Sofosbuvir Safe, Effective for HCV in Those With CKD

Diana Phillips

September 14, 2017

Sofosbuvir-based, direct-acting antiviral (DAA) therapy is safe and effective for treating hepatitis C virus (HCV) infection in patients with early-stage (1-3) chronic kidney disease (CKD), a study has shown.

Further, combination HCV treatment that includes the NS5B polymerase inhibitor may improve kidney function in some individuals, Meghan Sise, MD, from Massachusetts General Hospital, Boston, and colleagues report online September 7 in the Clinical Journal of the American Society of Nephrology.

The findings are notable because the active metabolite of sofosbuvir, which isexcreted through the kidneys, accumulates in kidney failure, leading to concerns about its suitability in this patient population, the authors write.

The investigators conducted a retrospective observational cohort study of patients at a large healthcare network who received care between November 2013 and December 2014. They defined CKD as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 or 30 mg albuminuria/g creatinine or higher or 200 mg proteinuria/g creatinine or higher.

The study sample was made up of 98 patients with stage 1 to stage 3 CKD and HCV infection who had received at least one dose of sofosbuvir. The specific antiviral treatment regimens included either simeprevir or ledipasvir, with or without ribavirin, depending on the HCV genotype, presence of cirrhosis, and prior treatment experience. The analysis excluded patients who received interferon.

Outcomes of interest included sustained virologic response (SVR), defined as an undetectable HCV RNA at least 12 weeks after therapy completion, adverse events, and eGFR changes with treatment.

Overall, 81% of participants achieved SVR. Patients with HCV genotype 1b demonstrated the highest SVR rate (89%), while those with genotypes 3 and 4 had the lowest rates (43% and 60%, respectively), although "numbers were small," the authors write.

The treatment regimen appeared to be more effective in patients whose CKD was more advanced. "In a multivariable model including a priori clinical characteristics known to predict sustained virologic response, each 10mL/min/1.73 m2 decline in baseline eGFR was associated with a 1.7 fold-increased odds of sustained virologic response (95% [confidence interval] CI 1.3 - 2.4)," the authors report. They hypothesize that the increased efficacy of DAA therapy in patients with lower eGFR may be a consequence of higher blood levels of sofosbuvir, because of less efficient elimination by the kidney.

"[I]t is important to note that this analysis was based on only a few individuals who were not cured. Other studies have not demonstrated statistically significant differences in sustained virologic response rates in patients with CKD compared to those without," they stress.

Kidney function was consistent for treatment compared to baseline. "While small fluctuations in creatinine on treatment were common, the average eGFR while on direct-acting antivirals was stable," the authors write. Although 26% of the population experienced a rise in creatinine of at least 0.3 mg/dL, "more significant nephrotoxicity was rare," they state.

In patients with stage 3 CKD, those with HCV cure had a 9.3 (95% CI, 0.44 - 18) mL/min/1.73 m2 improvement in eGFR 6 months after treatment completion.

Patients tolerated the HCV treatment regimen reasonably well, the authors report. Although 81% of the cohort reported an adverse event — most commonly among patients taking ribavirin — serious adverse events occurred in 17% and only 8% discontinued therapy. "Patients taking ribavirin had 2.9-fold increased odds of experiencing a [serious adverse event] SAE (P = 0.03)," the researchers explain, noting that comorbid diabetes was also associated with SAEs, although baseline eGFR was not.

On the basis of an HCV cure rate "that mirrors those observed in other real-world cohorts," and the observed safety profile of the treatment, the authors conclude that sofosbuvir-based DAA therapies for HCV infection are effective in patients with early-stage CKD.

The observed kidney benefit associated with the drug requires more research, the authors stress. "[O]ur conclusions are limited by the fact that there is no untreated control group," they write. "Larger studies will be needed to determine if eradication of HCV with direct-acting antiviral therapy slows or prevents progression to end stage kidney disease in patients with CKD and HCV."

The authors of an accompanying editorial echo this point. The occurrence of acute kidney injury warrants additional inquiry, Richard J Johnson, MD, from the division of renal diseases and hypertension, University of Colorado, Denver, and Michiko Shimada, MD, PhD, from the division of cardiology and nephrology, Hirosaki University Graduate School of Medicine, Japan, suggest. "[T]here was evidence of some [acute kidney injury] AKI, with a transient rise of serum creatinine of 0.3 mg/dl or more in a quarter of subjects and with 7 subjects having a rise in serum creatinine of 1.5 times greater than baseline," they write. "Unfortunately, there was no control group to determine if this was related to the treatments."

It is possible that sofosbuvir-based therapy may be useful for managing patients with CKD and HCV genotypes 1 and 4, and "we would like to see more studies investigating the potential nephrotoxicity of sofosbuvir," Dr Johnson and Dr Shimada write. "Furthermore, this latter regimen is not FDA-approved in the United States in the patient with CKD at this time."

The editorial authors note that several promising antiviral treatment options that include drugs not eliminated by the kidneys are currently being evaluated. "Alternative therapies are becoming available that may be safer and more effective," they write. "We predict that HCV, like hepatitis B virus and HIV, will slowly disappear as a major medical problem for patients with renal disease."

The study authors report relationships including research grant funding and scientific board participation with Gilead Sciences, AbbVie, Merck, Bristol-Myers Squibb and Janssen.

The editorial authors have disclosed no relevant financial relationships.

CJASN. Published online September 7, 2017. Abstract, Editorial

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