FDA approves the first new drug for the treatment of Influenza in nearly 2 decades

The U.S. Food and Drug Administration (FDA) today approved Roche Xofluza ™ (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

 “This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. With thousands of people getting the flu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical. This novel drug provides an important, additional treatment option,” said FDA Commissioner Scott Gottlieb, M.D. “While there are several FDA-approved antiviral drugs to treat flu, they are not a substitute for yearly vaccination. Flu season is already well underway, and the U.S. Centers for Disease Control and Prevention recommends getting vaccinated by the end of October, as seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family and your community from the flu and serious flu-related complications, which can result in hospitalizations. Yearly vaccination is the primary means of preventing and controlling flu outbreaks.”

Influenza is a severe infectious disease worldwide with annual epidemics of 3 to 5 million cases of severe disease, millions of hospitalizations and up to 650,000 deaths worldwide.

Xofluza is a first-in-class, single-dose oral medicine and acts by inhibiting the polymerase acidic endonuclease, an enzyme essential for viral replication. It has shown efficacy against a wide range of influenza viruses, including oseltamivir-resistant strains and avian strains (H7N9, H5N1) in non-clinical studies.

The safety and efficacy of this single dose, antiviral drug Xofluza, was proved by the results of two randomized controlled clinical trials of 1,832 patients recently published in the 6 September 2018 issue of the New England Journal of Medicine. In phase III CAPSTONE-1 trial, participants were randomized to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms.

Xofluza significantly reduced the duration of flu symptoms by more than one day (median time 54 hours versus 80 hours; p<0.001) as compared to placebo. The efficacy was comparable to oseltamivir when it comes to duration of symptoms, but Xofluza significantly reduced the viral load 1 day after the start of therapy.

In the other phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05).

Thus, single-dose baloxavir was superior to placebo in alleviating influenza symptoms and was superior to both oseltamivir and placebo in reducing the viral load one day after initiation of the trial regimen in patients with uncomplicated influenza.

The most common adverse reactions in patients taking Xofluza included diarrhea and bronchitis, nausea, common cold symptoms (nasopharyngitis) and headache.

 FDA approved Xofluza under priority review, and the drug will be available across the U.S. in the coming weeks. Xofluza was discovered by Japanese drug maker Shionogi & Co., Ltd and was its 10mg/20mg tablets were approved by the Ministry of Health, Labour and Welfare in Japan in February 2018 for the treatment of Influenza Types A and B. 

The drug is being further developed and commercialized globally in collaboration with the Roche Group (which includes Genentech in the US). Under the terms of this agreement, Roche holds worldwide rights to Xofluza excluding Japan and Taiwan, which will be retained exclusively by Shionogi & Co., Ltd.

FDA press release

Roche press release

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Society for Maternal-Fetal Medicine (SMFM) recommendations for screening, treatment, and prevention of vertical transmission of Hepatitis B in pregnancy

The Primary source of this article is the recommendation published by Society for Maternal-Fetal Medicine (SMFM) for screening, treatment and prevention of vertical transmission of Hepatitis B in the January issue of American Journal of Obstetrics and Gynecology by Dionne-Odom J. et al.

DOI: http://dx.doi.org/10.1016/j.ajog.2015.09.100

Nearly 240 million people worldwide are infected with hepatitis B virus (HBV).

Specific to pregnancy, an estimated prevalence of 0.7-0.9% for chronic hepatitis B infection among pregnant women in the United States has been reported, with >25,000 infants at risk for chronic infection born annually to these women.

While transmission through sexual intercourse and intravenous drug abuse are the major risk factors for acquisition of hepatitis B among adults in the United States, perinatal transmission is responsible for up to 50% of HBV infection worldwide

Vertical transmission of HBV from infected mothers to their fetuses or newborns, either in utero or peripartum, remains a major source of perpetuating the reservoir of chronically infected individuals globally.

From a global public health perspective, chronic HBV infection is the major source of hepatocellular carcinoma, leading to 50% of cases worldwide and 80% in high-endemic areas for HBV.

In contrast to HBV acquisition in adulthood, which more commonly leads to acute resolved infection and immunity, perinatal/neonatal HBV is more likely to lead to chronic infection and its long-term disease risks. Chronic hepatitis B infection will develop in up to 90% of exposed neonates who do not receive appropriate immunoprophylaxis, in contrast to 10-25% of infected children and only 5-10% of exposed immunocompetent adults.

Identification of pregnant women with chronic HBV infection through universal screening has had a major impact in decreasing the risk of neonatal infection. Recent data demonstrate that 95% of pregnant women are currently screened prior to delivery for evidence of chronic HBV infection, with rates of perinatal transmission decreasing significantly over the past 2 decades.

The recommendation of Society for Maternal-Fetal Medicine (SMFM) for screening, treatment and prevention of vertical transmission are:

(1) Perform routine screening during pregnancy for HBV infection with maternal HBsAg testing (grade 1A).

(2) Administer hepatitis B vaccine and HBV immunoglobulin within 12 hours of birth to all newborns of HBsAg-positive mothers or those with unknown or undocumented HBsAg status, regardless of whether maternal antiviral therapy has been given during the pregnancy (grade 1A).

(3) In pregnant women with HBV infection, suggest HBV viral load testing in the third trimester (grade 2B).

(4) In pregnant women with HBV infection and viral load >6-8 log 10 copies/mL, HBV-targeted maternal antiviral therapy should be considered for the purpose of decreasing the risk of intrauterine fetal infection (grade 2B).

(5) In pregnant women with HBV infection who are candidates for maternal antiviral therapy, tenofovir should be used as a first-line agent (grade 2B).

 (6) It is  recommend that women with HBV infection be encouraged to breast-feed as long as the infant receives immunoprophylaxis at birth (HBV vaccination and hepatitis B immunoglobulin) (grade 1C).

 (7) HBV infected women who have an indication for genetic testing, invasive testing (eg amniocentesis or chorionic villus sampling) may be offered–counseling should include the fact that the risk for maternal-fetal transmission may increase with HBV viral load >7 log 10 IU/mL (grade 2C).

(8) Cesarean delivery should not be performed for the sole indication for reduction of vertical HBV transmission (grade 2C).

Issues to be considered in a pregnant woman diagnosed as a chronic HBV carrier?

The majority of pregnant women diagnosed with chronic HBV infection will be asymptomatic and identified through routine screening with initial prenatal laboratory tests.

Identification of a pregnant woman as chronically HBV infected also presents an important opportunity to counsel her regarding risks to other family and household members. HBV is most easily transmitted via sexual exposure or blood exposure but can also be transmitted through casual shared use of household items such as eating utensils and toothbrushes, as well as through personal contact such as kissing or routine childcare. Therefore, family and household members should be evaluated for HBV status and referred for vaccination if found to be uninfected and nonimmune.

The pregnant woman herself should also be assessed for immunity status for hepatitis A and offered vaccination if not immune, since coinfection with another viral hepatitis results in compounded morbidity.

To aid in counseling regarding risks and potential management options as outlined above, baseline LFTs should also be drawn when a positive HBsAg test result is obtained, along with a baseline quantitative HBV-DNA level.

The woman should also be counseled regarding exposures to potentially hepatotoxic medications, even those available over the counter, such as acetaminophen, and to avoid the use of alcohol even when not pregnant.

Even if the maternal viral load is low and antiviral therapy during pregnancy is not recommended, the newborn should still receive standard prophylaxis with HBIG and HBV vaccine within 12 hours of birth, and ongoing surveillance of the woman’s hepatic function after pregnancy is indicated.

References:

Hepatitis B in pregnancy screening, treatment, and prevention of vertical transmission.Dionne-Odom, Jodie et al. American Journal of Obstetrics & Gynecology, Volume 214, Issue 1, 6 - 14