Hepatitis C (chronic) Search date August 2014 Alan Hoi Lun Yau, Vladimir Marquez-Azalgara, and Eric M. Yoshida 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 overview and aimed to answer the following clinical questions: What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection without cirrhosis? What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection with cirrhosis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: After deduplication and removal of conference abstracts, 30 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 11 studies and the further review of 19 full publications. Of the 19 full articles evaluated, two systematic reviews and one RCT were added. We performed a GRADE evaluation for two PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for 12 different intervention/comparison combinations, based on information relating to the effectiveness and safety of sofosbuvir (with or without ribavirin), sofosbuvir (with or without ribavirin) plus ledipasvir, and sofosbuvir (with or without ribavirin) plus simeprevir, all in people with and without cirrhosis.
QUESTIONS What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection without cirrhosis?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection with cirrhosis?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERVENTIONS INTERFERON-FREE TREATMENTS IN TREATMENTNAÏVE CHRONIC HCV WITHOUT CIRRHOSIS Likely to be beneficial
INTERFERON-FREE TREATMENTS IN TREATMENTNAÏVE CHRONIC HCV WITH CIRRHOSIS Likely to be beneficial
Sofosbuvir plus ribavirin versus placebo/no treatment (in genotype 2 and genotype 3) New . . . . . . . . . . . 5
Sofosbuvir plus ribavirin versus placebo/no treatment (in genotype 2; efficacy in genotype 3 is less clear) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Unknown effectiveness Sofosbuvir alone New . . . . . . . . . . . . . . . . . . . . . . . 5 Sofosbuvir plus ribavirin versus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Sofosbuvir plus ribavirin versus sofosbuvir plus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . . 9 Sofosbuvir plus simeprevir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Sofosbuvir plus ledipasvir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Unknown effectiveness Sofosbuvir alone New . . . . . . . . . . . . . . . . . . . . . . 11 Sofosbuvir plus ribavirin versus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Sofosbuvir plus ribavirin versus sofosbuvir plus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . 15 Sofosbuvir plus simeprevir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Sofosbuvir plus ledipasvir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
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. • This overview deals only with chronic HCV infection without liver decompensation. • The landscape of HCV antiviral therapy has changed rapidly in the past 3 years. The limited efficacy and tolerability of interferon-based antiviral regimens has prompted the recent development of direct-acting antiviral agents, such as sofosbuvir, simeprevir, and ledipasvir. During this time, several different direct-acting antiviral agents have been approved by the FDA as oral therapies for the treatment of hepatitis C. © BMJ Publishing Group Ltd 2015. All rights reserved.
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Clinical Evidence 2015;06:921
Infectious diseases
..................................................
• Recommendations in major national clinical guidelines in this field are often based on both RCT and non-RCT evidence and should be referred to for guidance on current routine clinical practice. However, for this overview, in line with most other BMJ Clinical Evidence overviews, we have only reported on evidence from RCTs and systematic reviews of RCTs. We have reported on selected direct-acting antiviral agents, but in this fast-moving field, we will consider broadening this list of interventions in future updates. • The following points are based on our search for evidence from RCTs and systematic reviews of RCTs. • In treatment-naïve people with HCV without cirrhosis: Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment, and increasing sustained virological response at up to 12 weeks (SVR12) after the end of treatment in treatmentnaïve people with HCV genotypes 2 or 3 without cirrhosis. However, this effect appears to be greater for HCV genotype 2 than for genotype 3. • In treatment-naïve people with HCV with cirrhosis: Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment in treatment-naïve people with HCV genotypes 2 or 3 with cirrhosis. Sofosbuvir plus ribavirin may be more effective than placebo at increasing sustained virological response at up to 12 weeks (SVR12) after the end of treatment in treatment-naïve people with HCV genotypes 2 and 3 with cirrhosis. However, this effect appears to be greater for HCV genotype 2 than for genotype 3. • Sofosbuvir plus ribavirin appears to be safe and well-tolerated, with an adverse event profile consistent with ribavirin alone. • We found no RCTs assessing the effectiveness of sofosbuvir alone, sofosbuvir plus simeprevir, or sofosbuvir plus ledipasvir in treatment-naïve people with chronic HCV with or without cirrhosis. • The Q80K polymorphism, associated with genotype 1a, confers resistance to simeprevir. Therefore, testing for this genetic variation may be important before considering treatment with this drug. Clinical context
GENERAL BACKGROUND 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. Complications of chronic HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma.
FOCUS OF THE REVIEW The landscape of HCV antiviral therapy has changed rapidly in the past 3 years, making an evidence overview valuable to medical professionals. The limited efficacy and tolerability of interferon-based antiviral regimens has prompted the recent development of direct-acting antiviral agents such as sofosbuvir, simeprevir, and ledipasvir, which were selected as interventions of this evidence update.
COMMENTS ON EVIDENCE This overview reviews the available RCT evidence on pre-selected interventions. This was limited in quantity and quality (low to very-low quality). Of the six known HCV genotypes, genotype 1 is the most common in developed countries; however, all the RCTs we found were in people with genotype 2 or 3 only. We have examined the evidence from RCTs and systematic reviews of RCTs only. However, it should be noted that there are a significant number of 'open-label' trials, which have not been included in this overview but have nonetheless been considered by the FDA in the drug approval process. Please refer to the Additional information section for more details, and to major national society guidelines for recommendations on current routine practice. RCTs comparing direct-acting antiviral agents with placebo or with older standard of care treatments are now unlikely to take place because it would be considered unethical to subject patients to the latter interventions, which are known to produce a substantially lower treatment effect.
SEARCH AND APPRAISAL SUMMARY The literature search was carried out in August 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. After deduplication and removal of conference abstracts, 30 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 11 studies and the further review of 19 full publications. Of the 19 full articles evaluated, two systematic reviews and one RCT were added.
ADDITIONAL INFORMATION © BMJ Publishing Group Ltd 2015. All rights reserved.
........................................................... 2
Infectious diseases
Hepatitis C (chronic)
Sofosbuvir is approved by the US Federal Drug Administration (FDA) for use with ribavirin for 12 weeks in people with chronic HCV genotype 2, and for 24 weeks in people with chronic HCV genotype 3. Sofosbuvir combined with simeprevir or ledipasvir, with or without ribavirin, for 12 weeks in people with chronic HCV genotype 1 has been found to produce a sustained virological response of more than 90%, irrespective of previous treatment history or [1] [2] [3] presence of cirrhosis. Data for sofosbuvir and ledipasvir are based on the open-label ION-1, ION-2, ION-3, [4] [5] LONESTAR, and ELECTRON trials, whereas data for sofosbuvir and simeprevir are based on the open-label [6] [7] [8] COSMOS trial. Another important FDA-approved drug regimen was the combination of ombitasvir, pari[9] taprevir, ritonavir, and dasabuvir with or without ribavirin (based on data from the open-label SAPPHIRE-II, [10] [11] [12] TURQUOISE-II, PEARL-IV, and AVIATOR trials). When given for 12 weeks, this drug regimen has been found to result in a sustained virologic response of more than 90% in genotype 1, irrespective of previous treatment history or presence of cirrhosis. Please refer to major national society guidelines for current recommendations on [13] [14] [15] practice. Considering the encouraging data on safety and efficacy for the newer direct-acting antiviral agents, it is envisioned that primary care physicians would take on a greater role in the treatment of HCV in the near future. Unfortunately, many of these direct-acting antiviral agents are currently associated with significant pharmaceutical costs, thereby limiting their availability at the present time. In addition, further research will be needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and establish the antiviral safety and efficacy in difficult-to-cure patient population. DEFINITION
Hepatitis C virus (HCV), identified in 1989, is a member of the flaviviridae family of spherical, en[16] [17] veloped, positive-strand RNA viruses. There are six different HCV genotypes with variable distribution worldwide; some genotypes have multiple subtypes. Genotype 1 is the most common [18] 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 in[17] fection. This review only deals with 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 (SVR24).The loss of detectable HCV RNA 12 weeks after the completion of treatment is termed SVR12, and this has been recommended by the FDA as the primary efficacy endpoint in recent clinical trials as it has a positive [19] predictive value of 98% for SVR24. 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 [20] world's population chronically infected. HCV prevalence varies throughout the world, with the [21] highest number of infections reported in Egypt (6%–28%). In the US, an estimated four million people are positive for HCV antibodies, reflecting a prevalence rate of 2%; and about 35,000 new [17] HCV infections are estimated to occur each year. In Europe, the prevalence of HCV infection [22] 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/ HCV is mainly blood borne, and transmission occurs primarily through exposure to infected blood. RISK FACTORS This exposure may occur because 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 [23] blood. As a result of HCV screening, the absolute risk of acquiring infection through blood [24] components or products is now small — less than 1/400,000 units of blood transfused. HCV [25] 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 [26] [27] infection. However, in some cases, no risk factors can be identified. Of the six known HCV genotypes, genotype 1 is the most common in developed countries, with values of 47% to 72%. [27] In North America (unlike Europe and Asia), genotype 1a is the most common and is associated [28] with Q80K polymorphism in 30% to 47% of people. The Q80K polymorphism confers resistance to the drug simeprevir (a second-generation NS3/4A protease inhibitor), which leads to a considerably lower SVR, such that testing for this genetic variation is recommended before commencement [28] of treatment. 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 decompen© BMJ Publishing Group Ltd 2015. All rights reserved. ........................................................... 3
Infectious diseases
Hepatitis C (chronic)
sated liver disease, and hepatocellular carcinoma. Studies suggest that one third of people with chronic HCV infection are 'rapid progressors' (time from infection to cirrhosis 50 years). Factors associated with disease progression include: older age at acquisition; male sex; co-infection with HIV, hepatitis B virus, or both; co-existing liver disease; and excessive alcohol consumption. In people who develop cirrhosis, the 5-year risk of [30] decompensation is 15% to 20%; the 5-year risk of hepatocellular carcinoma is 10%; and the [31] [32] annual risk of hepatocellular carcinoma is 1% to 5% per year. AIMS OF To eradicate HCV infection, prevent progression to end-stage liver disease, reduce HCV transmisINTERVENTION sion, prevent development of hepatocellular carcinoma, reduce the need for liver transplantation, improve quality of life, and reduce mortality, with minimal adverse effects. OUTCOMES
Virological response, defined as HCV RNA negativity and sustained virological response (SVR); hepatocellular carcinoma; end-stage liver disease; mortality; quality of life; adverse events.
METHODS
Search strategy BMJ Clinical Evidence search and appraisal date August 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to August 2014, Embase 1980 to August 2014, The Cochrane Database of Systematic Reviews 2014, issue 8 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as ‘open’, ‘open label’, or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update (optional section) At this update, we have removed the previously reported questions to focus on interferon-free interventions. Data and quality To aid readability of the numerical data in our overviews, we round many 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). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result.These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 20 ). 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).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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4
Infectious diseases
Hepatitis C (chronic)
QUESTION
What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection without cirrhosis?
OPTION
SOFOSBUVIR ALONE IN TREATMENT-NAÏVE PEOPLE WITH CHRONIC HCV WITHOUT CIRRHOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New
•
For GRADE evaluation of interventions for Hepatitis C (chronic), see table, p 20 .
•
We found no RCT evidence on the effectiveness of sofosbuvir alone in treatment-naïve people with chronic HCV without cirrhosis. Benefits and harms
Sofosbuvir alone versus placebo or no treatment: [33] We found two systematic reviews (both search date 2014),
[34]
neither of which identified any RCTs.
[34]
neither of which identified any RCTs.
Sofosbuvir alone versus peginterferon plus ribavirin: [33] We found two systematic reviews (both search date 2014), Sofosbuvir alone versus sofusbuvir plus peginterferon plus ribavirin: [33] [34] We found two systematic reviews (both search date 2014), neither of which identified any RCTs. Comment: OPTION
None. SOFOSBUVIR PLUS RIBAVIRIN VERSUS PLACEBO OR NO TREATMENT IN TREATMENTNAÏVE PEOPLE WITH CHRONIC HCV WITHOUT CIRRHOSIS. . . . . . . . . . . . . . . . . . . . . . New
•
For GRADE evaluation of interventions for Hepatitis C (chronic), see table, p 20 .
•
Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment, and increasing sustained virological response at up to 12 weeks (SVR12) after the end of treatment in treatmentnaïve people with HCV genotypes 2 or 3 without cirrhosis.
•
Sofosbuvir plus ribavirin appears to be safe and well tolerated, with an adverse event profile consistent with ribavirin alone. Benefits and harms
Sofosbuvir plus ribavirin versus placebo or no treatment: [33] [34] We found two systematic reviews (both with search dates from 2014), which both identified the same RCT comparing sofosbuvir plus ribavirin with placebo in treatment-naïve people with HCV genotype 2 or genotype 3 (see [35] Further information on studies). Virological response Sofosbuvir plus ribavirin compared with placebo or no treatment Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment, and at increasing sustained virological response at 12 weeks after the end of treatment in treatment-naïve people with HCV genotypes 2 and 3 without cirrhosis and who choose not to have interferon-based treatments, or for whom interferon-based treatments are not suitable (lowquality evidence).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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5
Infectious diseases
Hepatitis C (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
End of treatment virological response (EOTR) [35]
RCT 3-armed trial
278 people with HCV for whom interferon-based treatment was unsuitable or who had decided against treatment with an interferoncontaining regimen
Proportion of people achieving P
QUESTIONS What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection without cirrhosis?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection with cirrhosis?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERVENTIONS INTERFERON-FREE TREATMENTS IN TREATMENTNAÏVE CHRONIC HCV WITHOUT CIRRHOSIS Likely to be beneficial
INTERFERON-FREE TREATMENTS IN TREATMENTNAÏVE CHRONIC HCV WITH CIRRHOSIS Likely to be beneficial
Sofosbuvir plus ribavirin versus placebo/no treatment (in genotype 2 and genotype 3) New . . . . . . . . . . . 5
Sofosbuvir plus ribavirin versus placebo/no treatment (in genotype 2; efficacy in genotype 3 is less clear) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Unknown effectiveness Sofosbuvir alone New . . . . . . . . . . . . . . . . . . . . . . . 5 Sofosbuvir plus ribavirin versus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Sofosbuvir plus ribavirin versus sofosbuvir plus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . . 9 Sofosbuvir plus simeprevir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Sofosbuvir plus ledipasvir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Unknown effectiveness Sofosbuvir alone New . . . . . . . . . . . . . . . . . . . . . . 11 Sofosbuvir plus ribavirin versus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Sofosbuvir plus ribavirin versus sofosbuvir plus peginterferon plus ribavirin New . . . . . . . . . . . . . . . . . . . . . 15 Sofosbuvir plus simeprevir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Sofosbuvir plus ledipasvir (with or without ribavirin) New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
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. • This overview deals only with chronic HCV infection without liver decompensation. • The landscape of HCV antiviral therapy has changed rapidly in the past 3 years. The limited efficacy and tolerability of interferon-based antiviral regimens has prompted the recent development of direct-acting antiviral agents, such as sofosbuvir, simeprevir, and ledipasvir. During this time, several different direct-acting antiviral agents have been approved by the FDA as oral therapies for the treatment of hepatitis C. © BMJ Publishing Group Ltd 2015. All rights reserved.
..................... 1 .....................
Clinical Evidence 2015;06:921
Infectious diseases
..................................................
• Recommendations in major national clinical guidelines in this field are often based on both RCT and non-RCT evidence and should be referred to for guidance on current routine clinical practice. However, for this overview, in line with most other BMJ Clinical Evidence overviews, we have only reported on evidence from RCTs and systematic reviews of RCTs. We have reported on selected direct-acting antiviral agents, but in this fast-moving field, we will consider broadening this list of interventions in future updates. • The following points are based on our search for evidence from RCTs and systematic reviews of RCTs. • In treatment-naïve people with HCV without cirrhosis: Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment, and increasing sustained virological response at up to 12 weeks (SVR12) after the end of treatment in treatmentnaïve people with HCV genotypes 2 or 3 without cirrhosis. However, this effect appears to be greater for HCV genotype 2 than for genotype 3. • In treatment-naïve people with HCV with cirrhosis: Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment in treatment-naïve people with HCV genotypes 2 or 3 with cirrhosis. Sofosbuvir plus ribavirin may be more effective than placebo at increasing sustained virological response at up to 12 weeks (SVR12) after the end of treatment in treatment-naïve people with HCV genotypes 2 and 3 with cirrhosis. However, this effect appears to be greater for HCV genotype 2 than for genotype 3. • Sofosbuvir plus ribavirin appears to be safe and well-tolerated, with an adverse event profile consistent with ribavirin alone. • We found no RCTs assessing the effectiveness of sofosbuvir alone, sofosbuvir plus simeprevir, or sofosbuvir plus ledipasvir in treatment-naïve people with chronic HCV with or without cirrhosis. • The Q80K polymorphism, associated with genotype 1a, confers resistance to simeprevir. Therefore, testing for this genetic variation may be important before considering treatment with this drug. Clinical context
GENERAL BACKGROUND 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. Complications of chronic HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma.
FOCUS OF THE REVIEW The landscape of HCV antiviral therapy has changed rapidly in the past 3 years, making an evidence overview valuable to medical professionals. The limited efficacy and tolerability of interferon-based antiviral regimens has prompted the recent development of direct-acting antiviral agents such as sofosbuvir, simeprevir, and ledipasvir, which were selected as interventions of this evidence update.
COMMENTS ON EVIDENCE This overview reviews the available RCT evidence on pre-selected interventions. This was limited in quantity and quality (low to very-low quality). Of the six known HCV genotypes, genotype 1 is the most common in developed countries; however, all the RCTs we found were in people with genotype 2 or 3 only. We have examined the evidence from RCTs and systematic reviews of RCTs only. However, it should be noted that there are a significant number of 'open-label' trials, which have not been included in this overview but have nonetheless been considered by the FDA in the drug approval process. Please refer to the Additional information section for more details, and to major national society guidelines for recommendations on current routine practice. RCTs comparing direct-acting antiviral agents with placebo or with older standard of care treatments are now unlikely to take place because it would be considered unethical to subject patients to the latter interventions, which are known to produce a substantially lower treatment effect.
SEARCH AND APPRAISAL SUMMARY The literature search was carried out in August 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. After deduplication and removal of conference abstracts, 30 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 11 studies and the further review of 19 full publications. Of the 19 full articles evaluated, two systematic reviews and one RCT were added.
ADDITIONAL INFORMATION © BMJ Publishing Group Ltd 2015. All rights reserved.
........................................................... 2
Infectious diseases
Hepatitis C (chronic)
Sofosbuvir is approved by the US Federal Drug Administration (FDA) for use with ribavirin for 12 weeks in people with chronic HCV genotype 2, and for 24 weeks in people with chronic HCV genotype 3. Sofosbuvir combined with simeprevir or ledipasvir, with or without ribavirin, for 12 weeks in people with chronic HCV genotype 1 has been found to produce a sustained virological response of more than 90%, irrespective of previous treatment history or [1] [2] [3] presence of cirrhosis. Data for sofosbuvir and ledipasvir are based on the open-label ION-1, ION-2, ION-3, [4] [5] LONESTAR, and ELECTRON trials, whereas data for sofosbuvir and simeprevir are based on the open-label [6] [7] [8] COSMOS trial. Another important FDA-approved drug regimen was the combination of ombitasvir, pari[9] taprevir, ritonavir, and dasabuvir with or without ribavirin (based on data from the open-label SAPPHIRE-II, [10] [11] [12] TURQUOISE-II, PEARL-IV, and AVIATOR trials). When given for 12 weeks, this drug regimen has been found to result in a sustained virologic response of more than 90% in genotype 1, irrespective of previous treatment history or presence of cirrhosis. Please refer to major national society guidelines for current recommendations on [13] [14] [15] practice. Considering the encouraging data on safety and efficacy for the newer direct-acting antiviral agents, it is envisioned that primary care physicians would take on a greater role in the treatment of HCV in the near future. Unfortunately, many of these direct-acting antiviral agents are currently associated with significant pharmaceutical costs, thereby limiting their availability at the present time. In addition, further research will be needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and establish the antiviral safety and efficacy in difficult-to-cure patient population. DEFINITION
Hepatitis C virus (HCV), identified in 1989, is a member of the flaviviridae family of spherical, en[16] [17] veloped, positive-strand RNA viruses. There are six different HCV genotypes with variable distribution worldwide; some genotypes have multiple subtypes. Genotype 1 is the most common [18] 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 in[17] fection. This review only deals with 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 (SVR24).The loss of detectable HCV RNA 12 weeks after the completion of treatment is termed SVR12, and this has been recommended by the FDA as the primary efficacy endpoint in recent clinical trials as it has a positive [19] predictive value of 98% for SVR24. 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 [20] world's population chronically infected. HCV prevalence varies throughout the world, with the [21] highest number of infections reported in Egypt (6%–28%). In the US, an estimated four million people are positive for HCV antibodies, reflecting a prevalence rate of 2%; and about 35,000 new [17] HCV infections are estimated to occur each year. In Europe, the prevalence of HCV infection [22] 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/ HCV is mainly blood borne, and transmission occurs primarily through exposure to infected blood. RISK FACTORS This exposure may occur because 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 [23] blood. As a result of HCV screening, the absolute risk of acquiring infection through blood [24] components or products is now small — less than 1/400,000 units of blood transfused. HCV [25] 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 [26] [27] infection. However, in some cases, no risk factors can be identified. Of the six known HCV genotypes, genotype 1 is the most common in developed countries, with values of 47% to 72%. [27] In North America (unlike Europe and Asia), genotype 1a is the most common and is associated [28] with Q80K polymorphism in 30% to 47% of people. The Q80K polymorphism confers resistance to the drug simeprevir (a second-generation NS3/4A protease inhibitor), which leads to a considerably lower SVR, such that testing for this genetic variation is recommended before commencement [28] of treatment. 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 decompen© BMJ Publishing Group Ltd 2015. All rights reserved. ........................................................... 3
Infectious diseases
Hepatitis C (chronic)
sated liver disease, and hepatocellular carcinoma. Studies suggest that one third of people with chronic HCV infection are 'rapid progressors' (time from infection to cirrhosis 50 years). Factors associated with disease progression include: older age at acquisition; male sex; co-infection with HIV, hepatitis B virus, or both; co-existing liver disease; and excessive alcohol consumption. In people who develop cirrhosis, the 5-year risk of [30] decompensation is 15% to 20%; the 5-year risk of hepatocellular carcinoma is 10%; and the [31] [32] annual risk of hepatocellular carcinoma is 1% to 5% per year. AIMS OF To eradicate HCV infection, prevent progression to end-stage liver disease, reduce HCV transmisINTERVENTION sion, prevent development of hepatocellular carcinoma, reduce the need for liver transplantation, improve quality of life, and reduce mortality, with minimal adverse effects. OUTCOMES
Virological response, defined as HCV RNA negativity and sustained virological response (SVR); hepatocellular carcinoma; end-stage liver disease; mortality; quality of life; adverse events.
METHODS
Search strategy BMJ Clinical Evidence search and appraisal date August 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to August 2014, Embase 1980 to August 2014, The Cochrane Database of Systematic Reviews 2014, issue 8 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as ‘open’, ‘open label’, or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update (optional section) At this update, we have removed the previously reported questions to focus on interferon-free interventions. Data and quality To aid readability of the numerical data in our overviews, we round many 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). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result.These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 20 ). 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).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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Infectious diseases
Hepatitis C (chronic)
QUESTION
What are the effects of interferon-free treatments in treatment-naïve people with chronic hepatitis C infection without cirrhosis?
OPTION
SOFOSBUVIR ALONE IN TREATMENT-NAÏVE PEOPLE WITH CHRONIC HCV WITHOUT CIRRHOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New
•
For GRADE evaluation of interventions for Hepatitis C (chronic), see table, p 20 .
•
We found no RCT evidence on the effectiveness of sofosbuvir alone in treatment-naïve people with chronic HCV without cirrhosis. Benefits and harms
Sofosbuvir alone versus placebo or no treatment: [33] We found two systematic reviews (both search date 2014),
[34]
neither of which identified any RCTs.
[34]
neither of which identified any RCTs.
Sofosbuvir alone versus peginterferon plus ribavirin: [33] We found two systematic reviews (both search date 2014), Sofosbuvir alone versus sofusbuvir plus peginterferon plus ribavirin: [33] [34] We found two systematic reviews (both search date 2014), neither of which identified any RCTs. Comment: OPTION
None. SOFOSBUVIR PLUS RIBAVIRIN VERSUS PLACEBO OR NO TREATMENT IN TREATMENTNAÏVE PEOPLE WITH CHRONIC HCV WITHOUT CIRRHOSIS. . . . . . . . . . . . . . . . . . . . . . New
•
For GRADE evaluation of interventions for Hepatitis C (chronic), see table, p 20 .
•
Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment, and increasing sustained virological response at up to 12 weeks (SVR12) after the end of treatment in treatmentnaïve people with HCV genotypes 2 or 3 without cirrhosis.
•
Sofosbuvir plus ribavirin appears to be safe and well tolerated, with an adverse event profile consistent with ribavirin alone. Benefits and harms
Sofosbuvir plus ribavirin versus placebo or no treatment: [33] [34] We found two systematic reviews (both with search dates from 2014), which both identified the same RCT comparing sofosbuvir plus ribavirin with placebo in treatment-naïve people with HCV genotype 2 or genotype 3 (see [35] Further information on studies). Virological response Sofosbuvir plus ribavirin compared with placebo or no treatment Sofosbuvir plus ribavirin may be more effective than placebo at reducing HCV RNA levels at the end of treatment, and at increasing sustained virological response at 12 weeks after the end of treatment in treatment-naïve people with HCV genotypes 2 and 3 without cirrhosis and who choose not to have interferon-based treatments, or for whom interferon-based treatments are not suitable (lowquality evidence).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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5
Infectious diseases
Hepatitis C (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
End of treatment virological response (EOTR) [35]
RCT 3-armed trial
278 people with HCV for whom interferon-based treatment was unsuitable or who had decided against treatment with an interferoncontaining regimen
Proportion of people achieving P
