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

Ob/Gyn Updated Facebook page

ACOG releases new all-in-one resource on vaccinations in pregnancy

ACOG recently released the new all-in-one resource to help obstetrics care provider ensure that all pregnant women receive the vaccines they need—not only protect themselves but also their unborn child again preventable diseases.

ACOG recommends that all obstetrician should routinely assess the immunization status of their pregnant patients and address their concerns about vaccine safety during prenatal visits.

"Studies consistently demonstrate that when the recommendation and availability of vaccination during pregnancy comes directly from a woman's obstetrician or other obstetric care providers, the odds of vaccine acceptance and receipt are 5-fold to 50-fold higher," write the authors of ACOG committee opinion on vaccination.

During the first prenatal visit, the provider should assess the woman’s immunity status against rubella and varicella. If the woman is not immunized against measles-mumps-rubella (MMR) or varicella, she needs to get these vaccines in the postpartum period, because both the MMR and varicella vaccines are live attenuated vaccines and are contraindicated in pregnancy.

Women who are pregnant during influenza season should receive the flu vaccine during each pregnancy. Other vaccines that are to be given during each pregnancy are tetanus toxoid, reduced diphtheria toxoid and acellular pertussis given as early as possible in the 27 to 36 weeks of gestation window.

All live attenuated vaccines are contraindicated in pregnancy while inactivated virus, bacterial vaccines, or toxoids are entirely safe in pregnancy as indicated by a growing body of research data.

Vaccines that are given in every pregnancy

Inactivated Influenza

Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap)

Maybe given in pregnancy in particular population

Pneumococcal vaccine

Hepatitis A

Meningococcal disease

Hepatitis B

Contraindicated in pregnancy

Measles-mumps-rubella (MMR)

Varicella

Initiated during the postpartum period or when breastfeeding or both

HPV vaccination series

Inactivated Influenza

Tetanus toxoid reduced diphtheria toxoid and acellular pertussis (Tdap)

Pneumococcal vaccine

Hepatitis A

Meningococcal disease

Hepatitis B

Measles-mumps-rubella (MMR)

Varicella

Vaccines in development

Some vaccines that can significantly reduce infectious disease in neonates are in the process of development and are likely to become part of the maternal/newborn arsenal shortly. It includes:

Streptococcus agalactiae, or group B Streptococcus (GBS)

Respiratory syncytial virus (RSV)

ACOG committee opinion

Ob/Gyn Updated Facebook page

ACOG updates its recommendations on Influenza Vaccination During Pregnancy

The American College of Obstetricians and Gynecologists (ACOG) updated it committee opinion on influenza vaccination in pregnancy and post-exposure prophylaxis. This was published April 2018 and replaces Committee Opinion Number 608, September 2014.

This updated committee opinion is based on data that showed that only 54% of pregnant women in the USA were vaccinated during the 2016-2017 influenza season. This number needs to be worked on as the U.S. Health and Human Services’ Healthy People 2020 goal is vaccinating 80% of pregnant women against influenza.

Pregnant women are particularly susceptible to influenza infection and its resulting morbidities; therefore, influenza vaccination is an integral element of pre-pregnancy, prenatal, and postpartum care.

ACOG makes the following recommendations:

1) The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices and ACOG recommend that all adults receive an annual influenza vaccine. In addition, women who are pregnant or will be pregnant during the influenza season receive an inactivated influenza vaccine as soon as it is available.

2) Any of the licensed, recommended, inactivated influenza vaccine is safe during any trimester. Obstetrician-gynecologists and other health care providers should play an active part in counseling all pregnant women about the safety of influenza vaccine in pregnancy and its importance in protecting the newborn against the flu because of passive immunity.

3) It is recommended that every Obstetrician-gynecologist must get a flu vaccine every year and keep a stock of the vaccines in her office. If she is unable to provide the vaccination services, she should refer the patient to other provider, pharmacies or hospitals.

4) Patients who are allergic to egg and have had only hives can receive any licensed and recommended influenza vaccine that is otherwise appropriate for their age and health status.

5) In case the allergy symptoms are more serious than hives, the vaccine should be administered in an inpatient or outpatient medical setting including hospitals, clinics and physician offices.

6) Patients with flu-like illness should be started on antiviral medications, presuming it to be influenza. The provider should start the antiviral treatment based on clinical evaluation and not solely rely on the lab results.

7) All the office and hospital staff should also be encouraged to receive an influenza vaccine every year.

8) All pregnant women and women who are up to 2 weeks postpartum exposed to influenza virus because of close contact with an influenza patient should be started on post-exposure antiviral chemoprophylaxis (75 mg of oseltamivir once daily for 10 days). If oseltamivir is unavailable, zanamivir can be substituted, two inhalations once daily for 10 days.

Committee opinion

 Media courtesy: March of Dimes

Novel flu drug that kills the virus in 1 day get clearance in Japan

Japanese pharmaceutical company Shionogi claims that treatment with baloxavir marboxil, effectively kills influenza A and B virus in just 24 hours as opposed to the current user oseltamivir (sold under the brand name Tamiflu), which takes 72 hours to kill the virus.

Japan’s health ministry recently approved the drug and will be sold under the brand name Xofluza.

This is a welcome announcement in healthcare and pharma industry, in the midst of worst Flu season that the USA has experienced. Probably it could make the next flu season safer.  

Baloxavir marboxil prevents the replication of the virus by cap-dependent endonuclease activity of the viral polymerase unlike the existing drug oseltamivir (Tamiflu, Genentech), which acts by inhibiting the neuraminidase enzyme.

It’s prescription as single dose treatment irrespective of age greatly improves patients’ compliance as opposed to the twice-daily dose of oseltamivir for 5 days.

Baloxavir marboxil was tested in a randomized, double-blind, parallel-group, multicenter, placebo- and active-controlled study (CAPSTONE-1), which enrolled 1,436 otherwise healthy patients diagnosed with influenza. 

These patients with age between 20-64 years were randomized in a ratio of 2:1:2 to receive a single 1-time oral dose of 40 or 80 mg of baloxavir marboxil based on body weight or a placebo, or 75 mg BID of oseltamivir for 5 days.

Patients between 12-19 years of age were given baloxavir marboxil based on body weight. Those who weighed less than 80 kg received 40 mg of the drug while patients weighing more than 80 kg were given 80 mg.

The trial results showed that:

•   Patients who received Baloxavir marboxil had significantly lower viral titer at 1, 2 and 4 days
• Viral shedding in Baloxavir marboxil group was significantly less at 24 hours as compared to 72 hours in patients on oseltamivir and 96 hours in patients on placebo.
• The patients in the study group were afebrile in 24 hours vs 42 hours in the placebo group.
• The time to alleviation of symptoms (TTAS) was significantly shortened in the study group (53.7 hours) vs (80.2 hours) in the placebo group (p<0.0001). 
• The new drug was also well tolerated with significantly fewer side effects (20.7%) as compared to placebo (24.6%) or oseltamivir (24.8%).  

Shionogi is currently conducting another phase 3 trials with the drug in patients who are at high risk for Influenza.

Following the approval by Japanese health ministry in February, the drug could be on sale in Japan as early as May.

The head of co-developer Roche's pharma unit, Daniel O'Day, told Bloomberg, "The advantage is that it's one pill once, versus a course of therapy, so particularly for pandemic planning, this could be an advantage, you don't have the potential resistance that comes with not completing your course of therapy."

Shionogi and the Tamiflu maker Roche share the rights to sell Baloxavir marboxil in international market, but it will be almost a year before the drug enters US market.

Shionogi News Release

Novel emerging infectious diseases in pregnancy

Last two decades have seen epidemics of several infectious diseases which were previously not so prevalent worldwide. Pregnant mothers are especially prone to many infections because of anatomical and physiological changes that accompany pregnancy. The immune tolerance to semiallogenic fetus is because of down regulation of immunity, which puts the pregnant women at high risk of other infectious diseases reports a paper published in May 2017 issue of Journal Obstetrics and Gynecology.

The world has seen epidemics of four major and other minor emerging infectious diseases in the last two decades such as severe acute respiratory syndrome, the 2009 H1N1 pandemic influenza, Ebola virus, and, most recently, the Zika virus. Each of this infection has unique implications in pregnant women that are distinctly different from general population.

Each of this infectious disease has different clinical course, complications and future implications when occurring in pregnant women and requires special technique and skills and coordination at national and international levels to contain the outbreak, some basic principles are common to all for diagnosing and limiting the spread of these diseases.

A number of epidemiological factors have contributed towards emergence and widespread occurrence of these infection in pregnant women like global travel, development of microbial resistance and barriers towards vaccinations in pregnant women in-spite of increasing evidence of distinct benefits to mother and fetus.

Although the general principles of disease containment are common to all, some disease specific measures for treatment and prevention of individual infections in pregnancy are:

SARS: During the severe acute respiratory syndrome (SARS) outbreak by coronavirus in 2003, standard non-pharmaceutical measures were applied, and global containment was achieved in 5 months.

Influenza: All pregnant women should get influenza vaccine every year as soon as it is available and should not wait for the unpredictable influenza season to start. It is safe in all the trimester. The rapid influenza tests currently available has low sensitivity resulting in many false negative results. Hence, to err on the side of safety it is always recommended to prescribe oseltamivir as precaution and is recommended both by Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists.

Ebola virus: Women are always at high risk for contracting Ebola during an epidemic as they are the primary caregivers to other infectious family members. Women who are pregnant with the virus during acute Ebola epidemic usually transmit virus to the fetus, leading to intrauterine fetal death, stillbirth, or neonatal death. Ebola virus is also excreted in breast milk.

They also transmit the virus to healthcare providers and caregivers during labor or abortion. Standard precaution including the use of personal protective equipment (PPE) during labor and delivery for protection against blood and body fluids should be used along with rigorous hand hygiene, appropriate waste, sharps and laundry management and cleaning and decontamination.

WHO states that women who get pregnant after having being recovered from Ebola infection are not infectious but standard precautions and use of PPE should be implemented all the time during handling such patients. 

Zika virus: Zika virus is a flavivirus that has potential for sexual and vector born transmission by Aedes (Stegomyia) species of mosquitoes. It was declared as a public health emergency by the World Health Organization from 2016. A pregnant woman is susceptible to Zika virus in all three trimesters. Maternal Zika infection is associated with a range of adverse neonatal complications, most important of which is microcephaly. Peripartum transmission is also known to occur.

In absence of antiviral vaccine, CDC recommends that all pregnant women should postpone their travel to Zika infected areas and those who are in such areas should avoid mosquito bite especially during the day.

Pregnant women with laboratory-confirmed Zika virus infection can be offered amniocentesis to test for Zika virus RNA by RT-PCR after 15 weeks of gestation.

Deliveries of mothers with positive Zika infection should take place at specialized center.   

No specific antiviral treatment is available.

Abstract

Expert Discussion

WHO guide to Ebola disease in pregnancy

Media courtesy: InfectiousDiseaseAdvisor and Coherent news.

Vaccinations before, during and after pregnancy.

Prenatal screening

Women who are planning to become pregnant should make sure that they are up to date on their immunizations. This will protect them and the unborn child from many diseases.

The measles, mumps, rubella, and chickenpox (varicella) vaccines are particularly important for women of childbearing age, as these cannot be given when pregnant. If a woman is infected with any of this in pregnancy, particularly first trimester, it results in adverse pregnancy outcome. 

Patients should check with their physician, who can request a blood test to see the blood levels of antibodies against these viruses, because of prior vaccination or prior history of disease itself.

MMR- If you need to get the vaccine for Rubella, avoid getting pregnant for at least a month after receiving the MMR.

Varicella- Similarly, if you are not immune to chickenpox, get vaccinated at least a month before getting pregnant.

HPV Vaccine- The human papillomavirus (HPV) vaccine is recommended for nonpregnant girls and women 9 to 26 years of age. It is contraindicated during pregnancy, although evidence suggests it is safe if pregnant women receive it inadvertently.

Hepatitis B- A woman should get tested for anti-HBs before she is pregnant to see whether the vaccine was well taken and she is immune to infection.

Vaccines during pregnancy

The tetanus, diphtheria, acellular pertussis (Tdap) vaccine is recommended for every pregnant woman during each pregnancy. It should be given as early as possible between 27 and 36 weeks of gestation, to facilitate the passive transfer of maternal antibodies. Infants exposed in utero to Tdap vaccine were better protected against pertussis during the first year of life than infants not exposed in utero.

Influenza (flu)- Every pregnant woman who is pregnant around the influenza season should be vaccinated against the seasonal flu as she is at high risk for developing flu complications. The vaccine has no adverse effect on fetus, on the contrary the unborn baby is protected against flu for first 6 months of life, till the baby is eligible to receive the vaccine.

The nasal spray influenza vaccine is contraindicated as it is made of live virus.

Vaccines for special circumstances

Hepatitis A- Pregnant woman who is at risk for developing Hepatitis A should receive the vaccine as the virus can be passed on to fetus.

Hepatitis B- It is only recommended for pregnant women who are at high risk for developing the infection like unimmunized women who live with someone infected with hepatitis B and for completing the series if started before becoming pregnant.

Poliomyelitis- Although polio has been eradicated from most developed and some developing countries, polio vaccine is usually not given in pregnancy unless travel to an area where polio is prevalent is unavoidable. In such circumstances, she may receive the inactivated polio vaccine (IPV). 

Pneumococcus- Ideally the vaccine is given before pregnancy, but  if woman is at high risk for pneumococcal infection, the vaccine appears to be safe if given in second and third trimester.

Varicella- Because the effects of the varicella virus on the fetus are unknown, it is contraindicated in pregnant women.

Vaccines for travel

Yellow fever- May be given if benefit outweigh risk. 

BCG- contraindicated

Typhoid- Inadequate data to make any recommendations

Rabies – Pregnancy is not considered a contraindication for post-exposure prophylaxis. If risk of exposure is substantially high, pre-exposure prophylaxis could be considered.

Passive Immunization during pregnancy

No known risk exists for the fetus from passive immunization of pregnant women with immune globulin preparations.

Prenatal screening

Every Pregnant woman should be tested for immunity to rubella and varicella and be tested for the presence of HBsAg during every pregnancy. Women who are found susceptible to rubella and varicella should be vaccinated immediately after delivery.

If a woman is found to be HBsAg positive, the infant should receive HBIG and begins the hepatitis B vaccine series no later than 12 hours after birth.

Breastfeeding and vaccines.

Inactivated and live-virus vaccines are not contraindicated in pregnant woman, although the virus can replicate in mother, it is not excreted in human milk.

Small pox and yellow fever vaccines are contraindicated in lactating mother, although if travel to an area where Yellow fever is endemic is imminent, it can be given. 

Source: CDC Guidelines for Vaccinating Pregnant Women