Management of Chronic Hepatitis C in Patients With Contraindications to Anti-viral Therapy

Alimentary Pharmacology & Therapeutics

Review Article
Management of Chronic Hepatitis C in Patients With Contraindications to Anti-viral Therapy
V. CarreñoDisclosures

Aliment Pharmacol Ther. 2014;39(2):148-162.

Abstract and Introduction
Abstract 

Background There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects.
Aim To provide information on alternative treatments for the management of these patients.
Methods A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles.
Results Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies.
Conclusion There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.

Introduction
Treatment of chronic hepatitis C virus (HCV) is aimed to eradicate HCV and to prevent liver disease progression. All currently approved anti-viral therapies against HCV are pegylated-interferon (PEG-IFN)-based. Response rates in patients with genotype 1 have increased with the implementation of the triple therapy of PEG-IFN plus ribavirin (RBV) plus protease inhibitors. However, around 25% of naïve patients with HCV genotype 1 infection and about 70% of null responders to previous anti-viral treatment do not respond to triple therapy.^[1] In addition, there are patients in whom current therapies are contraindicated (low platelet count, advanced liver disease, coronary artery disease, autoimmunity, seizure disorders, pregnancy), or who are intolerant to IFN-based therapies or who refuse to be treated due to the side effects.^[2,3] IFN-free regimens are near approval for many patients but, while awaiting these new therapies, measures to slow liver disease progression (that could make future therapy difficult and less beneficial) should be adopted. Furthermore, there will be still some patients who could not be treated with these upcoming therapies. In the present review, other options for the treatment and clinical management of chronic hepatitis C are summarised.

Iron Depletion and Drug Interventions
Phlebotomy
Iron overload is a common finding in patients with chronic hepatitis C and elevated iron indices are correlated with the progression of liver disease.^[4,5] An excess of iron induces formation of reactive oxygen species that activate hepatic stellate cells, which contribute to hepatic fibrogenesis.^[6] Iron depletion via phlebotomy has been used as a collateral treatment of chronic hepatitis C. In the first report by Bacon et al.,^[7] eight patients who failed to respond to IFN were treated by weekly phlebotomy (500 mL) until iron deficiency was achieved (after 5–10 units of blood were removed). After phlebotomy, serum alanine amino transferase (ALT) fell in all but one patient, but serum HCV-RNA levels did not change. Following this report, several studies on iron depletion by phlebotomy in these patients have been published and the finding of that first report was confirmed.^[8–16]

Generally, phlebotomies (between 200 and 400 mL) have been applied in different studies (Table 1) with a weekly or monthly frequency to reach a decrease in ferritin up to 10 ng/mL,^[8,9,20] although in some studies the limit of reduction was 50–60 ng/mL.^[10,11] The limit of reduction in haemoglobin was 11 g/dL.^[13] In these studies, patients underwent repeated phlebotomies to maintain the iron deficiency state. Usually, the total amount of blood removed to achieve an iron deficiency state oscillated between 2.5 and 3.5 L and men needed around 0.5 L more blood removed than women.^{[8–11,14,17,18,21]} In all these studies, a significant reduction in ALT and ferritin levels (the majority of the included patients had increased basal values of ferritin) was achieved. Time required to obtain this iron depletion was 5 ± 2 months.^[9] The percentage of ALT normalisation oscillated between 10% and 69%.^[8,18] This percentage of normalisation increased with prolongation of therapy to maintain iron deficiency over time. These studies included patients who were nonresponders to anti-viral therapy or naïve patients with a similar response between them.^[8–10,18] Serum HCV-RNA levels did not change during or after treatment. No important secondary effects were observed during treatment. It has been reported ascitis development has been reported in two patients treated with phlebotomy who had a serum albumin <3.6 g/dL. Hence, in these type of patients, phlebotomy should be used with caution.^[17]
 
The effect of phlebotomy on the liver histology of patients with chronic hepatitis C has been demonstrated in several reports. Thus, Yano et al.^[20] treated 25 patients with maintained phlebotomies (5 years) and included a control group (n = 13) who were nonresponders to interferon. A second liver biopsy was obtained more than 3 years after the beginning of phlebotomies. They observed a significant reduction in the fibrosis score from 2.3 to 1.7 in the phlebotomy group, while this score increased from 1.7 to 2.0 in the controls. Moreover, the severity of inflammation increased significantly in the control group (from 2.0 to 2.9), but remained unchanged in the phlebotomy group. Similar results were obtained by other authors.^[19,22] A high hepatic iron concentration before treatment has been reported associated with histological improvement.^[19] Thus, up to 70% of patients with hepatic iron concentration greater than 20 μmol/g of dry tissue in the basal liver biopsy achieved histological improvement following mild iron depletion.

Some authors reported a high correlation between the baseline levels of ALT and their reduction after treatment and a trend towards a greater ALT reduction in patients with the highest baseline serum ferritin values.^[9,11] The possible effect of a low-iron diet (5–7 mg of iron per day) without phlebotomy in chronic hepatitis C has also been studied. Sumida et al.^[21] demonstrated that, in patients under a low-iron diet for 6 months, a significant decrease in ALT levels was achieved, although to a lesser extent than that achieved by phlebotomies.

As it is known that iron absorption is significantly increased in an iron-deficient state,^[23] several studies combined phlebotomies with a low-iron diet.^[17,18,24] It has been demonstrated that this combination induces an additional effect in iron reduction therapy for chronic hepatitis C. Furthermore, a high percentage of ALT normalisation (69%) was obtained with this combination.^[18] In one study, it was reported that, in patients with chronic hepatitis C and a partial response to phlebotomy, the addition of ursodeoxycholic acid (UDCA) might improve the biochemical parameters.^[25] A decrease in ALT levels by phlebotomy was observed from 137 ± 72 to 75 ± 23 IU/L and a further significant reduction to 42 ± 16 IU/L after combination with UDCA.

Also, phlebotomy may lower risk of development of hepatocellular carcinoma (HCC). Kato et al.^[18] treated 35 patients with chronic hepatitis C with weekly phlebotomy (200 mL), followed by maintenance phlebotomy for 44–144 months and a low-iron diet and they also studied a control group of 40 untreated chronic hepatitis C. They observed development of HCC in 8.6% of patients of the phlebotomy group and in 39% of the control group after 10 years of follow-up (P < 0.05).
In summary, all these data suggest that treatment with phlebotomy and low-iron diet during a prolonged time (3 years or more) may be useful for patients with chronic hepatitis C who are not eligible for PEG-IFN-based anti-viral therapy.

Ursodeoxycholic Acid
Ursodeoxycholic acid has a direct protective effect on hepatocytes against apoptosis induced by endogenous bile acids and stimulates bile acid secretion hence reducing retention of toxic bile acids and therefore, cell injury.^[26] Regarding HCV infection, Takano et al.^[27] reported a randomised, controlled-dose trial in naïve patients with chronic hepatitis C who received 150 (n = 20), 600 (n = 18) or 900 (n = 19) mg/day of UDCA for 16 weeks. A significant decrease in ALT and gamma-glutamyl transpeptidase (gamma-GTP) levels was observed with doses of 600 and 900 mg compared to 150 mg, but serum HCV-RNA remained unchanged. The adverse effects of UDCA were not serious and the doses used were well tolerated. In another controlled study, 18 patients were treated with 600 mg/day of UDCA for 12 months and a significant reduction in serum aminotransferases and gamma-GTP values during UDCA treatment was found compared with the placebo group.^[28] However, liver biopsies performed after 12 months of therapy did not demonstrate an improvement in the histological activity index scores with respect to the basal liver sample. Probably, the interval between both paired liver biopsies was too short to prove the effects of UDCA treatment on liver histology.

The majority of the posterior studies have confirmed that UDCA treatment in chronic hepatitis C decreases serum ALT and gamma-GTP levels, although with no anti-viral effect, 600 mg/day being the preferred UDCA dose.^[29–36] However, in a large double-blind trial, 596 patients with chronic hepatitis C (including nonresponders to IFN treatment) were treated with UDCA at 150, 600 or 900 mg/day for 24 weeks and it was found that, although changes in ALT and aspartate amino transferase (AST) were similar between doses of 600 and 900 mg/day, gamma-GTP decreased significantly more in the group receiving 900 mg/day.^[34] This suggests that increasing UDCA dose up to 900 mg/day may have additional benefits without compromising safety of therapy. Sato et al.^[35] performed a dose-up trial from 600 mg to 900 mg/day of UDCA in patients with chronic hepatitis C (n = 25) or compensated liver cirrhosis (n = 7) for 24 weeks and reported that administration of 900 mg/day was more effective than 600 mg/day of UDCA for reducing aminotransferases and gamma-GTP levels.
In most of the published trials, UDCA was administered for 24 weeks, but longer treatment periods (12 and 24 months) are well tolerated and safe.^[28,32,33] Omata et al.^[34] prolonged UDCA therapy up to 104 weeks in 247 patients. In this extended period, an initial dose of 600 mg/day was adopted that could be increased to 900 mg/day. The authors observed a maintained decrease in ALT, AST and gamma-GTP over that period. Unfortunately, it was not reported in how many of those patients the UDCA dose was increased to 900 mg/day and neither whether adverse events were more severe or not. In our clinical experience, treatment of patients with chronic hepatitis C with higher UDCA doses (up to 20 mg/kg/day) and for longer periods (more than 5 years) is well tolerated and safe, and may induce a persistent decrease in the biochemical parameters.

Only few articles have studied the predictive factors of response to UDCA in chronic hepatitis C, but results should be taken with caution because of the different UDCA schedules used and the heterogeneity of the patients (naïve patients, nonresponders to previous IFN therapy and patients with liver cirrhosis.). Thus, a better response to treatment has been associated with low basal ALT levels, high basal values of gamma-GTP, low histological activity index scores or even with the presence of liver cirrhosis.^[32–34] Also it was found that the response was independent of HCV genotypes or HCV-RNA levels.^[32,33]
 
As levels of aminotransferases have been associated with progression of liver fibrosis,^[37] the decrease in ALT levels with UDCA treatment could reduce the risk of development of HCC. Tarao et al.^[38] showed that, in 56 patients with early-stage liver cirrhosis due to HCV infection who received UDCA for 37.3 ± 15.9 months, the cumulative incidence of HCC over 5 years was significantly lower (10/56: 17.9%) than in the group of 46 patients who did not received UDCA (18/46: 38%). The results suggest that UDCA treatment may prevent HCC development in patients with chronic hepatitis C. Thus, UDCA treatment may be a possible alternative for patients with chronic hepatitis C who are not candidates for currently approved anti-viral treatments.

Other Agents
Several studies have assessed the possible role of RBV monotherapy in patients with chronic hepatitis C, either naïve or nonresponders to anti-viral therapy. These studies administered RBV twice daily, most of them using a dose of 1000–1200 mg.^[39–49] The treatment duration oscillated between 12 weeks up to 24 months.^[39,46] A significant decrease in ALT levels was observed in these studies, ranging from 30% (only 2 or 4 weeks of treatment) to 75%.^[47,48] The frequency of ALT normalisation during treatment usually was around 40–60%,^[44,45,48] reaching 66% after 24 months of treatment.^[46] The mean time to ALT normalisation was approximately 8 weeks,^[40,43,44] but in the majority of the studies, ALT levels returned to pre-treatment values in all patients within 2–3 months after discontinuation of therapy.^[40,43–46] During treatment, no effect of RBV on HCV-RNA was observed in most of the trials.^{[42–46,48,49]} It has also been reported that patients with basal lower levels of ALT and of serum HCV-RNA responded more frequently.^[44,45] Regarding liver histology, several studies demonstrated an improvement in hepatic inflammation and necrosis when comparing basal and final liver biopsies,^[42,44–46] especially among those patients who normalised ALT values, although no changes in fibrosis were noted.^[46,49] It should be remarked that an increase in hepatic iron has been documented in patients under RBV therapy.^[46,49] The most frequent secondary effects of RBV treatment were haemolysis, anaemia, skin disorders (pruritus, rash, dry skin), nervous system disorders (depression, insomnia, somnolence, vertigo), increases in bilirubin concentration, uric acid and platelets.^[43,45,49] All these effects disappeared when treatment was stopped.

In summary, RBV may decrease ALT levels and may improve liver histology in a proportion of patients with chronic hepatitis C. However, taking into account the relatively small number of patients included, the short administration period and the potentially harmful of hepatic iron accumulation with RBV treatment, the general use of this drug as monotherapy cannot be recommended for chronic hepatitis C.

Colchicine was found to be an anti-fibrotic agent in animal models. However, a meta-analysis of 15 randomised clinical trials concluded that colchicine should not be used, as it has no beneficial effect on liver fibrosis.^[50]
 
Amantadine is a symmetric tricyclic amine that inhibits replication of influenza A virus. This drug has been administered as monotherapy to naïve patients with chronic hepatitis C or nonresponders to IFN or IFN/RBV treatment, at doses of 200 mg/day for 6 or 12 months.^[51–54] In all these studies, although no anti-viral effect was found, a significant decrease in ALT levels was observed with respect to basal values. However, the total number of patients treated with amantadine alone is low and hence its use cannot be recommended.

The metabolic syndrome, which includes hepatic steatosis, hypercholesterolaemia, hypertriglyceridaemia and insulin resistance/diabetes, is a common feature in patients with chronic hepatitis C.^[55] As the metabolic syndrome is associated with hepatic inflammation and fibrosis,^[56] it is important to assess and lower increased cholesterol, triglycerides and glucose concentrations. Statins are potent drugs for reducing circulating low-density lipoprotein cholesterol levels. Statins also have anti-inflammatory, antioxidant and anti-thrombotic effects.^[57] Clinical studies have reported controversial results on the activity of statins against HCV.^[58–67] However, statins must be prescribed for high cholesterol levels to HCV-infected patients, as hypercholesterolaemia is associated with steatosis and potential progression of liver disease.

Pioglitazone and metformin are used to improve glycaemic control in patients with type-2 diabetes. Chojkier et al.^[68] studied whether pioglitazone has an anti-viral effect in chronic HCV infection. They included 20 overweight patients with genotype 4 chronic hepatitis C who received 30 mg daily of pioglitazone for 14 days. Serum HCV-RNA and ALT values were significantly decreased at the end of therapy with respect to basal levels. Metformin has been proven to be effective in reducing the incidence of HCC in patients with HCV-related cirrhosis and with type 2 diabetes.^[69] Both drugs seem to have a beneficial effect on liver disease progression in patients with chronic hepatitis C and type-2 diabetes, although further evidences are needed to confirm these findings.

Antioxidants
Oxidative stress is thought to play a role in the pathogenesis of chronic hepatitis C because oxidative stress occurs early during HCV infection and increases with disease progression and severity.^[70] Vitamin deficiencies are common among patients with chronic hepatitis C and thus vitamin supplementation provides a basis for their therapeutic use.^[71] Vitamins C, D and E are the most investigated as antioxidant therapy in chronic liver diseases. However, there are no studies on the efficacy of vitamin C as monotherapy, while vitamin D did not show beneficial effect when administered to patients with chronic hepatitis C.^[72] Vitamin E (1200 IU/day) administration for 8 weeks to nonresponder patients to IFN significantly decreased the index of oxidative stress in liver biopsy, but did not significantly affect ALT levels, HCV-RNA titres or the histological degree of hepatocellular inflammation or fibrosis.^[73] However, in another study, vitamin E at doses of 800 IU/day for 12 weeks reduced serum ALT values by 46% (and AST by 35%) at the end of treatment, although ALT and AST returned to baseline levels 1 month after therapy discontinuation.^[74] Oral vitamin E supplementation (500 mg/day) given for 3 months resulted in modest reduction in serum ALT levels and improved oxidative stress in those patients with initial ALT levels >70 IU/L.^[75] In patients with HCV-related cirrhosis, bedtime administration of 900 IU/day vitamin E for 6 months almost normalised ALT values, but only in the vitamin E-deficient individuals.^[76]
 
The preventive effect of vitamin E on hepatocarcinogenesis has been investigated in patients with HCV-related liver cirrhosis. ALT levels, platelet counts, serum albumin and total cholesterol were not different compared with controls, untreated patients during the 5-year survey. The administration of vitamin E did not improve liver function, suppress hepatocarcinogenesis or improve cumulative survival.^[77] Vitamin E is nontoxic even at elevated doses (≥500 mg/day) over extended periods of time (from 6 months up to 5 years).^[73–77] On the other hand, the efficacy of vitamin E is more evident among patients with vitamin E deficiency and in those with moderately elevated ALT values.^[75]
 
When combined, daily supplementation with vitamin C (500 mg) and vitamin E (800 mg) plus zinc (40 mg) for 6 months reduced ALT values in previously untreated HCV patients.^[78] In contrast, daily doses of ascorbic acid (500 mg), D-alpha-tocopherol (945 IU) plus selenium (200 μg) for 6 months had no significant effects on ALT values or the viral load.^[79] The hepatoprotective and anti-inflammatory effects of silybin-phospholipids and vitamin E complex (SPV complex) have been investigated in patients with chronic HCV infection. SPV complex administered for 3 months had a significant and persistent reduction in ALT and AST serum levels.^[80]
 
Multi antioxidant (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, l-glutathione and alpha-tocopherol) oral daily treatment for 20 weeks may decrease viral load and ameliorate necro-inflammation in some patients.^[81] Combined oral and intravenous antioxidant therapy was associated with a decline in ALT levels and mild anti-inflammatory effects in chronic hepatitis C patients who were nonresponders to IFN.^[82] Other antioxidants, such as resveratrol and astaxanthin, are not suitable as an antioxidant therapy for chronic hepatitis C.^[83]
 
In conclusion, the data available suggest some benefits of vitamin E in reducing serum ALT concentrations, most likely in cases with vitamin E deficiency. Most studies involving antioxidant therapy (including vitamin supplementation other than vitamin E) failed to show any beneficial effect on HCV-RNA levels or liver histology in chronic hepatitis C.^[71,84] The results of the clinical studies are difficult to interpret because of the small sample sizes, short follow-up duration, inadequate end points and, finally, failure to demonstrate tissue delivery and antioxidant efficacy.^[85]
 
Other compounds like S-adenosyl-methionine or acetylcysteine when administered alone do not show significant effect on ALT levels,^[86,87] and hence their use is not recommended.

Immune Modulators and Cytokines
Viusid, a nutritional supplement, may improve oxidative stress and immunological parameters in patients with chronic hepatitis C. In patients with HCV-related decompensated cirrhosis, it seems to improve survival, disease progression and prevent HCC development. However, low numbers of patients have been analysed and the studies did not show effects on HCV-RNA levels.^[88,89]
Interleukin (IL)-10 is a cytokine that down-regulates the pro-inflammatory immune response and has a modulatory effect on liver fibrogenesis. IL-10 treatment induced ALT normalisation in 86% of patients and improved liver histology, but an increase in HCV-RNA was observed.^[90,91] Hence, IL-10 treatment is discouraged for patients with chronic hepatitis C.

Interleukin-12 and Thymosin alpha 1 have also been administered to patients with chronic hepatitis C, with no effects on ALT values or HCV-RNA levels.^[92–94] Other molecules with immunomodulatory properties, such as the glycoconjugate AM3, have been investigated in vitro,^[95] but not administered therapeutically to patients with chronic hepatitis C.

Conclusions
Several approaches may be used to treat patients with chronic hepatitis C who are not candidates for PEG-IFN based therapy. Phlebotomies in combination with a low-iron diet may induce a beneficial effect. If a favourable response is achieved, a deficiency iron status should be maintained over a prolonged period. UDCA, at dose of 900 mg, may be useful in the management of these patients. Glycyrrhizin may be considered, but the intravenous administration route implies a limitation for its general use. Metabolic disorders, if present (increased levels of cholesterol, triglycerides, glucose), must be treated. In overweight patients with chronic hepatitis C, a diet to reduce weight is desirable. Physical exercise, even if no weight is lost, may be recommended in these patients. Finally, coffee consumption is helpful, while alcohol intake and smoking are strictly forbidden.