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

HCV Drugs Alan Franciscus, Editor-in-Chief

BMS Files NDA with FDA
On March 12, 2015 Bristol-Myers Squibb (BMS) announced that the Food and Drug Administration (FDA) had accepted their new drug application (NDA) for the combination of daclatasvir plus sofosbuvir for the treatment of HCV genotype 3.  In BMS’s phase 3 studies of genotype 3 patients—101 treatment-naïve, 51 treatment-experienced—the cure rates were 90% and 86% respectively.  However, in people who had cirrhosis (F-4) the cure rates were 63% to 73% leaving an unmet need for these patients. 

CROI
The Conference on Retroviruses and Opportunistic Infections (CROI) 2015 held in Seattle, WA, had a wealth of information about the treatment of people with HIV and HCV coinfection.  Since the introduction of interferon-free therapy the cure rates of HCV in people who are coinfected with HIV and HCV are the same as the cure rates in people who are HCV mono-infected, and importantly the studies presented at CROI reinforce this information.  

Daclatasvir/Sofosbuvir
DL Wyles et al., presented “Daclatasvir in Combination with Sofosbuvir for HIV/HCV Coinfection:  ALLY-2 Study.” The study included patients with HCV genotype 1 (1a-139 pts; 1b-29 pts), genotype 2 (19 pts), genotype 3 (19 pts) and genotype 4 (3 pts).  There were three arms in the study—two arms with 12 weeks treatment duration and one arm with an eight-week treatment period—there were no genotype 4 patients in the eight-week treatment arm.  Most of the patients were male (83-91%);

White (56-65%); and there were 29 patients with cirrhosis in the study. 

The cure rates were 97% in genotype 1, and 100% in genotypes 2, 3, and 4 in the groups treated for 12 weeks.  In the groups treated for eight weeks, the cure rates fell to 76%.  There was no impact based on genotype or type of prior treatment response.

Comments:  These are remarkable cure rates regardless of genotype, viral load, and other factors at least in the 12-week group.  Based on this data 8 weeks of Daclatasvir plus sofosbuvir is not effective. 

An unmet medical need is treatment of people with genotype 3 with cirrhosis—this information was not available.  Additionally,  there were very few genotype 3 patients in the study to draw any conclusions.   

Given the results of Harvoni (below) the niche for this combination may be narrow.  However, it was noted that, if approved, adjusting the dosing would be easier since these drugs are dosed separately especially for some people on HIV medications.  

Harvoni
S Naggie et al., present data from “Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected with HCV and HIV-1:  ION-4.”  This study was a phase 3 clinical trial of Harvoni (sofosbuvir/ledipasvir) for the treatment of HCV genotype 1 and 4 in people who are coinfected with HIV and hepatitis C.  A total of 335 patients were included in the trial—75% were genotype 1a; 23% genotype 1b; 2% genotype 4. The study included 45% treatment-naïve patients, 55% treatment-experienced patients, and 20% of the patients had compensated cirrhosis.  The mean age of the patients was 52yo; 82% were male, 34% were Black.

The overall cure rate was 96%.  There was little difference in cure rates between treatment naïve and treatment experienced (95% vs. 97%) and those with and without cirrhosis (94% vs. 96%).  There was a difference in cure rates between Blacks (90%) and non-Blacks (99%).  The most common side effects were headache, fatigue and diarrhea. 

Gilead is trying to determine the difference in the cure rates between Blacks and non-Blacks.  They have ruled out drug concentration levels in the blood and the possible interaction of the HIV medications.  During the question and answer period there were a couple of interesting comments about the lower response rates in Blacks:

• Perhaps Black patients coinfected with HIV and HCV may need to be treated longer
• Previous clinical trials have had lower Black patient populations that may not have given us a true picture of treatment cure in Blacks—more Blacks are needed in clinical trials period.  In the days of pegylated interferon and ribavirin therapy the cure rates were much lower.

Gilead stated that they are planning to file a New Drug Application (NDA) with the FDA based on the phase 3 data for the treatment of HCV in people with HIV.  

Comments:  Impressive cure rates and low side effects regardless of prior treatment response or degree of liver damage.  Once we learn more about the reason for the lower response rates in Blacks we will keep our readers informed. 

Delaying Treatment = More Deaths
Everyone is trying to come to terms with the impact of treating people who are the sickest.  Lately, there have been studies showing this approach may not be cost effective.  It certainly isn’t patient centered or tied to improving the quality of life for people living with hepatitis C.  A study presented at CROI—“Impact of Deferring HCV Treatment on Liver-Related Events in HIV+ Patients, by C Zahnd et al.”—sheds some light on the long-term health risk of  delaying treatment.  

The researchers in the study used a model to predict health outcomes from the Swiss HIV Cohort Study to simulate HIV/HCV patients from the time of acute infection through chronic infection and fibrosis stages using the Metavir system for staging fibrosis/cirrhosis (F0 through F4), decompensated cirrhosis, liver cancer, and death. They assumed that 100% of patients were treated with interferon-free therapies and of these patients 90% were cured.   

The highlights of their findings included:

• If patients were treated one month or 1 year after diagnosis—3% would die from liver-related deaths
• If HCV treatment was delayed until later stages, the percentages of patients who were predicted to die dramatically increased:  Treated at F-2 a 5% death rate; treated at F-3 a 10% death rate; treated at F-4 a 25% death rate. 

Comment:  It is a known fact that people cured of hepatitis C still have liver disease progression especially in later stages of cirrhosis.  The authors of the study believe that HIV/HCV coinfection may contribute to liver disease progression even after being cured.  This study and other studies which show the benefits of early treatment should be an important part of the discussion on evaluating the cost-effectiveness of treatment.  There is also a matter of public health:  Treating HCV can stop the transmission of HCV.  

http://hcvadvocate.org/news/newsLetter/2015/advocate0415.html#3

For Our Portuguese HCV Advocates : Entrevista: Francisco Martucci

Podcast: Interview with Francisco Martucci, President of "C HAVE TO KNOW HAVE TO HEAL C."

A campanha de combate a hepatite C realizada pela ONG "C tem que saber C tem que curar", recebeu mais de 3,7 milhões de "selfies" com pessoas tirando fotografias mostrando ou sinalizando com as mãos a letra "C".

Em entrevista à Rádio ONU, o presidente da ONG, Francisco Martucci, falou sobre os objetivos da iniciativa.

Ele disse que em primeiro lugar, a meta é divulgar a hepatite C através das redes sociais.
Martucci quer alertar a população e a sociedade brasileira e também mundial sobre o impacto social que a hepatite C causa no Brasil, com 12 óbitos por dia e 4 milhões de portadores. No mundo, são 500 mil mortes ao ano e 170 milhões de portadores.

O presidente da ONG falou também sobre a possibilidade de se resgatar a chance de cura de portadores que tentaram tratamentos com outros medicamentos e não conseguiram.
Ele falou também sobre como usar esse apoio popular para pressionar pela liberação de novos remédios.

Martucci explicou que o tempo desse novo tratamento é reduzido, passando de um ano, como acontece atualmente, para apenas três meses e sem efeitos colaterais.

Ele afirmou que esses novos remédios são importantes, principalmente, para os portadores de hepatite C que não conseguiram se curar em tratamentos anteriores.

Source:  http://www.unmultimedia.org/radio/portuguese/2015/04/entrevista-francisco-martucci-2/#.VR7JVuG2WQd

Doctor in deadly Las Vegas hepatitis C outbreak guilty of fraud conspiracy

Dr. Dipak Desai pleaded guilty in federal court Thursday in a health care fraud conspiracy stemming from the 2007 hepatitis C outbreak.

The hearing was held before Senior U.S. District Judge Larry Hicks in Reno, but broadcast through a video conference to a Las Vegas courtroom.

Desai, 65, who is already serving time in the Nevada prison system for a state conviction in the hepatitis outbreak, pleaded guilty to one felony count each of conspiracy and health care fraud.

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WHO Issues Guideline For Manufacturers Of Generic Hepatitis C Medicine

The World Health Organization has issued a guidance document on the design of bioequivalence studies for a leading hepatitis C medicine. Generic drug companies seeking prequalification by the WHO need to demonstrate that their generic version is equivalent to the originator drug.

According to a WHO official, the document provides technical guidance for the prequalification process as generics companies have to do bioequivalence studies to get prequalified.

The WHO has published an updated version (March 2015) of the patent situation for sofosbuvir in about 20 countries. This update, according to the WHO, is based on data received from national and regional patent offices, including the African Regional Intellectual Property Organization (ARIPO), Brazil, the Gulf Cooperation Council, Chile, Georgia, Morocco, The Organisation Africaine de la Propriété Intellectuelle (OAPI), the Philippines, and Tunisia.

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Canada: Hepatitis C: breakthrough drug coverage a lifesaver for B.C. man

Kaslo resident Desmond McKilligan contracted hepatitis C more than 40 years ago from a tainted blood transfusion, and just got a call saying he qualifies for Sovaldi.

"My liver doesn't have anywhere to go but cirrhosis," he told CBC News. "It was a great thing to be called about that."

McKilligan says it's a new lease on life, and is thrilled he may actually see his grandchildren in Montreal.

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HealthWise: Hepatitis C: Giving a Liver, Getting a Liver Lucinda K. Porter, RN

Years of living with chronic hepatitis C virus infection (HCV) destroyed my friend Rick’s liver. Last year, a liver transplant saved his life. A motor vehicle accident killed a 19-year-old man, and now Rick is healthy. Not a day passes, that Rick doesn’t say thank you for the life of the man whose liver restored Rick’s health.

The same year Rick received his liver, I lost three friends who would have lived had hepatitis C been diagnosed earlier and they could have had a chance at liver transplantation. Rick was incredibly fortunate to have received a liver, because there is a major organ shortage in the U.S. According to the American Liver Foundation, approximately 17,000 people are on the liver transplant list. Of these, 6000 people were transplanted; 1500 to 1700 people died before they could receive a liver.

Chronic liver failure caused by complications from HCV is the most common reason for adult liver transplantation in the United States. Cirrhosis caused by long-term alcohol abuse is the second leading cause. The majority of people living with HCV will never progress to the point where transplantation will be necessary. Liver transplantation is a complicated surgery, requiring lifelong follow-up care. Liver transplant patients have an approximately 86% one-year and 78% three-year survival rate.

Most liver transplants use deceased donors. However, the liver’s remarkable ability to regenerate allows us to use partial livers from living donors. A living donor doesn’t have to be a blood relative, but must have a compatible blood type. About 40% to 60% of the donor’s liver is removed. Within eight weeks, the livers of both the donor and the recipient are usually completely regenerated. The average donor recovers in about two months; recipients recover in roughly six to 12 months.

Although living liver transplantation sounds like the perfect way to address the organ shortage, it isn’t.  The potential risk to the donor is so high that live liver donations are done only when the potential risk to the donor is small and the potential benefit to the recipient is unquestionable. It is difficult to find current data on live liver transplantation, but it appears that there are 250 to 400 liver donor transplants a year. One in 300 donors die and about 30% suffer a complication. Many living donors who die are relatives of the recipients. One can only imagine how difficult it might be to live with the knowledge that you are alive, but your otherwise healthy donor is not. 

Although increasing the donor organ pool is important, a better plan is to reduce the organ demand. Screening, linkage to care, and treating hepatitis C patients will reduce the number of liver transplant procedures needed. When I began working in this field, hepatitis C patients who were transplanted would still have HCV. This meant the transplanted liver was reinfected, and in some cases, it too would progress to cirrhosis. Now we can cure hepatitis C, which greatly cuts down on the stress to the transplanted organ and diverts the need for a second transplant.

Other strategies that will reduce the demand for livers are:

• Immunizing all children against hepatitis B
• Implementing awareness programs to reduce liver-injury risk, such as from alcohol, drug, and dietary supplement use
• Raise awareness of the impact of diet on the liver. Fatty liver disease is on the rise in the U.S., which in turn causes a decrease in the number of viable livers.
• Increase the organ donor pool. For instance, countries that use an “opt-out” strategy have much higher donor rates. “Opt-out” means that everyone is a potential donor unless otherwise indicated. For instance, Germany uses an opt-in system and 12% of its population consents to donate. Neighboring Austria uses an opt-out system, and has a consent rate of nearly 100%. The U.S. uses an “opt-in” strategy.

In some cases, patients whose hepatitis C is cured, may be potential organ donors. This situation is considered if the organ is in good shape, and the recipient would otherwise die. The recipient is given the option to decline the HCV antibody-positive organ. Compared to HCV antibody-negative organs, the long-term survival rate in patients who received an HCV antibody-positive/viral load-negative organ are similar. So, if you are cured of HCV, celebrate by filling out your organ donor card. Ask family and friends to fill theirs out too.

Lucinda K. Porter, RN, is a long-time contributor to them HCV Advocate and author of Free from Hepatitis C and Hepatitis C One Step at a Time. Her blog is www.LucindaPorterRN.com

Additional Resources

• Donate Life America
  http://donatelife.net
• National Living
  Donor Assistance
  www.livingdonorassistance.org
• OrganDonor.gov
  www.organdonor.gov
• Organ Procurement and Transplant Network
  http://optn.transplant.hrsa.gov
• Transplant Living
  www.transplantliving.org
• United Network for Organ Sharing
  www.unos.org

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