Snapshots Alan Franciscus, Editor-in-Chief

Article: Hepatitis C in children in times of change—RD Baker et al.
  Source:  Curr Opin Pediatr. 2015 Jul 18. [Epub ahead of print]

Results and Conclusions
The main focus of the abstract was when to initiate treatment and when it is safe to wait for approval of the new highly effective direct-acting antiviral therapies to treat hepatitis C (HCV).

Pegylated interferon and ribavirin is the current standard of care to treat children with hepatitis C.  There are pediatric clinical trials of sofosbuvir/ledipasvir, ribavirin, and Vieikira Pak, with and without ribavirin. Approval of these drugs is expected in the near future.    

The authors make a good case for their recommendations:

• Wait: Children generally have a slow disease progression so in most cases it is safe to wait for the interferon- and ribavirin-free medications to be approved.
  
  
• Treat: In the case of children who do have serious disease progression treatment now is warranted.  Genotype information should be factored into the treatment decision process since genotype 2 and 3 cure rates are higher and treatment durations are shorter with pegylated interferon and ribavirin combination therapy.   

The Bottom Line
All children with HCV should be monitored on a regular basis.  Any treatment decisions for children should be evaluated on a case-by-case basis.

Editorial Comment
The general consensus is to wait (if possible) until the interferon- and ribavirin- free therapies are available. However, there is a small percentage of children with HCV who progress on to serious liver disease very quickly—this is why it is so important to identify and monitor children on a regular basis. 

It will be very interesting once the new therapies are approved to treat children with HCV.  Will insurance companies be as restrictive as they are with adults?  Hopefully not!  But if they are it just might be enough to raise the level of public ire to demand that they cover the medications for everyone.  It might also be enough that the public finally demand that the prices come down so that everyone affected by hepatitis C can afford the medications. 

Coming soon:  An Overview of HCV in Children

Article:  Prevalence of Cirrhosis in Hepatitis C Patients in the Chronic Hepatitis Cohort Study (CHeCS): A Retrospective and Prospective Observational Study—S C Gordon et. al
  Source:  Am J Gastroenterol. 2015 Jul 28. doi: 10.1038/ajg.2015.203. [Epub ahead of print]

Results and Conclusions
In the Chronic Hepatitis Cohort Study (CHeCS) there were 9,783 patients, 2,788 (28.5%) were cirrhotic by at least one method. Biopsy identified cirrhosis in only 661 (7%).  Other parameters, such as the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) were not assigned to the biopsy proven cirrhosis results. 

The Bottom Line
The authors noted that the since the ICD-9 codes may not be the best codes to indicate the prevalence of cirrhosis and that there may be a ‘fourfold’ higher prevalence of cirrhosis in studies previously reported. 

Editorial Comment
This is an important study.  We need to understand the true prevalence of cirrhosis in this country.  It will help to push for better funding and making sure that people are treated sooner rather than waiting until people become sick. 

Article:  Chronic Hepatitis C Virus Infection Is Associated with Subclinical Coronary Atherosclerosis in the Multicenter AIDS Cohort Study (MACS): a Cross-Sectional Study—RA McKibben
  Source: J Infect Dis. 2015 Jul 27. pii: jiv396. [Epub ahead of print]

 

Results and Conclusions
Eighty-seven men with chronic hepatitis C were evaluated for the risk of cardiovascular disease (CVD).

Note: the study also looked at HIV and HIV/HCV coinfected men but did not find an association. 

The men were assessed for coronary plaque using non-contrast coronary CT and CT angiography and evaluated the associations of CHC with measures of plaque (substances that lead to hardening of the veins/arteries), prevalence, extent, and stenosis (narrowing of the veins). It was found that all types of plaques were significantly higher in men with chronic hepatitis C.

Bottom Line
This is not the first study that has shown that there are cardiovascular problems associated with hepatitis C.  But it is important to remember that this is a small study.  It also needs to be replicated in a larger patient population and in women with HCV. 

Editorial Comment:
As we come to understand more and more about hepatitis C it becomes clear how much damage hepatitis C causes to many organs outside of the liver.  Everyone with hepatitis C needs to be monitored on a regular basis.  In this case men and women need to be monitored for cardiovascular disease.  This is another reason why people with hepatitis C should be treated before these types of health issues are allowed to begin.

http://hcvadvocate.org/news/newsLetter/2015/advocate0815_mid.html#4

Snapshots, by Alan Franciscus, Editor-in-Chief

Article:  Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: Results from the ION-1, -2, and -3 clinical trials—ZM Younossi—et. al
   Source: Hepatology 2015 Jun;61(6):1798-808. doi: 10.1002/hep.27724. Epub 2015 Mar 18.

Results and Conclusions:  In the phase 3 clinical trials of ledipasvir and sofosbuvir with and without ribavirin patient report outcomes were measured.  There was a total of 1,952 patients in the study.  Patients were treated for 8, 12 or 24 weeks. In the groups that received ledipasvir and sofosbuvir (without ribavirin) who had early viral load suppression there was improved quality of life that was maximized by the end of treatment.  In the group that received ledipasvir/sofosbuvir and ribavirin their quality of life decreased regardless of treatment duration until the end of treatment. 

The Bottom Line:  Ribavirin during treatment reduced quality of life, but achieving a cure improved quality of life for all of the groups including the groups who received ribavirin.

 

Editorial Comments:  This is a no-brainer, but we need more of these studies to show that being cured improved quality of life and improved overall survival.  I hope that insurance companies are hearing this and loosen up the restrictions.

Article:  Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity—P Skums
  Source: Proc Natl Acad Sci USA. 2015 May 26;112(21):6653-8.doi:10.1073/pnas.1422942112. Epub 2015 May 4.

 

Results and Conclusions:
Most people who become acutely infected with hepatitis C become chronically infected – up to 85%.  The reason there is such a high rate of chronic infection is not completely understood, but there are many theories.  The current paper presented a mathematical model to show how the virus contributes to hepatitis C chronicity. 

What is interesting is that various proteins of the hepatitis C virus seem to act together to escape the human host—that is certain proteins of the virus work together to draw off parts of the immune system cells so that other parts of the hepatitis C virus can survive and persist in the body and infect liver cells. This enables the hepatitis C virus to act as a network of parts to establish a chronic infection.   

The Bottom Line:  As with any discovery in science these findings need to be replicated.  If the exact mechanism can be understood an effective protective vaccine could be developed. 

Editorial Comment:  Isn’t science interesting?  The hepatitis C virus is a wily little bugger and endlessly fascinating.  The key would be to understand why this strategy works for some and not others.   This could lead to the development of an effective vaccine.

 

Article: Differentiation of acute from chronic hepatitis C virus infection by nonstructural 5B deep sequencing: A population-level tool for incidence estimation—V. Montoya et. al
   Source:  Hepatology Volume 61, Issue 6, pages 1842–1850, June 2015

 

Results and Conclusions:  In the current study the authors examined the viral proteins from 13 acute and 54 chronic individuals by sequencing the NS5B region of the virus.  They were able to differentiate the viral diversity between the acute and chronic infection.  The viral diversity was significantly different between acute vs. chronic infection. 

 
Editorial Comment:  This and the last issue of the HCV Advocate have discussed the difficult task of trying to diagnose an acute infection of HCV.  If this study is replicated and IF the tool is made available at a reasonable cost it could be a game changer in the way we understand how many people are acutely infected with hepatitis C.

Source:  http://hcvadvocate.org/news/newsLetter/2015/advocate0815.html#3

Snapshots, by Alan Franciscus, Editor-in-Chief

Originally published July 1, 2015

Article: Long-term treatment outcomes of patients infected with Hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a Sustained Virological Response–B Simmons, et. al
  Source:  Clin Infect Dis. 2015 May 17. pii: civ396. [Epub ahead of print]

Results and Conclusions:  In the current study the authors conducted an electronic search to identify if achieving a cure improved long term outcomes. The records of 33,360 patients from 31 studies were examined with a medium follow-up period of more than five years. The people who were cured were compared to those who were not cured. 

The Bottom Line:  The survival after five years from being cured was significant compared with those who did not achieve a cure.  This included three populations of people—those who were HCV mono-infected, those who had cirrhosis and those who were coinfected with HIV and hepatitis C. 

Editorial Comment:  In science studies are needed for everything, and this is an important one because it proves that successful treatment works to prolong lives.  More of these studies (with larger patient populations) are required to convince insurance companies and other payers that in the long run paying for treatment saves them money and, more importantly, lives.

Article:  Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial—RD Josiah
  Source: The Lancet DOI: http://dx.doi.org/10.1016/S0140-6736(14)62338-2

Results and Conclusions:  Methadone is used for withdrawal/substitute for opioid use.  In this study people who were entering Rhode Island Department of Corrections and who were currently enrolled in a methadone maintenance program at the time of arrest were asked to enroll in a study that would continue them on methadone maintenance while they were in prison.  Participants were only included in the study if they were to be incarcerated for more than 1 week but less than six months.  The participants in the study were randomized by a computer-generated program by sex and race.  The trial took place between June 2011 - April 2013.  

• The 114 participants in the methadone maintenance group were randomized to receive methadone at their regular dose.

After release from prison the study paid for ten weeks of methadone for the methadone group if financial help was needed.

• The 109 forced-withdrawal group followed standard guidelines forforced withdrawal. 

The standard withdrawal protocol was to receive methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg).

The Bottom Line: The participants who were given methadone were more than twice as likely than the forced withdrawal group to return to a community methadone clinic in their community within 1 month of release—96% vs. 78%.  There were no serious side effects in either group. 

• Methadone groups:  one death, one non-fatal overdose, one hospital admission and 11 emergency-room visits
• Forced-withdrawal groups:  no deaths, two non-fatal overdoses, four admissions to hospitals, 16 emergency-room visits

Editorial Comments:  Providing methadone seems very humane.  It also reduces hospital admission, emergency-room visits and greatly increases the chances that once a prisoner is released they would seek out a methadone clinic.

http://hcvadvocate.org/news/newsLetter/2015/advocate0715.html#3

Snapshots Lucinda K. Porter, RN

Article: Utility of Hepatitis C Viral Load Monitoring on Directly Acting Antiviral Therapy - S Sreetha Sidharthan, et al
  Source: Clinical Infectious Diseases first published online March 2, 2015

The National Institutes of Health (NIH) funded this small study. Researchers enrolled 114 subjects with chronic hepatitis C virus infection (HCV) who had genotype 1 and no prior treatment. The goal was to see if HCV RNA levels (viral load) at the end of treatment (EOT) negatively or positively predicted sustained virologic response (SVR12). Two viral load tests were used: The Roche COBAS TaqMan HCV test and the Abbott RealTime HCV assay.

To understand the results, it may help to define a couple of terms:

• LLOQ is lower limit of quantification, which is the lowest amount of virus that can be precisely counted.
• PPV is positive predictive value, which predicts the probability that the test will be positive. For instance, if there are 100 people and the PPV is 90%, this means that it is likely that 90 will test positive.
• NPV is negative predictive value, which predicts the probability that the test will be negative. If there are 100 people and the NPV is 2%, this means that it is likely that two will test negative.

Here are the various treatment arms and the results:

• Sofosbuvir and ribavirin for 24 weeks (n=55):
  All patients treated with sofosbuvir and ribavirin (55/55) had HCV RNA <LLOQ at EOT by the Roche and Abbott tests, but only 38 achieved SVR12 (PPV: 69%). Simply put, this means that if your viral load at EOT is less than the LLOQ, you have a 69% chance of having an SVR12.
• Harvoni (sofosbuvir and ledipasvir) for 12 weeks (n=20); Harvoni and GS-9669 for 6 weeks (n=20); Harvoni and GS-9451 for 6 weeks (n=19):
  In the Harvoni-based regimens +/- GS-9669 or GS-9451, 100% of the subjects (59/59) had HCV RNA <LLOQ at EOT, with one relapse (PPV: 98%). The Abbott assay had 90% (53/59) with HCV RNA <LLOQ with one relapse (PPV: 98%).

Here is the most important part: Six patients with HCV RNA ≥LLOQ at EOT achieved SVR12 (NPV: 0%).

The Bottom Line: In the past when using interferon-based treatments, a detectable viral load at EOT meant that treatment wouldn’t be successful. With Harvoni-based HCV treatment, this rule no longer applies—a detectable viral load at EOT DOES NOT mean that treatment will not be successful.

Editorial Comment: This research leads me to two points. First, don‘t despair if you have detectable virus during or at the end of HCV treatment. Second, be sure your doctor doesn’t stop treatment just because you have detectable HCV RNA. The HCV guidelines recommend viral load testing after 4 weeks of therapy and at 12 weeks following treatment completion.  If quantitative HCV viral load is detectable at week 4 of treatment, repeat viral load testing at treatment week 6. If viral load has increased by greater than 10-fold on repeat testing at week 6 (or thereafter), then discontinuation of HCV treatment is recommended. There are no other recommendations to stop or extend therapy based on viral load results.

Article: Treating HCV Infection in Children - Christine K. Lee and Maureen M. Jonas
  Source: Clinical Liver Disease January 2015; Volume 5, Issue 1, pages 14–16

Noting the successful treatment rate of adults with HCV, this study assessed treatment options in children with HCV. However, the newer, more effective, easier to tolerate HCV medications have not been approved for children.

The Bottom Line: Children don’t usually progress to advanced liver disease, so the researchers recommend deferring HCV treatment for children until interferon-free regimens are approved, or until children become adults. If treatment cannot be deferred, therapies using peginterferon and ribavirin can be given to children with compensated liver disease.

Editorial Comment: In last month’s HCV Advocate, I wrote about children with hepatitis C, chronicling the lack of safe HCV treatment options for kids. This new research supports my opinion that children need better options, and soon.

Article: Cost-Effectiveness and Budget Impact of Hepatitis C Virus Treatment with Sofosbuvir and Ledipasvir in the United States - Jagpreet Chhatwal, et al.
  Source: Annals of Internal Medicine March 17, 2015; 162(6):397-406

HCV treatment using Harvoni (sofosbuvir and ledipasvir) is safer and has higher cure rates than the old interferon-based treatments, but Harvoni is substantially more expensive. This NIH-funded study evaluated the cost-effectiveness and budget impact of Harvoni.

The Bottom Line: This research found that HCV treatment using Harvoni is cost-effective in most patients, but noted limitations of their research.

Editorial Comment: While I understand the value of measuring the financial impact of new HCV medications compared to the older drugs, I am reminded by words purportedly said by former U.S. Surgeon General, Julius Richmond, “Statistics are people with their tears wiped dry.”

Article: Predictors of poor mental and physical health status among patients with chronic hepatitis C infection: The Chronic Hepatitis Cohort Study - Joseph A. Boscarino
  Source: Hepatology March 2015; Volume 61, Issue 3, pages 802–811

The purpose of this study was to evaluate the extent and risk factors for depression and poor physical health among HCV patients. They collected survey data from 4,781 participants, averaging 57 years old, 71% White, and 57% male. Slightly more than half reported past injection drug use, a third were current smokers, and nearly 18% had abused alcohol in the previous year. Around, 47% had been previously treated for HCV and 15% had an SVR.

The Bottom Line: Nearly 30% of HCV patients met criteria for current depression and 25% were in poor physical health. These risks increased among men, Blacks, less educated, unemployed, stress, and little social support. These risks were lower in those who achieved an SVR.

Editorial Comment: Over the years, similar studies to this one have been done, yielding similar results. Depression scores tend to be higher even among HCV-positive people who are unaware that they have HCV. Reading this study on the heels of the previous one about the cost-effectiveness of HCV treatment, I can only shake my head, and ask, “When are we going to treat all HCV patients?”

http://hcvadvocate.org/news/newsLetter/2015/advocate0415.html#4

Snapshots —Alan Franciscus, Editor-in-Chief

Abstract: Low Risk of Liver Decompensation among Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients with Mild Fibrosis in the Short-Term.
  Authors: J Macias et al.  Hepatology. 2014 Dec 24. doi: 10.1002/hep.27674. [Epub ahead of print]

Results and Conclusions: The authors of this study wanted to find out which HIV/HCV patients can safely wait, or wait in the short term for treatment.  This study was conducted during the time that pegylated interferon was part of the treatment regime.  A total of 1729 patients were evaluated (683 patients by liver biopsy; 1046 by liver stiffness measurement) and followed over time. The authors concluded that patients who did not have advanced fibrosis were at “very low risk” of decompensated cirrhosis, at least in the short term.  In this population, a careful watchful waiting is appropriate—in the author’s opinion.

Editorial Comments: I find this study interesting and valuable.  But I think it is a dangerous game to play.  This is a population of patients who typically have faster disease progression—faster than people who are monoinfected.  It may be safe if people are followed very carefully.  But wouldn’t it be easier and safer to treat now and not take the chance of putting people at undue risk?

Abstract: Hepatitis C Virus (HCV) Antibody Dynamics Following Acute HCV Infection and Reinfection among HIV-Infected Men Who Have Sex with Men.
  Authors:  J. Vanhommerig et al. Clin Infect Dis. 2014 Dec 15;59(12):1678-85. doi: 10.1093/cid/ciu695. Epub 2014 Sep 3.

Results and Conclusions: This study identified 63 HIV/HCV coinfected patients who had tested positive for HCV antibodies and HCV RNA (viral load).  The patients were followed for 4 years.  Five of the patients spontaneously cleared HCV and 31 of 43 patients were treated and cured.  In 36 (5 spontaneously cleared; 31 cured) the antibody titers (the measurements) declined.  In 8 of the 31 patients the HCV antibody titers disappeared. 

Eighteen of the patients were re-infected with a dif­ferent strain than the initial one and devel­oped a surge in both antibodies and HCV RNA.  The researchers believed that one patient was re-infected three separate times after the first successful treatment. 

Editorial Comments:  I couldn’t find the entire journal article to find out what type of counseling efforts were offered to the study participants.  This study, however, should remind us we need to educate people about prevention measures.  But what was interesting is that 8 people had undetectable antibody titers in this small study.  On a personal note, I did a demonstration of an HCV antibody test.  I was cured of hepatitis C more than 10 years ago.  The results showed very low reactive results.  I wonder if my antibody titers will become undetectable after time.  This study made me wonder how many ‘Baby Boomers’ became infected many years ago, naturally cleared the virus, and when tested recently had antibody titers too low to register.

http://hcvadvocate.org/news/newsLetter/2015/advocate0115_mid.html#3