THERAPEUTIC ADVANCES IN THEPREVENTION OF HEPATITIS B: YEAST-DERIVED RECOMBINANT HEPATITIS B VACCINES Mark W. Garrison and Danial E. Baker
Hepatitis B
See also pages 628 and 671. ABSTRACf: Viral hepatitis is second to gonorrhea as the most
commonly reported infectious disease in the US. Hepatitis B accounts for the majority of viral hepatitis cases. Fortunately, the disease is selflimiting and frequently resolves completely with minimal complications; however, a significant number of individuals may experience long-term sequelae. Research utilizing genetic engineering has led to the development of yeast-derived recombinant DNA (YDR) hepatitis vaccines-a significant advancement in the control and prevention of hepatitis B. The recombinant process allows production of unlimited quantities of vaccine at considerably lower cost and without the potential threat of blood-borne illness. Clinical trials in various high-risk populations have demonstrated the effectiveness and safety of YDR vaccines. However, questions regarding optimal regimen and the need for periodic revaccination remain unanswered. Persons at risk should be adequately vaccinated against hepatitis B.
Dlep Ann Pharmacother 1991;25:617-27. HEPATITIS B is one of the most common infectious diseases and a worldwide healthcare problem. 1 Approximately 25000 cases are reported annually in the US alone, but because of the frequency of unreported cases and the large number of subclinicalhepatitis B infections, the true figure is estimated at 300 000 cases per year.' In addition, more than 300 million people throughout the world are believed to be chronic carriers of hepatitis B, serving as potential sources for continued spread of the disease.3 Our purpose is to reviewthe pathophysiology of hepatitis B; to provide information regarding efficacy, safety, and optimal dosing of the new recombinant hepatitis B vaccines; and to examine their role in providing active immunization against this disease. MARK W. GARRISON, Pharm.D., is an Assistant Professor of Pharmacy Practice: and DANIAL E. BAKER, Pharm. D., is the Director of the Drug Information Center, and an Associate ProfessorofPhannacy Practice, College ofPhannacy, Washington State University, Spokane, WA. Reprints: Mark W. Garrison, Pharm.D., College of Pharmacy, Washington State University, 601 W. First Ave., Spokane, WA99204.
This article is approved for continuing education credit
In addition to hepatitisB, other specifictypes of hepatitis include type A, type non-A-non-B (also known as type C), and delta hepatitis. The primary characteristics that differentiate the various types of hepatitis includeroute of transmission, onset and incubationperiod, antigenicproperties, and long-term sequelae. Infections involving hepatitis B virus (HBV) are typically transmitted percutaneously by exposure to contaminated blood or blood products of HBV carriers or persons with active infection. Moreover, HBV has been isolated from various body fluids, particularly semen, saliva, and tears; and thus, nonpercutaneous transmission may also result from intimate contact with these individuals." Blood transfusions, accidental needle sticks, shared use of contaminated needles (e.g., iv drug abuse, tattoos), and sexual contact, especially with multiple sex partners, are all common routes of transmission. A number of groups at high risk for HBV infection havebeen identified. These include healthcare personnel, residents and staff at institutions for the mentally handicapped, hemodialysis patients, household contacts and sexual partners of HBV carriers, homosexually active men, prison inmates, illicit parenteral drug users, and infants born to womenwho are HBV carriers.P" The onset of HBV infection is usually insidious and characterized by a relatively long incubation period,averaging 90 days (range 40-180). More than half of all individuals with HBV infection areeithercompletely asymptomatic orexperience a mild "flu-like" syndrome thatseldomresults in a visit to the physician's office.v" A few patients may also experiencea serumsickness-like illness witharthralgias and/orskin rashes, Symptomatic patients oftencomplain offatigue, malaise, abdominal pain, nausea, vomiting, and anorexia. Increases in liverfunction testsmayprecede or coincide with the onset of symptoms. Clinical jaundice develops in less than 50 percent of cases and usually affects the elderly or patients exposed to a large inoculum of HBY.4 Approximately 90 percent of adults with acute HBV infection
Dlep, The Annals ofPharmacotherapy •
1991 June, Volume 25 •
617
recover without complications. The remaining ten percent frequently becomechroniccarriers ofHBV and may develop chronicpersistenthepatitis or chronic active hepatitis, a seriousformofhepatitisthatmayfurtherprogresstocirrhosis,hepatocellularcarcinoma, or other complications. Fortunately, less than one percent of patients acutely infected with HBV progress to fulminant necrotizing hepatitis.2. 7 The percentage of chronic carriers dramatically increases in the pediatric population, approaching 90 percent for infected infants and approximately 25-50 percent in children less than five years of age. 8 Diagnosis is based on serologic testing for various antigenicmarkers.Three distinctantigenshavebeen identified in patientswithhepatitis B infections (Figure I). HepatitisB surface antigen (HBsAg), probably the most clinically useful antigen, becomesdetectable in the serum several weeksafter exposure and often priorto the onsetof symptoms.The duration of detectable serum HBsAg concentrations varies;however, in the majorityof cases, peak serum titers occur during the height of clinical illness and begin to decline during the convalescent phase. The presenceofHBsAg in the serum is diagnostic for activeHBV infection. Hepatitis B core antigen (HBcAg) exists within the intact virion and therefore is not clinically detectable in the serum. Currently, no commercially available serologic tests are able to identify HBcAg, and the clinicalsignificance of this antigen is unknown. The third antigen, hepatitisB e antigen(HBeAg), is foundonly in HBsAg-positive patients. HBeAg is indicative of a high degree of infectivity. Patients who are both HBsAg- and HBeAg-positive exhibit a greater than tenfold rate of infectivity than HBsAg-positive, HBeAg-negative patients.9 HBeAg is also a useful marker for disease chronicity, with prolonged presence suggesting the development of a chronic carrier state. In response to these circulating antigens, the immune system produces specific antibodies. Antibodies against the core antigen (anti-HBc) are the first to appear in serum, usually in conjunction with the onset of clinical symptoms (Figure I). Anti-HBc titers begin to fall during the convalescent stage of the disease but persist at low concentrations for several years, indicating recent hepatitis B infection. The secondantibody, againstHBeAg (anti-HBe), appearsas HBsAg titers begin to decline. Seroconversion of HBeAgpositivepatientsdoes not occur in those who becomechronic carriers of HBV and, therefore, persistence of HBeAg or absence of anti-HBe in the serum can be useful for carrier Jaundice, : : : : . . Increased LFT •
HBeAg
Antl·HBe
-
Ant~HBc
HBsAg
An~Bs
o
4
8
12
16
20
24
28
32
36
52
100
WeeksAlterExposure Figure I. Serologic and clinical characteristics of acute HBV infections. Anti-HBc = antibodies against the core antigen; Anti-HBe = antibodies against the e antigen; AntiHBs = antibodies against the surface antigen; HBeAg = e antigen; HBsAg = surface antigen; HBV = hepatitis B virus; LFf = liver function tests.
618 • Dltl}', The Annals ofPharmacotherapy •
identification. The presence of antibodies against the surface antigen (anti-HBs) indicates complete recovery, noninfectivity, and long-term immunity to HBY. Anti-HBs appears in the late convalescent stage after the disappearance of HBsAg and persists indefinitely. A critical "window period," ranging from a couple of days to several weeks, exists between the time HBsAg titers drop below detectable serum concentrations and the time anti-HBs titers become evident. During this period, the presence of anti-HBc is of vital importance and serves as the only effective indicator of active HBV infection. Therefore, it is necessary for the clinician not only to evaluate HBsAg and antiHBs titers, but also anti-HBc titers. There is no specific treatment for HBV infection; however, reports have suggested that interferon may be beneficial in managing patients with hepatitis B. to Antibiotics and corticosteroids are rarely, if ever, beneficialand are not advocated. Management of HBV infection is primarily achieved through preventive measure (i.e., active and passive immunization). In addition, proper handling of blood and body fluids, appropriate disposal of needles, and careful selection of sexual partners can greatly minimize the possibility of infection. Prevention of hepatitis B was based initially on passive immunoprophylaxis through administration of serum immune globulin (IG). IG is derived from pooled human serum and contains antibodies against hepatitis A virus and a varying degree of antibodies against HBY. The development of a more potent hepatitis B-specific IG, hepatitis B IG (HBIG), containing much higher titers of anti-HBs, represented a more effective means of establishing passive immunization. HBIG soon replaced IG. Significant advancement in the prevention of hepatitis B was made in 1982 with the development of a plasma-derived (PO) hepatitis B vaccine. The vaccine, marketed under the tradename Heptavax-B (Merck Sharp and Dohme), is a suspension of inactivated HBsAg particles purified from the plasma of chronic carriers. The recommended three-dose schedule of Heptavax-B provides immunity in over 90 percent of the recipients, representing an effective, although relatively expensive, means of active immunization. Continued progress led to the most recent generation of vaccine in 1986-the yeast-derived recombinant DNA (YDR) hepatitis B vaccine. Currently, there are two commercially availableYDR hepatitis B vaccines:Recombivax HB (Merck Sharp and Dohme) and Engerix-B (SmithKline Biologicals).Comparative studies with the PO vaccine demonstrate similar rates of antibody induction, decreased potential for adverse drug reactions, and greater availability of the recombinant vaccines at substantially lower cost. With the advent of YDR vaccines, the PO vaccine (no longer produced in the US) was initially restricted for use in hemodialysis and immunocompromisedpatients, and persons with significant allergies to yeast.2 However, at the time these guidelines were prepared, the only YDR vaccine availablewas a lO-f.Lg/rnL formulationthat resulted in an unacceptable4-rnL vaccinationdose. Currently,YDR vaccines are available in 20-f.Lg/rnL doses (Engerix-B) and a special au-ug/ml, formulation (Recombivax HB, Dialysis Formulation)for use in immunocompromisedand dialysis patients. Hence, the earlier recommendations for PO vaccine use should be revised to include only those persons with significant yeast allergies (personal communication,
1991 June. Volume 25
Yeast-Derived Hepatitis Vaccine
Linda Moyer, R.N., Nurse Epidemiologist, Centers for Disease Control, Hepatitis Branch, April 1990).
Yeast-Derived RecombinantDNA Hepatitis B Vaccines CLINICAL PHARMACOLOGY
The YDR hepatitis B vaccines are derived from common baker's yeast, Saccharomyces cerevisiase. A plasmid containing genetic material for HBsAg expression is inserted into the yeast cell and genetically cultured to produce unlimited quantities of HBsAg. In addition, the elaborate, costly, and time-consuming inactivation and purification procedures associated with the PD vaccine are avoided. Purification of the YDR antigen is achieved through a more economical, multiple-step process and the resultant HBsAg is prepared as a sterile suspension adsorbed on aluminum hydroxide and preserved with thimerosal. More than 95 percent of the yeast-derived constituents (i.e., proteins, lipids, polysaccharides, DNA) are removed in the process, leaving only trace amounts of contaminants in the final product.":" Because the YDR hepatitis B vaccines do not contain human-derived components, there is no risk of transmitting pathogenic organisms via blood or blood products. Seroconversion and seroprotection are terms used to describe the extent of a vaccine's effectiveness. For hepatitis B, seroconversion is defined as anti-HBs titers 2:1 lUlL and seroprotection, needed for immunity against the development of hepatitis B, is defined as anti-HBs titers 2:10 1U/L. 2 •u.u The rate of seroprotection may vary depending on the vaccine, dosage schedule, and the specific group of individuals vaccinated. Generally, 95 percent of healthy adults and pediatric patients achieve adequate protection (10 lUlL) against hepatitis B after receiving the full immunization schedule. Immunocompromised patients and those receiving hemodialysis tend to be poor responders and require either a higher dose of vaccine or the administration of four, rather than three, doses. This is also true for patients receiving the PD vaccine.F'" In vitro and in vivo immunologic evaluations demonstrate the YDR antigen to be qualitatively and quantitatively similar to the PD antigen in the induction of antibodies.P:" INDICATIONS
YDR hepatitis B vaccines are useful in preventing infections caused only by HBV and are not effective against other types of hepatitis. Theoretically, delta hepatitis requires the coexistence of HBV; thus, prevention of hepatitis B will indirectly protect against delta hepatitis. All persons at risk for HBV exposure should be actively immunized with a full YDR vaccination schedule. Persons for whom vaccination is highly recommended are listed in Table 1. Although physicians, dentists, nurses, laboratory personnel, and even ward secretaries are frequently included in most published recommendations for receiving hepatitis B vaccinations, pharmacists are often overlooked as being at risk for exposure. With increasing responsibilities now being assumed by pharmacists (e.g., phlebotomy, participation in cardiac resuscitation, active outpatient clinic involvement), these providers should also be recognized as a high-risk group in light of their increased likelihood of exposure to HBV.18
Table 1. Population Groups in Which Hepatitis B Vaccination is Recommended All healthcare personnel exposed to blood or other body fluids Patients requiring frequent blood transfusions (e.g., hemophiliacs) Clients and staff of institutions for the developmentally disabled Household and sexual contacts of HBsAg-positive patients Hemodialysis patients Morticians and embalmers Homosexually active men Prostitutes Heterosexual persons with multiple sexual partners International travelers to hepatitis B endemic areas Infants born to HBV-positive mothers Prison inmates Illicit intravenous drug users HBsAg = surface antigen; HBV = hepatitis B virus.
Although specific immunization programs aimed at high-risk groups have been implemented throughout the country, the annual incidence of HBV infection continues to rise. The number of HBV infections in certain high-risk groups, including homosexual men and healthcare personnel, are beginning to decrease;" however, it is difficult to attribute this reduction solely to vaccination. Attitudes regarding sexual practices and healthcare provision have been dramatically influenced by the threat of exposure to the human immunodeficiency virus (HIV). Unfortunately, hepatitis B cases associated with illicit intravenous drug use and heterosexual exposure continue to rise and are largely responsible for the increased incidence. 8 CLINICAL EFFICACY
Homosexuals. Homosexual men are a well-recognized high-risk group for HBV infection. Seventy percent of this population demonstrate positive serology from past or present infection. This rate is ten times higher than that for heterosexual men." However, the use of hepatitis B vaccine can decrease this risk substantially. The immunologic response to YDR hepatitis B vaccines tends to be lower in homosexual men versus women and heterosexual men. In one study,50 homosexual men, 58 women, and 54 heterosexual men were given three doses of YDR hepatitis B vaccine 20 J.Lg at zero, one, and six months. The median seroconversion rate observed after the last dose was significantly higher in women (100 percent), followed by heterosexual men (98.2 percent), and finally, homosexual men (92 percent). The reason for this variance is unclear. 20 A multicenter, open-labeled study conducted in Belgium evaluated the efficacy of two different doses of YDR hepatitis B vaccine in homosexual men. To be eligible for the study, individuals had to be healthy and sexually active with negative serology for HBsAg, anti-HBs, and anti-HBc. A total of 278 men qualified for participation in the study. Of these 278, 214 received the complete vaccination series and all necessary serologic testing. Patients were injected in the deltoid muscle with either 20 (143 subjects) or 40 J.Lg (71 subjects) of YDR hepatitis B vaccine at zero, one, and six months. Seroconversion was significantly higher at one month in the 40-J.Lg dose group than in the 20-J.Lg dose group (40 vs. 33 percent), but by the second month, the conversion rates were similar between the two groups (96 vs. 91 percent, respectively). One month after the final dose, the seroconversion rates reached 99 percent in both
DICP,TheAnnalsofPharmacotherapy • 1991 June. Volume 25 • 619
groups. Seroprotection rates were 99 (40-/-Lg dose group) and 97 percent (20-/-Lg dose group). None of the patients developed evidence of infection after completing the vaccination program; however, two individuals had positive indicators during the immunization period. In contrast, the annual incidence of hepatitis B infection was 12 percent in the historical control group. 21 Neonates. Perinatal transmission ofHBV commonly occurs in infants born to HBsAg-positive mothers. Approximately 65-90 percent of these infants become infected and virtually all become chronic carriers if immunoprophylaxis with hepatitis B vaccine is not initiated within 24 hours of birth. 22·24 Cadranel et a1. reported on 30 neonates born to HBsAgpositive mothers treated with a YDR hepatitis B vaccine 20 /-Lg within 24 hours of birth who received an additional 20ug dose at one and two months. Concurrent HBIG was not administered. Seroconversion and seroprotection were achieved in 100 percent of these patients after four months. At the completion of this study, none of the vaccinated newborns had developed hepatitis B. 25 In another study, 122 neonates born to HBsAg- and HBeAg-positive mothers were evaluated to determine efficacy of the PO and YDR hepatitis B vaccines. All neonates received HBIG 0.5 mL im within 24 hours of birth. Thirtynine neonates were given PO vaccine 10 ug at zero, one, and six months, and 83 neonates were given YDR hepatitis B vaccine 5 ug over the same schedule. An HBsAg carrier state developed in four (10.2 percent) of the PO vaccinees and four (4.8 percent) of those receiving YDR hepatitis B vaccine. Although these differences were not statistically significant, the data demonstrate YDR vaccine to be as effective as PO vaccine. None of the patients in either group developed HBV infection or clinical symptoms of hepati-
tis." In yet another study, 68 neonates born to HBsAg-positive mothers were given YDR hepatitis B vaccine 10 ug within 12hours of birth and at 1, 2, and 12months. Thirteen infants were lost to follow-up at the completion of the study. Of the remaining 55 neonates, 48 were seronegative for HBsAg; however, 2 infants subsequently became HBsAgpositive and were excluded from the analysis. Seroconversion titers were achieved in 22.2,95.7, and 100 percent of the remaining 46 infants after their first, second, and third dose, respectively. After 12 months, only one infant had an anti-HBs titer below the seroprotective concentration; subsequent administration of the IO-/-Lg booster dose produced significant elevation in anti-HBs titers in all of the infants. 24 In contrast, had immunoprophylaxis not been induced, an estimated 65-90 percent would have become chronic carriers. One hundred forty-six healthy neonates born to HBsAgand HBeAg-positive mothers in Thailand were enrolled in a study. These neonates received either YDR hepatitis B vaccine 10 /-Lg im (anterolateral thigh or deltoid region) or the same dose plus HBIG 0.5 mL within 12 hours of birth. All infants were given subsequent doses ofYDR hepatitis B vaccine 10 /-Lg at 1, 2, and 12 months. Neonates born to either HBsAg-positiveIHBeAg-negative, or HBsAg- and HBeAg-negative mothers were also vaccinated and served as controls. Seroconversion rates were similar for neonates of HBsAg- and HBeAg-positive mothers and those in the control group. By the fourth month, 95 percent had sero620
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protective titers. The booster dose at 12 months produced a further increase in antibody titers and within one month, 96.4 percent had antibody titers> 100 lUlL. A comparison of seroconversion rates between neonates receiving YDR hepatitis B vaccine alone and those receiving both the vaccine and HBIG at birth revealed no significant differences (98.8 and 100 percent, respectively). Of 58 infants born to HBsAg- and HBeAg-positive mothers and followed through month 13, 2 (3.4 percent) became chronically infected with HBV. In the group treated with both YDR hepatitis B vaccine andHBIG, 5 of the 48 infants (10.4 percent) were initially HBsAg-positive, but none were chronically infected by the ninth month and only 1(2.1 percent) became a chronic carrier. 26 These results indicate that all children at high risk for perinatal HBV transmission should be vaccinated with at least YDR hepatitis B vaccine. Addition of HBIG will increase the protection rate, but also the cost. The World Health Organization has concluded that the simplest and most effective strategy for the control and eventual eradication of HBV in Southeast Asia and the Pacific is to vaccinate all newborns with hepatitis B vaccine only. 26 Mentally Handicapped Patients. In 1985, a serologic survey of 770 residents at Belgian institutions for the mentally handicapped revealed that 32.6 percent of Down's syndrome patients were HBsAg-positive compared with only 7.2 percent of the other residents. An open-labeled study was conducted to evaluate the efficacy of YDR hepatitis B vaccine in institutionalized patients with Down's syndrome. Two hundred seventy-five residents from three institutions, including 18 patients with Down's syndrome, were evaluated. All patients were seronegative for HBsAg, anti-HBs, and anti-HBc and received YDR hepatitis B vaccine 20 /-Lg im (deltoid region) at zero, one, and six months. Sixteen Down's syndrome patients and 217 other residents completed the full vaccination schedule and underwent serologic evaluation. One month after the last dose (month 7), the seroconversion rate was 81.3 percent for the Down's syndrome patients and 97.7 percent for the remaining residents. Seroprotection rates were 75 and 93.5 percent, respectively. At 12 months, seroconversion and seroprotection were both 75 percent in the Down's syndrome patients and 97 and 89.1 percent, respectively, in the other mentally handicapped patients. Seroconversion rates at 24 months were 100 percent in 12 Down's syndrome patients and 98.7 percent in 151 other residents evaluated. Seroprotection rates were 66.7 and 96 percent, respectively. Patients who responded poorly (titers 100 lUlL) were given a booster dose of vaccine at 12 months (the above data does not include those patients receiving booster doses). A transient HBV infection occurred in one of the Down's syndrome patients during the irnrnunization period, but no other cases were observed in either group during the postvaccination period. 27 Hemodialysis Patients. A multicenter study was conducted in Spain to determine the efficacy of YDR hepatitis B vaccine in hemodialysis patients given two different doses over a 6-month period or the same dose administered over a 6-month versus a 12-month period. Two hundred thirty-seven patients were enrolled. One hundred thirtytwo were given YDR hepatitis B vaccine 20 ug: 98 received the vaccine at 0,1,2, and 6 months, and 34 received the vaccine atO, 1,2, and 12months. The remaining 105pa-
1991 June, Volume 25
Yeast-Derived HepatuisVaccine
tients were given YDR vaccine 40 IJ-g using similar schedules (0, 1,2, and 6 months, 56 patients; 0, 1,2, and 12 months, 49 patients). Potential differences were studied between: (l) 20- and 4O-lJ-g doses given over a 6-month period and (2) a 4O-lJ-g dose given over a 6- and a 12-month period. During the first month, seroconversion with 40 IJ-g was higher than that observed with 20 IJ-g in those patients on the six-month schedule (25 vs. 13 percent). However, after eight months, seroconversion rates were similar between the 40- and 20-lJ-g dose groups (86 and 80 percent, respectively). Seroprotection at eight months was achieved in 67 percent of patients receiving 40 IJ-g and 70 percent of those receiving 20 IJ-g. Evaluation of patients receiving 40 IJ-g over 6 versus 12 months also failed to reveal significant differences between the two vaccination schedules. Both schedules resulted in an 86 percent conversion rate and seroprotective titers were approximately 70 percent one month after the final dose; however, the six-month schedule resulted in more rapid antibody induction and was therefore recommended by the investigators for hemodialysis pa-
tients." Sixty-one patients with chronic renal failure not yet dependent on dialysis were tested to evaluate the efficacy of hepatitis B vaccination. Eligible patients had to be seronegative for HBsAg, anti-HBs, and anti-HBc with a normal serum alanine aminotransferase (ALT) concentration prior to vaccination. Patients with rapidly deteriorating renal function, those requiring immunosuppressants, or renal transplantation candidates were excluded. Participants were randomly assigned to one of three regimens: group I (21 subjects) was given YDR hepatitis B vaccine 20 IJ-g im, group II (20 subjects) was given YDR hepatitis B vaccine 40 IJ-g im, and group ill (20 subjects) was given PD vaccine 40 IJ-g im. Vaccinations were administered at zero, one, and six months. Eight patients failed to complete the study. One month after completing the regimen (month 7), seroconversion rates were 58 percent in group 1,75 percent in group II, and 81 percent in group ill; seroprotection was achieved in 42, 69, and 75 percent of participants, respectively. Twelve-month follow-up seroconversion rates were 56, 71, and 88 percent, and seroprotection rates, 17,53, and 81 percent, respectively. Based on these data, it appears that YDR
vaccine 20 IJ-g administered over six months may not be adequate for hemodialysis patients. However, despite the differences in seroprotection rate, none of the patients in the three groups developed clinical hepatitis or exhibited evidence of HBV infection based on serology. 28 Table 2 presents a summary of some of these studies. Hemophiliac and Thalassemic Patients. A multicenter study was conducted to evalute the efficacy of YDR hepatitis B vaccine in patients with hemophilia. Forty-one patients were enrolled in the study. Twenty-five had severe to mild factor Vlll deficiency, 2 had severe or mild factor IX deficiency, 3 had severe factor VII deficiency, and 11 had severe von Willebrand's disease. Prior to the study, 27 patients (65.9 percent) had not been treated with concentrate and thus were not at risk for HBV infection. At the completion of the study, 58.5 percent had never been treated with concentrate; the other 41.5 percent were treated with concentrate either before or during the study and thus had been potentially exposed to HBY. Each patient was given YDR hepatitis B vaccine 20 IJ-g at zero, one, and six months. The percentage of anti-HBs-positive patients one month after the first dose was 10 percent, one month after the second dose, 54 percent, and one month after the third dose, 98 percent. Only one patient failed to achieve seroprotection. This individual was a mild hemophiliac and had never been treated with concentrates or other blood products. Prior history of concentrate use or use of concentrate during the study had no effect on the individuals' response to the vac-
cine." Forty-one tranfusion-dependent thalassemic patients and two patients with spherocytosis were vaccinated with YDR hepatitis B vaccine 20 IJ-g at 0, 1, and 6 months (19 patients) or 0,1, and 2 months (abbreviated schedule), followed by a booster at 12 months (24 patients). In the first group, seroprotection rates of 24, 77, and 100 percent were achieved one month after each dose, respectively. Seroprotection was achieved in only 8, 59, and 64 percent, respectively, of those treated with the abbreviated schedule; however, data are not yet available to reflect the impact of the 12-month booster dose. The overall induction of antibodies in thalassemic patients produced by YDR hepatitis B vaccine is similar to the response obtained with PD vaccine. 30
Table 2. Clinical Trials Involving Hepatitis B Vaccines in Various Patient Populations PATIENT POPULATION
Homosexuals Neonates
Hemodialysis patients
OOSAGEREGIMEN
PATIENTS
SEROCONVERSION* >1 lUlL
SEROPROTECfION* >10 lUlL
(mo)
(0)
(%)
(%)
REF.
YDR-20 ILg (0, I ,6) YDR-40 ILg (0,1,6) YDR-IO ILg (0,1,2,6) no HBIG YDR-20 ILg (0,1,2) no HBIG YDR-IO ILg (0,1,2,12) no HBIG YDR-IO ILg (0, 1,2,12) + HBIG YDR-20 ILg (0,1,2,6) YDR-20 ILg (0,1,2,12) YDR-40 ILg (0,1,2,6) YDR-40 ILg (0,1,2,12) YDR-20 ILg (0, 1,6) YDR-40 ILg (0,1,6) PD-40 ILg (0,1,6)
143 71 46 30 68 78 98 34 56 49 21 20 20
97
21
99 99
99
100 lOOt 98.8 100 80 86 86 86 58 75 81
98 NA NA NA 70 NA 67 73 42 69 75
24 25 26 14
28
*Rates determined at one month after completion of vaccination (unless indicated otherwise). tSeroconversion rate determined at two months after completion of vaccination. HBIG = hepatitis B immune globulin; NA = not available; PD = plasma-derived vaccine; YDR = yeast-derived recombinant vaccine.
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COMPARATIVEE~CACY
Engerix-B Versus PD HepatitisB Vaccine. Just et al. reported on 300 healthy medical students assigned to one of six different hepatitis B vaccination regimens. Patients were either given Engerix-B (batch L) 10 ug, Energix-B (batch N) 10 ug, Engerix-B (batch L) 20 fJ-g, Engerix-B (batch N) 20 ug, Engerix-B (batch L) 40 ug, or PO vaccine 20 fJ-g. All doses were given into the deltoid muscle at zero, one, and six months. After the last dose, seroconversion was observed in 97.4 percent of the PO vaccine group and 100 percent of the Engerix-B groups. No difference was observed between doses or lots of Engerix-B; however, 20 fJ-g produced a slightly higher seroconversion rate compared with 10 fJ-g after one month. 31 In another study, 79 female nursing students were randomly vaccinated with either Engerix-B 20 ug im (50 students) or PO vaccine 20 fJ-g im (29 students) at zero, one, and six months (deltoid muscle). Seroconversion was achieved in 86 percent of those patients treated with Engerix-B at three months and 100 percent of patients at seven months compared with those treated with PO vaccine (93 and 100 percent, respectively). Seroprotection one month after completion of the schedule was achieved in 96 percent (Engerix-B) and 100 percent (PO vaccine) of patients. 32 . Similar results were observed in a comparison of Engerix-B 20 ug and PO vaccine 20 ug given at 0, 1, and 6 months or 0, 1, and 2 months with a booster at 12 months. 33 Recombivax HB Versus PD Hepatitis B Vaccine. Extensive studies have been performed comparing PO vaccine and Recombivax HB. Clinical trials conducted in healthy adults, adolescents, children, and infants illustrate that Recombivax HB and PO vaccine produce similar results in terms of seroconversion. A variety of Recombivax HB doses (2.5 to 20 ug) were evaluated to determine the optimal dose for adult and pediatric vaccinations. The vaccination schedule used in these studies consisted of intramuscular injections administered at zero, one, and six months. Antibody response between adults receiving lO-fJ-g doses and those receiving 20-fJ-g doses was not significantly different. Antibody titers two months after the final 10- and 20-fJ-g doses of Recombivax HB were severalfold greater than those achieved with Recombivax HB 2.5 and 5 u.g. The seroprotection rate at eight months in adults who received 10 ug was 96 percent, and the rate observed in infants and children who received 5-fJ-g doses of Recombivax HB was 100 percent after nine months. Based on these results, adult and pediatric doses of 10 and 5 ug, respectively, were adopted for vaccinations using Recombivax HB. 34 A randomized, multicenter, double-blind study was conducted in homosexual and bisexual men to evaluate the efficacy of PO vaccine and Recombivax HB. Only individuals seronegative for HBsAg, anti-HBs, and anti-HBc were eligible to participate. Patients received either PO vaccine 20 fJ-g im or Recombivax HB 10 u.g im (deltoid muscle) at zero, one, an~ six months. Both groups were similar in age, race, and anti-Hl'V and cytomegalovirus antibody status. One hundred fifty-eight patients completed all three doses and follow-up evaluations. At the end of nine months, seroprotection was achieved in 74 percent of the Recombivax HB patients and 88 percent of the PO vaccine patients. Ov~rall th~ Recombivax HB group had significantly lower anti-Hlss tlters than the PO vaccine group. Both vaccines were less effective in HIV-positive individuals, but the 622
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number of HIV-positive patients studied was insufficient to draw any meaningful conclusions." Based on the results of this study, it could be concluded that Recombivax HB is less immunogenic than PO vaccine; however, a more accurate interpretation is that 10 u.g of Recombivax HB although being thought of as equivalent, may not be equivalent to 20 fJ-g of PO vaccine. Recombivax HB was compared with PO vaccine in 78 mentally handicapped patients and 75 staff members of an institution for the mentally handicapped in the Netherlands. ~ll su?jects were HBsAg-, anti-HBs-, and anti-HBc-negative WIthnormal ALT concentrations prior to enrollment in the study. Group I was given Recombivax HB 10 ug im, group II ~as given Recombivax HB 20 fJ-g im, and group ill was given PO vaccine 20 ug im (deltoid region) at zero, one, and six months. Mentally handicapped patients in group I had seroprotection rates of 92.5 percent at 7 months and 88.9 percent at 12 months, whereas staff members exhibited seroprotection rates of 100 and 91.7 percent, respectively. In group II, patients achieved seroprotection rates of 88 percent at 7 months and 76 percent at 12 months. In contrast, seroprotection rates for staff members were 100 and 95.8 percent, respectively. Both patients and staff treated with PO vaccine (group ill) achieved seroprotection rates of 100 percent at 7 and 12 months." Engerix-B Versus Recombivax HB. Only a limited number of direct comparative trials between Engerix-B and Recombivax HB have been reported. In one such study, 146 students from two schools were vaccinated with either Recombivax HB, Engerix-B, or PO hepatitis B vaccine. These students were assigned to one of four groups: group A received Recombivax HB 10 ug, groups Band 0 received PO vaccine 20 fJ-g, and group C received Engerix-B 20 u.g, All doses were given intramuscularly (deltoid region) at zero, one, and six months. Only two subjects, both ~om gro~p A, failed to complete the study and were not mcluded m the efficacy analysis. Seroprotective titers were ~chieved in 93.3 percent of subjects in group A, 97 percent in group B, 96 percent in group C, and 100 percent in group D at the 7- to 8-month mark and remained unchanged at 12 months. Despite the slightly higher titers achieved with PO vaccine (groups B and D), the three vaccines were not found to be statistically different in their ability to produce
seroprotection." One hundred forty hospital employees were vaccinated with either Engerix-B or Recombivax HB in an openlabeled study. All subjects were negative for HBsAg, antiHBs, and anti-HBc and had normal ALT concentrations prior to enrollment. The first 70 subjects received EngerixB 2~ ug im at zer
Hepatitis B
See also pages 628 and 671. ABSTRACf: Viral hepatitis is second to gonorrhea as the most
commonly reported infectious disease in the US. Hepatitis B accounts for the majority of viral hepatitis cases. Fortunately, the disease is selflimiting and frequently resolves completely with minimal complications; however, a significant number of individuals may experience long-term sequelae. Research utilizing genetic engineering has led to the development of yeast-derived recombinant DNA (YDR) hepatitis vaccines-a significant advancement in the control and prevention of hepatitis B. The recombinant process allows production of unlimited quantities of vaccine at considerably lower cost and without the potential threat of blood-borne illness. Clinical trials in various high-risk populations have demonstrated the effectiveness and safety of YDR vaccines. However, questions regarding optimal regimen and the need for periodic revaccination remain unanswered. Persons at risk should be adequately vaccinated against hepatitis B.
Dlep Ann Pharmacother 1991;25:617-27. HEPATITIS B is one of the most common infectious diseases and a worldwide healthcare problem. 1 Approximately 25000 cases are reported annually in the US alone, but because of the frequency of unreported cases and the large number of subclinicalhepatitis B infections, the true figure is estimated at 300 000 cases per year.' In addition, more than 300 million people throughout the world are believed to be chronic carriers of hepatitis B, serving as potential sources for continued spread of the disease.3 Our purpose is to reviewthe pathophysiology of hepatitis B; to provide information regarding efficacy, safety, and optimal dosing of the new recombinant hepatitis B vaccines; and to examine their role in providing active immunization against this disease. MARK W. GARRISON, Pharm.D., is an Assistant Professor of Pharmacy Practice: and DANIAL E. BAKER, Pharm. D., is the Director of the Drug Information Center, and an Associate ProfessorofPhannacy Practice, College ofPhannacy, Washington State University, Spokane, WA. Reprints: Mark W. Garrison, Pharm.D., College of Pharmacy, Washington State University, 601 W. First Ave., Spokane, WA99204.
This article is approved for continuing education credit
In addition to hepatitisB, other specifictypes of hepatitis include type A, type non-A-non-B (also known as type C), and delta hepatitis. The primary characteristics that differentiate the various types of hepatitis includeroute of transmission, onset and incubationperiod, antigenicproperties, and long-term sequelae. Infections involving hepatitis B virus (HBV) are typically transmitted percutaneously by exposure to contaminated blood or blood products of HBV carriers or persons with active infection. Moreover, HBV has been isolated from various body fluids, particularly semen, saliva, and tears; and thus, nonpercutaneous transmission may also result from intimate contact with these individuals." Blood transfusions, accidental needle sticks, shared use of contaminated needles (e.g., iv drug abuse, tattoos), and sexual contact, especially with multiple sex partners, are all common routes of transmission. A number of groups at high risk for HBV infection havebeen identified. These include healthcare personnel, residents and staff at institutions for the mentally handicapped, hemodialysis patients, household contacts and sexual partners of HBV carriers, homosexually active men, prison inmates, illicit parenteral drug users, and infants born to womenwho are HBV carriers.P" The onset of HBV infection is usually insidious and characterized by a relatively long incubation period,averaging 90 days (range 40-180). More than half of all individuals with HBV infection areeithercompletely asymptomatic orexperience a mild "flu-like" syndrome thatseldomresults in a visit to the physician's office.v" A few patients may also experiencea serumsickness-like illness witharthralgias and/orskin rashes, Symptomatic patients oftencomplain offatigue, malaise, abdominal pain, nausea, vomiting, and anorexia. Increases in liverfunction testsmayprecede or coincide with the onset of symptoms. Clinical jaundice develops in less than 50 percent of cases and usually affects the elderly or patients exposed to a large inoculum of HBY.4 Approximately 90 percent of adults with acute HBV infection
Dlep, The Annals ofPharmacotherapy •
1991 June, Volume 25 •
617
recover without complications. The remaining ten percent frequently becomechroniccarriers ofHBV and may develop chronicpersistenthepatitis or chronic active hepatitis, a seriousformofhepatitisthatmayfurtherprogresstocirrhosis,hepatocellularcarcinoma, or other complications. Fortunately, less than one percent of patients acutely infected with HBV progress to fulminant necrotizing hepatitis.2. 7 The percentage of chronic carriers dramatically increases in the pediatric population, approaching 90 percent for infected infants and approximately 25-50 percent in children less than five years of age. 8 Diagnosis is based on serologic testing for various antigenicmarkers.Three distinctantigenshavebeen identified in patientswithhepatitis B infections (Figure I). HepatitisB surface antigen (HBsAg), probably the most clinically useful antigen, becomesdetectable in the serum several weeksafter exposure and often priorto the onsetof symptoms.The duration of detectable serum HBsAg concentrations varies;however, in the majorityof cases, peak serum titers occur during the height of clinical illness and begin to decline during the convalescent phase. The presenceofHBsAg in the serum is diagnostic for activeHBV infection. Hepatitis B core antigen (HBcAg) exists within the intact virion and therefore is not clinically detectable in the serum. Currently, no commercially available serologic tests are able to identify HBcAg, and the clinicalsignificance of this antigen is unknown. The third antigen, hepatitisB e antigen(HBeAg), is foundonly in HBsAg-positive patients. HBeAg is indicative of a high degree of infectivity. Patients who are both HBsAg- and HBeAg-positive exhibit a greater than tenfold rate of infectivity than HBsAg-positive, HBeAg-negative patients.9 HBeAg is also a useful marker for disease chronicity, with prolonged presence suggesting the development of a chronic carrier state. In response to these circulating antigens, the immune system produces specific antibodies. Antibodies against the core antigen (anti-HBc) are the first to appear in serum, usually in conjunction with the onset of clinical symptoms (Figure I). Anti-HBc titers begin to fall during the convalescent stage of the disease but persist at low concentrations for several years, indicating recent hepatitis B infection. The secondantibody, againstHBeAg (anti-HBe), appearsas HBsAg titers begin to decline. Seroconversion of HBeAgpositivepatientsdoes not occur in those who becomechronic carriers of HBV and, therefore, persistence of HBeAg or absence of anti-HBe in the serum can be useful for carrier Jaundice, : : : : . . Increased LFT •
HBeAg
Antl·HBe
-
Ant~HBc
HBsAg
An~Bs
o
4
8
12
16
20
24
28
32
36
52
100
WeeksAlterExposure Figure I. Serologic and clinical characteristics of acute HBV infections. Anti-HBc = antibodies against the core antigen; Anti-HBe = antibodies against the e antigen; AntiHBs = antibodies against the surface antigen; HBeAg = e antigen; HBsAg = surface antigen; HBV = hepatitis B virus; LFf = liver function tests.
618 • Dltl}', The Annals ofPharmacotherapy •
identification. The presence of antibodies against the surface antigen (anti-HBs) indicates complete recovery, noninfectivity, and long-term immunity to HBY. Anti-HBs appears in the late convalescent stage after the disappearance of HBsAg and persists indefinitely. A critical "window period," ranging from a couple of days to several weeks, exists between the time HBsAg titers drop below detectable serum concentrations and the time anti-HBs titers become evident. During this period, the presence of anti-HBc is of vital importance and serves as the only effective indicator of active HBV infection. Therefore, it is necessary for the clinician not only to evaluate HBsAg and antiHBs titers, but also anti-HBc titers. There is no specific treatment for HBV infection; however, reports have suggested that interferon may be beneficial in managing patients with hepatitis B. to Antibiotics and corticosteroids are rarely, if ever, beneficialand are not advocated. Management of HBV infection is primarily achieved through preventive measure (i.e., active and passive immunization). In addition, proper handling of blood and body fluids, appropriate disposal of needles, and careful selection of sexual partners can greatly minimize the possibility of infection. Prevention of hepatitis B was based initially on passive immunoprophylaxis through administration of serum immune globulin (IG). IG is derived from pooled human serum and contains antibodies against hepatitis A virus and a varying degree of antibodies against HBY. The development of a more potent hepatitis B-specific IG, hepatitis B IG (HBIG), containing much higher titers of anti-HBs, represented a more effective means of establishing passive immunization. HBIG soon replaced IG. Significant advancement in the prevention of hepatitis B was made in 1982 with the development of a plasma-derived (PO) hepatitis B vaccine. The vaccine, marketed under the tradename Heptavax-B (Merck Sharp and Dohme), is a suspension of inactivated HBsAg particles purified from the plasma of chronic carriers. The recommended three-dose schedule of Heptavax-B provides immunity in over 90 percent of the recipients, representing an effective, although relatively expensive, means of active immunization. Continued progress led to the most recent generation of vaccine in 1986-the yeast-derived recombinant DNA (YDR) hepatitis B vaccine. Currently, there are two commercially availableYDR hepatitis B vaccines:Recombivax HB (Merck Sharp and Dohme) and Engerix-B (SmithKline Biologicals).Comparative studies with the PO vaccine demonstrate similar rates of antibody induction, decreased potential for adverse drug reactions, and greater availability of the recombinant vaccines at substantially lower cost. With the advent of YDR vaccines, the PO vaccine (no longer produced in the US) was initially restricted for use in hemodialysis and immunocompromisedpatients, and persons with significant allergies to yeast.2 However, at the time these guidelines were prepared, the only YDR vaccine availablewas a lO-f.Lg/rnL formulationthat resulted in an unacceptable4-rnL vaccinationdose. Currently,YDR vaccines are available in 20-f.Lg/rnL doses (Engerix-B) and a special au-ug/ml, formulation (Recombivax HB, Dialysis Formulation)for use in immunocompromisedand dialysis patients. Hence, the earlier recommendations for PO vaccine use should be revised to include only those persons with significant yeast allergies (personal communication,
1991 June. Volume 25
Yeast-Derived Hepatitis Vaccine
Linda Moyer, R.N., Nurse Epidemiologist, Centers for Disease Control, Hepatitis Branch, April 1990).
Yeast-Derived RecombinantDNA Hepatitis B Vaccines CLINICAL PHARMACOLOGY
The YDR hepatitis B vaccines are derived from common baker's yeast, Saccharomyces cerevisiase. A plasmid containing genetic material for HBsAg expression is inserted into the yeast cell and genetically cultured to produce unlimited quantities of HBsAg. In addition, the elaborate, costly, and time-consuming inactivation and purification procedures associated with the PD vaccine are avoided. Purification of the YDR antigen is achieved through a more economical, multiple-step process and the resultant HBsAg is prepared as a sterile suspension adsorbed on aluminum hydroxide and preserved with thimerosal. More than 95 percent of the yeast-derived constituents (i.e., proteins, lipids, polysaccharides, DNA) are removed in the process, leaving only trace amounts of contaminants in the final product.":" Because the YDR hepatitis B vaccines do not contain human-derived components, there is no risk of transmitting pathogenic organisms via blood or blood products. Seroconversion and seroprotection are terms used to describe the extent of a vaccine's effectiveness. For hepatitis B, seroconversion is defined as anti-HBs titers 2:1 lUlL and seroprotection, needed for immunity against the development of hepatitis B, is defined as anti-HBs titers 2:10 1U/L. 2 •u.u The rate of seroprotection may vary depending on the vaccine, dosage schedule, and the specific group of individuals vaccinated. Generally, 95 percent of healthy adults and pediatric patients achieve adequate protection (10 lUlL) against hepatitis B after receiving the full immunization schedule. Immunocompromised patients and those receiving hemodialysis tend to be poor responders and require either a higher dose of vaccine or the administration of four, rather than three, doses. This is also true for patients receiving the PD vaccine.F'" In vitro and in vivo immunologic evaluations demonstrate the YDR antigen to be qualitatively and quantitatively similar to the PD antigen in the induction of antibodies.P:" INDICATIONS
YDR hepatitis B vaccines are useful in preventing infections caused only by HBV and are not effective against other types of hepatitis. Theoretically, delta hepatitis requires the coexistence of HBV; thus, prevention of hepatitis B will indirectly protect against delta hepatitis. All persons at risk for HBV exposure should be actively immunized with a full YDR vaccination schedule. Persons for whom vaccination is highly recommended are listed in Table 1. Although physicians, dentists, nurses, laboratory personnel, and even ward secretaries are frequently included in most published recommendations for receiving hepatitis B vaccinations, pharmacists are often overlooked as being at risk for exposure. With increasing responsibilities now being assumed by pharmacists (e.g., phlebotomy, participation in cardiac resuscitation, active outpatient clinic involvement), these providers should also be recognized as a high-risk group in light of their increased likelihood of exposure to HBV.18
Table 1. Population Groups in Which Hepatitis B Vaccination is Recommended All healthcare personnel exposed to blood or other body fluids Patients requiring frequent blood transfusions (e.g., hemophiliacs) Clients and staff of institutions for the developmentally disabled Household and sexual contacts of HBsAg-positive patients Hemodialysis patients Morticians and embalmers Homosexually active men Prostitutes Heterosexual persons with multiple sexual partners International travelers to hepatitis B endemic areas Infants born to HBV-positive mothers Prison inmates Illicit intravenous drug users HBsAg = surface antigen; HBV = hepatitis B virus.
Although specific immunization programs aimed at high-risk groups have been implemented throughout the country, the annual incidence of HBV infection continues to rise. The number of HBV infections in certain high-risk groups, including homosexual men and healthcare personnel, are beginning to decrease;" however, it is difficult to attribute this reduction solely to vaccination. Attitudes regarding sexual practices and healthcare provision have been dramatically influenced by the threat of exposure to the human immunodeficiency virus (HIV). Unfortunately, hepatitis B cases associated with illicit intravenous drug use and heterosexual exposure continue to rise and are largely responsible for the increased incidence. 8 CLINICAL EFFICACY
Homosexuals. Homosexual men are a well-recognized high-risk group for HBV infection. Seventy percent of this population demonstrate positive serology from past or present infection. This rate is ten times higher than that for heterosexual men." However, the use of hepatitis B vaccine can decrease this risk substantially. The immunologic response to YDR hepatitis B vaccines tends to be lower in homosexual men versus women and heterosexual men. In one study,50 homosexual men, 58 women, and 54 heterosexual men were given three doses of YDR hepatitis B vaccine 20 J.Lg at zero, one, and six months. The median seroconversion rate observed after the last dose was significantly higher in women (100 percent), followed by heterosexual men (98.2 percent), and finally, homosexual men (92 percent). The reason for this variance is unclear. 20 A multicenter, open-labeled study conducted in Belgium evaluated the efficacy of two different doses of YDR hepatitis B vaccine in homosexual men. To be eligible for the study, individuals had to be healthy and sexually active with negative serology for HBsAg, anti-HBs, and anti-HBc. A total of 278 men qualified for participation in the study. Of these 278, 214 received the complete vaccination series and all necessary serologic testing. Patients were injected in the deltoid muscle with either 20 (143 subjects) or 40 J.Lg (71 subjects) of YDR hepatitis B vaccine at zero, one, and six months. Seroconversion was significantly higher at one month in the 40-J.Lg dose group than in the 20-J.Lg dose group (40 vs. 33 percent), but by the second month, the conversion rates were similar between the two groups (96 vs. 91 percent, respectively). One month after the final dose, the seroconversion rates reached 99 percent in both
DICP,TheAnnalsofPharmacotherapy • 1991 June. Volume 25 • 619
groups. Seroprotection rates were 99 (40-/-Lg dose group) and 97 percent (20-/-Lg dose group). None of the patients developed evidence of infection after completing the vaccination program; however, two individuals had positive indicators during the immunization period. In contrast, the annual incidence of hepatitis B infection was 12 percent in the historical control group. 21 Neonates. Perinatal transmission ofHBV commonly occurs in infants born to HBsAg-positive mothers. Approximately 65-90 percent of these infants become infected and virtually all become chronic carriers if immunoprophylaxis with hepatitis B vaccine is not initiated within 24 hours of birth. 22·24 Cadranel et a1. reported on 30 neonates born to HBsAgpositive mothers treated with a YDR hepatitis B vaccine 20 /-Lg within 24 hours of birth who received an additional 20ug dose at one and two months. Concurrent HBIG was not administered. Seroconversion and seroprotection were achieved in 100 percent of these patients after four months. At the completion of this study, none of the vaccinated newborns had developed hepatitis B. 25 In another study, 122 neonates born to HBsAg- and HBeAg-positive mothers were evaluated to determine efficacy of the PO and YDR hepatitis B vaccines. All neonates received HBIG 0.5 mL im within 24 hours of birth. Thirtynine neonates were given PO vaccine 10 ug at zero, one, and six months, and 83 neonates were given YDR hepatitis B vaccine 5 ug over the same schedule. An HBsAg carrier state developed in four (10.2 percent) of the PO vaccinees and four (4.8 percent) of those receiving YDR hepatitis B vaccine. Although these differences were not statistically significant, the data demonstrate YDR vaccine to be as effective as PO vaccine. None of the patients in either group developed HBV infection or clinical symptoms of hepati-
tis." In yet another study, 68 neonates born to HBsAg-positive mothers were given YDR hepatitis B vaccine 10 ug within 12hours of birth and at 1, 2, and 12months. Thirteen infants were lost to follow-up at the completion of the study. Of the remaining 55 neonates, 48 were seronegative for HBsAg; however, 2 infants subsequently became HBsAgpositive and were excluded from the analysis. Seroconversion titers were achieved in 22.2,95.7, and 100 percent of the remaining 46 infants after their first, second, and third dose, respectively. After 12 months, only one infant had an anti-HBs titer below the seroprotective concentration; subsequent administration of the IO-/-Lg booster dose produced significant elevation in anti-HBs titers in all of the infants. 24 In contrast, had immunoprophylaxis not been induced, an estimated 65-90 percent would have become chronic carriers. One hundred forty-six healthy neonates born to HBsAgand HBeAg-positive mothers in Thailand were enrolled in a study. These neonates received either YDR hepatitis B vaccine 10 /-Lg im (anterolateral thigh or deltoid region) or the same dose plus HBIG 0.5 mL within 12 hours of birth. All infants were given subsequent doses ofYDR hepatitis B vaccine 10 /-Lg at 1, 2, and 12 months. Neonates born to either HBsAg-positiveIHBeAg-negative, or HBsAg- and HBeAg-negative mothers were also vaccinated and served as controls. Seroconversion rates were similar for neonates of HBsAg- and HBeAg-positive mothers and those in the control group. By the fourth month, 95 percent had sero620
•
DtC}', The Annals ofPharmacotherapy
•
protective titers. The booster dose at 12 months produced a further increase in antibody titers and within one month, 96.4 percent had antibody titers> 100 lUlL. A comparison of seroconversion rates between neonates receiving YDR hepatitis B vaccine alone and those receiving both the vaccine and HBIG at birth revealed no significant differences (98.8 and 100 percent, respectively). Of 58 infants born to HBsAg- and HBeAg-positive mothers and followed through month 13, 2 (3.4 percent) became chronically infected with HBV. In the group treated with both YDR hepatitis B vaccine andHBIG, 5 of the 48 infants (10.4 percent) were initially HBsAg-positive, but none were chronically infected by the ninth month and only 1(2.1 percent) became a chronic carrier. 26 These results indicate that all children at high risk for perinatal HBV transmission should be vaccinated with at least YDR hepatitis B vaccine. Addition of HBIG will increase the protection rate, but also the cost. The World Health Organization has concluded that the simplest and most effective strategy for the control and eventual eradication of HBV in Southeast Asia and the Pacific is to vaccinate all newborns with hepatitis B vaccine only. 26 Mentally Handicapped Patients. In 1985, a serologic survey of 770 residents at Belgian institutions for the mentally handicapped revealed that 32.6 percent of Down's syndrome patients were HBsAg-positive compared with only 7.2 percent of the other residents. An open-labeled study was conducted to evaluate the efficacy of YDR hepatitis B vaccine in institutionalized patients with Down's syndrome. Two hundred seventy-five residents from three institutions, including 18 patients with Down's syndrome, were evaluated. All patients were seronegative for HBsAg, anti-HBs, and anti-HBc and received YDR hepatitis B vaccine 20 /-Lg im (deltoid region) at zero, one, and six months. Sixteen Down's syndrome patients and 217 other residents completed the full vaccination schedule and underwent serologic evaluation. One month after the last dose (month 7), the seroconversion rate was 81.3 percent for the Down's syndrome patients and 97.7 percent for the remaining residents. Seroprotection rates were 75 and 93.5 percent, respectively. At 12 months, seroconversion and seroprotection were both 75 percent in the Down's syndrome patients and 97 and 89.1 percent, respectively, in the other mentally handicapped patients. Seroconversion rates at 24 months were 100 percent in 12 Down's syndrome patients and 98.7 percent in 151 other residents evaluated. Seroprotection rates were 66.7 and 96 percent, respectively. Patients who responded poorly (titers 100 lUlL) were given a booster dose of vaccine at 12 months (the above data does not include those patients receiving booster doses). A transient HBV infection occurred in one of the Down's syndrome patients during the irnrnunization period, but no other cases were observed in either group during the postvaccination period. 27 Hemodialysis Patients. A multicenter study was conducted in Spain to determine the efficacy of YDR hepatitis B vaccine in hemodialysis patients given two different doses over a 6-month period or the same dose administered over a 6-month versus a 12-month period. Two hundred thirty-seven patients were enrolled. One hundred thirtytwo were given YDR hepatitis B vaccine 20 ug: 98 received the vaccine at 0,1,2, and 6 months, and 34 received the vaccine atO, 1,2, and 12months. The remaining 105pa-
1991 June, Volume 25
Yeast-Derived HepatuisVaccine
tients were given YDR vaccine 40 IJ-g using similar schedules (0, 1,2, and 6 months, 56 patients; 0, 1,2, and 12 months, 49 patients). Potential differences were studied between: (l) 20- and 4O-lJ-g doses given over a 6-month period and (2) a 4O-lJ-g dose given over a 6- and a 12-month period. During the first month, seroconversion with 40 IJ-g was higher than that observed with 20 IJ-g in those patients on the six-month schedule (25 vs. 13 percent). However, after eight months, seroconversion rates were similar between the 40- and 20-lJ-g dose groups (86 and 80 percent, respectively). Seroprotection at eight months was achieved in 67 percent of patients receiving 40 IJ-g and 70 percent of those receiving 20 IJ-g. Evaluation of patients receiving 40 IJ-g over 6 versus 12 months also failed to reveal significant differences between the two vaccination schedules. Both schedules resulted in an 86 percent conversion rate and seroprotective titers were approximately 70 percent one month after the final dose; however, the six-month schedule resulted in more rapid antibody induction and was therefore recommended by the investigators for hemodialysis pa-
tients." Sixty-one patients with chronic renal failure not yet dependent on dialysis were tested to evaluate the efficacy of hepatitis B vaccination. Eligible patients had to be seronegative for HBsAg, anti-HBs, and anti-HBc with a normal serum alanine aminotransferase (ALT) concentration prior to vaccination. Patients with rapidly deteriorating renal function, those requiring immunosuppressants, or renal transplantation candidates were excluded. Participants were randomly assigned to one of three regimens: group I (21 subjects) was given YDR hepatitis B vaccine 20 IJ-g im, group II (20 subjects) was given YDR hepatitis B vaccine 40 IJ-g im, and group ill (20 subjects) was given PD vaccine 40 IJ-g im. Vaccinations were administered at zero, one, and six months. Eight patients failed to complete the study. One month after completing the regimen (month 7), seroconversion rates were 58 percent in group 1,75 percent in group II, and 81 percent in group ill; seroprotection was achieved in 42, 69, and 75 percent of participants, respectively. Twelve-month follow-up seroconversion rates were 56, 71, and 88 percent, and seroprotection rates, 17,53, and 81 percent, respectively. Based on these data, it appears that YDR
vaccine 20 IJ-g administered over six months may not be adequate for hemodialysis patients. However, despite the differences in seroprotection rate, none of the patients in the three groups developed clinical hepatitis or exhibited evidence of HBV infection based on serology. 28 Table 2 presents a summary of some of these studies. Hemophiliac and Thalassemic Patients. A multicenter study was conducted to evalute the efficacy of YDR hepatitis B vaccine in patients with hemophilia. Forty-one patients were enrolled in the study. Twenty-five had severe to mild factor Vlll deficiency, 2 had severe or mild factor IX deficiency, 3 had severe factor VII deficiency, and 11 had severe von Willebrand's disease. Prior to the study, 27 patients (65.9 percent) had not been treated with concentrate and thus were not at risk for HBV infection. At the completion of the study, 58.5 percent had never been treated with concentrate; the other 41.5 percent were treated with concentrate either before or during the study and thus had been potentially exposed to HBY. Each patient was given YDR hepatitis B vaccine 20 IJ-g at zero, one, and six months. The percentage of anti-HBs-positive patients one month after the first dose was 10 percent, one month after the second dose, 54 percent, and one month after the third dose, 98 percent. Only one patient failed to achieve seroprotection. This individual was a mild hemophiliac and had never been treated with concentrates or other blood products. Prior history of concentrate use or use of concentrate during the study had no effect on the individuals' response to the vac-
cine." Forty-one tranfusion-dependent thalassemic patients and two patients with spherocytosis were vaccinated with YDR hepatitis B vaccine 20 IJ-g at 0, 1, and 6 months (19 patients) or 0,1, and 2 months (abbreviated schedule), followed by a booster at 12 months (24 patients). In the first group, seroprotection rates of 24, 77, and 100 percent were achieved one month after each dose, respectively. Seroprotection was achieved in only 8, 59, and 64 percent, respectively, of those treated with the abbreviated schedule; however, data are not yet available to reflect the impact of the 12-month booster dose. The overall induction of antibodies in thalassemic patients produced by YDR hepatitis B vaccine is similar to the response obtained with PD vaccine. 30
Table 2. Clinical Trials Involving Hepatitis B Vaccines in Various Patient Populations PATIENT POPULATION
Homosexuals Neonates
Hemodialysis patients
OOSAGEREGIMEN
PATIENTS
SEROCONVERSION* >1 lUlL
SEROPROTECfION* >10 lUlL
(mo)
(0)
(%)
(%)
REF.
YDR-20 ILg (0, I ,6) YDR-40 ILg (0,1,6) YDR-IO ILg (0,1,2,6) no HBIG YDR-20 ILg (0,1,2) no HBIG YDR-IO ILg (0,1,2,12) no HBIG YDR-IO ILg (0, 1,2,12) + HBIG YDR-20 ILg (0,1,2,6) YDR-20 ILg (0,1,2,12) YDR-40 ILg (0,1,2,6) YDR-40 ILg (0,1,2,12) YDR-20 ILg (0, 1,6) YDR-40 ILg (0,1,6) PD-40 ILg (0,1,6)
143 71 46 30 68 78 98 34 56 49 21 20 20
97
21
99 99
99
100 lOOt 98.8 100 80 86 86 86 58 75 81
98 NA NA NA 70 NA 67 73 42 69 75
24 25 26 14
28
*Rates determined at one month after completion of vaccination (unless indicated otherwise). tSeroconversion rate determined at two months after completion of vaccination. HBIG = hepatitis B immune globulin; NA = not available; PD = plasma-derived vaccine; YDR = yeast-derived recombinant vaccine.
DlC]', The Annals ofPharmacotherapy
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/991 June, Volume 25
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COMPARATIVEE~CACY
Engerix-B Versus PD HepatitisB Vaccine. Just et al. reported on 300 healthy medical students assigned to one of six different hepatitis B vaccination regimens. Patients were either given Engerix-B (batch L) 10 ug, Energix-B (batch N) 10 ug, Engerix-B (batch L) 20 fJ-g, Engerix-B (batch N) 20 ug, Engerix-B (batch L) 40 ug, or PO vaccine 20 fJ-g. All doses were given into the deltoid muscle at zero, one, and six months. After the last dose, seroconversion was observed in 97.4 percent of the PO vaccine group and 100 percent of the Engerix-B groups. No difference was observed between doses or lots of Engerix-B; however, 20 fJ-g produced a slightly higher seroconversion rate compared with 10 fJ-g after one month. 31 In another study, 79 female nursing students were randomly vaccinated with either Engerix-B 20 ug im (50 students) or PO vaccine 20 fJ-g im (29 students) at zero, one, and six months (deltoid muscle). Seroconversion was achieved in 86 percent of those patients treated with Engerix-B at three months and 100 percent of patients at seven months compared with those treated with PO vaccine (93 and 100 percent, respectively). Seroprotection one month after completion of the schedule was achieved in 96 percent (Engerix-B) and 100 percent (PO vaccine) of patients. 32 . Similar results were observed in a comparison of Engerix-B 20 ug and PO vaccine 20 ug given at 0, 1, and 6 months or 0, 1, and 2 months with a booster at 12 months. 33 Recombivax HB Versus PD Hepatitis B Vaccine. Extensive studies have been performed comparing PO vaccine and Recombivax HB. Clinical trials conducted in healthy adults, adolescents, children, and infants illustrate that Recombivax HB and PO vaccine produce similar results in terms of seroconversion. A variety of Recombivax HB doses (2.5 to 20 ug) were evaluated to determine the optimal dose for adult and pediatric vaccinations. The vaccination schedule used in these studies consisted of intramuscular injections administered at zero, one, and six months. Antibody response between adults receiving lO-fJ-g doses and those receiving 20-fJ-g doses was not significantly different. Antibody titers two months after the final 10- and 20-fJ-g doses of Recombivax HB were severalfold greater than those achieved with Recombivax HB 2.5 and 5 u.g. The seroprotection rate at eight months in adults who received 10 ug was 96 percent, and the rate observed in infants and children who received 5-fJ-g doses of Recombivax HB was 100 percent after nine months. Based on these results, adult and pediatric doses of 10 and 5 ug, respectively, were adopted for vaccinations using Recombivax HB. 34 A randomized, multicenter, double-blind study was conducted in homosexual and bisexual men to evaluate the efficacy of PO vaccine and Recombivax HB. Only individuals seronegative for HBsAg, anti-HBs, and anti-HBc were eligible to participate. Patients received either PO vaccine 20 fJ-g im or Recombivax HB 10 u.g im (deltoid muscle) at zero, one, an~ six months. Both groups were similar in age, race, and anti-Hl'V and cytomegalovirus antibody status. One hundred fifty-eight patients completed all three doses and follow-up evaluations. At the end of nine months, seroprotection was achieved in 74 percent of the Recombivax HB patients and 88 percent of the PO vaccine patients. Ov~rall th~ Recombivax HB group had significantly lower anti-Hlss tlters than the PO vaccine group. Both vaccines were less effective in HIV-positive individuals, but the 622
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Dlep, The Annals ofPharmacotherapy
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number of HIV-positive patients studied was insufficient to draw any meaningful conclusions." Based on the results of this study, it could be concluded that Recombivax HB is less immunogenic than PO vaccine; however, a more accurate interpretation is that 10 u.g of Recombivax HB although being thought of as equivalent, may not be equivalent to 20 fJ-g of PO vaccine. Recombivax HB was compared with PO vaccine in 78 mentally handicapped patients and 75 staff members of an institution for the mentally handicapped in the Netherlands. ~ll su?jects were HBsAg-, anti-HBs-, and anti-HBc-negative WIthnormal ALT concentrations prior to enrollment in the study. Group I was given Recombivax HB 10 ug im, group II ~as given Recombivax HB 20 fJ-g im, and group ill was given PO vaccine 20 ug im (deltoid region) at zero, one, and six months. Mentally handicapped patients in group I had seroprotection rates of 92.5 percent at 7 months and 88.9 percent at 12 months, whereas staff members exhibited seroprotection rates of 100 and 91.7 percent, respectively. In group II, patients achieved seroprotection rates of 88 percent at 7 months and 76 percent at 12 months. In contrast, seroprotection rates for staff members were 100 and 95.8 percent, respectively. Both patients and staff treated with PO vaccine (group ill) achieved seroprotection rates of 100 percent at 7 and 12 months." Engerix-B Versus Recombivax HB. Only a limited number of direct comparative trials between Engerix-B and Recombivax HB have been reported. In one such study, 146 students from two schools were vaccinated with either Recombivax HB, Engerix-B, or PO hepatitis B vaccine. These students were assigned to one of four groups: group A received Recombivax HB 10 ug, groups Band 0 received PO vaccine 20 fJ-g, and group C received Engerix-B 20 u.g, All doses were given intramuscularly (deltoid region) at zero, one, and six months. Only two subjects, both ~om gro~p A, failed to complete the study and were not mcluded m the efficacy analysis. Seroprotective titers were ~chieved in 93.3 percent of subjects in group A, 97 percent in group B, 96 percent in group C, and 100 percent in group D at the 7- to 8-month mark and remained unchanged at 12 months. Despite the slightly higher titers achieved with PO vaccine (groups B and D), the three vaccines were not found to be statistically different in their ability to produce
seroprotection." One hundred forty hospital employees were vaccinated with either Engerix-B or Recombivax HB in an openlabeled study. All subjects were negative for HBsAg, antiHBs, and anti-HBc and had normal ALT concentrations prior to enrollment. The first 70 subjects received EngerixB 2~ ug im at zer
