Low risk of adverse events

Direct-acting antiviral (DAA) drugs do not appear to increase the risk of treatment-related adverse events in patients with chronic hepatitis C virus (HCV) infection and may even decrease this risk, depending on new data.

An examination of the results of a retrospective cohort of 33,808 patients with chronic HCV from three health care systems showed that patients treated with DAAs did not experience higher rates of adverse events in none of the categories considered, in particular hepatic, renal, cardiovascular or oncological. events.

ADA treatment also does not appear to increase the use of urgent, emergent or inpatient health care services, or be linked to reactivation of the hepatitis B virus (HBV), writes Elizabeth A. McGlynn , PhD, from Kaiser Permanente Research in Pasadena, California, and colleagues. The researchers report their findings in an article published online today in JAMA Network open now.

The authors note that patients receiving DAAs had consistently lower adverse event rates than those who did not receive treatment. However, they caution against the presumption of protective effect, due to the possibility of a selection bias in the study.

To estimate the risk of adverse events, McGlynn and her colleagues reviewed reimbursement claims and clinical data from January 1, 2012 to December 31, 2017 from three health care systems to identify patients who were elderly. 18 to 88 years in whom HCV infection and for whom HCV RNA or genotyping indicated an active infection.

They then compared the rates and types of adverse clinical events and the use of health care services over a 6-month period in patients to whom an AAD had been prescribed and those who did not. had not been. Specific outcomes of interest included death, multiple organ failure, liver cancer, hepatic decompensation, acute hepatic event on chronic, acute myocardial infarction (AMI), an accident ischemic or hemorrhagic cerebrovascular, arrhythmia, acute renal failure, cancer other than cancer and HBV reactivation, as well as hospitalizations and visits to the emergency.

In addition to time-event badysis, the investigators used marginal structural modeling to control confusion by indication. According to the author of an accompanying comment, this is an important element to take into account because some of the undesirable effects measured may have been not related to the treatment, but could have been caused by the actual HCV infection.

"Patients who receive DAAs inevitably differ from patients who do not receive them in a way that could potentially affect their risk of experiencing an adverse outcome during the treatment period," writes Lauren A. Beste, MD , from the VA Puget Sound Health System in Seattle, Washington, in the commentary. "The methods of study help overcome the biases inherent in large drug safety observational studies by minimizing the problem of confusion by indication to the extent that it is statistically feasible," she said. declared.

With a follow-up of 7207.2 person-years in the DAA group and 64 823.5 person-years in the non-DAA group, unadjusted and outcome-adjusted badyzes favored the DAA group.

The odds ratios (AOR) adjusted in the DAA group vs. non-DAA were 0.42 (95% confidence interval). [CI], 0.30 to 0.59) for death, 0.67 (95% CI, 0.49 – 0.90) for multiple organ failure, 0.61 (95% CI, 0.49 – 0). , 76) for hepatic decompression, 0.71 (95% CI, 0.56 – 0.91) for chronic liver and 0.47 (95% CI, 0.25 to 0.88) for 39; arrhythmia.

The AORs for liver cancer and AMI differed by health system. In two health care systems, the adjusted probabilities were significantly lower in the DAA group compared to the non-DAA group (0.51, 95% CI, 0.32 to 0.80 in system 1 and 0.44). 95% CI, 0.26 to 0.74 in system 2). In the third system, the badysis also suggested a lower risk with DAAs, but the difference did not reach statistical significance (aOR, 1.45, 95% CI, 0.65 – 3 , 22). For AMI, the only statistical difference was observed in system 2 (aOR, 0.41, 95% CI, 0.20 to 0.83).

Utilization of health resources was lower in patients treated with DAAs, for whom adjusted rate ratios were significantly lower for hospitalizations (0.71, 95% CI, 0.60 to 0, 84) and emergency visits (0.82, 95% CI, 0.77 – 0.87).

Constant trends in the different types of adverse events are expected to help alleviate concerns about the safety of DAAs from clinical trials in highly selected cohorts, according to the authors.

"Since clinical trials are generally conducted on participants whose demographic and health profiles differ from those of patients to whom drug therapy is proposed, the results of post-marketing studies, such as this one, based on Real-world patients and their experiences can contribute to a richer source of information for shared decision-making, "explain the authors.

The patient population in the current study was more racially and ethnically diverse than in most clinical trials conducted to date. The current study included patients with history or comorbidities who generally exclude enrollment in clinical trials. These factors include a history of liver cancer, liver transplantation or cirrhosis.

The lower risk of adverse events in the ADF group is particularly noticeable, writes Beste in his commentary, because "[p]Patients treated for HCV probably have more contact with the health system and closer monitoring of laboratory results, imaging and other diagnostic tests during their treatment. "

Clinicians need to consider these results to raise awareness about the risks and benefits of DAAs in treating HCV. "The long-term benefits of HCV treatment have been widely reported and include lower mortality, lower risk of liver cancer, and improved quality of life for patients in health," Beste writes. "Although no retrospective study of adverse drug effects can completely eliminate treatment selection bias, the findings of McGlynn and colleagues can help comfort clinicians in ensuring that treatment with DAA is not badociated with excessive risk to patients. "

The study was funded by the Center for Patient Centered Outcome Research (PCORI). McGlynn and co-author Elizabeth Shenkman, MD, have received funding for further research from PCORI. A co-author has received grants from Bristol-Myers Squibb, Allergan, Gilead and AbbVie. Another co-author received grants from AbbVie, Merck and Gilead during the conduct of the study and holds shares in Target PharmaSolutions. Beste did not reveal any relevant financial relationship.

JAMA Netw Open. Posted online June 7, 2019. Full text, commentary

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