January 7, 2014

Alimentary Pharmacology & Therapeutics

Volume 39, Issue 2, pages 148–162, January 2014

Review Article

Review article: management of chronic hepatitis C in patients with contraindications to anti-viral therapy

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V. Carreño*

Article first published online: 26 NOV 2013
DOI: 10.1111/apt.12562
© 2013 John Wiley & Sons Ltd

Summary

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 Baconet 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]

Capture

The effect of phlebotomy on the liver histology of patients with chronic hepatitis C has been demonstrated in several reports. Thus, Yanoet 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.

Natural products

Glycyrrhizin

Glycyrrhizin is a natural component extracted from the roots of Glycyrrhiza glabra that inhibits in vitro the release of infectious HCV particles.[96] Different studies have been published using glycyrrhizin as therapy in patients with chronic hepatitis C.[97-101] The pharmacological composition of the treatment with glycyrrhizin is a solution of 0.2% glycyrrhizin, 0.1% cysteine and 2% glycine in physiological solution.[97] Glycyrrhizin has been administered directly into a peripheral vein in a 3- to 5-min period,[100] but patients may be treated as out-patients. Several reports have demonstrated that glycyrrhizin significantly reduces ALT levels in patients with chronic hepatitis C.[97-103] However, different doses and schedules of administration have been used. Thus, van Rossum et al.[98] performed a double-blind randomised placebo-controlled trial giving 80, 160 or 240 mg of glycyrrhizin or placebo to 57 chronic hepatitis C patients (nonresponders to interferon or unlikely to respond). The medication was administered intravenously thrice weekly for 4 weeks. The mean ALT decrease at the end of the active treatment was 26%, which was significantly higher than that of the placebo group (6%), but after the end of therapy, a rebound in ALT levels was observed. The eficacy of the treatment was similar among doses of 80, 160 and 240 mg, but glycyrrhizin had no effect on HCV-RNA concentration. This finding has been confirmed in other studies.[99-101, 103] The time elapsed since the beginning of the treatment until ALT decrease varied between 2 days to 2 weeks,[98, 101] while the percentage of ALT normalisation oscillated between 10% and 35.7%.[97-99] It seems that the frequency of ALT normalisation depends on the duration of treatment. Thus, the highest frequency (35.7%) was achieved with a continuous administration of glycyrrhizin for a period of 2–16 years (median 10.1 years).[97]

Glycyrrhizin treatment schedules of six, five, three times per week or one time per week for 26–52 weeks have been evaluated. [100, 101]From both studies, it is concluded that the optimal schedule of glycyrrhizin administration is five to six times per week for a minimum of 26 weeks.

In relation to the response to glycyrrhizin, sex, age, HCV genotype, viral load, presence of liver cirrhosis, height, weight, body mass index, baseline ALT levels, inflammation or fibrosis were nonpredictive for ALT response.[100] Regarding the effect of glycyrrhizin on liver histology, an improvement in the necrosis score was found after 52 weeks of treatment in 45–46% of the patients when comparing basal and final liver biopsies.[101] ALT responders presented a tendency towards improvement of the inflammation score, while nonresponders had a deterioration.[100]

The possible efficacy of glycyrrhizin therapy to prevent the development of HCC in patients with chronic hepatitis C has been evaluated in several studies.[97, 104-107] Arase et al.[97] treated 84 patients with 100 mL of glycyrrhizin for 2–16 years (median 10.1 years) and compared the results with a control group of 104 patients of similar characteristics. They found a cumulative HCC incidence rate significantly lower in the treated group than in the controls (12% vs. 25%) after 15 years. In a similar study, Ikeda et al.[106] treated 244 patients with chronic hepatitis C and nonresponders to IFN therapy with intravenous glycyrrhizin for 6 years or longer and they also included an untreated group of 102 patients. They found that glycyrrhizin therapy significantly decreased the hepatocarcinogenesis rate. These results have also been reported by other authors,[104, 105] especially among those patients treated with glycyrrhizin who normalised ALT levels.[105] Also, the liver cirrhosis occurred less frequently in 178 patients than in 100 control patients after 15 years of glycyrrhizin treatment (28% vs. 40% respectively, P < 0.002).[104] With respect to the secondary effects of the treatment, it has been proven that it can induce pseudo-aldoteronism.[108] Thus, aggravated hypertension (8.7%), hypertension (5.1%) and hypokalaemia (3.6%) have been reported with a schedule of administration of five times per week of glycyrrhizin.[101] Other described side effects were arrhythmia and thrombophlebitis related to daily intravenous administration, although glycyrrhizin was generally well tolerated.[100]

Tsubota et al.[102] performed a randomised controlled study to determine whether the combination of glycyrrhizin plus UDCA may improve the efficacy of glycyrrhizin administration alone in chronic hepatitis C. Patients (n = 170) were treated with intravenous glycyrrhizin three times per week for 24 weeks alone or in combination with a daily oral dose of 600 mg of UDCA. Overall, AST and ALT decrease during treatment was significantly greater in the group receiving combined therapy than in the group receiving glycyrrhizin alone. Platelet count, serum total protein, albumin and bilirubin did not change in either group. Unfortunately, no further studies have been published using this combined treatment.

Finally, Tanaka et al.[109] conducted a randomised study to evaluate if addition of minor phlebotomy to glycyrrhizin treatment further reduced ALT values in chronic hepatitis C. A total of 36 patients were assigned to the group of glycyrrhizin plus phlebotomy and another 36 patients to glycyrrhizin alone. Phlebotomy was performed before every glycyrrhizin injection to a total 60 mL of blood per week until reaching a ferritin level of 20 ng/mL. If so, phlebotomy was suspended, but was resumed as needed to maintain that ferritin level. The volume of glycyrrhizin varied between 111 and 127 mL per week. Patients treated with phlebotomy and glycyrrhizin presented a significant decrease in ALT values, while no changes were seen in patients treated with glycyrrhizin alone. The tolerance was good. However, these results have not been confirmed.

Glycyrrhizin has also been administered as suppository (300 mg) for 12 weeks to 13 patients with chronic hepatitis C in comparison to another 13 patients who received it intravenously with a similar efficacy in both groups.[110] Xianshi et al.[111] showed that oral administration of glycyrrhizin (7.5 mg) twice a day can significantly improve liver tests in chronic hepatitis B, but its effect on chronic hepatitis C has not been documented.

In summary, glycyrrhizin may be useful to decrease ALT levels, to improve liver histology and to reduce the risk of HCC. However, the route of administration (intravenous) limits its possible application and there is a need to study its efficacy when administered by other routes (suppository, oral).

Silymarin/Silibinin

Silymarin, an extract of the milk thistle (Silybum marianum), and its components have anti-viral activity against HCV in vitro.[112-117] Apart from its anti-viral capacity, silymarin has antioxidant, anti-inflammatory, anti-proliferative, anti-fibrotic and immunomodulatory activities[112, 114] that may have hepatoprotective effects.

Oral silymarin has been used in the treatment of patients with chronic hepatitis C, either naïve or nonresponders to previous anti-viral therapy[118-122] at total daily doses ranging from 149 to 2.1 g for 1 week to 1 year. All these studies showed that silymarin was safe and well tolerated, but it had no effect on ALT or serum HCV-RNA levels. The lack of efficacy of oral silymarin in the treatment of chronic hepatitis C is probably due to the low bioavailability of this compound.[121]

The main component of silymarin is silibinin, which is a mixture of the flavonolignans silybin A and silybin B. To circumvent its rapid metabolisation after oral administration,[123] silibinin has been administered intravenously in the form of a water-soluble succinate conjugate. Some studies have reported the administration of intravenous silibinin at doses ranging from 5 to 20 mg/kg/day to nonresponder patients to PEG-IFN/RBV or to PEG-IFN + RBV + protease inhibitor therapy.[124-126] Silibinin had an important anti-viral activity, with clearance of serum HCV-RNA in up to 87% of the patients.

Regarding secondary effects, increase in serum bilirubin levels is observed during silibinin treatment, returning to basal values when the therapy is stopped. Other side effects are mild gastrointestinal symptoms (nausea, abdominal pain and diarrhoea) during the first day of administration.

Taking together, all these studies have shown that silibinin has anti-viral activity against HCV, but the total number of patients included in these studies (n = 88) is small and the effect of silibinin on ALT levels has not been reported. Moreover, predictive factor of response to silibinin and its impact on liver histology are unknown. An important drawback of silibinin is that it must be administered intravenously due to its rapid metabolisation after oral administration. Very recently, new methylated analogues of silybin B with higher bioactivity and anti-viral properties in vitro have been developed.[127] Whether these analogues have also a higher bioactivity in vivo has not been tested. In summary, although silibinin is a promising agent for the treatment of patients who cannot receive standard anti-viral therapy, it cannot be recommended, as the optimal dose of silibinin, duration of treatment and its effect on liver disease progression remain to be determined.

Other natural products

Several compounds extracted from plants and fruits, such as Epigallocatechin-3-gallate (green tea extracts), naringenin (a flavonone present in grapefruit), proanthocyanidin (isolated from blueberry leaves) or curcumin (a polyphenol isolated from the curry spice turmeric), have been shown to have anti-viral properties against HCV in vitro, but no clinical studies have been reported on their real efficacy and safety in patients with chronic hepatitis C.[128-136] Extracts of Spirulina platensis (a blue-green algae) and artichoke leaves have been shown to be ineffective when administered to patients with chronic hepatitis C in pilot studies.[137, 138]

Other herbal preparations have been tested in clinical trials,[139-141] and, although some of them seem to have anti-inflammatory or anti-viral activities, there are no convincing data to suggest a definite histological and/or virological improvement due to nonstandardised formulations and lack of information about the potential active compounds. In addition, the hepatotoxicity of herbal remedies is still a major concern.

Lifestyle interventions

Diet and exercise

Obesity is becoming a major health problem in Western countries. In patients with chronic HCV infection, obesity is associated with steatosis and progression of liver fibrosis.[142] Caloric restriction diet and/or physical activity induce an improvement in biochemical parameters and liver histology in individuals with non-alcoholic steatohepatitis.[143-145] Therefore, weight reduction could be a useful management strategy for overweight patients with chronic hepatitis C. In this regard, Hickman et al.[146] included 19 patients with chronic HCV infection and steatosis demonstrated by a liver biopsy in a 3-month weight reduction programme. The programme consisted of individualised energy restriction (from a mean of 2740 calories per day to a mean of 1620 calories per day) and exercise regimen for 12 weeks. In 10 of the patients, a second liver biopsy was obtained 3–6 months after completion of the programme. At the end of the intervention, weight loss was associated with a significant decrease in ALT levels. In the second liver biopsy, a significant reduction in steatosis was observed in 9/10 patients and fibrosis improved in 5 of them. In another study,[147] 35 overweight patients with chronic hepatitis C and steatosis were included in a 15-month lifestyle intervention: 3 months of an energy restriction diet with 150 min of aerobic exercise per week followed by 12 months of weight maintenance. It was found that weight loss correlated with a decrease in ALT levels. In those patients who maintained the weight loss after 15 months, ALT values remained significantly lower than the basal levels.

Regarding exercise alone, a study with 17 patients proved that exercise consisting of walking, synchronised breathing and focused attention (breathwalk) for an hour, three times a week for 6 months induced a significant decrease in ALT and bilirubin levels, even in patients who did not lose weight.[148] Also it has been shown that aerobic exercise (walking at least 8000 steps per day) for 6 months significantly reduces ALT values.[149] Lifestyle intervention aimed at weight loss could be of benefit in patients with chronic hepatic C as it reduces liver damage. Aerobic exercise may be recommended due to its effect on ALT levels.

Nutritional recommendations

An appropriate dietary intake is important not only to avoid development of liver steatosis but also because there are dietary nutrients that may have hepatoprotective effects or may cause hepatic injury.

Consumption of soft drinks with high fructose corn syrup must be moderate, as an excessive fructose intake is associated with development of non-alcoholic fatty liver disease[150] Resveratrol, a component of red wine, is a popular nutritional supplement due to its antioxidant effect.[151] In vitro studies have shown that resveratrol enhances HCV replication, but prevents HCV-induced steatosis.[83, 152] These contradictory results, and the lack of studies in patients with HCV, discourage recommendation of resveratrol in these patients. Foods rich in polyunsaturated fatty acids (olive oil, corn oil, oily fish etc.) are advisable, as these fatty acids improve lipid profile and may have anti-HCV activity.[153]

The effect of zinc supplementation in patients with chronic hepatitis C has also been assessed. In a first study,[154] 14 patients received 50 mg/day of zinc for 6 months and the authors found a significant decrease in ALT values with no anti-viral effect. In another study,[155] 32 patients with chronic hepatitis C or HCV-related liver cirrhosis were treated with 33.9 mg of zinc daily for 3 years and the patients experienced a significant reduction in AST and ALT levels, but not in HCV-RNA titres. These patients continued with zinc supplementation for a mean time of 7 years and it was found that the incidence of HCC was significantly lower in patients receiving zinc when compared with a control group.[156] No side effects were reported. However, the results of the studies have to be interpreted with caution as patients, both in the zinc supplementation group and control, were receiving other treatments such as UDCA, and hence it is not possible to determine if the observed effect is attributable only to zinc or to its combination with another drug.

As mentioned before, iron overload is common in chronic hepatitis C and it can accelerate liver damage. Some authors have reported that haemochromatosis gene (HFE) mutations in chronic HCV infection are independently associated with iron loading and the severity of liver disease,[157, 158] and hence a low-iron diet could be recommendable in these patients. However, other studies have not found such association.[159, 160] In any case, HCV-infected patients should avoid dietary compounds that may increase iron absorption, like citrate or ascorbate. By contrast, intake of compounds containing tannins, like tea, is advisable as they inhibit iron absorption.

Coffee consumption is beneficial in chronic hepatitis C. Thus, Freedman et al.[161] analysed the baseline characteristics of 766 patients with chronic hepatitis C and found that higher coffee consumption was associated with a lower AST/ALT ratio, less steatosis and lower levels of alpha-foetoprotein. After 4 years of follow-up, the authors showed that patients who drank three or more cups of coffee per day had a 53% lower risk of liver disease progression than those who took less than three cups. In another study in which 121 patients with chronic HCV infection were studied, Modi et al.[162] reported that coffee consumption was associated with a reduced hepatic fibrosis. The effect of coffee was not linear and the threshold below which no protective effect was observed was established in 308 mg of caffeine (two to three cups of coffee) per day. This protective effect was not observed in patients who consumed caffeine from other sources, such as tea or caffeine-containing sodas.[162] Finally, Costentin et al.[163] studied 218 patients with chronic hepatitis C and observed that coffee consumption was inversely correlated with the activity grade on the liver biopsy. In this study, the threshold for a beneficial effect on liver inflammation was 408 mg of caffeine (three to four cups of coffee) per day.

In the light of these results, consumption of two to four cups of regular coffee per day should be recommended to patients with chronic hepatitis C, as it may help slow liver disease progression.

Alcohol/smoking

Alcohol consumption, even moderate, and smoking must be forbidden in patients with chronic hepatitis C, as these habits increase the risk of histological progression of liver damage.[164-166]

A summary of the clinical management of patients with chronic HCV infection not suitable for current anti-viral therapies is shown in Figure 1.

apt12562-fig-0001

Figure 1. Management of patients with chronic hepatitis C who are not suitable for current interferon-based therapies.

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.

Authorship

Guarantor of the article: Vicente Carreño.

Author contribution: Vicente Carreño performed the literature review, analysed the data, wrote the paper and approved the final version of the manuscript.

Acknowledgement

Declaration of personal and funding interests: None.

References

Source

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Review Article

You have free access to this content

R. S. Koff*

Article first published online: 6 JAN 2014
DOI: 10.1111/apt.12601
© 2014 John Wiley & Sons Ltd

Summary

Background

The treatment of chronic hepatitis C is changing rapidly.

Aim

To review clinical studies of the efficacy and safety of sofosbuvir-containing regimens in the treatment of chronic hepatitis C.

Methods

Using PubMed and search terms ‘sofosbuvir,’ ‘emerging HCV treatment,’ and ‘HCV polymerase inhibitor,’ literature on the clinical development of sofosbuvir, as well as abstracts presented at the November 2013 annual meeting of the American Association for the Study of Liver Diseases (AASLD), was reviewed. The last search was undertaken on 15 November 2014.

Results

In a dose of 400 mg once daily, the drug has been safe and generally well tolerated with most adverse reactions attributable to the concurrent use of ribavirin or peginterferon plus ribavirin. A high barrier to resistance has been demonstrated. In genotype 1 (G1) patients, the addition of sofosbuvir to peginterferon plus ribavirin yielded sustained virological response rates at week 12 after discontinuation of treatment (SVR12) of about 90% with slightly lower levels in G1b and in patients with cirrhosis, but with no major impact of IL28B genotype, high viral load, body mass index (BMI), alanine aminotransferase (ALT) or race/ethnicity. In genotype 2 (G2), sofosbuvir and ribavirin for 12 weeks also resulted in SVR12 of 90% or better with little effect from cirrhosis. In contrast, genotype 3 (G3) was less responsive to 12 weeks of sofosbuvir plus ribavirin, especially in the presence of cirrhosis.

Conclusions

The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signals a new era in treatment.

Introduction

The emergence of a new and novel treatment for chronic hepatitis C signals a major change in the standard of care. In addition, our understanding of the definition and benefits of effective treatment has recently expanded. The goal of treatment in all infected individuals, regardless of which of the six major genotypes (G1-6) are present, has been and continues to be the achievement of a sustained virological response (SVR) in which circulating HCV RNA is undetectable with the use of a highly sensitive assay following treatment. Initially, SVR was measured at 24 weeks (SVR24) after the end of treatment. In 2013, sufficient data from clinical trials were available to demonstrate that SVR measured at 12 weeks post-treatment (SVR12) showed a high concordance with SVR24. In the United States, the Food and Drug Administration (FDA) has indicated that SVR12 is an appropriate primary end-point for registration trials seeking FDA approval.[1] It should, nonetheless, be noted that because concordance between SVR12 and SVR24 is not perfect, in clinical practice, assessment of SVR24 would still seem reasonable. It is now generally accepted that achievement of a SVR is highly predictive of eradication of infection. Long-term follow-up studies indicate that disease progression is interrupted, histological, clinical and laboratory features of advanced disease may be reversed, and life-expectancy may return towards normal. Nevertheless, it is now clear that among patients with advanced hepatic fibrosis (defined as Metavir F3 and F4), a risk of hepatocellular carcinoma remains for several years after achievement of a SVR.[2]

In the early years of chronic hepatitis C management, treatment with nonpegylated interferons without and later with ribavirin resulted in low efficacy and was poorly tolerated. Between 2001 and 2011, the standard of care became a combination of pegylated interferon (peginterferon) plus ribavirin, and treatment duration was determined by genotype. In general, with 48 weeks of combination therapy in genotype 1 (G1), SVR rates varied from 40 to 50%. Subtype G1a appeared slightly more responsive than G1b.[3] For genotypes 2 and 3 (G2, G3), with 24 weeks of combination treatment, SVR rates were 70–80%. Although the tolerability of peginterferon was better than that for the nonpegylated forms, many patients were peginterferon intolerant, and ribavirin regularly induced a haemolytic anaemia and other adverse events. Concerns about ribavirin's teratogenicity also complicated patient management. In 2011, a new standard of care for genotype 1 patients, consisting of treatment with an NS3/4A HCV serine protease inhibitor (either telaprevir or boceprevir), received FDA approval for use in combination with peginterferon plus ribavirin. In many patients, treatment could be shortened, but because peginterferon and ribavirin were still required and the protease inhibitors dramatically increased the severity and rapidity of the onset of haemolysis and carried other adverse events (rash, neutropenia, etc.), tolerability (and safety) remained an issue. Discontinuation rates due to adverse events were approximately 15%. Furthermore, both protease inhibitors had to be given with food multiple times throughout the day, drug–drug interactions complicated therapy[5] and resistant HCV variants emerged in those failing to achieve a SVR. The protease inhibitor-containing regimens resulted in SVR rates of 65–75% in previously untreated patients in registration trials, and lower rates (58–61%) among naïve patients in clinical practice[6] and even lower rates (50–52%) in United States veterans.[4]

Patients with histologically advanced disease had lower response rates. The protease inhibitors were ineffective in genotypes other than G1 and response rates were somewhat lower in G1a compared with G1b.

Although the introduction of the serine protease inhibitors for G1 resulted in incremental increases in efficacy in G1, even in this, the most common genotype, their anti-viral activity was limited. As a consequence, research efforts have sought viral and host targets other than the serine protease. These include the NS5B protein and the NS5A replication protein, both of which are essential for HCV replication. Both nucleos(t)ide and nonnucleoside NS5B inhibitors are under study. Because the catalytic site of the NS5B protein is highly conserved across all genotypes, the nucleos(t)ide inhibitors are active against all genotypes, although the in vitro and in vivo data on G5 and G6 are limited. The nucleotide inhibitors also have a higher barrier to resistance than do the nonnucleoside NS5B inhibitors. This review is focused on a single nucleotide NS5B inhibitor – sofosbuvir. It will be the first of the NS5B inhibitors to become commercially available in early 2014. In addition to studies of sofosbuvir in combination with peginterferon and ribavirin or with ribavirin alone, a handful of studies combining sofosbuvir with NS3/4A protease inhibitors or NS5A inhibitors will be briefly reviewed.

Sofosbuvir background information

Originally termed PSI-7977, sofosbuvir is a prodrug of a uridine nucleotide analogue inhibitor of the NS5B polymerase protein. In vivo, it is converted to the 5′-triphosphate derivative, which targets the catalytic site of NS5B and serves as a non-obligate chain terminator.[7]Following treatment with sofosbuvir plus ribavirin, levels of the triphosphate well above the inhibition level have been found in human livers.[8] Studies in replicon cells containing different HCV genotypes indicated that sofosbuvir demonstrated broad genotype coverage. However, cross-resistance studies indicated that sofosbuvir treatment of replicon cells selected the S282T change in G1b cells.[9]Although this reduced sofosbuvir activity, such mutants also had reduced replicative capacity, compared with wild-type-containing replicons.[10] Sofosbuvir activity was not reduced in replicons with mutations in NS3/4A or NS5A. In an analysis of patients who failed to achieve a SVR with sofosbuvir-containing regimens, the S282T substitution was not detectable at baseline or later, although other NS5B substitutions were rarely detected.[11]

These data indicate that sofosbuvir-containing regimens have a high barrier to resistance and that substitutions in the NS5B gene do not affect SVR rates. This observation suggested that sofosbuvir might be an effective anti-viral agent in patients with pre-existing or treatment-emergent NS3/4A or NS5A mutations when combined with other classes of inhibitors. It should not be used as monotherapy.

The pharmacokinetics of single- or multiple-dosing of sofosbuvir has been reviewed elsewhere.[7, 12, 13] In early studies, it was shown that sofosbuvir was rapidly absorbed and eliminated. The triphosphate metabolite of sofosbuvir was largely excreted in urine and no significant accumulation of sofosbuvir or its metabolites was observed. No dose modifications were needed for patients with mild-to-moderate renal impairment. For patients with creatinine clearances less than 30 mL/min and for those on dialysis, sofosbuvir is contraindicated. No dose modification was necessary in patients with impaired liver function or with compensated cirrhosis. No data are available for patients with decompensated cirrhosis as such patients were excluded from participation in clinical trials. Because the metabolism of sofosbuvir does not involve cytochrome P450 3A/4 (CYP3A/4), drug–drug interactions are not anticipated. In fact, no drug–drug interactions with a variety of drugs, such as cyclosporine, tacrolimus, drugs used in the treatment of HIV infection, methadone, or combined oral contraceptives containing ethinyl estradiol and norgestimate, have been identified to date.

It should be noted that in the discussion that follows both SVR12 and SVR24, data have been utilised in determining the efficacy of sofosbuvir-containing regimens. In fact, available data indicate a concordance of greater than 99% in studies of sofosbuvir. Hence, relapse alone, after SVR12 is achieved, is exceedingly rare.[14]

Genotype 1 Studies

Phase 2 Studies

Short-term (28 days), dose-ranging studies of treatment-naïve genotype 1 patients with sofosbuvir plus peginterferon and ribavirin suggested that a dose of 100 mg sofosbuvir was associated with virological breakthroughs on continuing treatment with peginterferon plus weight-based ribavirin after discontinuing sofosbuvir.[12] In these initial studies, viral suppression was greater in the sofosbuvir, peginterferon and ribavirin combination compared with peginterferon and ribavirin with placebo and occurred more rapidly. Furthermore, resistance monitoring failed to identify the S282T mutation either at baseline or during treatment, and sequencing of the entire NS5B protein failed to reveal any mutations that had been associated with resistance to nonnucleoside NS5B inhibitors. Adverse events were similar in frequency in the sofosbuvir-containing regimen compared to peginterferon plus ribavirin. Fatigue, nausea, headache, chills and arthralgias were the most frequently reported. No adverse events led to discontinuation of sofosbuvir.

Subsequently, the 200 mg sofosbuvir dose has been compared to the 400 mg dose, as neither was associated with virological breakthroughs. In one of these phase 2 studies,[15] 90% of G1 patients receiving the 200 mg dose achieved SVR12 with triple therapy for 12 weeks followed by 12 or 36 more weeks of peginterferon and ribavirin. The SVR12 for the 400 mg dose regimen was 91%. In comparison, SVR12 for patients receiving a sofosbuvir placebo with peginterferon plus ribavirin was 58%, significantly lower than for sofosbuvir-containing regimens. Although no patient experienced virological breakthrough while on sofosbuvir, 6% of patients who had received the lower 200-mg sofosbuvir dose experienced breakthrough while still on peginterferon and ribavirin. These findings support the notion that the 400-mg sofosbuvir dose provides more effective viral suppression. The 400-mg dose has been utilised in a number of phase 2 trials.[16, 17] In the open-label, multi-part ELECTRON trial, a small number of treatment-naïve and treatment-experienced patients were given a peginterferon-free regimen of sofosbuvir and ribavirin for 12 weeks.[16] In the treatment-naïve group, HCV RNA was undetectable by week 4 of treatment in 100%. SVR12 and SVR24 were identical at 84%. In contrast, among the treatment-experienced patients, only 10% had SVR12 and SVR24. These data suggested that for treatment-experienced G1 patients, peginterferon or the addition of another direct anti-viral agent would be required to achieve higher efficacy. In another phase 2 trial of sofosbuvir with peginterferon and ribavirin (ATOMIC) for new to treatment noncirrhotic G1 patients, the efficacy of sofosbuvir (400 mg daily) with peginterferon plus ribavirin given for 12 or 24 weeks was assessed.[17] In some patients who received 12 weeks of the combined treatment, the efficacy of an additional 12 weeks of sofosbuvir monotherapy or sofosbuvir plus ribavirin was evaluated. A SVR24 of 89% was achieved with 12 weeks of combination treatment with no additional benefit of treatment extension.

Patients with predictors of treatment failure, based on studies with peginterferon and ribavirin without or with protease inhibitors, had been largely excluded from these early trials. In one small-scale, randomised, open-label phase 2 trial, treatment-naïve G1 patients with unfavourable features of treatment success (African-American descent, high BMI, low frequency of IL28B CC genotype, high HCV RNA level and advanced liver disease) were treated with sofosbuvir and weight-based (1000–1200 mg daily) or low-dose (600 mg daily) ribavirin for 24 weeks.[18] Among patients with early-to-moderate hepatic fibrosis, SVR24 was 90%. Among patients with the full spectrum of hepatic fibrosis, viral suppression was achieved in 96% at week 4 of treatment. However, SVR24 rates were 68% in the ribavirin weight-based group and 48% in the ribavirin low-dose group due to high frequencies of relapse. These observations also support the need for the use of additional agents with sofosbuvir and ribavirin for some G1 patients.

The safety of sofosbuvir-containing regimens was studied in these phase 2 trials. Adverse events were common in all studies and were consistent with those associated with peginterferon plus ribavirin treatment. Major reported events included fatigue, headache, nausea, chills, insomnia and arthralgias. Most were considered by the investigators to be mild to moderate and most resolved. Drug discontinuations due to adverse events were rare and were generally associated with peginterferon plus ribavirin rather than with sofosbuvir. Similarly, rates of neutropenia, thrombocytopenia and anaemia were consistent with those seen in patients treated with peginterferon and ribavirin.

Phase 3 Studies

The principal phase 3 trial of sofosbuvir treatment of new to treatment G1 patients was termed NEUTRINO.[19] In this open-label, multicentre trial, 89% of patients had genotype 1; 9% had G4; and just 2% were G5 or G6. G1a was the predominant G1 subtype. Mean age, BMI, sex and self-reported race or ethnic group were typical of chronic hepatitis C patients. HCV RNA levels of 800,000 IU/mL or higher were found at baseline in 82%, and the unfavourable IL28B TT and TC genotypes were present in 71%. Approximately 50% of patients had ALT levels more than 1.5 times the upper limit of normal (ULN). Cirrhosis was present in 17%. All patients received 400 mg sofosbuvir, with peginterferon plus weight-based ribavirin for 12 weeks. SVR12 was defined as an HCV RNA level below the lower limit of quantification (25 IU/mL). Although it would have been of interest to have a control group comprising a serine protease inhibitor with peginterferon and ribavirin, this was not included. Rapid viral suppression was evident by week 2 of treatment with 91% of patients having undetectable HCV RNA, and by week 4 of treatment, 99% were HCV RNA undetectable. SVR12 was 90% and no virological breakthroughs occurred during treatment. SVR12 was higher in G1a at 92% vs. G1b at 82%. As shown in Table 1, efficacy rates were also high in populations with less favourable host and viral characteristics. As expected, SVR12 was reduced in patients with cirrhosis (79%) compared with those without cirrhosis (92%). SVR12 rates were highest in those with minimal fibrosis (F0–F2), lower in those with bridging fibrosis (F3) and lowest in cirrhosis (F4). Similarly, patients with the unfavourable non-CC IL28B genotypes had a lower SVR12 (87%) than those with the CC genotype (98%). SVR12 rates did not differ fundamentally when race or ethnicity was considered. Similarly, BMI, viral load and alanine aminotransferase (ALT) elevations did not importantly influence SVR-12 rates.

Capture

Among patients who relapsed after end-of-treatment, both population and deep sequencing studies failed to detect resistance-associated variants. Although 95% of patients experienced an adverse event, discontinuation of treatment as a result of adverse events occurred in just 2%. Adverse events occurring with a frequency of more than 20% included fatigue, headache, nausea, insomnia and anaemia. Haemoglobin levels below 10 g/dL were found in 23%, and neutropenia levels below 500/mm3 were seen in 15%.

Genotype 2 and 3 Studies

Although trials of treatment with interferons with or without ribavirin often considered HCV G2 and G3 patients as one group, a large body of observations indicated that response to treatment was lower in G3. Studies of sofosbuvir-containing regimens support the notion of a differential response rate in some G3 patients, particularly prior null responders and those with cirrhosis. (Table 2)

Capture

Phase 2 Studies

In a phase 2b trial of sofosbuvir with peginterferon plus ribavirin given for 12 weeks to a total of 25 naïve, noncirrhotic G2 and G3 patients, 95% were HCV RNA undetectable at week 4 of treatment and SVR24 was achieved in 23 of the 25 (92%).[15, 20] No virological breakthrough or relapse was reported. The two patients who did not achieve a SVR included one lost to follow-up and one in whom a nonprotocol HCV RNA assay was utilised. In a component of the phase 2a ELECTRON trial, 18 noncirrhotic treatment-naïve G2 and 42 noncirrhotic treatment-naïve G3 patients were randomised to receive sofosbuvir plus ribavirin for 12 weeks either without peginterferon or with peginterferon for 4, 8 or 12 weeks.[16] A fifth group received 12 weeks of sofosbuvir alone and a sixth group received 8 weeks of treatment with sofosbuvir, ribavirin and peginterferon. All groups were small with only 9–11 patients per arm. SVR12 and SVR24 was 100% in all arms receiving peginterferon and in one arm of sofosbuvir with ribavirin in the absence of peginterferon. However, monotherapy with sofosbuvir for 12 weeks reduced the SVR12 and SVR24 to 60%. In that group, 2 G2 and 2 G3 patients relapsed but only one, a G2b patient, had the S282T mutation.

Phase 3 Studies

In the phase 3 FISSION non-inferiority trial, nearly 500 of 527 screened, new to treatment G2 and G3 patients were randomised to treatment with either 400 mg of sofosbuvir plus weight-based ribavirin for 12 weeks or peginterferon plus 800 mg of ribavirin for 24 weeks.[19] Approximately 20% had cirrhosis; 87% were white; mean BMI was 28; 43% had IL28B CC genotype; and 57% had serum levels exceeding 1.5 × the ULN. Viral suppression was more rapid in the sofosbuvir and ribavirin group. At week 2 of treatment, 92% had undetectable HCV RNA compared with 32% of those receiving peginterferon and ribavirin. Overall, SVR12 was 67% in both groups, indicating non-inferiority of the two treatment regimens. For G2 patients receiving sofosbuvir plus ribavirin, the overall SVR12 was 97% vs. 78% for those receiving peginterferon plus ribavirin. However, in G2 patients receiving sofosbuvir and ribavirin without cirrhosis, SVR12 was 97%; in those with cirrhosis, it was 91%. In contrast, in G3 patients receiving sofosbuvir plus ribavirin, SVR12 was 61% in those without cirrhosis and 34% in those with cirrhosis, significantly lower rates. Resistance-associated variants were not detected in any of the patients who relapsed. Adverse events and haematological abnormalities were less frequent in the sofosbuvir plus ribavirin group compared with the peginterferon plus ribavirin group. The discontinuation of treatment rate due to adverse events was also lower in recipients of sofosbuvir plus ribavirin (1%) than in recipients of peginterferon plus ribavirin (11%).

G2 or G3 patients in whom treatment with peginterferon was not an option because of unacceptable side effects, or were deemed peginterferon ineligible because of concurrent medical conditions, or refused peginterferon were evaluated in a phase 3 trial called (POSITRON).[21] In this blinded, placebo-controlled study, sofosbuvir plus weight-based ribavirin given for 12 weeks was compared to a matching placebo. About 92% of patients were white; about 75% had high viral loads; about 45% had IL28B CC genotype; and 15% had cirrhosis at baseline. SVR12 was 78% in the sofosbuvir plus ribavirin group and 0% in the placebo group. As in the FISSION study, SVR12 was higher in G2 patients at 93% compared with 61% in G3. Among G2 patients without cirrhosis, the SVR12 was 92% vs. 94% of those with cirrhosis. In contrast, among G3 patients without cirrhosis, the SVR12 was 68%, but only 21% in those with cirrhosis.

In the phase 3 FUSION trial, treatment-experienced G2 and G3 patients were treated with sofosbuvir plus ribavirin for either 12 or 16 weeks.[21] In G2 patients without cirrhosis, the SVR12 after 12 weeks of treatment was 96%; for G2 patients with cirrhosis, SVR12 was 60%. SVR12 after 16 weeks of treatment in G2 patients yielded a rate of 100% in those without cirrhosis and 78% in those with cirrhosis. In sharp contrast, 12 weeks of treatment of G3 patients without cirrhosis resulted in a SVR12 of 37%; in those with cirrhosis, the rate was just 19%. SVR12 after treatment of G3 patients without cirrhosis for 16 weeks revealed a SVR12 of 63% and for those with cirrhosis 61%. These observations indicate that for treatment-experienced G3 patients with cirrhosis, sofosbuvir plus ribavirin treatment duration may need to be extended or the addition of other direct anti-viral agents or peginterferon may be necessary.

The efficacy and safety of extending treatment with sofosbuvir plus weight-based ribavirin in G3 patients for longer than 12 or 16 weeks was assessed in the phase 3 VALENCE study[22] The original treatment protocol, which included G2 and both treatment-naïve and treatment-experienced patients, was amended to permit extending treatment to 24 weeks in G3 patients. In G2 patients treated for 12 weeks, the overall SVR12 was 93%. In the treatment-naïve group, it was 97%. In the treatment-experienced group, SVR12 was 91% in the noncirrhotic patients and 88% in cirrhotic patients. Twelve weeks of sofosbuvir plus ribavirin was given to a small group of G3 patients before the protocol was amended. In this group, the SVR12 was just 27%. Among G3 patients treated for 24 weeks, the overall SVR12 was 85% and but was higher in treatment-naïve patients without or with cirrhosis (94% vs. 92%). Treatment-experienced noncirrhotic G3 patients treated for 24 weeks had a SVR-12 of 87%, whereas those with cirrhosis had a SVR12 of 60%. The drugs were well tolerated for 24 weeks and the safety profile was consistent with that for ribavirin. Furthermore, discontinuations due to adverse events occurred in less than 1% of those treated for 24 weeks. No evidence of resistance was identified in any patient in whom relapse occurred. These observations confirm the notion that for G3 treatment-experienced patients and especially for those with cirrhosis, 24 weeks of treatment with sofosbuvir plus ribavirin is optimal.

Genotype 4 studies

The NEUTRINO study, described above under G1 phase 3 trials, also included 28 patients with G4 infection, treated with triple therapy for 12 weeks.[19] In this small group, SVR12 was 96%. In a phase 2 study, 60 treatment-naïve and -experienced G4 patients were randomised to treatment with sofosbuvir plus ribavirin without peginterferon for 12 or 24 weeks.[23] Baseline viral load was high, as were BMIs; the majority of patients had unfavourable IL28B genotypes, and nearly 25% had cirrhosis. At week 4 on treatment, 98% had undetectable HCV RNA and 100% were undetectable at the end of treatment. In the treatment-naïve patients treated for 12 weeks, the SVR measured at 4 weeks post-treatment (SVR4) was 79%. Longer treatment for 24 weeks resulted in a SVR4 of 100%. In the treatment-experienced group, SVR4 was 59% for the 12-week regimen and 93% for the 24-week regimen. SVR12 data had not yet been report

Genotypes 5 and 6 studies

Data on the efficacy of sofosbuvir-containing regimens in G5 and G6 patients are exceedingly limited. In the NEUTRINO study, only 2% of patients were G5 or G6.[19] SVR12 was achieved with 12 weeks of treatment with sofosbuvir and peginterferon plus ribavirin in the single patient with G5 and in all 6 patients with G6. Larger studies will be needed to confirm these promising observations.

Sofosbuvir in combination with other direct anti-viral agents

The combination of sofosbuvir with NS5A inhibitors (either daclatasvir or ledipasvir) has been recently studied. Daclatasvir with sofosbuvir with or without ribavirin given for 12 weeks appeared to result in high SVR rates in noncirrhotic, naive G1 and G1-3 patients in early studies.[24, 25] In a phase 2 trial, termed ELECTRON, a fixed dose combination of 400 mg of sofosbuvir and 90 mg of ledipasvir for 12 weeks has been studied with or without ribavirin in a small number of G1 prior null responders with compensated cirrhosis and in naïve, noncirrhotic patients.[26] Among the 10 cirrhotic patients treated with the fixed dose combination plus ribavirin, the SVR12 was 100%, whereas in the absence of ribavirin, the SVR12 was 70%. In G1 previously untreated, noncirrhotic patients, 6 weeks of the fixed dose combination with ribavirin yielded a SVR12 of 68%. Treatment for a longer period, 8 weeks, yielded a SVR12 of 100%. These observations indicate that 6 weeks of treatment is inadequate. Of interest, the addition of a nonnucleoside NS5B inhibitor (GS-9669) to sofosbuvir permitted a ribavirin-free regimen that induced a SVR12 of 100% in patients with advanced hepatic fibrosis.

Another phase 2 evaluation of the fixed dose combination of sofosbuvir/ledipasvir with or without ribavirin was termed LONESTAR.[27, 28]In this study of a limited number of treatment-naïve, noncirrhotic G1 patients, treatment with 8 weeks of the combination without ribavirin was compared with 8 weeks of combination therapy with ribavirin. In a third arm, the combination without ribavirin was given for 12 weeks. Most (87%) of the patients were G1a. SVR12 was achieved in 95% of patients getting the 8-week fixed dose without ribavirin and 100% in those treated for 8 weeks with the fixed dose plus ribavirin. In the group treated for 12 weeks without ribavirin, the SVR12 was 95%. An additional group of patients who had been nonresponders to protease inhibitor regimens and in whom 55% had cirrhosis were treated with the fixed dose combination with or without ribavirin for 12 weeks. SVR12 and SVR24 was 100% for the group receiving ribavirin and 95% for the group not receiving ribavirin. Of interest, most of the protease inhibitor treatment-experienced patients had the Q80K variant, a polymorphism of G1a, along with other protease inhibitor resistance-associated variants; baseline NS5A resistance-associated variants were also found but in a lower frequency.[29] Despite these variants, the efficacy of sofosbuvir/ledispavir with or without ribavirin was not impaired. A phase 3 study is underway.

Preliminary data from a phase 2a randomised, open-label trial combining sofosbuvir with the once-a-day NS3/4A serine protease inhibitor – simeprevir – with or without ribavirin (the COSMOS study) suggest that this interferon-free and ribavirin-free regimen may be efficacious in G1 patients.[30] Noncirrhotic and cirrhotic, treatment-naïve and prior null responder patients were treated with 400 mg of sofosbuvir plus 150 mg of simeprevir with or without ribavirin for 12 or 24 weeks. Just over 75% of the patients were G1a and about 50% of these had the baseline Q80K polymorphism, which has been reported to reduce responsiveness to macrolide NS3/4A protease inhibitors such as simeprevir. SVR12 in prior null responders with F0-F2 fibrosis were 93% whether treated for 12 or 24 weeks with sofosbuvir plus simeprevir. No additional benefit was achieved with the use of ribavirin. All patients completing treatment were HCV RNA undetectable at the end of treatment and virological breakthroughs were not seen while on treatment. Among patients with advanced hepatic fibrosis, either treatment-naïve or prior null responders, SVR4 was achieved in 100% with sofosbuvir plus simeprevir for 12 weeks. Although SVR12 data for all treated cohorts are not yet available, the high efficacy of this combination in G1 patients without either peginterferon or ribavirin denotes a major advance in treatment.

Specific populations

Liver transplant recipients

Recurrence of HCV infection in liver transplant recipients in whom HCV RNA is detected at the time of transplantation has been nearly universal, and in a significant proportion of patients, recurrent HCV infection leads to cirrhosis and reduced survival within 5 years of transplantation. In a small phase 2 study of patients who were candidates for transplantation for hepatocellular carcinoma, and in whom cirrhosis was well compensated, the efficacy of pre-transplant treatment with sofosbuvir and ribavirin for as long as 48 weeks in an attempt to prevent recurrence was assessed.[31] A total of 41 patients, with any genotype, were HCV RNA undetectable at the time of transplant and 64% of these achieved SVR12. The longer the period on treatment with HCV RNA undetectability before transplant, the lower the relapse rate observed. The lowest relapse rates were seen in patients who had been HCV RNA negative for more than 30 days prior to transplantation. Treatment was well tolerated in these compensated cirrhosis patients and drug interactions with anti-rejection drugs were not observed.

Among mainly G1 patients with severe HCV recurrence or with fibrosing cholestatic hepatitis following liver transplantation, early initial data from a compassionate use program in which sofosbuvir was combined with ribavirin with or without peginterferon, the latter at the discretion of the treating physician, have been reported for the first 44 patients.[32] Clinical improvement was noted in 64% of patients and liver chemistry abnormalities also improved. Overall SVR12 was 56%; in those receiving sofosbuvir plus ribavirin, it was 60% and in those receiving triple therapy, it was 50%.

In a prospective, multicentre trial of sofosbuvir plus ascending doses of ribavirin (400–1000 mg daily) given for 24 weeks to patients with recurrent HCV infection after liver transplantation, 100% of patients had undetectable HCV RNA levels at week 4 of treatment.[33] HCV RNA undetectability at end-of-treatment was 100% and SVR4 was 77%. SVR12 data were not yet available. No net change in immunosuppression dose requirements was found.

To date, no studies of nonliver organ transplant recipients with chronic hepatitis C have been reported.

Decompensated cirrhosis and renal failure

Data on the efficacy and safety of sofosbuvir-containing regimens in decompensated cirrhosis or renal failure, with or without dialysis, are not available and for the latter, treatment is now considered contraindicated.

HIV/HCV coinfected

The efficacy and safety of sofosbuvir plus ribavirin, in the absence of peginterferon, has been assessed in human immunodeficiency virus (HIV) coinfected patients with HCV G1-3 in a preliminary study.[34] In this nonrandomised open-label trial, in which all patients were HIV stable and nearly all were on antiretroviral therapy (ART) for HIV, 63% of patients were G1. Multiple ART regimens were permitted, but relatively few patients had cirrhosis. Patients with G1 were treated with sofosbuvir plus ribavirin for 24 weeks, whereas those with G2 or G3 received the combination for 12 weeks. Treatment was completed in 90% of patients. At week 4 of treatment, 96–100% of patients had undetectable HCV RNA. SVR12 was 76% in G1, 88% in G2 and 67% in G3. SVR12 rates were higher in patients with G1a at 82% than with G1b at 54%. Response rates were lower in patients with cirrhosis. HCV virological breakthrough was identified in only one patient in whom non-adherence was documented. HIV breakthrough occurred in two patients, one with non-adherence. The other HIV breakthrough occurred in a patient who regained HIV control without a change in therapy. Regardless of genotype, all relapses occurred by week 4 after ending treatment. Sofosbuvir plus ribavirin was well tolerated. Additional studies of sofosbuvir-containing regimens, with peginterferon or direct anti-virals, will be necessary to determine the optimal management strategy for HIV-coinfected patients.

Paediatric

No studies in children have been reported to date.

Discussion

Sofosbuvir has now been studied in over 3000 patients and is generally safe and well tolerated. In addition to its favourable pharmacology profile, and the absence of evidence of drug–drug interactions, no effect of food on pharmacokinetics has been found. It is formulated as a 400-mg tablet, which can be given once-daily, by mouth. As is the case with other HCV NS5B polymerase inhibitors, HCV NS3/4A protease inhibitors and NS5A replication protein inhibitors, it should not be used as monotherapy. In combination with ribavirin or with peginterferon plus ribavirin, virological breakthrough is rare and resistance-associated variants are not seen. Viral suppression is so rapid that little benefit can be gained by early monitoring of viral load, except where noncompliance is suspected.[35] Initially, 12 weeks of treatment with sofosbuvir combined with ribavirin will be the new standard of care for both new-to-treatment and treatment-experienced G2 patients. For G3 patients, 12 or 16 weeks of sofosbuvir plus ribavirin does not seem optimal. Better results, particularly in treatment-experienced G3 patients, can be achieved with a 24-week course of therapy. The addition of peginterferon or another direct anti-viral may also be necessary for these difficult-to-treat patients. At least initially, G1 patients will be treated with sofosbuvir, ribavirin and peginterferon. As more information becomes available about the efficacy and safety of combining sofosbuvir with the NS3/4A protease inhibitor simeprevir or the NS5A inhibitor ledipasvir or daclatasvir, management strategies are likely to change.

Many questions remain unanswered. So few G5 or G6 patients have been studied to date that recommendations for use of sofosbuvir-containing regimens cannot be made with much confidence. Similarly, additional studies are needed to assess the efficacy, safety and optimal sofosbuvir regimens for the prevention and for the treatment of recurrent HCV infection in the liver transplant recipient and for HCV infection in nonliver organ transplant recipients. Whether sofosbuvir-containing regimens will be safe and effective in patients with decompensated cirrhosis remains to be determined.

More data on the efficacy and safety of sofosbuvir in HCV/HIV-coinfected patients are necessary to confirm the promising early results. The management of chronic hepatitis C in the dialysis patient will remain an issue because of sofosbuvir's renal excretion, and studies in paediatric populations would seem reasonable. In addition, long-term follow-up studies are necessary to confirm the durability of viral eradication in patients who achieve SVR12 and SVR24.

Authorship

Guarantor of the article: R. S. Koff.

Author contributions: The author approved the final version of the manuscript.

Acknowledgement

Declaration of personal interests: R. S. Koff had served as a speaker for Vertex Pharmaceuticals and Gilead Sciences.

Declaration of funding interests: None.

References

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