Pharmacology Consult

Hepatitis B vaccine shortage: Unknown impact on future disease

Drug shortages continue to inundate our health care system. They have paralyzed pharmacies and affected hundreds of thousands of patients. Although drug shortages are not new, they have significantly increased since 2007. From 2006 to 2007, there was nearly a 50% spike in shortages, and the number of shortages has remained high annually, with the highest number — 267 — reported in 2011. The cause of drug shortages is multifactorial and many times unpredictable. Manufacturing and quality issues, delays in production, raw product availability, discontinuations by manufacturers, and natural disasters are noted to be the major reasons for shortages. Drug shortages present a serious public health challenge and a strain on the health care system from a resource management perspective. Also, they contribute to an increase in overall health care costs. The FDA, professional organizations (eg, American Society of Health-System Pharmacists) and pharmaceutical companies have committed to manage and prevent shortages and are working to identify key strategies and solutions to minimize harm to patients.

The world of infectious diseases has been profoundly impacted by drug shortages. Antimicrobial agents are in the list of the top five active shortages by drug class. Some antimicrobial shortages have included critical medications where alternative treatments do not exist or are not considered first-line treatments. A recent drug shortage of recombinant hepatitis B vaccine (Recombivax HB, Merck) was reported, and it affects all available product strengths, including adult and pediatric/adolescent dosages (see Table 1). Merck has produced a pediatric dialysis formulation of Recombivax HB, and therefore, this special population will be affected by the shortage. Engerix-B (GlaxoSmithKline) is currently still available (see Table 2). These monovalent vaccines are considered interchangeable.

HBV is a viral infection that can cause life-threatening liver infection and lead to liver cancer or death from cirrhosis. WHO estimates that 257 million people were living with chronic HBV worldwide (hepatitis B surface antigen positive) in 2015, and HBV infection resulted in approximately 887,000 deaths that year. In the United States, the incidence of HBV infection had been decreasing until 2012. However, since then, the number of annual cases has increased to about 3,000 — possibly because of the opioid crisis, according to HHS. The CDC estimates that there were about 20,900 cases of new cases of HBV in 2016.

Recombivax HB and Engerix-B vaccines are approved as a three-dose series for both adults and children. HEPLISAV-B (Dynavax) is a recombinant, adjuvanted HBV vaccine, but it is approved for use only in adults aged 18 years and older as a two-dose series. The three-dose series for infants should begin immediately after birth (within 12-24 hours) and administered again between 1 to 2 and 6 to 18 months. A two- or three-dose series is recommended for vaccination if they have additional risk factors, including hepatitis C virus infection; chronic liver disease; HIV infection; current or recent injection drug use; exposure via sexual contact or to blood of an infected person; incarceration; or international travel to areas where HBV is endemic.

Kimberly Boeser

The adult vaccination series is given at 0, 1 and 6 months (minimum intervals: 4 weeks between doses one and two; 8 weeks between doses two and three; 16 weeks between doses one and three). An alternative to using Recombivax HB and Engerix-B vaccines is the combination vaccine for HAV and HBV — Twinrix (GlaxoSmithKline) — which is given at 0, 1 and 6 months (minimum intervals: 4 weeks between doses one and two; 5 months between doses two and three).

Many of the same risk factors for HAV apply to those for HBV; therefore, Twinrix is an alternative vaccine that could be used during a shortage. The Recombivax HB dialysis formulation is recommended for those who are predialysis or undergoing dialysis because this provides a higher dose of 40 µg/mL of vaccine and should be administered on the initial visit, followed by 1 and 6 months after the initial dose. In addition, a booster may be considered if anti-HBs concentrations obtained at 1 to 2 months after the third dose fall below 10 µg/mL. Alternative dosing with the Engerix-B vaccine of two doses (20 µg/mL) to achieve the 40-µg dose may be given at the same time. For children aged 11 years or older, two doses of Engerix-B vaccine (10 µg/mL) to achieve the 20-µg dose may be given at the same time; however, alternative age restrictions for those aged younger than 11 years are not clear, and vaccination should be considered on a case-by-case basis by a provider and pharmacist.

Despite the low incidence of HBV in the U.S., health care costs associated with infection have dramatically increased in the last several decades. Health care charges for outpatient visits and hospitalizations exceeded the $1 billion mark in 2003, likely due to advancements in treatment such as liver transplantation. The cost for HBV vaccines is low — approximately $25 per dose for pediatric/adolescent patients and $50 to $60 per dose for adults. The vaccine series is key to ongoing prevention of HBV infections and the long-term consequences of this disease.

So, what does a shortage of a critical vaccine mean for the epidemiology of HBV? Will having only one interchangeable product available put a strain on the supply chain of HBV vaccine? Drug shortages always strain the health care system, even when alternative products are available. For example, acute-care hospitals often try to limit the supply of the vaccine products they carry, offering a single formulary agent. This is due to overall cost containment, and it is also part of a safety strategy so the incorrect vaccine product is not dispensed to patients. When there is a shortage of a medication or vaccine, formulary shifts need to occur, the electronic medical record system needs to be modified, and providers and staff need to be educated about the changes. These shortages prove to be very difficult when alternative agents are not available, and although we understand that we may be giving an agent that is not considered first-line treatment, we do not fully understand the impact shortages have on outcomes. The strain of the HBV vaccine shortage on resources can be managed behind the scenes — as most shortages are — but we need to be alert for future increases in HBV infections, particularly in the very young and those who are considered to be at high risk. Providers will need to alter vaccination series and possibly offer catch-up vaccinations. As of now, the impact on the epidemiology of this disease is not known, but we will need to cognizant of its future impact.

Disclosure: Boeser reports no relevant financial disclosures.

Drug shortages continue to inundate our health care system. They have paralyzed pharmacies and affected hundreds of thousands of patients. Although drug shortages are not new, they have significantly increased since 2007. From 2006 to 2007, there was nearly a 50% spike in shortages, and the number of shortages has remained high annually, with the highest number — 267 — reported in 2011. The cause of drug shortages is multifactorial and many times unpredictable. Manufacturing and quality issues, delays in production, raw product availability, discontinuations by manufacturers, and natural disasters are noted to be the major reasons for shortages. Drug shortages present a serious public health challenge and a strain on the health care system from a resource management perspective. Also, they contribute to an increase in overall health care costs. The FDA, professional organizations (eg, American Society of Health-System Pharmacists) and pharmaceutical companies have committed to manage and prevent shortages and are working to identify key strategies and solutions to minimize harm to patients.

The world of infectious diseases has been profoundly impacted by drug shortages. Antimicrobial agents are in the list of the top five active shortages by drug class. Some antimicrobial shortages have included critical medications where alternative treatments do not exist or are not considered first-line treatments. A recent drug shortage of recombinant hepatitis B vaccine (Recombivax HB, Merck) was reported, and it affects all available product strengths, including adult and pediatric/adolescent dosages (see Table 1). Merck has produced a pediatric dialysis formulation of Recombivax HB, and therefore, this special population will be affected by the shortage. Engerix-B (GlaxoSmithKline) is currently still available (see Table 2). These monovalent vaccines are considered interchangeable.

HBV is a viral infection that can cause life-threatening liver infection and lead to liver cancer or death from cirrhosis. WHO estimates that 257 million people were living with chronic HBV worldwide (hepatitis B surface antigen positive) in 2015, and HBV infection resulted in approximately 887,000 deaths that year. In the United States, the incidence of HBV infection had been decreasing until 2012. However, since then, the number of annual cases has increased to about 3,000 — possibly because of the opioid crisis, according to HHS. The CDC estimates that there were about 20,900 cases of new cases of HBV in 2016.

Recombivax HB and Engerix-B vaccines are approved as a three-dose series for both adults and children. HEPLISAV-B (Dynavax) is a recombinant, adjuvanted HBV vaccine, but it is approved for use only in adults aged 18 years and older as a two-dose series. The three-dose series for infants should begin immediately after birth (within 12-24 hours) and administered again between 1 to 2 and 6 to 18 months. A two- or three-dose series is recommended for vaccination if they have additional risk factors, including hepatitis C virus infection; chronic liver disease; HIV infection; current or recent injection drug use; exposure via sexual contact or to blood of an infected person; incarceration; or international travel to areas where HBV is endemic.

PAGE BREAK
Kimberly Boeser

The adult vaccination series is given at 0, 1 and 6 months (minimum intervals: 4 weeks between doses one and two; 8 weeks between doses two and three; 16 weeks between doses one and three). An alternative to using Recombivax HB and Engerix-B vaccines is the combination vaccine for HAV and HBV — Twinrix (GlaxoSmithKline) — which is given at 0, 1 and 6 months (minimum intervals: 4 weeks between doses one and two; 5 months between doses two and three).

Many of the same risk factors for HAV apply to those for HBV; therefore, Twinrix is an alternative vaccine that could be used during a shortage. The Recombivax HB dialysis formulation is recommended for those who are predialysis or undergoing dialysis because this provides a higher dose of 40 µg/mL of vaccine and should be administered on the initial visit, followed by 1 and 6 months after the initial dose. In addition, a booster may be considered if anti-HBs concentrations obtained at 1 to 2 months after the third dose fall below 10 µg/mL. Alternative dosing with the Engerix-B vaccine of two doses (20 µg/mL) to achieve the 40-µg dose may be given at the same time. For children aged 11 years or older, two doses of Engerix-B vaccine (10 µg/mL) to achieve the 20-µg dose may be given at the same time; however, alternative age restrictions for those aged younger than 11 years are not clear, and vaccination should be considered on a case-by-case basis by a provider and pharmacist.

Despite the low incidence of HBV in the U.S., health care costs associated with infection have dramatically increased in the last several decades. Health care charges for outpatient visits and hospitalizations exceeded the $1 billion mark in 2003, likely due to advancements in treatment such as liver transplantation. The cost for HBV vaccines is low — approximately $25 per dose for pediatric/adolescent patients and $50 to $60 per dose for adults. The vaccine series is key to ongoing prevention of HBV infections and the long-term consequences of this disease.

So, what does a shortage of a critical vaccine mean for the epidemiology of HBV? Will having only one interchangeable product available put a strain on the supply chain of HBV vaccine? Drug shortages always strain the health care system, even when alternative products are available. For example, acute-care hospitals often try to limit the supply of the vaccine products they carry, offering a single formulary agent. This is due to overall cost containment, and it is also part of a safety strategy so the incorrect vaccine product is not dispensed to patients. When there is a shortage of a medication or vaccine, formulary shifts need to occur, the electronic medical record system needs to be modified, and providers and staff need to be educated about the changes. These shortages prove to be very difficult when alternative agents are not available, and although we understand that we may be giving an agent that is not considered first-line treatment, we do not fully understand the impact shortages have on outcomes. The strain of the HBV vaccine shortage on resources can be managed behind the scenes — as most shortages are — but we need to be alert for future increases in HBV infections, particularly in the very young and those who are considered to be at high risk. Providers will need to alter vaccination series and possibly offer catch-up vaccinations. As of now, the impact on the epidemiology of this disease is not known, but we will need to cognizant of its future impact.

PAGE BREAK

Disclosure: Boeser reports no relevant financial disclosures.