Wednesday, December 28, 2011

Optimization of Comorbidity Therapy to Achieve Sustained Viral Response in HCV Patients

Optimization of Comorbidity Therapy to Achieve Sustained Viral Response in HCV Patients

Claudio Ucciferri1,2, Jacopo Vecchiet2, Eligio Pizzigallo2 and Katia Falasca2
1Infectious Disease Unit, University of Molise, Campobasso, Italy
2Department of Medicine and Aging, Clinic of Infectious Diseases, “G. d’Annunzio”
University Cheti, Pescara, Italy
Corresponding author: Prof. Vecchiet Jacopo, Clinic of Infectious Diseases, Dept. of Medicine and Aging,
University “G. d’Annunzio” School of Medicine, Via dei Vestini, 66100 Chieti, Italy

KEY WORDS: Sartan; Hepatitis; Insulin-resistance; Hypertension.

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Several studies indicate that insulin resistance and diabetes influence sustained viral response in treatment for chronic HCV infection. We describe the case of a relapsed patient with HCV infection who achieved a sustained viral response due to an improvement in insulin resistance through modification of antihypertensive therapy. By improving insulin resistance with telmisartan, an ARB with PPAR gamma agonist propriety, sustained viral response was obtained with the same antiviral therapy. Optimization of comorbidity therapy is useful for improving the possibility of achieving a sustained viral response.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease worldwide,evolving in cirrhosis and increasing the risk of developing hepatocellular carcinoma (1,2). Effective antiviral therapy can cure HCV infection and prevent HCV infection complications (3,4).

Currently the most effective treatment for chronic HCV infection is the combination of pegylated interferon (peg-IFN) and ribavirin (RBV). This therapy obtains sustained virological response (SVR), especially genotype 2 (5). However, achieving SVR is influenced by several factors, such as viral factor, dose of RBV (6,7), cirrhosis and IL28b (8). An interesting issue is the role of obesity and insulin resistance in influencing SVR (9). Recent evidence shows that insulin resistance and obesity reduce SVR by 25-50% less than the otherwise expected rates (10). Insulin resistance and obesity are important risk factors for diabetes and metabolic syndrome. Their implications may be considerable in HCV infected individuals, increasing the risk of developing diabetes and cardiovascular diseases and leading to increased necroinflammatory activity of chronic liver disease (11). An increased rate of SVR is observed in subjects who obtain reduction of obesity and/or insulin resistance (12). Improving insulin resistance with changes in lifestyle or pharmacological approaches, such as metformin or PPAR gamma agonist, is an interesting and encouraging view. However, more definite data are still needed before translation of this approach in clinical practice (13). We describe the case of a chronically HCV infected patient treated with peg-IFN and RBV who obtained SVR by improving insulin resistance with the use of telmisartan, an antihypertensive drug with properties of PPAR gamma agonist.

M.M. is a 63 year-old Caucasian female with HCV infection detected by chance by presurgical screening in 2005. At first clinical examination the patient showed aspartate aminotransferases (AST) and alanine aminotransferases (ALT) serum levels in the normal range, WBC 5900cell/m3 and normal leukocyte formula, Hb 14.5g/dL, PLT 198000cell/m3 and HCV-RNA 1198130UI/mL, genotype 2. Moreover, she had body mass index (BMI) 33.1 and insulin resistance assessed by HOMA-IR 5.3 (Figure 1); total cholesterol (TCh) 251mg/dL, HDL cholesterol (HDL) 75mg/dL, LDL cholesterol (LDL) 155mg/dL and triglycerides (TG) 103mg/dL. She was taking antihypertensive therapy with 8mg candesartan daily with good control of blood pressure values and propafenone 150mg bis in die for previous episodes of arrhythmia.

Anti HCV treatment was started with peg-IFN 2A 180μg weekly plus RBV 1200mg/die (13.7mg/Kg/die) for 24 weeks. After one month of therapy HCV-RNA became negative, Hb dropped out at 10.5g/dL and HOMA-IR was 5.4. Therapy was continued without changes and
at the end of treatment HCV-RNA was persistently negative and Hb was 10.1g/dL. However, 3 months after the end of antiviral treatment she relapsed with HCV-RNA 559000 UI/mL. After a further 4 months, the patient had HCV-RNA 3360000UI/mL, Hb 13.9g/dL, TCh 221mg/dL, HDL 71mg/dL, TG 106mg/dL, LDL 129mg/dL, HOMA-IR 6.8, BMI 33.9 and suboptimal hypertension control. Thus, we decided to discontinue candesartan, introduce 40mg telmisartan daily in order to improve blood pressure control and reduce insulin resistance and start antiviral treatment after one mouth.

One month after the antihypertensive drug change, the patient showed good blood pressure control and improved metabolic conditions with HOMA-IR 5.2, TCh 211mg/dL, HDL 83mg/dL, LDL 110mg/dL and Tg 91mg/dL. Continuing treatment with telmisartan, it was decided to re-treat the patient with a new therapy of peg-IFN 2A 180μg weekly plus RBV 1200mg/die for 24 weeks. After four weeks of antiviral treatment, HCV-RNA was negative and patient showed Hb 10.3g/dL, TCh 153mg/dL, HDL 57mg/dL, LDL 75mg/dL, TG 103mg/dL and HOMA-IR 4.2. At the end of treatment, clinical parameters showed HCVRNA negative, Hb 9.8g/dL, TCh 182mg/dL, HDL 70mg/dL, LDL 87mg/dL, TG 122mg/dL,HOMA-IR 4.1 and good blood pressure control.

Six months after the end of anti-HCV treatment, the patient showed a sustained viral response with normal aminotransferases serum levels and negative viremia, persisting good blood pressure control and improved metabolic profile.

This case is particular, showing that improving insulin resistance is crucial for achieving the goal of SVR. In clinical practice, the approach to improving insulin resistance is still unclear. In this case, we used an antihypertensive drug, telmisartan, to influence insulin resistance.

Antihypertensive drugs are not all the same, since some of these molecules may have several
metabolic actions. In particular, telmisartan has the strongest PPAR gamma activating properties at the plasma concentration usually used. Several studies have shown that telmisartan, acting as a PPAR gamma agonist, improves insulin resistance and lipid profile both in the general population (14,15) and in special populations, such as HIV or HCV infected patients (16,17). In our patient the switch to telmisartan improved insulin resistance and achieved SVR without modification or discontinuation of anti HCV therapy.

This case demonstrated that optimizing the comorbidity therapy is useful for improving SVR. Thus, if further data confirm this observation, telmisartan may become the first choice therapy
in hypertensive HCV positive subjects with insulin resistance, since it improves metabolic profile steatohepatitis (16). Furthermore, telmisartan may be particularly useful in HCV patients who undergo antiviral treatment with peg-IFN and RBV, since its use seems to increase the possibility of achieving SVR.

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