1166
Position in SIR,—The studies dismissed in
your March 31 editorial entitled "Stand and deliver" were not inspired by a broad understanding of the physiology of parturition. It is not the position itself which seems to be important during the very last contractions but the need to be upright, which goes with a certain hormonal balance. When a woman can give birth in an atmosphere of privacy (small room, dim light, nobody giving orders or behaving as an observer) the "fetus ejection reflex"l is characterised by a sudden urge to adopt a vertical position. The need to be active and to grasp something, the need to drink, and complete dilatation of the pupils are strongly suggestive of a rush of catecholamines. The paradoxical oxytocic effect of adrenaline has been known for a long rime.2,3 Now it can even be explained. With high concentrations of adrenaline effects on the excitatory ot-receptors predominate. Also a rush of adrenaline triggers a transitory, non-selective release of free fatty acids. The dominant and most abundant such acid is arachidonic, the metabolites of which are usually stimulants of uterine concentrations. In easy and undisturbed deliveries the need to be upright often lasts several minutes after the birth, so that the mother is still alert at the time of the first contact with the baby. We need studies of the feeling of privacy and the need to be upright during the last contractions. This will not be easy.
Maternity Service, Centre Hospitaller General, 45300 Pithiviers, France
remaining 5 children without NANBH. 1 of the 14 children who did not seroconvert to HCV and 2 of the 24 children born to anti-HCV negative mothers had HIV infection without HIV-related disease throughout the follow-up. Our preliminary data suggest that changes in the matemal cellular immune system induced by HIV infection have the potential for increasing the extent of replication of HCV (when present as a chronic infection) and enhancing the risk of transmission of HCV to the newborn. HIV is the causative agent in AIDS but other factors may enhance infection or disease progression. In our series of infants bom to anti-HIV positive mothers, children whose mothers were anti-HCV positive were more likely to be infected with HIV (12/25 or 48%) than were those whose mothers were anti-HCV negative (2/24 or 8%). Moreover, hepatitis C seems to correlate with accelerated disease progression in HIV-infected children. Thus our findings suggest synergism between the two viruses. Perhaps HCV is lymphotropic-a view supported by the transmission of NANBH by plasma-free leucocyte preparations from the blood of patients with chronic NANBH.3 progress in the
delivery
M. R. ODENT
1. Odent MR. The fetus ejection reflex. Birth 1987; 14: 104-05. 2. Woodbury RA, Hamilton WF, Torpin R. The relationship between abdominal, uterine and arterial pressure during labor. Am J Physiol 1938; 121: 640. 3. Pose SV, Cibils LA, Zuspan FP. Effect of epinephrine infusion on uterine contractility and cardiovascular system. Am J Obstet Gynecol 1962; 84: 297-301.
Maternal-infant transmission of hepatitis C virus and HIV infections: a possible interaction
5th Paediatric Department, Institute of Virology, and Institute of Hygiene, University of Milan, 20142 Milan, Italy
MARCELLO GIOVANNINI ALESSANDRO TAGGER MARIA LISA RIBERO GIANVINCENZO ZUCCOTTI LAURA POGLIANI ANNALISA GROSSI PIERINO FERRONI ALESSANDRO FIOCCHI
Tong MJ, Thursby M, Rakela J, et al. Studies on the maternal-infant transmission of the viruses which cause acute hepatitis. Gastroenterology 1981, 80: 999-1004. 2. Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-64. 3. Hellings JA, van der Veen-du Pne J, Boender P. Transmission of non-A, non-B hepatitis by leucocyte preparations. In Zuckerman AJ, ed. Viral hepatitis and liver 1.
disease. New York: Alan R Liss, 1988: 543-49.
SIR,—The extent of maternal-infant transmission of blood-borne non-A, non-B hepatitis (NANBH) agent(s) is unknown. Transmission of NANBH has been observed in infants born to mothers with acute NANBH in the third but not in the second trimester of pregnancy.! However, transmission from carrier mothers to their children has not been reported. We describe here transmission of hepatitis C virus (HCV) in a large series of children born to mothers at risk of HCV infection by virtue of past or current intravenous drug use. In our area up to 75% of drug abusers are HCV antibody positive, irrespective of HIV seropositivity. 49 children born to HIV-positive mothers between 1987 and 1989 were enrolled in a prospective study of vertical transmission of HIV at the 5th paediatric department, University of Milan. We used an ELISA (Ortho Diagnostic Systems)2 to test for HCV antibody in stored sera collected from mothers and their infants at birth, 1,3, and then every 3 months. No mother showed any clinical evidence of liver disease. 25 (51%) mother/children pairs tested positive for HCV antibody; maternal HCV antibodies fell in these 25 infants to undetectable levels by 2-4 months of age. Active production of HCV antibodies (seroconversion) was found in 11infants between 6 and 12 months of age. Among these 11 seroconverters, 6 showed raised serum alanine transaminase values (70-195 IU/1) between 3 and 12 weeks after birth. NANBH was diagnosed on the usual exclusion criteria. HCV antibodies were still detectable in 8 children (6/6 with NANBH, 2/5 without NANBH), while abnormal transaminase values persisted in 2 of the 6 children with NANBH
throughout the follow-up. Of the 14 children not seroconverting to HCV none had NANBH. All 11children with HCV infection were simultaneously infected with HIV; infection with this virus developed between 4 and 8 months of age. Of the 6 children with NANBH and HIV infection 3 had progressed to AIDS at 12-20 months; 2 of these had died by the age of 2 years; and the remaining 3 (aged 10-16 months) had a more advanced stage of HIV infection. By contrast, HIV infection did not
Zidovudine in post-exposure prophylaxis of health-care workers SIR,- The risk of acquiring HIV infection after exposure to blood from infected patients in health-care settings is small but real.’ An Italian multicentre study estimated the rate of seroconversion to be 0-002 in 956 health-care workersCompliance with recommended precautions3 may reduce this risk but is unlikely to eliminate it. Zidovudine, the only licensed drug with demonstrated in-vivo efficacy against HIV, has been suggested as post-exposure prophylaxis.’*’’’ The risk of HIV infection by occupational exposure is so low that a huge number of exposed health-care workers would be needed to obtain convincing evidence of the efficacy of zidovudine prophylaxis. Moreover, little is known of the toxicity of this drug in healthy people, and data on long-term toxicity, including carcinogenic effects,’ are unknown. In AID S patients the major toxicity has been haemtological, dose-related, and reversible and is rarely in the first month of therapy,so serious acute toxicityis likely to be very unusual with short-course post-exposure prophylaxis in healthy workers in health-care settings. Few reports on zidovudine post-exposure prophylaxis have been published and further data are needed to establish the appropriate dosage and duration of the treatment.4,5 In Italy zidovudine can be dispensed only in licensed public centres. Some of them started to offer the option of prophylaxis to HIV-exposed health-care workers. A network has been established between these centres to collect details of the exposure, the dosage and duration of zidovudine prophylaxis, and adverse effects. 1 nurses, 9 physicians, 5 surgeons, and 1 other health-care worker, all accidentally exposed to blood from an HIV-infected patient, have been treated, after informed consent, in fifteen clinical departments All are being monitored by laboratory tests and clinically, and haB e been enrolled in a one year post-exposure follow-up.
1167
reported exposures were 27 needlesticks, 2 cuts with sharp mucus contaminations, and 2 open wounds. 6 of those given prophylaxis have been treated with a daily dose of 500-800 mg for 4-6 weeks; 4 received 1200 mg daily for 5, 6, 10, and 42 days; and 3 have been treated with 1000-2000 mg per day for the first 3 days, followed by a 4-week course with a reduced dose of 600 mg daily. Finally, 21 health-care workers have been treated with 1000 mg daily for between 5 days and 6 weeks; 17 of them have been treated for at least 28 days. No biochemical or haematological side-effects were recorded. 11 people on a dose of 1000-1200 mg and 1 of 3 during the high-dose stage of stepped treatment reported nausea (10), gastric pain (2), vomiting (2), asthenia (3), diarrhoea (1), or arthralgia (1). These effects were mild and transient; only 1 had to discontinue prophylaxis (just for a day, because of vomiting). The
instruments, 3
Neither seroconversion nor signs/symptoms of acute illness have been observed after follow-up averaging 6 months (range 2-12). The above data show a low and dose-related rate of adverse effects with short-term zidovudine prophylaxis in healthy mdividuals occupationally exposed to HIV. The wide variation in regimens prescribed suggests that clinicians are uncertain about what is an adequate schedule for zidovudine post-exposure prophylaxis, as others have reported too.’,s In the absence of clear data on efficacy, zidovudine prophylaxis cannot be regarded as a mandatory component of post-exposure management. The drug should be offered after high-risk exposures, but the decision rests with the health-care worker, who must be clearly informed about the risk of infection, the rationale for prophylaxis, and the state of knowledge on the short-term and long-term toxicity of the drug. Members of the study group are G. Angarano, C. Arici, A. Cargnel, P. D’Argemo, F. Fiaccadori, A. Ferlini, L. Fruttaldo, G. Macri’, L. Leporace, E. Mignani, P. Narciso, S. Ranieri, A. Scasso, A. Staiti, F. Suter, and S. Vella. The study is supported by the Italian Ministry of Health ISS AIDS Research Project (grant 4203.15ISS).
Coordinating Centre. AIDS Unit (LHU RM/10), Lazzaro Spallanzani Hospital for Infectious Diseases, 00149 Rome, Italy
V. PURO G. IPPOLITO, on
Study Group Occupational Risk of HIV Infection
(abstr). 3 Centers for Disease Control.
4
Institute of Medical Chemistry and University of Innsbruck, A-6020 Innsbruck, Austria
Biochemistry,
DIETMAR FUCHS GILBERT REIBNEGGER ERNST R. WERNER HELMUT WACHTER
the Italian
1. Marcus R. Transmission of human immunodeficiency virus (HIV) in health care settings worldwide. Bull WHO 1989; 67: 577-82. 2. Ippolito G, Angarano G, Arici C, et al. Risk of HIV infection in health care workers exposed to blood and body fluids: the Italian Multicentre Study. 2nd European Conference on Clinical Aspects of HIV Infection (Brussels, March 8-9, 1990): 104
Update: universal precautions for prevention of human hepatitis B virus, and other bloodborne pathogens in health-care setting. MMWR 1988; 37: 24. Henderson DK, Geberdin JL. Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: an interim analysis. J Inf Dis 1989; 160: immunodeficiency
dihydropteridine reductase (DHPR). These enzymes are necessary for the recycling of pterin-cofactors to form the biologically active tetrahydroderivatives. DHFR and DHPR can only reduce quinonoid 7,8 (6H)-dihydropterin derivatives,’4 which are chemically distinct from the common 7,8-dihydro forms. However, Fe3+ induces tautomerisation of 7,8-dihydropterins to the 7,8(6H)dihydro derivative.5 Thus, increased amounts of 7,8dihydroneopterin during cellular immune activation will increase the pool of 7,8(6H)-dihydroneopterin. The latter compound can competitively interfere with DHFR and DHPR.4 The possible relevance of the effects of 7,8(6H)dihydroneopterin on DHPR is further supported by the higher serum phenylalanine seen in HIV-1 seropositive patients than in healthy controls.6 The activity of phenylalanine hydroxylase is dependent on the availability of the cofactor 5,6,7,8tetrahydrobiopterin (BH4). Biopterin concentrations seem to be increased in HIV-1 seropositive patients.7 However, interference by 7,8(6H)-dihydroneopterin with DHPR will decrease the pool of biologically active BH consequently the enzymic conversion of L-phenylalanine to L-tyrosine is reduced. Further evidence of an interaction between 7,8-dihydroneopterin and DHRF and DHPR is provided by a child with atypical phenylketonuria due to 7,8-dihydrobiopterin deficiency who was successfully treated by supplementation with BH,. However, during an infectious episode phenylketonuria symptoms reappeared and BH4 supplementation had to be increased. We assume that during the infectious disease, cell-mediated immune response was induced and 7,8-dihydroneopterin concentrations were increased. 7,8-dihydroneopterin interfered with DHPR and the biochemical recycling ofBH4, and the activity of phenylalanine hydroxylase was reduced.
virus,
321-27. 5. Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine postexposure use MMWR 1990 (suppl 1, Jan
31).
Increased 7,8-dihydroneopterin and reduced methyl-group metabolism in HIV-1 infection SIR,-Dr Surtees and colleagues (March 17, p 619) report reduced methyl-group metabolism in children with HIV-1 infection. We also reported that raised neopterin levels in patients with HIV-1 infection were accompanied by parallel increased concentrations of 7,8-dihydroneopterin. In our study of 150 HIV-1 seropositive patients, 7,8-dihydroneopterin was present at a constant 3-fold higher concentration than neopterin.l This result accords with in-vitro data showing that macrophages on stimulation with interferon produce neopterin and 7,8-dihydroneopterin in a similar proportion .2 Folate concentrations are greatly increased in HIV-1seropositive patients.3 However, the reduced capacity of dihydrofolate reductase (DHFR) to produce the active cofactor may result in reduced bioavailability of 5-methyltetrahydrofolate, as Surtees et al describe. Reduced methyl-group metabolism can be explained by interaction of reduced neopterin derivatives with DHFR and
D, Milstien S, Kramer A, et al. Urinary neopterin concentrations vs total neopterins for clinical utility. Clin Chem 1989; 35: 2305-07. 2. Wemer ER, Werner-Felmayer G, Fuchs D, Hausen A, Reibnegger G, Wachter H. Parallel induction of tetrahydrobiopterin biosynthesis and indoleamine 2,3 dioxygenase activity in human cells and cell lines by interferon-gamma. BiochemJ 1989; 262: 861-66. 3. Beach RS, Mantero Atienza E, Eisdorfer C, Fordyce Baum MK. Altered folate metabolism in early HIV infection. JAMA 1988; 259: 519-20. 4. Vasudevan SG, Shaw DC, Armarego WFF. Dihydropteridine reductase from Escherichia coli. Biochem J 1988; 255: 581-88. 5. Armarego WLF, Randles D. Aerobic oxidation of 5,6,7,8-tetrahydroneopterin. In: Blair JA, ed. Chemistry and biology of pteridines. Berlin: de Gruyter, 1986: 1. Fuchs
423-27. 6.
Ollenschlaeger G, Jansen S, Schindler J, Rasokat H, Schrappe Baecher M, Roth E. Plasma amino add patterns in patients with HIV infection, Clin Chem
1988; 34: 1787-89. 7. Abita JP, Cost H, Milstien S, Kaufman S, Saimot G. Urinary neopterin and biopterin levels in patients with AIDS and AIDS-related complex. Lancet 1985; ii: 51. 8. Leupold D, Wang M, Niederwieser A. Tetrahydrobiopterin monotherapy in two siblings with dihydrobiopterin deficiency. In Wachter H, Curtius HC, Pfleiderer W, eds. Biochemical and clinical aspects of pteridines, vol 1. Berlin: de Gruyter, 1982: 307-17.
HTLV-I/II antibodies in French blood donors SIR,-Human T-lymphotropic virus type
a virus and tropical spastic paraparesis, myelopathy, and polymyositis has also been found in apparently healthy people in Japan, Africa, the Caribbean, and the USA.l,2 Transmission is via blood’ (by transfusion of cellular components or by sharing of needles and syringes among drug addicts), via sexual contact, or from mother to child by breastfeeding. We have looked for HTLV-1 antibody in blood donors in continental France. 45 033 samples were collected by twelve blood banks in different parts of the country and screened by gelatin particle agglutination (Fujirebio) or by ELISA (Abbott, DuPont de Nemours, Organon, or Pharmacia). Repeatedly reactive sera were tested by western blot (DuPont de Nemours) and radioimmunoprecipitation assay. A
associated with adult T-cell
I
(HTLV-I),
leukaemia/lymphoma,
Position in SIR,—The studies dismissed in
your March 31 editorial entitled "Stand and deliver" were not inspired by a broad understanding of the physiology of parturition. It is not the position itself which seems to be important during the very last contractions but the need to be upright, which goes with a certain hormonal balance. When a woman can give birth in an atmosphere of privacy (small room, dim light, nobody giving orders or behaving as an observer) the "fetus ejection reflex"l is characterised by a sudden urge to adopt a vertical position. The need to be active and to grasp something, the need to drink, and complete dilatation of the pupils are strongly suggestive of a rush of catecholamines. The paradoxical oxytocic effect of adrenaline has been known for a long rime.2,3 Now it can even be explained. With high concentrations of adrenaline effects on the excitatory ot-receptors predominate. Also a rush of adrenaline triggers a transitory, non-selective release of free fatty acids. The dominant and most abundant such acid is arachidonic, the metabolites of which are usually stimulants of uterine concentrations. In easy and undisturbed deliveries the need to be upright often lasts several minutes after the birth, so that the mother is still alert at the time of the first contact with the baby. We need studies of the feeling of privacy and the need to be upright during the last contractions. This will not be easy.
Maternity Service, Centre Hospitaller General, 45300 Pithiviers, France
remaining 5 children without NANBH. 1 of the 14 children who did not seroconvert to HCV and 2 of the 24 children born to anti-HCV negative mothers had HIV infection without HIV-related disease throughout the follow-up. Our preliminary data suggest that changes in the matemal cellular immune system induced by HIV infection have the potential for increasing the extent of replication of HCV (when present as a chronic infection) and enhancing the risk of transmission of HCV to the newborn. HIV is the causative agent in AIDS but other factors may enhance infection or disease progression. In our series of infants bom to anti-HIV positive mothers, children whose mothers were anti-HCV positive were more likely to be infected with HIV (12/25 or 48%) than were those whose mothers were anti-HCV negative (2/24 or 8%). Moreover, hepatitis C seems to correlate with accelerated disease progression in HIV-infected children. Thus our findings suggest synergism between the two viruses. Perhaps HCV is lymphotropic-a view supported by the transmission of NANBH by plasma-free leucocyte preparations from the blood of patients with chronic NANBH.3 progress in the
delivery
M. R. ODENT
1. Odent MR. The fetus ejection reflex. Birth 1987; 14: 104-05. 2. Woodbury RA, Hamilton WF, Torpin R. The relationship between abdominal, uterine and arterial pressure during labor. Am J Physiol 1938; 121: 640. 3. Pose SV, Cibils LA, Zuspan FP. Effect of epinephrine infusion on uterine contractility and cardiovascular system. Am J Obstet Gynecol 1962; 84: 297-301.
Maternal-infant transmission of hepatitis C virus and HIV infections: a possible interaction
5th Paediatric Department, Institute of Virology, and Institute of Hygiene, University of Milan, 20142 Milan, Italy
MARCELLO GIOVANNINI ALESSANDRO TAGGER MARIA LISA RIBERO GIANVINCENZO ZUCCOTTI LAURA POGLIANI ANNALISA GROSSI PIERINO FERRONI ALESSANDRO FIOCCHI
Tong MJ, Thursby M, Rakela J, et al. Studies on the maternal-infant transmission of the viruses which cause acute hepatitis. Gastroenterology 1981, 80: 999-1004. 2. Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-64. 3. Hellings JA, van der Veen-du Pne J, Boender P. Transmission of non-A, non-B hepatitis by leucocyte preparations. In Zuckerman AJ, ed. Viral hepatitis and liver 1.
disease. New York: Alan R Liss, 1988: 543-49.
SIR,—The extent of maternal-infant transmission of blood-borne non-A, non-B hepatitis (NANBH) agent(s) is unknown. Transmission of NANBH has been observed in infants born to mothers with acute NANBH in the third but not in the second trimester of pregnancy.! However, transmission from carrier mothers to their children has not been reported. We describe here transmission of hepatitis C virus (HCV) in a large series of children born to mothers at risk of HCV infection by virtue of past or current intravenous drug use. In our area up to 75% of drug abusers are HCV antibody positive, irrespective of HIV seropositivity. 49 children born to HIV-positive mothers between 1987 and 1989 were enrolled in a prospective study of vertical transmission of HIV at the 5th paediatric department, University of Milan. We used an ELISA (Ortho Diagnostic Systems)2 to test for HCV antibody in stored sera collected from mothers and their infants at birth, 1,3, and then every 3 months. No mother showed any clinical evidence of liver disease. 25 (51%) mother/children pairs tested positive for HCV antibody; maternal HCV antibodies fell in these 25 infants to undetectable levels by 2-4 months of age. Active production of HCV antibodies (seroconversion) was found in 11infants between 6 and 12 months of age. Among these 11 seroconverters, 6 showed raised serum alanine transaminase values (70-195 IU/1) between 3 and 12 weeks after birth. NANBH was diagnosed on the usual exclusion criteria. HCV antibodies were still detectable in 8 children (6/6 with NANBH, 2/5 without NANBH), while abnormal transaminase values persisted in 2 of the 6 children with NANBH
throughout the follow-up. Of the 14 children not seroconverting to HCV none had NANBH. All 11children with HCV infection were simultaneously infected with HIV; infection with this virus developed between 4 and 8 months of age. Of the 6 children with NANBH and HIV infection 3 had progressed to AIDS at 12-20 months; 2 of these had died by the age of 2 years; and the remaining 3 (aged 10-16 months) had a more advanced stage of HIV infection. By contrast, HIV infection did not
Zidovudine in post-exposure prophylaxis of health-care workers SIR,- The risk of acquiring HIV infection after exposure to blood from infected patients in health-care settings is small but real.’ An Italian multicentre study estimated the rate of seroconversion to be 0-002 in 956 health-care workersCompliance with recommended precautions3 may reduce this risk but is unlikely to eliminate it. Zidovudine, the only licensed drug with demonstrated in-vivo efficacy against HIV, has been suggested as post-exposure prophylaxis.’*’’’ The risk of HIV infection by occupational exposure is so low that a huge number of exposed health-care workers would be needed to obtain convincing evidence of the efficacy of zidovudine prophylaxis. Moreover, little is known of the toxicity of this drug in healthy people, and data on long-term toxicity, including carcinogenic effects,’ are unknown. In AID S patients the major toxicity has been haemtological, dose-related, and reversible and is rarely in the first month of therapy,so serious acute toxicityis likely to be very unusual with short-course post-exposure prophylaxis in healthy workers in health-care settings. Few reports on zidovudine post-exposure prophylaxis have been published and further data are needed to establish the appropriate dosage and duration of the treatment.4,5 In Italy zidovudine can be dispensed only in licensed public centres. Some of them started to offer the option of prophylaxis to HIV-exposed health-care workers. A network has been established between these centres to collect details of the exposure, the dosage and duration of zidovudine prophylaxis, and adverse effects. 1 nurses, 9 physicians, 5 surgeons, and 1 other health-care worker, all accidentally exposed to blood from an HIV-infected patient, have been treated, after informed consent, in fifteen clinical departments All are being monitored by laboratory tests and clinically, and haB e been enrolled in a one year post-exposure follow-up.
1167
reported exposures were 27 needlesticks, 2 cuts with sharp mucus contaminations, and 2 open wounds. 6 of those given prophylaxis have been treated with a daily dose of 500-800 mg for 4-6 weeks; 4 received 1200 mg daily for 5, 6, 10, and 42 days; and 3 have been treated with 1000-2000 mg per day for the first 3 days, followed by a 4-week course with a reduced dose of 600 mg daily. Finally, 21 health-care workers have been treated with 1000 mg daily for between 5 days and 6 weeks; 17 of them have been treated for at least 28 days. No biochemical or haematological side-effects were recorded. 11 people on a dose of 1000-1200 mg and 1 of 3 during the high-dose stage of stepped treatment reported nausea (10), gastric pain (2), vomiting (2), asthenia (3), diarrhoea (1), or arthralgia (1). These effects were mild and transient; only 1 had to discontinue prophylaxis (just for a day, because of vomiting). The
instruments, 3
Neither seroconversion nor signs/symptoms of acute illness have been observed after follow-up averaging 6 months (range 2-12). The above data show a low and dose-related rate of adverse effects with short-term zidovudine prophylaxis in healthy mdividuals occupationally exposed to HIV. The wide variation in regimens prescribed suggests that clinicians are uncertain about what is an adequate schedule for zidovudine post-exposure prophylaxis, as others have reported too.’,s In the absence of clear data on efficacy, zidovudine prophylaxis cannot be regarded as a mandatory component of post-exposure management. The drug should be offered after high-risk exposures, but the decision rests with the health-care worker, who must be clearly informed about the risk of infection, the rationale for prophylaxis, and the state of knowledge on the short-term and long-term toxicity of the drug. Members of the study group are G. Angarano, C. Arici, A. Cargnel, P. D’Argemo, F. Fiaccadori, A. Ferlini, L. Fruttaldo, G. Macri’, L. Leporace, E. Mignani, P. Narciso, S. Ranieri, A. Scasso, A. Staiti, F. Suter, and S. Vella. The study is supported by the Italian Ministry of Health ISS AIDS Research Project (grant 4203.15ISS).
Coordinating Centre. AIDS Unit (LHU RM/10), Lazzaro Spallanzani Hospital for Infectious Diseases, 00149 Rome, Italy
V. PURO G. IPPOLITO, on
Study Group Occupational Risk of HIV Infection
(abstr). 3 Centers for Disease Control.
4
Institute of Medical Chemistry and University of Innsbruck, A-6020 Innsbruck, Austria
Biochemistry,
DIETMAR FUCHS GILBERT REIBNEGGER ERNST R. WERNER HELMUT WACHTER
the Italian
1. Marcus R. Transmission of human immunodeficiency virus (HIV) in health care settings worldwide. Bull WHO 1989; 67: 577-82. 2. Ippolito G, Angarano G, Arici C, et al. Risk of HIV infection in health care workers exposed to blood and body fluids: the Italian Multicentre Study. 2nd European Conference on Clinical Aspects of HIV Infection (Brussels, March 8-9, 1990): 104
Update: universal precautions for prevention of human hepatitis B virus, and other bloodborne pathogens in health-care setting. MMWR 1988; 37: 24. Henderson DK, Geberdin JL. Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: an interim analysis. J Inf Dis 1989; 160: immunodeficiency
dihydropteridine reductase (DHPR). These enzymes are necessary for the recycling of pterin-cofactors to form the biologically active tetrahydroderivatives. DHFR and DHPR can only reduce quinonoid 7,8 (6H)-dihydropterin derivatives,’4 which are chemically distinct from the common 7,8-dihydro forms. However, Fe3+ induces tautomerisation of 7,8-dihydropterins to the 7,8(6H)dihydro derivative.5 Thus, increased amounts of 7,8dihydroneopterin during cellular immune activation will increase the pool of 7,8(6H)-dihydroneopterin. The latter compound can competitively interfere with DHFR and DHPR.4 The possible relevance of the effects of 7,8(6H)dihydroneopterin on DHPR is further supported by the higher serum phenylalanine seen in HIV-1 seropositive patients than in healthy controls.6 The activity of phenylalanine hydroxylase is dependent on the availability of the cofactor 5,6,7,8tetrahydrobiopterin (BH4). Biopterin concentrations seem to be increased in HIV-1 seropositive patients.7 However, interference by 7,8(6H)-dihydroneopterin with DHPR will decrease the pool of biologically active BH consequently the enzymic conversion of L-phenylalanine to L-tyrosine is reduced. Further evidence of an interaction between 7,8-dihydroneopterin and DHRF and DHPR is provided by a child with atypical phenylketonuria due to 7,8-dihydrobiopterin deficiency who was successfully treated by supplementation with BH,. However, during an infectious episode phenylketonuria symptoms reappeared and BH4 supplementation had to be increased. We assume that during the infectious disease, cell-mediated immune response was induced and 7,8-dihydroneopterin concentrations were increased. 7,8-dihydroneopterin interfered with DHPR and the biochemical recycling ofBH4, and the activity of phenylalanine hydroxylase was reduced.
virus,
321-27. 5. Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine postexposure use MMWR 1990 (suppl 1, Jan
31).
Increased 7,8-dihydroneopterin and reduced methyl-group metabolism in HIV-1 infection SIR,-Dr Surtees and colleagues (March 17, p 619) report reduced methyl-group metabolism in children with HIV-1 infection. We also reported that raised neopterin levels in patients with HIV-1 infection were accompanied by parallel increased concentrations of 7,8-dihydroneopterin. In our study of 150 HIV-1 seropositive patients, 7,8-dihydroneopterin was present at a constant 3-fold higher concentration than neopterin.l This result accords with in-vitro data showing that macrophages on stimulation with interferon produce neopterin and 7,8-dihydroneopterin in a similar proportion .2 Folate concentrations are greatly increased in HIV-1seropositive patients.3 However, the reduced capacity of dihydrofolate reductase (DHFR) to produce the active cofactor may result in reduced bioavailability of 5-methyltetrahydrofolate, as Surtees et al describe. Reduced methyl-group metabolism can be explained by interaction of reduced neopterin derivatives with DHFR and
D, Milstien S, Kramer A, et al. Urinary neopterin concentrations vs total neopterins for clinical utility. Clin Chem 1989; 35: 2305-07. 2. Wemer ER, Werner-Felmayer G, Fuchs D, Hausen A, Reibnegger G, Wachter H. Parallel induction of tetrahydrobiopterin biosynthesis and indoleamine 2,3 dioxygenase activity in human cells and cell lines by interferon-gamma. BiochemJ 1989; 262: 861-66. 3. Beach RS, Mantero Atienza E, Eisdorfer C, Fordyce Baum MK. Altered folate metabolism in early HIV infection. JAMA 1988; 259: 519-20. 4. Vasudevan SG, Shaw DC, Armarego WFF. Dihydropteridine reductase from Escherichia coli. Biochem J 1988; 255: 581-88. 5. Armarego WLF, Randles D. Aerobic oxidation of 5,6,7,8-tetrahydroneopterin. In: Blair JA, ed. Chemistry and biology of pteridines. Berlin: de Gruyter, 1986: 1. Fuchs
423-27. 6.
Ollenschlaeger G, Jansen S, Schindler J, Rasokat H, Schrappe Baecher M, Roth E. Plasma amino add patterns in patients with HIV infection, Clin Chem
1988; 34: 1787-89. 7. Abita JP, Cost H, Milstien S, Kaufman S, Saimot G. Urinary neopterin and biopterin levels in patients with AIDS and AIDS-related complex. Lancet 1985; ii: 51. 8. Leupold D, Wang M, Niederwieser A. Tetrahydrobiopterin monotherapy in two siblings with dihydrobiopterin deficiency. In Wachter H, Curtius HC, Pfleiderer W, eds. Biochemical and clinical aspects of pteridines, vol 1. Berlin: de Gruyter, 1982: 307-17.
HTLV-I/II antibodies in French blood donors SIR,-Human T-lymphotropic virus type
a virus and tropical spastic paraparesis, myelopathy, and polymyositis has also been found in apparently healthy people in Japan, Africa, the Caribbean, and the USA.l,2 Transmission is via blood’ (by transfusion of cellular components or by sharing of needles and syringes among drug addicts), via sexual contact, or from mother to child by breastfeeding. We have looked for HTLV-1 antibody in blood donors in continental France. 45 033 samples were collected by twelve blood banks in different parts of the country and screened by gelatin particle agglutination (Fujirebio) or by ELISA (Abbott, DuPont de Nemours, Organon, or Pharmacia). Repeatedly reactive sera were tested by western blot (DuPont de Nemours) and radioimmunoprecipitation assay. A
associated with adult T-cell
I
(HTLV-I),
leukaemia/lymphoma,
