Raphael Dolin

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)

The Safety and Efficacy of Zidovudine (AZT) in the Treatment of Subjects with Mildly Symptomatic Human Immunodeficiency Virus Type 1 (HIV) Infection: A Double-Blind, Placebo-Controlled Trial

OBJECTIVE To evaluate the efficacy and safety of zidovudine early in the treatment of human immunodeficiency virus type 1 (HIV) infection. DESIGN A double-blind, randomized, placebo-controlled trial with subject stratification by pretreatment CD4 T lymphocyte counts. SETTING Multicenter trial at AIDS Clinical Trial units. SUBJECTS Seven hundred eleven subjects with mildly symptomatic HIV infection. INTERVENTION Three hundred fifty-one subjects were assigned to placebo and 360 to zidovudine, 200 mg orally every 4 hours. The median duration of follow-up was 11 months. MEASUREMENTS AND MAIN RESULTS Fifty-one subjects developed the acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex, or death as a first critical event. For the stratum of subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 before treatment, 34 events occurred in placebo recipients and 12 in zidovudine recipients (P = 0.0002; relative risk [RR] estimate, 3.23 [95% CI, 1.67 to 6.24]). For the stratum of subjects with 500 to 799 CD4 T lymphocytes/mm3 before treatment, 2 events occurred in placebo recipients and 3 in zidovudine recipients. Candidiasis at study entry independently increased the risk for having an event (P = 0.005; RR estimate, 2.3 [95% CI, 1.29 to 4.12]); HIV antigenemia at study entry also increased this risk (P = 0.01; RR estimate, 2.1 [95% CI, 1.2 to 3.8]). Significant differences between the treatment groups in CD4 T-lymphocyte counts occurred in subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 after 4 weeks of therapy (P = 0.002). Differences persisted through week 52. Less prominent changes occurred in subjects with 500 or more CD4 T lymphocytes/mm3. Serum levels of HIV antigen decreased significantly in zidovudine recipients. Serious anemia and neutropenia occurred in 5% and 4% of zidovudine recipients, respectively, and in 0% and 1% of placebo recipients, respectively. CONCLUSION Zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3.

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)

A Controlled Trial of Amantadine and Rimantadine in the Prophylaxis of Influenza a Infection

Four hundred fifty volunteers participated in a placebo-controlled, double-blind, randomized trial of the prophylactic effects of rimantadine and amantadine during an outbreak of influenza A. The subjects received drugs orally at a dose of 100 mg twice a day for six weeks. Influenza-like illness occurred in 41 per cent of the subjects receiving placebo but in only 14 per cent of those receiving rimantadine and 9 per cent of these receiving amantadine (P less than 0.001 for either drug vs. placebo). Laboratory-documented influenza occurred in 21 per cent of placebo recipients, 3 per cent of rimantadine recipients, and 2 per cent of amantadine recipients (P less than 0.001). These findings represent efficacy rates of 85 per cent for rimantadine and 91 per cent for amantadine, as compared with placebo. More recipients of amantadine (13 per cent) than recipients of rimantadine (6 per cent; P less than 0.05) or placebo (4 per cent; P less than 0.01) withdrew from the study because of central-nervous-system side effects. On the basis of this study, rimantadine appears to be the drug of choice for the prophylaxis of influenza A.

A Controlled Trial Comparing Continued Zidovudine with Didanosine in Human Immunodeficiency Virus Infection

BACKGROUND Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

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).

Herpes Zoster-Varicella Infections in Immunosuppressed Patients

Abstract Herpes zoster infections (localized and disseminated) are more frequent and severe in immunosuppressed patients. Dissemination of virus may occur to skin and to viscera but is associated p...

Biological properties of Norwalk agent of acute infectious nonbacterial gastroenteritis.

Summary Acute infectious nonbacterial gastroenteritis was induced in adult volunteers through three serial passages by oral administration of bacteria-free stool filtrates. This suggested that a replicating agent of subbacterial size was responsible for the observed disease. The biophysical properties of the agent, as assayed in volunteers, were consistent with those of a small virus, most closely related to the parvovirus group among known animal viruses. The agent appeared to have a diameter less than 66 nm and likely less than 36 nm. It appeared to lack a lipid containing envelope and was acid stable. It was stable to heating at 60° for 30 min. The agent appeared to be relatively host specific for man and conferred at least short-term immunity. Because of the high frequency of disease induced in unselected volunteers, widespread natural immunity to this agent may be absent or perhaps incomplete. Preliminary evidence suggested that the Norwalk agent replicated in an in vitro system, human fetal intestinal organ culture. We gratefully acknowledge the cooperation of the volunteers and staff at the Maryland State House of Correction. We also thank Drs. David Fedson and Sheldon Wolff of the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, for their help with the study, Dr. Samuel Formal of the Walter Reed Army Institute of Medical Research for performing enterotoxin assays and monkey inoculations, and Dr. Robert Purcell of the Laboratory of Infectious Diseases for performing Australia antigen determinations.

Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults

A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV)-uninfected adults who were randomized to receive 10(6) or 10(7) TCID50 of canarypox (ALVAC) vector expressing HIV-1MN gp160 or 10(5.5) TCID50 of ALVAC-rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 microg of HIV-1SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1MN and HIV-1SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (<65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3-specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8+ T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway.