Use of amantadine in the therapy and prophylaxis of A2 influenza

Discussion Papers-Session VI Use of Amantadine in the Therapy and Prophylaxis of A2 Influenza by R. B. COUCH a If safe, effective vaccines and vaccination methods were available to prevent 90% of cases of influenza, there would be no need for a chemoprophylactic or chemotherapeutic agent. The fact that the current vaccines administered by the subcutaneous route do not approach this optimal result provides the justifi- cation for continued efforts, such as those presented at this Conference, to develop better vaccines. In addition, because it is uncertain whether improve- ments can be made in efficacy, continued efforts to develop chemoprophylactic and chemotherapeutic agents for influenza are also justified. The ultimate goal is control of influenza, and it may be that more than one means will be necessary to achieve this goal. Earlier papers have reported several advances in the areas of chemoprophylaxis and chemotherapy. I would like to present some data and considerations regarding amantadine in the therapy and prophylaxis of A2 influenza. In studies with amantadine hydro- chloride, Hornick et al. b indicated a therapeutic effect for this agent in influenza caused by A2 viruses. While a therapeutic effect is clear, and is supported by similar studies by our group and others, striking amelioration of clinical findings does not result from treatment. In the studies of Hornick et al. the frequency of virus isolations from the throat was similar in the treatment and placebo groups and in our studies the quantity of virus in specimens as well as the frequency of isolations were similar in the 2 groups; this is shown in the accom- panying figure. The frequency of virus-positive throat-swab specimens, and the mean quantity of virus present in specimens from 13 volunteers treated with 100 mg of amantadine twice daily, and 16 volunteers who received placebo, appear similar. However, when analysed further, the quantitative differences be- tween the treated and placebo groups appeared significant in the first 10 hours. Rhesus monkey kidney cultures were used for these studies, whereas embryonated eggs were used in the studies of a Departments of Microbiology and Medicine, Baylor College of Medicine, Texas Medical Center, Houston, Texas 77025, USA. b See paper by R. B. Hornick et al. on page 671 ofthis issue. CHANGE IN TITRE OF VIRUS AND FREQUENCY OF POSITIVE CULTURES FROM THROAT SWABS FROM PATIENTS ACCORDING TO TREATMENT WITH AMANTADINE OR PLACEBO 100 753.0 a4'4 ~50 -4 2.0 25 '' 0 L_ E 0 10 34 58 82 Length of treatment (hours) 11.0 0 0 10 34 58 82 Length of treatment (hours) WHO 91656 Amantadine Placebo Homick et al. These differences and the fact that treatment was usually started earlier after onset of illness in their studies may account for the different patterns of virus shedding. However, the essential fact is that in both studies little difference in virus shedding was noted between treated and control individuals. These virus-shedding results, combined with the minimal effect on the course of illness in these cases, suggest that amantadine in the 200 mg daily dosage cannot be recommended for routine use in treatment of uncomplicated influenza. Consider- ation should be given, however, to therapeutic 2426A 695 - 696 DISCUSSION PAPERS-SESSION VI studies in the high-risk group since in these individuals the disease may be more severe and complications are more likely to occur. In this regard, one must consider the toxicity of amantadine hydrochloride. In our studies and in those reported at this Conference, toxicity from amantadine was minimal to absent. I think that sufficient evidence is now available to say that toxicity is not the primary reason for limiting the use of amantadine for control of influenza. However, the risk of toxicity with diffe- rent age-groups and various chronic disease states is not clear. More pharmacological data are needed for such individuals. and these data could be col- lected in combination with the therapeutic trials just proposed. While antiviral therapy for influenza is desirable, chemoprophylaxis remains the major consideration of the proposed antiviral agents for influenza. The ability of amantadine to prevent infection with type A2 strains if given prior to exposure is established. Smorodincev c in extensive trials and Galbraith et al. d9 in detailed studies have provided data indicating that in open-community field trials amantadine is an effective prophylactic for A2 influenza. However, as with the current vaccines, the prophylactic effect is less than optimal. This finding, in combination with the observation that the prophylactic effect was better in those individuals c Unpublished. d See paper by A. W. Galbraith et al. on page 677 of this issue. with some pre-existing antibody, caused these investigators to suggest that a combination of influenza vaccine and amantadine might produce optimal protection. Obviously, since neither method of prophylaxis alone appears ideal, the combination should be tested. This investigation deserves high priority in prospective studies with amantadine. In addition, it should be noted that Solov'eve suggested that a combination of interferon and amantadine might produce optimal prophylaxis. At the present time amantadine has a limited but definite place in prophylaxis for human influenza. I believe that it should be recommended for ad- ministration to non-vaccinated individuals in the high-risk group when influenza A2 is identified in the community, a situation that occurred in extensive areas of the USA and other parts of the world in 1968-69. In addition, however, careful monitoring for toxicity should be performed and the drug dis- continued if toxicity occurs. Exceptions to this general recommendation are defined by the dis- tributor. In summary, I believe it possible that in the future an important role for antiviral com- pounds in influenza will be defined. Evaluation of available and emerging antiviral agents should continue because of the possibility that they may provide an important link in producing safe, effective, and optimal prophylaxis of human in- fluenza. e See paper by V. D. Solov'ev on page 683 of this issue. Use of Poly I poly C in the Prophylaxis and Treatment of Acute Viral Infections by M. R. HILLEMAN a Extensive investigations have been carried out in animal models in our laboratory to assess the potential usefulness in the prophylaxis and treatment of acute viral infections of poly I-poly C (poly- riboinosinic: polyribocytidylic acid complex; poly I: C; rlnrCn; rI: rC). a Merck Institute for Therapeutic Research, West Point, Pa., USA. The accompanying table presents an interpretative summary of tests in various animal models. The drug was given in a single dose, 3 hours prior to severe viral challenge. Various route combinations were employed and the test results are expressed in terms of findings (death, except for vaccinial tail lesions) 7-21 days after challenge. Strong activity was found against PVM, Columbia SK, vaccinia, and para- influenza viruses. Weak activity was found against 2426B