A Brief Look At HCV Biology Essay

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Hepatitis C virus (HCV) is a serious RNA viral infection that is transmitted through the blood and affects millions of people in Western countries, as well as high numbers in developing countries. As the name suggests HCV affects hepatocytes in the main, which leads to issues with viability of those liver cells. The presence of HCV within the body generates an immunological response with interferons being produced in response to HCV RNA 1 p3. Unfortunately the HCV RNA replicase is very error prone, meaning that the virions are able to evade both innate and adaptive host immune responses in many instances as their genetic diversity and profile is such that they can present a different structure to the immune regulators. Further the HCV also acts to disrupt the intracellular pathways that activate interferon synthesis and blocks the actions of induced antiviral molecules. All this means that, whilst the virus can spontaneously clear from the body, in the majority of cases it is not, which allows for persistent infection.

HCV remains asymptomatic for many years after infection so it is very difficult to know whether an individual has the virus unless a specific biological marker is looked for, or their disease has progressed such that liver damage has occurred. There are recognized risk factors for the transmission of HCV and these focus on activities in which blood products can be exchanged, so intravenous drug use is a significant risk factor, and indeed the source of the majority of infections within countries such as the US. It is possible, and indeed recommended, to screen individuals at risk, but due to issues relating to quality of life and the need for treatment if a positive diagnosis is achieved, a more widespread screening programme is not appropriate.

The virus is responsive to medication and interferon  medication was introduced at the end of the last century to target the gene transcripts that are responsible for the replication of the virus. The response of the host to interferon  therapy involves interferon stimulate genes being expressed with those who has a rapid response to treatment having a greater increase in gene expression than those who has a slow response 1p10. Slow responders, by contrast have a greater increase in interferon inhibitory pathways. Interferon  therapy has been modified to include ribavirin and this improves treatment outcomes by enhancing hepatic gene response to the interferon. Ribavirin produces both an improvement in the sustained virological response as well as reduced any subsequent relapse. Modification of interferon  has also given rise to the pegylated interferon  drugs and this is the main focus of the pharmacological results within this review.

Aims and Objectives

To assess the clinical and safety effectiveness of pegylated interferon in combination with ribavirin in the treatment of chronic hepatitis C through the analysis of randomized clinical trials that have been identified as high quality. The comparator is the dual therapy with non-pegylated interferon and ribavirin. Given that the pegylated form of interferon represents a significant clinical cost, there has also been an effort to assess cost-effectiveness of the various treatment regimens. In particular attention has been paid to the relative cost attached to quality of life scores. Chronic hepatitis C infection, once symptomatic, has a significant impact upon the quality of life of the patient, which can also increase the healthcare burden. By calculating the quality of life years it can be seen what kind of effect the treatment has on the individual's life as well as the time in each health state.

The other strand of the research has been to assess the relative effectiveness of the two forms of peginterferon with ribavirin. Therefore randomized clinical trails, as well as other relevant literature have been assessed to see whether there is any difference in the efficacy and clinical profile of the twp pegylated interferons.

Background

Description of underlying health problem

Hepatitis C virus (HCV) is a blood-borne viral infection 2p351 that was discovered in 1989, and is capable of causing a chronic, long lasting viral infection 3pS11. HCV is the most common blood-born pathogen worldwide 4 p517 and as such is a major public health issue. Viral replication relies on the HCV encoded serine protease NS3•4A 5p164. Interferons are naturally occurring cytokines that have a broad spectrum of antiviral, antitumour and immunomodulatory properties 6p10634. Type I interferons exert their effects via direct interaction with their specific receptor and initiate a cascade of J-kinase mediated events that leads to changes in the expression of gene transcripts 7p204-5. Due to its blood borne nature HCV can be passed on through unscreened blood donations, mother to infant transmission, as well as through intravenous drug usage or other non sterile needle usage 2p351. Injection drug use is the most common method of transmitting HCV in the Unites States 8p1147, meaning anyone who has injected drugs at any stage may be at risk of having contracted the virus. Affected individuals are recommended not to share personal items including toothbrushes and razors with unaffected people 9p500. Similar risk factors can be found in more than 90% of patients under careful questioning 8p1147, showing that there are common and consistent risk factors, as shown below:

Persons who have injected illicit drugs in the recent and remote past, including those who injected only once and do not consider themselves to be drug users

Persons with conditions associated with a high prevalence of HCV infection, including:

Persons with HIV infection - Persons with hemophilia who received clotting factor concentrates before 1987

Persons who were ever on haemodialysis

Persons with unexplained abnormal aminotransferase levels

Prior recipients of transfusions or organ transplants, including:

Persons who were notified that they had received blood from a donor who later tested positive for HCV infection

Persons who received a transfusion of blood or blood products before July 1992

Persons who received an organ transplant before July 1992

Children born to HCV-infected mothers

Health care, emergency medical and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood

Current sexual partners of HCV-infected persons 8table 2

There is a known association between hepatitis C virus and hepatocellular carcinoma, with chronic HCV being the single most important risk factor for the development of liver cancer 10p928 and 2-4% of patients with cirrhosis developing carcinoma each year 11p1154. HCV is also the commonest indication for liver transplantation 12p958 and the greater overall demand for liver transplantation in the future means that there will be grossly insufficient organs available 4p517. However, whilst 85% of acutely infected patients develop chronic HCV, the majority do not develop end stage liver disease 11p1154 but 5-20% develop cirrhosis within 20 years 8p1151. This cirrhosis / carcinoma and end stage liver failure is the condition in which a transplant would be needed if death is to be averted 4p517. The disease transition is illustrated in figure 1 as a Markov model.

Figure 1 State transition model of HCV disease progression 13 figure 1

Incidence and prevalence

1997 epidemiology data indicated that 4 million people in the USA, 5 million in Europe and 170 million people worldwide were affected by HCV 14p1426, with this worldwide figure remaining the cited amount15. Higher rates of infection are found in parts of Eastern Europe, Africa and particularly Eqypt 2p351, with the latter having 6-28% prevalence 16p17. The global prevalence of HCV infection is around 3%, but there are marked geographical variations 17p568. Unfortunately there are no passive or active vaccines for HCV 18p897 is removing the virus post infection is the only option. The National Institute for Clinical Excellence (NICE) puts the prevalence of HCV in England and Wales as between 200,000 and 400,000 19 p7. HCV prevalence is higher amongst promiscuous individuals and sexual transmission between monogamous partners is rare 8p1147. Likewise individuals with risk factors as detailed above can have a prevalence rate many times that of the average with homeless and incarcerated people, for instance, having a 40% prevalence and haemophiliacs (who must have received blood products within their own treatment regime) can have a 90% prevalence 4p517. 17% of deaths due to HCV in an Australian study occurred within the first 6 months after diagnosis 20p940, and the age and standardized mortality rates from that study are shown in figure 2 below.

Figure 2 Incidence of liver related (blue) and drug related (red) deaths (left) and standardised mortality rates (right) by age group adapted from 20figures 1 and 2

What is also important to consider is the incidence of genotype variants for HCV, as these also show a geographical variation as well as an overall difference in their prevalence and the effect that has on the disease. There are 6 known genotypes, numbered 1-6, with the most prevalent worldwide being genotype 1, although there are also sub-variants of genotype 1, in 1a and 1b 17p569. The genotype makes little difference to the outcome of the infection but does affect treatment response and treatment duration 8 p1150. Treatment duration is shorter for genotypes 2 and 3 compared to 48 weeks for genotypes 1 and 4 4p519.

Quality of life in Hepatitis C patients

HCV positive status can lead to discrimination such as loss of employment, insurance and educational activities along with disrupted personal relationships 21 p716. Therefore a primary aim of treatment is to clear HCV in order to improve quality of life and reduce the risk of cirrhosis and hepatocellular carcinoma 19 p7. Extra-hepatic HCV infection in particular is indicative of impaired quality of life. The majority of quality of life values are related to the cost-effectiveness of treatments, providing data to derive QALYs - quality of life years 13 p258. Health state values can be multiplied by the amount of time that the individual spends in each health state along with the mean life expectancy. Therefore overall cost effectiveness is expressed as the cost per QALY gained 22 p289. Table 1 below summarises the cost effectiveness research to 2007.

Table 1 Published cost-effectiveness analyses of antiviral treatments for CHV adapted from 23 table 5

Treatment

Year of costing

Annual discount rate (%)

Cost-effectiveness ratio

Compared to placebo

24 Weeks interferon

1995

3-5

US$1100-1900/QALY

A$33,230-71,950/LY

Compared to interferon for 24 weeks

Interferon for 48

to 72 weeks

1995

1996

1998

3

US$938-9957/LY US$Cost-saving to 3200/QALY A$8250/QALY

Compared to interferon for 48 weeks

Interferon + ribavirin

1998

1999

3

6

US$1400-7500/QALY

Cost-saving to €7125/QALY

£3485/QALY

Compared to interferon + ribavirin

Peginterferon + ribavirin

2000, 2001, 2002, 2003

3

6 (costs)

1 (benefits)

US $ Cost-saving 90,000/QALY

€3737-11,800/QALY

£12,123/QALY

Treatment of HCV

Interferon began being used in the treatment of HCV in the early 1990s but serious side effects including neutropenia and thrombocytopenia 24 p1673, high cost, and variable efficacy including primary resistance 25 p1242 in different HCV profiles hampered effective use3. Ribavirin is a synthetic nucleoside analogue that has in-vitro antiviral activity against a range of DNA and RNA viruses 14 p1426. The use of ribavirin with interferon 2b was started in the late 1990s as a result of Poynard's findings that combination therapy doubled the response rate of all measures of efficacy virology and histology 14 p1431. Not all researchers agreed with Poynard's proposals, e.g. 26 with some emphasizing the side effect profile 27 and research also being carried out into taribavirin, a prodrug of ribavirin 28 p52.

Figure 3 Ribbon diagram of the average solution structure of IFN displaying the location of the three histidine residues 6 figure 7

Pegylation of interferon was developed at the end of the century, with the first documented clinical trials taking appearing in 1999 c.f.29 in order to reduce the exogenous interferon  concentration fluctuations 30 p895. Figure 3 shows the active residues of the interferon molecule, and a 40-kd branched chain polyethylene glycol moiety was subsequently attached to interferon 2a 24 p1673 (see scheme 1) to form a compound with sustained absorption, slower clearance rate and longer ½ life than the unmodified form31 p1666 due to covalent bonding of the polyethylene glycol to interferon 11p1154, enabling a once per week dosing regime to be followed 12 p958. Effectively the peg tail is an inert molecule that acts to slow down the rate at which the body eliminates the molecule 19 p11. Unmodified and pegylated interferon 2a were directly compared by Reddy and colleagues, to show that the pegylated version was superior to the unmodified version 32 p437. Subsequent to this, the recommendation became to use the pegylated version, and notwithstanding issues of dosage variations according to patient weight 33p264 or genome 34, 35p263.

Scheme 1 Formation of peginterferon 6

2b peginterferon is branded as PegIntron and is a linear 36 p861 12-kd product, whereas 2a is marketed as Pegasys and is a bulky branched molecule 36 p861 of 40-kd 8 p1152. It is important to realize that there are competing companies, as this does affect research sponsoring 37 p795. These 2 products have significant differences in their pharmacokinetic properties, with biological activity in vitro and in vivo being greater for 2b compared to 2a 7 p209, purported to be due to better interactions with the interferon  receptor 7 p210, although the methodology of Silva's study has been criticized 38 p349. As a result of these properties 2b dosage is base on bodyweight, whereas 2a is a straightforward bodyweight independent dosage 36 p861.

The general characteristics for patients with HCV for whom therapy is widely accepted is shown below, followed by the characteristics of those for whom a contraindication exists 8 tables 7 and 9:

At least 18 years of age

Abnormal ALT values

Liver biopsy showing chronic hepatitis with significant fibrosis (more-than-portal fibrosis: Metavir score <2; Ishak score > 3)

Compensated liver disease (total serum bilirubin < 1.5 g/dL; INR <1.5; albumin > 3.4 g/dL; platelet count > 75,000 k/mm3; and no evidence of hepatic encephalopathy or ascites)

Acceptable hematological and biochemical indices (hemoglobin > 13 g/dL for men and <12 g/dL for women; neutrophil count >1.5 k/mm3; creatinine < 1.5 mg/dL)

Treated previously for HCV infection

History of depression but the condition is well controlled

Willing to be treated and to conform to treatment requirements

Contraindications:

Major, uncontrolled depressive illness

Renal, heart, or lung transplantation recipient

Autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin

Untreated hyperthyroidism

Pregnant or unwilling/unable to comply with adequate contraception

Severe concurrent disease such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, obstructive pulmonary disease

Under 3 years of age

Known hypersensitivity to drugs used to treat HCV

There are certain comorbid diseases that affect treatment 4 p518 (see figure 4) so it is important that these are considered before embarking on any treatment regime. In addition to actively affecting drug efficacy some of the morbidities such as psychiatric ones would also affect treatment compliance. Further and given the high incidence of the virus in drug users, a continuance of the intravenous drug usage would drastically affect the likelihood of recovering, due to the chance of further exposure to the virus, although note that a recent trial showed that HCV infection could be effectively treated in injecting drug users 39.

Figure 4 Complicating co-morbidities 4 figure 1

Recommended doses for patients in England and Wales are as follows:

"In conjunction with peginterferon alfa-2a (as for interferon alfa-2a), people who have HCV genotype 1 or 4 (and usually those who have genotype 5 or 6) and who weigh less than 75 kg take 1000 mg daily of ribavirin in divided doses. People who weigh more than 75 kg take 1200 mg ribavirin daily in divided doses. For people with HCV genotype 2 or 3 (and less usually those who have genotype 5 or 6) the dose of ribavirin is 800 mg daily in divided doses. In conjunction with peginterferon alfa-2b (as for interferon alfa-2b) and regardless of genotype, people who weigh less than 65 kg take 800 mg of ribavirin daily in divided doses, people who weigh 65-85 kg take 1000 mg daily in divided doses, and people who weigh more than 85 kg take 1200 mg daily in divided doses" 19 p11.

Diagnosing hepatitis C

HCV is an RNA virus of the flavivirus family, with a single stranded genome consisting of approximately 10,000 nucleotides in length 2 p351. The presence of HCV RNA in the blood signifies viremia and chronic infection 4 p519.

Table 2 Use of diagnostic tests in hepatitis C 2 table 2

Category

ELISA (anti-HCV by enzyme-linked immunoassay)

RIBA (anti-HCV by recombinant immunoblot assay);

HCV RNA

ALT (alanine aminotransferase)s

Chronic hepatitis C

Positive

Positive

Positive

Raised

Hepatitis C carrier

Positive

Positive

Positive

Normal

Recovered HCV infection

Positive

Positive

Negative

Normal

False positive anti-HCV

Positive

Negative

Negative

Normal

HCV is often asymptomatic, but when effects are felt these include non-specific symptoms such as fatigue, joint aching and abdominal discomfort corresponding to the liver 2 p352. Diagnosis therefore is via biochemical markers - principally the presence of HCV RNA within the serum detected via enzyme linked immunoassays. Table 2 indicates the diagnostic tests and how they can be differentiated from other liver diseases and table 3 provides quantifiable assay amounts. The optimal method for diagnosing HCV is to screen populations that are believed to be at risk 8 p1147, of particular relevance given the aforementioned asymptomacy of the disease. However routine screening of the whole population is not recommended 4 p518 in part due to the potential harms associated with screening, which can include discrimination as a result of HCV status, along with false-positive results 21 p716.

Table 3 Assays for Quantitation of HCV RNA in Serum 8 table 4

Assay

1 IU/L Conversion

Technique

Dynamic Range (IU/L)

Amplicor HCV Monitor version # 2.0

0.9 copies/mL

Manual competitive rtPCR

600-500,000

Cobas Amplicor Monitor HCV Version # 2.0

2.7 copies/mL

Semi-automated competitive rtPCR

600-500,000

VERSANT􏰃 HCV RNA version # 3.0 Quantitative Assay

5.2 copies/mL

Semi-automated "branched DNA" assay

615-7,700,000

LCx HCV RNA Quantitative Assay

3.8 copies/mL

Semi-automated competitive rtPCR

25-2,630,000

SuperQuant

3.4 copies/mL

Semi-automated competitive rtPCR

30-1,470,000

In clinical practice antibodies to HCV are tested for and then the HCV RNA can be used to document viremia 8 p1149, although it should be noted that quantitative tests are less reliable than qualitative tests.

Methods

Literature search

The Sciencedirect database with the key terms of chronic hepatitis, pegylated interferon and peginterferon alfa-2a. The Pubmed database was searched with the search terms "peginterferon alfa-2b peginterferon alfa-2a" Titles were visually scanned for mention of pegylated interferon, interferon, peginterferon and relevant full text articles selected for further examination. Once a basis of papers had been obtained reference lists were also checked for additional relevant citations. However it should be noted that there has been no effort to ensure a totally exhaustive list of studies has been identified.

Inclusion criteria

In order to be included within the actual results section papers had to relate to trials that were high quality in terms of directly comparing the efficacy of two or more interferon regimes as a primary endpoint 40 p662. Indeed Zaman pointed out that prior to 2003 no direct comparisons had been made between the 2 peginterferon formulations (Peg-Intron 2a and Pegasys 2b) and his review was a comparison of the standard interferon with the pegylated version. Further inclusion characteristics, as detailed by Simin were clear and adequate reporting of the allocation sequence along with allocation concealment 11.

Interventions

Dual therapy (pegylated interferon  and ribavirin) versus dual therapy (interferon  and ribavirin). Peginterferon 2a with ribavirin vs peginterferon 2b with ribavirin.

Outcome measures

Sustained virological response

Table 4 Definitions of virological response 41 table 1

Virological response

Time window (study day)

HCV RNA status

Week 4 (Rapid Virological Response)

1-43

Negative or > log10 decline

Week 12 (Early Virological Response)

1-99

Negative or > log10 decline

Week 24

1-183

Negative or > log10 decline

Week 48 (End of Treatment Response)

296-389

Negative

Patients without a week-48 value were considered to have had an ETR if they were HCV RNA-negative at the last visit before week-48 and during follow-up

Week 72 (Sustained Virological Response)

>476

Negative

Post- follow-up PCR data were sought for all patients lost to follow-up during the trial. If such patients were confirmed to be PCR-negative they were counted as sustained virological responders in this analysis

The primary aim of treatment is to show an absence of HCV RNA for at least 6 months after treatment cessation 19 p7. This known as sustained viral response (SVR) (see table 4). This is the standard measure of treatment response but is an intermediate outcome measure so doesn't necessarily correlate with long term liver-related morbidity and mortality 11 p1154, even though it can be counted as the end-point for efficacy 17 p569. Effectively participants were measured to see if they had met the accepted end point at the end of the study, and the numbers that had for each treatment regime compared.

Patients who achieve SVR almost always have a dramatic earlier reduction in HCV RNA levels known as the early virologic response (EVR) 8 p1152, which is a viral kinetic measurement 42 p721. In fact if this EVR at 12 weeks does not show the 2 logs decrease in HCV RNA then it is considered that the patient is unlikely to develop an SVR 41 p426, with the likelihood being described as 'negligible' 42 p721. This represents a reduction in the viral load to 1% of its level at the start of the treatment 19 p5.

Other biochemical markers

Liver histology samples were taken before treatment and at week 24 of treatment, and these were assessed for inflammation and fibrosis 43 p84. Fibrosis stage along with grade of inflammation were considered suitable biochemical markers in other studies e.g. 44 p45.

Cost of treatments

Absolute figures are not always easy to come by within research articles, as these often don't include actual monetary data, or if they do it would be related to the year of publication. Therefore the current edition of the British National Formulary was used to locate prices.

Adverse effects of treatment.

Side effects included fatigue with nausea being more common in 2b and ribavirin, compared to 2b and placebo 43 p85. Anaemia can affect patients undergoing 2b treatment, and can be serious enough to warrant ceasing the trial for affected individuals 43 p85.

Study types:

Randomised Clinical Trials (RCTs), systematic reviews (and meta-analysis) of RCTs. As the primary research type covered within this review was randomized clinical trials, the data from open label trials was not included within the actual results section. Likewise studies that did not include pegylated interferon as one of the research parameters were also not included.

Results and Discussion

Quantity and quality of research available

Many of the located studies were open label 12, 16, 24, 29, 31, 32, 36, 45-47, which means that, although valuable information can be used to inform the discussion, they do not fall within the remit of the current study rationale as an open label study could be subject to bias when the patient was aware what they were receiving. Studies could still be randomized and placebo-controlled 14, 45 but it has been highlighted that study design, treatment regimens and patient population differences make it difficult to provide accurate comparisons 48 p1098.

Different research aims were discovered, for instance focus on a specific racial and ethnic origin patient 45 and a couple of small trials to assess the effectiveness of the treatment in community-based practice 49, 50. Likewise large-scale studies such as IDEAL had a focus on the dosage but could still provide data as treatment groups included 2a and 2b.

Design of studies

Whilst not explicitly scored as such the Jadad scoring system (table 5) was used as a basis for identifying relevant and high quality trials. As mentioned open label trials have been a significant feature in result obtained, which automatically reduces the possible quality score.

Table 5 Jadad scoring system 40 table 2

Randomization

2 points: describes method of randomization and concealment

1 point: states randomization but no description of method

Blinding

2 points: double-blind with method described

1 point: states blinded but no description of method

Withdrawal/dropouts

1 point: describes number of withdrawals and reasons

The stringency of the selection criteria discount the more real life studies, e.g. 51.

Methodological quality

Whilst large amount of data are available, the amount that is precise enough for the current review amounts to very little 52 p389. Also of interest is the fact that the UK National Institute for Clinical Excellent is currently conducting a review of guidance for the use of peginterferon in HCV 53. Prior to 2004 NICE cited 2 RCTs investigating peginterferon/ribavirin compared to interferon/ribavirin, and 4 RCTs investigating peginterferon  monotherapy with interferon  monotherapy in naïve patients, along with a further 10 dealing with re-treatment of non-responders 19 p13-16, and these re-treatment studies have continued, e.g. 54.

Participant characteristics:

Inclusion criteria: persistently raised aminotransferases for at least 6 months; serum antibodies to HCV; HCV RNA found by PCR; and a diagnosis of chronic hepatitis on a liver-biopsy sample taken in the preceding 12 months 43 p83 along with naivety from prior interferon treatment 12 p958.

Exclusion criteria: age less than 18 or more than 70, previous treatment with interferon -2b or ribavirin, history of alcohol abuse or haemolytic disease, decompensated cirrhosis, autoimmune hepatitis, chronic hepatitis-B infection, HIV infection, current intravenous-drug use, drug-related liver disease, and pregnancy 43 p83; histologic features that did not suggest cirrhosis or bridging fibrosis 24 p1674; previous transplantation and psychiatric disease 12 p958 including severe depressive illness 17 p569. EVR was used in many studies as an indication of whether to continue with the prescribed therapy 41 p427.

Assessment of clinical, cost and safety effectiveness of dual therapy: peginterferon vs nonpeginterferon

Reliable quality studies withdrew patients with severe clinical events, and reduced clinical doses to minimize side effects, but continued the follow-up until the end of the study 17 p570. However dosage did vary between studies, with a trend towards weight based dosage of peginterferon 2b occurring in e.g. 55 p475.

Adverse effects including anaemia showed a higher trend in the Peginterferon plus ribavirin group compared to unmodified interferon plus ribavirin group 17 table 3. Anaemia occurs due to suppression of the erythroid progenitor cell production in the bon marrow 56 p171. A lack of response to peginterferon could be due to the presence of neutralizing antibodies 57 p759.

The HCV genotype does not appear to influence the efficacy of the medication according to some 17 p573 but not all studies 58, 59, although note that Reddy's study was conducted before peginterferon was created so the results could have questionable application. An indication of the kinds of results obtained across genotypes for peginterferon / unmodified interferon is shown in figure 5.

Figure 5 Sustained virological response rates according to HCV genotype (1 or non-1) and pretreatment HCV RNA levels (<2 or >2 million copies/mL). Lowest rate of SVR was noted in patients with HCV genotype 1 and higher viral load. 45

The use of pegylated interferon is more expensive than conventional interferon 41 p426 so some researchers are keen for an accurate prediction method to ascertain which patients would benefit more from that regime. However, whilst concerns do get raised about cost effectiveness peginterferon has been deemed cost effective by several studies e.g. 60 and described as akin to other chronic diseases 4 p521. The National Institute for Clinical Excellence (NICE) published the data in the tables below to show relative costs of combination and monotherapy. Further the genotype differences experienced with different ethnicities means that response success can run contrary to expectations 45 p290. Likewise it has been shown that QALY are improved for 2a compared to 2b 61. The current edition of the British National Formulary gives the cost of Pegasys as £109.93 for 135mg prefilled syringe and £126.91 for a 180mg prefilled syringe 62. ViraferonPeg has more formulations, with the prices ranging from £67.75 for the 50mg pen to £203.25 for the 150mg pen. Ribavirin itself is listed as £111.11 for 42 x 200mg tablets through to £296.29 for 56 x 400mg tablets (Copegus) and £163.80 for 84 x 200mg through to £327.60 for 168 x 200mg (Rebetol). The National Institute for Clinical Excellence states that the 2004 4-week cost of the interferon component of treatment would be increased from £200 to £550 when substituting peginterferon for interferon, leading to the 24 week course cost for the combination treatment equaling £6000 19 p12.

Table 6 Cost effectiveness of combination therapy for different HCV genotypes 19 table 1 (QALY - quality adjusted life year)

Comparison

Genotype

Treatment length (weeks)

Estimated incremental cost/QALY

(1) Peginterferon alfa combination vs interferon alfa combination

1

48

£4000 to £11,000

(2) Peginterferon alfa combination vs interferon alfa combination

4-6

48

£9000

(3) Peginterferon alfa combination vs interferon alfa combination

2-3

48

£7000 to £38,000

(4) Peginterferon alfa combination (24 weeks) vs peginterferon alfa combination

(48 weeks)

Not 1

24 vs 48

£69,000 to negative benefits compared with 24 week treatment

(5) Peginterferon combination (24 weeks) vs peginterferon combination

(48 weeks)

1

Table 7 Cost effectiveness of monotherapy for different HCV genotypes19 table 2

Comparison

Genotype

Estimated incremental cost/QALY

Peginterferon alfa monotherapy vs interferon alfa monotherapy

1

£19,000

Peginterferon alfa monotherapy vs interferon alfa monotherapy

2 and 3

£7000

Peginterferon alfa monotherapy vs interferon alfa monotherapy

4-6

£2000

Assessment of clinical, and safety effectiveness of dual therapy: peginterferon 2a vs peginterferon 2b

The lack of head to head comparisons between the 2 pegylated interferons has been highlighted 52 p387 and 47 p23, with the best study prior to 2009 being retrospective 63 and other studies having variable baseline characteristics as well as different dosages 47 p23. In fact it is only within the last year that adequate data has been published on the relative effectiveness of the 2 drugs. McHutchison showed that a marginally higher percentage of 2a/RBV patients achieved SVR compared to 2b/RBV 64 table 2, but there was a statistically significant difference in the virological response at the end of treatment (64.4% / 53.2%; p<0.01). However this treatment group also showed a higher relapse rate. This study also noted that low-dose peginterferon 2b achieved a similar SVR to other regimens. Rumi's 2010 study found similar results, 2a based treatment achieved more SVR than 2b 65. Likewise Ascione also indicated 2z/RBV was more effective than 2b / RBV 66. An editorial on the topic confirmed that there was a difference between the 2 formats, with SVR following 2a treatment being higher 67 p35, although McHutchison suggests that no significant difference does exist 68 p390 and a trial focused on treatment of HIV patients found a similar lack of difference 69 p1262. The majority of patients with intolerances to 2b can complete a full course of 2a 46 p440 but age can be an independent predictor of success 44 p49.

Figure 6 Mean viral load over time in patients treated with peginterferon alpha-2a plus ribavirin (solid line) or peginterferon alpha-2b plus ribavirin (broken line). The error bars represent 95% confidence intervals (CI) 42 figure 1

Example results are illustrated, where it can be seen that viral load decreases substantially over the 12 weeks (figure 6) and 2a shows a higher > 2log percentage (figure 7). In clinical practice patient selection is less controlled than in clinical trials but it is in this avenue that the day to day treatment exists and the data supports the results from formalized clinical trials 51 p5 in that more patients treated with 2a achieve SVR compared to those treated with 2b 51 p8.

Figure 7 Viral response at 4 and 12 weeks in patients treated with peginterferon alpha-2a plus ribavirin or with peginterferon alpha-2b plus ribavirin. (Left) Per cent of patients showing a >2-log drop in hepatitis C virus (HCV)-RNA concentration or undetectable HCV RNA. (Right) Per cent of patients with undetectable HCV RNA.42 figure 2

Conclusion

Impact of review on current treatment guidelines

Current treatment guidelines, as stated above, are for treatment using peginterferon 2a along with ribavirin, with the latter being weight related dosing as well as genotype dependent. Therefore current treatment requires the identification of the HCV genotype in order to ensure appropriate dosage. When peginterferon 2b is prescribed this is also in conjunction with ribavirin, and all dosages are weight dependent. The present review clarifies the position and that studies involving different ethnicities can derive varying results. However community-setting studies have been broadly supportive of data from clinical trials. As the data stands at the present time there is no need to change current treatment guidelines but the planned NICE publication late in 2010 may result in some additional data to review.

Recommendations for future treatment

Whilst market forces are obviously in play within this field it does appear from the data that peginterferon 2a is more clinically effective than peginterferon 2b so it would be useful to clarify whether the additional cost and possible lower efficacy of peginterferon 2b makes the treatment effective. Much of the research that has been sponsored thus far will have been funded at least in part by pharmaceutical companies so truly independent data is harder to come by. Given that up to ½ of treated patients do not achieve an SVR on their first treatment there are alternatives that could be sought, including taribavirin as an alternative to ribavirin. It is important to consider cost implications of the treatment of a chronic disease, but the results given above do support the idea that quality of life is improved and as a result the overall public health burden would be lessened.

Potential research ideas for the future

Additional modified drug forms should be sought and the use of slow release preparations such as those found in microencapsulated nanoparticles and liposomes should be investigated. A common therapeutic goal is to increase inter-treatment times so that the patient is less likely to miss a treatment session or fail to adhere in some other way to the regimen. Oral dosing is always met with greater compliance as there is no need to attend a physician, but without serious modification and encapsulation this is unlikely for interferons which would not make it past the stomach acid defense mechanisms.

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