Impaired response to hepatitis B vaccine in HIV infected children G . Z u i n **, N. Principi*, R. T o r n a g h i * , S. P a c c a g n i n i * , M. Re*, E. M a s s i r o n i * and M.C. Ragni t

Eighteen human immunodeficiencv virus ( HIV) vertically infected children ( H I V group) and 33 seroreverted children ( S R group), who had completed hepatitis B vaccination (Engerix B, 20 p9 dose) were studied. Four out o f 18 (22%) H I V children failed to develop protective antibody levels (anti-HBs titres < 10 m l U ml- 1) compared with 1 out o f 33 (3%) SR children (p < 0.05). Magnitude o f response among H I V children was significantly lower than among SR children. In H I V children the probability that anti-HBs titres persist above the protective levels was significantly lower than in the SR group at any time during the 24 month follow-up. These results show that H I V children have a suboptimal response to hepatitis B immunization and the protection is less durable. Further studies are needed to determine the optimal protocol for hepatitis B immunization in H I V children. Keywords: Humanlmmunodeficmncyvirus (HIV), hepatlUs B vaccine,impaired response,children

INTRODUCTION

SUBJECTS A N D M E T H O D S

The epidemiological similaratles of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections account for the risk of transmission of both infections in children born to HIV positive mothers. Such children therefore represent a population in which an HBV vaccination programme may be recommended. Unfortunately, HIV infected children may not respond optimally to immunization, thereby dimimshmg the efficacy of the vaccines 1-3. This is likely to be true also after HBV immumzation. Recent reports indicate that the antibody response is impaired after hepatitis B immunization of haemophilic adults and children with HIV infection4-6. Few data are available for children with vertically transmitted HIV infecnonV; babies immunized at birth developed a good response to the vaccine, but follow-up information is lacking8. The aim of this study was to examine specific antibody response to hepatitis B vaccine in infants and children born to HIV infected mothers. We examined whether the children's responsiveness to hepatitis B immunization and the persistence of postimmunization levels of antibody were influenced by coexisting HIV refection

Study groups

*Paediatrlc Department IV, University of Milan, and tLaboratory of Microbiology, Ospedale L Sacco, Via G.B GrassJ 74, 20157 Milano, Italy. tTo whom correspondence should be addressed. (Received 13 January 1992, revised 8 April 1992; accepted 12 May 1992)

0264-410)(/92/120857-04 ~ 1992 Butterworth-Hememann Ltd

We studied 51 infants and children, born to HIV infected mothers, who had completed hepatitis B vaccination. The children were classified according to the CDC criteria 9. At the time of the first dose of vaccine, 15 were considered to be asymptomatlc infected children (7 P1A and 8 P1B), eight were older than 18 months and had lost HIV antibodies, thus being seronegative; in the remaining 28 young children the stage of infection was indeterminate (P0). During the follow-up period, among the P0 group 25 children reverted to seronegativity and three, who demonstrated persistence of HIV antibodies and the occurrence of symptoms suggesting symptomatic HIV infection, were considered to be definitely infected. Thus two study groups were identified, the first consisted of 33 children who seroreverted and became seronegative (SR group) and the second of 18 HIV infected children (HIV group; 4 P2, 12 P1B, 2 P1A). There were 17 males in the SR group and eight males in the HIV group, respectively. At the beginning of the immunization schedule no child had serological markers of previous HBV infection. In 19 cases (17 SR and two HIV) the vaccination was initiated within the first 15 days of hfe; mean age (s.d.; range) at the time of the first immunizanon was 15.l (13.4; 1-44) months for the remaining SR children compared with 24.2 (18.3; 3-56) for the HIV group (p > 0.05 ). Three babies born to HBsAg posxtive mothers were also given passwe prophylaxis with hepatins B lmmunoglobulin (HBIG, 0.5 ml injecnon administered

Vaccine, Vol 10, Issue 12, 1992 857

Hepatttls B vaccmatton of HIV infected chtldren. G Zum et al

intramuscularly m a different site than the vaccine). Two HIV infected children were given anti-infective prophylaxis with intravenous lmmunoglobuhn (400 mg kg 1 body weight every 28 days) during the vaccination schedule to prevent sertous infecuons according to the recommendattons of the National Institute of Child Health 1o

Immunization schedule In all cases a recombinant vaccine (Engerix B, SmithKline Blologtcals, Rixensart, Belgium) was given as a series of three 20/~g intramuscular doses: the first two injections were administered a month apart, and the third dose was given 6 months after the first. The site of rejection was the buttock area for newborns and l-month-old infants and the deltoid region for older infants and children.

Statistical analysis Fisher's exact test was used for d~fferences between proportmns, and the Student's t test for differences between means; log transformation was applied to anubody tltres. Persistence over the ttme of protective antibody levels was explored by the K a p l a n - M e i e r product-limit method; the C o x - M a n t e l log-rank test was used to test the d~fference between the persistence functions of mfected and non-infected children. The 95% confidence intervals were also calculated for the differences between perststence proportions at some pre-selected ttmes. Pearson's correlation coefficients were calculated. RESULTS

Study design To assess the response to ~mmunization and the persistence of specific antibodxes, serum samples were obtained at 2-4, 6 8, 12, 18 and 24 months after the third dose of vaccine and assayed for anti-hepatitis B surface antigen antibodies (anta-HBs). Children who did not develop protective antl-HBs txtres ( > 10 m I U m l - 1 ) 2 4 months after full immunization were considered to be non-responders. A fourth (booster) dose of vaccine (Engenx B, 20/~g) was admlmstered in non-responders or in those children whose specific antibodies had fallen below the protective levels. Such chtldren were followed as a separate group from the ttme of the booster dose In these children serum samples were obtained 2 4 months after the booster dose Determination of lymphocyte subpopulations (CD4 + , C D 8 + , C D 1 9 + ) was made before the beginning, at the end of immunization schedule and before the booster dose in each patient.

Laboratory methods Levels of antl-HBs were measured usmg a commercially avadable enzyme lmmunoassay (IMx AUSAB, Abbott Laboratories, USA). Anti-HBs titres were expressed in m l U ml-1 Diagnosis of HIV mfection was made for children older than 15 months by both enzyme-linked tmmunosorbent assay (ELISA) and Western blot assay of antibody against HIV: for infants under 15 months,

Table 1

HIV infection was confirmed by both posltivlty of HIV antigen and polymerase chain reactmn.

Among the SR group, HB vaccine yielded a good antibody response, only 1 out of 33 ( 3 % ) SR infants and children failed to respond to vaccination (Table I ). In SR children, the interval between birth and start of the lmmumzatlon schedule did not influence antl-HBs levels 2 4 months after the third dose (r = 0.11; p > 0.05) HIV infected children showed a suboptimal response to vaccine; four of them (22%) faded to develop a protective antibody level (p < 0 . 0 5 versus SR); moreover, the magmtude of the response was sigmficantly lower than in SR children. Also m HIV children, age did not significantly influence antibody levels at 2 4 months (r = - 0 . 2 9 , p > 0.05). When HIV infected children were classified according to the stage of illness, two out of 14 ( 14% ) asymptomatac infected children ( P I ) and two out of four (50%) symptomatic cases (P2) showed no protecttve antt-HBs levels after full immunization. Following the three doses of vaccine, all P2 children had antl-HBs tltres < 1 0 0 m I U m l - t During the post~mmumzauon follow-up, geometric mean ant~-HBs titres (log mean _+ s.d.) in HIV compared with SR children were respectively 85 (4.4 + 1.82) versus 1631.7 (7.3 _+ 1.4) (p

Impaired response to hepatitis B vaccine in HIV infected children.

Eighteen human immunodeficiency virus (HIV) vertically infected children (HIV group) and 33 seroreverted children (SR group), who had completed hepati...
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