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May 2012 HCV Advocate

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In This Issue:

HCV-Related Deaths and Cost-Effectiveness of Testing and Treatment
Alan Franciscus, Editor-in-Chief

What You Don't Know, You Can Sell
Tracy Swan, TAG

HCV Snapshots
Lucinda K. Porter, RN

IN MEMORIAM: Michael Carden
1971-2012

Alan Franciscus, Editor-in-Chief

HealthWise: May is Hepatitis Awareness Month
Lucinda K. Porter, RN


Boceprevir and Telaprevir Improve Cure Rates for HIV/HCV Coinfected People
Liz Highleyman


HCV Advocate Eblast
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HCV-Related Deaths and Cost-Effectiveness of Testing and Treatment
—Alan Franciscus, Editor-in-Chief

Three research papers were recently published in the Annals of Internal Medicine that summarize key findings of studies about hepatitis C:  The cost-effectiveness of baby boomer testing and HCV treatment, and the number of HBV, HCV and HIV deaths between 1999 and 2007. 

Article:  The Increasing Burden of Mortality from Viral Hepatitis in the United States Between 1999 and 2007 – KN Lyn et al.

In this study the authors looked at the number of deaths caused by HBV, and HCV and compared them to the numbers of deaths caused by HIV.  The authors reviewed the U.S. multiple-cause mortality data between 1999 and 2007 (total ~22 million deaths) from the National Center for Health Science that included all U.S. states and the District of Columbia.  The causes of the deaths reported were listed as either a single underlying cause or the contributing cause.  HBV accounted for 1815 deaths, and HCV accounted for 15,106 deaths compared to the 12,734 deaths that were attributed to HIV.  The authors also observed that viral hepatitis deaths were probably under reported compared to deaths from HIV.  They also noted that when the cause of death was listed as HCV or HBV it was frequently in people coinfected with HIV, HBV, and/or HCV.  Approximately 75% of the deaths related to HCV occurred in a relatively young age group (46 to 64 year olds) and the authors concluded that this “portends a large and ever-increasing health care burden from what the current U.S. Assistant Secretary of Health has dubbed the ‘silent epidemic.’”

Comments:  Annual deaths from HCV are climbing and have outnumbered deaths from HIV or HBV although many of the people who died were also coinfected.  This report will hopefully drive more dollars into identifying those with hepatitis C so that they may seek medical care, which will lower the costs that future HCV-related illness will cause. 

Article:  The Cost-effectiveness of Birth-Cohort Screening for Hepatitis C Antibody in U.S. Primary Care Settings – DB Rein, et al.

The majority of people who are infected with hepatitis C—more commonly referred to as the “baby boomer” population—were born between 1945 and 1965.  In the above study, the cost-effectiveness of the entire spectrum of testing, medical management and antiviral therapy was measured using quality adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) to estimate future costs and potential savings.  Using these models it was estimated that an additional 808,580 people with HCV could be identified.  The screening cost per patient identified would be $2,874.  If the patients were to receive medical care and treatment with PEG/RBV, the screening QALYS would be increased by 348,000 and costs for treatment (estimated at $5.5 billion) would result in an ICER of $15,700 per QALY.  If the patients identified were treated with direct acting antivirals (boceprevir or telaprevir PEG/RBV triple therapy) then the QALY would increase by 532,200 and the increased costs of $19.0 billion for the DAA treatment would result in an ICER of $35,700 per QALY saved.

Comments:  We already have a risk-factor basis for testing of hepatitis C.  While risk factor assessment should always be an important part of screening for hepatitis C, it hasn’t worked to identify the vast majority of people who have HCV.  Implementation of birth-cohort screening as an additional screening tool would increase the number of people who could be identified and it would include the two largest at-risk groups who are infected with hepatitis C—newly infected and those who acquired HCV in the past.  The current study found that there would be a significant cost-savings for a one-time test of the baby boomers (1945-1965) in terms of dollars, productivity and human lives. 

Title:  New Protease Inhibitors for the Treatment of Chronic Hepatitis C – S Liu, et al.

This study looked the cost effectiveness of boceprevir/telaprevir protease inhibitor (PI) triple therapy and the IL28B testing that is used to predict treatment response.  The first part of the study tackled the question of whether PI therapy is cost-effective in preventing HCV-related liver cancer and increasing life expectancy.  The authors used the information from the Phase 3 studies of boceprevir and telaprevir to estimate effectiveness, but adjusted the cost-effectiveness for various factors (race, degree of fibrosis, etc.) and compared the outcomes to treatment with PEG/RBV therapy.  It was found that PI therapy reduced the lifetime risk of liver cancer by 38% for patients with mild fibrosis, and 28% for patients with advanced fibrosis.  PI therapy increased quality-adjusted life expectancy by 3% for those with mild fibrosis and 8% for those with advanced fibrosis. 

The authors also looked at the cost-effectiveness of IL28B gene testing to predict treatment response and found it was also cost effective, but to a lesser degree.

Comments:  This is an important study and finding since the new PI therapy is more expensive and has more side effects than PEG/RBV therapy.  The take away message on this study is that treatment with PI triple therapy will reduce future cases of liver cancer and death and in most cases it is cost-effective.


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What You Don't Know, You Can Sell
—Tracy Swan, TAG

Merck’s Cavalier Attitude towards the Welfare of HIV/HCV Coinfected Patients

In places where access to antiretroviral therapy is widespread, people living with HIV are now dying from a common and curable coinfection: hepatitis C virus (HCV). HIV increases the risk for, and accelerates the rate of, liver disease from hepatitis C. Pegylated interferon and ribavirin, medications used to treat HCV, are less effective in people with HIV than in their HCV-monoinfected counterparts.

In 2011, the first hepatitis C protease inhibitors, Merck’s boceprevir and Vertex’s telaprevir, were approved based on trials in people with hepatitis C monoinfection. Both drugs are being studied in coinfected people, thanks to pressure from the international HIV/HCV community and encouragement from regulatory agencies. (See www.clinicaltrials.gov for more information on HCV treatment trials for HIV/HCV-coinfected people.)

Despite outrage from activists, Merck refused to study drug-drug interactions (DDIs) between boceprevir (Victrelis), their HCV protease inhibitor, and drugs commonly used to treat HIV, putting coinfected study volunteers at risk for drug-drug interactions in their own clinical trial.

Drug-drug interactions can have serious consequences for HIV/HCV-coinfected people, who risk forfeiting current and future treatment options for HIV and possibly HCV as well. DDIs can lower drug concentrations to an ineffective level, leading to drug resistance, or increase drug concentrations, worsening side effects and leading to treatment discontinuation; they can even be life-threatening, as was the case with ribavirin and didanosine (DDI; Videx).

The boceprevir coinfection study opened in mid-2009, before Merck had performed drug-drug interaction studies with HIV protease inhibitors in healthy volunteers, a common step in drug development. Nonetheless, coinfected study volunteers were allowed to use them; in fact, by default, HIV protease inhibitors— or Merck’s own integrase inhibitor, raltegravir (Isentress)—were the only HIV treatment options for study volunteers, since non-nucleoside reverse transcriptase inhibitors were not allowed. Activists kept asking Merck to perform DDIs throughout boceprevir’s development, but Merck’s attitude remained cavalier; they did not launch key drug-drug interaction studies until two years later, months after boceprevir was approved.

The results of DDI studies with three ritonavir-boosted HIV protease inhibitors, atazanavir/r (Reyataz), darunavir/r (Prezista), and lopinavir/r (Kaletra) in healthy volunteers (rather than in the actual trial participants who were using boceprevir with HIV protease drugs for almost a year) were presented in March at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. The news was not good. Combining boceprevir with these HIV protease inhibitors lowered concentrations of each HIV protease inhibitor at both the highest and lowest (peak and trough) levels.

Boceprevir lowered the peak concentration of atazanavir/r by 25 percent, and the trough by 49 percent; darunavir/r peak decreased by 36 percent and trough by 59 percent; for lopinavir/r, coadministration with boceprevir dropped the peak concentration by 30 percent and trough by 43 percent. In turn, boceprevir levels dropped by 45 percent when co-administered with lopinavir/r and by 32 percent when administered with daruanvir/r; only atazanavir/r had no effect on the concentration of boceprevir.

Failure to characterize these drug-drug interactions put study participants—and coinfected patients—at an unacceptable level of risk, although the clinical implications—or the real-life impact on HIV and hepatitis C treatment outcomes—of these drug interactions are not clear. Nonetheless, the U.S. Food and Drug Administration warned that “drug interactions between the hepatitis C virus (HCV) protease inhibitor Victrelis (boceprevir) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can potentially reduce the effectiveness of these medicines when they are used together.”

Regulators from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) went a step further, recommending that:

 “[D]octors treating patients co-infected with hepatitis C and HIV should be aware of the findings of the drug interaction study. They should not co-administer Victrelis with ritonavir-boosted darunavir or lopinavir in HIV and hepatitis C co-infected patients. Co-administration of Victrelis with ritonavir-boosted atazanavir may be considered on a case-by-case basis if deemed necessary in patients with suppressed HIV viral loads and with an HIV strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring is warranted.”

Vertex’s rival protease inhibitor, telaprevir (Incivek) has outsold boceprevir: in the fourth quarter of 2011, telaprevir trounced boceprevir $456.8 million to $87 million. The opportunity to capture the coinfection market share may have motivated Merck’s decision to delay drug-drug interaction studies. HCV is more likely to be diagnosed and treated in HIV-positive people than people with HCV alone, for several reasons. HIV treatment guidelines recommend HCV testing for all HIV-positive people; the infrastructure to deliver treatment is already in place; and hepatitis C is known to be more aggressive in people with HIV, so physicians and patients are more game to try for a cure.

After Vertex reported drug interactions between telaprevir and ritonavir boosted HIV protease inhibitors, boceprevir became a more attractive option for co-infected people. Merck’s vice president of clinical research, Robin Issacs, alluded to off-label use in the company’s February 8 press release. “Though VICTRELIS is not indicated for the treatment of chronic HCV in those who are also infected with HIV, we recognize that some physicians have prescribed or may be considering prescribing VICTRELIS for patients taking ritonavir-boosted HIV protease inhibitors. We felt it was important to share these data as part of our commitment to patient safety and transparency.”

Where was Merck’s commitment to safety during boceprevir’s development? We can only hope that no patients have been harmed.

The boceprevir experience underscores the importance of timely DDI studies. There are other medications used by people with hepatitis C—whether or not they are coinfected with HIV—that warrant study, such as methadone, buprenorphine, and commonly prescribed psychiatric medications. Merck representatives have stated that the company will be more proactive with their promising second-generation hepatitis C protease inhibitor, MK-5172.

Activists have released a statement calling on regulatory agencies and pharmaceutical companies to study DDIs between experimental HCV drugs that are broken down by the body in a similar way with hormonal contraceptives, methadone, buprenorphine, lipid lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications in addition to HIV medications.

Reprinted with permission from tagline Spring 2012


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HCV Snapshots
—Lucinda K. Porter, RN

Article: Risk of Myocardial Infarction Associated with Chronic Hepatitis C Virus Infection: A Population-Based Cohort Study – Forde K A, Haynes K, Troxel A B, et al.
  Source: Journal of Viral Hepatitis April 2012; Volume 19, Issue 4, pages 271–277

Chronic hepatitis C virus (HCV) infection is an inflammatory disease, leading scientists to wonder if those with HCV are at increased risk of heart attack, or acute myocardial infarction (MI). This retrospective study conducted in the United Kingdom analyzed data collected from 4809 subjects with HCV and 71,668 without HCV, from 1996 through 2008.

The Bottom Line: HCV was not associated with an increased risk of incident MI.

Editorial Comment: It is great to read some good news about HCV. However, heart disease is a huge problem in the U.S., so although there is no apparent increased risk for an MI, HCV patients still have the same risk as the general population. Remember, what is good for the heart is good for the liver, EXCEPT for red wine.

Article: Increasing Rates of Hepatitis C Past or Present Infection Reports Among Adolescents and Young Adults in Pennsylvania – Boktor S W, Waller K O, Ostroff  SM
  Source: International Conference on Emerging Infectious Diseases’ Program and Abstracts Book, March 2012

Note: This HCV Snapshot comes from a conference abstract. Abstracts represent part of the story and unless and until these studies are published in a peer-reviewed journal, these data and conclusions are considered preliminary.

This study conducted in Pennsylvania examined chronic HCV case reports from 2003-2010. In seven years, the number of new cases of chronic HCV for people ages 15-34 years nearly doubled (1,384 in 2003 to 2,393 in 2010). However, overall rates for all age groups combined declined in the same period. Rural areas appear to have the greatest increases of chronic HCV among the 15-34 y/o population.

The Bottom Line: The number of reported cases of adolescents and young adults in Pennsylvania with chronic HCV has doubled, especially in rural areas.

Editorial Comment: This report begs for more research along with a comprehensive intervention strategy.

Article: Combination PEG-IFN a-2b/Ribavirin Therapy Following Treatment of Hepatitis C Virus-Associated Hepatocellular Carcinoma is Capable of Improving Hepatic Functional Reserve and Survival – Ishikawa T, Higuchi K, Kubota T, et al.
  Source: Hepatogastroenterology March- April 2012; Pages 529-32

Liver cancer or hepatocellular carcinoma (HCC) in patients with HCV recurs frequently despite HCC treatment. In this study, investigators studied 54 subjects with HCV-associated Stage 1-2 HCC. One group of 29 subjects received combination peginterferon (PEG-IFN) and ribavirin following HCC treatment; the other 25 received nothing further after HCC treatment.

The Bottom Line: After three years, the PEG-IFN group had significantly better survival rates and liver function tests than the non-PEG-IFN group.

Editorial Comment: With liver cancer rates increasing, it is vital that we develop effective ways to treat patients with HCC. This research represents a potentially new approach to managing HCC by using combination peginterferon (PEG-IFN) and ribavirin off-label.

Article: AIDS Info: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
  Source: U.S. Department of Health and Human Services http://aidsinfo.nih.gov/guidelines (Last updated: 3/28/2012; last reviewed:3/28/2012)

Note: This HCV Snapshot is based on the latest HIV/HCV co-infection treatment guidelines, rather than a summary of original research. The decision to include this was based upon its importance.

These guidelines take into consideration the newly approved HCV protease inhibitors (PIs) boceprevir and telaprevir and recommend the latest treatment guidelines for HIV/HCV co-infected patients. These recommendations include:

  • Antiretroviral therapy (ART) should be considered as ART may slow HCV progression.
  • HCV treatment may be deferred for patients with no or mild liver damage.
  • ART regimen may need to be modified if HCV treatment is introduced.
  • Patients taking ART and with boceprevir or telaprevir are at high risk for drug-drug interactions and need to be carefully monitored.
  • Patients taking certain ART regimens should not take boceprevir. (See guidelines)

The Bottom Line: HCV treatment has increased challenges for patients with HIV/HCV co-infection when using peginterferon and ribavirin with or without telaprevir or boceprevir. These challenges include increased pill burden, toxicities, and potential drug interactions.

Editorial Comment: The information in this Snapshot is very simplistic. More details may be found on the provided link.

Article: Liver-Induced Inflammation Hurts the Brain – Garcia-Martinez R, Cordoba J
  Source: Journal of Hepatology March 2012; Volume 56, Issue 3, Pages 515-517

Note: This HCV Snapshot summarizes an editorial rather than original research. The editorial underscores important concepts in HCV research.

Scientists are gathering more information on HCV’s affect on the central nervous system (CNS), and the authors of this editorial review some of the pathways of this. A thumbnail sketch of this process is that HCV infection stimulates an immune response, first locally (in the liver) and then systemically (the entire body). This may lead to inflammation in the CNS.

The Bottom Line: Persistent CNS inflammation may have harmful effects on the brain. The authors recommend evaluation of therapies that may reduce or eliminate inflammation, peripherally, systemically, and/or neurologically.

Editorial Comment: It may be frightening to read about HCV’s potential to harm the brain, an organ that is not as resilient as the liver. However, reading about the potential damage HCV may cause does not mean that we are helpless against it. And although there is no specific research to this claim, common sense suggests that good nutrition, daily exercise, stress reduction, adequate sleep, humor and a positive attitude may offset some of HCV’s inflammatory reaction. What is good for the liver is also good for the brain.


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IN MEMORIAM: Michael Carden
1971-2012

Alan Franciscus, Editor-in-Chief

It is with deep sadness that I announce that my friend and colleague, Michael Carden, died suddenly on Monday April 09, 2012.   Michael was an incredible person—loved by family, friends, and colleagues.  

I met Michael a couple of years ago at a conference.  We shared a lot in common and soon became fast friends.  Michael was real.  He dedicated his life to helping underserved populations.  The focus of his work was with injection drug users and he treated everyone with compassion and respect.  His work in advocacy inspired me and many others through his many leadership roles in which he spoke for the populations he represented.   

Michael always advocated for people first.  He was one of the few who advocated for injection drug users and HCV on a local and national level.  His work was admired, respected and made a difference.  With the death of Michael we have lost a true champion for equal treatment for all people with hepatitis C.  Personally, I have lost a kind, compassionate and loving friend.  I miss you Michael.  

Alan  


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HEALTHWISE: May is Hepatitis Awareness Month
—Lucinda K. Porter, RN

As unscientific as this sounds,  I don’t know how else to say this—a lot of people have chronic hepatitis C virus infection (HCV). I wish I could say with certainty what that number is. The Centers for Disease Control and Prevention (CDC) estimate the number of people in the U.S. with chronic HCV at 3.2 million.1 Other research places the figure closer to 5 million or more.2,3 What these data have in common is that both represent a lot of people.

One thing that experts do agree on is this—the majority of those with HCV have yet to be diagnosed. Once again, they don’t agree on the estimate, with the number of people who are unaware that they have HCV ranging from 50% to 75%. Regarding chronic viral hepatitis (hepatitis B and C), the U.S. Department of Health and Human Services states, “65%–75% of infected Americans remain unaware of their infection status and are not receiving care and treatment.”4

No diagnosis means patients aren’t aware that they risk infecting others. It may mean decreased quality of life. No diagnosis means no treatment. Diagnosis leads to choice, and choice leads to health. For instance, in the CDC’s efforts to gather better data, they learned that the majority of those who are HCV antibody-positive admit to drinking an average of more than two drinks daily.

To which I would ask, if you had hepatitis C, wouldn’t you want to know? Even if you didn’t have insurance or the financial means to treat HCV, wouldn’t you want the opportunity to make lifestyle changes to try to arrest further damage the virus was doing? Wouldn’t you want to know if only to protect family members and others from possible infection?  Perhaps you wouldn’t want to give up drinking, but wouldn’t you want to know that if you did, your health might improve?

I know I would. I am fortunate because I knew I had hepatitis C pretty soon after I contracted it. This knowledge motivated me to choose a healthy lifestyle, one free of alcohol and other liver-unfriendly substances. As the saying goes, knowledge is power.

Hepatitis C has been making the headlines quite a bit this year with news that more people in the U.S. die from HCV than from HIV. HCV-related deaths are increasing, an outcome that isn’t necessarily inevitable since generally, HCV can be managed and treated. The CDC is trying to avert this crisis, with programs such as the first National Hepatitis Testing Day on May 19, 2012. 

I am thrilled about the CDC’s efforts, and I want to help them. How? By talking about HCV—a lot—to anyone and everyone who will listen. What if we acted like Paul Revere, shouting to the world, “Hep C is here, hep C is here.” Granted, if we ran through the streets on horseback, we might be locked up. Still, what Paul Revere did was warn people, giving them the chance to save themselves. 

I talk about HCV so much, that I am becoming a bore. I talk about it at church, at my Jazzercise class, at Toastmasters and in my writers’ group. It comes up on planes, parties, and during bridge games. Granted, the subject pops up easily since I work in this field. It’s not as if I am playing cards, and casually slip in the words “hepatitis C” after a “no trump” bid. I know many people whose lives changed because they followed-up with their doctors after talking to hepatitis C advocates.

I am not proposing that everyone with HCV get on a soapbox or declare a manifesto. There are huge personal and professional risks with self-disclosure. In fact, before you tell anyone you have HCV, be sure to read the Hepatitis C Support Project’s A Guide to HCV Disclosure. There is a time and place to mention this virus, as well as ways to bring it up.

If you are considering revealing your HCV status, perhaps you’ll be inspired by Hank Johnson’s story. Johnson is a U.S. Congressman from Georgia. While serving in the House of Representatives, he announced he had HCV, went through treatment, launched his reelection campaign while on treatment, and won. I figure if he could be so brave and honest, just about anyone can.

Congressman Johnson was born in the years where there is the greatest prevalence of HCV—1945 through 1965. These Baby Boomers are becoming Senior Boomers, and some of them will be very sick. This generation, known for social activism and speaking out against injustice, will face yet another cause. This time, we will be fighting for our lives.

If you want to help, here are a few suggestions.

  • Check out the Helpful Links at www.hcvadvocate.org/library
    /links.asp

  • Take care of your health. This is the top priority and the foundation that all activism rests on.

  • Be informed. Learn whatever you can about HCV. Look at reliable sources of information. For information and links to other good sources, check out www.hcvadvocate.org. Click on the “Advocacy” link for information on the latest issues, as well as sample letters you may use.

  • Come out of the closet. If you are comfortable with disclosure, tell others. You may be surprised to see how many people have or know of someone who has HCV. If you are the first person they have encountered with this, you may be the voice of hope.

  • Express your opinion to elected officials. Ask them to support and fund hepatitis C programs. To prepare for this, see the amazing link below to the Caring Ambassadors Program’s Hepatitis C by the Numbers Advocacy Map. The map provides hepatitis B and C population information for congressional districts, along with links to information to contact elected officials. 

  • Write a letter for the opinion pages of your local newspaper.

  • Record a public service announcement (PSA) for your local radio.

  • Add a PSA to the signature line of your email. Feel free to use mine, which says, “Hepatitis C causes more deaths in the U.S. than HIV does. The majority of people with hepatitis C do not know they have it; most were born from 1945 through 1965. Don’t get scared—get tested.”

  • Use social media to spread the word. Post information on Facebook and Twitter. Follow other hepatitis activists and retweet their posts. The CDC’s Twitter handle is @cdchep 

  • Get involved. There are many fine organizations devoted to education, advocacy, and other vital needs surrounding hepatitis C and other types of viral hepatitis. A few noteworthy organizations are listed under Additional Resources at the end of this article.

Finally, encourage people born between 1945-1965 to be tested for viral hepatitis. I do not see the point of waiting for the medical establishment to recommend universal testing. We screen for colon cancer, a test that involves massive preparation, sedation, time, and so on. We screen for breast cancer, a test that is also costly. A simple blood test for HCV is inexpensive and so much less trouble than bowel preparation and getting your breasts squashed.

Please join me and other activists who are working to increase the public’s awareness about viral hepatitis. Together we can change the world.

Lucinda K. Porter, RN is the author of
Free from Hepatitis C

Notes:

  1. http://www.cdc.gov/hepatitis/C
    /cFAQ.htm#statistics
  2. Chak E, Talal AH, Sherman KE, et al. Hepatitis C infection in USA: an estimate of true prevalence Liver International 2011;31:1090-1101
  3. Edlin BR Perspective: test and treat this silent killer Nature 2011;474:S18-19
  4. U.S. Department of Health and Human Services Combating the Silent Epidemic of Viral Hepatitis

 

Additional Resources



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Boceprevir and Telaprevir Improve Cure Rates for HIV/HCV Coinfected People
—Liz Highleyman

Adding the HCV protease  inhibitors boceprevir (Victrelis) or telaprevir (Incivek) to pegylated interferon/ribavirin (PEG/RBV) significantly increases the likelihood of sustained response for HIV/HCV coinfected patients, according to findings presented at the recent 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

An estimated one-third of people with HIV also have chronic hepatitis C. HIV/HCV coinfected individuals experience more rapid liver disease progression compared with HCV monoinfected people and they do not respond as well to interferon-based therapy.

Last year’s approval of the first direct-acting antiviral agents for HCV ushered in a new era of treatment. Not only do they increase the chances of a cure for people with difficult-to-treat HCV genotype 1, they also allow many to receive shorter therapy.

HIV-positive people have eagerly awaited data showing whether this also holds true for the coinfected population. Boceprevir and telaprevir were approved only for people with HCV monoinfection. Clinicians can prescribe approved drugs to anyone, but most are hesitant to do so without safety data.

Interim results from clinical trials of boceprevir and telaprevir were reported in 2011, but the data presented at CROI are the first to show that the protease inhibitors improve cure rates for coinfected people. While these 12-week sustained virological response (SVR-12) data fall short of the “gold standard” 24-week SVR cut-off, the U.S. Food and Drug Administration now recognizes undetectable HCV RNA at 12 weeks after completion of treatment as a good indicator of a cure.

BOCEPREVIR
Mark Sulkowski from Johns Hopkins presented findings from a Phase 2 trial of boceprevir triple therapy in HIV/HCV coinfected patients (abstract 47). In this study 100 previously untreated participants with HCV genotype 1 were randomly assigned to receive 800 mg oral boceprevir three times daily or placebo, plus weekly pegylated interferon alfa-2b (PegIntron) and weight-adjusted ribavirin.

Everyone started with a four-week PEG/RBV lead-in, followed by triple therapy with boceprevir for 44 more weeks. While HIV-negative patients who achieve early HCV suppression can stop treatment sooner, prior studies suggest that people with HIV respond more slowly to interferon, and everyone in this trial was treated for 48 weeks.

All participants were taking antiretroviral therapy (ART). Based on prior pharmacokinetic datawhich later turned out to be inadequate, as discussed below,people were limited to regimens containing a ritonavir-boosted HIV protease inhibitor plus two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

Most participants (about 70%) were men and the median age was 44 years; 65% had HCV genotype 1a. Most had high HCV RNA and about 5% had cirrhosis at baseline. The median CD4 T-cell count was nearly 600, indicating good immune function, and almost all had undetectable HIV viral load.

At 12 weeks after completion of treatment, 61% of participants in the boceprevir triple therapy arm achieved SVR compared with just 27% in the placebo arm (toward the lower end of sustained response rates in prior dual therapy coinfection studies).

Two people in the boceprevir arm and one in the placebo group experienced HCV relapse after completing treatment. Three patients taking boceprevir and four taking placebo experienced HIV viral load rebound. Absolute CD4 T-cell counts fell in both groups–a known side effect of interferon–but CD4 cell percentages remained stable.

People on boceprevir experienced more side effects overall. Seven people (21%) taking boceprevir and 11 (17%) taking placebo had serious adverse events. However, the researchers concluded, the safety of boceprevir in coinfected patients is “consistent with that observed in [HCV] monoinfected patients.”

TELAPREVIR
Douglas Dieterich from Mount Sinai School of Medicine presented findings from a Phase 2 trial that tested telaprevir plus PEG/RBV in 60 previously untreated coinfected patients with HCV genotype 1 (abstract 46).

Part A included 13 coinfected participants with CD4 counts of at least 500 who were not yet on HIV treatment. Part B included 47 people on ART. Based on findings from drug-drug interaction studies, 24 patients took the NNRTI efavirenz (Sustiva) plus tenofovir (Viread) and emtricitabine (Emtriva), while 23 took the ritonavir-boosted HIV protease inhibitor atazanavir (Reyataz) plus NRTIs.

Here too, most participants were men, the average age was about 45 years, and about two-thirds had genotype 1a. Most had high baseline HCV viral load and about 10% had advanced liver fibrosis or cirrhosis. Median CD4 cell counts were high and patients on ART had suppressed HIV viral load.

Participants were randomly assigned to receive oral telaprevir or placebo plus weekly pegylated interferon alfa-2a (Pegasys) and ribavirin. People taking atazanavir received the standard 750 mg three-times-daily telaprevir dose, while those taking efavirenz increased their dose to 1125 mg to compensate for a known drug-drug interaction. Triple therapy lasted 12 weeks, followed by PEG/RBV alone through week 48. Again, all participants were assigned to the full course regardless of early response.

Overall, 74% of coinfected patients taking telaprevir triple therapy achieved SVR-12, compared with 45% of those taking PEG/RBV alone (near the high end of rates seen in dual therapy coinfection studies).

Among participants in Part A not taking ART, SVR-12 rates were 71% with telaprevir and 33% with PEG/RBV alone. By ART regimen, 69% of those using efavirenz and 80% of those using boosted atazanavir achieved SVR-12 with telaprevir, compared with 50% of those taking placebo.

Three people taking telaprevir experienced HCV RNA breakthrough while on treatment, and one telaprevir recipient and two placebo recipients experienced HCV relapse after completing therapy. No one showed evidence of HIV rebound. Again, absolute CD4 cell counts fell across the board but percentages remained stable.

As with boceprevir, telaprevir triple therapy recipients experienced more side effects. Three people on telaprevir, but none in the placebo group, discontinued due to adverse events; however, no one experienced severe rash, and anemia was equally common at 18%.

Drug-Drug Interactions
One factor that has hampered development of new HCV therapies for the coinfected population is concern about drug-drug interactions. Because of the way they are processed by enzymes in the liver, some drugs can raise or lower concentrations of other agents. This can lead to elevated drug levels that worsen side effects or reduced drug levels that allow viral breakthrough.

Interactions should be evaluated in laboratory studies and healthy uninfected volunteers before new drugs are tested in HIV/HCV coinfected patients. But despite demands of advocates and encouragement from regulatory agencies, this does not always happen.

The risks of inadequate interaction studies recently came to light regarding boceprevir. While telaprevir was tested with HIV antiretrovirals in humans prior to coinfection trials, decisions about which HIV drugs to use in the boceprevir coinfection trial were based on educated guesses from laboratory data.

Studies in uninfected volunteers later revealed that coadministration of boceprevir with three widely used ritonavir-boosted HIV protease inhibitors–atazanavir, darunavir (Prezista), and lopinavir/ritonavir (Kaletra) reduced concentrations of the HIV drugs by up to 59%. Conversely, coadministration with lopinavir/ritonavir or darunavir/ritonavir decreased boceprevir total concentrations by 32% to 45%.

Before these findings were reported at CROI (abstract 771LB), Merck issued a “Dear Health Care Professional letter” in February describing the data and stating that the company “does not recommend” coadministration of boceprevir with ritonavir-boosted HIV protease inhibitors.

However, as Sulkowski reported, boceprevir triple therapy appeared safe and effective for coinfected people taking boosted HIV protease inhibitors in the Phase 2 trial. A small number of participants experienced HIV viral breakthrough, but this was actually less common in the boceprevir arm (three of 64 patients) than in the placebo arm (four of 34 patients).

Researchers also presented data at CROI from drug-drug interaction studies looking at novel HCV agents in the development pipeline.

Researchers from Janssen tested interactions between antiretrovirals and the next-generation HCV protease inhibitor TMC435 (abstract 49). In studies of 48 healthy volunteers, 150 mg once-daily TMC435 did not significantly affect levels of rilpivirine (Edurant), raltegravir (Isentress), tenofovir, or efavirenz. TMC435 levels did not change when combined with the first three drugs, but coadministration with efavirenz reduced total TMC435 concentration by about 70%.

The integrase inhibitor raltegravir–among the most well-tolerated and least prone to interactions of HIV drugs–has also shown minimal interference with either boceprevir or telaprevir.

Bristol-Myers Squibb researchers reported on interactions with the promising experimental HCV NS5A inhibitor daclatasvir (formerly BMS-790052) (abstract 618). In studies of 49 healthy volunteers, 60 mg once-daily daclatasvir did not significantly change concentrations of atazanavir/ritonavir or efavirenz, and both daclatasvir and tenofovir remained within expected ranges when used together. Daclatasvir levels rose modestly with atazanavir/ritonavir but declined with efavirenz; the researchers calculated that daclatasvir dose adjustments should compensate for these interactions.

Changing Guidelines
Taken together, these findings indicate that HIV/HCV coinfected people can nearly double their likelihood of sustained response to hepatitis C treatment by adding boceprevir or telaprevir to PEG/RBV. In fact, sustained response rates approach those for HIV-negative people, showing that HCV direct-acting antivirals can help overcome factors that predict poor interferon response.

Reassuringly, HIV/HCV coinfected patients did not experience worse side effects with boceprevir or telaprevir than people with hepatitis C alone, alleviating one of the key concerns about treating this population.

“I don’t think we expected results for either drug to be so good,” Dieterich said at CROI. Cure rates were “shockingly comparable” in HIV/HCV coinfected and hepatitis C monoinfected people and adverse event rates were “virtually the same.”

Drug-drug interactions with telaprevir and especially boceprevir remain an important issue, and conflicting findings make it difficult to establish firm guidelines.

As described in the March 2012 HCV Advocate, a group of HIV and HCV experts developed guidance on hepatitis C treatment of coinfected patients for the state of Maryland, published in the December 14, 2011, advance online edition of Clinical Infectious Diseases. But after the boceprevir interaction findings were revealed, the guidance was withdrawn before going to press.

The latest update to the U.S. Department of Health and Human Services adult antiretroviral treatment guidelines, published March 27, for the first time includes recommendations for using HCV protease inhibitors in HIV-positive people. (See “HCV Snapshots” in this issue.) For coinfected patients not on ART or taking raltegravir, the panel recommends either boceprevir or telaprevir. Due to uncertainty about boceprevir interactions, the panel advises people on ART to use telaprevir with either atazanavir or efavirenz.

However, Dieterich suggested in a post-CROI interview that “it’s perfectly appropriate to use either boceprevir or telaprevir” for coinfected people on ART, “as long as you’re cognizant of drug-drug interactions” and frequently monitor both HIV and HCV viral load.

Fortunately, new HCV agents in the pipeline will be better tolerated, more convenient, and less likely to interact with medications for HIV or other conditions common among people with chronic hepatitis C. But if coinfected people need treatment due to progressive liver disease, they should not wait. Most experts don’t expect interferon-free oral regimens to be approved for at least three years, with another couple of years added for a coinfection indication.

While there’s a lot of promise in the pipeline, we’re already entering an era of effective therapies, according to Kenneth Sherman from the University of Cincinnati. “They are not always easy to take, but they are very effective...We don’t want patients to give up that opportunity in the hopes that a great thing will come along.”

References

  • Dieterich, D. et al. Telaprevir in Combination with Pegylated Interferon-alfa-2a + Ribavirin in HCV/HIV-coinfected Patients: A 24-Week Treatment Interim Analysis. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 46.
  • Sulkowski, M. et al. Boceprevir + Pegylated Interferon + Ribavirin for the Treatment of HCV/HIV-coinfected Patients: End of Treatment (Week 48) Interim Results. CROI 2012. Abstract 47.
  • Hulskotte, E. et al. Pharmacokinetic Interaction Between the HCV Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Lopinavir, and Darunavir. CROI 2012. Abstract 771LB.
  • Ouwerkerk-Mahadevan, S. et al. The Pharmokinetic Interactions of HCV Protease Inhibitor TMC435 with RPV, TDF, EFV, or RAL in Healthy Volunteers. CROI 2012. Abstract 49.
  • Bifano, M. et al. Assessment of HIV ARV Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile Which Supports Co-administration with Tenofovir Disoproxil Fumarate, Efavirenz, and Atazanavir/Ritonavir. CROI 2012. Abstract 618.



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