Hirsch Ms

Isolation of HTLV-III from Cerebrospinal Fluid and Neural Tissues of Patients with Neurologic Syndromes Related to the Acquired Immunodeficiency Syndrome

We conducted virus-isolation studies on 56 specimens from the nervous system of 45 patients in order to determine whether human T-cell lymphotropic virus Type III (HTLV-III) is directly involved in the pathogenesis of the neurologic disorders frequently encountered in the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. We recovered HTLV-III from at least one specimen from 24 of 33 patients with AIDS-related neurologic syndromes. In one patient, HTLV-III was isolated from the cerebrospinal fluid during acute aseptic meningitis associated with HTLV-III seroconversion. HTLV-III was also isolated from cerebrospinal fluid from six of seven patients with AIDS or its related complex and unexplained chronic meningitis. In addition, of 16 patients with AIDS-related dementia, 10 had positive cultures for HTLV-III in cerebrospinal fluid, brain tissue, or both. Furthermore, we cultured HTLV-III from the spinal cord of a patient with myelopathy and from the sural nerve of a patient with peripheral neuropathy. These findings suggest that HTLV-III is neurotropic, is capable of causing acute meningitis, is responsible for AIDS-related chronic meningitis and dementia, and may be the cause of the spinal-cord degeneration and peripheral neuropathy in AIDS and AIDS-related complex.

Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections.

A double-blind, placebo-controlled trial of interferon prophylaxis against viral infections was conducted in renal-transplant recipients receiving standard immunosuprressive therapy with or without antithymocyte globulin. Interferon was administered for six weeks, beginning on the day of transplantation. Cytomegalovirus excretion began earlier and viremia was more frequent in placebo-treated than in interferon-treated patients. Cytomegalovirus viremia correlated with clinical syndromes was more frequent in recipients of antithymocyte globulin. In contrast, neither interferon nor antithymocyte globulin altered excretion of herpes simplex virus. Reversible leukopenia and thrombocytopenia occurred in seven interferon recipients. Patient and graft survival were comparable in interferon and placebo groups. There preliminary results suggest that a six-week course of prophylactic interferon delays shedding of cytomegalovirus and decreases the incidence of viremia after transplantation. In contrast, antithymocyte globulin appears to increase the severity of infection from cytomegalovirus among these patients.

Glomerulopathy Associated with Cytomegalovirus Viremia in Renal Allografts

Abstract We investigated the relation between cytomegalovirus (CMV) infection and renal-allograft dysfunction in 14 patients. In seven instances (including two successive transplants in one patient), allograft dysfunction occurred during clinically manifest, viremic CMV infection. In five of these, biopsies revealed little or no tubulointerstitial change but a distinctive, diffuse glomerulopathy characterized by enlargement or necrosis of endothelial cells and accumulation of mononuclear cells and fibrillar material in glomerular capillaries. Two of these allografts recovered their function, both with cessation of high-dose immunosuppression. Biopsies in the other 10 patients revealed predominantly tubulointerstitial changes typical of cellular rejection, and most of these patients did not have viremia. One additional patient, studied prospectively, manifested both forms of allograft injury: tubulointerstitial changes occurring two weeks after transplantation and responding to increased immunosuppression,...

RECOMBINANT HUMAN INTERFERON ALFA-A SUPPRESSES HTLV-III REPLICATION IN VITRO

Recombinant human interferon alfa-A (rIFN alpha A) had a dose-related suppressive effect on human T lymphotropic virus type III (HTLV-III) replication in vitro in normal peripheral-blood mononuclear cells (PBMC). Both single-dose and multiple-dose regimens were inhibitory. Such inhibitory concentrations (4-1024 units/ml) were not toxic to PBMC in culture, and were within the ranges achievable in blood after injection. These studies suggest that clinical trials of rIFN alpha A in early HTLV-III infection are warranted.

ISOLATION OF HTLV-III/LAV FROM CERVICAL SECRETIONS OF WOMEN AT RISK FOR AIDS

Cervical secretions from 14 women seropositive for HTLV-III/LAV were obtained between days 7 and 21 of the menstrual cycle and cultured for virus. HTLV-III/LAV was isolated from cervical secretions in 4 of 14 women, as well as from blood of 7 of 13 women tested. Female genital secretions may therefore be a source for sexual transmission of the virus to men.

Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon.

Both recombinant alpha A interferon and azidothymidine inhibit the replication of human immunodeficiency virus in peripheral blood mononuclear cells. Combinations of recombinant alpha A interferon and azidothymidine at concentrations that are easily achievable in patients synergistically inhibit human immunodeficiency virus in vitro with minimal toxicity. Combinations of antiretroviral compounds that act by different mechanisms may prove useful in the treatment of acquired immunodeficiency syndrome-related disorders.

Risk of nosocomial infection with human T-cell lymphotropic virus III (HTLV-III)

Abstract Infection with human T-cell lymphotropic virus III (HTLV-III) is closely linked to the acquired immunodeficiency syndrome (AIDS). We evaluated the risk of nosocomial infection with HTLV-III by testing for antibodies to HTLV-III among hospital employees, including victims of needle-stick exposure, endoscopists, pathologists, and laboratory workers. Assays for antibody against the virus were performed by enzyme-linked immunosorbent assay and electrophoretic (Western blot) techniques. Although all 22 of our patients with AIDS and 6 of 7 with AIDS-related complex were found to have antibodies to HTLV-III when both assays were employed, none of the 85 employees with nosocomial exposure to specimens from patients with AIDS were positive for HTLV-III antibody. These studies must be regarded as preliminary, but they suggest that when current hospital isolation procedures are employed, the risk of nosocomial transmission of HTLV-III is low. (N Engl J Med 1985; 312: 1–4.)

INHIBITION OF HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE III IN VITRO BY PHOSPHONOFORMATE

Phosphonoformate, an inhibitor of reverse transcriptase in a number of retroviruses, was shown to have a dose-related inhibitory effect on human T-cell lymphotropic virus type III (HTLV-III) replication in the H9 cell line in vitro. HTLV-III replication was eliminated at a concentration of 680 mumol, a non-cytotoxic dose. A lower dose of 132 mumol inhibited HTLV-III replication by more than 98%, as measured by reverse transcriptase activity, compared with untreated infected cultures. Reverse transcriptase activity in HTLV-III particles was completely inhibited by 5.0 mumol phosphonoformate.

Effects of Interferon-Alpha on Cytomegalovirus Reactivation Syndromes in Renal-Transplant Recipients

We have previously demonstrated that six weeks of prophylaxis with interferon-alpha delays cytomegalovirus excretion and decreases viremia in recipients of kidney transplants. In a double-blind trial to evaluate the effects of a longer course of prophylaxis, we gave either 3 X 10(6) units of interferon or placebo intramuscularly to 42 patients before transplant surgery was performed. After surgery, doses were given three times a week for six weeks and then twice a week for eight weeks (total of 102 X 10(6) units). Clinical signs of cytomegalovirus infection were markedly reduced in interferon recipients. These signs developed in 7 of 22 placebo recipients and 1 of 20 interferon recipients (P = 0.03). Opportunistic superinfections (Aspergillus fumigatus and Pneumocystis carinii) occurred only in patients given placebo. Cytomegalovirus-associated glomerulopathy developed in one interferon recipient and three placebo recipients. Survival of patients and grafts was equivalent in both treatment groups, and minimal toxicity was observed with interferon. In seropositive renal-transplant recipients, interferon-alpha affords effective prophylaxis against serious cytomegalovirus infections.

Factors indicative of outcome in a comparative trial of acyclovir and vidarabine for biopsy-proven herpes simplex encephalitis

SummaryA total of 208 patients underwent brain biopsy for presumptive herpes simplex encephalitis and were randomized to receive either vidarabine, vira-A, at 15 mg/kg/day, or acyclovir, at 30 mg/kg/day for ten days. 69 patients (33%) had biopsy-proven disease; 37 received vira-A and 32 acyclovir. With the exception of age, patient populations were balanced for demographic characteristics. Overall survival for acyclovir recipients was 72% compared with 46% for vira-A-treated patients 18 months after therapy (p=0.008). After adjustment for differences of age between treatment populations by multivariant regression analyses, acyclovir treatment remained superior to vidarabine therapy (p=0.041). Mortality varied according to the level of consciousness at the onset of therapy. For lethargic, semicomatose and comatose patients, mortality was 42%, 46%, and 67%, respectively, for the vira-A-treated patients and 0%, 25% and 25%, respectively, for acyclovir-treated patients. Six months post-therapy morbidity assessments revealed five (14%) vira-A versus 12 (38%) acyclovir recipients who had returned to normal function, while eight (22%) and three (9%), respectively, had moderate debility. Outcome differences were significant (p=0.02; Wilcoxon, 2-sample test) using an adapted scoring system. Age and Glasgow coma scale > 10 predicted the best outcome following acyclovir treatment. Disoriented patients who flex and respond by eye to pain had no mortality and 50% returned to normal. These data indicate that acyclovir is the treatment of choice for biopsy-proven herpes simplex encephalitis.ZusammenfassungBei 208 Patienten wurde wegen Verdachts auf Herpes simplex-Enzephalitis eine Gehirnbiopsie durchgeführt. Nach Randomisierung wurde entweder mit Vidarabin in einer Dosierung von 15 mg/kg pro Tag oder mit 30 mg/kg/Tag Aciclovir für zehn Tage behandelt. Bei 69 der biopsierten Patienten (33%) wurde die Diagnose bestätigt, von ihnen erhielten 37 Vidarabin und 32 Aciclovir. Die demographischen Charakteristika der beiden Gruppen waren mit Ausnahme des Alters vergleichbar. 18 Monate nach der Therapie waren 72% der mit Aciclovir behandelten und 46% der mit Vidarabin behandelten Patienten am Leben (p=0,008). Nach Ausgleich der Altersunterschiede in den beiden Patientengruppen mittels Multivarianten-Regressionsanalyse blieb Aciclovir gegenüber Vidarabin immer noch therapeutisch überlegen (p=0,041). Je nach Grad der Bewußtseinsstörung zu Beginn der Therapie war die Sterblichkeit unterschiedlich hoch. Die Letalität nahm von Lethargie zu Semikoma und Koma von 42% auf 46% und 67% bei mit Vidarabin und von 0% auf 25% und 25% bei mit Aciclovir behandelten Patienten zu. Nachuntersuchungen bezüglich Restschäden sechs Monate nach Therapie ergaben bei fünf mit Vidarabin (14%) und 12 mit Aciclovir (38%) behandelten Patienten eine vollkommene Wiederherstellung und bei acht (22%) bzw. drei (9%) eine mäßiggradige zerebrale Funktionseinschränkung. Die Unterschiede der Therapieergebnisse erwiesen sich bei Anwendung eines angepaßten Punktesystems als signifikant mit p=0,02 (Zwei-Proben-Test nach Wilcoxon). Bei einer Punktezahl von mehr als 10 im Glasgow Koma-Schema war das Ergebnis nach Aciclovir-Behandlung am günstigsten. Bei bewußtseinsgestörten Patienten mit erhaltenen Reflexen und Augenreaktionen auf Schmerzreiz traten keine Todesfälle auf, 50% der Patienten wurden völlig wiederhergestellt. Aufgrund dieser Daten ist Aciclovir als Therapie der Wahl bei bioptisch gesicherter Herpes simplex-Enzephalitis anzusehen.