Welcome to HCV Advocate’s hepatitis blog. The intent of this blog is to keep our website audience up-to-date on information about hepatitis and to answer some of our web site and training audience questions. People are encouraged to submit questions and post comments.

For more information on how to use this blog, the HCV drug pipeline, and for more information on HCV clinical trials
click here

Be sure to check out our other blogs: The HBV Advocate Blog and Hepatitis & Tattoos.


Alan Franciscus

Editor-in-Chief

HCV Advocate



Showing posts with label CROI. Show all posts
Showing posts with label CROI. Show all posts

Friday, April 3, 2015

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

Monday, February 23, 2015

Results from AbbVie's Study of VIEKIRA PAK™ (ombitasvir, paritaprevir, ritonavir tablets; dasabuvir tablets) in Chronic Hepatitis C Patients with HIV-1 Co-Infection (TURQUOISE-I) Published Online in JAMA; Sub-analyses to be Presented at the Annual Conference on Retroviruses and Opportunistic Infections (CROI)

- In adult patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1), TURQUOISE-I, using VIEKIRA PAK with ribavirin (RBV), demonstrated sustained virologic response rates 12 weeks post-treatment (SVR12) of 94 percent with 12 weeks of treatment and 91 percent with 24 weeks of treatment, respectively

 - TURQUOISE-I results published online today in The Journal of the American Medical Association (JAMA) - 

Additional sub-analyses of TURQUOISE-I data to be presented this week at the Annual Conference on Retroviruses and Opportunistic Infections (CROI)



NORTH CHICAGO, Ill., Feb. 23, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that results from part one of the Phase 2 portion of its Phase2/3 open-label study, TURQUOISE-I, in genotype 1 chronic hepatitis C patients with human immunodeficiency virus type 1 (HIV-1) co-infection were published online in The Journal of the American Medical Association (JAMA). Additional sub-analyses also will be presented in both oral and poster presentations on Feb. 26, at the Annual Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Wash.

As published today in JAMA, and originally presented at The Liver Meeting® 2014, the TURQUOISE-I study showed patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) and HIV-1 receiving VIEKIRA PAK™ and ribavirin (RBV) for 12 weeks or 24 weeks achieved sustained virologic response rates 12 weeks post-treatment (SVR12) of 94 percent (n=29/31) and 91 percent (n=29/32), respectively. The SVR12 rates were 91 percent (n=51/56) for subjects with HCV GT1a infection and 100 percent (n=7/7) for those with HCV GT1b infection.

"It is common for people to live with both GT1 chronic HCV and HIV, but data supporting treatment of chronic HCV in these co-infected patients have been limited," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "TURQUOISE-I is one of the few dedicated studies looking specifically at this historically difficult-to-treat population and we are proud to offer the HCV community an important new treatment option."

VIEKIRA PAK is contraindicated with efavirenz (Sustiva) because co-administration is poorly tolerated and results in liver enzyme elevations. The ritonavir component of VIEKIRA PAK is an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance. To reduce this risk, HCV/HIV-1 co-infected patients should also be on a suppressive antiretroviral (ART) drug regimen. The most common adverse events occurring in at least 10 percent of patients in TURQUOISE-I were fatigue (48%), insomnia (19%), nausea (17%), headache (16%), itching (13%), cough (11%), irritability (10%), and yellowing of the eyes (10%).

Sub-analyses of these data will be presented later this week at CROI in oral and poster presentations:
  • High SVR Regardless of Time to Suppression with Paritaprevir/r/Ombitasvir & Dasabuvir + RBV Oral Presentation #147
    February 26, 2015, 10:30-10:45 p.m. PST, Room 6AB 
    Analysis of time to HCV suppression in HCV/HIV co-infected patients in TURQUOISE-I
  • Hematologic Analysis of Paritaprevir/r/Ombitasvir and Dasabuvir + RBV in TURQUOISE-I Poster #691
    February 26, 2015, 2:30-4 p.m. PST, Poster Hall 
    In this analysis of the TURQUOISE-I study, certain laboratory values in patients taking paritaprevir/r/ombitasvir and dasabuvir with RBV were examined, including hemoglobin, CD4+ T cells, and lymphocyte count
About TURQUOISE-I  TURQUOISE-I is an ongoing Phase 2/3, multi-center, randomized, open-label study evaluating the efficacy and safety of VIEKIRA PAK (ombitasvir, paritaprevir, ritonavir (25/150/100 mg once daily) and dasabuvir (250 mg twice daily) with RBV (weight based dosing of 1000 mg or 1200 mg per day divided twice daily) for 12 or 24 weeks in adult patients with chronic GT1 HCV infection with or without compensated liver cirrhosis who are also infected with HIV-1.

Study patients were either new to therapy (treatment-naïve) or had failed previous treatment with pegylated interferon and RBV (treatment-experienced), had a stable immune status (CD4+ counts of ≥200 cells/mm3 or CD4+ % ≥14%). Patients were on a stable HIV-1 ART regimen that included tenofovir disoproxil fumarate plus emtricitabine or lamivudine, administered with ritonavir-boosted atazanavir or raltegravir. Patients on atazanavir stopped the ritonavir component of their HIV-1 ART regimen upon initiating treatment with VIEKIRA PAK + RBV. Atazanavir was taken with the morning dose of VIEKIRA PAK. The ritonavir component of the HIV-1 ART regimen was restarted after completion of treatment with VIEKIRA PAK and RBV. Of the five patients who were non-responders, one experienced virologic failure, one discontinued treatment, one experienced relapse and two patients had evidence of HCV reinfection post-treatment. Based on the results of this study, prescribers should follow the same dosing recommendations for mono-infected patients as outlined in the VIEKIRA PAK prescribing information.

Elevations in total bilirubin were the most common laboratory abnormality, were mainly composed of indirect bilirubin, and were not associated with elevations in commonly measured liver enzymes. Reductions in RBV dose because of anemia or reduced hemoglobin occurred in 10 percent of patients (n=6/63); all six patients achieved SVR12.