0036-9330/92/33921138 $2.00 in USA © 1992 Scottish Medical Journal
Scot Med J 1992; 37: 138-141
ZIDOVUDINE THERAPY IN COMBINATION WITH INTRAVENOUS IMMUNOGLOBULIN IN HIV INFECTED CHILDREN N. Croft, PL. Yap*, J.Y.Q. Mok, R.A. Hague#, S.M. Burns**. Regional Infectious Diseases Unit, City Hospital, Edinburgh, *Edinburgh & S.E. Scotland Blood Transfusion Service, #Department of Paediatrics, Royal Victoria Hospital, Newcastle on Tyne, **Regional Virus Laboratory, City Hospital Edinburgh.
Abstract: There is little published data on the concomitant use ofzidovudine and intravenous immunoglobulin (IVIgG). In this paper we review our experience offour HIV-1 infected children treated with zidovudine for periods of 19-33 months (mean 26.5 months) subsequent to starting IV IgG for period of18-20 months (mean 19 months). In these children the only clear benefit wefound was in one child who had developed HIV encephalopathy which resolved after starting zidovudine. The respective roles ofzidovudine and intravenous immunoglobulin in HIV-1 infected children need to be clarified in larger comparative trials. Key words: Children, HlV-l, zidovudine, intravenous immunoglobulin
Introduction
Z
idovudine (azidothymidine) has been shown to delay the progression ofHlV disease in both symptomatic and asymp1 tomatic adults. ,2 Although zidovudine can be safely administered to children with advanced HlV disease3 the indications, dosage, benefits and side effects of zidovudine in children with less severe disease are less clearly defined. Data on the long term (more than 18 months) usage of zidovudine on children is also limited. Intravenous immunoglobulin (IV IgG) therapy has been shown to be beneficial prior to starting zidovudine4,5but no information is available on the additional use of zidovudine to IV IgG therapy in children. We have therefore assessed the benefits and side effects of adding zidovudine treatment to HlV infected children already on IV IgG infusions.
Patients and methods Four HlV infected patients were studied from January 1986 to December 1990, the relevant patient details are shown in Table I. The patients (Cases 1-4) were on zidovudine for 19 to 33 months (mean 26.5 months) with a total usage of 106 months. All four patients were on IV IgG therapy (200 mg/kg every three weeks) 4 for recurrent bacterial infections as previously described which preceded the zidovudine by 18 to 20 months (mean 19 months). The indications for starting zidovudine differed between the four cases. All showed persistently falling CD4 counts with at least two absolute counts of less than 1.0 x 109/1. Case 2 showed increasing mv antigenaemia and loss ofHlV core antibody. Case 3 also had widespread molluscum contagiosium and case 4 developed a gross motor deficit with a nuclear magnetic resonance scan showing cerebral atrophy. The initial dosage used in all four patients was 14mg/kg/day (approximately 2/day) 300mg/m given in three doses. Subsequent dosage changes were based on recommendations from the manufacturers (Wellcome, Beckenham UK) according to experience from other clinical trials and are documented in Table 1. Case 4 remained on the same dosage throughout because of an initial good clinical response as shown by resolution of his clinical and radiological Correspondence to: N. Croft, Regional Infectious Diseases Unit, City Hospital, Greenbank Drive, Edinburgh EHIO 5SB.
138
findings. From March 1988 until March 1989, an intravenous preparation (20 mg/ml) was used, added to flavoured drinks. Subsequently, an oral syrup (lOmg/ml) became available. All four patients were seen for clinical review and IV IgG at three weekly intervals. At each visit a history of symptoms was taken, with specific enquiry for any infection. Medical examination (including height and weight) was performed and blood was taken for full blood count, CD4 and CDs lymphocyte counts, serum immunoglobulins, HlV antibody and HlV antigen. HlV culture was performed every three months. Viral and bacteriological cultures of the nose the throat were sent on alternate visits, or if clinically indicated.
Results Clinical Although the intravenous preparation used initially was said to taste extremely unpleasant, compliance was good. During the study period there were no gastro-intestinal side effects such as nausea and vomiting previously reported in adult patients. No change in dosage or cesssation of therapy was required. One patient (case 3) developed headache, muscle pains and lethargy for two weeks after starting zidovudine but this settled spontaneously without dosage alteration. Compliance of all patients appeared to be good as shown by significant and sustained increase in their mean corpuscular volumes after starting treatment (Mean MCV prior to zidovudine 80fl, nine months aftger commencing therapy 101 £1). Case 4, who had developed a gross motor deficit suggestive of HIV encephalopathy had a magnetic resonance scan performed that showed cortical atrophy and periventricular high intensity signals. Within six months of starting zidovudine his gross motor deficit had fully recovered and follow up MRI scan was reported as normal. Cases 2, 3 and 4 showed a reduction of hepatosplenomagaly during the follow up period. In the four cases on zidovudine the rate ofweight gain, frequence of proven bacterial and viral infections, reported infections (without laboratory confirmation), and number of days spent in hospital (see Table II) were studied using paired t tests comparing the period on IV IgG only and IV IgG plus zidovudine. In all these
Croft, Yap, MOk, Hague, Burns
Zidovudinetherapy
Patient 2
parameters there was no significant change between the two periods.
.p~la:.:.te=l:::.et:.=s--=x~10=--9....:./-=L
---,
400,... 360
Laboratory No child developed recognised haematological side effects of zidovudine such as anaemia or neutropenia apart from Case 2 who did so only after starting chemotherapy for a Ewing's sarcoma. Three of the four patients were thrombocytopenic during the study period. The platelet count (Fig 1) in cases 2 and 4 showed a gradual increase after starting zidovudine although this trend had started prior to the initiation of therapy. Case 3 showed a temporary increase of platelet count but has lately returned to pre-treatment levels. The CD4lymphocyte counts (Fig 2) in cases 3 and 4 showed a transient increase and have since stayed stable. Case 1 showed no change in CD4 count whereas CD4 counts in case 2 gradually decreased over the period studied. However, these latter two cases had shown rapid falls in the CD4count prior to commencing treatment which may have helped stabilise the counts. The serum IgG, IgA and IgM levels showed no change in any of the patients. Cases 2 and 3 have both become mv antigen positive after starting zidovudine. The freqnency of positive mv cultures in all patients was unchanged.
300 260 200 160 100 60 o.l....----,--.,---r--.------r--,---.---.-----,--,----' ~ ~ ~ ~ 0 6 ro ~ ro 25 30 35
Months on Zidovudine
Patient 3 Platelets x 10 9/L
400r--------~-------__,
350 300 250 200 150 100
60 oL---'-_.L---'-_.L---'-_.L---'-_..L---L_-'---...... ~ ~ 4 ~ 0 a ro ~ ro 25 30 36
Discussion
Months on Zidovudlne
There is relatively little published data on the use of zidovudine in paediatric HIV infection at present. In adults, recent recommendations for starting zidovudine include two successive CD4 lympocyte counts of
Scot Med J 1992; 37: 138-141
ZIDOVUDINE THERAPY IN COMBINATION WITH INTRAVENOUS IMMUNOGLOBULIN IN HIV INFECTED CHILDREN N. Croft, PL. Yap*, J.Y.Q. Mok, R.A. Hague#, S.M. Burns**. Regional Infectious Diseases Unit, City Hospital, Edinburgh, *Edinburgh & S.E. Scotland Blood Transfusion Service, #Department of Paediatrics, Royal Victoria Hospital, Newcastle on Tyne, **Regional Virus Laboratory, City Hospital Edinburgh.
Abstract: There is little published data on the concomitant use ofzidovudine and intravenous immunoglobulin (IVIgG). In this paper we review our experience offour HIV-1 infected children treated with zidovudine for periods of 19-33 months (mean 26.5 months) subsequent to starting IV IgG for period of18-20 months (mean 19 months). In these children the only clear benefit wefound was in one child who had developed HIV encephalopathy which resolved after starting zidovudine. The respective roles ofzidovudine and intravenous immunoglobulin in HIV-1 infected children need to be clarified in larger comparative trials. Key words: Children, HlV-l, zidovudine, intravenous immunoglobulin
Introduction
Z
idovudine (azidothymidine) has been shown to delay the progression ofHlV disease in both symptomatic and asymp1 tomatic adults. ,2 Although zidovudine can be safely administered to children with advanced HlV disease3 the indications, dosage, benefits and side effects of zidovudine in children with less severe disease are less clearly defined. Data on the long term (more than 18 months) usage of zidovudine on children is also limited. Intravenous immunoglobulin (IV IgG) therapy has been shown to be beneficial prior to starting zidovudine4,5but no information is available on the additional use of zidovudine to IV IgG therapy in children. We have therefore assessed the benefits and side effects of adding zidovudine treatment to HlV infected children already on IV IgG infusions.
Patients and methods Four HlV infected patients were studied from January 1986 to December 1990, the relevant patient details are shown in Table I. The patients (Cases 1-4) were on zidovudine for 19 to 33 months (mean 26.5 months) with a total usage of 106 months. All four patients were on IV IgG therapy (200 mg/kg every three weeks) 4 for recurrent bacterial infections as previously described which preceded the zidovudine by 18 to 20 months (mean 19 months). The indications for starting zidovudine differed between the four cases. All showed persistently falling CD4 counts with at least two absolute counts of less than 1.0 x 109/1. Case 2 showed increasing mv antigenaemia and loss ofHlV core antibody. Case 3 also had widespread molluscum contagiosium and case 4 developed a gross motor deficit with a nuclear magnetic resonance scan showing cerebral atrophy. The initial dosage used in all four patients was 14mg/kg/day (approximately 2/day) 300mg/m given in three doses. Subsequent dosage changes were based on recommendations from the manufacturers (Wellcome, Beckenham UK) according to experience from other clinical trials and are documented in Table 1. Case 4 remained on the same dosage throughout because of an initial good clinical response as shown by resolution of his clinical and radiological Correspondence to: N. Croft, Regional Infectious Diseases Unit, City Hospital, Greenbank Drive, Edinburgh EHIO 5SB.
138
findings. From March 1988 until March 1989, an intravenous preparation (20 mg/ml) was used, added to flavoured drinks. Subsequently, an oral syrup (lOmg/ml) became available. All four patients were seen for clinical review and IV IgG at three weekly intervals. At each visit a history of symptoms was taken, with specific enquiry for any infection. Medical examination (including height and weight) was performed and blood was taken for full blood count, CD4 and CDs lymphocyte counts, serum immunoglobulins, HlV antibody and HlV antigen. HlV culture was performed every three months. Viral and bacteriological cultures of the nose the throat were sent on alternate visits, or if clinically indicated.
Results Clinical Although the intravenous preparation used initially was said to taste extremely unpleasant, compliance was good. During the study period there were no gastro-intestinal side effects such as nausea and vomiting previously reported in adult patients. No change in dosage or cesssation of therapy was required. One patient (case 3) developed headache, muscle pains and lethargy for two weeks after starting zidovudine but this settled spontaneously without dosage alteration. Compliance of all patients appeared to be good as shown by significant and sustained increase in their mean corpuscular volumes after starting treatment (Mean MCV prior to zidovudine 80fl, nine months aftger commencing therapy 101 £1). Case 4, who had developed a gross motor deficit suggestive of HIV encephalopathy had a magnetic resonance scan performed that showed cortical atrophy and periventricular high intensity signals. Within six months of starting zidovudine his gross motor deficit had fully recovered and follow up MRI scan was reported as normal. Cases 2, 3 and 4 showed a reduction of hepatosplenomagaly during the follow up period. In the four cases on zidovudine the rate ofweight gain, frequence of proven bacterial and viral infections, reported infections (without laboratory confirmation), and number of days spent in hospital (see Table II) were studied using paired t tests comparing the period on IV IgG only and IV IgG plus zidovudine. In all these
Croft, Yap, MOk, Hague, Burns
Zidovudinetherapy
Patient 2
parameters there was no significant change between the two periods.
.p~la:.:.te=l:::.et:.=s--=x~10=--9....:./-=L
---,
400,... 360
Laboratory No child developed recognised haematological side effects of zidovudine such as anaemia or neutropenia apart from Case 2 who did so only after starting chemotherapy for a Ewing's sarcoma. Three of the four patients were thrombocytopenic during the study period. The platelet count (Fig 1) in cases 2 and 4 showed a gradual increase after starting zidovudine although this trend had started prior to the initiation of therapy. Case 3 showed a temporary increase of platelet count but has lately returned to pre-treatment levels. The CD4lymphocyte counts (Fig 2) in cases 3 and 4 showed a transient increase and have since stayed stable. Case 1 showed no change in CD4 count whereas CD4 counts in case 2 gradually decreased over the period studied. However, these latter two cases had shown rapid falls in the CD4count prior to commencing treatment which may have helped stabilise the counts. The serum IgG, IgA and IgM levels showed no change in any of the patients. Cases 2 and 3 have both become mv antigen positive after starting zidovudine. The freqnency of positive mv cultures in all patients was unchanged.
300 260 200 160 100 60 o.l....----,--.,---r--.------r--,---.---.-----,--,----' ~ ~ ~ ~ 0 6 ro ~ ro 25 30 35
Months on Zidovudine
Patient 3 Platelets x 10 9/L
400r--------~-------__,
350 300 250 200 150 100
60 oL---'-_.L---'-_.L---'-_.L---'-_..L---L_-'---...... ~ ~ 4 ~ 0 a ro ~ ro 25 30 36
Discussion
Months on Zidovudlne
There is relatively little published data on the use of zidovudine in paediatric HIV infection at present. In adults, recent recommendations for starting zidovudine include two successive CD4 lympocyte counts of
