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Evaluation of Proton Pump Inhibitor Use on Treatment Outcomes with Ledipasvir and Sofosbuvir in a Real-World Cohort Study
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Hepatology accepted article not fully proof read yet Aug 17 2016
Elliot B. Tapper,(1), Bruce R. Bacon (2), Michael P. Curry (1), Douglas T. Dieterich (3), Steven L. Flamm (4), Lauren E. Guest (5), Kris V. Kowdley (6), Yoori Lee (5), Naoky C. Tsai (7), Zobair M. Younossi (8), Nezam H. Afdhal(1)
Abstract
Many patients with chronic hepatitis C (HCV) are on prolonged proton-pump inhibitor (PPI) therapy, and wish to remain on PPI therapy once treatment for HCV starts. A preliminary report recently suggested decrease rates of sustained virologic response (SVR) for patients taking concomitant PPI and Ledipasvir/Sofosbuvir (LDV/SOF). We sought to determine the effect of PPI use on the rate of SVR in a real-world cohort of 1,979 patients with chronic HCV treated with LDV/SOF. We collected clinical data and pharmacy dispensing records on patients taking 8, 12 or 24 weeks of LDV/SOF±Ribavirin. The primary outcome was SVR12 in a per-protocol analysis in order to determine the effect of PPI use adjusted for confounders. Statistical adjustment was performed in propensity-matched analysis. In the per-protocol analysis, SVR12 was achieved in 441 (97.1%) of PPI recipients compared with 1497 (98.2%) in PPI non-recipients (p = 0.19). Neither low nor high dose PPI was associated with decreased SVR. Although, patients taking twice daily PPI achieved a lower SVR12 rate: 91.2%, CI (77.0 - 97.0, p = 0.046). After propensity-matching for PPI use, there were no significant associations between SVR12 and any dose or frequency of PPI use. However, in a sensitivity analysis focusing on patients with cirrhosis, twice daily PPI use was associated with lower odds ratio for SVR12 0.11 95% CI (0.02 - 0.59).
Conclusion
These data from a cohort of real-world patients receiving anti-HCV therapy with LDF/SOF±Ribavirin support the prescription labeling suggesting that patients take no more than low dose (20 mg omeprazole equivalents) PPI daily. This article is protected by copyright. All rights reserved.
In conclusion, these data confirm the effectiveness of LDV/SOF+Ribavirin in a large real-world cohort and affirm the package labeling with respect to PPI use. Despite the lack of statistical association observed, we recommend that PPIs be prescribed no more frequently than once daily for patients receiving anti-HCV therapy with LDV/SOF.
Data were collected through Trio Health's Innervation Platform, a proprietary platform designed as a portal for specialty pharmacies (SP) and physicians to collaborate, communicate and manage patient information for the purpose of improving patient care.
Discussion - We sought to determine the effect of PPI therapy on LDV/SOF effectiveness given the biological plausibility - decreased absorption of ledipasvir at higher gastric pH - and the decreased SVR rate attributed to PPI therapy in a report from the HCV-TARGET. This study of 1,979 patients from a real-world cohort with chronic HCV treated with LDV/SOF clarifies the relationship between PPI and SVR. First, we show that PPI usage overall is not associated with SVR, irrespective of treatment duration. Second, we demonstrate an unadjusted association between twice daily PPI use and decreased SVR that is no longer significant after adjustment for propensity to receive PPIs.
These findings must be interpreted in the context of the study design. First, propensity matching seeks to balance the cohort in order to yield similar groups for comparison. This process involves discarding patients from analysis who were extremely likely to receive or not receive PPI. Furthermore, despite most variables achieving balance, some were not (academic practice, decompensated cirrhosis). There are two reasons why these factors should not affect the assessment of our data. One, the unmatched analyses on the treatment completers failed to yield differences based on PPI use save for twice daily usage. Two, the misbalancing after matching favored patients not taking PPI, yet no difference was observed. Second, despite observed refill rates, we cannot be certain that patients were taking their PPI as prescribed. Third, we cannot be certain whether non-PPI users were using over-the-counter PPI unless recorded by the specialty pharmacy and, admittedly, over the counter use is not infrequent. Fourth, we lack data on the patients' specific timing of PPI use relative to LDV-SOF dosing. This could be important as the raised pH of any dose PPI may raise the gastric pH > 4 for 10-14 hours.(18)
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