Diabetes mellitus and advanced liver fibrosis are risk factors for severe anaemia during telaprevir-based triple therapy.

Crismale JF, Martel-Laferrière V, Bichoupan K, Schonfeld E, Pappas A, Wyatt C, Odin JA, Liu LU, Schiano TD, Perumalswami PV, Bansal M, Dieterich DT, Branch AD.

Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

BACKGROUND & AIMS: Adding telaprevir to pegylated-interferon and ribavirin increased both response rates and side effects of hepatitis C virus (HCV) treatment. We identified variables associated with severe anaemia during telaprevir-based triple therapy.

METHODS: An observational study was performed on 142 HCV-infected patients between June 2011 and March 2012. All subjects completed 12 weeks of telaprevir-based triple therapy or discontinued early because of anaemia. Severe anaemia was defined by a haemoglobin≤8.9 g/dl; advanced fibrosis was determined by Fib-4≥3.25.

RESULTS: The 47 (33%) patients who developed severe anaemia were similar to those who did not in sex, race, and prior response to dual therapy, but they were more likely to have diabetes (23.4% vs. 6.3%, P<0.01), advanced fibrosis (46.8% vs. 29.5%, P=0.04) and a history of anaemia during previous dual therapy (29.7% vs. 11.4%, P=0.02). Patients developing severe anaemia were older (59 vs. 56 years, P=0.02), had lower baseline platelet counts (134 vs. 163×10(9) /L, P=0.04), haemoglobin (14.0 vs. 15.0 g/dl, P<0.01), estimated glomerular filtration rate (79 vs. 90 ml/min/1.73 m2, P=0.03) and a higher median ribavirin/weight ratio (14.9 vs. 13.2 mg/kg, P<0.01). In multivariable logistic regression, presence of diabetes (OR=5.61, 95% CI: 1.59-19.72), Fib-4≥3.25 (OR=3.09, 95% CI: 1.28-7.46), higher ribavirin/weight ratio (OR=1.31 per mg/kg, 95% CI: 1.13-1.52) and lower baseline haemoglobin (OR=0.57 per g/dl, 95% CI, 0.41-0.80) were independently associated with developing severe anaemia.

CONCLUSIONS: Severe anaemia occurred in one-third of patients receiving telaprevir-based triple therapy. Risk was greater in patients with diabetes, advanced liver fibrosis, higher ribavirin/weight ratio and lower baseline haemoglobin.

KEYWORDS: anaemia; diabetes mellitus; hepatitis C virus; pegylated-interferon; ribavirin; telaprevir; triple therapy

PMID: 24118693

Supplement

The addition of the first-generation protease inhibitor telaprevir (TVR) to dual therapy with pegylated-interferon (PEG-IFN) and ribavirin (RBV) improved sustained virological response (SVR) rates in patients with chronic hepatitis C virus infection (HCV) [1], but led to an increased number of side effects [2]. Among adverse events related to TVR-based triple therapy, severe anemia and the management thereof is a significant driver of morbidity and cost. Anemia contributes to a variety of symptoms including fatigue, shortness of breath, and palpitations, and occurs about twice as frequently during TVR-based triple therapy as during dual therapy with PEG-IFN/RBV. Treatment-related anemia can reduce health-related quality of life. Therefore, treatment with TVR-based triple therapy requires frequent monitoring of hemoglobin levels. Management of severe anemia may include a reduction in the dose of RBV, the introduction of erythrocyte-stimulating agents, or transfusion of packed red blood cells [3]. Each of these interventions carries attendant risks, which must be weighed against the risks of anemia and treatment discontinuation.

Our study was among the first to identify risk factors for severe, clinically significant anemia (defined in our study as Hb≤8.9g/dL) in patients undergoing TVR-based triple therapy outside of a registration trial. Through physician referrals and queries applied to a large electronic medical record database, we identified 142 patients with genotype 1 HCV infection who were treated with TVR-based triple therapy at the Mount Sinai Medical Center between June 2011 and March 2012, who completed at least 12 weeks of treatment or discontinued early because of anemia. We obtained clinical data on patient demographics, comorbid medical conditions, history of anemia with prior PEG-IFN/RBV dual therapy, and dosing of TVR, PEG-IFN, and RBV during triple therapy. Clinical laboratory data were collected at baseline and at weeks 2, 4, 8, 12, and 24 during treatment. We also calculated degree of fibrosis using the FIB-4 score, with a score ≥3.25 suggesting advanced fibrosis or cirrhosis.

We found that among the 142 patients included in our analysis, 33% developed severe anemia, while 67% maintained hemoglobin≥8.9. In comparing the baseline characteristics of both groups, those who developed severe anemia had lower baseline hemoglobin, platelet count, and eGFR, and were more likely to have a history of anemia during prior dual therapy. Patients who developed severe anemia began treatment at a higher RBV dose for their body weight (RBV/weight ratio). A greater percentage of them had diabetes mellitus and/or advanced liver fibrosis or cirrhosis as determined by a FIB-4 score ≥3.25. In multivariable logistic regression with severe anemia as the outcome, the presence of diabetes mellitus, FIB-4 ≥3.25, a higher RBV/weight ratio at the start of treatment and lower baseline hemoglobin were independently associated with developing severe anemia. Lower baseline eGFR also approached statistical significance. Of the patients who developed severe anemia, 40% required blood transfusion, and 83% required treatment with ESAs.

Our data yield a number of important clinical findings. The incidence of severe anemia in our study is much higher than seen in the initial registration trials. In ADVANCE and REALIZE, rates of severe anemia were 9% and 11%, respectively, compared to 33% in our population. The higher incidence of anemia we observed is most likely a result of including an older patient population with more comorbidities and higher degrees of liver fibrosis. Other studies have also shown that advanced fibrosis and cirrhosis are associated with the development of severe anemia on TVR-based triple therapy [3]. Since the publication of our study, Ogawa et al have demonstrated that lower baseline hemoglobin, eGFR, and inosine triphosphatase CC genotype are predictive of severe anemia [4]. Our study is unique in the demonstration of diabetes mellitus as an independent risk factor for the development of severe anemia.

The mechanistic basis of the association we observed between diabetes mellitus and severe anemia is not clear, but several possibilities warrant consideration. Diabetic neuropathy can disrupt splanchnic innervation of the kidney, which may alter endogenous erythropoietin production [5]. Furthermore, several commonly prescribed medications may increase risk of anemia in diabetics. Inhibition of the renin–angiotensin–aldosterone system with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may potentiate anemia by interfering with the erythropoietic effects of angiotensin II [6]. Thiazolidinediones may lead to a dilutional decrease in hemoglobin concentration via increased fluid retention, and metformin, in rare case reports, has been linked to the development of severe hemolytic anemia [7]. A combination of these factors may promote the development of anemia in patients on TVR-based triple therapy who have pre-existing diabetes.

Since the time these data were published, several new direct-acting antiviral drugs for the treatment of chronic HCV have come to market. The superior response rates and side-effect profiles of the newer direct-acting antiviral agents such as ledipasvir-sofosbuvir, which can be used without PEG-IFN and RBV have in large part made TVR-based triple therapy a much less utilized treatment option, especially when the toxicity of TVR-based triple therapy is considered. However, this regimen may still be used in resource-limited settings. In such cases, careful attention must be paid to adverse effects, including severe anemia.

References

1. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. New England Journal of Medicine 2011; 364: 2405–16.
2. Aghemo A, Degasperi E, Colombo M. Directly acting antivirals for the treatment of chronic hepatitis C: unresolved topics from registration trials. Digestive and Liver Disease 2013; 45: 1–7.
3. Jacobson IM, Kowdley KV, Kwo PY. Anemia management in the era of triple combination therapy for chronic HCV. Gastroenterology and Hepatology 2012; 8: 1–16.
4. Ogawa E, Furusyo N, Nakamuta M., et al. Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy. Journal of Hepatology 2013; 59(4): 667-74
5. Deray G, Heurtier A, Grimaldi A, et al. Anemia and Diabetes. American Journal of Nephrology 2004; 24: 522–6.
6. Vlahakos DV, Marathias KP, Madias NE. The Role of the renin-angiotensin system in the regulation of erythropoiesis. American Journal of Kidney Disease 2010; 56: 558–65.
7. Kashyap A, Kashyap S. Hemolytic anemia due to metformin. Postgraduate Medical Journal 2000; 76: 125–6.