Treatment of hepatitis C virus infection: Updated Swedish Consensus recommendations

Abstract

In a recent expert meeting, Swedish recommendations for the treatment of HCV infection were upgraded. The panel recommends vaccination against both hepatitis A and B in patients with HCV. Therapy for symptomatic acute HCV infection should be initiated if spontaneous resolution has not occurred within 12 weeks, whereas asymptomatic acute HCV should be treated upon detection. Patients with genotype 2/3 infection should generally be treated for 24 weeks. In patients with a very rapid viral response (vRVR), i.e. HCV RNA below 1000 IU/ml on d 7, treatment can be shortened to 12–16 weeks, provided that no dose reduction has been made. For genotype 1 patients with rapid viral response (RVR), 24 weeks treatment is recommended. For patients with a complete early viral response (cEVR), 48 weeks treatment is recommended, whereas 72 weeks treatment should be considered for patients with partial early viral response (pEVR). For patients with difficult-to-treat disease and with pronounced anaemia, erythropoietin can be used to maintain the ribavirin dose. In HCV-HIV coinfected patients, combination therapy for HCV should, if possible, be initiated before anti-retroviral therapy (ART) is indicated. For liver transplant patients pre-emptive therapy is not recommended; hence, treatment should be deferred until histological recurrence.

Introduction

Hepatitis C virus (HCV) infection is a worldwide health problem with a global prevalence of approximately 2% with large regional variations. In total, an estimated 170 million are chronically infected with HCV [1]. In high endemic areas such as Egypt and southern Italy local prevalence may reach 30%. In Sweden the prevalence of HCV is believed to be ≤0.5%, corresponding to approximately 40,000 individuals. Intravenous drug use is the predominant route of infection, with HCV accounting for approximately 20% of acute hepatitis cases. The development of chronic hepatitis and late sequelae are the most significant consequences of HCV infection. HCV induced liver cirrhosis and hepatocellular carcinoma currently account for 30% of all liver transplants in Sweden.

HCV infection is a disease with variable progression rate and long-term outcome. Spontaneous resolution within the first y of infection may occur in 15–40% of cases, with the remaining cases developing a chronic infection. A majority of patients with chronic infection has a slow disease progression during the first 2 decades of infection, with up to 25% of patients remaining asymptomatic with normal ALT levels and with mild liver histopathological changes. Also, a considerable proportion of patients with elevated liver transaminases have only mild to moderate signs of liver injury. However, 20–30% of patients with chronic HCV infection progress to cirrhosis within 20 y. Without effective intervention these patients are at risk of requiring liver transplantation or dying of liver related complications. A small proportion of patients may rapidly develop cirrhosis within a few y after acquiring HCV. Children and young women generally have a slower rate of progression. Fibrosis progression is not linear, but rather tends to accelerate with increasing age [2]. Among cirrhotic patients, 1–4% will develop hepatocellular carcinoma annually. High age at the time of infection, male gender, high-to-moderate alcohol consumption, and coinfection with hepatitis B virus (HBV) or HIV increase the risk of progression to cirrhosis. Additionally, extrahepatic manifestations of HCV, such as cryoglobulinaemia and lymphoma [3], [4], may adversely affect the outcome. In contrast, HCV genotype and viral load are not considered to influence the long-term prognosis.

Which patients should be treated?

Treatment during the acute phase may prevent the development of chronic HCV infection. Approximately half of the patients with symptomatic acute HCV spontaneously resolve their infection within 3–4 months [5]. If HCV RNA remains detectable 3 months after the onset of symptoms, however, treatment is recommended. Since patients with asymptomatic acute HCV seldom resolve their infection spontaneously, treatment is recommended upon detection.

The primary therapeutic goal is prevention of cirrhosis and further sequelae. However, not all patients with chronic HCV require therapy since the infection does not universally affect life expectancy, quality of life, or psychosocial well-being. Current therapy is often lengthy and has considerable side-effects. Therefore, it is crucial to determine whether the patient will benefit from and be able to comply with treatment.

The need for therapeutic intervention against chronic HCV infection has often relied on histopathological assessment of a liver biopsy. For this evaluation a semi-quantitative scoring system that separates necroinflammation (grade) and fibrosis (stage) is recommended (Table I) [6].

Table I.  Simplified system for histopathological assessment of chronic hepatitis (Hans Glaumann).

	Inflammation grade
Score	Portal inflammation	Interface hepatitis	Lobular inflammation/necrosis	Fibrosis stage
0	None	None	None	None
1	Minimal	Minimal	Only inflammation	Portal fibrosis
2	Mild	Mild	Mild necrosis	Periportal fibrosis
3	Moderate	Moderate	Marked necrosis	Septal fibrosis
4	Severe	Severe	Severe with bridging	Cirrhosis with nodules

HCV genotypes 2 or 3 respond favourably to standard of care (SOC) treatment, hence a baseline liver biopsy is optional and not required for a treatment decision. For HCV genotypes 1 or 4, information about the fibrosis stage and inflammation grade is generally required for decision-making regarding antiviral therapy. Treatment is generally recommended if the fibrosis stage equals or exceeds 2 (range 0–4) [6], [7]. In patients with less advanced fibrosis, therapy should be considered if the inflammation exceeds or equals grade 2 (range 0–4). In milder disease therapeutic intervention may be deferred, provided that the patient consents. For such patients, annual check-ups with a repeat liver biopsy every third to fifth y are recommended.

When a liver biopsy has been performed, it is essential that an experienced liver pathologist perform the evaluation, that sufficient biopsy material is available (>1.5 cm), and that the risk of sampling error is considered. Non-invasive evaluation of liver fibrosis will probably reduce the need for biopsies in the near future.

Besides liver histopathology, factors such as quality of life and psychosocial well-being must also be taken into account when considering therapeutic intervention. The increased likelihood of achieving sustained viral response (SVR) if therapy is initiated earlier in adult life should also be acknowledged.

Vaccination against hepatitis A and B

Patients with chronic HCV infection have an increased risk of a severe disease if infected with hepatitis A virus (HAV) [8] or hepatitis B virus (HBV) [9], [10]. Hence, vaccination against both of these agents is recommended for HCV-infected patients [11].

Evaluation prior to treatment in eligible patients

Prior to initiation of antiviral therapy the duration of infection, the need for treatment, and potential contraindications should be elucidated.

Medical need, the likelihood of sustained viral response (SVR), and the risk of side-effects should be considered. Genotyping should be performed early in the evaluation, since it has a major impact on the response rate to therapy. Other factors affecting SVR include baseline HCV RNA level, fibrosis stage, age, and the presence of the metabolic syndrome [12]. Prior to or at the time of the initiation of therapy, the following analyses are recommended:

• HCV genotyping (if not previously performed), in order to determine initial drug dosing and the tentative treatment duration.

• Quantification of HCV RNA (alternatively a plasma or serum sample may be frozen for possible subsequent testing at week 12).

• Liver biopsy to evaluate the need for therapy, especially for HCV genotype 1 infected patients. If laboratory, radiologically, endoscopically, or clinically obvious cirrhosis is present, a liver biopsy is not warranted.

• Additional analyses including anti-HIV, hepatitis B surface antigen (HBsAg), anti-HBs, anti-HBc IgG, anti-HAV IgG, haemoglobin, white blood cells (WBC) with differential count, platelets, serum albumin, prothrombin time (PK-INR), serum creatinine, creatinine clearance, aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase, serum bilirubin, immunoglobulin G (IgG), antinuclear antibodies (ANA), smooth-muscle antibodies (SMA), antimitochondrial antibodies (AMA), thyroid stimulating hormone (TSH), thyroxin, and serum uric acid.

Monitoring of liver elasticity (FibroScan), possibly in combination with fibrosis markers in peripheral blood, may in the future become an alternative to conventional liver biopsies, in order to exclude significant fibrosis or to diagnose cirrhosis.

Prior to initiation of treatment, it is essential that patients are well informed about possible adverse events and the importance of adherence to therapy.

Treatment recommendations for adult patients

Treatment of acute hepatitis C

Therapy should be initiated in symptomatic patients if HCV RNA remains detectable 3 months after the first appearance of symptoms [5]. Delaying treatment initiation beyond 12 weeks will decrease the likelihood of SVR. Patients with asymptomatic acute HCV infection seldom clear their infection spontaneously; hence, treatment upon detection is recommended.

Monotherapy with pegylated interferon (peg-IFN) is recommended, either with peg-IFN α-2a (40 kDa) 180 µg/week or with peg-IFN α-2b (12 kDa) 1.5 µg/kg body weight per week during 24 weeks [13]. A shorter treatment duration may be considered for patients infected with HCV genotypes 2 and 3 with a rapid viral response (RVR), i.e. undetectable HCV RNA at treatment week 4 [14].

Treatment of chronic hepatitis C: treatment naïve patients

Results reported from pivotal clinical trials evaluating HCV treatment with peg-IFN and ribavirin combination therapy are presented in Table II, [15–17]. Factors associated with a less favourable response include infection with HCV genotype 1, high body weight, increasing age, significant liver fibrosis, and a high pretreatment viral load [18]. For peg-IFN α-2a, the impact of varying treatment duration and ribavirin dose has also been studied (Table III).

Table II.  Sustained virological response (%) after combination therapy with pegylated interferon (peg-IFN) and ribavirin or IFN and ribavirin: results from 2 randomized, controlled 48-week trials.

	Peg-IFN α-2b vs IFN^a		Peg-IFN α-2a vs IFN^b
	Peg-IFN α-2b	IFN α-2b	Peg-IFN α-2a	IFN α-2b
	1.5 µg/kg/week	3×10^6 U 3 times weekly	180 µg/week	3×10^6 U 3 times weekly
	+ ribavirin	+ ribavirin	+ ribavirin	+ ribavirin
	800 mg	1000–1200 mg	1000–1200 mg	1000–1200 mg
	(n =511)	(n =505)	(n =453)	(n =444)
All	54	47	56	44
Genotype 1	42	33	46	36
Genotype 2/3	82	79	76	61
Genotype 4/5/6	50	38	77	36

^aManns et al. Lancet 2001;358:958–65. ^bFried et al. N Engl J Med 2002;347:975–82.

Table III.  Sustained virological response (%) after combination therapy with pegylated interferon α-2a (peg-IFN α-2a) and ribavirin, grouped according to treatment duration and ribavirin dose.

	Peg-IFN α-2a (180 µg/week, 24 weeks)		Peg-IFN α-2a (180 µg/week, 48 weeks)
	Ribavirin 800 mg (n =207)	Ribavirin 1000-1200 mg (n =280)	Ribavirin 800 mg (n =361)	Ribavirin 1000-1200 mg (n =436)
Genotype 1	29	41	40	51
Genotype non-1	78	78	73	77

Modified from Hadziyannis et al. Ann Intern Med 2004;140:346–55.

Based on these pivotal studies, combination therapy with peg-IFN and ribavirin is recommended as standard treatment with the doses suggested for HCV genotype 1 in Table IV. Several as yet unpublished studies have compared the efficacy of peg-IFN α-2a (40 kDa) and peg-IFN α-2b (12 kDa) head-to-head, but conclusive data are currently lacking.

Table IV.  Recommended treatment doses.

	Genotype 2 or 3
Genotype 1 or 4	12-16 weeks treatment duration	24 weeks treatment duration
Peg-IFN α-2a 180 µg/week and Ribavirin 1000 mg daily if <75 kg and 1200 mg if ≥ 75 kg	Peg-IFN α-2a 180 µg/week	Peg-IFN α-2a 135 µg/week
or	or	or
Peg-IFN α-2b 1.0–1.5^a µg/kg/week, and ribavirin 800 mg daily if 40–64 kg, 1g if 65–85 kg, 1.2 g if 86–105 kg, and 1.4 g if >105 kg	Peg-IFN α-2b 1.5 µg/kg/week in combination with Ribavirin 800 mg daily^b	Ribavirin 800 mg daily^b

^aWhen analysing the total study population, both doses of Peg-IFN α-2b gave similar SVR in the IDEAL study.

^bPost -hoc analysis of several studies indicate that a weight based dosing of ribavirin (≥11 mg/kg body weight daily) may result in improved outcome.

For patients infected with genotype 1, the standard treatment duration is 48 weeks [16]. However, in patients with a rapid decline in viral load as manifested by undetectable HCV RNA after 4 weeks of therapy (RVR), treatment duration can be shortened to 24 weeks, especially when HCV RNA levels at baseline are below 600,000 IU/ml (Table V) [19–22]. For patients who have detectable HCV RNA after 12 weeks treatment but a ≥ 2 log₁₀ reduction from baseline (pEVR), prolonged treatment to 72 weeks should be considered, provided that HCV RNA is undetectable at week 24 [23].

Table V.  Recommended treatment duration.

Virological response	Definition	Genotype 1 or 4	Genotype 2 or 3
vRVR	HCV RNA < 1000 IU/mL d 7		12–16 weeks^a
RVR	HCV RNA undetectable^b week 4	24 weeks	24 weeks
cEVR	HCV RNA undetectable^b week 12	48 weeks	≥24 weeks
pEVR	HCV RNA ≥2 log10 reduction week 12	consider 72 weeks	consider ≥48 weeks

Patients not achieving pEVR or having detectable HCV RNA after 24 weeks of therapy should discontinue treatment.

^aIf dose reductions have been avoided and RVR is also achieved. ^bLimit of detection of HCV RNA analysis ≤15 IU/ml.

In the IDEAL study, comparing peg-IFN α-2b (12 kDa) 1.0 and 1.5 µg/kg body weight per week in combination with ribavirin for HCV genotype 1 infected patients, there was no major difference in SVR rate between these 2 groups [24].

For patients infected with genotypes 2 or 3, the standard treatment duration is 24 weeks [16]. A lower dose of peg-IFN (peg-IFN α-2a 135 µg/week or peg-IFN α-2b 1.0 µg/kg body weight per week) may be given in combination with ribavirin 800 mg daily (Table IV) [25], [26]. A higher weight based dosing of ribavirin (≥11 mg/kg) may result in improved response rates [27].

Table VI.  Recommended start doses for ribavirin in patients with renal impairment according to creatinine clearance in a patient weighing 70 kg.

Creatinine clearance (ml/min)	80	60	40	20
Ribavirin start dose (mg/d)	800	600	400	400 three times weekly

Modified from Bruchfeld et al. Therapeutic Drug Monitoring 2002;24:701–8.

For genotype 2 and 3 infected patients with a very rapid viral response (vRVR), i.e. HCV RNA below 1000 IU/ml at d 7 prior to the second peg-IFN dose, treatment duration may be shortened to 12–16 weeks, provided that dose reductions can be avoided [28], [29]. Patients with detectable HCV RNA at week 4, but undetectable at week 12 (cEVR), have a lower SVR rate when treated for 24 weeks than those who have achieved negative HCV RNA already at week 4. It is uncertain if extended treatment duration is of benefit in this situation. However, prolonging treatment beyond 24 weeks may be considered.

Patients infected with HCV genotype 4 should be treated in the same way as patients infected with genotype 1 [19], [30]. The same applies for patients infected with the less common genotypes 5 and 6.

Generally, patients should be encouraged to abstain from alcohol while on therapy since alcohol is assumed to impair outcome [31].

If ribavirin is contraindicated, monotherapy with peg-IFN during 48 weeks is recommended. When IFN is contraindicated, no therapeutic alternatives are currently available.

Retreatment of chronic hepatitis C: patients with relapse or non-response to previous interferon monotherapy

Patients with relapse after prior monotherapy with IFN achieve similar SVR rates with peg-IFN and ribavirin combination therapy as do treatment naïve patients [32]. Patients with a previous non-response, however, have a less favourable outcome (SVR 10–15%) than patients with prior relapse. In spite of this, treatment with current combination therapy should be considered in these patients [33], [34].

Retreatment of chronic hepatitis C: patients with relapse or non-response to previous IFN or peg-IFN and ribavirin combination therapy

For patients with relapse or non-response to previous combination therapy, decisions regarding retreatment should be based on the degree of optimization of the initial therapy, adherence, and the type of response achieved. In general, higher response rates are noted among relapsers than non-responders, patients with non-significant fibrosis, and patients infected with genotype 2 or 3 [35], [36]. The best outcome is seen among previous relapsers with mild fibrosis infected with HCV genotype 2 or 3 (≈50% SVR), and the worst among prior non-responders infected with genotype 1 with advanced fibrosis (≈5% SVR). Adherence often needs to be improved and treatment duration extended if SVR is to be achieved.

Treatment of chronic hepatitis C: patients with cirrhosis

Data concerning the efficacy and risks of treatment of patients with compensated cirrhosis (Child-Pugh A) are limited, but reports indicate a generally poorer outcome than among non-cirrhotic patients [37–39]. Dose comparisons among patients with cirrhosis are lacking for peg-IFN α-2a. However, for peg-IFN α-2b, a subgroup analysis of the IDEAL study showed significantly better outcome among genotype 1 infected patients with compensated cirrhosis following therapy with an initial dose of 1.0 µg/kg body weight/week compared to 1.5 µg/kg body weight/week [24]. This difference, however, may have been exaggerated due to baseline imbalances between treatment groups.

Decompensated cirrhosis (Child-Pugh B-C) constitutes a relative contraindication to peg-IFN and ribavirin combination therapy [40]. Patients with a prior history of decompensation should only be considered for therapy under special circumstances. If treatment is conducted, this should be performed together with a liver transplant centre [39].

Maintenance therapy with low dose interferon as a preventive measure against fibrosis progression is not generally recommended.

Cirrhotic patients achieving SVR following therapy should continue to be monitored regularly because of the remaining risk of developing hepatocellular carcinoma (HCC). Possible exceptions are patients demonstrating marked regression of liver fibrosis after achieving SVR. The risk of developing HCC is considerably reduced if SVR is achieved.

Treatment of chronic hepatitis C: patients with renal impairment

Interferon treatment is contraindicated in renal transplant patients. Hence, antiviral therapy should be considered prior to kidney transplantation.

Peg-IFN α-2a is the recommended fist line treatment of patients with renal impairment. A standard dose regimen can be used in patients with creatinine clearance (CrCL) above 20–40 ml/min, whereas in patients with advanced renal disease undergoing haemodialysis, doses exceeding 135 µg/week should be avoided. Peg-IFN α-2b should only be used with great caution, and in reduced doses in patients with CrCL below 50 ml/min.

Ribavirin was previously contraindicated if CrCL was below 50 ml/min, due to the risk of accumulation and the consequent risk of severe side-effects, particularly anaemia. Limited data are available on treatment with interferon and ribavirin in patients with renal impairment and in those undergoing haemodialysis. In these settings, ribavirin should only be used with markedly reduced initial doses (Table VI). Furthermore, ribavirin plasma levels and serum haemoglobin should be closely monitored. Ribavirin induced anaemia can be treated with erythropoietin.

Table VII.  Contraindication to combination therapy with peg-IFN and ribavirin.

Absolute contraindications	Pregnancy^a, decompensated cirrhosis (interferon), autoimmune hepatitis (interferon), solid organ transplant excluding liver (interferon), severe anaemia (ribavirin), hypersensitivity to interferon or ribavirin, children below 3 y of age (peg-IFN α-2a due to bensylalcohol additive).
Relative contraindications	Depression or over-serious psychiatric disorder, seizures, cardiac disdease, anaemia (<100 g/l), neutropenia (<0.75×10^9/l), thrombocytopenia (<50×109/l), haemoglobinopathy (ribavirin), renal impairment (see text), suboptimally treated thyroid disease, suboptimally treated diabetes mellitus, other automimmune disease, psoriasis, sarcoidosis, ongoing or recent illicit drug use.

^aContraception for all patients is important through therapy, and 4 months after for female patients and their partners; and 7 months after for male patients because of the teratogenic effect of ribavirin.

Clearance of ribavirin is strongly dependent on renal function. Consequently ribavirin should primarily be dosed based on renal function rather than based on body weight.

Antiviral therapy for HCV in patients with renal disease and CrCL below 50 ml/min should only be initiated and managed in close collaboration with experienced physicians.

Contraindications and side-effects

Contraindications for combination therapy with peg-IFN and ribavirin are listed in Table VII, and drug-related adverse reactions are numerous as previously reported [7]. The safety profiles of peg-IFN α-2a and α-2b are comparable. In general, 15% of patients discontinue combination therapy due to adverse events, and in 20% of patients dose reductions are required, most frequently due to anaemia or neutropenia.

Severe psychiatric and central nervous system side-effects, particularly depression, behavioural changes, suicidal ideation, and attempted suicide have been observed in some patients during peg-IFN therapy as well as after treatment discontinuation (mainly during the 6-month follow-up period). Therefore, patients should be closely monitored for signs and symptoms of psychiatric disorders. If severe symptoms appear, discontinuation of combination therapy is recommended and psychiatric consultation should be undertaken. Anti-depressive therapy should be considered in cases of mild depression and, if commenced, be continued throughout the course of antiviral therapy.

Multidisciplinary teams including infectious disease specialists, psychiatrists, nurses, social workers, and dietitians should be used to increase adherence to antiviral therapy and ensure a favourable outcome.

Monitoring and dose adjustments

The recommended basal monitoring of clinical, virological, and laboratory events during therapy, as outlined in Table VIII, may need to be adjusted in patients with other underlying illnesses, e.g. HIV coinfection, diabetes mellitus, or renal impairment.

Table VIII.  Basic monitoring during combination therapy.

HCV RNA quantification	D 7 (i.e. just prior to 2nd dose of peg-IFN for genotypes 2/3), weeks 4, 12, 24, end of treatment, and 2 independent samples ≥6 months after discontinuation of therapy.
Physical examination (including weight)	Every third month
Haemoglobin, WBC neutrophil count, platelet count	Weeks 1, 2, 4, and thereafter at least every 4th week
ALT, serum bilirubin	Every 4th week
TSH, thyroxin	Every 3rd month and 6 months after discontinuation of therapy

A trained nurse should conduct the monitoring during combination therapy in close contact with the patients and the treating physician. Clinical examination of the patients is recommended every third month.

Monitoring of HCV RNA

The virological response should be regularly monitored (at baseline, during and after treatment) using a highly sensitive method (i.e. with a limit of detection of ≤ 15 IU/ml). Suggested time-points for serum or plasma sampling are listed in Table VIII.

Monitoring of ribavirin concentrations

It is presently unclear whether concentration-guided dosing of ribavirin improves outcome. Similarly, the impact of measuring concentrations on the occurrence of adverse events has not been established. Thus, routine monitoring of ribavirin concentration during combination therapy cannot currently be recommended.

However, concentrations of ribavirin should be obtained if pharmacokinetics is likely to be altered and if adequate dosing is unclear, e.g. in patients with renal impairment or with significantly deviating body size. Samples should be taken as trough levels (i.e. at the end of a dosing interval, just prior to the next dose). In the absence of validated data linking concentration to effect, the ribavirin levels reached under normal pharmacokinetic conditions are recommended as targets.

At steady state, which occurs after more than 4 weeks of treatment in patients with normal renal function, a trough ribavirin concentration of 2–3 mg/l (8–12 µmol/l) is generally achieved when weight based dosing of ribavirin (1000–1200 mg daily) is employed [41], [42]. In patients with impaired renal function, the half-life of ribavirin is prolonged, and therefore also the time to steady state, which may be several months in the presence of severely impaired renal function [43]. This must be taken into consideration when interpreting plasma concentrations.

Dose adjustments due to side-effects

Dose reductions are likely to impair the SVR rate less than temporary withdrawals. Therefore, temporary cessations, particularly for peg-IFN, should be avoided if possible.

Dose adjustments due to neutropenia and/or thrombocytopenia

In pivotal trials for peg-IFN α-2a and α-2b, the following guidelines for dose reductions were applied: 1) in the event of neutrophil count declining to 0.5–0.75 × 10⁹/l or the platelet count to 25–50×10⁹/l, the peg-IFN dose was reduced by 50–75%. When the neutrophil count fell to ≤0.5×10⁹/l or the platelet count to ≤25×10⁹/l, peg-IFN was temporarily withdrawn. In clinical practice, full doses of peg-IFN have been continued at lower neutrophil and platelet counts than the above-mentioned guidelines, and thus dose reductions should be determined on an individual basis.

Dose adjustments due to anaemia

Ribavirin doses have generally been reduced if haemoglobin decreases to 85–100 g/l and temporarily withdrawn when below 85 g/l. Ribavirin concentrations, however, have a great impact on outcome of therapy. To avoid large dose reductions or temporary withdrawals, an early drop in haemoglobin (>20–30 g/l during the first 2–3 weeks of treatment) should prompt a reduction of the ribavirin dose by 200 mg. In risk patients, e.g. those with coronary artery disease, ribavirin dose reduction should be considered at an earlier stage. Haematopoietic growth factors (e.g. erythropoietin) may be administered to minimize the need for dose reductions.

The use of haematopoietic growth factors

Erythropoietin is recommended for patients who develop significant anaemia, in order to minimize the need for dose reductions of ribavirin. This is of particular importance in patients who have negative prognostic factors at baseline [44–46]. By ‘significant anaemia’ is meant haemoglobin levels below 100 g/l, a severe and rapid reduction in haemoglobin levels, and/or symptomatic anaemia. Erythropoietin is also recommended for patients at increased risk of developing significant anaemia, i.e. patients receiving high-dose regimens of ribavirin and patients with renal impairment or solid organ transplants. In these patient groups, erythropoietin should be started a few weeks prior to initiation of antiviral therapy for HCV, due to the 2-week delay in the haemoglobin enhancing effect.

Currently there is no approved dose of erythropoietin licensed for treatment during antiviral therapy for HCV. Erythropoietin 10,000–40,000 IE subcutaneously per week has been used, and it is likely that darbepoetin-α given at equivalent dosages has a similar effect [47].

Prior to the initiation of erythropoietin therapy, contraindications as well as rare serious adverse effects such as pure red cell aplasia (PRCA) and thromboembolic complications should be considered.

Owing to the limited experience with the use of growth factors for neutropenia [48] and thrombocytopenia [49], no general recommendation is currently warranted

Thyroid dysfunction during therapy

Approximately 5% of patients develop thyroid dysfunction during antiviral therapy, usually in the form of hypothyroidism. In the event of hypothyroidism, combination therapy for HCV can often be continued with the addition of substitution treatment. Hypothyroidism is occasionally reversible after cessation of antiviral therapy. If hyperthyroidism develops consultation with an endocrinologist is warranted.

Post-therapy follow-up

HCV RNA should be evaluated at the end of treatment (EOT). Patients with undetectable HCV RNA at this time-point should be monitored with ALT after 1 and 3 months. If increased serum transaminase levels are noted, HCV RNA should be measured. Otherwise HCV RNA should be monitored 6 months after the discontinuation of combination therapy, and at 1 additional time-point. If HCV RNA remains undetectable during the follow-up, the HCV infection is considered resolved. Anti-HCV antibodies, however, remain detectable. Therefore, patients are not accepted as donors of blood or solid organs. Patients should also be informed that they are not immune to reinfection with HCV.

Children with chronic hepatitis C

The prevalence of HCV among European children is less than 0.5% [50], whereas up to 10% has been reported for parts of Africa [51]. Approximately 200 children with HCV born 1990 or thereafter have been registered in Sweden. In light of the expected number of cases of vertical transmission from mother to child [52], it is likely that this represents an underestimate of the true prevalence among Swedish children.

Children infected with HCV have few if any symptoms. The chronicity rate among children (55–80%) is similar to that in adults, but spontaneous resolution of the infection may occur.

Pretreatment analyses and decision-making regarding treatment

The same criteria apply for the diagnosis of HCV infection in children as in adults. However, serological evaluations early in life are often hampered by the persistence of maternal antibodies until 15 months of age. Therefore, serological sampling at 18 months is recommended for the screening of children born to HCV infected mothers. Children with verified chronic HCV should be monitored annually for HCV RNA and liver function tests.

When considering antiviral therapy, the same contraindications apply for children as for adults [53], [54]. Due to the risk of interferon induced growth retardation [55], treatment is not recommended during periods of intense growth, i.e. before the age of 3 y and during puberty [56]. A prerequisite for initiation of antiviral therapy is the presence of a well-motivated family where the child can receive adequate support.

If contraindications are lacking, therapy is recommended during early school age. Considering the potential serious long-term prognosis and favourable outcome following therapeutic intervention, treatment should be considered in all children infected with HCV genotypes 2 or 3. For children infected with genotypes 1 or 4, only half of whom achieve SVR following combination therapy, a liver biopsy may be helpful to select patients deemed appropriate for treatment.

Choice of therapy

Paediatric clinical trials report overall SVR rates of approximately 50%, with 80% noted for genotype 2 and 3 infections. Therapy with peg-IFN and ribavirin in children has not been demonstrated to be more efficacious than conventional IFN and ribavirin. However, considering the need for fewer injections, peg-IFN is preferred in paediatric patients. The approved dose of ribavirin is 15 mg/kg/d administered orally daily in 2 divided doses. Currently there is no approved dose for peg-IFN in children. Based on published results from clinical trials, the recommended dose for peg-IFN α-2a is 100 µg/m²/week subcutaneously. Peg-IFN α-2b in combination with ribavirin has been evaluated in 2 separate paediatric clinical trials using doses of 1.0 and 1.5 µg/kg/week subcutaneously, with no obvious difference in treatment response.

Pretreatment testing and monitoring during therapy are similar to those recommended for adults with the addition of registration of length and weight at each sampling time-point. Currently the predictive value of HCV RNA determination after 4 weeks of therapy in children is unknown. Therefore, the recommended treatment duration for genotypes 1 and 4 is 48 weeks, and for genotypes 2 and 3, 24 weeks.

Decisions regarding treatment should be performed in close collaboration with paediatric centres experienced in the treatment of children with chronic HCV infection.

Coinfection with hepatitis C and HIV

Due to the improved and highly effective antiretroviral therapy (ART) for HIV, complications from HCV coinfection have emerged as a major cause of morbidity and mortality among HIV infected patients [57], [58]. In Sweden, 15% of HIV patients are coinfected with HCV.

Treatment of HCV in HIV infected patients should be a collaborative effort between physicians familiar with treatment of the respective infections.

Which patients should be treated and when?

The same recommendations regarding indications and contraindications apply for patients coinfected with HIV as for HCV mono-infected patients. Similarly, the same baseline parameters (i.e. genotype, baseline viral load, fibrosis stage) affect therapeutic outcome [59].

Ideally, antiviral therapy for HCV should be initiated prior to ART being indicated. A prerequisite, however, is that combination therapy for HCV will be completed before the patient's immune status warrants the introduction of ART. With improved knowledge of drug-drug interactions, concomitant treatment of both viral infections is generally no longer problematic.

Patients with ongoing ART should have stable HIV treatment and preferably have undetectable plasma HIV RNA levels when combination therapy for HCV is initiated. Also, certain antiretroviral agents should be avoided (listed below) so as not to impair the therapeutic outcome for HCV.

CD4 cell counts do not impact on outcome of therapy for HCV genotypes 2 or 3 [60]. In contrast, for patients coinfected with genotype 1, SVR rates are probably somewhat lower when low CD4 cell counts are present [61]. However, a low CD4 cell count, in spite of lengthy and successful inhibition of HIV replication, is not a contraindication for HCV combination therapy.

Preparations prior to therapy

With regard to mono-infected HCV patients, a biopsy is generally recommended for patients infected with HCV genotype 1, but is less important for those infected with genotypes 2 or 3.

The following concurrent HIV medications should be avoided during HCV combination therapy, and adjustment of ART should be performed well in advance of initiating HCV treatment:

• Zidovudine: the risk of developing anaemia from ribavirin is markedly increased when used concurrently with zidovudine [62].

• Didanosine: the risk of developing lactic acidosis is increased if didanosine is given simultaneously with ribavirin [63], [64].

• Abacavir: several studies have reported poorer outcome of HCV treatment following concurrent therapy with abacavir [65]. Both abacavir and ribavirin are guanosine analogues and thus intracellular interference may result in lower levels of the active phosphorylated moiety.

• Atazanavir: increased risk of developing manifest icterus [66]; ribavirin may cause haemolysis and atazanavir inhibits the conjugation of bilirubin.

Treatment

Duration

The same stopping rules, if adequate response is not achieved, apply to coinfected patients as for HCV mono-infected patients For patients infected with HCV genotype 1, 48 weeks of combination therapy is recommended even if HCV RNA is undetectable at week 4 (RVR) [67]. In genotype 1, infected patients with detectable HCV RNA at week 12, but not at week 24 (pEVR), extended treatment duration to 72 weeks should be considered, although the prospect of achieving SVR is relatively low. For patients infected with HCV genotypes 2 or 3 who achieve RVR, 24 weeks of combination therapy is recommended, while 48 weeks should be considered for those not achieving RVR [67].

Dosing

Peg-IFN α-2a 180 µg/week or peg-IFN α-2b 1.5 µg/kg/week in combination with ribavirin 1000 mg daily if <75 kg, or 1200 mg daily if ≥75 kg, is recommended regardless of genotype. In the event of side-effects, reducing peg-IFN α-2a to 135 µg/week or peg-IFN α-2b to 1.0 µg/kg/week probably has a minor impact on outcome. However, an adequate ribavirin exposure is important for successful outcome [68], and is a prerequisite for 24 weeks of therapy (i.e. for patients infected with genotypes 2 or 3) [67]. Hence, dose reductions for ribavirin should be avoided as far as possible and, if needed, erythropoietin should be considered to maintain adequate doses.

Monitoring

HCV therapy does not adversely affect the virological control of HIV regardless of whether or not ART is ongoing. On the contrary, in patients without ongoing ART, lower HIV RNA levels are often detected during HCV therapy. During peg-IFN therapy the absolute number of CD4+ T-cells generally decreases. This, however, does not entail impaired immune function; the CD4+ percentage remains unchanged or somewhat increased. Thus, routine monitoring of HIV RNA and T-cell count every 4–6 months is recommended in addition to the same on-treatment HCV monitoring as for non-HIV infected patients.

Retreatment of coinfected patients with previous relapse or non-response

There have been no specific studies addressing this issue. Therefore the same recommendation as for HCV mono-infected patients apply.

Chronic hepatitis C and liver transplantation

The evaluation prior to liver transplantation should include HCV genotyping, HCV RNA quantification, as well as an ultrasound examination with contrast enhancement, CT or MRI, to screen for hepatocellular carcinoma (HCC).

Combination therapy prior to liver transplantation

The possibility of initiating HCV therapy prior to liver transplantation should be discussed with the transplant centre. This is primarily an option for patients with HCC and Child-Pugh A cirrhosis, with the goal of achieving undetectable HCV RNA prior to liver transplantation.

Combination therapy after liver transplantation

Patients with detectable HCV RNA prior to liver transplantation universally remain viraemic after transplantation [69]. Currently, no studies indicate that early HCV treatment, so-called pre-emptive therapy, prevents histological recurrence [70]. Therefore, it is recommended that combination therapy for HCV should only be initiated following histological evidence of recurrence. To this end, annual protocol liver biopsies should be undertaken, and thus the first decision with regard to therapy should follow the liver biopsy 1 y post-transplant (or earlier in the event of clinical signs of recurrence).

Adherence to therapy is often poor post-transplant, due to considerable side- effects. However, if adherence can be maintained, similar treatment outcome as in non-transplanted patients may be expected, i.e. patients infected with HCV genotypes 2 or 3 generally having more favourable outcomes than those infected with genotypes 1 or 4 [71].

Treatment recommendations

Combination therapy with peg-IFN and ribavirin should be given for 48 weeks in patients infected with genotypes 1 or 4, and for 24 weeks in patients infected with genotypes 2 or 3. The need for dose reduction due to renal impairment is less for peg-IFN α-2a than for peg-IFN α-2b. The tolerability of ribavirin varies in this group of patients, and thus commencing therapy with erythropoietin 2 weeks prior to initiation of antiviral treatment is warranted. The same monitoring of HCV RNA as for non-transplanted patients should be undertaken. If HCV RNA remains detectable after 12 weeks of therapy, the likelihood of a favourable outcome after 48 weeks of therapy is poor. Therefore, discontinuation of therapy should be considered [72].

New options in treatment of hepatitis C

Currently available therapy is insufficient, especially for patients infected with HCV genotype 1. Thus, there is an unmet need for new treatment options. Although much remains to be elucidated regarding the modes of action of peg-IFN and ribavirin, both appear to have direct antiviral effects in addition to immunomodulating properties. Most new drugs under development (e.g. protease and polymerase inhibitors) directly target specific viral proteins. Numerous such agents are now undergoing phases I through III clinical trials, but pending their possible licensing, improved outcome as well as reduction in cost may be achieved through continued efforts to optimize current combination therapy.

Optimizing current combination therapy

Optimizing the use of peg-IFN and ribavirin can in part be accomplished by individualized dosing. Adjustment of the treatment according to the early virological response is of great importance. The shortening of duration to 24 weeks for HCV genotype 1 infected patients who achieve RVR was a first step in this direction. There is also evidence supporting that extension of the treatment duration to 72 weeks for patients with genotype 1 and a slow viral response will increase the response rate.

Another approach to further refine and individualize the treatment duration would be to utilize early viral kinetic data, to calculate the decay of viral levels, i.e. the slope by which viral levels decline. This information can be used to calculate the time-point when serum HCV RNA levels will become undetectable and the appropriate duration of treatment needed in the individual patient.

Response-guided therapy is appealing, since predictive factors at baseline (age, fibrosis stage, and baseline HCV RNA level) all have an impact on viral kinetics and are integrated in the kinetic response. For example, a rapid decline in HCV RNA levels in an elderly patient with advanced fibrosis indicates that a shorter-than-standard duration of therapy may be used in spite of otherwise unfavourable predictive factors for a treatment response. In genotype 1 infection, sampling after 2, 3, and 4 weeks gives an appropriate estimation of the slope for the HCV RNA level decline. For genotypes 2 or 3, sampling after 7 and 14 d is more optimal since the majority of patients will have undetectable HCV RNA already after 4 weeks treatment.

New drugs under development

The specifically targeted antiviral therapies for HCV (STAT-C) that are furthest in development are protease inhibitors. Although these have shown great potency as antiviral agents, their use in monotherapy is associated with rapid selection of resistant variants. Thus, they need to be used in combination with other antiviral agents. Phase III trials of protease inhibitors are being conducted in combination with peg-IFN and ribavirin. Currently available data show substantially increased SVR rates in patients with genotype 1 virus [73–75]. Also in patients with previous non/null response to present standard of care, preliminary data are promising, although response rates are lower than in previously treatment-naïve patients or relapsers [76]. In patients failing therapy including protease inhibitors, resistant variants are generally found. The long-term consequences of these, e.g. for future treatment attempts, are presently not fully elucidated.

No clinical data have yet been reported using combinations of new antiviral agents. However, in vitro data are encouraging, with no development of resistance when combinations of protease and polymerase inhibitors are utilized.

In conclusion, several new STAT-C drugs are under development and undergoing phases I through III trials. Thus, in the y to come, the paradigm of hepatitis C treatment is likely to change, with more potent therapies available, particularly for patients with genotype 1 infection.

Acknowledgements

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.