Saturday, March 25, 2017

Hep C Weekend Reading: Favorite quote of the week “Fight to treat your patients as early as possible.”

HCV Weekend Reading
Hope you all had a wonderful week, sit back and catch up on what you may have missed over the last week in this issue of Weekend Reading.

In a recent article published in Clinical Infectious Diseases, data suggested that delaying hepatitis C treatment regardless of fibrosis stage may be detrimental to patients, ya think?  Reuters Health reported: "Mortality is increased in patients with moderate or severe liver disease related to chronic hepatitis C, and progression from mild/moderate to severe disease cannot be predicted reliably." Here is a quote from Dr. Cepeda, a key author of the study; “Fight to treat your patients as early as possible.” Read the rest of the article, here.

Annals of Internal Medicine, reported high cure rates, with few side effects, in a review article on various FDA approved regimens to treat chronic hepatitis C. Sustained virologic response (SVR) for genotype 1 (using different approved HCV regimens) was reported at over 95%. Sofosbuvir plus velpatasvir  or daclatasvir for 12 weeks in genotype 3 patients without cirrhosis appeared to seem most effective, for geno 3's with cirrhosis, a regimen of velpatasvir-sofosbuvir had higher response rates, the latter is  also highly effective (99% response rate) for genotypes 2, 4, 5, and 6, this summary was published in NEJM Journal Watch, read the full text article; Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV.

Weekly News Coverage
HEP offers hepatitis C research with daily news, a great place to start learning about HCV.
Over at HepCBC, each Friday a nice summary of news is available, read this weeks: Weekly Bull.

Healio
Daily news, updates and more over at Healio.
Check out the following March publications as well.
HCV Next
Healio Gastroenterology
Infectious Disease News

News Re-Cap
Author: Richard Pizzi Family Practice News
Publish date: March 21, 2017 - Hepatitis Outlook Late February 2017
Here’s a quick look at some notable news items and journal articles published over the past month, which cover a variety of the major hepatitis viruses.

Week Ending March 21, 2017
AGA Reading Room

Blog Updates
Don't miss recent articles written by your favorite bloggers over at HEP blogs.
HepatitisC.net is a great site for patient resources and personal stories with daily articles.

In Case You Missed It

MD Whistleblower
Medical Marijuana Use - Ready, Fire, Aim!
Michael Kirsch, MD
Promoting medical marijuana use is hot – smokin’ hot. States are racing to legalize this product, both for recreational and medical use. In my view, there’s a stronger case to be made for the former than the latter.

Presently, marijuana is a Schedule I drug, along with heroin, LSD and Ecstasy. The Food and Drug Administration (FDA) defines this category as drugs with no acceptable medical use and a high potential risk of addiction. Schedule I contains drugs that the FDA deems to be the least useful and most dangerous. Schedule V includes cough medicine containing codeine.

Hepatitis C Foundation
How to Find a Liver Specialist Who Really Knows Hepatitis B
March 22, 2017
By Christine Kukka
If you have chronic hepatitis B or are newly-diagnosed, it’s important to see a liver specialist who has experience with hepatitis B.

Having a specialist with hepatitis B expertise on your team not only safeguards your health, it also lessens the stress of having a chronic liver disease. “My specialist gave me all the possible scenarios, but most importantly, he gave me my life back,” one hepatitis B patient recalled.

Podcast
Date Released: Mar 8 2017
HCV Management In Liver Transplantation
Dr. Robert Brown discusses management of hepatitis C infection in patients undergoing liver transplantation, Dr. Nancy Sokol hosts.
Listen here...

Learning Activity
Watch - Release Date: 3/15/2017
Hepatitis C: New Paradigms for Evaluation & Management
Dr. Naudia Jonassaint discusses the new paradigms in regards to the evaluation and management of Hepatitis C. She reviews the basic epidemiology & scope of Hepatitis C, appropriate screening for Hepatitis C, basic Hepatitis C treatment options , identification of special populations, and post SVR Monitoring
Quick View, watch here...



Healthy You

Behind The Headlines
Overweight young men 'more likely to get severe liver disease'
"Men who are overweight in their late teens have a higher risk of developing liver cancer in later life, new research suggests," reports ITV News. Swedish researchers also found a link to other serious types of liver disease…

Updates On This Blog
HCV vaccines—back to the future?
Effects of Melatonin on Liver Injuries and Diseases
Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?
Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C
Study - Statin use may lead to: Decreased fibrosis and Reduced risk of developing liver cancer
Watch - Hepatitis C Overview
Chronic Hepatitis C And Functional Dyspepsia (FD) - A Feeling Of Discomfort In The Upper Abdomen
HCV - Fatty liver disease and genotype 3
HCV Genotypes/Treatment
Is There A Natural Way To Improve Liver Fibrosis?

Check back for updates, enjoy the rest of your weekend.

HCV vaccines—back to the future?

Editorial
HCV vaccines—back to the future

Paul Klenerman

Received: 12 February 2017; Accepted: 15 February 2017; Published: 16 March 2017.
doi: 10.21037/aob.2017.02.01


View Full Text Article Online

HCV is a huge global problem. Major advances have been made in recent years in the drug therapy for chronic HCV infection (1). If patients have access to such directly acting antiviral agents, there is a very high chance of cure in most settings, even in patients with advanced disease or with previous treatment failures. However, in order to effectively get on top of the epidemic, such therapy is likely only one weapon, as there is still a substantial amount of ongoing transmission and undiagnosed disease, often in populations that are hard to reach. Virologic cure through the new agents does not lead to host immunity, so approaches to prevention of new or repeat infections are still needed. For this reason, a vaccine for HCV still has an important place at the table (2,3).

The classical approach to vaccines has been to use either a live strain with attenuated pathogenicity—as in the case of smallpox vaccine—or to use a killed or inactivated vaccine. Both approaches have been very effective. Live strains—such as the yellow fever vaccine—produce long lasting immunity, and combine typically cellular immunity with humoral responses. While this is advantageous, for many pathogens there is no clear way of safely attenuating the virus, so the risks outweigh the benefits. Inactivated vaccines, for example the Salk polio vaccine, similar to the toxoids used for tetanus, induce a strong antibody response, although the induction of cytotoxic T cells is limited. In the end, the efficacy of the vaccine depends on the dominant form of protection. In the case of HBV vaccines, a recombinant protein approach is highly effective, as the levels of antibody generated are sufficient to provide robust immunity (4). Recombinant protein approaches mimic the killed vaccines in providing a non-replicating antigen, together with sufficient adjuvant to activate the innate immune responses needed for immunologic priming. For HBV the field is relatively well off as the antibodies represent a clear “correlate of protection”—i.e., their presence predicts efficacy (4). Unfortunately, we do not have very well defined correlates of protection in HCV infection, although there is a wealth of data that innate and adaptive immune responses are important, including a role for T cells. This includes studies of animal models, host immunogenetics, viral evolution and numerous correlative studies in acute and chronic disease, as well as challenge studies (5-7).

For HCV, there have been limited attempts to date to develop preventive vaccines, compared for example to HIV, and there are no simple live-attenuated avenues to explore (3,8,9). HCV is persistent, highly mutable, and difficult to grow in culture. It is also in many patients a relatively poor inducer of immune responses, partly because of its hepatotropism. In common with other complex infections such as HIV and malaria, a viral vector approach has been taken by a few groups, using HCV antigens expressed in the context of another virus, such as a poxvirus or adenovirus. This allows the immunogen to be presented in an optimal form to generate cellular immune responses, and in humans, adenoviral vectors have been shown to be quite effective at priming both CD4+ and CD8+ T cell responses (10,11). Currently a preventive HCV vaccine based on priming with a chimpanzee adenoviral vector expressing HCV non-structural proteins 3-5B, and boosting with a modified vaccinia Ankara (MVA) vector expressing the same proteins is in phase 2 trials in the USA (https://clinicaltrials.gov/ct2/show/NCT01436357).

Antibodies also have a role to play in protection against HCV, and in an ideal world a vaccine that induced a high-titre antibody response capable of blocking infection of a wide range of HCV strains—so-called broadly neutralising antibody (bNAbs)—would be very effective. Attempts have been made to generate antibodies using recombinant HCV envelope proteins, and bNAbs have been generated with this approach (12,13). However, high level production of these protein targets is not trivial and so this area is still open for development, including attempts to focus the antibody response on targets within envelope which are highly conserved and block infection (14).

On this background the recent study by Yokokama et al. in Gut is of interest as it combines new and old approaches to try and induce protective immunity against HCV (15). While it is not possible to routinely culture HCV, certain strains—notably JFH, first generated by Wakita, a co-author on the current study—can replicate in specific cell lines, and this technology has been further developed to allow different genotypes to be cultured (16). The authors were able to make high level stocks of a cell culture strain (HCVcc), purify it and then inactivate it using UV light for safe use as a vaccine. In order to improve its immunogenicity, they combined it with different adjuvants, one the classical album, and a second, based on stimulation by DNA motifs known as CpG presented in nano-particulate form. CpG motifs bind Toll like receptor 9 (TLR9) and induce strong innate immune activation, enhancing immunogenicity—in particular when presented in nanoparticulate form (17). They analysed immunogenicity of such a vaccine in mice and then in marmosets.

The study showed a number of important features. Animals receiving vaccinations using the alum based vaccine did generate some antibodies against HCV, although the levels of neutralisation were overall quite low. However, using the CpG based nanoparticle adjuvant K3-SPG, the same inactivated HCVcc preparation did induce neutralising antibody which was able to block infection. The levels of neutralisation in vitro reached around 60%, so blockade was not complete, but interestingly the sera did block infection by strains bearing envelopes from diverse genotypes, which would be an important attribute of any vaccine. There was also some evidence of T cell responses against components of the vaccine, capable of making interferon-gamma (IFNg). Analyses of marmoset T cell responses is difficult, so the overall levels of such responses are hard to gauge compared to human studies, but once again they were much more evident using the CpG based nanoparticle adjuvant K3-SPG. Induction of IFNg in response to HCV antigens does correlate with successful immune control of HCV in many human studies, was an important readout in the challenge studies performed previously using virally vectored vaccines, and remains the major measure immunogenicity in the development of HCV T cell vaccines in human trials (11).

This vaccine approach therefore is in many ways classical, but also relies heavily on the new adjuvant for its immunogenicity. The issue is to assess the potential for protection. This was not addressed in the marmoset model, although such animals can be infected with chimeric HCV/GBV-C viruses and that may be one possible approach (18). Additional pre-clinical models also include transgenic mouse strains which support HCV infection, some of which are immunologically intact (19). Given the lack of a clear correlate of protection, it would be very valuable to have more preclinical data before engaging in human studies. However, if it is possible to scale up and provide a highly robust safety profile for such a vaccine, immunogenicity studies in humans, followed by trials in populations at risk are really the only way to answer the question regarding protection. Possibly the blend of old and new approaches used in this study could pave the way for such future vaccines.

Friday, March 24, 2017

Healio Updates Non-Alcoholic Fatty Liver Disease (NAFLD) - Non-alcoholic steatohepatitis (NASH)

Non-Alcoholic Fatty Liver Disease (NAFLD) - Non-alcoholic steatohepatitis (NASH)
VIDEO: Physician discusses upcoming noninvasive modalities, treatments for NASH
In this exclusive video from Emerging Trends in Non-Alcoholic Fatty Liver Disease, Zobair M. Younossi, MD, MPH, FAASLD, chairman of the department of medicine at Inova Fairfax Hospital and vice president of research at Inova Health System, discusses topic highlights from the meeting, particularly steatohepatitis and future treatments.

VIDEO: Debate continues NAFLD treatment clinical trials’ construction
WASHINGTON — In this exclusive video from Emerging Trends in Non-Alcoholic Fatty Liver Disease, Kris V. Kowdley, MD, FAASLD, of the Swedish…

VIDEO: Hispanic patients at higher risk for developing fatty liver disease
“There are substantial differences in the likelihood of having fatty liver disease across various ethnicities,” Sanyal said. “People of Hispanic origin, or particularly those who are not of European origin, have a high prevalence of fatty liver disease. Not only do they have more fatty liver disease, but it can progress faster to cirrhosis, and this is closely linked to the prevalence of obesity and type 2 diabetes in this population.”

Imaging modalities provide confirmative results of NAFLD, NASH
Imaging modalities, such as magnetic resonance imagining and magnetic resonance elastography, provided significantly confirmative…

NASH recurrence does not hinder liver transplantation success
“In long-term studies, the highest frequency of graft loss related to recurrence of NASH appears to be around 5%. This is in stark contrast with hepatitis C ... with a 3rd of patients with HCV dying, requiring retransplantation or having cirrhosis due to recurrence of HCV within 5 years,” Michael R. Charlton, MD, of the department of medicine at the University of Chicago, said during his presentation. “Knowing that NASH itself is not an important cause of transplant graft failure and death, those other causes we looked at earlier — cardiovascular disease, neoplasia, renal insufficiency — these are much more common causes of death following liver transplantation, particularly in patients with fatty liver disease.”

Children diagnosed with non-alcoholic fatty liver disease between the ages 7 and 12 years presented with worse steatohepatitis and other factors than…

View all updates, here....

Effects of Melatonin on Liver Injuries and Diseases

Review article
Effects of Melatonin on Liver Injuries and Diseases
Jiao-Jiao Zhang, Xiao Meng  Ya Li, Yue Zhou, Dong-Ping Xu, Sha Li 2 and Hua-Bin Li

Int. J. Mol. Sci. 2017, 18(4), 673; doi:10.3390/ijms18040673

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This review summarizes the effects of melatonin on liver injuries induced by various factors and liver diseases, including liver steatosis, non-alcohol fatty liver, hepatitis, liver fibrosis, liver cirrhosis, and hepatocarcinoma, focusing on the mechanisms of action, such as antioxidant, anti-inflammation, anticancer, antiproliferation, and pro-apoptosis.

Abstract
Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.

Continue to full text article...

Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?

Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?
Pérez AB, Chueca N, García F.

GERMS 2017;7(1):40-44. doi: 10.18683/germs.2017.1107

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Abstract
The need to test for resistance associated substitutions (RAS) has been intensively debated in the past two years. In the absence of pangenotypic combinations, it seems reasonable that, if available, RAS testing in the NS5A gene at baseline for genotypes 1a and 3 may help to avoid overtreatment in terms of ribavirin usage and/or prolonged treatment duration. When patients fail treatment, RAS testing may also be useful to guide the selection of the new regimen, especially for those that need urgent retreatment and that have failed a combination including an NS5A inhibitor. However, there are new drugs in the pipeline that in combination are pangenotypic, very potent and with a high genetic barrier to resistance. In this new scenario, RAS testing may not play such an important role.

Keywords: HCV, RAS, DAA, baseline, failure, new drugs

The key to achieve sustained viral response (SVR) in the treatment of chronic hepatitis C with direct anting antivirals (DAAs) is to eliminate all the hepatitis C virus (HCV) quasispecies that infect the patient; if this is achieved, and the entire viral population has been eradicated, there is no opportunity for viral relapse and the patient is cured of HCV infection. Achieving SVR is a multifactorial event relying not only on virological factors, but also on factors related to the host and the drugs used for treating chronic hepatitis C.1 Being infected by genotypes 1a or 3, cirrhotic, and previously exposed to interferon-containing regimens are predictors of non-response. Among other virological factors that may impact SVR, the presence of resistance associated substitutions (RAS) may be clinically relevant, both before the patient is going to start the first DAA regimen and when the patient has failed treatment.

Although phenotypic tests may be performed to assess resistance to DAAs, genotyping (e.g. sequencing of the HCV genomic region of interest) is considered the gold standard to detect RASs. Next generation sequencing is now available for DNA sequencing and many laboratories have adopted this technology; however, unlike other scenarios, next generation sequencing has not been proven clinically relevant for HCV RASs testing; in fact, the detection of RASs present with a low relative frequency in the quasispecies viral population, below a 15% cutoff, failed to demonstrate any impact on SVR.2,3 In addition, to score resistance in HCV, the type of RAS is also critical, especially for the NS5A inhibitors, where class RASs (all substitutions in NS5A with a fold-change (FC) greater than 2.5X to any drug in the class) do not necessarily have the same impact as drug specific RASs (specific RASs for each drug in the class, in general with FC values above 100X).

The need to test for RASs at baseline has been highly debated through the last two years. In general, expert opinion at major conferences has always been that baseline RAS testing has no or a minimum impact on SVR, and therefore baseline RAS testing was not needed for clinical practice.

However, clinical guidelines from the American Association for the Study of Liver Diseases4(AASLD) recommend testing for Q80K in genotype 1a prior to using simeprevir in interferon-containing regimens, and more recently in cirrhotic patients that are going to start sofosbuvir (SOF) and simeprevir (SIM). For NS5A inhibitors, AASLD guidelines recommend to test for RASs in NS5A if the combination grazoprevir (GZR) and elbasvir (EBR) is going to be used, as the detection of clinically relevant RASs against EBR will aid to decide if prolonging treatment to 16 weeks and adding ribavirin (RBV) is necessary.

For other regimens, such as the AbbVie combination (paritaprevir/r-dasabuvir-ombitasvir, known as 3D) RAS testing is not necessary as there is no impact for HCV genotype 1b treatment, as there also isn´t for all the other DAA combinations and genotype 1b. For genotype 1a, the 3D approved regimen always includes RBV to make the regimen more potent and overcome the effect of RASs. Guidelines from the European Association for the Study of Liver diseases5 (EASL) have been updated September 2016; EASL panel state that if RAS testing is accessible, reliable and interpretable, then testing for baseline RAS for HCV genotypes 1a, 4, 5 and 6 will help to decide on extending treatment duration and adding RBV for any of the SOF and ledipasvir (LDV), SOF and daclatasvir (DCV) combinations, and as AASLD for GZR/EBR for genotype 1a.

Very recently, Zeuzem et al.3 clearly showed that HCV genotype 1a infected patients starting SOF/LDV with LDV specific RASs (15% cutoff) and prior interferon treatment experience, irrespective of the cirrhosis status, and those interferon-naïve with cirrhosis, are prone to achieve lower SVR rates when compared to HCV genotype 1b infected patients or treatment-naïve non cirrhotic genotype 1a, who achieve SVR rates of 96-98%.

Results for treatment-naïve and treatment-experienced genotype 1 infected patients, with and without liver cirrhosis are illustrated in Figure 1.

Figure 1. SVR12 rates achieved considering LDV specific RAS and a 15% cutoff. Data are presented in relation to prior interferon treatment (TN=treatment naïve; TE= treatment experienced), and cirrhosis status (C=cirrhosis; NC=non cirrhosis)

HCV genotype 3 is also difficult to treat with currently available DAAs. NS5A baseline RAS, especially Y93H, may condition lower SVR12 rates (75%) when starting SOF/DCV in real life conditions.6Data from the ASTRAL 3 study,7 where SOF and velpatasvir (VEL) were used for the treatment of genotype 3 infected patients, have also shown the impact on SVR12 of the Y93H RAS in NS5A (88%). In fact, AASLD guidelines recommend testing for Y93H before genotype 3a cirrhotic patients start any SOF/NS5A inhibitor combination, to decide whether extending treatment duration and adding RBV may be necessary.

Regarding patients that have failed a prior DAA regimen, and that are in urgent need of retreatment, there is a general consensus that RAS testing provides added value for clinical practice. Lawitz et al.8 addressed the retreatment with SOF/LDV and RBV for 24 weeks in patients that had failed a previous course of SOF/LDV for 8-12 weeks ± RBV; although only 41 patients were studied, the results showed a clear impact of the number and the type of RAS in NS5A on SVR12: patients that had no RASs at failure achieved 100% SVR12 rates when they were retreated with the same regimen they had failed, but with a 24 week duration and with RBV. Some other trials such as QUARTZ-I9 and CSWIFT-retreatment10 have also addressed the retreatment of patients failing the 3D regimen or GZR/EBV with the addition of SOF and RBV, with excellent results. Real-life studies have also addressed the importance of resistance testing for the retreatment of patients who have failed a first line DAA therapy: Vermehren et al.11showed excellent results in a German real life cohort when retreatment was resistance-guided; in a similar way, Cento et al.12 and Perez et al.13 also show data on resistance-guided retreatment of first line DAA failures in large Italian and Spanish cohorts, respectively.

Although resistance has been proven to play a role on both initial treatment and retreatment, there are some important caveats for the introduction of resistance testing in clinical practice that need to be highlighted. As EASL guidelines underline, the test needs to be reliable and interpretable. Reliability is certainly an issue, and only accredited laboratories with sufficient expertise both on technical issues on DNA sequencing and HCV RAS interpretation should provide results. Variability of interpretation is also important, as no clinically validated rules of interpretation are available so far. Although the Lontok et al. consensus14on HCV interpretation may help for a uniform interpretation of the results, the document is now outdated, as new drugs that are currently available, and new RASs that have been described, are not in the text. Several actions aiming to provide guidance on sequencing methods and RAS interpretation are currently being evaluated for publication in high impact HCV journals and will soon be available for public use. Hopefully, these guidance documents may help to make resistance testing for HCV more reliable and interpretable, and will certainly contribute to improve access to resistance testing in many settings.

New combinations of drugs, including very potent and pangenotypic drugs, such as voxilaprevir (VOX), glecaprevir (GLE), pibrentasvir (PIB), ruzasvir (RZR), uprifosbuvir (MK-3682), are currently in different phases of drug development and have entered phase II/III clinical trials. Some of these combinations are proving to be extremely efficacious for the treatment of interferon treatment-experienced, cirrhotic patients infected with the difficult to treat genotypes 1a and 3, and have already shown excellent SVR rates for treating patients that have also failed interferon free DAA containing regimens (Table 1). Presumably, when these combinations become available, RAS testing may not play an important role for clinical practice. However, we do not know yet how these drugs will be used, and how will they be rolled-out across different countries. In the meantime, until they are here, there is a clear role of RAS testing in the clinical practice, and a need to improve access to reliable testing and interpretation. HCV infected patients will certainly benefit from it.

Table 1. New drug combinations that have demonstrated high SVR rates in patients who have failed a prior course of interferon free DAA regimen


Authors’ contributions statement: ABP and NC drafted the paper; FG reviewed and edited the paper. All authors read and approved the final version of the manuscript.

Conflicts of interest: all authors – none to declare.

Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C

World J Hepatol. 2017 Mar 8;9(7):352-367. doi: 10.4254/wjh.v9.i7.352.

Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C.
Ponziani FR1, Mangiola F1, Binda C1, Zocco MA1, Siciliano M1, Grieco A1, Rapaccini GL1, Pompili M1, Gasbarrini A1.

Published online: March 8, 2017
Full Text
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Core tip: The approval of new direct acting antivirals with high rates of virological clearance and excellent tolerability has dramatically improved hepatitis C virus (HCV) infection curability, especially for patients with advanced liver disease and for liver transplant recipients. The aim of this review is to draw the possible future scenery in HCV-related liver disease, focusing our attention on the impact of second generation direct acting antivirals on liver fibrosis, hepatocellular carcinoma and liver transplantation.

Abstract
Hepatitis C virus (HCV) infection has been a global health problem for decades, due to the high number of infected people and to the lack of effective and well-tolerated therapies. In the last 3 years, the approval of new direct acting antivirals characterized by high rates of virological clearance and excellent tolerability has dramatically improved HCV infection curability, especially for patients with advanced liver disease and for liver transplant recipients. Long-term data about the impact of the new direct acting antivirals on liver fibrosis and liver disease-related outcomes are not yet available, due to their recent introduction. However, previously published data deriving from the use of pegylated-interferon and ribavirin lead to hypothesizing that we are going to observe, in the future, a reduction in mortality and in the incidence of hepatocellular carcinoma, as well as a regression of fibrosis for people previously affected by hepatitis C. In the liver transplant setting, clinical improvement has already been described after treatment with the new direct acting antivirals, which has often led to patients delisting. In the future, this may hopefully reduce the gap between liver organ request and availability, probably expanding liver transplant indications to other clinical conditions. Therefore, these new drugs are going to change the natural history of HCV-related liver disease and the epidemiology of HCV infection worldwide. However, the global consequences will depend on treatment accessibility and on the number of countries that could afford the use of the new direct acting antivirals.

Continue to full text article....

Study - Statin use may lead to: Decreased fibrosis and Reduced risk of developing liver cancer

Rationale for the use of statins in liver disease
Robert Schierwagen, Frank Erhard Uschner, Fernando Magdaleno, Sabine Klein, Jonel Trebicka

Published 9 March 2017
Full Text Article
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Statin drugs are widely used to manage high cholesterol and reduce the risk of cardiovascular disease. But in a new review of more than 50 studies, researchers cite reductions in liver inflammation and improvements in other related factors as reasons why statins make good candidates for treating chronic liver disease. The article is published ahead of print in the American Journal of Physiology—Gastrointestinal and Liver Physiology.

Reducing cholesterol can have a positive effect on many chronic liver disorders, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, as well as in biliary disorders. In some studies, the research team found that statins reduced inflammatory molecules that are typically elevated with liver disease and improved inflammation in the endothelium (cells that line the blood vessels). Statin use may also lead to:
  • Decreased fibrosis (hardening or scarring of tissue),
  • Less development of fatty liver,
  • Slowed or halted spread of hepatitis C virus,
  • Improvement of portal hypertension (high blood pressure in the liver's blood vessels),
  • Destruction of existing liver tumor cells, and
  • Reduced risk of developing liver cancer.
The researchers acknowledge that statin drugs can contribute to liver damage in some people, but for people with advanced liver disease, "[s]tatins are cost-effective, generally well-tolerated by patients and the benefits of statin treatment in most patients outweigh their potential hepatotoxic risk."

Summary
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Robert Schierwagen et al. Rationale for the use of statins in liver disease, American Journal of Physiology - Gastrointestinal and Liver Physiology (2017). DOI: 10.1152/ajpgi.00441.2016
            

Thursday, March 23, 2017

Watch - Hepatitis C Overview



HealthTalk 545 - Hepatitis C
Norwalk Hospital

Published on Mar 22, 2017
Learn more about Hepatitis C from Director of Gastroenterology, Dr. William Hale.

Watch the webinar – Injection drug use, comprehensive HIV and HCV prevention in rural US communities

Injection drug use, comprehensive HIV and HCV prevention in rural US communities

This webinar by Treatment Action Group (TAG) and HIV PJA presents local and state leaders’ perspectives on the response to the HIV outbreak in southern Indiana, and discusses how best to implement a comprehensive and community-led response to HIV, hepatitis C, and injection drug use in rural America.

Thank you to our moderator Jeremiah Johnson from Treatment Action Group and our speakers Dr. Carrie Ann Lawrence, Tony Gillespie and Daniel Raymond. Also, thank you to all attendees for submitting questions.

Chronic Hepatitis C And Functional Dyspepsia (FD) - A Feeling Of Discomfort In The Upper Abdomen

Functional Dyspepsia (FD)
Given the fact that liver pain, abdomen complaints and fatigue are all common symptoms for people living with hepatitis C, even in those who have undergone successful HCV treatment, you may wonder if there are conditions associated with the virus that share these symptoms.

Gallbladder disease and fatty liver disease both cause pain or discomfort in the upper abdomen, sometimes under the ribs. Studies have shown that people with chronic liver disease, especially those with cirrhosis have a greater tendency to develop gallstones, and non-alcoholic fatty liver disease (NAFLD) is a well known feature of chronic hepatitis C. The more severe form of NAFLD, called non-alcoholic steatohepatitis (NASH) - tends to develop in people who have certain risk factors, such as obesity, hyperlipidemia, and insulin resistance, both can accompany HCV.

However, pain in the liver area can be caused by many different conditions, some of which are serious, it is important for you to contact your health care provider to address the underlying cause, especially for people that suffer with both HCV and cirrhosis, learn more here.

Another somewhat familiar disorder called Functional Dyspepsia (FD), can cause discomfort in the upper abdomen as well and may be associated with chronic hepatitis C, according to a research article published in BMC Gastroenterology.

The prevalence of functional dyspepsia using Rome III questionnaire among chronic hepatitis C patients
The review article included 252 patients with chronic hepatitis C and 150 healthy volunteers, the prevalence of functional dyspepsia (FD) among patients with hepatitis C was evaluated using recorded clinical and laboratory data, all patients and controls were administered a questionnaire of FD according to Rome III criteria.

In short, the study found the percentage of hepatitis C patients with Functional Dyspepsia (FD) was significantly higher than in people without the hepatitis C virus. In addition, obese, chronic HCV patients and those with higher fibrosis scores are more likely to suffer with the condition. 
Read the full text article, here.

Functional Dyspepsia
The medical term, dyspepsia simply means bad digestion, the symptoms vary, but are frequently described as a full or bloated feeling felt in the upper belly during a meal or around 30 minutes later.

The term functional dyspepsia (FD) is used to describe chronic and persistent upper abdominal pain for which there is no clearly identifiable cause such as peptic ulcer disease. Because peptic ulcer disease produces similar symptoms, functional dyspepsia is sometimes called non-ulcer dyspepsia.

To learn more about this condition listen to Dr. Brian E. Lacy discuss FD in the following patient friendly podcast, available in the patient resource section of the American Journal of Gastroenterology (AGA) website.

Highlights
What is Dyspepsia?
What is the difference between Dyspepsia and Functional Dyspepsia?
20% of the U.S. population suffers with Dyspepsia sometime throughout the year.
What causes Dyspepsia?
What are the classic symptoms of Dyspepsia?
Dyspeptic symptoms may develop due to an organic process peptic ulcer disease, gastritis, occult acid reflux.
Could the symptoms be caused by underlying disease; liver problems?
Is there anything a patient could do to help Dyspepsia?
Treatment options
When to seek medical advice.

Listen here....

All Programs - American Journal of Gastroenterology (AGA)

Recommended Reading
Functional Dyspepsia Overview

Extrahepatic Manifestations
Recently published in Journal of Advanced Research is a nice collection of review articles on the extrahepatic manifestations of HCV.
Volume 8, Issue 2, March 2017, Pages 85–87

Until next time.
Tina

Delaying HCV treatment regardless of fibrosis stage may be detrimental given increased risk of mortality

Media Coverage Of This Article

Reuters Health Information
Increased Mortality With Moderate, Severe Hep C-related Liver Disease
By Will Boggs MD
March 24, 2017
“Although increased mortality was evident among individuals with severe fibrosis/cirrhosis, we observed some increased risk of mortality even among those with moderate fibrosis,” the researchers note. “These findings, and our inability to identify with sufficiently high prognostic accuracy individuals who would transition from a lower mortality risk state (minimal liver disease) to a higher mortality risk state (moderate or severe liver disease), may not support withholding HCV treatment until that transition occurs.” 
“Fight to treat your patients as early as possible,” Dr. Cepeda urged.
NEW YORK (Reuters Health) - Mortality is increased in patients with moderate or severe liver disease related to chronic hepatitis C, and progression from mild/moderate to severe disease cannot be predicted reliably, according to the ALIVE study.

"We were surprised by the amount of morbidity and mortality in the group with moderate fibrosis, many of whom would have difficulties receiving highly curative treatment,” Dr. Javier A. Cepeda from the University of California, San Diego, in La Jolla, told Reuters Health by email.

Despite expert-group recommendations to treat nearly everyone chronically infected with hepatitis C virus (HCV), most U.S. states restrict the use of oral direct-acting antivirals (DAAs) to patients with advanced fibrosis or cirrhosis, Dr. Cepeda and colleagues note in Clinical Infectious Diseases, online March 10. This is based on an assumption of no medical consequence to low-stage HCV infection and that liver fibrosis progression can be safely monitored until advanced fibrosis/cirrhosis is detected, they add.

The team used data from 964 individuals chronically infected with HCV with a history of injection drug use to characterize mortality rates by liver disease severity before widespread availability of DAAs.

At baseline, 63% of participants had no or mild liver fibrosis, 23% had moderate fibrosis, and 15% had severe fibrosis/cirrhosis.

During a median 5.9 years of follow-up, all-cause mortality was highest among participants with severe fibrosis/cirrhosis at baseline (6.21 deaths/100 person-years), intermediate among those with moderate fibrosis at baseline (3.59 deaths/100 py) and not elevated among those with no/mild fibrosis at baseline (2.21 deaths/100 py).

After adjusting for all other prognostic variables, severe fibrosis/cirrhosis remained associated with significantly elevated mortality risk, whereas the association with moderate fibrosis was attenuated and lost statistical significance.

Among individuals with no/mild fibrosis at baseline, 19% experienced significant progression during follow-up. Factors associated with an increased risk of progression had low predictive accuracy (C statistic=0.66), and a risk score in the top quintile was only 32% sensitive for predicting transition from no/mild to moderate fibrosis at five years.

“Although increased mortality was evident among individuals with severe fibrosis/cirrhosis, we observed some increased risk of mortality even among those with moderate fibrosis,” the researchers note. “These findings, and our inability to identify with sufficiently high prognostic accuracy individuals who would transition from a lower mortality risk state (minimal liver disease) to a higher mortality risk state (moderate or severe liver disease), may not support withholding HCV treatment until that transition occurs.”

“Fight to treat your patients as early as possible,” Dr. Cepeda urged.

SOURCE: http://bit.ly/2nMIEey
Clin Infect Dis 2017.

Mortality in Persons with HCV & Liver Disease
Clin Infect Dis; ePub 2017 Mar 10; Cepeda, et al
Publish date: March 22, 2017

Delaying treatment for persons chronically infected with hepatitis C virus (HCV) regardless of fibrosis stage may be detrimental, a recent study suggests, given the increased risk of mortality even for those with moderate disease and the inability to predict the transition from mild to moderate disease. In this cohort study, transient elastography was performed on 964 persons chronically infected with HCV and with a history of injection drug use. Liver stiffness was evaluated semiannually from 2006 to 2014 using validated cutoffs from moderate fibrosis and severe fibrosis/cirrhosis. Researchers found:
  • Among the study population, 62%, 23%, and 15% had baseline measurements suggestive of no/mild fibrosis, moderate fibrosis, and severe fibrosis/cirrhosis, respectively.
  • All-cause and non-accidental mortality were elevated in persons with moderate fibrosis (aHRs, 1.42, 1.66, respectively) after adjustments.
  • The transition from mild to moderate fibrosis could not be sufficiently predicted.
Citation: Cepeda JA, Thomas DL, Astemborski J, Sulkowski MS, Kirk GD, Mehta. Increased mortality among persons with chronic hepatitis C with moderate or severe liver disease: A cohort study. [Published online ahead of print March 10, 2017]. Clin Infect Dis. doi:10.1093/cid/cix207.
Article source - http://www.mdedge.com/idpractitioner/clinical-edge/summary/hepatitis/mortality-persons-hcv-liver-disease

Abstract
Increased mortality among persons with chronic hepatitis C with moderate or severe liver disease: a cohort study
Javier A. Cepeda, PhD, MPH David L. Thomas, MD, MPH Jacquie Astemborski, MS Mark S. Sulkowski, MD Gregory D. Kirk, MD, PhD Shruti H. Mehta, PhD, MPH

Background:

Despite the availability of curative treatment for hepatitis C virus (HCV) infection, because of cost, treatment is often denied until liver fibrosis has progressed to at least moderate fibrosis and in some cases cirrhosis. That practice is justified on assumptions that there are no medical consequences to having moderate disease and that disease stage transitions can be anticipated.

Methods:
We performed transient elastography on 964 people chronically infected with HCV with a history of injection drug use living in Baltimore, Maryland. Liver stiffness was evaluated semiannually from 2006 to 2014 using validated cutoffs for moderate fibrosis (8.0 – 12.3 kPa) and severe fibrosis/cirrhosis (>12.3 kPa).

Results:
Among 964 persons, 62%, 23% and 15% had baseline measurements suggestive of no/mild fibrosis, moderate fibrosis and severe fibrosis/cirrhosis, respectively. All-cause and non-accidental mortality were elevated in persons with moderate fibrosis (adjusted hazard ratio [aHR]: 1.42, 95% CI: 0.96 – 2.11; aHR: 1.66, 95%CI: 1.06 – 2.59, respectively) after adjustment for sociodemographics, substance use, and HIV status. Despite the increased risk of mortality among those with moderate fibrosis, no combination of demographic, behavioral, clinical factors, nor changes in stiffness measurements themselves could predict the transition from mild to moderate fibrosis with sufficiently high diagnostic accuracy (C-statistic =0.72 for best performing model).

Conclusions:
Delaying treatment for anyone chronically infected with HCV regardless of fibrosis stage may be detrimental given the increased risk of mortality even for those with moderate disease and the inability to predict the transition from mild to moderate disease.

https://academic.oup.com/cid/article-abstract/doi/10.1093/cid/cix207/3065487/Increased-mortality-among-persons-with-chronic?redirectedFrom=fulltext

Wednesday, March 22, 2017

Hepatitis C Cures Lag While New Drugs Wait in the Wings

Hepatitis C Cures Lag While New Drugs Wait in the Wings
By Jessica Wapner On 3/22/17 at 12:28 PM

Four years ago, the first curative pills for hepatitis C virus (HCV) were handed to patients. These drugs were a breakthrough for people infected with this pathogen. Lacking in serious side effects and eradicating the virus from the body in just 12 weeks, these so-called direct-acting antivirals (DAAs) offered a clean escape from this potentially fatal liver illness.

But with numerous DAAs now available—along with their long trail of clinical trial data—primary care physicians are left to navigate a crowded and confusing landscape for treating HCV. Controversy surrounding the cost of these drugs has also become a concern.
Continue reading..

Harvoni Study: 97% of Hepatitis C Patients Cured

Of Interest
Mar 20, 2017
Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.
Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.

Prime Therapeutics Study Finds 97 Percent of Hepatitis C Patients Cured with Harvoni® Treatment
Mar 21, 2017

Real-world data show nearly all patients completing therapy were cured.

ST. PAUL, Minn. – Nearly all patients who completed at least eight weeks of hepatitis C treatment with Gilead’s Harvoni® (ledipasvir/sofosbuvir) were cured of the disease, according to Prime Therapeutics LLC (Prime). Prime, a pharmacy benefit manager (PBM) serving nearly 20 million members nationally will present the data next week at the Academy of Managed Care Pharmacy’s 2017 Annual Meeting. The results are similar to clinical trial data on the treatment, which found cure rates of 94 to 99 percent.

For the study, Prime researchers reviewed data from 311 individuals who received at least eight weeks of Harvoni therapy and had a sustained virologic response (SVR) test result provided to the pharmacy between 12 to 24 weeks following Harvoni use. The SVR is used determine treatment response. Researchers found 301 of 311 members (96.8 percent) had a SVR laboratory result indicating a cure.

“Prime’s real-world data reflect findings from clinical trials. Our members who received at least eight weeks of Harvoni through Prime Therapeutics Specialty PharmacyTM had a very high likelihood of being cured of this disease,” said Cathy Starner, PharmD, principal health outcomes researcher at Prime.
Download (PDF)

Tuesday, March 21, 2017

“Waiting for DAAs”: A retrospective chart review of patients with untreated hepatitis C in Rwanda

“Waiting for DAAs”: A retrospective chart review of patients with untreated hepatitis C in Rwanda
Neil Gupta , Jules Kabahizi, Constance Mukabatsinda, Timothy David Walker, Emmanuel Musabeyezu, Athanase Kiromera, Jennifer Ilo Van Nuil, Kevin Steiner, Joia Mukherjee, Sabin Nsanzimana, Aimable Mbituyumuremyi

Full Text Article
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View Article Online

Published: March 21, 2017
http://dx.doi.org/10.1371/journal.pone.0174148

Abstract
Background
Access to treatment for hepatitis C virus (HCV) in sub-Saharan Africa is extremely limited. With the advent of direct acting antivirals (DAAs), highly effective and easy-to-deliver oral regimens are now available on the global market. This study was conducted to understand the background and characteristics of a national cohort of patients with HCV infection enrolled in care and awaiting therapy with DAAs.

Methods and findings
We conducted a retrospective chart review of all adult patients with confirmed HCV infection who were currently enrolled in care and treatment at the four existing hepatitis referral centers in Rwanda. Patient charts at these centers were reviewed, and routinely collected data were recorded and analyzed. Overall, 253 patients were identified; median age was 56 years (IQR: 43, 65), and 149 (58.9%) were female. Median viral load was 688,736 IU/ml and 96.7% were HCV genotype 4. As classified by FIB-4 score, 64.8% of the patients had moderate to severe fibrosis. Fibrosis stage was associated with age (OR 1.12, CI 1.09–1.17), but not with time since diagnosis, gender, treatment center, or type of insurance. There was a low frequency of documented co-morbid conditions, including hypertension, diabetes, HIV, and hepatitis B virus.

Conclusions
Compared to an estimated 55,000 patients eligible for HCV treatment in Rwanda, this study identified only 253 patients currently diagnosed and engaged in care, highlighting an immense treatment gap in HCV, likely due to the lack of accessible and affordable screening, diagnostic, and treatment modalities. The patients that were enrolled in care had a disproportionately advanced fibrosis stage, possibly indicating late presentation to care or lack of treatment options. In the context of newly available and effective treatment options, this study supports the overall need to accelerate access to HCV screening, diagnostics, and care and treatment services in resource-limited settings in sub-Saharan Africa.

Continue To Article Online...

ZEPATIER® now covered in Quebec for the treatment of chronic hepatitis C 

ZEPATIER® now covered in Quebec for the treatment of chronic hepatitis C 

KIRKLAND, QC, March 21, 2017 /CNW Telbec/ - Merck Canada Inc. today announced that ZEPATIER® (elbasvir/grazoprevir) will be listed among the drugs covered by Quebec's health insurance board, the Régie de l'assurance maladie du Québec (RAMQ), as of March 22. Quebec joins other jurisdictions that have approved the product for reimbursement under their public healthcare plans for chronic hepatitis C patients presenting with recognized criteria. Zepatier is indicated for the treatment of chronic infection by genotypes 1, 3 or 4 of the hepatitis C virus in adults.

The product monograph, including detailed product information and indication, is available online by clicking here.

"This announcement reflects the hepatitis C agreement between Merck and the pan-Canadian Pharmaceutical Alliance (pCPA). We are proud to contribute a solution in the fight against this disease, all the while helping reduce the cost pressure on the healthcare system," says Chirfi Guindo, President and Managing Director of Merck Canada Inc.

Hepatitis C patients without significant hepatic fibrosis who present with certain comorbidities or specific conditions will be eligible for the treatment, including those who have chronic kidney disease, who are co-infected with the human immunodeficiency virus (HIV) or the hepatitis B virus (HBV), who have undergone an organ transplant or who present with extrahepatic manifestations of the disease.

"Zepatier, which was approved in Canada in 2016 for cirrhotic and non-cirrhotic patients with a genotype 1a, 1b or 4 infection who were not previously treated or who experienced relapse after previous treatment meets the unmet needs of some groups, including renally impaired and dialysis patients," adds Dr. Marc Poliquin, a gastroenterologist with the Clinique médicale du Quartier Latin. "It also makes it possible to continue simple anti-reflux treatments, especially for patients who cannot change their acid reflux therapy without interfering with the effectiveness of hepatitis C treatment."

If not treated in time, hepatitis C can lead to serious complications, such as cirrhosis, liver cancer or the need for a liver transplant.2 In 2013, costs related to HCV complications were estimated at $161.4 million in Canada (estimates range from $85.4 million to $251.5 million).

High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men

Media Coverage On This Article
TUESDAY, March 21, 2017 (HealthDay News) -- Overweight and obese young men are at increased risk for serious liver disease or liver cancer later in life, and those with diabetes have an even higher risk, a new study warns.

Study

High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men
Hannes Hagström1,2, Per Tynelius3,4, Finn Rasmussen5

Full Text Available Online

Significance of this study

What is already known on this subject?
  • Overweight and obesity is increasing in prevalence worldwide.
  • A high body mass index (BMI) is associated with an increased risk for future severe liver disease and hepatocellular carcinoma in adults.
  • A high BMI also increases the risk for type 2 diabetes mellitus (T2DM), which in turn is associated with an increased risk of severe liver disease.

What are the new findings?
  • High BMI in late adolescence is associated with future severe liver disease in a non-linear relationship.
  • This risk is even higher in men who also develops T2DM, but also relevant in men who do not develop T2DM.
  • High BMI in late adolescence is also associated with an increased risk of subsequent hepatocellular carcinoma.

How might it impact on clinical practice in the foreseeable future?
  • Men who are overweight in young adulthood should be informed about an increased risk of future severe liver disease, including hepatocellular carcinoma. This could affect future public health decisions.
  • Men who develop T2DM, independent of BMI early in young adulthood or midlife, is at increased risk of severe liver disease, should be informed of this risk and possibly screened for presence of manifest liver disease to prevent future mortality in liver disease.

Abstract
Objective A high body mass index (BMI) is associated with an increased risk for severe liver disease. It is unclear if this risk differs across BMI categories, and if the association is partially attributed to development of type 2 diabetes mellitus (T2DM).
Design We used register data from more than 1.2 million Swedish men enlisted for conscription between 1969 and 1996. Data regarding new events of severe liver disease and T2DM during follow-up were obtained by record-linkage of population-based registers. We used Cox regression to estimate adjusted HRs for future inpatient care and mortality in severe liver disease and incidence of hepatocellular carcinoma (HCC) across BMI categories, using BMI of 18.5–22.5 kg/m2 as reference.
Results During a follow-up of more than 34 million person-years, 5281 cases of severe liver disease including 251 cases of HCC were identified. An association with severe liver disease was found for overweight (HR 1.49, 95% CI 1.35 to 1.64) and for obese men (HR 2.17, 95% CI 1.82 to 2.59). Development of T2DM further increased the risk for severe liver disease across all BMI categories, for instance, men with obesity and T2DM had a higher risk of severe liver disease (HR 3.28, 95% CI 2.27 to 4.74) than men with obesity free of T2DM (HR 1.72, 95% CI 1.72 to 2.54).
Conclusions A high BMI in late adolescent men was associated with an increased risk of future severe liver disease, including HCC. Development of T2DM during follow-up was associated with a further increased risk of severe liver disease, independent of baseline BMI.

Full Text Article Available, here.

Monday, March 20, 2017

2017 / Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV

Media Coverage Of This Article
Wednesday, March 22, 2017
Hepatitis C Cures Lag While New Drugs Wait in the Wings
Will new hepatitis C treatments eliminate the virus for good?

NEJM Journal Watch
All FDA-Approved, Oral Direct-Acting Antivirals for Hepatitis C Safe and Effective for Genotype 1
By Kelly Young
Edited by Jaye Elizabeth Hefner, MD   
The FDA-approved interferon-free regimens for treating hepatitis C appear to be safe and effective, suggests an Annals of Internal Medicine review.

Researchers examined 42 randomized trials of oral hepatitis C treatments that included at least two direct-acting antivirals. Among the findings:
  • For genotype 1 infection, the most common HCV type, sustained virologic response rates were above 95% for six regimens.
  • For patients with HCV genotype 3 and without cirrhosis, sofosbuvir plus velpatasvir or daclatasvir for 12 weeks seemed to be most effective.
  • For genotype 3 with cirrhosis, velpatasvir-sofosbuvir had higher response rates. That drug combination was also highly effective (99% response rate) for genotypes 2, 4, 5, and 6.
  • Patient groups traditionally considered difficult to treat — including those with HIV, severe kidney disease, or liver transplant — had high response rates and limited adverse events.
Editorialists conclude that "hepatitis C is down but not out," noting that screening for HCV is not yet routine, and the drugs are still priced high.
NEJM Journal Watch

Editorials |21 March 2017
Annals of Internal Medicine
Hepatitis C: Down but Not Out
Jay H. Hoofnagle, MD; Averell H. Sherker, MD                   
Within the past 4 years, no fewer than 10 potent, orally available antiviral drugs have received U.S. Food and Drug Administration (FDA) approval as therapy for chronic hepatitis C virus (HCV) infection. These small molecules are directed at 1 of 3 HCV targets: NS3/4A protease (“-previrs” [simeprevir, paritaprevir, and grazoprevir]), NS5B RNA polymerase (“-buvirs” [sofosbuvir and dasabuvir]), or NS5A polypeptide (“-asvirs” [daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir]). Most important, combinations of 2 or 3 of these agents have proven highly effective in inducing a sustained virologic response (SVR), with persistent loss of HCV RNA from serum. Long-term follow-up of patients who have achieved SVR shows resolution of the accompanying liver disease and permanent loss of HCV RNA from both serum and the liver, suggesting a “cure” of the chronic viral infection. These new all-oral regimens typically have SVR rates of 95% or more with only 8 to 12 weeks of treatment and minimal adverse effects; in contrast, previous interferon-based regimens yielded rates of 50% to 60%, but only in highly selected patients and after 48 weeks of poorly tolerated treatment with serious adverse effects and significant contraindications. The new antiviral regimens have transformed management of chronic HCV infection.
http://annals.org/aim/article/2613307/hepatitis-c-down-out

Annals of Internal Medicine
Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review
Oluwaseun Falade-Nwulia, MBBS, MPH (*); Catalina Suarez-Cuervo, MD (*); David R. Nelson, MD; Michael W. Fried, MD; Jodi B. Segal, MD, MPH; Mark S. Sulkowski, MD
View Full Text Article Online

Abstract
Background:

Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection.Purpose:
To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection.

Data Sources: MEDLINE and EMBASE from inception through 1 November 2016.Study Selection:

42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs.

Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently.

Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.

Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling.

Conclusion:
Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.

Primary Funding Source:Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711)

In the United States, 3.2 to 5 million people are chronically infected with hepatitis C virus (HCV) and are at risk for cirrhosis, liver cancer, and death if untreated (1, 2). Infection with HCV is the primary indication for liver transplantation and causes more deaths than all other notifiable infectious diseases in the United States combined (3, 4). Cure of this infection, defined as the absence of detectable HCV RNA in the blood at least 12 weeks after treatment completion (sustained virologic response [SVR]), is strongly associated with reduced liver-related morbidity and mortality (5, 6). The development of drugs that directly inhibit key steps in viral replication has led to availability of several oral HCV treatment regimens (7). We systematically reviewed the efficacy and safety of oral interferon-free HCV treatment regimens that have been approved by the U.S. Food and Drug Administration (FDA) and include at least 2 direct-acting antivirals (DAAs). We also assessed the effect of ribavirin on rates of SVR and adverse events. We reviewed phase 2 and 3 clinical trial data for patients infected with HCV genotypes 1 to 6 and patients previously considered difficult to cure with decompensated cirrhosis, HIV infection, renal failure, or liver transplantation.

Methods
Data Sources and Searches
We developed a protocol for this systematic review and registered it in PROSPERO (CRD42014009711). We searched MEDLINE and EMBASE for literature published in English from inception through 1 November 2016. The search strategy included terms for HCV infection and the medications of interest (Figure 1). We also searched ClinicalTrials.gov and hand-searched the reference lists of included articles and related systematic reviews.

Study Selection

We included English-language, single-group, randomized, controlled trials (RCTs) of adults with chronic HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. We included trials that used DAA combinations—including inhibitors of HCV NS3 protease (grazoprevir, paritaprevir, and simeprevir), NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B polymerase (sofosbuvir and dasabuvir), as well as the oral antiviral ribavirin—and for which the primary outcome was SVR. We excluded studies published only as abstracts; dose-finding studies; those in which the primary outcome was pharmacokinetics; or those in which the regimens included interferon, DAAs that were not FDA-approved, or only 1 DAA (for example, sofosbuvir plus ribavirin). Trials were included regardless of participants' cirrhosis, HIV, or liver transplantation status, but trials of limited populations (for example, DAA-experienced patients or those of a single race) were excluded.

Data Extraction and Quality Assessment

Two reviewers independently screened titles and abstracts and then the full text of potentially eligible articles to identify studies meeting inclusion criteria. Using standardized forms, 1 reviewer extracted information from the selected studies about study characteristics, design, outcomes, and the funding source. A second reviewer confirmed the accuracy of the extractions. Differences were resolved through consensus. Two reviewers independently assessed risk of bias for each selected study by using 5 items from the Cochrane risk-of-bias tools for RCTs and a Cochrane tool for assessment of risk of bias in nonrandomized trials and observational studies (8, 9).

Data Synthesis and Analysis

Detailed evidence tables were generated, and studies were summarized by outcomes. The results were organized by genotype and then by the specific population studied. The heterogeneity of the interventions precluded quantitative pooling of results.

Role of the Funding Source

The Patient-Centered Outcomes Research Institute (PCORI) funded the study and reviewed the report but did not participate in the formulation of the review's questions, data searches, study appraisals, evidence interpretation, or the preparation or approval of the manuscript for publication.

Results
Study and Quality Characteristics

Of 1796 citations evaluated, we included 42 studies published in 40 articles (Figure 1). All but 1 of the studies were funded by industry (10). Ten were open-label, single-group studies (10–19); 5 had a placebo group with deferred treatment (20–24); 11 evaluated different durations of therapies and the addition of ribavirin (for example, 8 vs. 12 weeks or 12 vs. 24 weeks of therapy with or without ribavirin) (25–35); 5 evaluated the same duration of therapy with and without ribavirin (36–39); 6 evaluated different durations with ribavirin (40–45); and 3 evaluated different durations of therapy without ribavirin (46–48). Only 2 studies had an active comparator group receiving an HCV treatment regimen other than that being evaluated in the trial (49). Three studies had 48 weeks of posttreatment follow-up, whereas the remainder had 12 or 24 weeks of follow-up.

Of the 42 studies, 19 had low risk of bias and 23 had moderate risk. Sources of possible bias included single-group design (n = 10), lack of information on sequence generation or concealment of the allocation scheme (n = 11), and selective reporting of outcomes (n = 5). Because SVR is a highly objective outcome measure, lack of blinding was not considered an important threat to validity. Rates of loss to follow-up were low (<10% for all studies).

HCV Genotype 1 Infection

Thirty-two studies enrolled persons with HCV genotype 1 infection (Table; Figure 2, continued Figure 2; and Table 1 of the Supplement). Download Supplemental Content

Regimens That Include NS3/4A Protease Inhibitors

Grazoprevir–Elbasvir.

Grazoprevir is an NS3 protease inhibitor that is available in a fixed-dose combination with elbasvir, an NS5A inhibitor. This regimen was studied in 4 multicenter randomized trials published in 6 articles (11, 20, 21, 25–27). Risk of bias was moderate in 3 of these studies due to lack of a comparator group (n = 1) and selective reporting (n = 2). Daily grazoprevir–elbasvir for 12 weeks was associated with SVR rates of 92% and 99% to 100% in treatment-naive and treatment-experienced patients with genotype 1a and 1b infection, respectively (20, 26, 27). Among patients with genotype 1a but not genotype 1b infection, lower SVR rates were associated with pretreatment presence of naturally occurring resistance-associated substitutions (RASs) at positions 28, 30, 31, and 93 of the NS5A region (20, 27). Prolongation of therapy to 16 weeks and addition of ribavirin led to SVR among 49 treatment-experienced patients, including all 6 patients with baseline NS5A RASs (27). Ribavirin was associated with greater incidence of anemia (3% to 16% vs. 0%), fatigue, and nausea (25–27). With the exception of patients with genotype 1a infection with baseline RASs, the SVR rate was similar in those treated with or without ribavirin. Cirrhosis was not associated with lower SVR rates (14, 16).

Paritaprevir–Ritonavir–Ombitasvir and Dasabuvir.

Paritaprevir is an NS3 protease inhibitor that is coformulated with ritonavir (to provide pharmacologic boosting) and ombitasvir (an NS5A inhibitor). For patients with genotype 1 infection, dasabuvir (a nonnucleoside NS5B polymerase inhibitor) was added. We identified 1 study with low risk of bias that used the two-DAA regimen without dasabuvir (45) and 9 studies (5 with low risk of bias and 4 with moderate risk of bias) that used the three-DAA regimen for 12 or 24 weeks (12, 13, 22, 23, 37, 38, 40, 41). Moderate risk of bias was due to lack of a comparator group (n = 2) and unclear sequence generation and allocation scheme concealment (n = 2). The three-DAA regimen without ribavirin yielded lower SVR rates in persons with genotype 1a infection (90%) than those with genotype 1b infection (99%); however, with the addition of ribavirin, the SVR rate among noncirrhotic patients with genotype 1a infection increased to 97% (38). Compared with placebo, ribavirin was associated with more anemia, fatigue, insomnia, and rash (22, 38). Among cirrhotic patients with genotype 1a infection, the three-DAA regimen plus ribavirin for 24 weeks led to higher SVR rates than 12 weeks of treatment (94.2% vs. 88.6%) (41). High rates of SVR were seen among cirrhotic and noncirrhotic patients with genotype 1b infection treated for 12 weeks with the three-DAA regimen alone or with ribavirin (97% to 100%) (22, 23, 37, 38, 41, 45).

Simeprevir and Sofosbuvir.

Simeprevir is an NS3 protease inhibitor that is used once daily in combination with sofosbuvir, a nucleoside analogue NS5B polymerase inhibitor. We identified 3 studies using this regimen (14, 28, 46). Risk of bias was moderate in 2 studies due to unclear sequence generation (n = 1) and lack of a comparator group (n = 1). When used for 12 weeks, the regimen was associated with high rates of SVR (97%) in persons with HCV genotype 1a or 1b infection without cirrhosis (46). In this population, pretreatment presence of naturally occurring simeprevir RASs at position 80 of the NS3 region (Q80K) was not associated with lower SVR rates (46). However, lower SVR rates were observed among patients with cirrhosis (79% to 88%) and, in this population, the presence of the Q80K RAS was associated with lower SVR rates in patients with genotype 1a infection (74% with Q80K and 92% without) (14).

Regimens That Do Not Include NS3/4A Protease Inhibitors

Daclatasvir and Sofosbuvir.

Daclatasvir is an NS5A inhibitor used with sofosbuvir. Clinical trial data on this combination are limited but suggest high SVR rates with 12- and 24-week treatment (96% to 100%), based on data from 2 studies with moderate risk of bias (29, 48). Among patients with advanced liver disease, SVR rates were lower (82%) (15).

Ledipasvir–Sofosbuvir.

Ledipasvir, an NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. Eight studies (4 with low risk of bias and 4 with moderate risk of bias) evaluated different treatment durations (8, 12, and 24 weeks) and the addition of ribavirin (17, 30–34, 43, 44). Moderate risk of bias was due to lack of a comparator (n = 1) and unclear sequence generation or allocation scheme concealment (n = 3). In treatment-naive patients, SVR rates were greater than 95% with 12 weeks of treatment, and longer treatment did not yield higher rates (30, 31, 33). Although 8 weeks of therapy was assessed in 1 RCT and was found to lead to high SVR rates in noncirrhotic persons with pretreatment HCV RNA levels less than 6 × 106 IU/mL (33), the most data on efficacy are for 12 weeks. In treatment-naive patients, ribavirin was not associated with higher SVR rates regardless of cirrhosis status, whereas in treatment-experienced patients, either longer therapy (24 weeks) with ledipasvir–sofosbuvir or the addition of ribavirin to the regimen for 12 weeks was associated with higher SVR rates in patients with cirrhosis (97% vs. 96%) (34). The addition of ribavirin led to more adverse events, notably anemia, fatigue, and insomnia (31–33).

Velpatasvir–Sofosbuvir.

Velpatasvir, a pangenotypic NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. This regimen for 12 weeks was associated with high SVR rates (97% to 99%) in patients with HCV genotype 1a or 1b infection, including those with cirrhosis and prior treatment experience (24). In this placebo-controlled, double-blind trial with low risk of bias, the incidence of adverse events was similar in patients receiving velpatasvir–sofosbuvir and those receiving placebo.

HCV Genotype 2 Infection

Six studies enrolled patients with HCV genotype 2 infection (Table and Figure 3); 3 studies (2 with low risk of bias and 1 with moderate risk of bias) evaluated the fixed-dose combination of velpatasvir–sofosbuvir (24, 35, 49), and 3 with moderate risk of bias evaluated daclatasvir plus sofosbuvir (15, 29, 48).

Daclatasvir and Sofosbuvir

In the ALLY-2 study, all 13 HIV-infected patients with genotype 2 infection who were treated for 12 weeks achieved SVR (48). In another study, 24 of 26 (92%) treatment-naive, noncirrhotic, HIV-seronegative patients treated for 24 weeks with or without ribavirin achieved SVR; 2 patients were lost to follow-up (29).

Velpatasvir–Sofosbuvir

The ASTRAL-1 and ASTRAL-2 studies reported SVR in 237 of 238 patients (99%) with genotype 2 infection who received velpatasvir–sofosbuvir for 12 weeks; 1 patient was lost to follow-up (24, 49). Rates of SVR were not affected by cirrhosis or prior treatment experience. In an RCT, velpatasvir–sofosbuvir was superior to sofosbuvir plus ribavirin (SVR of 99% vs. 94%) and was associated with fewer adverse events (49).

HCV Genotype 3 Infection

Eight studies enrolled patients with HCV genotype 3 infection (Table and Figure 3).

Daclatasvir and Sofosbuvir

In a phase 2 study, 16 of 18 noncirrhotic patients treated with or without ribavirin for 24 weeks achieved SVR (29). In the single-group ALLY-3 trial, which had moderate risk of bias, 94% to 97% of noncirrhotic treatment-naive and treatment-experienced patients achieved SVR with 12 weeks of treatment (16). In the same study, cirrhosis was associated with a marked reduction in SVR (58% to 69%) (16). The addition of ribavirin to the regimen for 12 or 16 weeks in patients with advanced liver disease led to SVR in 86% of cirrhotic patients (n = 36) in the ALLY-3+ study, which had moderate risk of bias due to unclear sequence generation and allocation scheme (42).

Ledipasvir–Sofosbuvir

In a single-center study with low risk of bias, all 26 treatment-naive patients treated with ledipasvir–sofosbuvir plus ribavirin for 12 weeks achieved SVR (39). The SVR rate was lower without ribavirin (64%) and in treatment-experienced patients (82%) (39).

Velpatasvir–Sofosbuvir

In a phase 3 RCT with 552 patients and low risk of bias, velpatasvir–sofosbuvir for 12 weeks (95%) was superior to sofosbuvir plus ribavirin for 24 weeks (80%) and was associated with fewer adverse events, particularly less anemia (49). Lower SVR rates were observed in patients with pretreatment presence of velpatasvir NS5A RASs, particularly at position 93 (88%), compared with those without RASs (97%).

HCV Genotype 4 Infection

Twelve studies enrolled persons with HCV genotype 4 infection (Table and Figure 3).

Grazoprevir–Elbasvir

In the C-EDGE study, efficacy of grazoprevir–elbasvir was demonstrated among 18 of 18 treatment-naive patients with genotype 4 infection (SVR of 100%) who received the regimen for 12 weeks; baseline presence of NS5A RASs did not affect SVR (20). Among treatment-experienced patients in a randomized trial of 12 or 16 weeks of the regimen with or without ribavirin, SVR rates were below 95% in all groups except patients who received 16 weeks of the regimen with ribavirin (27).

Paritaprevir–Ritonavir–Ombitasvir

In 1 trial with low risk of bias, paritaprevir–ritonavir–ombitasvir plus ribavirin resulted in high efficacy (SVR of 100%) in both treatment-naive (n = 42) and treatment-experienced (n = 44) patients with genotype 4 infection (36). The absence of ribavirin was associated with a lower SVR rate (91%).

Simeprevir and Sofosbuvir

In an RCT with moderate risk of bias due to unclear sequence generation and allocation scheme concealment, simeprevir plus sofosbuvir was associated with SVR in all 43 patients (100%) treated for 12 weeks, including those with cirrhosis (n = 23); however, SVR rates were lower in 20 patients treated for 8 weeks (75%) (47).

Ledipasvir–Sofosbuvir

In a single-group trial of 21 patients, 95% who received 12 weeks of ledipasvir–sofosbuvir achieved SVR; the study included few patients with cirrhosis (n = 7) or prior treatment experience (n = 8) (10). In a similar trial conducted in France, 41 of 44 patients (93%) who were treated for 12 weeks achieved SVR (19). No serious adverse events were reported in these studies (10, 19).

Velpatasvir–Sofosbuvir

In the ASTRAL-1 RCT, which had low risk of bias, velpatasvir–sofosbuvir led to SVR in all 116 treatment-naive and treatment-experienced patients (100%) who were treated, including those with cirrhosis (24).

HCV Genotype 5 and 6 Infection

Six studies enrolled persons with HCV genotype 5 and/or 6 infection (18, 20, 24, 27, 35, 39) (Figure 3).

Ledipasvir–Sofosbuvir

This combination led to high SVR rates in persons with genotype 5 (n = 41; SVR of 95%) and genotype 6 (n = 25; SVR of 96%) infection (18, 39). Although the numbers of patients in these subgroups were small, SVR rates were high in treatment-experienced patients (≥95%) and those with cirrhosis (89%) (18).

Velpatasvir–Sofosbuvir

In 1 RCT with low risk of bias, patients with genotype 5 (n = 35) and genotype 6 (n = 41) infection achieved high rates of SVR (97% and 100%, respectively) with 12 weeks of treatment; only 1 patient did not achieve SVR (death unrelated to treatment) (24).

Subpopulations

Patients With HIV Co-infection

Direct-acting antiviral regimens used for 12 or 24 weeks showed high SVR rates (91% to 98%) and low adverse event rates (<10%). These rates were similar to those observed in persons without HIV (11, 17, 26, 40, 48). Shorter therapy (8 weeks) was evaluated in 1 RCT of daclatasvir plus sofosbuvir and led to lower rates of SVR (76%) than 12 weeks of therapy (97%) (48).

Patients With Decompensated Cirrhosis

Relatively few patients with decompensated liver disease (for example, those with jaundice, ascites, encephalopathy, or variceal hemorrhage) have been enrolled in DAA trials. Because of impaired metabolism, NS3 protease inhibitors are not recommended (simeprevir) or are contraindicated (paritaprevir or grazoprevir) in patients with Child–Turcotte–Pugh class B and C disease. These patients have been treated in trials of sofosbuvir plus NS5A inhibitors, including daclatasvir, ledipasvir, and velpatasvir (15, 35, 43, 44). In 1 RCT, velpatasvir–sofosbuvir with ribavirin for 12 weeks was more effective than velpatasvir–sofosbuvir alone for 12 or 24 weeks; however, ribavirin was associated with more treatment discontinuation due to adverse events (35). Across all studies, rates of serious adverse events were higher in patients with decompensated cirrhosis (10% to 52%) than in the general HCV patient populations (<10%).

Patients After Liver Transplantation

Four trials evaluated DAAs in patients who had undergone liver transplantation. Overall, SVR rates observed in these trials were similar to those reported in patients without a transplant (12, 15, 43, 44). However, among liver transplant patients with decompensated liver disease due to recurrent HCV infection, SVR rates were lower (50% to 80%) and adverse event rates were higher (16% to 75%) than those observed in liver transplant patients with compensated cirrhosis or those with minimal liver disease (6% to 21%) (12, 43, 44).

Patients With Chronic Kidney Disease

In 2 studies of patients with advanced renal dysfunction, including those receiving hemodialysis, high SVR rates were reported in those with HCV genotype 1 infection (13, 21). In 1 study with low risk of bias, grazoprevir–elbasvir for 12 weeks resulted in SVR in 94% of patients (n = 111) (21). In a smaller study with moderate risk of bias due to lack of a comparator group, a regimen of paritaprevir–ritonavir–ombitasvir and dasabuvir was effective (SVR of 90%), but ribavirin, which was used for patients with genotype 1a infection, was poorly tolerated and was discontinued due to adverse events in 8 of 14 patients (48).

Discussion
Multiple interferon-free, oral DAA regimens are available for treatment of chronic HCV infection. We found high SVR rates for all FDA-approved DAA regimens, with some evidence of variable response influenced by specific patient and virus characteristics. Rates of serious adverse events (<10%), loss to follow-up (<10%), and treatment discontinuation (<5%) were low even in patients with comorbid conditions, such as HIV infection and cirrhosis.

The evidence was robust for persons with genotype 1 infection, which is the most common genotype worldwide, infecting approximately 84 million persons (50). We reviewed 6 distinct DAA regimens for genotype 1 infection, with SVR rates greater than 95% for most drug combinations and patient populations. Our findings represent an important update of other systematic reviews of DAA regimens with and without interferon for treatment of HCV genotype 1 infection, which reported SVR rates in the range of 95% (50, 51) and 92% (52). The high treatment response rates in persons with genotype 1 infection are particularly important in light of the historically poor SVR rates observed with interferon in this population.

In contrast, fewer DAA regimens are available and effective for the treatment of HCV genotype 3 infection, which is the second most prevalent HCV genotype globally, infecting approximately 54 million persons. Our findings indicate that the most effective DAA regimens for patients who have genotype 3 infection without cirrhosis are sofosbuvir plus the NS5A inhibitors velpatasvir or daclatasvir for 12 weeks, whereas higher SVR rates were observed with velpatasvir–sofosbuvir in patients with cirrhosis. This agrees with recent systematic reviews, identified through MEDLINE searches from 2014 to 2016, that identified velpatasvir–sofosbuvir as the most effective treatment for genotype 3 infection (51, 52). Our findings also suggest that lower SVR rates were achieved in patients with compensated and decompensated cirrhosis, prior treatment experience, or NS5A RASs; the addition of ribavirin and longer treatment duration were associated with higher SVR rates in these patient groups (42, 53).

Although relatively few studies enrolled patients with genotype 2, 4, 5, or 6 infection, high rates of SVR (>92%) were observed for all regimens administered for at least 12 weeks. Rates of SVR were particularly high (99%) for patients with genotype 2, 4, 5, or 6 infection treated with velpatasvir–sofosbuvir (24). For treatment of genotype 4 infection, all but 1 of the DAA regimens (paritaprevir–ritonavir–ombitasvir) led to high SVR rates (93% to 100%) without ribavirin and were associated with minimal adverse effects in treatment-naive patients.

Oral DAA regimens also showed high SVR rates and minimal adverse events in patient populations that were poorly responsive or could not be treated with interferon, including those with HIV co-infection, decompensated cirrhosis, severe chronic kidney disease, and a liver transplant. Patients co-infected with HIV and HCV and those receiving immunosuppressive agents after liver transplantation had SVR rates similar to those of persons without immune dysfunction, suggesting that oral DAAs mitigate the effect of an impaired HCV immune response (54–56). Direct-acting antiviral options for persons with severe chronic kidney disease remain limited, and although high SVR rates (85% to 100%) were observed in 2 RCTs for persons with HCV genotype 1 infection, no trials were identified in persons with genotype 2 or 3 infection, for whom interferon is still recommended (57). Treatment options also remain limited in patients with decompensated liver disease. Current NS3 protease inhibitors are hepatically metabolized and are contraindicated in this population; as such, trials have been restricted to sofosbuvir plus NS5A inhibitors. The evidence indicates that these regimens provide high rates of SVR (>85%), but serious adverse events are common (10% to 52%). In addition, questions remain with regard to the long-term clinical benefit of cure of HCV infection in persons with severe liver dysfunction.

Across multiple trials, our findings indicate that ribavirin continues to have a role in maximizing SVR rates in certain patients, including those with genotype 1a or 3 infection, cirrhosis, or prior treatment experience. Clinical trials for patients with decompensated cirrhosis and a liver transplant have also largely included ribavirin. Although ribavirin was associated with an increase in anemia, fatigue, and insomnia, the rates of serious adverse events and treatment discontinuation were similar in patients treated with and without it.

Limitations of this study include the fact that safety data from clinical trials may not fully represent patient experience in clinical practice. Persons with chronic hepatitis B virus infection were excluded from trials, and the risk for hepatitis B virus reactivation was not examined. We also included noncontrolled trials; however, spontaneous cure of HCV infection is rare. Most of the studies were industry-funded; such studies are more likely to be published if results are favorable (58), but we are not aware of large, unpublished studies in this field and the risk of bias with the objective outcome of SVR is low. The heterogeneity of the interventions studied also prevented quantitative pooling of results, and the relatively short follow-up limits our ability to comment on late relapse of HCV infection. Several studies were also population-specific, thus limiting generalizability of findings to all patients. Given the multitude of effective oral DAA regimens with similar rates of SVR and adverse events, RCTs will be needed to determine the best HCV treatments for different patient populations. One such trial, the PRIORITIZE study (ClinicalTrials.gov: NCT02786537), is under way in persons with genotype 1 infection (59).

Finally, our systematic review is limited by the rapidly evolving HCV treatment landscape and the inability to include all DAA regimens in ongoing or recently completed clinical trials that we identified on ClinicalTrials.gov (Table 7 of the Supplement). These ongoing clinical trials include 2 novel nucleotide analogue NS5B polymerase inhibitors, MK-3682 and AL-335, which are being evaluated in combination with approved NS3 protease inhibitors and novel NS5A inhibitors (ruzasvir and odalasvir), as well as 2 novel pangenotypic NS3 protease inhibitors, voxilaprevir and glecaprevir, which are being evaluated in combination with approved (sofosbuvir–velpatasvir–voxilaprevir) and novel (glecaprevir–pibrentasvir) DAAs (60).

In conclusion, oral DAA regimens that are highly efficacious, well-tolerated, and relatively short in duration are now available for all HCV genotypes and for patient populations historically considered difficult to cure. The ease of dosing, safety profile, and effectiveness of these agents provide an opportunity to expand the number of patients who can be treated for HCV infection and the pool of treating providers. Rapid developments in oral DAA therapies can be beneficial only if they are linked to efforts to improve rates of HCV detection, linkage to care, and access to DAA therapy.

References
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