Boceprevir and personalized medicine in hepatitis C virus infection

Figures & data

Figure 1 Milestones in HCV research and Direct-Acting Antivirals development.

Abbreviations: HCV, hepatitis C virus; NS3, non-structural protein 3; IFN-α, interferon-alpha; PEG-IFN-α, pegylated IFN-α.

Table 1 Example of drug interactions with boceprevir and side effects

Class	Example of drug	Drug–drug interactions	Adverse effects
Immunosuppressants	Tacrolimus*	Boceprevir ↑ [tacrolimus]	Nephro- and neurotoxicity, hypertension
Antiretrovirals	Efavirenz*	Efavirenz ↓ [boceprevir]	Decreased efficacy of HCV treatment
Antimycobacterials	Rifabutin*	Rifabutin ↓ [boceprevir]	Decreased efficacy of HCV treatment
		Boceprevir ↑ [rifabutin]
HMG-CoA reductase inhibitors	Atorvastatin	Boceprevir ↑ [atorvastatin]	Myopathy (rhabdomyolysis)
Oral contraceptive	Drosperinone	Boceprevir ↑ [drosperinone]	Hyperkalemia
Antidepressants	Trazodone	Boceprevir ↑ [trazodone]	Dizziness, hypotension, syncope
Antipsychotics	Pimozide	Boceprevir ↑ [pimozide]	Cardiac arrhythmia
Anxiolytics and sleep aids	Midazolam	Boceprevir ↑ [midazolam]	Sedation/respiratory depression
Opioid replacements	Methadone	Boceprevir ↑ or ↓ [methadone]	Nausea, diarrhea, difficulty breathing

Notes: All these drugs need to be used with caution and their dose have to be adapted.

* Concomitant use with boceprevir is not recommended. Data obtained from.^{24,28,61,62,63}

Abbreviations: HCV, hepatitis C virus; HMG-CoA reductase inhibitor, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor.

Figure 2 Phase III trials design.

Notes: Patients from SPRINT-2 (naïve patients) and RESPOND-2 (previously-treated patients) studies were randomly divided into 3 groups. All subjects received PEG-IFN-α + RBV for 4 weeks (lead-in period). Then, patients were administered with: PEG-IFN-α + RBV and placebo for 44 weeks: control group; PEG-IFN-α + RBV and boceprevir for 44 weeks: fixed-duration therapy group; PEG-IFN-α + RBV and boceprevir for 28 (naïve patients) or 36 (previously-treated patients) weeks: response-guided therapy group. Subjects with a detectable viral load at weeks 8 and 24 (naïve patients) or at week 8 (previously-treated patients) received PEG-IFN-α + RBV and placebo until week 48. Treatment failure was considered for previously-treated patients with a detectable viral load at week 12, resulting in discontinuation of the treatment. All other patients were followed-up until week 72. Adapted from Poordad et al and Bacon et al.^36,37
Abbreviations: HCV, hepatitis C virus; PEG-IFN-α, pegylated interferon-alpha; RBV, ribavirin; LOD, limit of detection.

Table 2 SVR rates according to treatment group and cohorts in phase III clinical trials

Trial	Cohort	Control (group 1)	Response-guided therapy (group 2)	Fixed-duration therapy (group 3)
SPRINT-2
Naïve patients	Non-black cohort	40%	67%	68%
	Black cohort	23%	42%	53%
	Combined cohorts	38%	63%	66%
RESPOND-2
Previously-treated patients	Prior relapse	29%	69%	75%
	Prior nonresponse	7%	40%	52%
	Poor response to lead-in	0%	33%	34%
	Good response to lead-in	25%	73%	79%
	Combined cohorts	21%	59%	66%

Notes: Prior relapse corresponds to an undetectable viral load at the end of prior therapy but without achieving SVR. Prior nonresponse corresponds to a reduction of viral load of at least 2 log₁₀ IU/mL with then the persistance of detectable HCV RNA during follow-up. Poor response to PEG-IFN-α corresponds to a reduction of viral load of less than 1 log₁₀ IU/mL after the lead-in period. Good response to PEG-IFN-α corresponds to a reduction of viral load greater than 1 log₁₀ IU:mL after the lead-in period. Data drawn from Poordad et al and Bacon et al.^36,37

Abbreviations: HCV, hepatitis C virus; SVR, Sustained Virological Response; PEG-IFN-α, pegylated interferon-alpha.

Table 3 Predictive factors of SVR in naïve and previously non-responders patients in phase III clinical trials

Trial	Variable	Odds ratio (95% CI)	P value
SPRINT-2
Naïve patients	Age ≤40 vs >40 years	1.5 (1.0–2.1)	0.03
	No cirrhosis vs cirrhosis	2.5 (1.4–4.6)	0.003
	Black vs nonblack cohort	0.5 (0.3–0.7)	<0.001
	IL28B genotype: CC vs TT^Table Footnote*	2.6 (1.3–5.1)	0.006
	CC vs CT*	2.1 (1.2–3.7)	0.01
	Statin use vs no statin use	3.4 (1.1–10.7)	0.04
	HCV genotype: 1b vs 1a^Table Footnote*	2.0 (1.2–3.4)	0.005
	Baseline viral load ≤400,000 vs >400,000 IU/mL	3.9 (2.1–7.1)	<0.001
	Decline in viral load at week 4 (≥1 vs <1 log10 decline)	9.0 (6.3–12.8)	<0.001
RESPOND-2
Previously-treated patients	Previous relapse vs previous non-response	3.2 (1.9–5.4)	<0.001
	Baseline viral load ≤800,000 vs >800,000 IU/mL	2.4 (1.1–5.3)	0.04
	Decline in viral load at week 4 (≥1 vs <1 log10 decline)	5.2 (NC-NC)	<0.001

Note:

* Data obtained retrospectively.

Data obtained from^36,37,46.

Abbreviations: HCV, hepatitis C virus; SVR, Sustained Virological Response; CI, confidence interval; NC, not communicated.

Figure 3 Duration of therapy following the registration of boceprevir by the FDA and stopping rules during boceprevir treatment in naïve and previously treated patients with response-guided therapy.

Notes: Both naïve and previously-treated patients are tested for viral load at days 8, 12 and 24 to determine whether therapy is continued or not. Although boceprevir treatment of naïve patients without an eRVR was stopped at day 28 in the SPRINT-2 trial, the FDA recommends these patients to be treated with boceprevir until week 36. Data obtained from⁶⁰.
Abbreviations: HCV, hepatitis C virus; PEG-IFN-α, pegylated interferon-alpha; RBV, ribavirin; LOD, limit of detection.

Table 4 Types of adverse events according to treatment group in phase III clinical trials

Trial	Events	Control (group 1)	Response-guided therapy (group 2)	Fixed-duration therapy (group 3)
SPRINT-2
Naïve patients	One or more AE	98%	99%	99%
	Serious AE	9%	11%	12%
	Dose modification due to AE	26%	40%	35%
	Discontinuation due to AE	16%	12%	16%
	Death	1%	<1%	<1%
RESPOND-2
Previously-treated patients	One or more AE	96%	99%	100%
	Serious AE	5%	10%	14%
	Dose modification due to AE	14%	29%	33%
	Discontinuation due to AE	2%	8 %	12%
	Death	0%	1%	0%

Note: Data obtained from Poordad et al and Bacon et al.^36,37

Abbreviation: AE, adverse event.

Table 5 Major adverse events related to boceprevir treatment in phase III clinical trials*

Trial	Adverse event	Control (group 1)	Response-guided therapy (group 2)	Fixed-duration therapy (group 3)
SPRINT-2
Naïve patients	Anemia	29%	49%	49%
	Dysgeusia	18%	37%	43%
	Decreased hemoglobin concentration at week 12 (g/dL)^§	−3.0	−4.0	−3.9
	Decreased hemoglobin concentration at week 24 (g/dL)^§	−3.1	−4.1	−3.9
	Erythropoietin use	24%	43%	43%
	Decreased absolute neutrophile count (500 to <750 per mm^3)	14%	24%	25%
RESPOND-2
Previously-treated patients	Anemia	20%	43%	46%
	Dysguesia	11%	43%	45%
	Decreased hemoglobin concentration at week 12 (g/dL)^§	−2.89	−4.02	−3.96
	Decreased hemoglobin concentration at week 24 (g/dL)^§	−2.69	−4.36	−4.31
	Erythropoietin use	21%	41%	46%

Notes:

* Data are presented as percentages from the total number of subjects per group (except §). Only adverse events associated with a P value < 0.001 are reported in this table;

§ data are expressed as mean change in hemoglobin concentration from baseline. Data drawn from Poordad et al and Bacon et al.^36,37

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