Friday, January 6, 2017

Hepatitis C eradication with sofosbuvir leads to significant metabolic changes

World J Hepatol. Dec 18, 2016; 8(35): 1557-1563
Published online Dec 18, 2016. doi: 10.4254/WJH.v8.i35.1557

Hepatitis C eradication with sofosbuvir leads to significant metabolic changes
Amilcar L Morales, Zachary Junga, Manish B Singla, Maria Sjogren, Dawn Torres

Core tip: In our retrospective study, we evaluated the changes in glucose and lipid metabolism in a group of hepatitis C patients treated and cured with a sofosbuvir-containing regimen. We used hemoglobin A1c (HgA1c) and lipid panels to assess those two parameters. Six months post eradication, we found a statistically significant drop in HgA1c and an increase in low-density lipoprotein and total cholesterol. The use of HgA1c, although not perfect, is easy to understand and is frequently used by primary care doctors as a tool to assess glucose control.

Abstract
AIM
To assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control.

METHODS
This is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis.

RESULTS
Two hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P < 0.005). Those treated with SOF/LDV had a lower HbA1C response than those treated with other regimens (0.26% ± 0.53% vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P < 0.001; TC: 171.6 ± 32.5 mg/dL vs 199.7 ± 40.0 mg/dL, P < 0.001). Pre-treatment body-mass index (BMI) did not differ from post-treatment BMI (P = 0.684).

CONCLUSION
Eradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.

Key Words: Hepatitis C, Sofosbuvir, Hyperlipidemia, Hemoglobin A1c, Low-density lipoprotein

Discussion Only
Full Article (HTML)

The main finding of this retrospective study was a significant decrease in HbA1C up to six months post-HCV eradication. The mechanism responsible for this improvement in glycemic control is unknown although likely multifactorial. It is well known that HCV alters glucose metabolism by inducing inflammatory cascades and promoting IR. Defects in pathways important in hepatic gluconeogenesis such as Pi3K and AKT phosphorylation have been reported in patients infected with HCV. Insulin receptor substrates 1 and 2 are closely related to the Pi3K/AKT pathways; these two receptors are key components in the development of IR in patients infected with HCV. The virus can degrade these two receptors, directly affecting the PI3K/AKT pathways[32-34]. Eradication of the virus restores homeostasis of these pathways, leading to an improvement in IR.

In the interferon/RBV era, several studies have demonstrated an improvement of IR with SVR. Early work by Thompson et al[17] demonstrated a 10% decrease in IR in genotype1 patients who achieved SVR, which was supported by the more recent results from Chien et al[35] that showed a significant decrease in HOMA-IR at EOT after eradication of the virus with this combination. Similarly, a study by Meissner et al[31] demonstrated a small but significant decrease in HbA1c in patients treated with SOF/RBV (5.58% ± 0.08% to 5.45% ± 0.91%; P = 0.0046). While the majority of these patients were non-diabetic or pre-diabetics, the patients included in this analysis had a significantly higher rate of diabetes, at 56%. When compared to the non-diabetic patients, the diabetics had a greater improvement in HbA1C. Gender, race, HCV genotype, and HCV RNA did not affect HbA1C drop.

In a subgroup analysis, patients treated with the SOF/LDV had a lower drop in HbA1C when compared to SOF/RBV and SOF/SIM groups. One possible explanation is the relationship between the new DAA and its target. The non-structural proteins of the virus NS5A and NS5B are key components in the activation of inflammatory cascades promoting insulin resistance[34]. It is plausible that the interaction of the medication or the duration of therapy alters the effects of insulin resistance, although further study is required.

Although this study was not designed to identify the long-term implications of hepatitis C eradication in glucose control, it is possible that these changes could have long-term implications regarding medical management. One of 16 patients on medical therapy for diabetes required a decrease in insulin therapy post viral eradication and another was taken off completely of therapy. The savings from a drop of even 0.5% of HbA1c are significant, and many oral hypoglycemics maximum efficacy is only a 1% improvement in Hba1c. Even more important than potential cost savings are the implications of better glucose control in the development of microvascular and macrovascular disease as small drops in HbA1C can alter the course of these complications. Primary care physician should monitor diabetic patients post HCV eradication to assess if changes in medical management are required and to prevent complications such as hypoglycemia.

The implications of insulin resistance, especially in diabetic patients infected with HCV, are well established. Huang et al[36] showed an increased risk of liver disease progression to cirrhosis in HCV-infected patients with diabetes. Hui et al[3] demonstrated that insulin resistance was an independent predictor for the degree of fibrosis and fibrosis progression in HCV-infected patients. Everhart et al[37] showed that not only hepatic steatosis was associated with liver disease progression, but also the degree of insulin resistance. They suggested that addressing these two issues might modify disease progression[37]. Taking into account this information and the results of our study, we should consider adding diabetic HCV-infected patients to the high-risk group that would benefit from priority in treatment.

These results also correlate with previous studies evaluating the effects of HCV eradications and lipids. An increase in TC and LDL post therapy was demonstrated irrespective of anti-viral therapy or genotype. Chronic infection with HCV has been implicated in the development of hypolipidemia[38,39]. A reversal of these findings has been reported in patients treated with INF/RBV regimens, as well as SOF/RBV regimens that have achieved SVR, suggesting this is most likely related to viral clearance rather than a medication effect[22,23,31]. The implications of these alterations in cardiovascular and cerebrovascular disease are beyond the scope of this retrospective study but should be further investigated.

The study does have several limitations including its retrospective nature and the small number of patients. Even though all lipids were drawn during the morning time, fasting was unable to be confirmed. Other parameters that could have altered the results, such as dietary changes and exercise, were not available. Medication reconciliation was not directly obtained, but an evaluation of several encounters from the electronic medical record from different providers was performed, looking for adequate medication reconciliation. The length of analysis was also limited to six months post-HCV therapy, so an analysis of the long-term implications of these results cannot be made.

This analysis did strengthen the knowledge pertaining to the metabolic effects of SOF-based regimens and confirmed that eradication of the virus could have extra-hepatic benefits. Even though HOMA-IR is a more direct measurement of IR, HbA1C is a more practical parameter that can be used to assess glucose control, and this study confirmed an improvement in HgA1c with SVR.

In conclusion, this study showed a significant drop in HbA1C up to six months after the eradication of HCV with SOF-based regimens. Future studies are needed to see if this change is sustainable. The effects of virus eradication on lipid panels were also determined, and they confirmed previous analyses that showed an increase in lipid panels, including LDL and TC, with SVR. This study suggests that physicians treating HCV patients should reassess preventive medicine measures after therapy, as the benefits of eradicating HCV may extend beyond eliminating the effects of chronic liver inflammation.

View Full Article

No comments:

Post a Comment