Twinrix

CLINICAL PHARMACOLOGY

Mechanism Of Action

Hepatitis A

The course of infection with hepatitis A virus (HAV) is extremely variable, ranging from asymptomatic infection to fulminant hepatitis.3

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. Seroconversion is defined as antibody titers equal to or greater than the assay cut-off (cut-off values vary depending on the assay used) in those previously seronegative.

Hepatitis B

Infection with hepatitis B virus (HBV) can have serious consequences including acute massive hepatic necrosis and chronic active hepatitis. Chronically infected persons are at increased risk for cirrhosis and hepatocellular carcinoma.

Antibody concentrations ≥ 10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B virus infection.4

Clinical Studies

Immunogenicity: Standard 0-, 1-, And 6-Month Dosing Schedule

In 11 clinical trials, sera from 1,551 healthy adults 17 to 70 years of age, including 555 male subjects and 996 female subjects, were analyzed following administration of 3 doses of TWINRIX on a 0-, 1-, and 6-month schedule. Seroconversion (defined as equal to or greater than assay cut-off depending on assay used) for antibodies against HAV was elicited in 99.9% of vaccinees, and protective antibodies (defined as ≥ 10 mIU/mL) against HBV surface antigen were detected in 98.5% of vaccinees, 1 month after completion of the 3-dose series (Table 2).

Table 2: Seroconversion and Seroprotection Rates in Worldwide Clinical Trials

TWINRIX Dose N % Seroconversion for Hepatitis Aa % Seroprotection for Hepatitis Bb
1 1,587 93.8 30.8
2 1,571 98.8 78.2
3 1,551 99.9 98.5
a Anti-HAV titer ≥ assay cut-off: 20 mIU/mL (HAVAB Test) or 33 mIU/Ml (ENZYMUN-TEST®).
b Anti-HBsAg titer ≥ 10 mIU/mL (AUSAB® Test).

One of the 11 trials was a comparative trial conducted in a US population given either TWINRIX (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 the 773 adults (18 to 70 years of age) 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 and 269 subjects received HAVRIX and ENGERIX-B. Seroconversion rates against HAV and seroprotection rates against HBV are presented in Table 3; GMTs are presented in Table 4. The absolute difference in anti-HAV seropositivity rates between groups was 0.36% (90% CI: -1.8, 3.1). Non-inferiority in terms of anti-HAV response was demonstrated (lower limit of the 90% CI was higher than the prespecified non-inferiority criterion of -4.3%). The absolute difference in anti-HBsAg seroprotection rates between groups was 2.8% (90% CI: -1.3, 7.7). Non-inferiority in terms of anti-HBV response was demonstrated (lower limit of the 90% CI was higher than the prespecified non-inferiority criterion of -9.4%).

Table 3: Seroconversion and Seroprotection Rates in a US Clinical Trial

Vaccine N Timepoint % Seroconversion for Hepatitis Aa (95% CI) % Seroprotection for Hepatitis Bb (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)
CI = Confidence Interval
a Anti-HAV titer ≥ assay cut-off: 33 mIU/mL (ENZYMUN-TEST).
b Anti-HBsAg titer ≥ 10 mIU/mL (AUSAB Test).

Table 4: Geometric Mean Titers in a 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)
GMT = Geometric mean titer; CI = Confidence Interval

Since the immune responses to hepatitis A and hepatitis B induced by TWINRIX were non-inferior to the monovalent vaccines, efficacy is expected to be similar to the efficacy for each of the monovalent vaccines.

The antibody titers achieved 1 month after the final dose of TWINRIX were higher than titers achieved 1 month after the final dose of HAVRIX in this clinical trial. This may have been due to a difference in the recommended dosage regimens for these 2 vaccines, whereby TWINRIX 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.

Immunogenicity: Accelerated Dosing Schedule (Day 0-, 7-, and 21-30, Month 12)

In 496 healthy adults, the safety and immunogenicity of TWINRIX 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, seroprotection rates for hepatitis B and seroconversion rates for hepatitis A at month 13 following TWINRIX were non-inferior to the control group. The absolute difference in anti-HBs seroprotection rates between groups (HAVRIX + ENGERIX-B minus TWINRIX) was -2.99 (95% CI: -7.80, 1.49). Non-inferiority was demonstrated as the upper limit of the 95% CI was lower than the pre-defined limit of 7%. The absolute difference in anti-HAV seroprotection rates between groups (HAVRIX + ENGERIX-B minus TWINRIX) was 0 (95% CI: -1.91, 1.94). Non-inferiority was demonstrated as the upper limit of the 95% CI was lower than the pre-defined limit of 7%. The immune responses are presented in Table 5.

Table 5: Seroconversion and Seroprotection Rates up to One Month After the Last Dose of Vaccines (According To Protocol Cohort)

  Timepoint TWINRIXa
(N = 194-204)
HAVRIX and ENGERIX-Bb
(N = 197-207)
% Seroconversion for Hepatitis Ac(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 Bd (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)
CI = Confidence Interval
a TWINRIX given on a 0-, 7-, and 21- to 30-day schedule followed by a booster at month 12.
b 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.
c Anti-HAV titer ≥ assay cut-off: 15 mIU/mL (anti-HAV Behring Test).
d Anti-HBsAg titer ≥ 10 mIU/mL (AUSAB Test).

Immunogenicity In Adults Older Than 40 Years Of Age

The effect of age on immune response to TWINRIX was studied in 2 trials. The first trial evaluated subjects 41 to 63 years of age (N = 72; mean age = 50). All subjects were seropositive for anti-HAV antibodies following the third dose of TWINRIX. For the hepatitis B response, 94% of subjects were seroprotected after the third dose of TWINRIX.

The second trial included subjects 19 years of age and older with a comparison between those older than 40 years of age (N = 183, 41 to 70 years of age; mean age = 48) with those 40 years of age or younger (N = 191; 19 to 40 years of age; mean age 33). Over 99% of subjects in both age groups achieved a seropositive response for anti-HAV antibodies and GMTs were comparable between the age groups. In the older subjects who received TWINRIX, 92.9% (95% CI: 88.2, 96.2) achieved seroprotection against hepatitis B compared to 96.9% (95% CI: 93.3, 98.8) of the younger subjects. The GMT was 1,890 mIU/mL in the older subjects compared to 2,285 mIU/mL in the younger subjects.

Duration Of Immunity

Two clinical trials involving a total of 129 subjects demonstrated that antibodies to both HAV and HBV surface antigen persisted for at least 4 years after the first vaccine dose in a 3-dose series of TWINRIX, 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.

REFERENCES

3. Lemon SM. Type A viral hepatitis: new developments in an old disease. N Engl J Med. 1985;313(17):1059-1067.

4. Frisch-Niggemeyer W, Ambrosch F, Hofmann H. The assessment of immunity against hepatitis B after vaccination. J Bio Stand. 1986;14(3):255-258.

Last reviewed on RxList: 8/29/2014
This monograph has been modified to include the generic and brand name in many instances.

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