VALENCE

Published

Zeuzem S, et al. "Sofosbuvir and ribavirin in HCV genotypes 2 and 3". The New England Journal of Medicine. 2014. 370(21):1993-2001.
PubMed • Full text • PDF

Clinical Question

Among patients with HCV genotypes 2 or 3, does sofosbuvir plus ribavirin result in sustained virologic response?

Bottom Line

Among patients with HCV genotypes 2 or 3, sofosbuvir plus ribavirin resulted in high rates of sustained virologic response.

Major Points

Historically, approximately three-quarters of patients with HCV genotypes 2 or 3 treated with peginterferon alfa-2a (IFN) plus ribavirin achieved a sustained virologic response (SVR). However, IFN-related toxicities, including influenza-like symptoms, depression, anemia, thrombocytopenia, and autoimmune thyroiditis, were prohibitive. In the 2010s, novel antiviral therapies were being developed, including the viral RNA synthesis inhibitor sofosbuvir, with marked efficacy and reasonable tolerability. Sofosbuvir's single-agent activity and its efficacy in combination with ribavirin led to a flurry of publications touting an IFN-free cure for HCV. Its use in North America and other centers in the FISSION studies established sofosbuvir-ribavirin as a reasonable IFN-sparing regimen among patients with HCV genotypes 2 or 3.

VALENCE was designed as phase 3 study randomizing patients with HCV genotypes 2 or 3 to sofosbuvir plus either ribavirin or placebo for a total of 12 weeks. However, results of the FUSION study suggested that genotype 3 patients should receive 24 rather than 12 weeks of therapy, and therefore the protocol was amended such that genotype 3 patients received sobosbuvir-ribavirin for 24 weeks; consequently, the genotype 3 arm was changed to a descriptive study. Although the genotype 2 arm could have theoretically remained a randomized study, the investigators modified this as well by removing the placebo group and providing 12 weeks of sofosbuvir-ribavirin to consenting patients with genotype 2 infections. After 12 weeks of therapy, SVR was achieved in 93% of genotype 2 patients and in 27% of genotype 3 patients. Among genotype 3 patients treated for 24 weeks, SVR was 85%. In general, the therapy was well tolerated; adverse events led to treatment discontinuation in about 1% of each arm.

The high cost of sofosbuvir has been a matter of controversy as it retails for $1,000 per pill in the US. However, this has not precluded its incorporation into US guidelines.

Guidelines

AASLD/IDSA HCV (2014-10, adapted)

• Initial HCV treatment:
  • Genotype 2:
    • Recommended: Sofosbuvir-ribavirin x 12 weeks (class I, level A)
    • Alternative: None
  • Genotype 3:
    • Recommended: Sofosbuvir-ribavirin x 24 weeks (Ilass B, level )
    • Alternative: Sofosbuvir-ribavirin plus IFN x 12 weeks (class IIa, level A)
• Retreatment of HCV in IFN/ribavirin non-responders:
  • Genotype 2:
    • Recommended: Sofosbuvir-ribavirin for 12 weeks; consider extension to 16 weeks in patients with cirrhosis (class I, level A)
    • Alternative: Sofosbuvir-ribavirin plus IFN x 12 weeks (class IIa, level B)
  • Genotype 3:
    • Recommended: Sofosbuvir-ribavirin for 24 weeks (class IIa, level A)
    • Alternative: Sofosbuvir-ribavirin plus IFN w eekly for 12 weeks (class IIa, level B)

Design

• Multicenter, blinded, randomized (initially), controlled phase 3 trial, later amended to an unblinded descriptive study with the placebo group terminated
• N=419 patients with genotype 2 or 3
  • Genotype 2 on sofosbuvir + ribavirin for 12 weeks (n=73)
  • Genotype 3 on sofosbuvir + ribavirin for 12 weeks (n=11)
  • Genotype 3 on sofosbuvir + ribavirin for 24 weeks (n=250)
  • Genotype 2 or 3 on placebo (n=85)
• Setting: 77 centers in Europe
• Enrollment: 2012-2013
• Follow-up: Weeks 2 and 4 during treatment; weeks 4 and 12 after treatment
• Analysis: Not explicitly stated, presumably intention-to-treat
• Primary outcome: HCV RNA <25 IU/mL 4 and 12 weeks after completing 12 weeks of treatment

Population

Inclusion Criteria

• Age ≥18 years
• Chronic HCV genotype 2 or 3, regardless of prior treatments for HCV
• Data:
  • HCV RNA ≥10,000 IU/mL
  • BMI ≥18 kg/m²
  • HbA1c ≤10%
  • EKG without clinically-significant findings
  • ALT and AST ≤10×ULN
  • Hgb ≥12 g/dL for male, Hgb ≥11 g/dL for female
  • Plts >50×10³/mm³
  • INR ≤1.5×ULN (unless known hemophilia or stable anticoagulant regimen)
  • Albumin ≥3 g/dL
  • Direct bilirubin ≤1.5×ULN
  • CrCl ≥60 mL/min

Exclusion Criteria

• Prior treatment with an antiviral medication targeting NS5B polymerase
• Pregnant or nursing female or male with a pregnant female partner
• Non-HCV-related chronic liver disease
• HBV or HIV infection
• RBV contraindication
• Cancer diagnosed or treated in prior 5 years (except cervical carcinoma in situ or non-melanoma skin cancer)
• Clincially-significant hemoglobinopathy
• Chronic immunosuppression
• Drug or alcohol abuse within 12 moths
• Solid organ transplant
• History of hepatic decompensation (eg, uGIB)
• Clinically-significant illness or other disorder that would prevent with trial participation
• GI disorder that would prevent drug absorption
• Significant pulmonary or cardiac disease
• Porphyria
• >3 drinks of alcohol/day if female or >4/day if male
• Difficulty with blood collection
• Loss or donation of >400 mL/blood in the prior 2 months
• Use of prohibited medications that cause medication concentration modifications

Baseline Characteristics

From the placebo group. Groups were similar.

• Demographics: Age 49 years, White race 95%, Hispanic or Latino 12%
• Health data: BMI 26 kg/m²
• HCV data: Genotype 2 (21%), genotype 3 (79%), RNA 6.5 log₁₀IU/mL, cirrhosis 20%, ALT >1.5x ULN 62%
• Prior IFN treatment: None 41%, yes 59% (discontinuation for side effects 0%, no response 21%, relapse or breakthrough 38%)

Interventions

• The original design randomized patients in a 4:1 ratio to a group with stratification by cirrhosis and prior HCV treatment:
  • Sofosbuvir + ribavirin - Originally for 12 weeks though amended to be up to 24 weeks if genotype 3, as the FUSION trial suggested a benefit from longer therapy in this group
  • Placebo
• Given the results of the FUSION trial, the trial was redesigned as a descriptive study with no hypothesis testing and the placebo arm was terminated

Outcomes

Comparisons are genotype 2 vs. genotype 3. Data is from the active treatment groups only as placebo viral loads were not measured.

Primary Outcome

HCV RNA <25 IU/mL 4 weeks after 12 weeks of treatment

93% vs. 45%

HCV RNA <25 IU/mL 12 weeks after 12 weeks of treatment

93% vs. 27%

Secondary Outcomes

HCV RNA <25 IU/mL 4 weeks after 24 weeks of treatment

Genotype 3: 87% (95% CI 82-91%)

HCV RNA <25 IU/mL 12 weeks after 24 weeks of treatment

Genotype 3: 85% (95% CI 80-89%)

HCV RNA <25 IU/mL 2 weeks into 12 weeks of treatment

78% vs. 55%

HCV RNA <25 IU/mL 2 weeks into 24 weeks of treatment

Genotype 3: 86% (95% CI 81-90%)

HCV RNA <25 IU/mL 4 weeks into 12 weeks of treatment

100% in both genotypes

HCV RNA <25 IU/mL 4 weeks into 24 weeks of treatment

Genotype 3: 99% (95% CI 96-99%)

Adverse Events

Presented as placebo vs. sofosbuvir + ribavirin for 12 weeks vs. sofosbuvir + ribavirin for 24 weeks.

Any

71% vs. 86% vs. 92%

Resulting in discontinuation: 1% vs. 1% vs. <1%

Serious: 2% vs. 0% vs. 4%

Most common

Headache: 27% vs. 29% vs. 30%

Fatigue: 19% vs. 23% vs. 30%

Pruritis: 9% vs. 24% vs. 27%

Asthenia: 5% vs. 25% vs. 21%

Nausea: 11% vs. 31% vs. 13%

Insomnia: 2% vs. 11% vs. 16%

Criticisms

• Original design was revised providing no hypothesis testing nor formal statistical comparisons
• Few liver biopsies in this population
• Among patients with genotype 2 infection, it is unclear if longer duration or addition of IFN would benefit patients

Funding

Gilead Sciences, the manufacturers of Sovaldi (the brand name of sofosbuvir)