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DAA use decreases risk for cardiovascular events in patients with advanced fibrosis, HCV

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Lam L, et al. Abstract OS006. Presented at: International Liver Congress; June 22-26, 2022; London (hybrid meeting).

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Healio was unable to confirm relevant financial disclosures at the time of publication.


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LONDON — Direct-acting antiviral treatment correlated with a decreased risk for cardiovascular outcomes among patients with hepatitis C virus and advanced fibrosis but an increased risk for arrhythmias and conduction disorders.

“Several studies have revealed that hepatitis C virus can induce chronic inflammation and immune dysregulation, and this immune dysregulation and chronic inflammation explained the development of extrahepatic manifestations in chronic hepatitis C patients, including cardiovascular disease,” Laurent Lam, MD, a physician and doctoral researcher at the Pierre Louis Institute of Epidemiology and Public Health at Sorbonne University in Paris, told attendees at the International Liver Congress. “Few data are available regarding the long-term impact of DAAs on the occurrence of non-liver events.”

Using the prospective ANRS CO22 HEPATHER cohort, which derived individual data from the French National Health Insurance Database, Lam and colleagues analyzed 8,148 patients with chronic HCV between August 2012 and December 2015 for cardiovascular events and cancer incidence. The primary outcome was the association between DAA use and extrahepatic events.

Among 22,326 and 12,905 person-years of DAA and no DAA exposure, analysis showed DAA exposure correlated with a reduced risk for peripheral arterial disease (HR = 0.54; 95% CI, 0.33-0.89), an overall beneficial effect on cardiovascular among patients with HCV/advanced fibrosis (adjusted HR = 0.58; 95% CI, 0.42-0.79) and an increased risk for arrhythmias and conduction disorders (HR = 1.46; 95% CI, 1.04-2.04).

Lam and colleagues observed no association between DAA use and extrahepatic cancer (HR = 1.23; 95% CI, 0.5-3.03).

“Direct-acting antiviral exposure reduced the risk for peripheral arterial disease, overall cardiovascular events and increased risk for arrhythmias and conduction disorders,” Lam concluded. “Direct acting antivirals are not associated with extrahepatic cancer development or reduction in our study.”

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Fatigue in patients with advanced NASH may increase risk for adverse events

HGI0522Younossi_Graphic_01


Disclosures:
The study was funded by the Center for Outcomes Research in Liver Diseases and Gilead Sciences.


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Worse fatigue at baseline among patients with nonalcohol steatohepatitis-related advanced fibrosis and cirrhosis correlated with a higher risk adverse clinical events, according to published results.

“Although generally considered asymptomatic, almost half of patients with NASH have clinically significant fatigue which, in turn, has a profound negative impact on the overall patient experience,” Zobair M. Younossi, MD, president of Inova Medicine Services and professor and chairman of the department of medicine at Inova Fairfax Medical Campus in Virginia, and colleagues wrote in Clinical Gastroenterology and Hepatology. “In this context, ongoing clinical trials aim at finding a drug-based therapy for NASH that may reverse fibrosis and could also potentially improve fatigue. Given that, patient-reported outcome instruments are now commonly included in these trials in order to provide a comprehensive assessment of the impact of the investigational drugs on patients and their experience.”


HGI0522Younossi_Graphic_01



For 2 years, Younossi and colleagues followed 1,679 patients with biopsyconfirmed NASH, 802 had bridging fibrosis (F3) and 877 compensated cirrhosis (F4). Fatigue was quantified at baseline with the Chronic Liver Disease Questionnaire (CLDQ)- NASH fatigue domain. Time to liver-related clinical eventssuch as progression to histologic cirrhosis or hepatic decompensation in F3F4 was assessed with Cox proportional hazard model.

median follow-up of 16 months, 15% (n=123) of NASH F3 patients experienced liver-related events and 3.5% (n=31) of NASH F4 patients experienced hepatic decompensation. Among F3 patients, the mean baseline CLDQ-NASH fatigue score was 4.77hose who experienced liver-related events lower baseline scores 4.47 4.83. Among patients withF4, the mean fatigue score was 4.56 who decompensated3.74 4.59.

fter for confounders, correlation between lower fatigue scores and risk liver-related or decompensation events adjusted HR 0.85, per 1 point in fatigue score in F3; aHR = 0.62 in F4.

“This suggests that, in addition to commonly used clinical parameters, presence of clinically significant fatigue can identify NASH patients at risk for adverse events,” the authors wrote. “Since fatigue also negatively impacts patients [health-related quality of life] and work productivity, it adds to the disease burden related to NASH. Given the critical importance of fatigue in NASH, clinical trials of regimens for NASH should not only show improvement of surrogates of clinical endpoints, such as the stage of fibrosis or resolution of NASH, but also improvement in patient-reported endpoints, such as fatigue.”

 

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Adverse Events with IO-TKI Combination Regimens for Advanced RCC and Their Management

Adverse Events with IO-TKI Combination Regimens for Advanced RCC and Their Management

Arnab Basu, MD: Dr Anakwah, can you please talk about the dosing for lenvatinib and pembrolizumab in your practice? What is a typical starting dose, and how does it compare to the CLEAR trial?

Shawnta Anakwah, MD: I haven’t had a lot of experience, but the patients I’ve tried it on, typically my patients are more frail, have a lot more comorbid conditions. One particular patient I had was on dialysis but she had a very high disease burden, so I started her lenvatinib dose at 10 mg instead of 20 mg as per the CLEAR trial. She tolerated it very well. I tend to start lower and then try to titrate up in my patient population.

Arnab Basu, MD: That’s a great strategy.

Shawnta Anakwah, MD: Exactly.What are the commonly observed adverse effects with IO/TKI [immunotherapy/tyrosine kinase inhibitor] combinations, and how do you manage them in your clinical practice?

Arnab Basu, MD: Good question. The adverse effects of combination therapy would be from the VEGF inhibitor or from the systemic immunotherapy. Speaking of VEGF adverse effects, hypertension is very common, and I try to see if the patient can tolerate a calcium channel blocker. This appears to be the mechanism of choice for VEGF-mediated hypertension. We do a nitric oxide release. I use that as a first-line agent. As a second line, I try to use an ACE [angiotensin-converting enzyme] inhibitor based on patient comorbidities, if possible. Other than hypertension, fatigue is unfortunately a difficult problem, and there’s no good way to address that other than through dose reductions or sometimes through some regimens that are friendlier to the patient, like taking a few days off of therapy, for example.

For stomatitis, which our patient here had, I typically use a dexamethasone mouthwash, 0.5 mg twice a day. The data for this come from some of the mTOR inhibitor trials, although there are some data in VEGF inhibitors as well. It is important not to swallow, as this can impair the TKI absorption. And you must be careful in prescribing, especially in patients with a likelihood of future fungal infections or viral infections. If you don’t want to use dexamethasone, you could certainly use magic mouthwash, or viscous lidocaine in these patients for mild symptoms. Another VEGF adverse effect is hand-foot syndrome. I suggest using moisturizers for mild symptoms. For moderate symptoms, I do some dose reductions or interruptions as necessary. And for GI [gastrointestinal] effects like diarrhea, Imodium is usually the first one, then Lomotil.

In regard to immunotherapy adverse effects, as you know, these are varied and unpredictable, but recognizing these early and intervening with steroids is associated with the best outcomes, in my experience. Dr Anakwah, when do you dose reduce some of these TKIs such as lenvatinib?

Shawnta Anakwah, MD: I try to reserve it for patients who have severe adverse effects, to the point where it’s affecting their quality of life. I agree with the management of the stomatitis. With patients, typically I’ll interrupt the dose, treat them with the supportive care, and then once their symptoms resolve or improve, I typically would try to start them at a lower dose.

Arnab Basu, MD: Do you ever revert their dose to their starting dose?

Shawnta Anakwah, MD: Typically, I don’t. From my understanding, in clinical trials, when patients have adverse effects and must be dosed reduced, typically they don’t dose escalate back up in the trials. It’s not allowed.

Arnab Basu, MD: Absolutely, this is why there’s no grade 1 evidence in this field. This is always an important question because we do think that the dose density of the TKI would be important in clinical outcomes. But once someone has demonstrated they’re not tolerating that dose, perhaps keeping going on that would essentially lead to the same problem down the line again. That’s a great point.

Transcript edited for clarity.