- Email: [email protected]
Zidovudine concentrations in human fetal tissue: implications for perinatal AIDS
1280
Failed prophylactic zidovudine after needlestick injury SiR,—The risk of HIV infection after an accident with a needle contaminated with infected blood has been estimated at only 0.47%.1 Even so it is recommended practice in many hospitals to prescribe zidovudine after such injuries in an attempt to reduce the risk of infection.2 This practice is based on limited animal data and on the hope that doing something may be better than doing nothing. We describe a case where the timely administration of zidovudine was not successful. A health-care worker sustained a deep needlestick injury after taking blood from a patient with AIDS. The puncture wound bled and it was washed with alcohol. The worker sought immediate advice and after consultation decided on a course of zidovudine 250 mg 6-hourly; this was started within 6 hours of the accident. Blood taken from the injured worker at that time was negative for HIV-1I antibody while the patient was confirmed as being seropositive. During follow-up compliance with the drug regimen was confirmed verbally and by the observation of a rising mean cellular volume. Minor side-effects of lethargy and gastric discomfort were reported. 5 weeks after the accident, influenza-like symptoms and generalised lymphadenopathy developed. The white blood cell count was 6000/ul (41% granulocytes, 49% lymphocytes, 10% monocytes) and slight macrocytosis (100fl) and occasional atypical lymphocytes were noted. 6 weeks after the accident seroconversion was demonstrated by an ELISA screening test for HIV-1 antibody, a positive radioimmunoprecipitation test (core and envelope antibodies), and an indeterminate western blot. The western blot was repeated 2 weeks later, when it was clearly positive. Zidovudine was stopped 8 weeks after the accident. Symptoms improved over the next 3 weeks and have now disappeared. Failure of prophylactic zidovudine in this case may be due to an inadequate dose. Since this incident we have noted suggestions that recommend up to 2-4 g daily in 4-hourly doses. The drug may need to be given immediately after the accident if virus replication is to be prevented. Another possibility is that since the index patient had been taking zidovudine for many months the strain of virus may have had reduced sensitivity to zidovudine.4 Finally zidovudine may be ineffective even under ideal circumstances. Zidovudine cannot be relied upon as an effective agent for prophylaxis after a needlestick injury. Strategies to prevent occupationally acquired HIV-1 infection must be directed at preventing the injury, and post-exposure treatment remains experimental and unproven. Department of Clinical Microbiology and Infectious Diseases, Queen Elizabeth Hospital, Woodville South, South Australia 5011, Australia
D. F. M. LOOKE D. I. GROVE
1. Centers for Disease Control. Guidelines for the prevention of transmission of human
immunodeficiency virus and hepatitis B virus to health care and public safety workers. MMWR 1989; 38 (suppl S6). 2. Henderson DK, Gerberding JL. Prophylactic zidovudme after occupational exposure to the human immunodeficiency virus: an interim analysis. J Infect Dis 1989; 160: 321-27. 3. Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine post-exposure use. MMWR 1990; 39 (suppl
RR1). BA, Darby G, Richman DD. HIV with reduced sensintivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731-34.
4. Larder
HIV and needlestick
injuries
SIR,-Dr Cobelens (April 14, p 924) and Mr Bailey (May 5, p 1104) discuss the risk of HIV being transmitted after occupational Every year in the USA 12 000 health-care workers contract hepatitis B while caring for patients, and some 250 die of liver-related illnesses as a result. Although perhaps 1 million people in the US are infected with HIV the reported transmission rate to health-care workers remains low, with 17 cases in the US (and 1 in the UK).2 Anecdotal evidence suggests that needlestick injury with blood from a patient infected with both hepatitis B virus and HIV resulted in hepatitis B infection only in the injured health-care exposure.
worker. This may be directly related to the amount of circulating virions present in patient blood. In hepatitis B 1013 infectious particles/ml may be present, compared with only 104/ml for HIV. HIV infection may require a substantial transfer of blood so that infusion of infected blood may always cause infection while inoculation with small quantities of HIV-seropositive blood in the end of a hollow needle could have a transmission rate below 0-5% and a subcutaneous prick with a suture needle may present a very low risk. In-vitro tests are being developed which measure the amount of cell-associated and cell-free virus in patients with HIV infection or AIDS. Such tests may give some guide to infectivity; it seems that some individuals have only about one tissue culture infectious unit/ml blood3 and at least 0’1 ml of blood may be required to transmit HIV. In contrast, as little as 000004 ml of HBV-positive blood may cause infection after needlestick injury. It is quite likely therefore that the risk of seroconversion after a needlestick injury is related to the type of accident, as Cobelens suggests. Bailey confirms that needlestick injury reporting rates may vary considerably for different categories of staff, and he presents some figures for high-risk exposure among workers at a London hospital. The very high rate for doctors is interesting in view of previous underreporting but is corroborated by a study of paediatric house-physicians in the USA 4which found that 70 % had sustained needle injuries. Lack of experience may be an important factor; the rate of injury in "learner nurses" is twice that in trained nurses.5 Since it has been estimated that 2000 needlestick injuries happen every day in the USA alone, it is important for health-care workers to be able to assess their own occupational risks. I have taken part in an American risk assessment project, the results of which will be published shortly. Although consensus was reached on several factors that can influence risk, the prevention of "sharps" injuries remain difficult to achieve. A true picture of HIV transmission will emerge only with full accident reporting, epidemiological surveillance, and detailed long-term follow-up studies of injuries in
health-care workers worldwide. The most important requirement for risk reduction is the provision of a comprehensive sharps injury control programme. This will require the removal of all used needles and sharps from the work area immediately after use, without resheathing; the provision of 100% safe sharps containers; and training in the use of sharps and their disposal, which should be introduced for students of medicine and nursing before clinical duties are undertaken. Reinforcement of safety training via posters and written safety codes will be needed; as will refresher training.6 National codes of practice will be essential. Professional and Scientific Division, British Medical Association, London WC1 H 9JP, UK
DAVID R. MORGAN
1. Centers for Disease Control. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers. MMWR Rec Rep 1989; 38 (S-6). 2. Gill N, Porter K. Occupational transmission of HIV: summary of published reports. London: PHLS Communicable Disease Surveillance Centre, 1989. 3. Bayliss GJ, Jesson WJ, Mortimer PP, McLean KA, Evans BA. Cultivation of human immunodeficiency virus from whole blood: effect of anticoagulant and inoculum size on virus growth. J Med Virol (m press). 4. Melzer SM, Vermund SH, Shelov SP. Needle injuries among pediatnc housestaff physicians m New York. Pediatrics 1989; 84: 211-14. 5. Collins CH, Kennedy DA. Microbiological hazards of occupational needlestick and ’sharps’ injuries. J Appl Bacteriol 1987; 62: 385-402. 6. Morgan DR. Needlestick injuries: how can we teach people better about nsk assessment? J Hosp Infect Soc 1988; 12: 301-09.
Zidovudine concentrations in human fetal tissue: implications for perinatal AIDS SIR,-Neurological dysfunction is the pre-eminent finding in children with AIDS,’ and the predominant
young
neuropathological findings in such children include cortical atrophy, calcifications in the basal ganglia, and changes in periventricular white-matter. Treatment after birth may be too late if HIV-1infection and neuropathological changes have occurred in early pregnancy. One initiative is to try to protect the fetus by giving zidovudine to HIV-infected pregnant women. The drug can slow
1281
of HIV-1-associated disease2.3 but the pharmacokinetics of zidovudine in the fetus are unknown. We have studied the tissue distribution of zidovudine in the fetus of a woman given that drug during pregnancy. With local ethical committee approval and the patient’s informed consent, fetal tissue was obtained at the time of elective termination of pregnancy from an HIV-1seropositive woman (13-week fetus) and from controls (fetuses of similar gestational age). The HIV-1 seropositive woman, with a history of drug abuse, was taking methadone and zidovudine (100 mg four times daily), which had been started 6 weeks before the termination of pregnancy solely because of her HIV status. The patient took 100 mg as scheduled at 1100 hours and the abortion was complete by 1445. Plasma and tissue were assayed for zidovudine and its 5’ - glucuronide metabolite by radioimmunoassay kit (’ZDV-Trac’; INCSTAR Corp). Glucuronide levels were calculated from the difference in concentration before and after the conversion of glucuronide to parent drug with glucuronidase. The lower limit of detection for the assay is 0-01 )imol/l (0-01 nmol/g). HIV-1-specific nucleic acid sequences were sought by polymerase chain reaction (PCR)4 with gag oligonucleotides SK38 and SK39 as primers, primer and probe (SK19) being kindly donated by Dr John Sninsky (Cetus Corporation). Sections of brain and liver were fixed for light and electron microscopy. Concentrations of zidovudine and its glucuronide in plasma, amniotic fluid, and fetal liver, muscle, and CNS tissue were as follows: the
progression
Concentrations in J.1I71ol/ or nmol/ g Zidovudine Glucuronide
Sample Maternal plasma
Zidovudine and its
0-90 116 0-16 0 50 0-05
0 35 0-31 0-14 0 26 0-01
Amniotic fluid Fetal liver Fetal muscle Fetal CNS
glucuronide
not
detected
in
control matenal
HIV-1-specific nucleic acid sequences were found in CNS and in lung (figure) but not in fetuses of HIV-1-seronegative females. CNS tissue from the zidovudine-exposed abortus had evidence of abundant neuroblasts and germinal matrix cells. However, the
neuroblasts had hypertrophic nuclei with clumped chromatin, and extracellular areas suggestive of spongiform degeneration were observed adjacent to developing white-matter tracks. Electron microscopy revealed cytotoxic oedema, but without any evidence of inflammatory exudate or disruption of the blood-brain barrier. Our fmdings indicate that HIV-1 infection may occur early in fetal life and confirm that access of zidovudine to the CNS interstitial fluid may be very restricted.’ The HIV-1 DNA found in the fetal brain probably does not represent contamination with maternal blood: other tissues from this abortus were negative for HIV-1DNA and a larger series (unpublished) indicates that maternal blood contamination of fetal tissue is not a major confounder. The observation of significant CNS lesions in fetal brain supports the view that HIV-1 may be directly, or indirectly, associated with the neuropathogenesis and pathophysiology of paediatric AIDS. The finding of zidovudine and its glucuronide in amniotic fluid and fetal liver and muscle during pregnancy in a woman taking zidovudine supports the view that this drug can pass the placental barrier. However, the data are discouraging in respect of the treatment of fetal CNS infection because HIV-1 infection of fetal CNS tissue and neuropathological changes were found despite the presence of transplacental zidovudine. HIV-1 infection of the fetus may have predated the start of zidovudine treatment (13-week fetus, 6 weeks of treatment). If it is demonstrated that zidovudine is consistently below effective antiviral concentrations in the CNS tissue of fetuses from patients put on zidovudine before pregnancy, a potentially devastating aspect of intrauterine HIV-1 infection may escape the benefits of therapy. We thank Mr Steven S. Good (Burroughs Wellcome) for the drug assays and for helpful comments; Dr John Sninsky and Dr Shirley Kwok for the oligonucleotides and information about DNA amplification; and Mrs Agnes Geoghan for secretarial assistance. We also acknowledge cooperation from New York City Health and Hospitals Corporation and the Bronx Municipal Hospital Center, especially its nurses at the Van Etten and Jacobi Hospitals.
Supported in part by grants DA 05583, MH 46815, DA 04583, NS 11920, AI 27671, AI 20671, NS 25873, and the Diamond Foundation. WILLIAM D. LYMAN KATHRYN E. TANAKA Departments of Pathology, Neuroscience, YVONNE KRESS Obstetrics and Gynecology, Pediatrics, WILLIAM K. RASHBAUM Microbiology and Immunology, and Medicine, ARYE RUBINSTEIN Albert Einstein College of Medicine, Bronx NY 10461, USA RUY SOEIRO 1. Michaels J, Sharer LR,
Epstein LG. Human immunodeficiency virus type 1 (HIV-1) infection of the nervous system: a review. Immunodeficiency Rev 1988; 1: 71-104. 2. Pizzo PA, Eddy J, Falloon J, et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 1988; 319: 889-96 3.
4.
Purdy BD, Plaisance KI. Infection with the human immunodeficiency virus: epidemiology, pathogenesis, transmission diagnosis, and manifestations. Am J Hosp Pharmacy 1989; 46: 1185-209. Kwok S, Mack DH, Mullis KB, et al. Identification of HIV-1 viral sequences using in vitro enzymatic amplification and oligomer cleavage detection. J Virol 1987; 61: 1690-94.
T, Pardridge WM. Restricted transport of 3’-azido-3’-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J Infect Dis 1988; 158:
5. Terasaki
630-32.
Suppression of HIV antigenaemia by AL721 SIR,-Dr Peters and colleagues’ results with AL721 in the (March 3, p 545) contrast with our experience in 16 HIV seropositive patients at different clinical stages who were treated for over 12 months with AL721 10 g daily. In 5 of the 9 antigenaemic patients the p24 antigen fell quickly to the limit of detection and, after over 24 months of AL721 treatment, these 5 responders remain non-antigenaemic. In 2 of the 4 non-responding antigenaemic patients, who had advanced AIDS, zidovudine was added and p24 disappeared within a few weeks. The remaining 7 patients lacked HIV antigen in serum and were symptom-free: none of these became antigenaemic over the 24 months of treatment with AL721. No toxic or adverse effects of this lipid mixture were treatment of AIDS
DNA
amplification studies.
1 Ilg DNA from fetal CNS and
lung tissue was subjected to thirty cycles amplification along with a negative control or HIV-1-positive DNA (1ng). Amplified products were hybndised in solution with radiolabelled probe (SK19) and hybrids were electrophoretically separated on an ’Agarose’ gel and subjected to autoradiography of
Lane 1 = fetal CNS DNA from treated female; lane 2=fetal CNS DNA from abortus of HIV-1 seropositive female not treated with zidovudine; lane 3=lung DNA from zidovudine-exposed abortus, lane 4=control, HIV-1-negative DNA, and lane 5=control, HIV-1-positive DNA. Lanes 1-3 were exposed with amplifying screen to enhance signal for lung hybrid DNA.
observed.
Failed prophylactic zidovudine after needlestick injury SiR,—The risk of HIV infection after an accident with a needle contaminated with infected blood has been estimated at only 0.47%.1 Even so it is recommended practice in many hospitals to prescribe zidovudine after such injuries in an attempt to reduce the risk of infection.2 This practice is based on limited animal data and on the hope that doing something may be better than doing nothing. We describe a case where the timely administration of zidovudine was not successful. A health-care worker sustained a deep needlestick injury after taking blood from a patient with AIDS. The puncture wound bled and it was washed with alcohol. The worker sought immediate advice and after consultation decided on a course of zidovudine 250 mg 6-hourly; this was started within 6 hours of the accident. Blood taken from the injured worker at that time was negative for HIV-1I antibody while the patient was confirmed as being seropositive. During follow-up compliance with the drug regimen was confirmed verbally and by the observation of a rising mean cellular volume. Minor side-effects of lethargy and gastric discomfort were reported. 5 weeks after the accident, influenza-like symptoms and generalised lymphadenopathy developed. The white blood cell count was 6000/ul (41% granulocytes, 49% lymphocytes, 10% monocytes) and slight macrocytosis (100fl) and occasional atypical lymphocytes were noted. 6 weeks after the accident seroconversion was demonstrated by an ELISA screening test for HIV-1 antibody, a positive radioimmunoprecipitation test (core and envelope antibodies), and an indeterminate western blot. The western blot was repeated 2 weeks later, when it was clearly positive. Zidovudine was stopped 8 weeks after the accident. Symptoms improved over the next 3 weeks and have now disappeared. Failure of prophylactic zidovudine in this case may be due to an inadequate dose. Since this incident we have noted suggestions that recommend up to 2-4 g daily in 4-hourly doses. The drug may need to be given immediately after the accident if virus replication is to be prevented. Another possibility is that since the index patient had been taking zidovudine for many months the strain of virus may have had reduced sensitivity to zidovudine.4 Finally zidovudine may be ineffective even under ideal circumstances. Zidovudine cannot be relied upon as an effective agent for prophylaxis after a needlestick injury. Strategies to prevent occupationally acquired HIV-1 infection must be directed at preventing the injury, and post-exposure treatment remains experimental and unproven. Department of Clinical Microbiology and Infectious Diseases, Queen Elizabeth Hospital, Woodville South, South Australia 5011, Australia
D. F. M. LOOKE D. I. GROVE
1. Centers for Disease Control. Guidelines for the prevention of transmission of human
immunodeficiency virus and hepatitis B virus to health care and public safety workers. MMWR 1989; 38 (suppl S6). 2. Henderson DK, Gerberding JL. Prophylactic zidovudme after occupational exposure to the human immunodeficiency virus: an interim analysis. J Infect Dis 1989; 160: 321-27. 3. Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine post-exposure use. MMWR 1990; 39 (suppl
RR1). BA, Darby G, Richman DD. HIV with reduced sensintivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731-34.
4. Larder
HIV and needlestick
injuries
SIR,-Dr Cobelens (April 14, p 924) and Mr Bailey (May 5, p 1104) discuss the risk of HIV being transmitted after occupational Every year in the USA 12 000 health-care workers contract hepatitis B while caring for patients, and some 250 die of liver-related illnesses as a result. Although perhaps 1 million people in the US are infected with HIV the reported transmission rate to health-care workers remains low, with 17 cases in the US (and 1 in the UK).2 Anecdotal evidence suggests that needlestick injury with blood from a patient infected with both hepatitis B virus and HIV resulted in hepatitis B infection only in the injured health-care exposure.
worker. This may be directly related to the amount of circulating virions present in patient blood. In hepatitis B 1013 infectious particles/ml may be present, compared with only 104/ml for HIV. HIV infection may require a substantial transfer of blood so that infusion of infected blood may always cause infection while inoculation with small quantities of HIV-seropositive blood in the end of a hollow needle could have a transmission rate below 0-5% and a subcutaneous prick with a suture needle may present a very low risk. In-vitro tests are being developed which measure the amount of cell-associated and cell-free virus in patients with HIV infection or AIDS. Such tests may give some guide to infectivity; it seems that some individuals have only about one tissue culture infectious unit/ml blood3 and at least 0’1 ml of blood may be required to transmit HIV. In contrast, as little as 000004 ml of HBV-positive blood may cause infection after needlestick injury. It is quite likely therefore that the risk of seroconversion after a needlestick injury is related to the type of accident, as Cobelens suggests. Bailey confirms that needlestick injury reporting rates may vary considerably for different categories of staff, and he presents some figures for high-risk exposure among workers at a London hospital. The very high rate for doctors is interesting in view of previous underreporting but is corroborated by a study of paediatric house-physicians in the USA 4which found that 70 % had sustained needle injuries. Lack of experience may be an important factor; the rate of injury in "learner nurses" is twice that in trained nurses.5 Since it has been estimated that 2000 needlestick injuries happen every day in the USA alone, it is important for health-care workers to be able to assess their own occupational risks. I have taken part in an American risk assessment project, the results of which will be published shortly. Although consensus was reached on several factors that can influence risk, the prevention of "sharps" injuries remain difficult to achieve. A true picture of HIV transmission will emerge only with full accident reporting, epidemiological surveillance, and detailed long-term follow-up studies of injuries in
health-care workers worldwide. The most important requirement for risk reduction is the provision of a comprehensive sharps injury control programme. This will require the removal of all used needles and sharps from the work area immediately after use, without resheathing; the provision of 100% safe sharps containers; and training in the use of sharps and their disposal, which should be introduced for students of medicine and nursing before clinical duties are undertaken. Reinforcement of safety training via posters and written safety codes will be needed; as will refresher training.6 National codes of practice will be essential. Professional and Scientific Division, British Medical Association, London WC1 H 9JP, UK
DAVID R. MORGAN
1. Centers for Disease Control. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers. MMWR Rec Rep 1989; 38 (S-6). 2. Gill N, Porter K. Occupational transmission of HIV: summary of published reports. London: PHLS Communicable Disease Surveillance Centre, 1989. 3. Bayliss GJ, Jesson WJ, Mortimer PP, McLean KA, Evans BA. Cultivation of human immunodeficiency virus from whole blood: effect of anticoagulant and inoculum size on virus growth. J Med Virol (m press). 4. Melzer SM, Vermund SH, Shelov SP. Needle injuries among pediatnc housestaff physicians m New York. Pediatrics 1989; 84: 211-14. 5. Collins CH, Kennedy DA. Microbiological hazards of occupational needlestick and ’sharps’ injuries. J Appl Bacteriol 1987; 62: 385-402. 6. Morgan DR. Needlestick injuries: how can we teach people better about nsk assessment? J Hosp Infect Soc 1988; 12: 301-09.
Zidovudine concentrations in human fetal tissue: implications for perinatal AIDS SIR,-Neurological dysfunction is the pre-eminent finding in children with AIDS,’ and the predominant
young
neuropathological findings in such children include cortical atrophy, calcifications in the basal ganglia, and changes in periventricular white-matter. Treatment after birth may be too late if HIV-1infection and neuropathological changes have occurred in early pregnancy. One initiative is to try to protect the fetus by giving zidovudine to HIV-infected pregnant women. The drug can slow
1281
of HIV-1-associated disease2.3 but the pharmacokinetics of zidovudine in the fetus are unknown. We have studied the tissue distribution of zidovudine in the fetus of a woman given that drug during pregnancy. With local ethical committee approval and the patient’s informed consent, fetal tissue was obtained at the time of elective termination of pregnancy from an HIV-1seropositive woman (13-week fetus) and from controls (fetuses of similar gestational age). The HIV-1 seropositive woman, with a history of drug abuse, was taking methadone and zidovudine (100 mg four times daily), which had been started 6 weeks before the termination of pregnancy solely because of her HIV status. The patient took 100 mg as scheduled at 1100 hours and the abortion was complete by 1445. Plasma and tissue were assayed for zidovudine and its 5’ - glucuronide metabolite by radioimmunoassay kit (’ZDV-Trac’; INCSTAR Corp). Glucuronide levels were calculated from the difference in concentration before and after the conversion of glucuronide to parent drug with glucuronidase. The lower limit of detection for the assay is 0-01 )imol/l (0-01 nmol/g). HIV-1-specific nucleic acid sequences were sought by polymerase chain reaction (PCR)4 with gag oligonucleotides SK38 and SK39 as primers, primer and probe (SK19) being kindly donated by Dr John Sninsky (Cetus Corporation). Sections of brain and liver were fixed for light and electron microscopy. Concentrations of zidovudine and its glucuronide in plasma, amniotic fluid, and fetal liver, muscle, and CNS tissue were as follows: the
progression
Concentrations in J.1I71ol/ or nmol/ g Zidovudine Glucuronide
Sample Maternal plasma
Zidovudine and its
0-90 116 0-16 0 50 0-05
0 35 0-31 0-14 0 26 0-01
Amniotic fluid Fetal liver Fetal muscle Fetal CNS
glucuronide
not
detected
in
control matenal
HIV-1-specific nucleic acid sequences were found in CNS and in lung (figure) but not in fetuses of HIV-1-seronegative females. CNS tissue from the zidovudine-exposed abortus had evidence of abundant neuroblasts and germinal matrix cells. However, the
neuroblasts had hypertrophic nuclei with clumped chromatin, and extracellular areas suggestive of spongiform degeneration were observed adjacent to developing white-matter tracks. Electron microscopy revealed cytotoxic oedema, but without any evidence of inflammatory exudate or disruption of the blood-brain barrier. Our fmdings indicate that HIV-1 infection may occur early in fetal life and confirm that access of zidovudine to the CNS interstitial fluid may be very restricted.’ The HIV-1 DNA found in the fetal brain probably does not represent contamination with maternal blood: other tissues from this abortus were negative for HIV-1DNA and a larger series (unpublished) indicates that maternal blood contamination of fetal tissue is not a major confounder. The observation of significant CNS lesions in fetal brain supports the view that HIV-1 may be directly, or indirectly, associated with the neuropathogenesis and pathophysiology of paediatric AIDS. The finding of zidovudine and its glucuronide in amniotic fluid and fetal liver and muscle during pregnancy in a woman taking zidovudine supports the view that this drug can pass the placental barrier. However, the data are discouraging in respect of the treatment of fetal CNS infection because HIV-1 infection of fetal CNS tissue and neuropathological changes were found despite the presence of transplacental zidovudine. HIV-1 infection of the fetus may have predated the start of zidovudine treatment (13-week fetus, 6 weeks of treatment). If it is demonstrated that zidovudine is consistently below effective antiviral concentrations in the CNS tissue of fetuses from patients put on zidovudine before pregnancy, a potentially devastating aspect of intrauterine HIV-1 infection may escape the benefits of therapy. We thank Mr Steven S. Good (Burroughs Wellcome) for the drug assays and for helpful comments; Dr John Sninsky and Dr Shirley Kwok for the oligonucleotides and information about DNA amplification; and Mrs Agnes Geoghan for secretarial assistance. We also acknowledge cooperation from New York City Health and Hospitals Corporation and the Bronx Municipal Hospital Center, especially its nurses at the Van Etten and Jacobi Hospitals.
Supported in part by grants DA 05583, MH 46815, DA 04583, NS 11920, AI 27671, AI 20671, NS 25873, and the Diamond Foundation. WILLIAM D. LYMAN KATHRYN E. TANAKA Departments of Pathology, Neuroscience, YVONNE KRESS Obstetrics and Gynecology, Pediatrics, WILLIAM K. RASHBAUM Microbiology and Immunology, and Medicine, ARYE RUBINSTEIN Albert Einstein College of Medicine, Bronx NY 10461, USA RUY SOEIRO 1. Michaels J, Sharer LR,
Epstein LG. Human immunodeficiency virus type 1 (HIV-1) infection of the nervous system: a review. Immunodeficiency Rev 1988; 1: 71-104. 2. Pizzo PA, Eddy J, Falloon J, et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 1988; 319: 889-96 3.
4.
Purdy BD, Plaisance KI. Infection with the human immunodeficiency virus: epidemiology, pathogenesis, transmission diagnosis, and manifestations. Am J Hosp Pharmacy 1989; 46: 1185-209. Kwok S, Mack DH, Mullis KB, et al. Identification of HIV-1 viral sequences using in vitro enzymatic amplification and oligomer cleavage detection. J Virol 1987; 61: 1690-94.
T, Pardridge WM. Restricted transport of 3’-azido-3’-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J Infect Dis 1988; 158:
5. Terasaki
630-32.
Suppression of HIV antigenaemia by AL721 SIR,-Dr Peters and colleagues’ results with AL721 in the (March 3, p 545) contrast with our experience in 16 HIV seropositive patients at different clinical stages who were treated for over 12 months with AL721 10 g daily. In 5 of the 9 antigenaemic patients the p24 antigen fell quickly to the limit of detection and, after over 24 months of AL721 treatment, these 5 responders remain non-antigenaemic. In 2 of the 4 non-responding antigenaemic patients, who had advanced AIDS, zidovudine was added and p24 disappeared within a few weeks. The remaining 7 patients lacked HIV antigen in serum and were symptom-free: none of these became antigenaemic over the 24 months of treatment with AL721. No toxic or adverse effects of this lipid mixture were treatment of AIDS
DNA
amplification studies.
1 Ilg DNA from fetal CNS and
lung tissue was subjected to thirty cycles amplification along with a negative control or HIV-1-positive DNA (1ng). Amplified products were hybndised in solution with radiolabelled probe (SK19) and hybrids were electrophoretically separated on an ’Agarose’ gel and subjected to autoradiography of
Lane 1 = fetal CNS DNA from treated female; lane 2=fetal CNS DNA from abortus of HIV-1 seropositive female not treated with zidovudine; lane 3=lung DNA from zidovudine-exposed abortus, lane 4=control, HIV-1-negative DNA, and lane 5=control, HIV-1-positive DNA. Lanes 1-3 were exposed with amplifying screen to enhance signal for lung hybrid DNA.
observed.