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Combined therapy with ganciclovir and foscarnet for cytomegalovirus polyradiculomyelitis in patients with AIDS
;
) BRIEF CLINICAL OBSERVATIONS
Combined Therapy With Ganciclovir and Foscarnet for Cytomegalovirus Polyradiculomyelitis in Patients With AIDS
was normal. The CD4 cell count was ~/FL. Cerebral, dorsal, and lumbar magnetic resonance imaging were normal. CSF contained 56 white blood cells/n& (72% of polymorphonuclear leukocytes), 80 mg/dL protein, 5 mmol/L glucose. CSF cultures for bacteria, fungi, parasites, were negative, as well as CSF Venereal Disease Research Laboratories (V’DRL) and cryptococcal antigen tests. CMV, however, was cultured from CSF and peripheral blood, and detection of CMV DNA by PCR was also positive in CSF. Intravenous ganciclovir was started at a dose of 5 mgkg every 12 hours. On day 6 of therapy, the patient’s neurological condition worsened with complete flaccid paraplegia (MRC grade 0), although CMV was no longer cultured from either CSF or blood. CMV DNA was, however, still detected in CSF. Foscarnet was then added to ganciclovir at a dose of 90 mgkg twice a day. Following 13 days of combined therapy, partial return of motor function was observed in both legs (MRC grade 2) and CSF contained only 8 leukocytes, with negative CMV culture from CSF and peripheral blood, as well as negative CMV DNA deteetion by PCR. The patient was discharged on day 23, on a maintenance foscarnet regimen (90 mg/kg/d), and he was able to walk using a frame (MRC grade 4). He committed suicide a few weeks later.
Marina Karmochkine,MD, Jean-MichelMolina, MD, CatherineScieux, MD, Yves Welker, MD, Ft+d&ic Morinet, MD, Jean-MarieDecazes, MD, Philippe Lagrange,MD, LaurenceSchnell, Jacques Modai, MD, 1-6pitaf Saint-his, Paris, France ytomegalovirus (CMV) is the most common C cause of opportunistic viral diseases in patients with HIV infection and contributes to acquired immunodeficiency syndrome (AIDS)-related morbidity and mortality.’ Although retinitis and gastrointestinal tract infections are the most common clinical manifestations of CMV infection, neurological involvement has been increasingly reported.2A CMV-related polyradiculomyelitis has typical clinical presentation and cerebrospinal fluid (CSF) findings, which should suggest the diagnosis in patients with AIDS.S5 CMV isolation from the CSF and/or detection of CMV DNA sequences by polymerase chain reaction (PCR) in the CSF will confirm this diagnosis and allow early initiation of anti-CMV therapy.6,7 Recovery from CMV-related polyradiculomyelitis has, however, rarely been reported with the currently available anti-CMV drugs.8-10 We describe here two patients in whom early recognition of CMV-polyradiculomyelitis and initiation of combined anti-CMV therapy allowed significant clinical benefit.
Patient 2 A 33-year-old HIV-l-infected homosexual was admitted to our clinic in July 1992, 7 days after the onset of progressive paraparesia, urinary difficulties, and dysphonia. Kaposi sarcoma and pneumocystis pneumonia were diagnosed in March 1991. CMV retinitis developed in April 1991, and improved with foscarnet therapy. The patient has since remained on a foscarnet maintenance regimen (100 mg/kg/d). He was afebrile. Physical examination revealed a cauda equina syndrome with severe bilateral leg weakness (MRC grade 2). Multiple right cranial palsies (VII, IX, and X) were also observed. Fundoscopy did not find active retinitis. Magnetic resonance imaging of brain and spinal cord was normal. CSF analysis disclosed 280 white blood cells/n& (75% of polymorphonuclear leukocytes), total protein was 540 mg/dL, and glucose 1.5 mmol/L. CSF cultures for bacteria, fungi, CMV, and parasites were negative, as well as CSF VDRL test. However, CMV DNA was detected in CSF by PCR, and blood and urine CMV cultures were positive. Combined therapy was immediately initiated: foscarnet regimen was increased (200 mg/kg/d) and ganciclovir was started (10 mg/kg/d). On day 10 of combined therapy, CSF contained 100 white blood cells/ml (43% polymorphonuclear cells), total protein was 280 m&g, and glucose 2.2 mmol/L. CMV detection in CSF, by either culture or PCR, was negative, as was CMV culture in peripheral blood, and cranial palsies and paraparesia improved (MRC grade 4). On
CASE REPORTS Patient 1 A 46yearold bisexual HIV-l-infected man was referred to our clinic in January 1992 for difficulty in walking and urinary retention. Non-Hodgkin’s lymphoma of small bowel was diagnosed in 1988 and was in complete remission. He was receiving cotrimoxazole for Pnmmcgstti car&ii pneumonia prophylaxis and didanosine (400 mg/day). He manifested progressive weakness and pain in his right leg 12 days before admission. Bilateral weakness of the lower limbs and urinary difficulties appeared 9 days before admission. On examination, the patient was afebrile and had severe bilateral motor deficit of the lower limbs. Muscle strength, as expressed according to the Medical Research Council (MRC) scale, was grade 1 in distal muscles and 3 in proximaI muscles. Leg tendon reflexes were absent and plantar responses flexor. A complete cauda equina syndrome was present with perianal anesthesia, and urinary retention. Fundoscopic examination 196
August
1994
The American
Journal
of Medicine@
Volume
97
BRIEF CLINICAL OBSERVATIONS
day 20, the patient was able to walk. On day 40, CSF only contained 1 white blood cell/n& protein 75 mg/dL, glucose 2.9 mmol/L, and ganciclovir and foscarnet were delivered on a maintenance regimen. The patient was then discharged. He died from a respiratory distress syndrome 6 months later. No autopsy was performed.
In conclusion, use of combination anti-CMV therapy in our two patients with (XV-related polyradiculomyelitis led to clinical improvement and eradication of CMV from the CSF. Further studies would be needed to evaluate the potential benefit of such combination therapy in severe CMV infections.
REFERENCES
COMMENTS Our 2 patients presented with typical CMV-associated polyradicuIomyelitis.55 The diagnosis was based on the presence of a distinct clinical presentation of an acute severe cauda equina syndrome, associated with CSF pleocytosis with predominance of polymorphonuclear leukocytes, in HIV-infected patients with severe immune deficiency. The detection of CMV in CSF, by either culture or PCR confirmed this diagnosis.617Recovery from CMV polyradiculomyelitis remains deceptive, however, despite treatment with antiCMV agents. De Gans et al* noted clinical deterioration in 4 patients receiving gancicloti started 3 to 6.5 weeks after onset of symptoms. Only 1 patient with minor paraparesis improved when ganciclovir was started 1 week after onset of symptoms. Thus, early recognition and treatment of this syndrome appears to be an important factor for a better outcome.“” In our 2 patients, therapy was instituted 7 and 12 days following onset of clinical symptoms, and that could, by itself, explain some of the clinical benefit observed. However, ganciclovir or foscarnet did not appear to be beneficial to other patients with severe paraparesis, as was the case in our 2 patients.*ag Both patients also received initially monotherapy with either ganciclovir of foscaxnet without improvement. We, therefore. initiated combined therapy with high doses of both ganciclovir and foscarnet. This strategy of combined antiviral therapy has been used with some success in CMV retinitis and encephalitis, 12-14as well as in HlV infection.15 Combined therapy with ganciclovir and foscarnet has synergistic activity against CMV in vitro16,17that might explain the clinical benefit observed in vivo. Alternatively, while pharmacokinetics of both drugs have indicated variable concentrations in the CSF1*,lg that could be responsible for suboptimal clinical efficacy of monotherapy in CMV polyradiculomyelitis, combined therapy might achieve a higher anti-CMV activity in the CSF. Also, combined therapy might overcome resistant strains of CMV to either ganciclovir or foscarnet, since ganciclovir-resistant strains of CMV are sensitive to foscaxnet and vice versa.20,21We observed a clear and sustained clinical benefit in our patients following the flit 10 to 12 days of combined therapy. This combined regimen has been well tolerated, and CSF abnormalities returned to normal values. Also, CMV was no longer detected in the CSF using standard cultures or detection of CMV DNA by PCR.
1. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1988;108:585-594, 2. Masdeu JC, Small CB, Weiss J, et al. Multifocal cytomegalovirus encephalitis in AIDS. Ann Neuroi. 1988;23:97-99. 3. De Gans J, Tiessens G, Portegies P, et al. Predominance of polymorphonuclear leukocytes in cerebrospinal fluid of AIDS patients with cytomegalovirus polyradiculomyelitis. JAcquir Immune Defic Syndr. 1990;3:1155-1158. 4. Sabd G, Lacroix C, Chemouilli P, et al. Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study. Ann Neural. 1991;29:139-146. 5. Behar R, Wiley C, MC Cutchan A. Cytomegalovirus polyradiculoneuropathy in acquired immunodeficiency syndrome. Neurology. 1987;37:557-561. 6. Gozlan J, Salord JM, Roullet E, et al. Rapid detection of cytomegalovirus DNA in cerebrospinal fluid of AIDS patients with neurologic disorders. J Infect Dis. 1992;166:1416-1421. 7. Wolf DG, Spector SA. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis. 1992;166:1412-1415. 8. De Gans J, Portegies P, Tiessens G, et al. Therapy for cytomegalovirus polyradiculomyelitis in patients with AIDS: treatment with ganclclovir. AIDS. 1990;4:421-425. 9. Fuller GN, Gill SK, Guiloff RJ, et al. Ganciclovir for lumbosacral polyradiculopathy in AIDS. Lancet. 1990;1:48-49. 10. Miller RG, Storey JR, Greco CM. Ganciclovir in the treatment of progressive AIDS-related polyradiculopathy. Neurology. 1990;40:569-574. 11. Graveleau P, Perol R, Chapman A. Regresslon of cauda equina syndrome in AIDS patient being treated with ganciclotir. Lancet. 1989;1:511-512, 12, Nelson MR, Barter G, Hawkins D, Gazzard BG. Simultaneous treatment of cytomegalovirus retinitis with ganciclovir and foscarnet. Lancei. 1991; 338:250. Letter. 13. Enting R, de Gans J, Reiss P, et al. Ganciclovir/foscarnet for cytomega lovirus meningoencephalitis in AIDS. Lancet 1992;340:559-560. 14. Peters M, Schtirman D, Pohle HD, et al. Combined and alternating ganciclovir/foscarnet in HIV-related cytomegalovirus encephalitis. Lancet. 1992;340:970. 15. Fischl M, Collier A, Stanley K, et al. The safety and efficacy of zidovudine (ZDVI and zalcitabine (DDC) or DDC alone versus ZDV. Presented at the Ninth International Conference on AIDS; June 1993; Berlin. 16. Freitas VR, Fraser-Smith EB, Matthews TR. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovirus and herpes simplex virus type 2 in vitro and in vivo. Antivir Res. 1989;12:205-212. 17. Manischewitz JF, Quinnan GV, Lane HC, Wittek AE. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother. 1990;34:373-375. 18. Fletcher C, Sawchuk R, Chinnock B, et al. Human pharmacoklnetics of the antiviral drug DHPG. Clin Pharmacol Ther. 1986;40:281-286. 19. Sjovall J, Karlsson A, Ogenstad S, et al. Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus. Cbn Pharmacol Ther. 1988;44:65-73. 20. Jacobson MA, Drew WL, Feinberg J, et al. Foscarnet therapy for ganciclovlr-resistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis. 1991;163:1348-1351. 21. Sullivan V, Coen DM. Isolation of foscarnet-resistant human cytomegalovirus patterns of resistance and sensitivity to other antiviral drugs. J Infect Dis. 1991;164:781-784. This study has been supported in part by the Centre d’Etudes et de Recherches en Infectiologie, The Universib of Paris VII, Lariboisikre-Saint-Louis, and SIDA Urgence. Manuscript received July 6, 1993, and accepted in revised form September 24, 1993.
August
1994
The American
Journal
of Medicine”
Volume
97
197
) BRIEF CLINICAL OBSERVATIONS
Combined Therapy With Ganciclovir and Foscarnet for Cytomegalovirus Polyradiculomyelitis in Patients With AIDS
was normal. The CD4 cell count was ~/FL. Cerebral, dorsal, and lumbar magnetic resonance imaging were normal. CSF contained 56 white blood cells/n& (72% of polymorphonuclear leukocytes), 80 mg/dL protein, 5 mmol/L glucose. CSF cultures for bacteria, fungi, parasites, were negative, as well as CSF Venereal Disease Research Laboratories (V’DRL) and cryptococcal antigen tests. CMV, however, was cultured from CSF and peripheral blood, and detection of CMV DNA by PCR was also positive in CSF. Intravenous ganciclovir was started at a dose of 5 mgkg every 12 hours. On day 6 of therapy, the patient’s neurological condition worsened with complete flaccid paraplegia (MRC grade 0), although CMV was no longer cultured from either CSF or blood. CMV DNA was, however, still detected in CSF. Foscarnet was then added to ganciclovir at a dose of 90 mgkg twice a day. Following 13 days of combined therapy, partial return of motor function was observed in both legs (MRC grade 2) and CSF contained only 8 leukocytes, with negative CMV culture from CSF and peripheral blood, as well as negative CMV DNA deteetion by PCR. The patient was discharged on day 23, on a maintenance foscarnet regimen (90 mg/kg/d), and he was able to walk using a frame (MRC grade 4). He committed suicide a few weeks later.
Marina Karmochkine,MD, Jean-MichelMolina, MD, CatherineScieux, MD, Yves Welker, MD, Ft+d&ic Morinet, MD, Jean-MarieDecazes, MD, Philippe Lagrange,MD, LaurenceSchnell, Jacques Modai, MD, 1-6pitaf Saint-his, Paris, France ytomegalovirus (CMV) is the most common C cause of opportunistic viral diseases in patients with HIV infection and contributes to acquired immunodeficiency syndrome (AIDS)-related morbidity and mortality.’ Although retinitis and gastrointestinal tract infections are the most common clinical manifestations of CMV infection, neurological involvement has been increasingly reported.2A CMV-related polyradiculomyelitis has typical clinical presentation and cerebrospinal fluid (CSF) findings, which should suggest the diagnosis in patients with AIDS.S5 CMV isolation from the CSF and/or detection of CMV DNA sequences by polymerase chain reaction (PCR) in the CSF will confirm this diagnosis and allow early initiation of anti-CMV therapy.6,7 Recovery from CMV-related polyradiculomyelitis has, however, rarely been reported with the currently available anti-CMV drugs.8-10 We describe here two patients in whom early recognition of CMV-polyradiculomyelitis and initiation of combined anti-CMV therapy allowed significant clinical benefit.
Patient 2 A 33-year-old HIV-l-infected homosexual was admitted to our clinic in July 1992, 7 days after the onset of progressive paraparesia, urinary difficulties, and dysphonia. Kaposi sarcoma and pneumocystis pneumonia were diagnosed in March 1991. CMV retinitis developed in April 1991, and improved with foscarnet therapy. The patient has since remained on a foscarnet maintenance regimen (100 mg/kg/d). He was afebrile. Physical examination revealed a cauda equina syndrome with severe bilateral leg weakness (MRC grade 2). Multiple right cranial palsies (VII, IX, and X) were also observed. Fundoscopy did not find active retinitis. Magnetic resonance imaging of brain and spinal cord was normal. CSF analysis disclosed 280 white blood cells/n& (75% of polymorphonuclear leukocytes), total protein was 540 mg/dL, and glucose 1.5 mmol/L. CSF cultures for bacteria, fungi, CMV, and parasites were negative, as well as CSF VDRL test. However, CMV DNA was detected in CSF by PCR, and blood and urine CMV cultures were positive. Combined therapy was immediately initiated: foscarnet regimen was increased (200 mg/kg/d) and ganciclovir was started (10 mg/kg/d). On day 10 of combined therapy, CSF contained 100 white blood cells/ml (43% polymorphonuclear cells), total protein was 280 m&g, and glucose 2.2 mmol/L. CMV detection in CSF, by either culture or PCR, was negative, as was CMV culture in peripheral blood, and cranial palsies and paraparesia improved (MRC grade 4). On
CASE REPORTS Patient 1 A 46yearold bisexual HIV-l-infected man was referred to our clinic in January 1992 for difficulty in walking and urinary retention. Non-Hodgkin’s lymphoma of small bowel was diagnosed in 1988 and was in complete remission. He was receiving cotrimoxazole for Pnmmcgstti car&ii pneumonia prophylaxis and didanosine (400 mg/day). He manifested progressive weakness and pain in his right leg 12 days before admission. Bilateral weakness of the lower limbs and urinary difficulties appeared 9 days before admission. On examination, the patient was afebrile and had severe bilateral motor deficit of the lower limbs. Muscle strength, as expressed according to the Medical Research Council (MRC) scale, was grade 1 in distal muscles and 3 in proximaI muscles. Leg tendon reflexes were absent and plantar responses flexor. A complete cauda equina syndrome was present with perianal anesthesia, and urinary retention. Fundoscopic examination 196
August
1994
The American
Journal
of Medicine@
Volume
97
BRIEF CLINICAL OBSERVATIONS
day 20, the patient was able to walk. On day 40, CSF only contained 1 white blood cell/n& protein 75 mg/dL, glucose 2.9 mmol/L, and ganciclovir and foscarnet were delivered on a maintenance regimen. The patient was then discharged. He died from a respiratory distress syndrome 6 months later. No autopsy was performed.
In conclusion, use of combination anti-CMV therapy in our two patients with (XV-related polyradiculomyelitis led to clinical improvement and eradication of CMV from the CSF. Further studies would be needed to evaluate the potential benefit of such combination therapy in severe CMV infections.
REFERENCES
COMMENTS Our 2 patients presented with typical CMV-associated polyradicuIomyelitis.55 The diagnosis was based on the presence of a distinct clinical presentation of an acute severe cauda equina syndrome, associated with CSF pleocytosis with predominance of polymorphonuclear leukocytes, in HIV-infected patients with severe immune deficiency. The detection of CMV in CSF, by either culture or PCR confirmed this diagnosis.617Recovery from CMV polyradiculomyelitis remains deceptive, however, despite treatment with antiCMV agents. De Gans et al* noted clinical deterioration in 4 patients receiving gancicloti started 3 to 6.5 weeks after onset of symptoms. Only 1 patient with minor paraparesis improved when ganciclovir was started 1 week after onset of symptoms. Thus, early recognition and treatment of this syndrome appears to be an important factor for a better outcome.“” In our 2 patients, therapy was instituted 7 and 12 days following onset of clinical symptoms, and that could, by itself, explain some of the clinical benefit observed. However, ganciclovir or foscarnet did not appear to be beneficial to other patients with severe paraparesis, as was the case in our 2 patients.*ag Both patients also received initially monotherapy with either ganciclovir of foscaxnet without improvement. We, therefore. initiated combined therapy with high doses of both ganciclovir and foscarnet. This strategy of combined antiviral therapy has been used with some success in CMV retinitis and encephalitis, 12-14as well as in HlV infection.15 Combined therapy with ganciclovir and foscarnet has synergistic activity against CMV in vitro16,17that might explain the clinical benefit observed in vivo. Alternatively, while pharmacokinetics of both drugs have indicated variable concentrations in the CSF1*,lg that could be responsible for suboptimal clinical efficacy of monotherapy in CMV polyradiculomyelitis, combined therapy might achieve a higher anti-CMV activity in the CSF. Also, combined therapy might overcome resistant strains of CMV to either ganciclovir or foscarnet, since ganciclovir-resistant strains of CMV are sensitive to foscaxnet and vice versa.20,21We observed a clear and sustained clinical benefit in our patients following the flit 10 to 12 days of combined therapy. This combined regimen has been well tolerated, and CSF abnormalities returned to normal values. Also, CMV was no longer detected in the CSF using standard cultures or detection of CMV DNA by PCR.
1. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1988;108:585-594, 2. Masdeu JC, Small CB, Weiss J, et al. Multifocal cytomegalovirus encephalitis in AIDS. Ann Neuroi. 1988;23:97-99. 3. De Gans J, Tiessens G, Portegies P, et al. Predominance of polymorphonuclear leukocytes in cerebrospinal fluid of AIDS patients with cytomegalovirus polyradiculomyelitis. JAcquir Immune Defic Syndr. 1990;3:1155-1158. 4. Sabd G, Lacroix C, Chemouilli P, et al. Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study. Ann Neural. 1991;29:139-146. 5. Behar R, Wiley C, MC Cutchan A. Cytomegalovirus polyradiculoneuropathy in acquired immunodeficiency syndrome. Neurology. 1987;37:557-561. 6. Gozlan J, Salord JM, Roullet E, et al. Rapid detection of cytomegalovirus DNA in cerebrospinal fluid of AIDS patients with neurologic disorders. J Infect Dis. 1992;166:1416-1421. 7. Wolf DG, Spector SA. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis. 1992;166:1412-1415. 8. De Gans J, Portegies P, Tiessens G, et al. Therapy for cytomegalovirus polyradiculomyelitis in patients with AIDS: treatment with ganclclovir. AIDS. 1990;4:421-425. 9. Fuller GN, Gill SK, Guiloff RJ, et al. Ganciclovir for lumbosacral polyradiculopathy in AIDS. Lancet. 1990;1:48-49. 10. Miller RG, Storey JR, Greco CM. Ganciclovir in the treatment of progressive AIDS-related polyradiculopathy. Neurology. 1990;40:569-574. 11. Graveleau P, Perol R, Chapman A. Regresslon of cauda equina syndrome in AIDS patient being treated with ganciclotir. Lancet. 1989;1:511-512, 12, Nelson MR, Barter G, Hawkins D, Gazzard BG. Simultaneous treatment of cytomegalovirus retinitis with ganciclovir and foscarnet. Lancei. 1991; 338:250. Letter. 13. Enting R, de Gans J, Reiss P, et al. Ganciclovir/foscarnet for cytomega lovirus meningoencephalitis in AIDS. Lancet 1992;340:559-560. 14. Peters M, Schtirman D, Pohle HD, et al. Combined and alternating ganciclovir/foscarnet in HIV-related cytomegalovirus encephalitis. Lancet. 1992;340:970. 15. Fischl M, Collier A, Stanley K, et al. The safety and efficacy of zidovudine (ZDVI and zalcitabine (DDC) or DDC alone versus ZDV. Presented at the Ninth International Conference on AIDS; June 1993; Berlin. 16. Freitas VR, Fraser-Smith EB, Matthews TR. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovirus and herpes simplex virus type 2 in vitro and in vivo. Antivir Res. 1989;12:205-212. 17. Manischewitz JF, Quinnan GV, Lane HC, Wittek AE. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother. 1990;34:373-375. 18. Fletcher C, Sawchuk R, Chinnock B, et al. Human pharmacoklnetics of the antiviral drug DHPG. Clin Pharmacol Ther. 1986;40:281-286. 19. Sjovall J, Karlsson A, Ogenstad S, et al. Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus. Cbn Pharmacol Ther. 1988;44:65-73. 20. Jacobson MA, Drew WL, Feinberg J, et al. Foscarnet therapy for ganciclovlr-resistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis. 1991;163:1348-1351. 21. Sullivan V, Coen DM. Isolation of foscarnet-resistant human cytomegalovirus patterns of resistance and sensitivity to other antiviral drugs. J Infect Dis. 1991;164:781-784. This study has been supported in part by the Centre d’Etudes et de Recherches en Infectiologie, The Universib of Paris VII, Lariboisikre-Saint-Louis, and SIDA Urgence. Manuscript received July 6, 1993, and accepted in revised form September 24, 1993.
August
1994
The American
Journal
of Medicine”
Volume
97
197