Showing posts with label relapse. Show all posts
Showing posts with label relapse. Show all posts

Monday, January 29, 2018

Hepatitis C virus re-treatment in the era of direct-acting antivirals: projections in the USA


ORIGINAL ARTICLE
Hepatitis C virus re-treatment in the era of direct-acting antivirals: projections in the USA
Authors J. Chhatwal, Q. Chen, T. Ayer, E. D. Bethea, F. Kanwal, K. V. Kowdley, X. Wang, M. S. Roberts, S. C. Gordon

First published: 29 January 2018

Summary
Background
The introduction of oral direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment. However, a small percentage of patients fail to achieve sustained virologic response (SVR). Understanding the number of people who fail on DAAs and require re-treatment is important for budget impact and disease burden projections.

Aim
To quantify the number of HCV patients who fail to achieve SVR on oral DAAs (NS5A vs. non-NS5A) and require re-treatment.

Methods
We used a mathematical model to simulate clinical management of HCV in the USA, which included the implementation of HCV screening, treatment, and disease progression. We simulated different waves of DAA treatment and used real-world data to extract SVR rates and market shares of available therapies.

Results
Our model projected that the number of people living without viraemia (i.e. cured) would increase from 0.70 million in 2014 to 1.78 million by 2020. Between 2014 and 2020, 1.50 million people would receive treatment with DAAs, of whom 124 000 (8.3%) are projected to fail to achieve SVR. Among those treatment failures, 66 600 (53.7%) patients would fail treatment with NS5A inhibitors and 69 600 (56.1%) would have cirrhosis. During the same period, 34 200 people would progress to decompensated cirrhosis and 27 300 would develop hepatocellular carcinoma after failing to achieve SVR.

Conclusions
Even in the era of highly effective DAAs, a significant number of patients will fail to achieve SVR and will require re-treatment options. Timely and effective re-treatment is essential to prevent the long-term sequelae of HCV.

DISCUSSION

The availability of well-tolerated and highly effective DAAs offers a new hope to eliminate HCV as a public health threat. However, even with the newer generations of DAAs, a small proportion of patients will fail to achieve SVR and could develop advanced sequelae such as decompensated cirrhosis and HCC. In this study, we simulated the current clinical landscape of HCV treatment and projected the number of patients in the USA who would receive treatment, achieve SVR, or require re-treatment. We found that in the era of DAAs, a total of 1.50 million people would receive treatment between 2014 and 2020 and around 124 000 (8.3%) would fail to achieve SVR; the majority of those who fail treatment would have been exposed to NS5A inhibitors. Timely and effective retreatment of these patients could prevent the long-term sequelae of HCV.

Earlier studies have estimated the number of patients who would remain viraemic in the era of DAAs,[6] and projected disease burden under different screening and treatment scenarios.[5, 6, 25, 26] This study adds new information by estimating the number of patients who would fail to achieve SVR, especially with NS5A inhibitors, and require retreatment in the era of DAAs. Providing this data allows payers to assess the budget impact of HCV treatment and disease burden projections. Although the DAAs have been shown to be cost-effective/saving,[27, 28] budget needed to treat all HCV patients remains challenging in some settings.[29]

We observed that under current clinical practice, the number of patients receiving treatment would drop to 61 000 by 2020 in spite of the fact that around 844 000 patients would still be viraemic in that year. This is because the majority of viraemic patients aware of their status would have received treatment by this time, whereas, those unaware of their HCV status would not be able to avail the benefits of DAA therapy. This finding emphasises the need to update the current screening policies to diagnose patients who otherwise would remain unaware and untreated. In addition, there is a need to remove treatment barriers for patients who are already aware of their HCV status but not yet linked to care, such as many injection drug users and people in prisons.

National and global health policy initiatives have stressed the desirability of eliminating HCV as a public health threat by 2030. To achieve this goal, a comprehensive strategy of patient identification, linkage to care and treatment access is required.[30] In addition, the availability of effective treatment options for patients who fail to achieve SVR after initial therapy is necessary. Although the number of such patients is relatively small compared with the current burden of HCV, these patients could become a nonsignificant portion of the viraemic population in the future. Successful retreatment of these patients, who are already linked to care, could reduce the risk of long-term clinical sequelae. While viral clearance would prevent development of advanced sequelae from chronic HCV, other external factors such as abuse of alcohol or drugs would also need to be addressed via appropriate interventions to achieve the full benefits of viral clearance with DAA therapy.

Our study also shows a growing population of patients alive following HCV cure. As this patient population increases, disease management efforts focused on regular surveillance of persons with pre-treatment advanced fibrosis or cirrhosis is important, as they remain at risk of developing hepatocellular carcinoma.[31] In addition, the burden of management for these patients may also shift from specialists to general practitioners. If this transition does take place, future efforts should also focus on increasing the awareness among general practitioners and internists regarding appropriate medical care for patients cured of HCV.

This modelling-based study has some limitations. First, the analysis only included non-institutionalised HCV-infected persons as estimated by the NHANES studies. Therefore, our results likely underestimated the number of viraemic patients. Secondly, recent data suggest that the uptake of birth-cohort screening in practice remains low, therefore, our model may have over-estimated the number of patients who would become aware of their HCV status. Thirdly, we did not include in the model HIV-HCV co-infection, which is beyond the scope of the current work. Fourth, we did not consider the possibility of regression of fibrosis after SVR, which is unlikely to effect the results presented in this study. Finally, we made assumptions about future treatment capacity, which could vary over time.

In conclusion, we found that even in the era of highly effective DAAs, there are still going to be challenges. To achieve HCV elimination a national strategy will need to support the development of systems aimed at increasing the diagnosis of HCV and plans outlining the effective and timely retreatment of patients who have failed on DAAs.

Read full text article online: http://onlinelibrary.wiley.com/doi/10.1111/apt.14527/full
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Wednesday, March 29, 2017

Care of Patients Who Have Achieved a Sustained Virologic Response (SVR) Following Antiviral Therapy for Chronic Hepatitis C Infection

AGA Institute releases practice update for managing patients cured of HCV infection
The American Gastroenterological Association (AGA) Institute released a practice update on managing patients with chronic hepatitis C virus (HCV) infection who have attained a sustained virologic response (SVR) after antiviral treatment. The clinical practice update was published in Gastroenterology.

Direct-acting antiviral (DAA) regimens for chronic HCV infection achieve high rates of SVR and have replaced interferon (IFN) in many countries. The current definition of SVR is undetectability of HCV RNA at 12 weeks after treatment (SVR12). Patients who achieve an SVR have a less than 1% risk of relapse and are considered cured.

Patients cured of HCV may experience reductions in the risk for death and hepatocellular carcinoma (HCC), as well as regression of liver changes including fibrosis or cirrhosis, but may still have higher rates of HCV-related complications than the general population. Patients who have already developed liver damage at the time of achieving SVR may be particularly at risk for future complications.
Continue reading.....

Updated
May 2017
Full Text Online
Expert Review
American Gastroenterological Association Institute Clinical Practice Update—Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection

Online

Gastroenterology
Articles in Press

AGA Institute Clinical Practice Update: Care of Patients Who Have Achieved a Sustained Virologic Response (SVR) Following Antiviral Therapy for Chronic Hepatitis C Infection
Ira M. Jacobson M.D., Joseph K. Lim, M.D., and Michael W. Fried, M.D.

ACCEPTED MANUSCRIPT
DOI: http://dx.doi.org/10.1053/j.gastro.2017.03.018

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Abstract
Chronic hepatitis C virus (HCV) infection is well-recognized as a common blood borne infection with global public health impact, affecting 3 to 5 million persons in the U.S. and over 170 million persons worldwide. Chronic HCV infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma (HCC). Current therapies with all-oral directly acting antiviral agents (DAAs) are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, HCC, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored versus discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic HCV who have achieved SVR.

Index
Assessment of HCV RNA after SVR12 has been attained
With the initiation of trials of DAA regimens, initially in combination with interferon and later
without it, the attainment of SVR 12 weeks after completion of treatment replaced SVR24 as
the primary endpoint, defined as undetectable HCV RNA on a highly sensitive PCR assay (lower
limit of detection <12 IU/mL).  This transition was based upon the rarity of relapse after follow
up week 12, and it helped move the field ahead by shortening the intervals between successive
trials in development programs (22). It has become apparent that late relapse beyond this time
point is no more common, and perhaps less so, than it was after interferon-based therapy

Ongoing surveillance for hepatocellular carcinoma after SVR
Is HCC risk after SVR exclusive to patients with advanced fibrosis and cirrhosis?
Can HCC surveillance ever be discontinued?
How should screening for, and management of, varices be affected by SVR?
Should patients be routinely monitored for regression of advanced fibrosis or
cirrhosis?

Recurrent HCC After SVR
Reinfection
Lifestyle Measures
Conclusions
Continue reading...

Full Text Articles
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A link to the above full text PDF article was tweeted today.

Tuesday, March 7, 2017

Barriers to treatment of failed or interferon ineligible patients in the era of DAA: single center study

Clin Mol Hepatol > Epub ahead of print
Seo, Yun, Li, Lee, Han, and Park

Original Article
Clin Mol Hepatol 2017; : cmh.2016.0052.
Published online: March 3, 2017

DOI: https://doi.org/10.3350/cmh.2016.0052

Barriers to treatment of failed or interferon ineligible patients in the era of DAA: single center study
Kwang Il Seo1, Byung Chul Yun1, Weiquan James Li1, 2, Sang Uk Lee1, Byung Hoon Han1, Eun Taek Park1

Received August 11, 2016 Revised January 9, 2017 Accepted January 16, 2017
Copyright © 2017 by The Korean Association for the Study of the Liver

View full text article

Abstract
Background/Aims
Interferon-based treatment is not appropriate for a large number of patients with chronic hepatitis C for various medical and social reasons. Newly developed directly acting antivirals (DAAs) have been used to treat chronic hepatitis C without severe adverse effects and have achieved a sustained viral response (SVR) rate of 80-90% with short treatment duration. We were interested to determine whether all patients who failed to respond to or were ineligible for interferon-based therapy could be treated with DAAs.

Methods
Medical records of patients with positive serum anti-hepatitis C virus (HCV) or HCV RNA between January 2009 and December 2013 were reviewed. Demographic, clinical, and treatment data were collected for analysis.

Results
A total of 876 patients were positive for both anti-HCV and HCV RNA. Of these, 244 patients were eligible for interferon, although this was associated with relapse in 39 (16%) of patients. In total, 130 patients stopped interferon therapy (67% adverse effects, 28% non-adherent, 4% malignancy, 1% alcohol abuse) and 502 patients were ineligible (66% medical contraindications, 25% non-adherent, 5% socioeconomic problems). Among 671 patients who were ineligible for or failed to respond to interferon therapy, more than 186 (27.7%) could not be treated with DAA due to financial, social, or cancer-related conditions.

Conclusions
Newly developed DAAs are a promising treatment for patients with chronic hepatitis C who are ineligible for or failed to respond to interferon-based therapy. Nevertheless, not all chronic hepatitis C patients can be treated with DAAs due to various reasons.

Discussion Only
View full text article...
The prevalence of blood-borne HCV infection is estimated to be about 3% worldwide. Although DAAs that target nonstructural protein of HCV have potent antiviral efficacy and few adverse effects, the eradication of HCV is supposed to be difficult because most acute and chronic HCV infection is asymptomatic, and screening programs are limited in most countries. In a prospective, multicenter cohort at five university hospitals from January 2007 to December 2011, 1,173 patients age >18 years who were positive for anti-HCV antibody were enrolled to investigate the epidemiological and clinical characteristics of HCV infection of Korea. The rate of antiviral therapy for HCV was 42.8% of the HCV cohort [7]. At our center, 876 patients were diagnosed in a chronic viremic state, and 374 (42.6%) were treated with interferon-based therapy.

PegIFN-α and ribavirin combination therapy have absolute contraindications including uncontrolled depression; psychosis or epilepsy; pregnancy or couples unwilling to use adequate contraception; severe concurrent medical diseases; and co-morbidities including retinal disease, autoimmune thyroid disease, and decompensated liver disease [8]. After considering the contraindications for interferon-based therapy, a large number of patients diagnosed with chronic hepatitis C could not have treatment. Therefore, the proportion of patients initiating treatment was 31.0% in Swiss cohort study [9], and 33.0% in Danish cohort study [10].

According to Falck-Ytter et al. [4], 72% of chronic hepatitis C patients were not treated. Of these, 37% did not adhere to medical recommendations, 34% were medically or psychologically ineligible, 13% had ongoing alcohol or drug abuse, and 11% refused treatment. Only 28% of chronic hepatitis C patients were treated and 13% had a sustained viral response. Narasimhan et al. [11] retrospectively reviewed the charts of all HCV patients who underwent liver biopsies. About 60% were not treated with interferon-based therapy because of loss to follow-up or non-compliance (31%), patient preference (22%), etc. In other words, chronic hepatitis C treatment largely depended on patients’ intention to treat, not medical decisions made by doctors. Restrepo et al. [12] reported that approximately 85% of patients co-infected with HCV and human immunodeficiency virus were not treated. Of these, 40% were noncompliant with medical schedules, 15% were actively abusing drugs or alcohol, and 15% refused antiviral treatment.

In our study, 876 patients were diagnosed with chronic hepatitis C having positive results for both anti-HCV and HCV RNA. Of the 876 patients, 244 were eligible for interferon, but 39 (16%) diagnosed with HCV relapse. 632 patients could not be treated appropriately with interferon-based antiviral therapy (Fig. 1). The reasons for stopping or not receiving interferon-based antiviral treatment include malignancy (30%), co-morbidity (23%), interferon-related reasons (15%) and non-adherence (26%).

The most prevalent malignancy in our cohort was HCC (81%) (Table 2). In the interferon era, HCC was a relative contraindication for antiviral therapy; however, treating chronic hepatitis C with interferon was considered to reduce HCC recurrence and improve survival [13]. The recent introduction of DAA has been expected to reduce the incidence of HCC in HCV-related cirrhotic livers. Unfortunately, DAA-induced clearance of HCV was not able to reduce the occurrence of HCC in patients with HCV-related cirrhotic livers [14]. In spite of DAA treatment, high rate of early HCC recurrence was noted in patients previously treated for HCC [14,15]. Therefore DAA therapy in HCC patients has yet to be determined.

Patients with severe co-morbidities could not be treated with interferon-based therapy because of possible severe adverse effects. About 49% of patients had advanced or decompensated liver cirrhosis that was a contraindication to interferon therapy (Fig. 4). However, an oral DAA regimen could be safe and highly effective in treating patients who are ineligible for interferon-based antiviral therapy due to HCV-related cirrhosis, decompensation. In addition to advanced liver diseases, DAA could be administered safely in patients with symptomatic cardiovascular disease, chronic renal disease, uncontrolled diabetes, extra-hepatic transplantation and psychiatric disorders [16].
Non-adherence, financial problems and alcohol abuse are also reasons to prevent antiviral therapy. With short treatment duration and all oral regimens, improved compliance is expected in patients using DAA. On the other hand, DAA is so expensive that it would be difficult for a physician to prescribe to all chronic hepatitis C patients. Therefore, a part of compliance and socioeconomic problems would be remained in DAA era.

Therefore, we could suppose that at least 42% of patients who were ineligible or failed to interferon-based antiviral therapy due to co-morbidity (22%), interferon intolerability (14%) and HCV relapse (6%) would be treated with DAAs. However, a large portion of patients who were non-adherent (25%), had alcohol abuse (2%), or had financial concerns (2%) would not be able to get a chance to use the DAA (Fig. 5). Unlike hepatitis B virus-related HCC, patients with HCC occurred with HCV (23%, 156/671) have not been determined to be treated with DAA. This study has some limitations, including a retrospective design and that it was conducted in a single, tertiary hospital. The combined co-morbidity and malignancy rates were higher than in other Korean studies [7,17]. Therefore, the results cannot be accepted generally. In spite of the limitation, this study has a clear message considering limitation of DAA therapy in chronic hepatitis C patients who were ineligible or failed to interferon based antiviral therapy.

In conclusion, only 27.7% of patients diagnosed with chronic hepatitis C in our study were treated with an interferon-based regimen. With the advent of DAAs, at least 42% of patients who were ineligible or failed to interferon and experienced HCV relapse would be able to use DAA. However nonmedical reasons, including noncompliance, financial problems, substance abuse and hepatocelluar carcinoma remain obstacles to treat chronic hepatitis C. Our study suggests that, in spite of DAA development, eradicating HCV would be difficult due to various unexpected reasons.

Wednesday, January 4, 2017

Late Relapse After Hepatitis C Virus Treatment Is Rare


Article Summary Source - NEJM Journal Watch

Late Relapse After Hepatitis C Virus Treatment Is Rare

January 3, 2017
Neil M. Ampel, MD reviewing Sarrazin C et al. Clin Infect Dis 2017 Jan 1.
Few patients treated with a sofosbuvir-containing regimen for hepatitis C virus infection had late recurrent viremia, and most occurrences appeared to be reinfections.

Neil M. Ampel, MD
Use of direct antiviral agents (DAAs) for the treatment of hepatitis C virus (HCV) infection has been associated with sustained viral suppression by 12 weeks after therapy (SVR12) in >90% of patients. Because HCV infection does not confer full protective immunity, it is important to determine the frequency of recurrences after SVR12 is achieved and to distinguish between posttreatment relapse and reinfection.

To explore these issues, researchers in Germany, Russia, France, and the U.S. conducted an industry-supported study, examining samples from 11 phase III trials that used the NS5B inhibitor sofosbuvir, alone or in combination. To distinguish late relapse from reinfection, they conducted NS5B deep sequencing analysis, short-fragment NS5B population sequencing, and phylogenetic analyses.

Among 3004 patients, only 12 (0.4%) were found to have detectable HCV RNA by 24 weeks after SVR12. Deep genetic sequencing and phylogenetic analyses revealed that 5 of these 12 patients had HCV with minimal genetic changes in the NS5B sequence, suggesting that the recurrence was due to relapse. In the other 7, the sequences prior to and after DAA therapy were significantly unrelated, indicating reinfection.

Comment
This well-performed study indicates that absence of detectable HCV RNA by 12 weeks after DAA therapy is a good measure of SVR. It also demonstrates that most cases of recurrence are due to reinfection. Unfortunately, the tools needed to distinguish reinfection from relapse are not generally available to clinicians, suggesting the need for longer follow-up of patients after DAA therapy and better strategies to prevent reinfection.

Late Relapse Versus Hepatitis C Virus Reinfection in Patients With Sustained Virologic Response After Sofosbuvir-Based Therapies

Thursday, March 13, 2014

Gene variants protect against relapse after treatment for hepatitis C

Gene variants protect against relapse after treatment for hepatitis C

 News: Mar 11, 2014

Researchers at the Sahlgrenska Academy have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment.

More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients.
Prevents incorporation in DNA

Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatas (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA.

Unexpectedly they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection.
Five times lower risk

Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment.
Relapse a significant problem

The study encompassed over 300 patients and was carried out in cooperation with hepatitis researchers in several Nordic countries.

- Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable, Martin Lagging said.
Important to other virus infections

According to Martin Lagging, the discovery may also have significance for other virus infections.

- A medication that interferes with the enzyme’s activity could have a broad antiviral effect, but this must be further investigated in future studies.

The article Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3 was published online in the journal Hepatology on 13 January 2014.

Link to the article

Contact:
Martin Lagging, researcher at The Sahlgrenska Academy, University of Gothenburg
martin.lagging@medfak.gu.se

BY: Krister Svahn
+4631786 38 69

Wednesday, January 30, 2013

Interferon May Be Harmful in Retreatment of Hepatitis C

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C

Some patients with chronic hepatitis C progress from a relatively benign condition to a life-threatening illness. Interferon has been used to try to prevent this but researchers have struggled to investigate its effects reliably. Ron Koretz from Granada Hills in the USA, tells us about the January 2013 update of the relevant Cochrane Review, outlining what the authors did to try to solve this and what they found.

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Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C Updated
Koretz RL, Pleguezuelo M, Arvaniti V, Barrera Baena P, Ciria R, Gurusamy KS, Davidson BR, Burroughs AK
 
Published Online:
January 31, 2013
 
Antiviral treatment for chronic hepatitis C infections is currently judged as being successful if, at least six months after therapy, blood tests for hepatitis C viral RNA are negative; this has been called a sustained viral response. In the past, other outcomes for treatment have included improvements in biochemical tests (especially liver enzyme tests such as the serum alanine aminotransferase) or evidence of reduced inflammation and/or fibrosis on subsequent liver biopsies. All of these outcomes are tests, and it has been assumed that if the test gets better the patient will as well. However, there is no direct evidence that has proven that these outcomes are valid because there have been no long-term trials that have shown that an improvement in these tests translates into reduced mortality or morbidity. Patients who fail to have sustained viral responses after an initial course of therapy do become potential candidates for retreatment; some of them may be intolerant to ribavirin, and possibly even the newer protease inhibitors, so retreatment would have to be with interferon alone. It has also been speculated that long-term treatment (namely treatment for several years) might be beneficial; such long-term therapy would be further complicated if multiple drugs were used because of the additional drug toxicities and costs, so interferon alone could be considered.....
 
Continue to updated material @  Cochrane Summaries

Related-

Chronic hepatitis C: Interferon may be harmful in re-treatment

People with hepatitis C and chronic liver disease who relapsed or failed to respond to initial treatment are unlikely to improve on interferon retreatment. In fact, they may face an increased risk of dying sooner, and are likely to experience a variety of adverse effects, according to an updated systematic review published in The Cochrane Library.

Hepatitis C affects around 170 million people worldwide. In some cases, infection leads to chronic liver disease, liver failure or liver cancer, eventually resulting in death. Treatment is based on antiviral drugs.

Interferon monotherapy, meaning using interferon alone, is not the first choice of therapy for most clinicians, but it is used in some patients when other drugs cannot be used. Despite costing thousands of dollars to treat one patient for a year, there is currently little evidence that it works. Treatment is considered to have been successful if the virus cannot be detected in a patient's blood six months after treatment. This outcome is known as sustained viral response (SVR). However, it has never been confirmed that SVR leads to an improvement in the patient's disease state or their chances of survival.

The authors of the review analysed data from seven trials involving a total of 1,976 patients with chronic hepatitis C liver disease who were being retreated with interferon monotherapy having previously been treated unsuccessfully. When they included all trials in their analysis, the risk of death was no higher for interferon than for placebo or no treatment. However, the researchers also performed a further analysis, leaving out studies that had a high risk of bias and gave less reliable estimates of effect. For example, one of these trials was not blinded, was stopped before the planned number of patients had been enrolled, and did not have all of those who had been enrolled counted in the final analysis. This left the two largest trials, together incorporating 1,676 patients. Focusing only on these trials, the risk of death was significantly higher at 9.4% for interferon retreatment compared to 6.7% for placebo or no treatment.

"It was troubling to see that in those trials providing the most reliable estimates of treatment effects, interferon seemed to increase the risk of death," said lead researcher Ronald Koretz of Granada Hills in California, US. "Based on these results, interferon monotherapy cannot be recommended for chronic hepatitis C patients who have already failed one course of treatment and are being retreated. Furthermore, patients who are receiving interferon as part of a combination therapy should be informed about this potential adverse effect."

Interferon treatment did seem to reduce levels of hepatitis C virus in the blood compared to controls, resulting in what would be considered successful treatment or SVR. However, since this response was not associated with an improvement in disease or risk of death, the review suggests that SVR may be inadequate as an indicator of a successful treatment outcome. "Sustained viral response did not suggest that a patient who was destined to develop symptoms or death from hepatitis C was cured, at least in this setting. This tells us that as a treatment outcome it is not universally reliable and needs to be validated before it can be viewed as the goal of any therapy in other clinical scenarios," said Koretz.

Patients in the treatment group were also more likely to suffer adverse effects. Although the drug did appear to reduce the incidence of nonfatal internal bleeding, the researchers conclude that it is so expensive that it may be hard to justify based on this one small benefit.

http://www.eurekalert.org/pub_releases/2013-01/w-chc012813.php

Interferon May Be Harmful in Retreatment of Hepatitis C

Medscape

When patients with hepatitis C and chronic liver disease suffer relapses or fail to respond to initial treatment, monotherapy with interferon may not be a good idea, according to results from a recent meta-analysis. In fact, employing that approach may raise the risks for death and adverse effects.

The review is published in the January issue of the Cochrane Database of Systematic Reviews and was conducted by Ronald Koretz, MD, professor of medicine, digestive diseases and gastroenterology, David Geffen School of Medicine, University of California, Los Angeles, and colleagues.

"The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated," the authors write.

The lack of validation is not surprising, the authors say, because very few randomized clinical trials evaluating clinical outcomes (mortality or manifestations of cirrhosis) have been conducted, as patients usually do not die or develop cirrhosis until years after they have been infected.

Patients who undergo initial therapy but do not produce sustained viral responses become potential candidates for retreatment, the authors note, but for some patients in whom standard treatment with ribavirin or protease inhibitors cannot be tolerated, clinicians often consider retreatment with interferon to be a reasonable option.

All-Cause Mortality Worse
To find out more about the actual clinical effects of retreatment with interferon, the investigators reviewed data from 7 clinical trials in which monotherapy retreatment with interferon was compared with placebo or no treatment.

Two of the trials (the Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C] and Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3] trials) were considered to be at low risk for bias. Together, those trials included 1676 patients. Both assessed the clinical outcomes of patients with severe fibrosis who underwent long-term low-dose retreatment with pegylated interferon therapy.

The other 5 trials included a total of 300 patients and were considered to be at high risk for bias.
Dr. Koretz and colleagues report that when they included all trials with published outcomes in their review they saw no significant difference in all-cause mortality (78/843 [9.3%] vs 62/867 [7.2%]; risk ratio [RR], 1.30; 95% confidence interval [CI], 0.95 - 1.79; 3 trials). They also did not find a significant difference in hepatic-related mortality (41/532 [7.7%] vs 40/552 [7.2%]; RR, 1.07; 95% CI, 0.70 - 1.63; 2 trials).

However, when the reviewers included only the 2 trials considered at low risk for bias, they noted that all-cause mortality was significantly higher among patients who received interferon (78/828 [9.4%] vs 57/848 [6.7%]; RR, 1.41; 95% CI, 1.02 - 1.96).

They do note, however, that there was less variceal bleeding in patients who received interferon (4/843 [0.5%] vs 18/867 [2.1%]; RR, 0.24; 95% CI, 0.09 - 0.67; 3 trials). Still, the researchers comment that the prohibitive cost of interferon would not justify it for this indication alone.
Patients administered interferon were no more likely to develop ascites, encephalopathy, or hepatocellular carcinoma or to need liver transplants.

Only one of the trials included quality-of-life data, and in that trial pain scores were significantly worse in patients receiving interferon, the reviewers write. Patients receiving interferon were also more likely to suffer adverse effects, most commonly hematologic complications, infections, influenza-like symptoms, and rashes.

SVR a Surrogate Marker?
Interferon therapy did appear, however, to be associated with significantly better viral responses (20/557 [3.6%] vs 1/579 [0.2%]; RR, 15.38; 95% CI, 2.93 - 80.71; 4 trials). In addition, METAVIR activity scores, gauging degree of inflammation as well as the extent of fibrosis, also improved (36/55 [65%] vs 20/46 [43.5%]; RR, 1.49; 95% CI, 1.02 - 2.18; 2 trials). However, the reviewers say they saw no significant differences in histologic assessments of fibrosis.

The authors stress that the clinical data they reviewed were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon.

"In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events," the authors note.

In conclusion, they write, "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated."

The authors have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2013:1:CD003617.

 

Sunday, October 21, 2012

Telaprevir had greater relative efficacy than boceprevir in patients who had previously relapsed

Clin Infect Dis. 2012 Oct 16. [Epub ahead of print]

The Relative Efficacy of Boceprevir and Telaprevir in the Treatment of HCV Genotype 1.

Schmitz S, O'Leary A, Walsh C, Bergin C, Norris S.

Source

Department of Statistics, Trinity College Dublin, Ireland.

Abstract

Background. 
The licensing of direct-acting anti-virals heralds a new era in the treatment of HCV genotype 1. There are no head-to-head trials examining their comparative efficacy and there are none currently registered. We undertook a mixed treatment comparison to examine the relative efficacy among current treatments for HCV.

Methods. 
A systematic literature review identified relevant studies. Meta-analyses were planned in treatment-naïve and treatment-experienced patients. Study arms which evaluated telaprevir or boceprevir for unlicensed durations or without both pegylated-interferon and ribavirin at standard doses were excluded. A Bayesian mixed treatment comparison model was fitted for each patient population. Potential influence of confounders was analysed using meta-regression.

Results. 
499 studies were identified, 10 studies met inclusion criteria. In the subgroup of prior treatment "relapsers" telaprevir had greater relative efficacy than boceprevir (Odds Ratio 2.61(1.24, 5.52)).

There were no statistically significant differences detected in relative efficacy for other patient categories. Treatment-naïve patients: boceprevir versus standard-of-care (n= 1417) Odds Ratio 3.06(2.43, 3.87); telaprevir versus standard-of-care (n=1309) Odds Ratio 3.24(2.56, 4.10); telaprevir versus boceprevir Odds Ratio 1.06(0.75, 1.47). Total treatment-experienced population: boceprevir versus standard-of-care (n=604) Odds Ratio 6.53(4.20, 10.32); telaprevir versus standard-of-care (n=891) Odds Ratio 8.32(5.69, 12.36); telaprevir versus boceprevir Odds Ratio 1.27(0.71, 2.30).

Conclusions. 
Telaprevir had greater relative efficacy than boceprevir in patients who had previously relapsed. There was insufficient evidence to detect a difference in treatment outcomes between the two agents in the overall population. It was not possible to determine relative efficacy for subgroups such as cirrhotics due to small numbers.

Sept 29 2012
Efficacy of telaprevir and boceprevir in treatment-naïve and treatment-experienced genotype 1 chronic hepatitis C patients : an indirect comparison using Bayesian network meta-analysis.

Monday, October 1, 2012

Hepatitis C - Response to Interferon-α/Ribavirin Does Not Decrease on Retreatment

Response to Interferon-α/Ribavirin Does Not Decrease on Retreatment of Hepatitis C

Among study participants with the same end-of-study response status, HCV RNA declines at 4 weeks were similar between treatment-naive patients and treatment-experienced ones.
Participants in treatment studies of hepatitis C virus (HCV) infection are generally categorized as treatment naive or treatment experienced, based on previous receipt of an interferon-based regimen such as pegylated interferon-α plus ribavirin (P/R). Treatment-experienced individuals with P/R treatment failure can be further subdivided into relapsers, partial responders, and null responders, based on plasma HCV RNA concentrations during and after therapy.

To date, no data have emerged to indicate resistance to interferon-α–based therapy, suggesting that the response rate to P/R should not be lower with retreatment than with initial therapy. To examine this issue, investigators at the FDA examined data for participants in eight earlier trials (2996 treatment-naive and 754 treatment-experienced patients with genotype-1 HCV infection who had completed P/R treatment and had week-4 viral load data available).

In both treatment-naive and treatment-experienced patients, the HCV RNA change from baseline at 4 weeks was strongly correlated with the likelihood of achieving a sustained viral response (i.e., an undetectable viral load 24 weeks after the end of treatment). When therapy response was compared between treatment-experienced patients (stratified according to previous treatment outcomes) and treatment-naive patients (stratified based on end-of-treatment outcomes), the 4-week decline in HCV RNA was similar between the corresponding groups.

Comment: Despite its retrospective nature, this study suggests that responsiveness to Interferon-α/Ribavirin  (P/R) does not decrease with retreatment. As the authors point out, this finding has implications for trials of interferon-based triple therapy — P/R plus one of the newer direct-acting antivirals emerging for HCV.

Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases September 19, 2012

Citation(s):
Liu J et al. Interferon responsiveness does not change in treatment-experienced hepatitis C subjects: Implications for drug development and clinical decisions. Clin Infect Dis 2012 Sep 1; 55:639.

Friday, September 28, 2012

Protease Inhibitors - Maximizing Treatment Benefit in HCV

Alimentary Pharmacology & Therapeutics

Despite Poor Interferon Response in Advanced Hepatitis C Virus Infection, Models of Protease Inhibitor Treatment Predict Maximum Treatment Benefit

I. A. Rowe; D. D. Houlihan; D. J. Mutimer
Posted: 09/28/2012; Aliment Pharmacol Ther. 2012;36(7):670-679. © 2012 Blackwell Publishing

Source-Medscape

Abstract

Background Protease inhibitors have improved sustained virological response (SVR) rates for subjects with genotype 1 hepatitis C virus infection (HCV). There is however uncertainty regarding how, and in whom, these agents should be used. In previously treated subjects, prior response to interferon has a major effect on SVR rates with protease inhibitor therapy.
Aim To assess the benefits of treatment and to understand the utility of a stopping rule for subjects with a poor interferon response following a 4-week lead-in with pegylated interferon and ribavirin.
Methods Treatment responses and long-term outcomes were modelled using hypothetical 1000 subject cohorts with 5 years of follow-up. Treatment strategies were compared with number needed to treat (NNT) and comparative effectiveness approaches.
Results Over 5 years of follow-up the NNT to prevent liver-related mortality for subjects with advanced fibrosis was substantially lower than that for subjects with all fibrosis stages (18 vs. 60) indicating particular benefit in this high-risk population. The use of a stopping rule for subjects with advanced fibrosis and a poor interferon response after a 4-week lead-in reduces the number of subjects exposed to a protease inhibitor by 55%. However, 33% fewer liver-related deaths are prevented using this strategy, indicating that there is unacceptable harm associated with this approach over a 5-year follow-up period.
Conclusions Subjects with advanced fibrosis should be prioritised for triple therapy on the basis of need. Treatment should be continued regardless of initial interferon response to maximise the early prevention of hepatitis C virus-related mortality.

Introduction
Hepatitis C virus (HCV) infection affects up to 200 million individuals worldwide and is an important cause of both morbidity and mortality.[1] Indeed up to 30% will develop cirrhosis with the attendant risks of liver failure and the development of hepatocellular cancer (HCC).[2, 3] Antiviral treatment has improved during the last two decades, but sustained virological response (SVR) rates remained below 50% for individuals infected with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Since these were until recently the only available treatments many patients have been treated and not cured. Many of these individuals have cirrhosis, are at significant risk from liver related mortality and are prime candidates for more efficacious treatments that will reduce this mortality risk. To estimate this risk reduction it is crucial to understand the impact of the surrogate outcome of SVR on liver-related morbidity and mortality. This understanding permits well-informed discussion with patients who are considering retreatment.[4]

In the last year, the first generation of directly acting antiviral (DAA) agents has been licensed for treatment of patients with genotype 1 HCV infection. These are NS3 serine protease inhibitors that, when used with pegylated interferon and ribavirin, substantially improve response rates and have the potential to cure many individuals who would not have been cured with the previous standard of care.[5, 6] This increased cure rate comes at the expense of increased adverse events and an increased pill burden. Furthermore, DAAs have the potential to cause drug resistance, analogous to that seen with antiviral treatment for human immunodeficiency virus and hepatitis B virus (reviewed in).[7]

Resistant species are associated with antiviral treatment failure, but the long-term ramifications of resistance are not known. It is possible that resistance to these agents will compromise the chance of treatment success with regimens that contain similar agents in the future. To limit the development of resistance, all of the phase II and III studies employed strict stopping rules to prevent futile drug exposure. Despite this up to 50% of those treated and who were not cured still developed drug resistant variants although these were frequently short-lived in the plasma.[8]

In the boceprevir development programme and in the phase III study of previously treated subjects with telaprevir, a 4-week lead-in phase with pegylated interferon and ribavirin was employed.[8–10] This strategy confirmed that interferon responsiveness was a key determinant of successful treatment. It has been suggested that the lead-in could be used to identify individuals with poor interferon response where treatment with first-generation protease inhibitors should be avoided, thus eliminating the risk of drug resistance and reducing the frequency and severity of treatment-associated adverse events.[11–13] Indeed, some experts would use the 4-week lead-in with both telaprevir and boceprevir where poor interferon response might be expected to aid decision making.[14] This approach is the subject of intense debate as some patients with poor response during the lead-in phase are subsequently cured with DAA containing treatment.

The aims of this study were therefore twofold: first to quantify the benefit associated with protease inhibitor treatment in previously treated subjects to aid patient selection for treatment, and second to evaluate the benefits and risks of using a lead-in phase with interferon and ribavirin dual therapy to identify patients who will benefit from addition of a protease inhibitor. The comparative effectiveness of treatment strategies was assessed using hypothetical patient cohorts over a clinically relevant 5-year follow-up period.

Maximizing Treatment Benefit in HCV: Methods

Methods
Treatment Strategy
All patients who had previously failed treatment with interferon and ribavirin were considered suitable for treatment. The proportions of subjects with previous null response (<2log10 decline in plasma HCV RNA during 12 weeks of dual therapy), partial response (>2log10 decline in plasma HCV RNA but without achieving plasma HCV RNA PCR negativity) and relapse (PCR negativity at end of antiviral treatment, but subsequent relapse) were estimated at 45%, 20%, 35% respectively.[15–17] There is no head-to-head comparison of boceprevir and telaprevir, and treatment responses appear comparable.[8–10, 18] As patients with prior null response to dual therapy were not included in the registration studies of boceprevir we planned treatment using a prototypic protease inhibitor modelled on telaprevir. Sustained virological response rates were estimated from studies in previously treated subjects and their subgroup analyses (Table 1, and supplementary information).[9, 19] The utility of treating subjects with advanced fibrosis (defined as METAVIR F3/F4) was first determined using these SVR estimates and by comparison with treatment of subjects with all stages of fibrosis.

Treatment regimens with and without a stopping rule after the 4-week pegylated interferon and ribavirin lead-in phase (<1log10 reduction in HCV RNA) in subjects with advanced fibrosis were then assessed. The variables included in this analysis are shown in Table 2 (and are summarised in Supplementary Figure S1). Standard stopping rules to avoid futile treatment were left in place (i.e. HCV RNA greater than 1000 IU/mL at either 4 weeks or 12 weeks after the start of triple therapy[20]) but were not explicitly modelled. In each case, analyses were done containing only those showing previous partial or null response since it was considered likely that previous relapsers would receive full treatment regardless of response to lead-in pegylated interferon and ribavirin (SVR rates in this population are very high regardless of baseline fibrosis stage).[9] Frequency of poor interferon response was extracted from a subgroup analysis of the REALIZE trial.[9, 19]

Table 1. Calculation of estimated rates of sustained virological response (SVR) for previously treated subjects

Prior treatment responseTreat allAdvanced fibrosis only
Measured SVR (%)Number of subjects with SVR per 100 subjectsMeasured SVR (%)Number of subjects with SVR per 100 subjects
Relapse85.730.084.829.7
Partial responder56.711.3428.4
Null responder31.314.12511.3
Total (%)55.449.4

Pooled measured SVR rates of protease inhibitor treated subjects9 were used to estimate SVR rates from an unselected, previously treated, HCV-infected population. Frequency of prior responses was determined as above: relapse 35%, partial response 20% and null response 45%.

Outcomes After Treatment
Estimations of the rates of liver-related mortality, hepatic decompensation, and for the development of HCC were reported in a meta-analysis of previously treated patients,[21] and more recently in a prospective study of patients entered into clinical trials in a single centre.[22] These data allow the calculation of the absolute risk reduction (ARR) for each of these clinical events with successful treatment. For instance in the meta-analysis,[21] in previously treated subjects with advanced fibrosis and who do not achieve SVR the annual risk of liver-related mortality is estimated at 2.7%. For individuals with SVR the annual risk reduction is estimated at 0.19, or an annual mortality risk of 0.5% thus giving an ARR of liver-related mortality of 2.2% in those with SVR. The ARR for each outcome is given in Table 2. Adverse outcomes were calculated considering a follow-up duration of 5 years as it is unlikely that additional classes of DAAs will be licensed in that timeframe, and since it is interferon failure in this group that governs poor treatment response this is likely the minimum time until interferon-free regimens are licensed.

Table 2. Variables included in the analysis of a stopping rule after a 4-week lead-in with pegylated interferon and ribavirin

VariableBase case (%)Sensitivity (%)Reference
Previous treatment response[15–17]
Partial response2920–40
Null response7160–80
Interferon sensitivity: <1log10 After 4-week P/R lead-ina[9, 19]
Previous partial response3730–40
Previous null response6260–75
SVR with protease inhibitor[9, 19]
Previous partial response
<1log10 After 4-week P/R lead-in5650–60
>1log10 After 4-week P/R lead-in5950–65
Previous null response
<1log10 After 4-week P/R lead-in1510–20
>1log10 After 4-week P/R lead-in5450–60
Annual ARR following SVR[21, 39]
Liver related mortality2.22–4
Decompensation2.52–5
Hepatocellular carcinoma2.22–5
Risk of treatment emergent adverse events[27–29]
Decompensation21–3
Death10.5–2

ARR, absolute risk reduction; P/R, pegylated interferon and ribavirin; SVR sustained virological response.

*Estimate includes all subjects receiving pegylated interferon and ribavirin for 4 weeks, i.e. control group and lead-in arm.

Comparison of Treatment Regimens
Calculations were based on hypothetical cohorts of 1000 subjects, and were compared using a decision analysis and comparative effectiveness approach.[23–25] These cohorts were assigned to receive treatment according to the regimens defined above. Treatment benefit was estimated using a number needed to treat (NNT) approach.[26] The NNT was calculated using the formula below accounting both for the ARR associated with successful treatment (i.e. the SVR) and also the relative probability of that success.



Since the ARR is expressed per annum, to account for 5-year follow-up, the NNT was divided by 5 to give a 5-year NNT for each outcome.
The rate of clinical events in each cohort was then calculated using the NNT and compared by treatment regimen. The rate of the treatment related serious adverse events of hepatic decompensation (2%) and death (1%)[27–29] were also compared using this approach.

Sensitivity Analyses
Selected parameters in the base case analysis were varied within plausible limits (Table 2). For instance, rates of ARR for liver-related mortality and HCC varied from 2% to 4%, and 2% to 5%, respectively, in line with recently published data.[21, 22] As relatively few subjects with advanced fibrosis were included in the phase III studies, and those that were had well-preserved liver function, SVR rates varied from 10% to 20% in previous null responders and from 40% to 60% in partial responders. The proportion of subjects not achieving a 1log10 reduction at 4 weeks also varied from 32% to 45% in partial responders and from 55% to 70% in null responders. The relative proportion of null and partial responders included varied from 80/20 to 60/40 splits. Finally, the rate of treatment emergent adverse events varied between 1% and 3% for hepatic decompensation and 0.5% and 2% for treatment-related death.

Maximizing Treatment Benefit in HCV: Results

Results
Mortality Reduction After Treatment
The effect of antiviral treatment on mortality has been assessed in relatively few studies due to the slowly progressive nature of HCV infection and the consequent use of SVR as a surrogate endpoint. To assess the treatment benefit of protease inhibitor containing triple therapy in previously treated subjects, we calculated the 5-year NNT for two groups: those with any stage of liver disease, and those with advanced fibrosis.[30] For those treated with a protease inhibitor, the 5-year NNT for those with any stage of liver disease is 60 to prevent one liver-related death whereas it is 18 when considering those with advanced fibrosis, despite a reduced SVR (Table 3). The impact of the NNT is highlighted when the number of deaths prevented in each treatment strategy is calculated in hypothetical patient cohorts: more than threefold more deaths are prevented when treating only subjects with advanced disease. These data highlight the importance of considering treatment in this high-risk group and indicate that this group should be prioritised for treatment on the basis of need.

Table 3. Comparison of liver-related mortality benefit in treatment of previously treated subjects with HCV infection stratified by fibrosis stage

Treatment groupAnnual ARR in liver-related mortality (%)21SVR (%)a95-year NNT to prevent 1 deathHCV deaths prevented per 1000 patient cohort over 5 years
Treat all0.655.46017
Advanced fibrosis only2.249.41854

ARR, annual risk reduction; NNT, number needed to treat; SVR, sustained virological response.
*Calculated SVR based on estimated proportion of prior null and partial responders as described.

Comparative Effectiveness of Including a Stopping Rule After the 4-week Lead-in
The outcomes of subjects treated with protease inhibitor containing triple therapy are shown in Figure 1. The strategy of treating all patients regardless of response after the 4-week lead-in with pegylated interferon and ribavirin results in the maximal prevention of death (Figure 1a). Employing the virological response to a 4-week lead-in with dual therapy as a stopping rule (Figure 1b) allows treatment to be stopped in the majority of this difficult-to-treat population thus reducing protease inhibitor exposure, and reducing the total number of treatment emergent adverse events. However, there is a notable increase in the efficacy of protease inhibitor containing therapy if treatment is stopped in subjects not achieving a >1log10 reduction in HCV RNA. As those with unfavourable responses are excluded from protease inhibitor containing treatment SVR rates for subjects treated with triple therapy are increased from 37.9% in the treat all strategy to 56.1% when the 4-week stopping rule is applied (Figure 1a,b).



Figure 1.
Flow diagram of the hypothetical 1000 subject cohort based on two strategies. (a) All 1000 subjects were treated with protease inhibitor containing triple therapy regardless of initial interferon response, and (b) after a 4-week lead-in treatment was stopped in subjects not achieving >1log10 reduction in HCV RNA. The number needed to treat for each scenario of completed treatment was calculated. After 5-year follow-up the number of deaths prevented was also assessed. F/U, follow-up; NNT, number needed to treat; P/R, pegylated interferon and ribavirin; SVR, sustained virological response.

There is however a significant reduction in overall clinical effectiveness associated with using the 4-week stopping rule. The number of patients achieving SVR is reduced by 37% as a result of excluding those subjects who would otherwise have been cured by continued treatment (SVR 'missed', Figure 1b). As this is a high-risk group and subjects who are not cured remain at significant risk of liver related morbidity and mortality we calculated the effects of the 4-week stopping rule on these parameters (Table 4). For subjects treated with triple therapy but without a stopping rule at week 4, 42 deaths are prevented over 5-year follow-up. However, only 28 deaths are prevented when the 4-week stopping rule is applied, a reduction of 33%. This indicates that by using the 4-week stopping rule 14 premature deaths occur that would have otherwise have been prevented by treating in the absence of the stopping rule.

Table 4. Effect of treatment emergent adverse events on clinical outcomes after antiviral treatment in previously treated HCV infected subjects with advanced fibrosis

Clinical eventTreatment strategyEvents incurred by using 4-week stopping rule*
Treat allStop if <1log10 reduction after 4 weeks
Prevented HCV death422814
On treatment death105-5
Net32239
Prevented HCV decompensation473215
On treatment decompensation209-11
Net27234
Prevented HCC422814
On treatment HCC000
Net422814

HCC, hepatocellular carcinoma; HCV, hepatitis C virus.
Calculations are based on a hypothetical 1000 subject cohort with 5-year follow-up after antiviral treatment.
*Negative values indicate events that are reduced when the stopping rule is applied.

The Impact of Treatment Emergent Adverse Effects on Outcome
This difficult to treat population is at risk of treatment emergent adverse effects that can negatively impact on the outcome of treatment. In similar studies of dual therapy hepatic decompensation occurs in approximately 2% of those treated and death occurs in approximately 1%.[28, 29] These data are supported by the initial safety data reported in the early expanded access to protease inhibitor programmes in France.[27] The impact on these episodes is summarised in Table 4. For instance, treatment emergent hepatic decompensation (i.e. decompensation precipitated by treatment) decreases overall treatment effectiveness. In effect there is an approximately 40% reduction in the net number of decopmensation episodes prevented by treatment in the treat-all strategy. When the 4-week stopping rule is employed there is a reduction in treatment-related decompensation episodes, but the advantage of treating all subjects regardless of response at week 4 of treatment remains. The impact on death is similar and these data indicate that the development of treatment emergent adverse effects does not significantly reduce the comparative benefit that is achieved by treating subjects regardless of virological response at treatment week 4.

Sensitivity Analyses
In sensitivity analyses, the overall benefit of continued treatment despite poor virological response at treatment week 4 was maintained despite variation in the proportion of null and partial responders, low SVR rates to protease inhibitor containing treatment, and also in cohorts containing an increased frequency of subjects not achieving >1log10 reductions at treatment week 4. However, in scenarios where there was greater mortality associated with treatment, and particularly where this was associated with low treatment efficacy, there was no difference in overall mortality between those treated regardless of virological response and those treated according to the 4-week stopping rule (Table 5). These analyses support not using the 4-week lead-in as a universal stopping rule but rather individualising treatment where subjects at high risk of on-treatment mortality due to the presence of advanced cirrhosis and portal hypertension[28, 29] should have interferon sensitivity considered in treatment planning.

Table 5. Outcomes of sensitivity analyses

Sensitivity parameterNet deaths prevented by treatment strategyDeaths incurred by using 4-week stopping rule
Treat allStop if <1log10 reduction after 4 weeks
Base case32239
High ARR death765125
Low ARR death28217
Low SVR rates26206
Increased prior null response29227
Increased poor interferon response281810
High on-treatment mortality22193
Low SVR AND high on-treatment mortality16160

SVR, sustained virological response.
Calculations are based on a hypothetical 1000 subject cohort with 5-year follow-up after antiviral treatment. Outcomes presented here are based on the extremes of the sensitivity parameters provided in Table 2.

Maximizing Treatment Benefit in HCV: Discussion

Discussion
The development of novel DAA agents targeting HCV has the potential to significantly improve outcomes for subjects with HCV infection.[5, 6] There are however a number of questions regarding how, and in whom, these agents should be used.[13, 14, 31] This analysis provides a clear rationale for prioritising subjects with advanced fibrosis who are at significant risk of liver-related morbidity and mortality for treatment. This group represents at least 25% of infected subjects at current estimates[32] and targeted treatment offers the potential to reduce liver-related mortality in a relevant timeframe. Our modelling cautions against the use of the 4-week lead-in phase as a universal decision point in subjects with advanced fibrosis as this strategy will disadvantage as many as 37% of subjects who would otherwise ultimately have derived benefit from continued treatment.

Recent licensing of DAA agents has brought further complexity to the management of genotype 1 HCV infection. In addition, the rapid development of new agents has led to uncertainty regarding which subjects to treat now, and which patients might be deferred from treatment.[33] Using the analyses presented here we have illuminated this difficult topic, particularly highlighting the benefits of treating subjects with advanced fibrosis. This population is in need of effective treatment and the benefit of this analysis is that it clarifies the clinical outcome that results as a consequence of treatment vs. no treatment in a clinically relevant timeframe. There is clinical heterogeneity in a group containing all subjects with advanced fibrosis (METAVIR F3/F4), however, the data included in the model are supported by clinical data drawn directly from this population. For instance, treatment responses are from randomised controlled data, and long-term follow-up data are from a meta-analysis of more than 1400 subjects.[9, 21] Using these analyses to support clinical decision making and the prioritisation of subjects for treatment should allow clinicians to maximise treatment benefit through mortality reduction in the next 5 years despite relatively low SVR rates and whilst further developments in therapy occur. Furthermore, the analyses provide critical information in the explanation of the potential benefits (and risks) of treatment for clinicians to share with subjects with advanced fibrosis who are considering treatment.

The rationale for using the 4-week lead-in phase for decision making has been based on concerns regarding increased toxicity in subjects with advanced disease, and also concerns about the evolution and persistence of drug resistant variants.[11–13] The registration studies for both boceprevir and telaprevir included patients with advanced fibrosis, albeit at a relatively low frequency, and these patients had well compensated liver disease. In subjects treated with pegylated interferon and ribavirin dual therapy there is evidence that the treatment emergent adverse effects of hepatic decompensation and death are more common in those with advanced cirrhosis and portal hypertension.[28, 29] Our analysis indicates that allowing for treatment-associated decompensation at a rate of 1 in 50 treated patients and mortality at 1 in 100 (in keeping with reports from early access programs),[27] there remains a benefit in continuing treatment regardless of treatment response at treatment week 4. The development of resistant variants is more difficult to model since the consequences of these frequently short-lived variants are uncertain. Whilst there is the potential for these variants to persist and to impact on future protease inhibitor containing treatment[7] and candidacy for future clinical trials of perhaps more effective therapies, the likelihood is that for many of the subjects included in this analysis this would be the last opportunity for treatment (prior to liver transplantation or death). This is especially apparent as it is interferon sensitivity that governs the poor responses to treatment in this group and that pegylated interferon is likely to remain a component of standard of care therapy for the next 5 years at least.

This analysis is limited by several factors. The data are extracted from several studies, none of which were intended to address this particular question. Furthermore, none of the studies contained large numbers of patients with advanced fibrosis and indeed the boceprevir development programme did not address treatment responses in prior null responders. The treatment responses for boceprevir and telaprevir appear broadly similar and we therefore considered a prototypic protease inhibitor based on the published data that were available. In sensitivity analyses, we varied the proportions of prior null and partial responders, the SVR rates and the rates of treatment emergent adverse effects to address the areas where there were uncertainty in the primary reports. These analyses indicated that there was benefit of continued treatment regardless of virological response at treatment week 4. There were however important exceptions to this, and that is in scenarios where there are high rates of treatment emergent mortality. In these situation there was no benefit to continued treatment following a <1log10 reduction in HCV RNA when considering 5-year follow-up. These scenarios might be represented by subjects with advanced cirrhosis and significant portal hypertension where treatment is already risky and where a failure to respond to the 4-week lead-in could be considered an indication to stop treatment. The analyses presented here therefore provide important evidence to support individualised treatment decision making in this difficult population. Further studies addressing this population should be carefully designed to ensure that stopping rules are implemented both for virological failure and to protect those included from excessive treatment related morbidity and mortality.

This analysis contains a relatively crude assessment of benefit and harm. Whilst this is based on important clinical outcomes of death, hepatic decompensation and the development of HCC rather than the surrogate measure of SVR it is likely that the lasting benefits of SVR are underestimated. Whilst several investigators have studied the effects of SVR on more relevant outcomes, such as serum biochemistry[34] and fibrosis stage,[35, 36] the overall clinical outcomes of SVR are seldom reported. We therefore utilised a meta-analysis of clinical outcomes after SVR.[21] A more recent prospective report suggests that both the annual risk of liver-related mortality, and the ARR in mortality might be greater than we considered[22] suggesting that the mortality reductions in the base case analysis might underestimate the true effect of treatment. Furthermore considering follow-up of only 5 years duration will underestimate the overall benefit of treatment. This parameter was however set at 5 years to permit decisions to be made in this clinically relevant timeframe. Additional data indicating that productivity is decreased and absenteeism is increased in HCV infected subjects suggests significant additional benefit from successful treatment.[37, 38] Although these outcomes are difficult to model the benefit we have highlighted in continuing treatment regardless of response at treatment week 4 is likely increased when all factors are considered. Of course, additional treatment emergent adverse events will also be incurred through continued treatment of this population regardless of virological response at week 4, and some of these will be severe. In those subjects with advanced disease these are likely to be more frequent, and to contribute to treatment emergent decompensation and death. These events, however, do not negate the benefit of treatment. A decision to wait for further treatment developments in this high-risk group therefore has the potential to cause the greatest harm when compared with any of the treatment strategies presented here and the mortality reduction noted with treatment strongly cautions against that approach.

These analyses describe previously treated subjects with prior null and partial responses. As the absolute risk reduction in mortality associated with successful treatment in the untreated population is likely to be similar[39] these findings are generalisable to all subjects with advanced fibrosis undergoing treatment with protease inhibitor containing treatment. The findings are however not applicable to subjects with early fibrosis where the harms of treatment manifest through treatment emergent adverse effects, or the development of resistant variants, may outweigh the benefits of continued treatment in poor interferon responders. Whilst information on the significance of resistance is emerging there are concerns that the harms relating to resistant variants may be significant and individualised decision making is appropriate until such data are available.

In summary, this analysis indicates that subjects with advanced disease should be prioritised on the basis of need. Furthermore, when considering protease inhibitor treatment of previously treated subjects with advanced fibrosis, this should be done without consideration of interferon responsiveness following the 4-week lead-in. This analysis provides critical information regarding both selection and on-treatment decision making for previously treated subjects that should be included in guidance for physicians using protease inhibitors to treat subjects with HCV infection.

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