VALENCE

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Zeuzem S, et al. "Sofosbuvir and ribavirin in HCV genotypes 2 and 3". The New England Journal of Medicine. 2014. 370(21):1993-2001.
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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).[1] However, IFN-related toxicities, including influenza-like symptoms, depression, anemia, thrombocytopenia, and autoimmune thyroiditis, were prohibitive.[2] 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[3] 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.[4] However, this has not precluded its incorporation into US guidelines.

Guidelines

AASLD/IDSA HCV (2014-10, adapted)[5]

  • 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[6] 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.[7]

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)

Further Reading