Real-world impact of sofosbuvir HCV regimens

Posted on July 12, 2015

New study addresses the real-world effectiveness of sofosbuvir (SOF)-based anti-HCV regimens in a diverse patient population consisting of difficult to treat patients. More than a quarter of the assessed US Veterans Affairs (VA) population with chronic HCV infection were African American, almost 90% were over the age of 55, over a third were overweight, and substantial proportions were treatment experienced and had advanced liver disease. Overall, SVR rates in the VA with SOF-based regimens were substantially higher than with prior HCV anti-viral regimens, but lower than the rates reported in clinical trials.

Early treatment discontinuation rates likely contributed to the lower SVR rates observed in the VA cohort compared with the clinical trials, highlighting that real-world effectiveness may be substantially undermined by issues such as patient tolerability, social or behavioral factors, adverse events and baseline characteristics predisposing patients to failure.

While SVR rates for genotype 1 and 2 HCV-infected veterans treated nationwide with SOF-based regimens were lower than reported in clinical trials for either genotype, they were still substantially higher than rates reported previously in similar VA cohorts with boceprevir- or telaprevir-based regimens.

Understanding the real-world effectiveness of the newer direct acting anti-viral therapies for chronic hepatitis C virus is essential to provide practical information to better inform HCV treatment decisions. The rapid uptake of sofosbuvir (SOF)-based regimens across healthcare settings, and the underrepresentation of important HCV-infected populations in clinical trials, prompted Dr Lisa Backus and her colleagues at the Department of Veterans Affairs (VA) in Palo Alto, California, to examine the real-world outcomes of the diverse, genotype 1 and 2 HCV-infected US veteran population receiving SOF-based regimens in routine medical practice. This observational, intent-to-treat cohort analysis of data from the VA’s Clinical Case Registry for HCV was recently published in the journal Alimentary Pharmacology and Therapeutics (Backus LI, et al. Aliment Pharmacol Ther. 2015 Jun 26. [Epub ahead of print]).

  • Eligible subjects (N = 4045) included all veterans from any VA facility in the US with HCV genotype 1 (n = 3203) or genotype 2 (n = 823) who initiated a VA-prescribed SOF-based anti-viral treatment regimen with a recommended duration of 12 weeks between 1 January 2014 and 9 October 2014 and had stopped treatment by 31 December 2014
    • Patients were excluded from the analysis if they changed regimens, had SOF added to an existing regimen, had a baseline HCV RNA ≤1000 IU/mL, had HIV infection or had a liver transplant
    • Among genotype 1 patients, the mean age was 61 years, 96% were male, 31% were African American, 7% had a history of decompensated liver disease, 34% had diabetes, 37% were treatment experienced, 13% had prior protease inhibitor (PI) experience, 31% had an APRI >2 and 53% had a FIB-4 > 3.25
    • Among genotype 2 patients, the mean age was 61 years, 97% were male, 9% were African American, 6% had a history of decompensated liver disease, 27% had diabetes, 23% were treatment experienced, 21% had an APRI >2 and 38% had a FIB-4 > 3.25
    • 12-week, SOF-based anti-viral treatment regimens initiated at VA facilities included SOF + peginterferon (PEG) + ribavirin (RBV) for genotype 1 and 2, SOF + simeprevir (SIM) ± RBV for genotype 1, and SOF + RBV for genotype 2.

Patients were considered to have SVR if they had undetectable HCV RNA on all HCV RNA tests after the end of treatment (EOT) including at least one test at least 12 weeks or more after the EOT. Overall, SVR rates in the VA with SOF-based regimens were substantially higher than with prior HCV anti-viral regimens, but lower than the rates reported in clinical trials. Discontinuation rates for anti-HCV therapies in the VA population (between 9.9% – 14.3%) were markedly higher than those observed in clinical trials (0 – 3.6%). Early treatment discontinuation rates likely contributed to the lower SVR rates observed in the VA cohort compared with the clinical trials, highlighting that real-world effectiveness may be substantially undermined by issues such as patient tolerability, social or behavioral factors, adverse events and baseline characteristics pre-disposing patients to failure.

  • Overall SVR rates among the genotype 1 VA patients:
    • 66.8% for SOF + PEG + RBV
    • 75.3% for SOF + SIM
    • 74.1% for SOF + SIM + RBV
    • SVR rates were higher for patients receiving SOF + SIM ± RBV compared with SOF + PEG + RBV (75.1% vs. 66.8%, P < 0.001)
  • Genotype 1 patients with the following were less likely to achieve SVR:
    • BMI ≥30 (OR 0.64, 95% CI 0.49–0.84, P < 0.001)
    • A history of decompensated liver disease (OR 0.51, 95% CI 0.36–0.71, P < 0.001)
    • Treatment experience (OR 0.58, 95% CI 0.48–0.71, P < 0.001)
    • APRI >2 (OR 0.44, 95% CI 0.36–0.55, P < 0.001)
    • Age, sex, race/ethnicity, diabetes, and genotype subtype did not predict SVR
  • In genotype 1, treatment-naïve patients receiving SOF + PEG + RBV, the SVR rate was 73.7%. However, the SVR rate in genotype 1, treatment-experienced VA patients receiving SOF + PEG + RBV was 55.6%, much lower than the estimated 71% which was predicted using data from treatment-naïve patients with multiple baseline factors traditionally associated with a lower response to interferon-based therapy.
    • The SOF + PEG + RBV regimen has not been evaluated in clinical trials in treatment-experienced genotype 1 patients, and so this analysis represents one of the first reports of SVR in this population
    • In multivariate models to control for differences in baseline patient characteristics, SOF + PEG + RBV was associated with more than a 50% decrease in the odds of achieving SVR compared with SOF + SIM. These comparative effectiveness data provide further support for the use of interferon-free regimens over triple therapy with a direct acting anti-viral plus PEG + RBV.
  • Overall SVR rate among the genotype 2 VA patients (the largest cohort of genotype 2 patients treated with SOF + RBV in the published literature to date):
    • 79.0% for SOF + RBV
  • Genotype 2 patients with the following were less likely to achieve SVR:
    • Prior treatment experience (OR 0.55, 95% CI 0.35–0.88, P = 0.009)
    • APRI >2 (OR 0.39, 95% CI 0.25–0.62, P < 0.001)
  • In genotype 2, treatment-naïve patients receiving SOF + RBV, the SVR rate was 81.6%. However, the SVR rate in genotype 2, treatment-experienced VA patients receiving SOF + RBV was 70.9%. These rates are lower than the 92–97% and 82–90% reported from smaller published cohorts of naïve and experienced patients, respectively.
  • In multivariate analysis, the odds of achieving SVR in genotype 2 VA patients were reduced by 45% in those with prior treatment experience and by approximately 60% in those with advanced disease by APRI or FIB-4 score

Advanced liver disease has a dramatic effect on SVR and may identify a gap in currently available treatment. In multivariate models, across genotype and regimens, the presence of advanced liver disease as assessed by these simple laboratory tests independently reduced the likelihood of achieving SVR by more than 50%.

  • Study authors suggest that in clinical practice, calculation of APRI and/or FIB-4 scores may be useful in discussions with patients regarding the likelihood of treatment success

Detectable 4 week on-treatment HCV RNA≥43 IU/mL was independently associated with a greater reduction in the odds of SVR, for both genotype 1 and genotype 2, than advanced liver disease or prior treatment experience – a finding that has not been previously reported.

  • Detectable HCV RNA ≥43 IU/mL at week 4 predicted an over 60% decrease in the odds of achieving SVR for genotype 1 patients and nearly an 80% decrease in the odds of SVR for genotype 2 patients

The authors of this study made the following conclusions: “In this large real-world cohort, genotype 1 and 2 HCV infected veterans with advanced liver disease, prior treatment experience or detectable week 4 on-treatment HCV RNA were significantly less likely to achieve SVR. For genotype 1, use of SOF + SIM RBV was associated with a higher likelihood of SVR compared with SOF + PEG + RBV. Overall, SVR rates in the VA with SOF-based regimens were substantially higher than with prior HCV anti-viral regimens but lower than the rates reported in clinical trials. The differences observed in VA with regard to patient characteristics, early treatment discontinuations and lower SVR rates reflect the differences between clinical trials and clinical practice. Thus, patient and provider expectations in real-world settings may need to be tempered accordingly depending on the population being treated. The reporting of real-world experience in VA, the largest provider of HCV care in the USA, is essential to provide practical information to better inform HCV management strategies. Given the public health impact of effective HCV treatment, real world outcomes data will help inform clinicians and policy makers beyond VA.”


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