End-stage liver disease is a concern for people with HIV and hepatitis B or C co-infection

People with HIV and hepatitis B or C virus co-infection are more likely to progress to end-stage liver disease (ESLD), or liver failure, than those with HIV alone, and individuals triply infected with all three viruses face the greatest risk, according to study findings presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA.

Due to overlapping transmission routes, many people with HIV also have hepatitis B virus (HBV), hepatitis C virus (HCV) or both. Over years or decades, chronic hepatitis B or C can cause serious liver disease including cirrhosis, liver cancer, and potentially liver failure and the need for a liver transplant. In addition to viral hepatitis, other factors such as drug toxicity and heavy alcohol consumption can also contribute to serious liver damage.

Prior research has shown that HBV- and HCV-related liver disease progression is more rapid and possibly more severe in people with HIV. Since the advent of effective antiretroviral treatment (ART), as fewer people with HIV succumbed to opportunistic infections and other AIDS complications, liver disease has become a leading cause of morbidity and mortality in this population.

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High Price Of Specialty Drugs Prompts Backlash

An unusual coalition of patient advocates and health plans, groups often at odds, are calling for greater transparency in drug pricing. They want to know why the drugs cost so much in the United States when in other parts of the world -- including Europe, Canada and Egypt -- Sovaldi and Harvoni are sold for a fraction of the price.

"We feel like there hasn't been a lot of explanation why drugs are priced at this rate," said Nicole Kasabian Evans, vice president for communications at the California Association of Health Plans. "There are about 12 blockbuster drugs set to launch this year, and we think it's important to peel back the onion and get a better understanding of why drugs are priced this way."

Medicines to treat rare conditions, called "orphan drugs," for years have been priced high to recoup the expense of developing a drug for a relatively small number of patients. But until Sovaldi, it was unheard of for a drug aimed at a commonplace disease to cost so much, critics said.

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Overview – Preparing for Treatment: Part 1 – Alan Franciscus, Editor-in-Chief

Treatment of hepatitis C has made great advances from the early days.  Back when interferon was first approved, the cure rates were about 10%.  The list of just the most common side effects could take up an entire page.  Now, we have medications that can cure 90 to 100% of patients who undergo therapy.  Even better, the side effects of the newer treatments are much easier to tolerate.  This article will discuss what it takes to prepare for treatment. 

Support and Resources
Start by gathering resources.  Trusted resources such as your medical provider, a support group, and a reliable internet site are safe places to start.  An important issue for people thinking about treatment is to learn as much as possible about treatment.  Talk to others who have been on treatment—they are some of the best experts.  Facebook is another resource where you can learn about treatment and receive support.  There are various Facebook accounts for the brand name drugs—HARVONI and VIEKIRA PAK—that provide a wealth of information about what people are experiencing while on treatment.  A caveat: Sometimes the sickest patients may use these sites more than those who feel well, and may have more side effects and complaints.

The pharmaceutical companies also have many resources that can be useful for investigating treatment issues and receiving support.  

Financial Preparations 
Whether you are dealing with your pharmacy, insurance company, medical provider or a patient assistance program—be prepared to provide the following information:

• Patient’s name
• Patient’s address
• Patient’s phone number (home and cell)
• Patient’s date of birth
• Identifying number—social security account number or a membership number.

Note:  Every time you call your insurance company or medical office, keep comprehensive notes—include the date, name and any issues that you discussed.  If it was over email, print it out and keep it with your other records.  If your medical office has an online record keeping system, print it off and keep it in a secure place. 

Insurance
HCV treatment is very expensive; some insurance companies have exclusivity agreements for individual HCV medications.  Check with your insurance carrier if there is a preferred HCV drug.  This could limit the choice of drugs.  Find out how much your share of expenses will be.  Additionally there are costs associated with medical appointments and lab tests.  Factor all these costs into what you have to pay.

Try to get answers to the following questions:

• Do you have prescription coverage?
• If so, what will your out-of-pocket expenses be?
• Do you have any reason to think your medical insurance will stop during treatment, such as a probable job lay off or a reduction in work hours?
• If you do not have prescription coverage, what is the cost of HCV treatment?
• How often will you have lab tests done and what is the co-pay?
• How often will you need to see your medical provider and what is the co-pay?  Remember, HCV treatment is typically 12 weeks but for some people it can range from 8 to 24 weeks.
• Insurance or not, can you afford the costs associated with HCV treatment?

Patient Assistance Programs:
The pharmaceutical companies that make the drugs to treat hepatitis C have programs that can provide the medications if you qualify.  Additionally, there are other programs that help with the co-pays.  A list of the Patient Assistance Programs can be found below and on our website.  There are also programs that can help people through the entire process of physician visits, insurance issues, and specialty doctors. 

The Workplace
In the past, some patients were unable to work while on interferon-based therapies.  Now that we have interferon-free therapies with fewer side effects, this is mostly an issue for people with more advanced liver disease.  In fact for most people, the workplace issue will mainly involve scheduling medical appointments and lab work. 

Remember you do not have to tell your employer you have hepatitis C or that you are taking hepatitis C medications.  Everyone has the right to time off for medical reasons.  However, it is not always that easy, so you should check in with your employer about your rights and responsibilities.  Also check in with your state health department about your rights.  It is also important to think through the worst-case scenario.  Some people are worried that they may feel sick especially at the beginning of therapy.  This is normal.  It might help to schedule a couple of days off at the beginning of treatment.  Talk with your employer about your sick leave policy, how much you have available and what your employer’s policies are.  You may also be able to use your vacation.  There is also the Family and Medical Leave Act (FMLA)—see if you qualify for this benefit. 

The most important issue is likely to be the time that you will need to take off for doctor appointments and lab tests. 

Part 2 of this article will discuss Medical Tests, Medications and Side Effect Management, among other things.

Resources:

Help with Medicines

Patient Assistance Programs

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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