Liver Meeting Highlights: New Hep C Drugs, NAFLD, Liver Cancer, Acetaminophen Toxicity, Benefits of Coffee
- Category: Hepatitis B
- Published on Monday, 12 November 2012 00:00
- Written by Liz Highleyman
The American Association for the Study of Liver Diseases Liver Meeting is the premier annual U.S. conference on hepatology, covering all aspects of liver disease including viral hepatitis, fatty liver, hepatocellular carcinoma, and liver transplantation. Kicking off the meeting on Saturday, AASLD President Guadalupe Garcia-Tsao offered a media overview of some highlights selected from the more than 2000 abstracts to be presented during the week.
Approximately 10% of Americans have some form of liver disease, making it a major public health burden, Garcia-Tsao noted as background. Over the past few years, experts have warned that advanced liver disease due to hepatitis B and C is increasing -- both in the U.S. and worldwide -- underlining the need for more research, better prevention, and more effective treatments.
Last year's approval of the first hepatitis C virus (HCV) protease inhibitors -- boceprevir (Victrelis) and telaprevir (Victrelis) -- ushered in a new era of treatment, but the near future holds even greater changes.
These first generation drugs, which must be used in combination with pegylated interferon and ribavirin, have approved dose schedules of 3-times-daily, or every 8 hours. This schedule is inconvenient for patients, and missed doses can lead to drug resistance. But the OPTIMIZE trial (presented as a late-breaker poster) found that twice-daily dosing was non-inferior to thrice-daily for previously untreated people with hard-to-treat HCV genotype 1.
Interferon-free HCV Therapy
Numerous pharmaceutical companies are working on combinations of direct-acting agents that target different steps of the HCV lifecycle, allowing potent, all-oral therapy without the difficult side effects of interferon. Garcia-Tsao highlighted 3 such regimens.
Abbott Laboratories is working on an experimental combo of ABT-450 (a ritonavir-boosted protease inhibitor) plus ABT-267 (an NS5A inhibitor) and/or ABT-333 (a non-nucleoside polymerase inhibitor), with or without ribavirin. At an oral late-breaker session on Monday, researchers will present data showing that 12-week combination therapy can produce as-treated sustained response rates up to 99% for treatment-naive patients and 93% for prior null responders with genotype 1 HCV.
Another late-breaker at the same session will provide results from a study of an all-oral regimen combining Bristol-Myers Squibb's promising NS5A replication complex inhibitor daclatasvir, the HCV protease inhibitor asunaprevir, and the non-nucleoside polymerase inhibitor BMS-791325. Again, after 12 week of treatment the short-term 4-week sustained response rate reached 94% for patients new to treatment.
One of the most effective interferon-free regimens tested to date combines daclatasvir plus Gilead Sciences' nucleotide polymerase inhibitor sofosbuvir (formerly GS-7977). While the combo has produced 12-week cure rates up to 100% in some patient groups, Gilead disappointed attendees at the EASL International Liver Congress this past spring when it announced that it would not move forward with further testing of this regimen.
Community advocates speculated that the company would rather pair sofosbuvir with an NS5A inhibitor of its own, likely in a coformulation. Indeed, Gilead announced in a November 10 press release that researchers will present data Tuesday showing that sofosbuvir combined with its NS5A inhibitor GS-5885 and ribavirin yielded a 4-week sustained response rate of 100% for treatment-naive patients. The company added that a Phase 3 study of a fixed-dose combination tablet is underway.
Over years or decades, chronic hepatitis B or C infection can lead to severe liver disease including advanced fibrosis and hepatocellular carcinoma (HCC), a form of primary liver cancer.
Researchers at AASLD will present findings showing that people with chronic hepatitis B do not necessarily have to develop fibrosis before they get liver cancer. While several studies have shown that treatment with nucleoside/nucleotide analogs can reduce the risk of HCC, treated hepatitis B patients can still develop cancer if they are over age 60 or if they had pre-existing liver damage before starting therapy.
Garcia-Tsao suggested that we may be seeing a light at the end of the tunnel for HCC, thanks in part to more widespread hepatitis B vaccination and better hepatitis C treatment. Chemotherapy for liver cancer is also improving. Researchers at AASLD will present data from a randomized controlled trial showing that tivantinib can extend the life of people who previously failed treatment with sorafenib (Nexavar), although survival is still only measured in months.
Acetaminophen overdose is a leading cause of acute liver failure and a major indication for liver transplantation in the U.S. While some overdoses are suicide attempts, a recent study found that many patients take accidental overdoses because they do not realize how many products contain the drug.
In addition to Tylenol and its generic equivalents, acetaminophen is also an ingredient in several prescription pain-relievers (for example, combined with oxycodone in OxyContin and Percocet, and with hydrocodone in Vicodin), as well as a plethora of over -the-counter cold, flu, and cough remedies.
A survey showed that many people were not aware that their medications contained acetaminophen, presenting a risk of unintentional "double dipping." Garcia-Tsao noted that drug labels can be confusing and inconsistent (with acetaminophen going by other names including paracetamol and APAP) and that provider communication about this issue is often inadequate.
Also on the acetaminophen front, another AASLD presentation will describe a study showing that people who undergo bariatric surgery for weight loss are at increased risk for acute liver failure due to acetaminophen poisoning.
Non-alcoholic fatty liver disease (NAFLD) is a major -- and growing -- cause of liver disease, with prevalence increasing in conjunction with the U.S. and global obesity epidemics. Garcia-Tsao explained that NAFLD is the third most common cause of HCC, and people with fatty liver disease can develop liver cancer even in the absence of liver fibrosis.
A growing body of evidence links obesity, diabetes, and metabolic syndrome with NAFLD. Researchers at this week's conference will present findings from a mouse study showing that obese mothers can confer a propensity for developing NAFLD to their offspring, which is related to disruption of circadian rhythms, or the body's biological clock.
But the news is not all bad: A study of nearly 800 adults showed that coffee consumption was associated with a lower risk of serious liver fibrosis among people with NAFLD who did not have insulin resistance.
"The potential for beneficial effects of coffee is becoming more evident," said Garcia-Tsao. This research shows that not only genetic factors, but also environmental factors influence development of NAFLD and its complications.
M Buti, A Kosh, YJ Horsmans, et al. OPTIMIZE trial: Non-inferiority of twice-daily telaprevir versus administration every 8 hours in treatment-naïve, genotype 1 HCV infected patients. AASLD 2012. Abstract LB-8.
K Kowdley, E Lawitz, F Poordad. A 12-Week Interferon-free Treatment Regimen with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-Naive Patients and 93% in Prior Null Responders with HCV Genotype 1 Infection. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract LB-1.
GT Everson, KD Sims, M Rodriguez-Torres, et al. An Interferon-free, Ribavirin-free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of 94% in Treatment-Naive Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection. AAISLD 2012. Abstract LB-3.
MS Sulkowski, DF Gardiner, M Rodriguez-Torres, et al.High Rate of Sustained Virologic Response with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naïve Patients Chronically Infected With HCV Genotype 1, 2, or 3. AASLD 2012. Abstract LB-2.
I Borbath, C Porta, L Rimassa, et al. Randomized Controlled Phase 2 Study (RCT) with Tivantinib in pre-treated hepatocellular carcinoma (HCC): Efficacy, Safety, and MET-analysis. AASLD 2012. Abstract 114.
M Serper, JP King, MS Wolf, et al. Active Ingredient Confusion for Acetaminophen-Containing Medications: A Cause of Double Dipping. AASLD 2012. Abstract 1906.
EW Holt and TJ Davern. Prior Bariatric Surgery Increases the Risk of Acute Liver Failure from Acetaminophen Poisoning. AASLD 2012. Abstract 4.
K Bambha, L Wilson, A Unalp et al. Coffee Consumption in NAFLD Patients with Lower Insulin Resistance is Associated with Lower Risk of Severe Fibrosis. AASLD. Abstract 99.
Gilead Sciences. Gilead Announces 100 Percent Sustained Virologic Response Rate (SVR4) for an Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C Infected Patients. Press release. November 10, 2012.