Twinrix

CLINICAL PHARMACOLOGY

Several hepatitis viruses (A, B, C, D, and E) are known to cause a systemic infection resulting in major pathologic changes in the liver. Features of hepatitis A and hepatitis B are described below.

Hepatitis A: The hepatitis A virus (HAV) belongs to the picornavirus family.

Hepatitis A is a highly contagious disease with the predominant mode of transmission being person-to-person via the fecal-oral route. Infection has been shown to be spread (1) by contaminated water or food; (2) by infected food handlers1; (3) after breakdown in usual sanitary conditions or after floods or natural disasters; (4) by ingestion of raw or undercooked shellfish (oysters, clams, mussels) from contaminated waters2; (5) during travel to areas of the world with poor hygienic conditions3; (6) among institutionalized children and adults4; (7) in day-care centers5; (8) by parenteral transmission, either blood transfusions or sharing needles with infected people6; and (9) sexually, especially among men who have sex with men.7

The incubation period for hepatitis A averages 28 days (range: 15 to 50 days).7 The course of hepatitis A infection is extremely variable, ranging from asymptomatic infection to icteric hepatitis and death.8

Chronic shedding of HAV in feces has not been demonstrated, but relapses of hepatitis A can occur in as many as 20% of patients9,10 and fecal shedding of HAV may recur at this time.9 Approximately 70% of pediatric patients less than 6 years of age infected with hepatitis A are asymptomatic, and serve as a reservoir for infection among adults.7

The presence of antibodies to HAV (anti-HAV) confers protection against hepatitis A disease. However, the lowest titer needed to confer protection has not been determined. Natural infection provides lifelong immunity even when antibodies to hepatitis A are undetectable. At present, studies show the duration of protection afforded by TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) against hepatitis A lasts at least 4 years.11

Hepatitis B: The hepatitis B virus (HBV) belongs to a family of genetically related DNA-containing animal viruses, which are hepatotropic. The incubation period of hepatitis B ranges between 30 and 180 days.12

HBV infection occurs throughout the world with highly variable prevalences. A human reservoir of persistently infected persons is present in nearly all communities of the world. In the United States, parenteral drug abuse, unprotected sexual activity, occupationally acquired infection, or travelers returning from high prevalence countries may be the principal mechanisms of HBV transmission.

Modes of transmission of hepatitis B virus include sexual contact with an infected person, percutaneous or mucosal exposure to infectious blood, and perinatal exposure to an infected mother. Antibody concentrations ≥10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B.13

Clinical infection with hepatitis B may occur in 2 major forms: Asymptomatic or symptomatic hepatitis. Asymptomatic HBV infection can be subclinical or inapparent. In subclinical infection, patients have abnormal liver enzymes without jaundice, while inapparent asymptomatic infection is identified only by serological testing. One in 4 adults who has symptomatic disease has jaundice (anicteric/icteric hepatitis).

HBV infection can have serious consequences including acute massive hepatic necrosis, chronic active hepatitis, and cirrhosis of the liver. As many as 90% of infants and approximately 5%of adults who are infected with HBV will become HBV carriers.7 More than 350 million people are chronic carriers of HBV worldwide.7 The Centers for Disease Control and Prevention (CDC) estimates that there are approximately 1 million to 1.25 million chronic carriers of HBV in the United States.7 The annual number of unreported infections may be 10 times greater than the number of reported cases.7 Close contact (sexual contact or household contact) or exposure to blood from infected individuals is associated with increased risk of infection.7 Those patients who become chronic carriers can infect others and are at increased risk of developing primary hepatocellular carcinoma. Among other factors, infection with HBV may be the single most important factor for development of this carcinoma.7,14

Reduced Risk of Hepatocellular Carcinoma: According to the Centers for Disease Control and Prevention (CDC), hepatitis B vaccine is recognized as an anti-cancer vaccine because it can prevent primary liver cancer.15 In a Taiwanese study, the institution of universal childhood immunization against hepatitis B virus has been shown to decrease the incidence of hepatocellular carcinoma among children.16 In a Korean study in adult males, vaccination against the hepatitis B virus has been shown to decrease the incidence and risk of developing hepatocellular carcinoma in adults.17

Clinical Trials: Immunogenicity in Adults: Sera from 1,551 healthy adult volunteers ages 17 to 70, including 555 male subjects and 996 female subjects, in 11 clinical trials were analyzed following administration of 3 doses of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) on a 0-, 1-, and 6-month schedule. Seroconversion for antibodies against HAV was elicited in 99.9% of vaccinees, and protective antibodies against HBV were detected in 98.5%, 1 month after completion of the 3-dose series.

Table 1. Immunogenicity in TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) Worldwide Clinical Trials

TWINRIX Dose N % Seroconversion for Hepatitis A* % Seroprotection for Hepatitis B†
1 1587 93.8 30.8
2 1571 98.8 78.2
3 1551 99.9 98.5
*Anti-HAV titer ≥assay cut-off: 20 mIU/mL (HAVAB Test) or 33 mIU/mL (ENZYMUN-TEST®).
†Anti-HBsAg titer ≥10 mIU/mL (AUSAB®).

One of the 11 trials was a comparative trial conducted in a US population given either TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) (on a 0-, 1-, and 6-month schedule) or HAVRIX (0- and 6-month schedule) and ENGERIX-B (0-, 1-, and 6-month schedule). The monovalent vaccines were given concurrently in opposite arms. Of a total of 773 adults (ages 18 to 70 years) enrolled in this trial, an immunogenicity analysis was performed in 533 subjects who completed the study according to protocol. Of these, 264 subjects received TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) and 269 subjects received HAVRIX and ENGERIX-B. Seroconversion against HAV and seroprotection against HBV are shown in Table 2.

Table 2. Percentage of Seroconversion or Seroprotection Rates in the TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) US Clinical Trial

Vaccine N Timepoint % Seroconversion for Hepatitis A*
(95% CI)
% Seroprotection for Hepatitis B†
(95% CI)
TWINRIX 264 Month 1 91.6 17.9
Month 2 97.7 61.2
Month 7 99.6 (97.9-100.0) 95.1 (91.7-97.4)
HAVRIX and ENGERIX-B 269 Month 1 98.1 7.5
Month 2 98.9 50.4
Month 7 99.3 (97.3-99.9) 92.2 (88.3-95.1)
*Anti-HAV titer ≥assay cut-off: 33 mIU/mL (ENZYMUN-TEST®). †Anti-HBsAg titer ≥10 mIU/mL (AUSAB®).

Since the immune responses to hepatitis A and hepatitis B induced by TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) were non-inferior to the monovalent vaccines, efficacy is expected to be similar to the efficacy for each of the monovalent vaccines (Table 3).

Table 3. Geometric Mean Titers in the TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) US Clinical Trial

Vaccine N Timepoint GMT to Hepatitis A (95% CI) GMT to Hepatitis B (95% CI)
TWINRIX 263 Month 1 335 8
259 Month 2 636 23
264 Month 7 4756 (4152-5448) 2099 (1663-2649)
HAVRIX and ENGERIX-B 268 Month 1 444 6
269 Month 2 257 18
269 Month 7 2948 (2638-3294) 1871 (1428-2450)

It was noted that the antibody titers achieved 1 month after the final dose of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) were higher than titers achieved 1 month after the final dose of HAVRIX in these clinical trials. This may have been due to a difference in the recommended dosage regimens for these 2 vaccines, whereby TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) vaccinees received 3 doses of 720 EL.U. of hepatitis A antigen at 0, 1, and 6 months, whereas HAVRIX vaccinees received 2 doses of 1440 EL.U. of the same antigen (at 0 and 6 months). However, these differences in peak titer have not been shown to be clinically significant.

Two clinical trials involving a total of 129 subjects demonstrated that antibodies to both HAV and HBV persisted for at least 4 years after the first vaccine dose in a 3-dose series of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) , given on a 0-, 1-, and 6-month schedule. For comparison, after the recommended immunization regimens for HAVRIX and ENGERIX-B, respectively, similar studies involving a total of 114 subjects have shown that seropositivity to HAV and HBV also persists for at least 4 years.

The effect of age on immune response to TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) was studied in 2 trials comparing subjects over 40 years of age (n = 183, mean age = 48 in one trial and n = 72, mean age = 50 in the other) with those ≤40 (n = 191; mean age 32.5). The response to the hepatitis A component of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) declined slightly with age, but >99% of subjects achieved protective antibody levels in both age groups, and antibody titers were comparable to 2 doses of hepatitis A vaccine alone in age matched controls.

The response to hepatitis B immunization is known to decline in vaccinees over 40 years of age. TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) elicited a seroprotective response to hepatitis B in 97% of younger subjects and 93% to 94% of the older subjects, as compared to 92% of older subjects given hepatitis B vaccine alone. Geometric mean titers elicited by TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) were 2,285 in the younger subjects and 1,890 or 1,038 for the older subjects in the 2 trials. Hepatitis B vaccine alone gave titers of 2,896 in younger subjects and 1,157 in those over 40 years of age.

It has been shown in open randomized clinical trials that combining the hepatitis A antigen with the hepatitis B surface antigen in TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) resulted in comparable anti-HAV or anti-HBsAg titers, relative to vaccination with the individual monovalent vaccines or the concomitant administration of each vaccine in opposite arms.

Accelerated Dosing Schedule: In 496 healthy adults, the safety and immunogenicity of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) given on a 0-, 7-, and 21- to 30-day schedule followed by a booster dose at 12 months (N = 250), was compared to separate vaccinations with monovalent hepatitis A vaccine (HAVRIX at 0 and 12 months) and hepatitis B vaccine (ENGERIX-B at 0, 1, 2, and 12 months) as a control group (N = 246).

Following a booster dose at month 12, the seroprotection rate for hepatitis B and seroconversion rate for hepatitis A at month 13 (the coprimary endpoints) following TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) were non-inferior as compared to the control group. The immune responses for the According to Protocol (ATP) cohort for immunogenicity are shown in Table 4 and Figure 1.

At day 37, following 3 doses of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) , the seroprotection rate for hepatitis B was 63.2% and in the control group, who received 2 doses of ENGERIX-B, was 43.5%. This difference of 19.76% [95% CI for the difference is 10.16% to 28.99%] is statistically significant (p <0.001). No statistical significant difference in the hepatitis A seroconversion rates was observed between groups at day 37. At day 90, the hepatitis A seroconversion rate following TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) was 100% compared to 95.6% in the control group (p = 0.004). At month 12 before the booster dose, the hepatitis A seroconversion rates between groups, 96.9% following TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) and 86.9% in the control group, were statistically significantly different (p <0.001).

Table 4. Seroconversion and Seroprotection Rates Up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

  Timepoint TWINRIX* HAVRIX and ENGERIX-B†
    (N = 194-204) (N = 197-207)
% Seroconversion for Hepatitis A‡
(95% CI)
Day 37 98.5 (95.8-99.7) 98.6 (95.8-99.7)
Day 90 100 (98.2-100) 95.6 (91.9-98.0)
Month 12 96.9 (93.4-98.9) 86.9 (81.4-91.2)
Month 13 100 (98.1-100) 100 (98.1-100)
% Seroprotection for Hepatitis B§
(95% CI)
Day 37 63.2 (56.2-69.9) 43.5 (36.6-50.5)
Day 90 83.2 (77.3-88.1) 76.7 (70.3-82.3)
Month 12 82.1 (75.9-87.2) 77.8 (71.3-83.4)
Month 13 96.4 (92.7-98.5) 93.4 (89.0-96.4)
*TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) given on a 0-, 7-, and 21- to 30-day schedule followed by a booster at month 12.
†HAVRIX 1440 EL.U./1 mL given on a 0- and 12-month schedule and ENGERIX-B, 20 mcg/1 mL) given on a 0-, 1-, 2-, and 12-month schedule.
‡Anti-HAV titer =assay cut-off: 15 mIU/mL (anti-HAV Behring).
§Anti-HBsAg titer =10 mIU/mL (AUSAB®).

Figure 1. Seroconversion and Seroprotection Rates Up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

Seroconversion and Seroprotection Rates Up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

Immune Response to Simultaneously Administered Vaccines: Limited immunogenicity data are available on the concurrent administration of TWINRIX (hepatitis a inactivated & hepatitis b (recombinant) vaccine) with other vaccines.

References

1. Dienstag JL, Routenberg JA, Purcell RH, et al. Foodhandler-associated outbreak of hepatitis type A. An immune electron microscopic study. Ann Intern Med 1975;83:647-650.
2. Mackowiak PA, Caraway CT, Portnoy BL. Oyster-associated hepatitis: Lessons from the Louisiana experience. Am J Epidemiol 1976;103(2):181-191.
3. Woodson RD, Clinton JJ. Hepatitis prophylaxis abroad. Effectiveness of immune serum globulin in protecting Peace Corps volunteers. JAMA 1969;209(7):1053-1058.
4. Krugman S, Giles JP. Viral hepatitis. New light on an old disease. JAMA 1970;212(6):1019-1029.
5. Hadler SC, Erben JJ, Francis DP, et al. Risk factors for hepatitis A in day-care centers. J Infect Dis 1982;145(2):255-261.
6. Hadler SC. Global impact of hepatitis A virus infection changing patterns. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore, MD: Williams & Wilkins; 1991:14-20.
7. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. 10th ed. Washington DC: Public Health Foundation; 2007:197-234.
8. Lemon SM. Type A viral hepatitis. New developments in an old disease. N Engl J Med 1985;313(17):1059-1067.
9. Sjogren MH, Tanno H, Fay O, et al. Hepatitis A virus in stool during clinical relapse. Ann Intern Med 1987;106:221-226.
10. Chiriaco P, Guadalupi C, Armigliato M, et al. Polyphasic course of hepatitis type A in children. J Infect Dis 1986;153(2):378-379.
11. Data on file (TWR101), GlaxoSmithKline.
12. Koff RS. Hepatitis B and hepatitis D. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia, PA: WB Saunders Company; 1992:709-716.
13. Frisch-Niggemeyer W, Ambrosch F, Hofmann H. The assessment of immunity against hepatitis B after vaccination. J Bio Stand 1986;14(3):255-258.
14. Beasley RP, Hwang LY, Stevens CE, et al. Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo-controlled trial. Hepatology 1983;3(2):135-141.
15. Centers for Disease Control and Prevention. Proposed vaccine information materials for hepatitis B, Haemophilus influenza type B (Hib), varicella (chickenpox), and measles, mumps, rubella (MMR) vaccines. Federal Register September 3, 1998;63(171):47026-47031.
16. Chang MH, Chen CJ, Lai MS. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336(26):1855-1859.
17. Lee MS, Kim DH, Kim H, et al. Hepatitis B vaccination and reduced risk of primary liver cancer among male adults: A cohort study in Korea. Int J Epidemiol 1998;27:316-319.

Last reviewed on RxList: 4/30/2007
This monograph has been modified to include the generic and brand name in many instances.

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