We read with great interest the article by Romero-Gomez et al.1 They found that treating female patients infected with hepatitis C genotype 1 and who had insulin resistance with metformin on top of standard of care could improve insulin sensitivity and double the sustained virologic response (SVR) rate. In addition, those who reached a homeostasis model assessment of insulin resistance (HOMA-IR) score lower than 2 at week 24 of triple therapy had higher SVR rates. Their results indeed provide important data to improve our understanding about the relationship among metformin, insulin resistance, and SVR; however, several issues deserve further discussion.
First, although women with triple therapy of metformin, peginterferon alfa-2a, and ribavirin had twice the SVR rate than those without (58% versus 29%), this doubling effect seemed to be confounded by the very low SVR rate in women without adding metformin. These results should thus be cautiously interpreted, and the authors may compare the variables between female and male patients who did not receive metformin, in order to understand more about the reasons behind this very low SVR rate.
Second, it is generally believed that optimal dose of ribavirin is important to achieve SVR, especially in the early phase of therapy, and weight-based ribavirin is strongly recommended in the clinical practice.2 In this study, the dosage of ribavirin was between 1000 and 1200 mg/day, and the mean body weight was around 80 kg. Therefore, the dosage of ribavirin seemed relatively lower in achieving the best SVR rate. In addition, metformin is known to cause more short-term weight loss in women than in men.3 Taken together, whether female patients have an improved SVR rate with metformin due to the drug itself or secondary to weight loss accompanied by higher dose of ribavirin per kilogram body weight awaits further examination. The authors may provide data regarding the change of body weight and ribavirin dose during the course of triple therapy to clarify their impact on SVR rate.
Third, patients who reached a HOMA-IR score of less than 2 at week 24 of therapy had a significantly higher SVR rate, suggesting that an increase in insulin sensitivity might exert a positive effect on the SVR rate. Our previous study has shown a positive correlation between serum hepatitis C virus (HCV) RNA level and HOMA-IR.4 The possible mechanisms of improving insulin resistance therefore include metformin itself, concomitant weight loss during treatment, or reduction of HCV RNA level. To further address this interesting and important issue, the authors could provide data for analysis about viral load decline and the amount of weight loss at week 24 of therapy.
In summary, several potentially effective agents have been added to improve the SVR rate in difficult-to-cure patients with chronic hepatitis C. These agents include protease inhibitors to increase the antiviral effect5 or insulin sensitizers to increase insulin sensitivity. In addition, the optimal dose of ribavirin should be carefully adjusted on the basis of body weight and with adverse effects in mind, to achieve the highest possible SVR rate. However, further studies are still needed to optimize the combination regimens with currently available agents.