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December 2013 HCV Advocate

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In This Issue:

AASLD: Focus on "Breakthrough Therapies"
Alan Franciscus, Editor-in-Chief

HEALTHWISE: Liver Meeting 2013 Update
Lucinda K. Porter, RN


Snapshots: AASLD Special
Lucinda K. Porter, RN

HIV/HCV Coinfection at AASLD 2013
Liz Highleyman

Simeprevir (Olysio): FDA Approved!
Alan Franciscus, Editor-in-Chief



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AASLD: Focus on "Breakthrough Therapies"
—Alan Franciscus, Editor-in-Chief

This year’s American Association for the Study of Liver Diseases (AASLD) conference was probably the most exciting yet informative meeting in the history of the annual conference.  The most talked about studies released at AASLD were the direct-acting antiviral medications that are being combined with and without pegylated interferon and/or ribavirin. 

 In this article I’m going to discuss the three drug combinations to treat HCV that have been awarded “breakthrough therapy” status by the Food and Drug Administration (FDA):

  • AbbVie’s ABT-450/r, ABT-267, ABT-333,

  • Bristol-Myers Squibb (BMS), daclatasvir, asunaprevir, BMS-791325, and

  • Gilead’s sofosbuvir and ledipasvir combination. 

Note:  Most of the medications above are being co-formulated to reduce the number of pills that need to be taken.

What is “Breakthrough Therapy”?
The Food and Drug Administration (FDA) awards “breakthrough therapy” status to a drug(s) that is in early development to treat a serious medical condition where the drug(s) has been shown to provide a substantial improvement over currently available drugs.  The designation comes with many perks such as working closely with the pharmaceutical company to streamline development, and accelerating the approval process.

AbbVie
AbbVie’s direct-acting antiviral (DAAs) combination—ABT -450/r, ABT-267, ABT333—used with and without ribavirin to treat hepatitis C was presented at multiple sessions.  The dosing is as follows: ABT-450/r ((ritonavir) once-a-day); ABT-267, ABT-333 (twice-a-day) and weight-based dosing of ribavirin 1,000/1,200 divided into doses taken twice a day. 

AVIATOR: 
A Phase 2 study of the combination of the above AbbVie DAA drugs with ribavirin.  There was a total of 571 HCV genotype 1 treatment-naïve and treatment-experienced patients in 9 study arms that included various AbbVie DAA drugs with and without ribavirin.  Treatment duration was 8, 12 or 24 weeks.  All the patients were followed for 48 weeks post-treatment.

The cure rates were very high in both the treatment-naïve group (93%) and prior null-responders (96%). 

  • In one sub-study that reviewed ribavirin dose-reductions in the groups that were treated for 12 or 24 weeks it was found that 10% of patients had ribavirin dose reductions, but the viral cure rates were similar between the two groups. 

  • Another sub-study that analyzed the relapse rates found that the cure rates seen at week 12 were the same for the rates seen at week 24.  Note: some patients were lost to follow-up and could not be counted in the sub-analysis. 

  • Yet another analysis looked at the medication adherence rate in the group that received 12 and 24 weeks of treatment.  As expected there was a lower adherence rate in the group that received 24 weeks of treatment, but importantly the cure rates were still similar between the 12 and 24 week treatment groups.  

PEARL:
In this study, 42 treatment-naïve and 40 treatment-experienced genotype 1b patients were treated with the two drug combination of ABT-450/r plus ABT-267 (no ribavirin) for 12 weeks. Both drugs were dosed once-a-day. 

The cure rates in the treatment-naïve group were 95% (40 of 42 patients) and 90% (36 of 40 patients) in the prior non-responder group. 

The drugs were well-tolerated—the most common side effects were headache and nausea.  There were no treatment discontinuations related to the study drugs.

The studies are currently in Phase 3 and AbbVie is expected to apply to the Food and Drug Administration for marketing approval next year.

POST-AASLD:
A press release issued by AbbVie reported on the first of six Phase 3 studies that AbbVie is conducting.   The press release contained information about SAPPHIRE-1, a study that included treatment for 12 weeks with AbbVie’s interferon-free combination therapy of ABT-333 (twice daily), ABT-450/ritonavir co-formulated with ABT267 (once-daily) plus ribavirin (dosed twice a day) for the treatment of HCV genotypes 1a and 1b.  

The overall cure rates were 96% (455 of 473 patients)—95% in HCV genotype 1a and 98% in HCV genotype 1b.  

The most common side effects reported were fatigue, headache and nausea.  The treatment discontinuations were similar in the group that received the study drugs and the group that received placebo (.6%).  The relapse rate was also considered low—1.7% of those who received AbbVie’s combination therapy.

BMS
BMS has three drugs—daclatasvir (once-a-day), asunaprevir (twice daily) and BMS-791325 (twice daily) in development to treat hepatitis C genotype 1. There were two different studies presented at AASLD.  The first was a dose ranging study of BMS-791325 (75 mg and 150 mg) that included 166 HCV genotype 1 treatment-naïve patients.  Eighty-two percent were genotype 1a and 18% were genotype 1b.  Genotype 1a is considered the more difficult to treat among people with HCV genotype 1. 

The viral cure rates were the same regardless of subtype—92% cure rates.  The viral relapse rates were also similar between the two arms.  The most common side effects were headache, diarrhea, fatigue and nausea—none were classified as severe or led to treatment discontinuations.  Based on the data from this trial the 75 mg dose of BMS-791325 was selected for the Phase 3 studies. 

The other study was a Phase 3 interferon-free study conducted  in Japan.  Note:  BMS has recently applied to the Japanese drug regulatory agency for marketing approval. 

The study included daclatasvir plus asunaprevir for the treatment of HCV genotype 1b.  There are an estimated 1.2 million people in Japan with chronic hepatitis C and the most prevalent genotype 1 subtype in Japan is 1b.  

The study included 222 patients who were prior null-responders and prior partial-responders. The study also included patients who were interferon-intolerant or who were ineligible for interferon treatment.  Ten percent of the patients in the study had cirrhosis.

The viral cure rate (HCV RNA undetectable 24 weeks post-treatment) was 81% in the group of patients who were prior non-responders, and partial-responders, and 87% in the group comprising interferon-intolerant/ineligible patients.  Eight percent of trial participants relapsed post treatment.  Treatment discontinuation rates were 5%.  The most common side effects were upper respiratory infection, elevated liver enzymes, headache, fever and diarrhea.  There was a very low rate of treatment induced anemia. 

Gilead
Treatment with sofosbuvir plus ledipasvir with and without ribavirin has produced very high viral cure rates in both treatment-naïve and treatment-experienced patients with difficult to treat genotype 1a and 1b with and without cirrhosis. 

LONESTAR: 
Group 1: The first study group included 60 treatment-naïve genotype 1 patients without cirrhosis, and most had the more difficult to treat HCV genotype 1a.  The study participants received sofosbuvir/ledipasvir (without ribavirin) daily for 12 weeks or sofosbuvir/ledipasvir plus ribavirin for 8 weeks.  Ninety-five percent of the patients who received either of the above therapies achieved a viral cure—HCV RNA negative 12 weeks post-treatment.  

Group 2: The patients in this group are considered the more difficult to treat because the majority (55%) had cirrhosis and did not achieve a viral cure with a previous course of boceprevir or telaprevir containing treatment.  The 40 patients in this study received 12 weeks of sofosbuvir/ledipasvir or sofosbuvir/ledipasvir plus ribavirin daily for 8 weeks.  The viral cure rates (12 weeks post-treatment) were 95% in the group that received sofosbuvir/ledipasvir without ribavirin and 100% in the sofosbuvir/ledipasvir and ribavirin containing group.  Three patients did not achieve a viral cure—two genotype 1a patients in the group that did not receive ribavirin and 1 person who was lost to follow-up. 

There were no treatment discontinuations and most of the side effects were related to ribavirin. 

VALENCE
Previous studies of sofosbuvir plus ribavirin to treat HCV genotype 3 produced lower cure rates compared to earlier studies with pegylated interferon and ribavirin.  It has been suggested that the length of treatment was the reason for the lower than expected cure rates in the interferon-free studies.  The VALENCE trial evaluated treatment periods of 12 weeks for genotype 2 and 24 weeks for genotype 3.  In the genotype 2 group that received 12 weeks of sofosbuvir plus ribavirin the cure rate was 93%. 

The good news is that in the genotype 3 group that received 24 weeks of treatment, the overall cure rate was 85%—broken down as follows:

  • 94% cure rates in treatment-naïve patients without cirrhosis; 92% cure rates in treatment-naïve patients with cirrhosis

  • 87% of treatment-experienced patients without cirrhosis; 60% of treatment experienced with cirrhosis

This study proved that increasing the treatment duration to 24 weeks for people with genotype 3 resulted in a substantial increase in overall cure rates.  But still, more effective treatments are needed for people with genotype 3 who are prior non-responders with cirrhosis.

Interferon/Ribavirin-Free
Now that it has been proven that high cure rates are obtainable without interferon, attention is being turned to therapies that do not include interferon or ribavirin.  Ribavirin produces most (but not all) of the side effects seen in interferon-free therapies.  In addition, adding another direct-acting antiviral inhibits another HCV replication site which should increase the cure rates for all HCV patients, even those who are the most difficult to cure. 

AbbVie has already proved that the combination of their direct acting antivirals without ribavirin can cure 93 to 96% of people with HCV genotype 1b.

Below are the results of a study by Gilead containing sofosbuvir/ledipasvir plus ribavirin or sofosbuvir/ledipasvir plus GS-9669 to treat treatment-experienced HCV genotype 1 patients with fibrosis or cirrhosis—the most difficult to treat patients.  There were two groups in the study.

Group 1:  20 genotype 1 treatment-experienced patients with cirrhosis received sofosbuvir/ledipasvir with or without ribavirin for 12 weeks. 

  • 100% cure rates in the regime that contained ribavirin;  70% in those who did not receive ribavirin

Group 2:  50 treatment-experienced patients with advanced fibrosis or cirrhosis were treated with sofosbuvir/ledipasvir with ribavirin or GS-9669 for 12 weeks. 

  • 100% cure rates in all of the groups

The side effects reported included headache, fatigue, and nausea.  The drugs were considered generally safe and well-tolerated.  Anemia was common in the ribavirin containing groups.  It appears that the addition of GS-9669 (without ribavirin) for a treatment duration of 12 weeks can push the cure rates up to 100% in patients who are the most difficult to treat even without the use of ribavirin. 

The results of the interferon-free clinical trials in this article are spectacular and offer hope that a cure for everyone living with hepatitis C is on the horizon–and this includes curing the most difficult to treat people with HCV. 

Please see our Guide to Treatment Updates from AASLD 2013 for more information about research that was released at this year’s conference:  www.hcvadvocate.org/news/
reports/AASLD_2013.pdf

Source:  Multiple sources were used for this article including AASLD, company press releases and conference coverage provided by www.hivandhepatitis.com; and
www.natap.org
.



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HEALTHWISE: Liver Meeting 2013 Update
—Lucinda K. Porter, RN

This year’s Liver Meetingwas brimming with news, gleaned from thousands of abstracts.  This annual gathering hosted by the American Association for the Study of Liver Diseases (AASLD) is the premier event for those with a stake in liver disease, benefiting anyone with a liver, which is to say, everyone. The December HCV Advocate is devoted to highlights from the meeting.

Much of the news is good, especially for those with chronic hepatitis C viral (HCV) infection who are waiting for all-oral treatments. Alan Franciscus reviews some of the drugs that are in development. I focus on general aspects of hepatitis C and liver disease.

I’ll begin with a mystery. It’s a mystery I’d like solved, but unfortunately data does not care about my impatience.  Nearly every year, there is at least one presentation showing that patients who have a sustained virologic response (SVR) or virologic cure have improved health markers. This year added more presentations to support this, including findings of reduced risk of fibrosis, cirrhosis, and hepatocellular carcinoma (liver cancer). A large study published in JAMA Internal Medicine (The Risk of Long-term Morbidity and Mortality in Patients with Chronic Hepatitis C; Jeffrey McCombs, et al. November 2013) found that patients with an SVR had improved morbidity and mortality rates.

The mysterious part is the two Liver Meeting posters showing that an SVR does not necessarily give HCV patients a clean slate.  (You can find more about these in the HCV Snapshots.) If this isn’t bad enough, The Journal of Infectious Diseases issued a preliminary report suggesting that the re-emergence of HCV years after an SVR may not be reinfection, but a relapse. The implications of this are distressing, but this was a small study (103 subjects) and this research needs to be confirmed. Until then, I strongly recommend that we each strive to live as healthy a lifestyle as possible. I know it is hard, but it pays off.

This leads me to another sore subject—fatty liver disease. This condition is on the rise, with both non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) crowding out other liver diseases with its increasing incidence. Add fatty liver disease to hepatitis C and the risk of cirrhosis and hepatocellular carcinoma increases substantially. Fatty liver disease is placing a burden on the liver transplant system, since not only is this condition creating an increased need for organs, but the number of viable livers is reduced because of the high prevalence of fatty livers.

In short, although we are making significant progress in our understanding and treatment of HCV, fatty liver disease is threatening livers. The good news is that we can do something about this. A healthy diet, normal weight, and an active lifestyle are the best medicine for managing and preventing fatty liver. Granted, this is easier said than done. But, compared to cirrhosis or cancer, lifestyle changes offer the chance to feel good.

As we head into the holidays, give yourself the miracle of health. Instead of sweets, eat fruit. Reduce portions of high fat foods, fill up on vegetables, and choose whole grain carbs rather than refined ones. 

In addition to giving yourself the gift of health, please consider giving to The Tides Center/Hepatitis C Support Project. We depend on your generosity, and the more you give, the more we can do to carry the message of hope and support to those touched by hepatitis C. 

Wishing you a healthy, peaceful end of 2013. See you here in 2014, when we usher in a new era of hepatitis C treatment.

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

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Snapshots: AASLD Special
—Lucinda K. Porter, RN

December’s Snapshots typically features abstracts presented at the recent Liver Meeting. The research presented here was gathered from conference posters, presentations and abstracts. They 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.

Abstract #2036: Effect of Enhanced Risk Communication on Patient Comprehension of Concomitant Use Warnings for Acetaminophen-Containing Products
  Author(s) Marina Serper, et al.

Results and Conclusion:
Acetaminophen (APAP) is the leading cause of acute liver failure in the U.S. Although most of these cases are from suicide attempts, some cases are due to unintentional misuse.  This study evaluated labeling and counseling methods to communicate proper use of APAP-containing products. The researchers concluded that label warnings failed to provide sufficient consumer protection and recommended verbal counseling and more intensive public health measures to promote consumer understanding.

Editorial Comments: I have been a proponent of safe acetaminophen use. However, this abstract along with other recent reports are showing that safe acetaminophen use may be easier said than done, particularly because of the high number of APAP-containing products. I will be writing more about this in the January HCV Advocate.

Abstract #2219: Dietary Cholesterol Intake Is Associated with Death and Liver Transplantation in Chronic Hepatitis C Virus Infection: Analysis of Extended Follow-Up Data from the HALT-C Trial
  Author(s) Lei Yu, et al.

Results and Conclusion: The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial has provided data on patients with advanced fibrosis or compensated cirrhosis. A retrospective analysis of HALT-C found that higher dietary cholesterol intake was associated with increased risk of death and liver transplantation in patients with chronic hepatitis C virus (HCV) infection.

Editorial Comments: Recent studies report that HCV patients have an increased risk of cardiovascular death. This HALT-C analysis, along with increased incidence of fatty liver disease and increased risk of cardiovascular death, suggests that the role of diet may be an important tool for long-term health. 

Abstract # 360: An International Effort to Assess Hepatotoxicity Associated with Some Herbalife® Products 
  Author(s) M. Vega, et al.

Results and Conclusion: Herbalife is a company that sells nutritional and weight management supplements.  This review of reports of hepatotoxicity (liver injury) since 1990 found 16 cases of possible connection with Herbalife, with one death and no need for liver transplantation.

Editorial Comments: I was reluctant to mention this abstract since the number of those with liver injury is small and no one estimated the real risk. Moreover, we don’t know if these injuries occurred to those with healthy livers or pre-existing liver disease.  I included it since most of the HCV Advocate readers have liver disease and should exercise extra caution when using dietary supplements. 

Abstract # 2210: The Burden of Hepatitis C Infection in the 21st Century in the United States
  Author(s) Mina Kabiri, et al.

Results and Conclusion: Researchers developed a model to project the burden of HCV in the U.S. through 2040. They estimated that the peak prevalence of decompensated cirrhosis will reach 64,800 cases in 2017, and hepatocellular carcinoma (liver cancer) cases will peak at 24,000 cases in 2016. The number of deaths due to HCV is expected to peak at 19,700 by 2018. These researchers predicted that new therapies and the implementation of birth-cohort screening will mean that HCV will become a rare disease in the U.S. by 2040.

Editorial Comments: I very much want to believe this prediction, but I need more evidence. Despite the Affordable Care Act, good health care continues to be inaccessible to everyone in the U.S., particularly those affected by mental illness, poverty, drug-dependency, and incarceration. This optimistic research did not address these factors sufficiently.

Abstract # 2251: HCV Transmission among People Who Inject Drugs in New York City: The Swan Project
  Author(s) Brian R. Edlin, et al.

Results and Conclusion:  This study recruited injection drug users in New York from 2005-2012. The data showed an extraordinarily high incidence of HCV among people who inject drugs, especially those who are young, started injecting recently, or have riskier injection practices. Incidence decreased the longer participants remained in the study. Methadone maintenance and safe injection facilities may decrease transmission.

Editorial Comments: Multiple global studies show that the war on drugs is an anti-health policy, and access to safe injection facilities reduces drug use. This study adds credence to the argument that the U.S. needs to reform its drug policy.

Abstract # 1449: Changes in Characteristics of Hepatitis C Patients Referred to Liver Centers in the United States in the Past Decade 
  Author(s) Nizar Talaat, et al.

Results and Conclusion: This U.S. study found that compared to a decade ago, HCV patients newly referred to liver clinics are older, more likely to be infected with genotype 1a, have more advanced liver disease and an 8-fold higher prevalence of hepatocellular carcinoma.  Despite the fact that these patients have been diagnosed for a longer period and had access to medical care, 75% had not received any treatment.

Editorial Comments: The low rate of treatment among these HCV patients is disturbing especially in the light of Thierry Poynard’s AASLD presentation, “Long term survival of liver fibrosis after virological cure (SVR) in patients with chronic hepatitis C (CHC): The avenue of the scars?”  Poynard found that HCV patients who had significant fibrosis and a viral cure were still at risk for liver fibrosis/cirrhosis and hepatocellular carcinoma. The concern is that treatment delay may be risky. See the next abstract for more about this.

Abstract #1983: Incidence and Risk Factors for Hepatocellular Carcinoma in Patients with Chronic Hepatitis C after the Eradication of HCV
  Author(s) Hidenori Toyoda, et al.

Results and Conclusion: This Japanese study investigated the development of hepatocellular carcinoma (HCC) in 522 chronic hepatitis C patients who had achieved sustained virologic response (SVR). HCC occurred in 16 patients over 10 years, and was significantly lower than that of HCV-infected patients with persistently normal ALT levels. Diabetes, age 40 and above, and fibrosis of 2 or more were associated with higher HCC risk.

Editorial Comments: These results are inconsistent with other studies that show an SVR in patients without advanced liver damage decreases their morbidity and mortality risk to roughly that of the general population. However, this presentation adds weight to Poynard’s findings that HCV patients who had significant fibrosis and a viral cure were still at risk for liver fibrosis/cirrhosis and hepatocellular carcinoma. 

This study is particularly disturbing since patients are postponing HCV treatment as they wait for approval of all-oral regimens.  However, waiting may be risky if it means that there is still a risk of HCC even with an SVR. More research is needed to assess the durability of these findings.

Abstract #LB6: Screening in Emergency Department Identifies a Large Cohort of Unrecognized Chronic HCV Infection among Baby Boomers
  Author(s) James W Galbraith, et al.

Results and Conclusion: This study performed HCV screening on 565 Baby Boomers with no known HCV who were seen in the Emergency Department of a Birmingham, AL hospital in a 15-day period. Approximately one in eight screened positive for HCV.

Editorial Comments: This rate is higher than anticipated. It will be interesting to see what the real HCV rate is when the CDC recommendations to test Baby Boomers is fully implemented.


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HIV/HCV Coinfection at AASLD 2013
Liz Highleyman

The 64th annual AASLD Liver Meeting this month in Washington, DC, held much good news for people with hepatitis C, including difficult-to-treat populations such as people with cirrhosis, liver transplant recipients, and people with HIV/HCV coinfection.

Coinfected people experience more rapid liver disease progression on average and do not respond as well to interferon-based therapy as people with HCV alone. Direct-acting antiviral agents (DAAs) have the potential to dramatically improve response rates for coinfected patients, but this population faces additional issues related to adverse events and drug-drug interactions with antiretroviral therapy (ART).

Sofosbuvir + Ribavirin
Mark Sulkowski from Johns Hopkins (abstract 212) reported findings from a Phase 3 trial testing an interferon-free regimen of Gilead Sciences' sofosbuvir (formerly GS-7977) plus ribavirin. Unlike some other DAAs, sofosbuvir does not significantly affect the CYP3A4 enzyme and so does not cause clinically relevant interactions with widely used antiretrovirals.

PHOTON-1 enrolled 114 coinfected patients with HCV genotype 1 (mostly harder-to-treat subtype 1a) who were not previously treated for hepatitis C. They received 400 mg once-daily sofosbuvir plus 1000-1200 mg weight-based ribavirin for 24 weeks. The study also included 26 treatment-naive people with genotype 2 and 42 with genotype 3 who received the same regimen for 12 weeks. About one-third had the favorable IL28B CC gene variant and 4% (genotype 1 and 2) to 14% (genotype 3) had cirrhosis. Participants had well-controlled HIV and more than 90% were on ART.

End-of-treatment response rates were very high: 100%, 96%, and 98%, respectively, for people with genotypes 1, 2, and 3. But about one-quarter relapsed after finishing therapy, resulting in 12-week post-treatment sustained virological response (SVR12) rates of 76%, 88%, and 67%. Sofosbuvir plus ribavirin was generally safe and well-tolerated; about 15% developed anemia.

PHOTON-1 co-investigator Douglas Dieterich from Mt. Sinai School of Medicine said that this regimen "may have the potential to help us overcome the clinical challenge of treating HCV/HIV co-infection."

However, Jean-Michel Pawlotsky from the University of Paris commented that these response rates fell short of those seen in several recent all-oral studies, suggesting that coinfected people may need an additional direct-acting antiviral. Sofosbuvir has shown high response rates with ledipasvir (GS-5885) and GS-9669 in people with HCV alone, and these combinations will likely be tested in coinfected patients in the near future.

Faldaprevir + Pegylated Interferon/Ribavirin
While new direct-acting antivirals will eventually be combined in all-oral regimens, some coinfected people with advanced liver disease may not have time to wait for interferon-free therapy.

In the STARTVerso4 trial, Jürgen Rockstroh from the University of Bonn and colleagues (abstract 1099) tested Boehringer Ingelheim's HCV protease inhibitor faldaprevir (formerly BI 201335) plus pegylated interferon/ribavirin for coinfected people who either were never treated for hepatitis C or relapsed after prior therapy.

This study enrolled 308 genotype 1 coinfected patients who were either on stable ART (96%) or had a high enough CD4 T-cell count that they did not yet need HIV treatment. About one-third had the IL28B CC gene variant, 79% had HCV subtype 1a, and 29% had advanced fibrosis or cirrhosis.

Participants received once-daily faldaprevir with pegylated interferon and weight-based ribavirin. Based on previous drug interaction studies, they were assigned to take either 120 mg or 240 mg faldaprevir depending on which antiretrovirals they were using. Everyone who received 120 mg faldaprevir stayed on triple therapy for 24 weeks. Those who took 240 mg were randomized to 12 or 24 weeks. People who experienced "early treatment success" were randomly assigned to either stop all drugs at 24 weeks or continue on pegylated interferon/ribavirin alone through week 48, as did all patients without early treatment success.

Overall, 74% of patients achieved early sustained response at 4 weeks after completing therapy (SVR4), with rates ranging from 71% for treatment-naive people to 87% for prior relapsers. Furthermore, 80% of randomized participants achieved early treatment success, and among these the SVR4 rate reached 88%. (Relapse can still occur after this point, however; regulators consider SVR12 to indicate a cure.)

SVR4 rates were statistically similar regardless of faldaprevir dose or treatment duration. Unlike some other direct-acting antivirals, SVR4 rates were comparable for people with HCV subtypes 1a and 1b (74% vs 77%) and patients with and without cirrhosis (76% vs. 74%). Response rates did not differ significantly according to ART regimen.

Faldaprevir triple therapy was generally safe and well-tolerated, with a safety profile comparable to that of patients with HCV alone in other studies. One-tenth experienced serious adverse events and 7% discontinued treatment for this reason.

These results "suggest that faldaprevir plus pegylated interferon/ribavirin may become an important option for the treatment of chronic HCV genotype-1 infection in patients coinfected with HIV," the researchers concluded.

Existing Therapy
Response rates in both PHOTON-1 and STARTVerso4 were much higher than cure rates seen in historical clinical trials of pegylated interferon/ribavirin dual therapy for coinfected patients, which exceed response rates in real-world use.

For example, George Ioannou and colleagues (abstract 37) looked at 619 HIV/HCV coinfected U.S. veterans treated with the old standard of care between 2002 and 2007. The overall SVR rate in this real-world analysis was only 17% for genotype 1 patients and 44% for those with genotypes 2 or 3.

Adding one of the first two approved DAAs—the HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek)—to pegylated interferon/ribavirin raises response rates for coinfected people, but these drugs interact with some widely used antiretrovirals and add their own toxicities.

Marisa Montes from Hospital La Paz in Madrid (abstract 38) presented findings from the Phase 3 Spanish INSIGHT trial, in which genotype 1 coinfected people (including 30% with advanced fibrosis or cirrhosis) were treated with telaprevir plus pegylated interferon/ribavirin for 12 weeks. This was followed by pegylated interferon/ribavirin alone through week 24 or 48, determined by response-guided therapy. The ribavirin dose used in this study was 800 mg/day, lower than the standard weight-based dose.

Interim results at treatment week 12—the end of triple therapy—showed response rates ranging from 57% for prior null responders to 80% for treatment-naive patients and 83% for prior partial responders. Safety and tolerability were comparable to previous studies of patients with HCV alone, but with less anemia (15%) using the lower ribavirin dose.

Laurent Cotte and colleagues (abstract 1108) presented the latest findings from the Phase 2 French TelapreVIH trial, looking at 69 genotype 1 HIV/HCV coinfected patients who did not respond to prior pegylated interferon/ribavirin. About one-quarter had cirrhosis, but prior null responders with cirrhosis—the most difficult-to-treat group—were excluded.

Participants used ART regimens that included atazanavir (Reyataz), efavirenz (Sustiva), or raltegravir (Isentress)—antiretrovirals shown to have minimal interaction with telaprevir. They received telaprevir triple therapy for 12 weeks, using a 1000-1200 weight-based dose of ribavirin, followed by pegylated interferon/ribavirin alone for a duration determined by response-guided therapy.

The end-of-treatment response rate at 48 weeks was 83%, with no significant differences according to extent of fibrosis, HCV subtype, type of prior response, or ART regimen. One-quarter discontinued early, mostly due to side effects including anemia.

The companion BocepreVIH study, presented by Isabelle Poizot-Martin and colleagues (abstract 1105), included 64 coinfected individuals; 17% had cirrhosis, and null responders with cirrhosis were again excluded. Due to drug-drug interactions, ART was limited to atazanavir or raltegravir.

Participants received a 4-week lead-in of pegylated interferon and 800-1400 mg/day weight-based ribavirin, followed by boceprevir triple therapy for 44 weeks, with an additional "tail" of pegylated interferon/ribavirin according to response-guided therapy.

At week 48, the end-of-treatment response rate was 56%. Unlike TelapreVIH, in this study response was influenced by HCV subtype (50% for 1a vs. 79% for 1b), type of prior response (ranging from 33% for prior null responders to 90% for prior relapsers) and ART regimen. A larger proportion (45%) stopped treatment early.

Another small study by Teresa Maria Antonini and colleagues (abstract 1959) looked at seven HIV-positive patients who experienced severe HCV recurrence after liver transplantation. They were treated with pegylated interferon/ribavirin plus either telaprevir (five patients) or boceprevir (two patients). After 12 weeks of triple therapy, four telaprevir recipients reached undetectable HCV RNA. The other three patients stopped treatment early. All experienced anemia requiring erythropoietin and ribavirin dose reduction.

Finally, Daniel Fierer from Mt. Sinai Medical Center presented findings from a pilot study testing telaprevir triple therapy for acute hepatitis C in people with HIV. Fierer's team has been following HIV-positive gay and bisexual men with sexually transmitted acute hepatitis C for a decade, reporting that some have experienced unusually rapid liver disease progression.

This open-label study included 34 such men. They were first observed for several weeks to see if they would spontaneously clear HCV, which five did. Nineteen men were treated with telaprevir, pegylated interferon, and weight-based ribavirin for 12 weeks. Seven men could not receive telaprevir (due to genotypes other than 1, lack of insurance coverage, or other reasons) and were included in a comparator group receiving pegylated interferon/ribavirin alone.

The triple therapy response rate was 84% at the end of treatment and again at 12 weeks post-treatment, indicating no relapses. In the pegylated interferon/ribavirin comparator group the SVR12 rate was 63%. Another group of 14 HIV-positive men treated with triple therapy after the initial pilot study had an SVR12 rate of 86%.

Fierer concluded that adding telaprevir improves the cure rate for acute hepatitis in coinfected people and cuts treatment duration in half. But he acknowledged that telaprevir is on its way out, and said he is planning a follow-up study using sofosbuvir.


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Simeprevir (Olysio): FDA Approved!
—Alan Franciscus, Editor-in-Chief

On November 22, 2013 the Food and Drug Administration approved simeprevir—brand name Olysio—and pegylated interferon plus ribavirin for the treatment of HCV genotype 1 patients. 

Simeprevir is a second-generation HCV protease inhibitor that should only be taken with pegylated interferon and ribavirin.

Simeprevir is taken once-a-day (one pill), pegylated interferon is an injectable medication taken once-a-week, and ribavirin consists of pills taken twice-a-day.  There are no food requirements for simeprevir or pegylated interferon.  Ribavirin should be taken with food. 

The viral cure rates ranged from 79% to 81%.  Eighty-five per cent to 93% were able to shorten the treatment duration to 24 weeks. 

More information is available on our website and fact sheets.



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