George J. Galasso

Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study.

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.Abstract We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

Herpes Simplex Encephalitis: Vidarabine Therapy and Diagnostic Problems

To learn more about the treatment of herpes simplex encephalitis with vidarabine, we conducted an uncontrolled study of 132 patients referred to 22 hospitals because of suspected disease. All had a brain biopsy and were started on vidarabine, but only 75 were diagnosed by isolation of virus from a brain-biopsy specimen. Cumulative mortality in the latter group was 39 per cent at one year. Other than therapy, levels of consciousness and age were the major variables that influenced outcome. Of 23 patients under 30 years of age who were lethargic at the initiation of therapy, two died and 16 returned to normal. Of 26 patients over 30 years of age who were lethargic at the outset, nine died and 10 returned to normal. Semicoma and coma were associated with worse outcomes, especially in older patients. Our data suggest that outcome is improved with treatment; they provide more support for the use of brain biopsy to diagnose the infection and indicate a need for better therapy.

Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.Abstract We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

Adenine arabinoside therapy of herpes zoster in the immunosuppressed. NIAID collaborative antiviral study.

We evaluated adenine arabinoside treatment of herpes zoster in immunodeficient patients in a randomized, controlled crossover study. The two study groups had similar characteristics. In spite of rapid natural healing, those receiving adenine arabinoside over the first five days had accelerated clearance of virus from vesicles (P = 0.01), and cessation of new vesicle formation (P = 0.004), and a shorter time to total pustulation (P = 0.001). Factors modifying the response to therapy included age, underlying disease, and the duration of zoster prior to therapy. Clinical toxicity was minimal. Laboratory assessment of bone-marrow, liver and renal function showed insignificant alterations as a result of therapy. These studies show that adenine arabinoside is a drug with promise for therapy of systemic herpes zoster in immunocompromised patients. It is most efficacious when administered during the first six days of disease (P = 0.001) to those who have reticuloendothelial neoplasia (P = 0.001) and are less than 38 years of age (P = 0.001).

Summary of the II International Symposium on Cytomegalovirus.

Human cytomegalovirus (HCMV) is a highly species-specific DNA virus belonging to the Betaherpesvirinae subfamily of the herpesviridae family. Like other herpesviruses, primary infection with HCMV is followed by persistence of the virus in a latent form. The sites of latency are still largely undefined, but they probably include bone marrow progenitor cells and peripheral blood monocytes. From these sites, the virus can reactivate, resulting in renewed shedding of the virus, or, in immunocompromized persons, development of disease. Humans are the only reservoir of HCMV and transmission occurs by person-to-person contact. Infection with HCMV is common. In most developed countries, HCMV seroprevalence steadily increases after infancy and 10-20% of children are infected before puberty. In adults, the prevalence of antibodies ranges from 40 to 100%. Although HCMV has a world-wide distribution, infection with HCMV is more common in the developing countries and in areas of low socioeconomic conditions, which is predominantly related to the closeness of contacts within these populations. Except for a mononucleosis-like illness in some persons, infection with HCMV rarely causes disease in immunocompetent individuals. However, HCMV can cause severe morbidity and mortality in congenitally infected newborns and immunocompromized patients, most notably transplant-recipients and HIV-infected persons. This article provides a review of the information presented at the Second International Symposium on Cytomegalovirus organized and convened by The Macrae Group (New York City, NY) in Acapulco, Mexico on 24-28 April 1998. During this symposium, the state-of-the-art knowledge on diagnosis, treatment and prophylaxis of HCMV infections were discussed, and, based on this information, attempts to highlight the future directions in basic and clinical research areas that need to be stimulated to facilitate advancement in prevention and treatment of CMV disease.

ADENINE ARABINOSIDE THERAPY OF HERPES SIMPLEX ENCEPHALITIS: NIAID COLLABORATIVE ANTIVIRAL STUDY GROUP

Adenine arabinoside was evaluated for the treatment of herpes simplex encephalitis in a randomized controlled study. Of 50 patients with a presumptive clinical diagnosis and undergoing brain biopsy, 25 cases were proved by isolation of virus from the brain specimen. Adenine arabinoside treatment reduced mortality from 75 percent, 6 of 8, in placebo recipients to 29 percent, 5 of 17, in drug recipients (P = 0.027). Both groups were comparable for age, sex, race and concomitant therapy as well as the presenting signs and symptoms of the disease. Fifty percent of treated survivors were left with minor to moderate sequelae, returning home and to gainful activity. The level of consciousness at the time of biopsy and institution of therapy was the major determinant of outcome. At biopsy, the mortality rate of comatose patients was 66 percent while those lethargic or semi-comatose was 25 percent. Prognosis was not influenced by age or sex. These beneficial effects were achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of herpes simplex encephalitis. Drug must be given early in the course of infection before the advent of coma and seizures in order to attain a satisfactory outcome. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary therapy of encephalitides which mimick herpes.

Antiviral Agents: Why Not a “Penicillin” for Viral Infections?

The question asked most frequently by the lay person of someone involved in research on antiviral agents is “When are you going to do something about the common cold?”; the lay press contributes “Why isn’t there something like penicillin for the treatment of viral infections?” The answer usually given is a simple explanation of virus replication and the difficulty of disrupting viral replication without affecting normal cellular functions. For many years it was believed that virus production depended exclusively on cellular metabolic processes. However, this pat answer is only a partial response; it certainly is no longer adequate for the virologist. We have seen from the preceding presentations that many viruses have specific targets which can be identified and characterized, and for which specific blocking agents can be synthesized. Why, then, have we not been more effective in developing new antiviral agents? Again, there is a simple answer — clinicians and virologists have been skeptical about the potential of antivirals, believing effective antivirals would also be toxic; further, we are only now learning sufficient details of the molecular biology of viruses to identify specific blocks. Thus, the effort to date to develop new agents has been minimal. To be successful, greater effort must be expended. All the compounds identified thus far are largely a result of serendipity. None are truly the result of a concentrated effort to develop targeted antiviral agents against a specific virus. Most have come through large screening programs with the production analogs of those substances which show some promise.

Antiviral Agents: A New Beginning

Review of the statements I made at the last meeting four years ago showed that the major change that has occurred since then is not so much one of increased knowledge on antiviral drugs, but more importantly, one of attitude. The prevailing skepticism of the past has given way to optimism and determination. This determination is partially due to recent successes in the field, but more likely results from the acquired immunodeficiency syndrome (AIDS) epidemic.

VARICELLA VACCINE: PROTECTIVE EFFICACY IN CHILDREN WITH LEUKEMIA

Varicella may be severe in children with leukemia, with 10% mortality. We therefore evaluated the efficacy of live attenuated varicella vaccine in children with acute lymphocytic leukemia (ALL) in remission. We immunized 53 children with ALL off chemotherapy and 138 with ALL with chemotherapy suspended for 2 weeks, with 1000 pfu of varicella-zoster (VZ) (Oka) vaccine. After 1 dose of vaccine 82% seroconverted; 95% seroconverted after 2 doses, as detected by the fluorescent antibody to membrane antigen (FAMA) assay.The only significant side effect was rash, which occurred in 4% off chemotherapy, and in 36% with chemotherapy suspended. Rashes were not severe, but spread of VZ virus occurred to 4/129 (3%) of susceptible siblings. There was no increase in ALL relapse or incidence of zoster in vaccinees compared to a control ALL group after natural varicella. There were 22 household exposures to VZ virus in vaccinees, after which the incidence of mild varicella (average # of vesicles 50) was 18%, significantly lower than the usual 80-90% attack rate. Mild varicella occurred even in vaccinees with VZ antibody at exposure. This vaccine was 80% effective in preventing clinical varicella and 100% effective in preventing severe varicella in children with ALL, even those on chemotherapy.

In Remembrance of LOWELL GLASGOW, M.D.

Lowell Glasgow, M.D., was born August 28, 1932. He died suddenly on February 4, 1982. His passing was unexpected to all of us. He began his research career with Herbert Morgan, studying delayed hypersensitivity in experimental mumps infection. From 1960 to 1962, he was a research associate at NIH in Karl Habels laboratory where he began his research on interferon, an area in which he specialized and continued to the end. The early work concerned interferon production in vivo and in vitro . But, he was far from narrow in his research outlook; Lowell had close to 150 publications in a broad range of microbiology and clinical medicine.