinuations due to treatment failure vs. adherence to t.d.s. dosing interval with boceprevir.

Table S3. Impact on SVR rates of adherence to t.d.s. dosing interval with boceprevir before or after treatment week 8.

Table S4. Impact on resistance of adherence to ≥80% or <80% of the t.d.s. dosing interval with boceprevir before treatment week 8 vs. after treatment week 8.

Table S5. Impact on resistance of adherence to duration of therapy.

Table S6. Impact on resistance of adherence to the t.d.s. dosing interval with boceprevir.

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