Hepatitis C (chronic)

Abstract

Introduction

About 60% to 85% of people infected with hepatitis C virus will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions in treatment-naïve people with chronic hepatitis C infection, but without liver decompensation? What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who have not responded to interferon treatment? What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who relapse after interferon treatment? What are the effects of interventions in people with chronic hepatitis C infection who also have HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 35 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: interferon monotherapy; interferon alfa plus ribavirin; peginterferon monotherapy; and peginterferon plus ribavirin.

Key Points

Chronic hepatitis C virus (HCV) infection is defined as persistent, detectable serum HCV RNA for a period greater than 6 months, with or without derangement in liver function tests.

• About 60% to 85% of people infected with HCV will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.

• Complications of chronic HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma.

• Many people chronically infected with HCV remain asymptomatic, including a significant proportion of those who progress to cirrhosis, so routine screening of people in high-risk groups is advisable.

Interferon monotherapy produces a sustained virological response in both treatment-naïve people and people with cirrhosis or advanced fibrosis compared with placebo or no treatment.

• Interferon also improves liver histology, although it may not be effective in preventing hepatocellular carcinoma in people with cirrhosis.

• Efficacy is dependent on duration of treatment, with treatment for 12 months seeming more effective than treatment for 6 months. However, treatment for 12 months is associated with an increase in adverse effects.

• A dose of 6 MU of interferon three times weekly seems no more effective at achieving sustained virological response than 3 MU three times weekly, and is associated with an increased risk of adverse effects.

Adding ribavirin to interferon regimens further increases the likelihood of achieving sustained virological response, but also increases the risk of anaemia.

• Efficacy of combination therapy depends on genotype, with genotype 1-infected people typically requiring longer duration of treatment compared with genotype 2- and genotype 3-infected people.

Peginterferon monotherapy increases the proportion of treatment-naïve people who achieve sustained virological response compared with standard interferon monotherapy.

Adding ribavirin to peginterferon increases the likelihood of achieving sustained virological response compared with either peginterferon alone or standard interferon plus ribavirin. This is currently the standard recommended therapeutic approach.

In people previously non-responsive to interferon monotherapy, treatment with interferon alfa plus ribavirin increases the likelihood of achieving sustained virological response compared with interferon alone.

• This effect seems greater when the interferon dose is higher than 3 MU three times weekly, or the duration of the treatment is 12 months or greater.

• We don't know whether peginterferon as a monotherapy, or in combination with ribavirin, is effective in non-responders to interferon monotherapy. We don't know whether peginterferon plus ribavirin is more effective than interferon alfa plus ribavirin.

In people who relapse after interferon monotherapy, treatment with interferon plus ribavirin is more likely than interferon treatment alone to achieve sustained virological response (SVR).

• There is general consensus that peginterferon plus ribavirin is likely to improve the probability of achieving SVR in people who relapse after interferon monotherapy.

• We don't know whether peginterferon alone is effective at achieving SVR in people who relapse after interferon monotherapy.

In people co-infected with HCV and HIV, peginterferon plus ribavirin seems more effective than standard interferon plus ribavirin treatment or peginterferon alone at achieving SVR.

• Although interferon plus ribavirin seems less effective than peginterferon plus ribavirin, the proportion of people achieving SVR suggests that interferon plus ribavirin may be effective in people with HCV and HIV.

• We don't know whether interferon alone is effective in people co-infected with HCV and HIV.

About this condition

Definition

Hepatitis C virus (HCV), identified in 1989, is a member of the flaviviridae family of spherical, enveloped, positive-strand RNA viruses. There are six different HCV genotypes. Genotype 1 is the most common and the most resistant to treatment. Chronic HCV infection is defined as persistent, detectable serum HCV RNA for a period greater than 6 months, with or without derangement in liver function tests. This is in contrast to acute HCV infection, in which serum HCV RNA clears within 6 months. Prospective studies have shown that 60% to 85% of HCV-infected people will develop chronic infection. This review only deals with interventions used to treat chronic HCV infection without liver decompensation. The effect of treatment is measured by the presence or absence of detectable serum HCV RNA. The loss of detectable HCV RNA at the end of the treatment period is defined as the end of treatment virological response (EOTR). The loss of detectable HCV RNA 24 weeks or greater after the completion of treatment is termed the sustained virological response (SVR). Response to treatment is defined as the loss of detectable serum HCV RNA. Non-response is defined as a failure to clear serum HCV RNA during the treatment period. A relapse from treatment is defined as loss of serum HCV RNA during treatment, which reappears during the follow-up period, typically within 24 weeks of treatment episode.

Incidence/ Prevalence

HCV has emerged as a major viral pandemic over the past two decades, with about 3% of the world's population chronically infected. HCV prevalence varies throughout the world, with the highest number of infections reported in Egypt (6%–28%). In the USA, an estimated four million people are positive for HCV antibodies, reflecting a prevalence rate of 2%; and about 35,000 new HCV infections are estimated to occur each year. In Europe, the prevalence of HCV infection ranges from about 0.5% to 2%. Diagnosis of HCV infection is often the result of active screening, because many people chronically infected with HCV remain asymptomatic, including a significant number of those who progress to cirrhosis. The true incidence of HCV is therefore difficult to calculate accurately, because this relates to the prevalence of risk factors for HCV transmission, in particular injection drug use.

Aetiology/ Risk factors

HCV is mainly blood borne and transmission occurs primarily through exposure to infected blood. This exposure may occur because of the use of infected needles used for injection drug use, blood transfusion or solid organ transplantation from infected donors in the absence of universal screening procedures, maternal (vertical) transmission, unsafe medical practices, and occupational exposure to infected blood. As a result of HCV screening, the absolute risk of acquiring infection through blood components or products is now small — less than 1/400,000 units of blood transfused. HCV vertical transmission is uncommon, with a transmission rate of less than 6%. Poverty, high-risk sexual behaviour, and having less than 12 years of education are linked to an increased risk of infection. However, in some cases, no risk factors can be identified. There are six known HCV genotypes with variable distribution worldwide. Genotype 1 is the most common type in developed countries with values of 47% to 72%.

Prognosis

The spectrum of liver disease and the rate of disease progression vary in people with chronic HCV infection. Complications of chronic HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma. Studies suggest that one third of people with chronic HCV infection are “rapid progressors” (time from infection to cirrhosis <20 years); one third are “intermediate progressors” (time to cirrhosis 20–50 years); and one third are “slow or non-progressors” (time to cirrhosis greater than 50 years). Factors associated with disease progression include: older age at acquisition; male sex; co-infection with HIV, hepatitis B virus, or both; coexisting liver disease; and excessive alcohol consumption. In people who develop cirrhosis, the 5-year risk of decompensation is 15% to 20%, and the 5-year risk of hepatocellular carcinoma is 10%; and, in those who develop cirrhosis, the annual risk of hepatocellular carcinoma is 1% to 5% a year.

Aims of intervention

To eradicate HCV infection, prevent progression to end-stage liver disease, reduce HCV transmission, prevent development of hepatocellular carcinoma, reduce the need for liver transplantation, improve quality of life, and reduce mortality, with minimal adverse effects.

Outcomes

Primary outcomes: Virological response defined as HCV RNA negativity and sustained virological response (SVR); hepatocellular carcinoma; liver disease. Secondary outcome: Liver histological response. Biochemical outcomes are not reported in this review.

Methods

Clinical Evidence search and appraisal April 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2008, Embase 1980 to April 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, and containing more than 100 individuals, with a follow-up of at least 6 months. We did not exclude studies on the basis of proportion of participants lost to follow-up. We included all studies described as "open" and "open label". We searched for RCTs comparing interventions versus placebo, no treatment, or other listed interventions. We also searched for RCTs comparing different doses or durations of interferon alone or peginterferon plus ribavirin in people who were treatment naïve, and also for interferon retreatment in people who were non-responsive to interferon. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Hepatitis C (chronic).

Important outcomes	Haematological adverse effects, Hepatocellular carcinoma, Liver disease, Liver histological response, Virological response
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of interventions in treatment-naïve people with chronic hepatitis C infection but without liver decompensation?
11 (651)	Virological response	Interferon versus placebo or no treatment	4	0	0	0	+1	High	Effect-size point added for odds ratio >5
6 (290)	Liver histological response	Interferon versus placebo or no treatment	4	0	0	0	+1	High	Effect-size point added for odds ratio >5
1 (122)	Hepatocellular carcinoma	Interferon versus placebo or no treatment	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (1056)	Virological response	Different durations of interferon treatment versus each other	4	0	0	0	0	High
1 (747)	Virological response	Different interferon dosage regimens versus each other	4	0	0	0	0	High
20 (4785)	Virological response	Interferon plus ribavirin versus interferon alone	4	–1	0	0	0	Moderate	Quality point deducted for short follow-up in some RCTs
7 (2900)	Liver histological response	Interferon plus ribavirin versus interferon alone	4	–1	0	0	0	Moderate	Quality point deducted for short follow-up in some RCTs
31 (5140)	Haematological adverse effects	Interferon plus ribavirin versus interferon alone	2	0	0	–1	0	Moderate	Directness point deducted for inclusion of people treated after non-response or relapse.
5 (3219)	Virological response	Peginterferon versus interferon	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
3 (1013)	Liver disease	Peginterferon versus interferon	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting. Directness point deducted for inclusion of different disease states
1 (331)	Liver histological response	Different peginterferon dosage regimens versus each other	4	0	0	–1	0	Moderate	Directness point deducted for assessment of a secondary outcome
1 (491)	Virological response	Peginterferon plus ribavirin versus placebo or no treatment	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (877)	Virological response	Peginterferon plus ribavirin versus peginterferon plus placebo	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
at least 12 (at least 4136)	Virological response	Peginterferon plus ribavirin versus standard interferon plus ribavirin	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and inclusion of data reported in only abstracts
2 (5248)	Virological response	Different doses of peginterferon plus ribavirin versus each other	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for comparison of different peginterferon and ribavirin doses in one RCT
9 (4772)	Virological response	Different durations of peginterferon plus ribavirin treatment versus each other	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for wide variation in treatment durations compared
What are the effects of interventions to treat people with chronic hepatitis C infection, but without liver decompensation, who have not responded to interferon treatment?
20 (2103)	Virological response	Interferon alfa plus ribavirin versus interferon alone	4	0	0	0	0	High
2 (257)	Virological response	Different durations of interferon treatment versus each other	4	0	0	0	0	High
2 (363)	Virological response	Peginterferon plus ribavirin versus interferon plus ribavirin	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of data reported in only abstract
What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who relapse after interferon treatment?
12 (1208)	Virological response	Interferon alfa plus ribavirin versus interferon monotherapy	4	0	0	0	0	High
What are the effects of interventions in people with chronic hepatitis C infection who also have HIV?
6 (1456)	Virological response	Peginterferon plus ribavirin versus standard interferon plus ribavirin	4	0	–1	0	0	Moderate	Consistency point deducted for statistical heterogeneity among RCTs included in meta-analysis
1 (267)	Liver histological response	Peginterferon plus ribavirin versus standard interferon plus ribavirin	4	0	0	–1	0	High	Directness point deducted for assessment of a secondary outcome
2 (710)	Virological response	Peginterferon plus ribavirin versus peginterferon alone	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (269)	Liver histological response	Peginterferon plus ribavirin versus peginterferon alone	4	0	0	–1	0	High	Directness point deducted for assessment of a secondary outcome

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Child–Pugh cirrhosis

Scoring system to assess the severity of liver cirrhosis. Points (1, 2, or 3) are given for each of the following: bilirubin level (less than 2 mg/dL, 2–3 mg/dL, greater than 3 mg/dL), albumin level (greater than 35 g/L, 30–35 g/L, less than 30 g/L), ascites (absent, moderate, severe), encephalopathy (absent, moderate, severe), and prothrombin (less than 4 seconds prolonged clotting time, 4–6 seconds, greater than 6 seconds). Child–Pugh class A: 5–6 total points; Child–Pugh class B: 7–9 total points; Child–Pugh class C: 10–15 total points.

Compensated liver disease

Indicates a diseased or cirrhotic, but functional liver. This may or may not be accompanied by the accumulation of fluid in the abdominal cavity (ascites).

Decompensated liver disease

Indicates a diseased non-functional liver. This is accompanied by fluid accumulation in the abdominal cavity (ascites); jaundice; failure of the blood clotting mechanism (coagulopathy); increased risk of bleeding from oesophageal varices; and in severe cases, mental confusion, disorientation, and insomnia caused by toxic waste products normally cleared by the liver (hepatic encephalopathy).

Early virological response

A 2 log10 unit decrease in viral load from baseline hepatitis C virus RNA titre at week 12 of treatment.

End of treatment virological response

Loss of detectable hepatitis C virus RNA at the end of the treatment period.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Interferon

Interferon alfa (unless otherwise stated).

Interferon naïve

People not previously treated with interferon or any other interferon combination treatment for hepatitis C virus infection.

Interferon non-responsive people

People who have failed to achieve suppression of hepatitis C virus ribonucleic acid replication from serum at the end of a treatment course consisting of at least three million units (MU) of interferon three times weekly for at least 12 weeks.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Pegylated interferons (peginterferon)

These are protein conjugates containing a polyethylglycol molecule (molecular weight 12–40 kD) conjugated to an interferon molecule in a 1:1 ratio. Peginterferon has a 10-fold longer plasma half life than interferon alfa, although maintaining its antiviral activity in humans. The delayed clearance formulation allows for once-weekly dosing.

Relapse from treatment

Failure to maintain suppression of hepatitis C virus RNA replication 6 months after the end of treatment in people showing an end of treatment response.

Sustained virological response (SVR)

Loss of detectable hepatitis C virus ribonucleic acid 6 months or more after the completion of treatment.

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