Showing posts with label svr durability. Show all posts
Showing posts with label svr durability. Show all posts

Friday, February 10, 2017

Mortality in Hepatitis C Populations: Another Battle Against Drugs and Alcohol.

Under Hot News

2017 Jan-Mar;19(1):54-55.

Mortality in Hepatitis C Populations: Another Battle Against Drugs and Alcohol.
1Department of Infectious Diseases, University Hospital Crosshouse, Kilmarnock, Scotland.

In the era of efficacious and well-tolerated treatment for chronic hepatitis C virus (HCV) infection, there is an expanding population of individuals who achieve viral eradication. This in turn has generated a need to determine the impact of liver-related morbidity and mortality, particularly liver decompensation and hepatocellular carcinoma, in populations achieving sustained viral response (SVR), and how they correlate with that of the general population.

|Full Article in PDF|

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.

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

Sunday, April 3, 2016

Getting Up to Speed on HCV Therapies - Experts discuss HCV before, during and after treatment.

Good day folks, if you have been diagnosed with HCV and either considering treatment, on treatment or have completed treatment you may benefit greatly from viewing this easy to follow video program over at Clinical Care Options.

The presentation; "Getting Up to Speed on HCV Therapies"offers a look see at various HCV patient scenarios. Experts discuss the use of current HCV therapies before, during and after treatment.

As an example in the first video "Treatment for HCV" a noncirrhotic 50-year-old genotype 1a patient who would prefer to be treated with sofosbuvir/ledipasvir is reviewed. In the second module it's all about pre-treatment considerations in patients taking other medications. Next up an overview of adherence during treatment and finally in the post-treatment section "Cure" is defined. In addition experts discuss the benefit of SVR in relation to reducing liver-related mortality in persons with advanced liver damage. Closing with the importance of follow up care, testing, liver wellness, and alcohol use.

Sit back and view experts; Sherilyn C. Brinkley, MSN, CRNP; Elizabeth K. Goacher, PA-C, MHS; Jennifer Katzianer, PharmD, BCPS; and Andrew J. Muir, MD, discuss the following topics

  • Considerations Influencing Choice of Oral Therapy for HCV Infection
  • Pretreatment Support for HCV-Infected Patients
  • On-Treatment Management of HCV Therapy
  • Posttreatment Care Following HCV Cure
During the presentation participants can easily skip follow up questions by clicking the "NEXT" button located at the bottom of the page or click on the "Table of Contents" to continue with the activity.

Free registration is required, begin here, view video module, here.

Wednesday, February 17, 2016

Hepatitis C Virus Relapse Uncommon After Sustained Virological Response

Hepatitis C Virus Relapse Uncommon After Sustained Virological Response
By Will Boggs MD
February 16, 2016

NEW YORK (Reuters Health) - Late relapse of hepatitis C virus (HCV) infection is very uncommon after achieving a sustained virological response (SVR), according to a systematic review and meta-analysis including more than 9,000 patients.

SVR at 12 or 24 weeks after completion of antiviral therapy is associated with an improved prognosis, compared with no treatment or failed therapy.

Bryony Simmons from Imperial College London, U.K., and colleagues used data from 59 studies of post-SVR recurrence to provide recurrence rates for three risk groups of HCV-infected patients: low-risk patients (with monoinfection and no recognized risk factors for reinfection); high-risk patients (with monoinfection and at least one identified risk factor for reinfection, such as injecting drug users and prisoners); and coinfection with HCV and HIV.

For the low-risk group, the pooled estimate was 0.82/1,000 person-years of follow-up (PYFU) for late relapse and 0.00/1,000 PYFU for reinfection, which yielded five-year rates of 0.40% for late relapse and 0.00% for reinfection.

The high-risk group had an even lower rate of late relapse (0.00/1,000 PYFU), but the pooled estimate for reinfection was far higher (19.06/1,000 PYFU). The risk of reinfection was highest for prisoners (45.48/1,000 PYFU), the researchers report in Clinical Infectious Diseases, online January 19.

Late relapse rates were also low for those with HCV/HIV coinfection (0.00/1,000 PYFU), and reinfection rates were high (32.02/1,000 PYFU).

Combining these outcomes, five-year recurrence rates remained very low for low-risk patients (0.95%), but were higher for high-risk patients (10.67%) and HCV/HIV coinfected patients (15.02%).

"Thus, despite higher recurrence rates in those with identified ongoing risk behaviors and/or HIV infection, SVR is durable, and the great majority of patients have SVR at 5 years post-treatment," the researchers note.

"The current analysis suggests that the greater recurrence risk in the high-risk and HIV coinfected populations is driven by an increased likelihood of reinfection, highlighting the need for prevention campaigns targeted at individuals who continue to place themselves at high-risk of HCV re-exposure," they write.

It's important to note that most studies included in the analysis evaluated recurrence after treatment with interferon-based therapies, which are being supplanted by interferon-free regimens.

Dr. Havard Midgard from Akershus University Hospital in Lørenskog, Norway, who was not involved in the new work, told Reuters Health by email that the "results are consistent with a very recent study published by our group, which was not included in this review. We performed a 7-year follow-up of 138 Norwegian patients who had obtained SVR in a treatment study in 2004-06. Of 94 individuals with a history of injection drug use (IDU) prior to treatment, 37 had relapsed to IDU after treatment. We identified 10 cases of persistent reinfection, all of which occurred in the subgroup who had relapsed to IDU post SVR."

"Scaling up HCV treatment among people who inject drugs (PWID) is essential to control the HCV epidemic, and I think it is 'the nature of the game' that some individuals will get reinfected," Dr. Midgard said. "However, the issue should be addressed systematically when providing HCV care for high-risk groups. To prevent infection, HCV treatment in PWID should be linked to harm reduction (opioid substitution therapy and needle and syringe program), and individuals should be educated about the risk of reinfection associated with sharing of needles and all kinds of injections paraphernalia."

"Although reinfection might compromise treatment outcomes at the individual level, treating HCV in high-risk individuals may actually prove great prevention benefits at the population level," Dr. Midgard concluded. "As high-risk transmitters are 'kept out of the pool,' onwards transmission will be prevented for a shorter or longer period. In a public health perspective, high-risk individuals should thus be targeted and prioritized for treatment. This approach is now highlighted in international guidelines for HCV treatment."

Simmons did not respond to a request for comments.


Clin Infect Dis 2016.

Thursday, November 12, 2015

Is cure of hepatitis C with medications possible? What defines a cure?

Is cure of hepatitis C with medications possible?
What defines a cure?

By Donald Jensen, MD
Hepatitis Expert

The term ‘cure’ is such a powerful word with such important implications that liver specialists and virologists avoided using it for decades to describe one outcome of hepatitis C therapy (WebMD). The hepatitis C virus is virus that needs to continue to replicate in the liver to survive. There is no ability of HCV to become dormant or go into a state of suspended animation. Therefore, if HCV is suppressed with treatment for a sufficient period of time, the virus cannot survive.

Monday, May 18, 2015

SVR durability using new interferon-free DAAs in comparison to SVR with interferon-based regimens

SVR durability using new interferon-free DAAs in comparison to SVR with interferon-based regimens

In this month's issue of HCV Next, Michael S. Saag, MD., writes about SVR durability using new all-oral, interferon-free DAAs in comparison to SVR with interferon-based regimens, noting some experts suggest there may be a difference.

Here is the editorial;The Unintended Consequences of Conservatism

Each issue of "HCV Next" offers information on a range of topics which include hepatitis C therapies, side effects, drug/drug interaction, guidelines, fatty liver disease and more.

Check out the following articles that appeared in the May 2015 print edition of HCV Next published online at Healio.

Table of Contents

Why should we doubt that SVR due to DAA therapy is any different than an SVR obtained with interferon-based therapy?

A Conversation with Andrea L. Cox, MD, PhD
Many organizations, including the CDC, have endorsed expanding widespread screening for hepatitis C virus, but experts writing in The BMJ warn that physicians should resist screening until more evidence on the risk-benefit ratio and long-term clinical improvements with antiviral therapy becomes available.

A number of recent studies demonstrated that, when treated with direct-acting antivirals, there were comparable response rates in patients with hepatitis C virus genotype 4 as those reported for other genotypes. That is, upward of 95%. However, experts remain confounded by a host of obstacles that stand in the way of marginalizing — or eradicating — hepatitis C virus genotype 4.

Model Accurately Predicts Rapid Response in HCV at 4 Weeks
Multiple variables, including IL28B genotype with viral load, HCV genotype, Forns’ Index and HIV coinfection were used to construct a model that accurately predicted virological response at 4 weeks in patients with hepatitis C virus infection treated with pegylated interferon alfa-2a and ribavirin, according to study data.

PAD Risk Higher for Patients with HCV
Hepatitis C virus infection was associated with a greater risk for peripheral arterial disease, or PAD, in Taiwanese patients, with a nearly 12-fold increased risk in patients older than 65 years, according to study data published in theJournal of Hepatology.
In a prospective cohort study, patients who experienced hepatitis C virus infection clearance after treatment with pegylated interferon and ribavirin also had improved mixed cryoglobulinemia, according to data published in Hepatology.
HCV and Metabolic Syndrome
Studies have shown that HCV may directly influence glucose metabolism, increase the risk for diabetes and predispose patients to obesity. Beyond the metabolic factors, patients with chronic HCV and insulin resistance may have higher viral loads based on retrospective studies.

FDA Warns of Hepatic Failure, Bradycardia with Simeprevir
The FDA has approved changes to the warnings and precautions label for simeprevir for the treatment of hepatitis C virus infection, indicating that it can cause hepatic decompensation and failure, and serious symptomatic bradycardia when co-administered with sofosbuvir and amiodarone, according to a news release from the FDA.

Rapid HCV Test gets European Approval

FDA Grants New Breakthrough Therapy Designations for Grazoprevir/Elbasvir
The FDA originally granted breakthrough therapy designation for the drug combination in October 2013. However, in February, Merck announced the FDA’s intent to rescind that designation due to the availability of other new drugs for HCV. The new breakthrough designations for grazoprevir and elbasvir (MK-5172, MK-8742; Merck) are geared towards treating patients with chronic HCV genotype 1 with end-stage renal disease on hemodialysis and patients with chronic HCV genotype 4, according to the release.
The Japanese Ministry of Health, Labour and Welfare has approved sofosbuvir to suppress viremia in patients with chronic hepatitis C virus genotype 2 infection, with or without compensated cirrhosis, according to a press release from the drug maker.

Friday, April 17, 2015

Long-term follow-up of successful hepatitis C virus therapy: waning immune responses and disappearance of liver disease are consistent with cure

Long-term follow-up of successful hepatitis C virus therapy: waning immune responses and disappearance of liver disease are consistent with cure

Download full text article @ NATAP

Alimentary Pharmacology & Therapeutics March 2015

M. Hedenstierna*,, O. Weiland*,, A. Brass, D. Bankwitz, P. Behrendt, I. Uhnoo, S. Aleman**, K. Cardell,
A. Fryden, G. Norkrans, A. Eilard, H. Glaumann, T. Pietschmann, M. Sallberg & E. D. Brenndorfer
*Department of Infectious Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Department of Infectious Diseases, Akademiska University Hospital, Uppsala, Sweden.

**Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna and Huddinge, Stockholm, Sweden.

Department of Infectious Diseases, University Hospital, Linkoping, Sweden. Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden.

Clinical Pathology and Cytology, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.



A sustained viral response (SVR) after interferon-based therapy of chronic hepatitis C virus (HCV) infection is regarded to represent a cure. Previous studies have used different markers to clarify whether an SVR truly represents a cure, but no study has combined a clinical work-up with highly sensitive HCV RNA detection, and the determination of immune responses.


To determine clinical, histological, virological and immunological markers 5-20 years after SVR.


In 54 patients, liver biochemistry, histology and elastography were evaluated. Liver biopsies, plasma and peripheral blood mononuclear cells (PBMCs) were tested for minute amounts of HCV RNA. HCV-specific T-cell responses were monitored by ELISpot and pentamer staining, and humoral responses by measuring HCV nonstructural (NS)3-specific antibodies and virus neutralisation.


Liver disease regressed significantly in all patients, and 51 were HCV RNA-negative in all tissues tested. There was an inverse association between liver disease, HCV-specific T-cell responses and HCV antibody levels with time from SVR, supporting that the virus had been cleared. The three patients, who all lacked signs of liver disease, had HCV RNA in PBMCs 5-9 years after SVR. All three had HCV-specific T cells and NS3 antibodies, but no cross-neutralising antibodies.


Our combined data confirm that a SVR corresponds to a long-term clinical cure. The waning immune responses support the disappearance of the antigenic stimulus. Transient HCV RNA traces may be detected in some patients up to 9 years after SVR, but no marker associates this with an increased risk for liver disease.

Full Text Available @ NATAP

Thursday, August 8, 2013

Sustained virological response after treatment in chronic hepatitis C - five year follow up

Sustained virological response after treatment in patients with chronic hepatitis C infection - a five year follow up


Rahman MZ1, Ahmed DS1, Masud H1, Parveen S2, Rahman MA1, Chowdhury MS1, Barua R1, Ishaque SM1 1Department of Gastroenterology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, 2Department of Paediatrics, BSMMU, Dhaka.

Vol 39, No 1 (2013)

Peginterferon α-2a and ribavirin combination therapy achieves a sustained virological response (SVR) in patients with chronic hepatitis C. Little is know about long-term durability of hepatitis C virus – Ribonucleic acid (HCV-RNA) negativity in patient treated with pegylated interferon and ribavirin therapy.

Aim of this study was to evaluate the durability of virologic response in patients with SVR to anti-viral therapy treated at our centre. A total of 52 patients with chronic hepatitis C virus infection who had obtained SVR after Peginterferon α-2a and ribavirin combination therapy were followed up to 5 years with annual HCV-RNA testing. During this follow up period, 4 of 52 patients with initial SVR developed late relapse of hepatitis C virus infection. Relapse was more common in patients who has cirrhosis (3/6 [50%]) vs (1/46 [2.17%]) without cirrhosis.

In conclusion, SVR is durable in most patients, but some patients do have late relapse; long term follow up may be particularly important in a subset of patients with hepatitis C virus infection who have liver cirrhosis.

Discussion Only
Full text available here, or Download PDF file here

Infection with hepatitis C virus is a leading cause of liver disease worldwide1,2. Progression to chronic hepatitis C occurs in most people acutely infected with HCV and persistent infection is an important cause of cirrhosis, end stage liver disease and hepatocellular carcinoma. Thus, early detection and treatment is of great importance. The goal of treatment is to prevent complications of HCV infection3,4.

There have been substantial improvements in the success of HCV treatment and there are currently several treatment regimens approved by the FDA. In randomized clinical trials, the highest overall SVR rated have been achieved with the combination of weekly subcuataneous injection of long acting peginterferon α-2a and daily oral ribavirin, which represents the current standard of care12-14. Nevertheless, little is known on the outcome of patients treated with PEG-IFN/ribavirin combination therapy.

Recently, swain et al. evaluated the durability of SVR after the treatment with peginterferon α-2a ± ribavirin in 845 patients, who had participated in pivotal trials15 and achieved SVR.

Only in seven patients (<1%), HCV-RNA was detected (after 391-1076 days of treatment). All these data indicate that the late relapse after SVR in chronic hepatitis C patients following anIFN-based anti-viral therapy is rare16-19.

This is the first study from Bangladesh on long term outcomes of anti-viral therapy for chronicHCV infection.

Our study shows that SVR is durable in a majority of patients but late relapses do occur. These relapses occur more commonly in patients with cirrhosis. Our study revealed late relapses in 7.69% over 5 year follow up. One reason for high late relapse in our study could be due to presence of poor baseline predictors of response: obesity i.e., BMI>30 (n=3), alcohol intake (n=1) and cirrhosis (n=3). In addition, on retrospective analysis we found that mean dose of ribavirin and peginterferon used in these patients was suboptimal as dose reductions were required more frequently due to severe adverse effects.

A theoretical explanation for late relapse could be persistence of undetected occult hepatitis C virus in hepatocytes, PBMCs, lymphocytes or macrophages.

There are several limitations of the study. Liver biopsy was not done. So histological relapse could not be seen. Similarly, retesting of genotype/sequencing was not done and possibility of reinfection cannot be ruled out.

SVR once achieved is sustained in majority of patients. The treating hepatologist need to be aware of occurrence of late relapses in patients with chronic HCV infection with cirrhosis.

Full Text - Download this PDF file

Of Interest - July 2013
Durability of sustained virologic response in chronic hepatitis C.

Wednesday, July 31, 2013

Durability of sustained virologic response in chronic hepatitis C.

Gut Liver. 2013 Jul;7(4):458-61. doi: 10.5009/gnl.2013.7.4.458. Epub 2013 Jun 20.

Durability of sustained virologic response in chronic hepatitis C

Uyanikoglu A, Kaymakoglu S, Danalioglu A, Akyuz F, Ermis F, Pinarbasi B, Demir K, Besisik F, Cakaloglu Y.

Department of Gastroenterology, Harran University Faculty of Medicine, Sanliurfa, Turkey.


The aim of this study is to investigate the rate of sustained virologic response (SVR) in chronic hepatitis C patients receiving antiviral treatment.

The files of patients with chronic hepatitis C treated with interferon±ribavirin between 1995 and 2009 were reviewed retrospectively. Six months after the end of treatment, patients with negative hepatitis C virus (HCV)-RNA (<50 IU/mL, as determined by the polymerase chain reaction method) were enrolled in the study.

The mean age of 196 patients (89 males) was 46.13±11.10 years (range, 17 to 73 years). In biopsies, the mean stage was 1.50±0.94; histological activity index was 7.18±2.43. In total, 139 patients received pegylated interferon (IFN)+ribavirin, 21 patients received classical IFN+ribavirin, and 36 patients received IFN alone. The HCV genotypes of 138 patients were checked: 77.5% were genotype 1b, and 22.5% were other genotypes. After achievement of SVR, the median follow-up period was 33.5 months (range, 6 to 112 months), and in this period relapse was only detected in two patients (1.02%) at 18 and 48 months after treatment.

In total, 98.9% of patients with SVR in chronic hepatitis C demonstrated truly durable responses over the long-term follow-up period of 3 years; relapsed patients had intermittent or low-grade viremia.

Chronic hepatitis C, Interferons
PMID: 23898387 [PubMed]

Discussion Only
Full Text Available Here

Regular and long-term follow-up of patients with SVR was not well documented. The current study evaluates the long term results of SVR. In standard interferon or IFN/ribavirin combination therapies, HCV-RNA was negative for 92% to 100% of patients during the follow-up of 1 to 12 years following SVR in patients with chronic hepatitis C.

Recent studies reported that cure for HCV infection was achieved with SVR. Additionally, histological improvement was detected in 94% of the patients and persistently normal ALT levels were detected in 93%.

Our results also confirmed these data and HCV-RNA level was not detectable in the long term for 99.4% of the patients. ALT was determined to be within normal limits for 153 patients (94%) in the final control.

The available data was relatively less for PEG-IFN/ribavirin combination. In a study by Swain et al follow-up of 845 patients who achieved SVR with interferon alpha 2a±ribavirin revealed that HCV-RNA was detected in only seven patients (<1%) within 391 to 1,076 days after treatment. For treatments based on PEG-IFN, it was concluded that late relapse was rare after achievement of SVR. More than half (65%) of our patients received PEG-IFN/ribavirin treatment, with results supporting this study. PEG-IFN + ribavirin treatment appears to have good long term results.

In chronic hepatitis C treatment, it is still uncertain whether complete elimination is achieved as a result of the treatment or whether a small number of viruses persist. In former studies using less sensitive tests, 95% of the patients with SVR had undetectable levels of HCV-RNA in the liver within 1 to 2 years after treatment. Only two of the seven patients with HCV-RNA detected in the liver after treatment relapsed after 4 years. In another study, none of the 17 patients with negative HCV-RNA detected in the liver after treatment relapsed at the end of 12 years.

On the other hand, only two of the 17 patients with negative HCV-RNA resulting from IFN+ribavirin had negative HCV-RNA in all of their body components including hepatocyte, serum, peripheral blood mononuclear cell, lymphocyte, and macrophage cultures. This suggests that there is a probability of relapse after many years.

The clinical significance of low-level HCV-RNA persistence is unknown and further studies must be performed for this issue. For two of our 196 patients with SVR, HCV-RNA was determined to be positive at a low level at months 18 and 48; however, when both observations were repeated after 3 months they were noted to be negative. The exact reason for transient positivity of HCV-RNA was not clear. It was determined that patients with SVR demonstrated truly durable viral responses and relapsed patients had intermittent and low-grade viraemia.

SVR presumably prevents HCC development. None of our patients with SVR demonstrated HCC on long term follow-up. Improvements in liver fibrosis, biochemical indicators, fatigue, and life quality
were detected with SVR. In our batch, no data was available concerning improvements in fibrosis, as there were no adequate end-of-therapy control liver biopsies.

When pretreatment ALT levels were compared with ALT on the last control (101.72±78.84 IU/mL [range, 12 to 465 IU/mL] vs 22.52±11.73 IU/mL [range, 8 to 84 IU/mL]), further improvement was observed (p<0.05).

In conclusion, it was found that patients with SVR in chronic hepatitis C demonstrated truly durable responses in the long term follow-up period of 3 years on average and that there was no complication related with liver disease throughout this period

Gut and Liver 2013 Jul; 7(4): 458-461/ Download Full Text

Thursday, June 20, 2013

SVR after triple therapy maintained long-term durability in HCV patients

SVR after triple therapy maintained long-term durability in HCV patients

Rutter K. Aliment Pharmacol Ther. 2013;38:118-123.

Source - Healio

June 20, 2013

Nearly all patients with chronic hepatitis C who achieved sustained virologic response to therapy with pegylated interferon, ribavirin and direct-acting antivirals continued to have undetectable HCV RNA over long-term follow-up in a recent study.

Researchers followed 103 white patients with chronic HCV who had participated in randomized, controlled trials or an extended access program in which they achieved sustained virologic response (SVR) at 24 weeks after completing combination therapy with peginterferon alfa-2a and ribavirin and a direct-acting antiviral (DAA). Evaluated DAAs included protease inhibitors (90.3% of cases), NS5B polymerase inhibitors (6.8%) and both in combination (2.9%). Patients were followed for a median of 21 months after achieving SVR (range 7 to 64 months).

The cohort included 80 treatment-naive patients, 17 who had been nonresponsive and six who had relapsed during prior therapy. Nearly all patients were infected with HCV genotype 1, including 34 with genotype 1a and 67 with 1b, while two patients had genotype 4.

Relapse occurred in two patients who had genotype 1b and had been treated with faldaprevir. Both patients achieved undetectable HCV RNA levels at 4 weeks, and cloning sequencing after relapse indicated identical sequences to those observed at baseline. Viral resistance was unseen in either case.

One treatment-naive, noncirrhotic woman who relapsed had detectable HCV RNA 8 months after therapy cessation, which increased to pretreatment levels in subsequent months. Retreatment with 24 weeks of peginterferon, ribavirin and telaprevir resulted in undetectable RNA levels. The second relapser, a treatment-naive cirrhotic man, had detectable HCV RNA 12 months after therapy ended that returned to pretreatment levels shortly after detection.

“To the best of our knowledge, this is the first study reporting long-term virological outcomes in patients with hepatitis C after successful antiviral triple therapy,” the researchers wrote. “Our study shows that HCV eradication by triple therapy remains durable and confirms an excellent long-term prognosis of HCV patients with SVR. To assess the long-term clinical benefit of triple therapy, studies with a longer follow-up and larger patient numbers are needed.”

Disclosure: See the study for a full list of relevant disclosures.


William Carey
Sustained virological response, historically, has been tantamount to a cure in patients who are treated for hepatitis C. The problem, of course, is that with every change in therapy, it's necessary to validate that the concept of SVR - no virus detectable in the blood 6 months after stopping treatment - actually applies. It applies for pegylated interferon and ribavirin, and now we're seeing evidence that it also applies when we're using direct-acting antiviral agents in addition.

[This is] an important study to do. I think the strength of it is that it has at least a moderate number of patients, over 100, and they found, not surprisingly, that SVR 24 weeks after stopping treatment seems to be associated with permanent eradication of detectable virus. Again, this is not surprising, but still an important detail that needs to be hammered out, and the study goes a long way toward doing that.

The limitations of the study are that they looked at many different direct-acting agents, and so the number of patients treated with any particular direct-acting agent is somewhat limited. This really comes into focus when we look at the two breakthrough patients: They were both treated with the same drug. So [the study] raises, but doesn't answer the question: "Is faldaprevir different than the other agents that were tested?" It's really impossible to say, because the numbers are too small, but it raises the question of whether this agent is going to be associated with a higher rate of breakthrough than the other agents tested here.

Instead of 100 patients, I'd like to see 1,000, and certainly there are many many hundreds of patients who have been in randomized trials, and this data is or will soon become available. So I think that this is a good beginning, but we just need to see larger numbers, and we need to see numbers that are specific to each and every direct-acting antiviral drug.

William Carey, MD

 Professor of medicine, Cleveland Clinic Liver College of Medicine

Founding member, Cleveland Clinic Hepatology section

Disclosures: Dr. Carey reported no relevant financial disclosures.

Friday, January 14, 2011

Hepatitis C:Impact of a sustained virological response on the long-term outcome

Impact of a sustained virological response on the long-term outcome of hepatitis C
Alfredo Alberti
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02378.x
© 2011 John Wiley & Sons A/S

A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2>
However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage. The primary endpoint of antiviral therapy for chronic hepatitis C is achieving sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA in serum 24 weeks after stopping antiviral therapy (SVR-24w). This is the endpoint used in all clinical trials to assess therapeutic interventions as well as by clinicians treating patients.
This is because a large body of evidence exists that SVR-24w is an excellent surrogate endpoint to identify a permanent virological cure in most patients, with a clear clinical benefit in many of them. While it has been fairly easy to show that SVR-24w is associated with an extremely low risk of persistent HCV or recurrence during longer follow-up, data on the impact of SVR for more specific clinical endpoints have been limited by the heterogeneity of the initial presentation and rate and speed of chronic hepatitis C disease progression. It is clear from studies on the natural history of HCV that a minority of patients with chronic infection develop significant life-long clinical complications, and it is also well known that current clinical practice has extended the indication to start antiviral therapy to patients with the mild or moderate hepatitis C, whose risk of progression is often difficult to define.
When these patients receive antiviral therapy, data show that SVR improves quality of life and reduces the risk of histological progression. Although there is no direct evidence, outcome modelling suggests that there may be significant effects on clinical complications and survival in a subgroup of patients at risk of more rapid disease progression. On the other hand, solid evidence shows that the risk of developing end-stage liver disease, portal hypertension and hepatocellular carcinoma (HCC) is reduced in patients with more advanced liver disease or cirrhosis who achieve SVR with antiviral therapy. In this chapter, we briefly discuss the data on the impact of SVR on long-term HCV eradication as well as on biochemical, histological and clinical outcomes in patients with hepatitis C depending on the phase of liver disease when therapy was begun.

There is good evidence that HCV permanently disappears from serum when antiviral therapy is successful. Most experts consider this to be the expression of complete and permanent viral eradication, while data on a persistent occult form of HCV in the liver and/or peripheral blood mononuclear cells (PBMC) are not fully convincing. Because HCV-RNA may be negative in serum during and at the end of antiviral therapy and reactivate after treatment withdrawal in a subgroup of patients with incomplete clearance (relapsers), viral negativity must be confirmed during off-therapy follow-up to confirm a definitive cure of hepatitis C. SVR is the primary goal of antiviral therapy in chronic hepatitis C and is classically defined as the absence, by the most sensitive polymerase chain reaction assay, of HCV-RNA in serum, 24 weeks after therapy has been withdrawn (SVR-24w) (1). This has been the definition since standard interferon (IFN) monotherapy was implemented and remained valid for IFN plus ribavirin combination therapy and more recently for pegylated interferon (PEG-IFN) plus ribavirin combination regimens. The SVR-24w definition of response to therapy will be maintained when new strategies of HCV treatment, including direct antiviral agents, are introduced into clinical practice. Indeed, most published studies as well as extensive clinical experience show that an absence of HCV-RNA in serum 6 months after therapy is the best indicator of HCV clearance, whatever the HCV genotype, patient characteristics, type and duration of treatment. This has been confirmed in several studies evaluating the long-term virological profile in large cohorts of patients treated with different schedules of IFN-based therapies and tested for HCV recurrence several months or years after having achieved SVR-24w.

Recently, Welker and Zeuzem (2) reviewed available data on the rates of late virological relapse in hepatitis C patients treated with IFN (or PEG-IFN) therapy with a sustained response based on the 24 week off-therapy rule. The authors identified 44 studies, including more than 4200 patients who had been followed up to 108 months after the end of therapy. Overall, late virological relapses were rare (3%). There was considerable heterogeneity among the different studies, with some of the smaller series reporting the highest rates of HCV recurrence. On the other hand, the larger series and those with the most stringent criteria to define SVR conclude that negative HCV-RNA in serum 24 weeks after the end of therapy is associated with a durable response and no recurrence of HCV during follow-up in more than 98% of cases.

Some studies have suggested that HCV-RNA may persist in the liver and/or in PBMC in patients who achieve SVR after antiviral therapy and with undetectable HCV-RNA in serum (3, 4). The significance of these findings is uncertain but most available data suggest that they are not clinically significant, at least in the immunocompetent host.

Thus, patients achieving SVR-24w with antiviral therapy can be considered clinically cured of viral infection, with an extremely low risk of late virological recurrence. If this occurs, reinfection rather than a ‘true’ relapse could be suspected and should be evaluated carefully.

Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the sustained virological response in patients with hepatitis C virus receiving PEG-IFN and ribavirin (5).

Alanine transaminase (ALT)/aspartate aminotransferase (AST) levels markedly improve in most patients who achieve SVR with antiviral therapy and permanently normalize in many (6, 7). The mean ALT and AST activities after therapy are significantly lower than the pretreatment baseline levels even in HCV carriers who began antiviral therapy with ‘normal’ ALT levels (8). Indeed, eradication of HCV by antiviral therapy in these cases is associated with a significant improvement in liver enzyme levels, which decrease from pretreatment ‘high normal’ to post-treatment ‘low normal’ levels. These findings suggest the presence of ongoing marginal liver disease activity even in HCV carriers with ‘normal’ range ALT levels, in agreement with histological findings of inflammation and fibrosis in around 15–25% of these patients (9).

On the other hand, liver enzymes may not normalize completely in patients with cirrhosis who achieve SVR. The discrepancy between biochemical and virological outcomes does not exclude a clinical benefit and is probably a sign of profound irreversible changes in hepatocyte metabolism from advanced cirrhosis.

As a general rule, other causes of liver damage (coinfections, alcohol, drugs, metabolic abnormalities) should be investigated in patients who achieve SVR with antiviral therapy but still have elevated ALT and/or AST.
Many studies have described the histological outcome following antiviral therapy for chronic hepatitis C and have clearly identified some major differences among non-responders, partial responders, relapsers and sustained responders (10–15). Although the benefit to disease activity and progression with a partial or a transient virological response remains controversial, these studies clearly confirm that SVR is associated with histological improvement in disease activity and associated fibrosis. Liver steatosis is also improved when it is directly linked to HCV as for HCV-3.

The type and degree of histological benefit after SVR is highly dependent on pretreatment activity, the stage of liver disease and the interval between end of therapy and liver biopsy. Improvement in liver inflammation is more evident when a liver biopsy is obtained years rather than months after the end of therapy. The effect of time is even more evident for the regression of liver fibrosis. Available studies indicate that liver inflammation resolves in most, if not all, patients after SVR while improvement in fibrosis (regression) is found in 25–80%, worsening (progression) in only 0–12, and 16–68% remain stable. These results are significantly different from those in patients who do not achieve SVR. Table 1 describes some studies that have evaluated histological outcome after SVR using paired liver biopsies before and at different intervals after antiviral therapy. Available cumulative data on progression to cirrhosis have indicated that the risk after 1–10 years is reduced from 7–10% in non-responders to 0.5–1% in sustained responders, although it should be emphasized that patients who achieve SVR might have a milder and less progressive form of liver disease compared with non-responders.

Table 1. Histological changes in the liver in patients achieving sustained virological response during antiviral therapy for chronic hepatitis C Authors
Click to Enlarge Table 1

Reversal of histological cirrhosis has been reported in patients achieving SVR with antiviral therapy. Although in most patients the benefit was limited to regression to METAVIR stage 3, i.e. advanced fibrosis with bridging, a histological sampling error cannot be excluded, other patients have been shown to achieve more marked and permanent histological benefit with regression from signs of cirrhosis to minimal-mild fibrosis.

Recent non-invasive markers of liver fibrosis, such as the FibroTest and FibroScan, have become important new tools for the management of patients with chronic hepatitis C. Results in patients receiving antiviral therapy have confirmed a marked improvement in liver fibrosis indexes following SVR (16, 17). Further validation for the optimized use of these methods during and after antiviral therapy is ongoing in several centres

Sustained virological response and clinical outcomes
Morbidity and mortality in chronic hepattis C infection are mainly associated with the complications of cirrhosis and the development of HCC, as well as an increased risk in liver-related deaths. It is therefore essential to assess the impact of SVR on these clinical outcomes. Because of the heterogeneity of the clinical presentation of chronic HCV infection, the slow and unpredictable progression and the lack of longitudinal studies of adequate size and duration, the impact of antiviral therapy and SVR on liver-related complications and mortality has been difficult to determine, especially in patients with milder forms of HCV-related liver disease. Although the endpoint of SVR is clearly associated with reduced histological disease progression in these patients, there is no clear evidence that this will result in reduced morbidity and mortality. At present, many patients with mild chronic hepatitis C are treated with antiviral therapy, especially younger patients or those infected with easy to clear HCV genotypes.

High SVR rates are achieved in these patients and outcome modelling also suggests that successful antiviral therapy could reduce the clinical burden of their disease. On the other hand, there are also convincing results associating a marked improvement in quality of life with SVR after antiviral therapy. This effect is largely independent of the stage of disease when treatment is begun (18). The clinical benefit associated with HCV clearance at any stage of chronic HCV infection is supported by recent results in a large population-based survey by Omland and Krarup (19), showing that overall life-long mortality as well as liver-and HCC-related mortality were significantly lower in HCV patients who showed a clearance of viraemia than in those with chronic viraemia.

Unlike the data for patients with milder forms of chronic hepatitis C, several studies have clearly shown that antiviral therapy with SVR is associated with a marked improvement in clinical outcomes in patients with advanced fibrosis or compensated cirrhosis. Indeed, most studies show that ascites, hepatic encephalopathy, jaundice or gastrointestinal bleeding are extremely rare after SVR has been achieved. Development of hepatocellular carcinoma is also significantly reduced, but patients with cirrhosis who clear HCV during antiviral therapy are still at a risk of developing HCC. Although the risk is certainly much lower than in age/gender/race-matched patients with active disease, continued monitoring is recommended
One of the most recent reports on the impact of combination PEG-IFN and ribavirin therapy on clinical outcome and complications in patients with chronic hepatitis C and advanced fibrosis is that of Cardoso et al. (20). These authors describe long-term outcomes in 307 patients with chronic hepatitis C and advanced fibrosis (127 cases) or cirrhosis (180 cases) treated with PEG-IFN plus ribavirin and followed up for a mean 3–5 years after treatment. SVR-24w was found in 33% of the cases, with no significant differences between patients with advanced fibrosis (37%) and cirrhosis (30%). During follow-up, the incidence of liver-related complications, HCC and liver-related deaths per 100 person – years was 0.63, 1.24 and 0.61, respectively, in patients with SVR and 4.16, 5.85 and 3.66, respectively, in patients without SVR. The difference for each outcome was statistically significant P less then 0.001
These results confirm those of several previous studies based on cohorts of patients treated with standard IFN, standard IFN plus ribavirin or PEG-IFN plus ribavirin, showing that antiviral treatment provides a definitive clinical advantage to patients with compensated cirrhosis who tolerate treatment and achieve an SVR. Another recent study published by Bruno et al. (21) reported the effect of antiviral therapy and SVR on portal hypertension in HCV patients with cirrhosis. The authors reported results in 218 patients with cirrhosis who were untreated or treated with IFN--based therapy and followed up for a median 11.4 years. All patients had compensated cirrhosis when therapy began without oesophageal varices. Endoscopic monitoring was performed at 3-year intervals.
None of the patients who achieved SVR developed oesophageal varices during follow-up compared with 32% of untreated patients and 39% of treated patients who did not achieve SVR, showing that SVR clinically improved the development of portal hypertension. In conclusion, SVR improves the clinical outcomes in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis. On the other hand, most studies assessing whether a partial response or long-term maintenance therapy with PEG-IFN without viral eradication is beneficial have failed to demonstrate any significant improvement in clinical outcomes (22, 23).
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