Predictors of Response to Chronic Hepatitis C Treatment

Ezequiel Ridruejo

Future Virology. 2012;7(11):1089-1101.

Abstract and Introduction

Abstract

Chronic hepatitis C is a growing health problem worldwide that has attracted increased attention in recent years. Treatment with peginterferon and ribavirin combination had previously been the standard of care. In 2011, a new treatment with protease inhibitors, telaprevir and boceprevir was approved, and a new standard of care was defined. Previous predictors of response have been redefined, and while IL28B, fibrosis stage and hepatitis C virus viral load testing continue to have their value, viral kinetics during treatment defining viral response have emerged as the strongest predictor for achieving sustained virologic response with the new treatment. New therapies are expected in the near future, and current treatment predictors of response may soon change.

Introduction

Chronic hepatitis C is a growing health problem worldwide that has attracted increased attention in recent years. Approximately 3% of the world's population (130–170 million people) is chronically infected with HCV.^[1,2] HCV is one of the most prevalent blood-borne infections, with a higher prevalence than HIV (~1.1 million infected) and HBV (0.8–1.4 million infected) in western countries.^[3] Chronic HCV infection progresses asymptomatically, and almost 75% of patients are unaware of the diagnosis when they present with complications of cirrhosis, portal hypertension or develop a hepatocellular carcinoma (HCC) many years later.^[4] In western countries HCV infection is one of the most frequent causes of death from end-stage liver diseases and HCC.^[5] In the last decade, HCV-related morbidity doubled, and HCC related to HCV increased almost threefold.^[6] Its impact on liver-related morbidity and mortality is expected to reach its peak in the next decade.^[7]

The objective with antiviral therapy is to obtain a sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks after the end of treatment. In the last decade, treatment with pegylated interferon 2a or 2b (pegIFN) combined with weight-based ribavirin (RBV) for 48 weeks (genotypes 1, 4, 5 and 6) or 24 weeks (genotypes 2 and 3), has been considered the standard of care (SOC) for HCV treatment. With pegIFN/RBV treatment, SVR rates were 40–50% in genotype 1 and 70–80% in genotypes 2/3-infected patients in western countries.^[8] Some studies showed that prolonging treatment up to 72 weeks in genotype 1 slow responders (HCV RNA detectable at week 12 but undetectable at week 24), can increase SVR rates.^[9–12] But, prolonged treatment is associated with higher costs, increases in adverse events, and cannot be used in treatment-intolerant patients.

Many viral and host factors affect treatment response, and not achieving a SVR might be related to a combination of them. HCV genotype and IL28B host genotype are the strongest predictors of pegIFN/RBV therapy outcome.^[13]IL28B designates single-nucleotide polymorphisms (SNPs) in the interferon λ gene region in chromosome 19, and it is related to interferon responsiveness. Other factors such as high viral load, older age, black race and advanced fibrosis or cirrhosis negatively influence SVR rates.^[14,15]

In 2011 the US FDA and the EMA approved telaprevir (TVR) (Incivek/Incivo™, Vertex) and boceprevir (BOC) (Vitrelis™, Merck) for its use in HCV genotype 1 infected patients. These two NS3/4A serine protease inhibitors (PIs) are the first generation of direct-acting antiviral (DAA) drugs to be approved for its use in clinical practice. Used in combination with pegIFN/RBV, PIs increased SVR rates up to 68–75% in naive patients and to 41–52% in previous nonresponders.^[16–19] With the new treatment regime of PI-based triple therapy, some of the predictors of response to dual pegIFN/RBV-based therapy are less important. In fact, some host factors are used differently. Nonetheless, baseline host and viral factors and early viral kinetics are still important determinants for patient counseling and management using BOC or TVR combination treatment.

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Next Section

Abstract and Introduction
Why Do We Need Predictors of Response to Treatment?
Pretreatment Predictors of Response
On-treatment Predictors of Response
Conclusion
Future Perspective
References
Sidebar

Table 1. Baseline and on-treatment predictors of sustained virologic response with pegylated interferon/ribavirin in genotype 1 patients.
Variable	OR (95% CI)	p-value	Ref.
*Baseline predictors*
IL28B CC versus non-CC genotypes	5.93 (4.57–7.69) 2.66 (1.54–4.61)	<0.001 0.001	[40] [53]
Baseline HCV RNA level ≤400,000 versus >400,000 IU/ml	3.9 (2.1–7.1)	<0.001	[53]
Baseline HCV RNA level ≤600,000 versus >600,000 IU/ml	3.1 (2.3–4.1)	<0.001	[40]
Metavir F0–2 versus F3–4	2.7 (1.8–4.0) 2.6 (1.27–3.34)	<0.001 0.003	[40] [53]
*On-treatment predictor*
RVR versus non-RVR	9.1 (5.8–14)	<0.001	[40]
RVR versus non-RVR	5.35 (2.8–10.1)	<0.001	[53]

OR: Odds ratio; RVR: Rapid virologic response.
Adapted with permission from [40,53].

Table 2. Determinants of the response to HCV protease inhibitors, pegylated interferon and ribavirin for the treatment of chronic HCV genotype 1 infections.
Variable	SVR (%)		Variable	SVR (%)
Variable	B44PR48	PR48	Variable	T12PR24–48	PR48
Genotype: 1a 1b	71 79	41 48	Genotype 1a 1b	63 70	35 40
Viral load: <800,000 IU/ml >800,000 IU/ml	78 74	70 36	Viral load <800,000 IU/ml >800,000 IU/ml	85 63	64 33
Age: <45 years >45 years	83 70	52 38	Age <40 years >40 years	69 65	52 34
Race: Nonblack Black	75 62	46 25	Race Nonblack Black	68 53	40 23
Fibrosis: 0–2 3–4	77 62	47 33	Fibrosis 0–2 3–4	67 52	38 38
BMI: <25 kg/m² 25–30 kg/m² >30 kg/m²	83 67 71	44 45 41	BMI <25 kg/m² 25–30 kg/m² >30 kg/m²	67 65 66	47 33 33

B44PR48: Boceprevir for 44 weeks and peginterferon and ribavirin for 48 weeks; PR48: Peginterferon and ribavirin for 48 weeks; SVR: Sustained virologic response; T12PR24–48: Telaprevir for 12 weeks and peginterferon and ribavirin for 24–48 weeks.
Adapted with permission from [33] with some data adapted from [16,17].

Table 3. Logistic regression for baseline predictors of sustained virologic response, baseline predictors of interferon response (≥1 log ₁₀ decline at week 4) and predictors of sustained virologic response, including treatment week 4 response.
Previously untreated patients (SPRINT-2)			Previous treatment failure patients (RESPOND-2)
Variable	Odds ratio (95% CI)	p-value	Variable	Odds ratio (95% CI)	p-value
*Logistic regression for baseline predictors of SVR with triple therapy*
Baseline HCV RNA level ≤400,000 versus >400,000 IU/ml	11.6 (1.5–87.8)	0.02	Baseline HCV RNA level ≤800,000 versus >800,000 IU/ml	2.6 (0.8–8.9)	0.12
IL28B CC versus TT	2.6 (1.3–5.1)	0.006	IL28B CC versus TT	2.0 (0.6–6.7)	0.27
IL28B CC versus CT	2.1 (1.2–3.7)	0.01	IL28B CC versus CT	2.3 (1.0–5.5)	0.06
No cirrhosis versus cirrhosis	4.3 (1.6–11.9)	0.004	No cirrhosis versus cirrhosis	2.0 (0.7–5.3)	0.18
Genotype 1a versus 1b	2.0 (1.2–3.4)	0.005	Genotype 1a versus 1b Previous treatment response (relapser versus nonresponder)	1.1 (0.6–2.1) 2.6 (1.3–5.0)	0.77 0.006
**Logistic regression for baseline predictors of good interferon response ( ≥ 1 log₁₀ decline at week 4) with triple therapy**
Baseline HCV RNA level ≤400,000 versus >400,000 IU/ml	10.3 (1.3–80.5)	0.03	Baseline HCV RNA level ≤800,000 versus >800,000 IU/ml	3.3 (0.8–12.8)	0.09
IL28B CC versus TT	26.5 (7.6–92.6)	<0.001	IL28B CC versus TT	9.3 (2.3–37.1)	0.002
IL28B CC versus CT	16.4 (5.0–55.6)	<0.001	IL28B CC versus CT	3.8 (1.2–12.0)	0.02
No cirrhosis versus cirrhosis	3.7 (1.2–11.1)	0.02	No cirrhosis versus cirrhosis	1.0 (0.3–3.1)	0.97
Genotype 1a versus 1b	1.0 (0.6–1.7)	0.92	Genotype 1a versus 1b Previous treatment response (relapser versus nonresponder)	0.7 (0.3–1.3) 2.6 (1.3–5.5)	0.25 0.009
*Logistic regression model of predictors of SVR including treatment week 4 response with triple therapy*
Baseline HCV RNA level ≤400,000 versus >400,000 IU/ml	8.4 (1.0–68.6)	0.046	Baseline HCV RNA level ≤800,000 versus >800,000 IU/ml	2.3 (0.7–7.9)	0.20
IL28B CC versus TT	1.2 (0.6–2.7)	0.59	IL28B CC versus TT	1.3 (0.4–5.0)	0.65
IL28B CC versus CT	1.1 (0.6–2.1)	0.76	IL28B CC versus CT Previous treatment response (relapser versus nonresponder)	2.0 (0.8–4.9) 2.2 (1.1–4.4)	0.13 0.02
No cirrhosis versus cirrhosis	3.5 (1.1–11.3)	0.04	No cirrhosis versus cirrhosis	2.1 (0.8–5.7)	0.16
Genotype 1a versus 1b	2.1 (1.2–3.6)	0.08	Genotype 1a versus 1b	1.2 (0.6–2.4)	0.54
Decline in HCV-RNA level at week 4, ≥1 versus <1 log₁₀ decline	8.2 (4.5–15)	<0.001	Decline in HCV-RNA level at week 4, ≥1 versus <1 log₁₀ decline	2.7 (1.2–5.7)	0.01

SVR: Sustained virologic response.
Adapted with permission from [44].

Table 4. Virologic response definitions with pegylated interferon/ribavirin-based therapy.
Response	Definition
SVR	HCV RNA undetectable by sensitive assay 24 weeks after treatment end
RVR	HCV RNA undetectable at week 4
EVR	>2 log₁₀ IU/ml reduction in HCV RNA at week 12
cEVR	HCV RNA detectable at week 4, but undetectable at week 12
Null response	HCV RNA decline <2 log₁₀ IU/ml from baseline at week 12
Partial response	HCV RNA decline >2 log₁₀ IU/ml from baseline at week 12, but HCV RNA detectable at weeks 12 and 24
Viral breakthrough	HCV RNA detectable at any time during treatment after being undetectable
Relapse	HCV RNA detectable after withdrawing treatment in a patient who was undetectable at end of treatment
*New response categories with PI-based therapy*
eRVR with boceprevir	HCV RNA undetectable at weeks 8 and 24 of therapy
eRVR with telaprevir	HCV RNA undetectable at weeks 4 and 12 of triple therapy
Week 8 response	Among boceprevir-treated patients, HCV RNA undetectable at week 8 of the overall treatment course (i.e., after 4 weeks of pegIFN/RBV lead-in and 4 weeks of triple therapy)
Lead-in RVR	HCV RNA undetectable at week 4 for patients who had a pegIFN/RBV lead-in phase of therapy

cEVR: Complete early virologic response; EVR: Early virologic response; eRVR: Extended rapid virologic response; pegIFN: Pegylated interferon; PI: Protease inhibitor; RBC: Ribavirin; RVR: Rapid virologic response; SVR: Sustained virologic response.
Reproduced with permission from [102].

Table 5. Stopping rules for protease inhibitor-based therapy.
Time	TVR + PegIFN/RBV	BOC + PegIFN/RBV
Week 4	Discontinue all therapy if HCV RNA >1000 UI/ml	No action
Week 12		Discontinue all therapy if HCV RNA >100 UI/ml
Week 24	Discontinue all therapy if HCV RNA is detectable
Anytime	Discontinue protease inhibitor if pegIFN/RBV is discontinued for any reason

BOC: Boceprevir; PegIFN: Pegylated interferon; RBV: Ribavirin; TVR: Telaprevir.
Reproduced with permission from [102].

Box 1. Factors associated with response to peginterferon and direct antiviral agent-based therapy.
*Viral factors* Genotype Genotype 1 subtypes (only with PIs) Baseline HCV RNA levels (>400,000–800,000 IU/ml) Specific viral mutations *Host factors* Fixed Age Sex Race Fibrosis IL28B genotype Gene expression profile (ISG preactivation) IP-10 titer ITPA genotype Previous response to pegIFN/RBV (only in nonresponders) Potentially modifiable BMI Insulin resistance Adherence Coffee consumption Vitamin D status
PegIFN: Pegylated interferon; PI: Protease inhibitor; RBV: Ribavirin.