Prevention and treatment of experimental influenza A virus infection in volunteers with a new antiviral ICI 130,685

Abstract

The initial prophylactic and therapeutic trials of ICI 130,685 against influenza A virus infection are reported. Prophylaxis with either 200 mg/day (38 volunteers received drug and 40 received placebo) or 100 mg/day (28 volunteers received drug and 28 received placebo) for seven days significantly reduced illness, mean clinical score and nasal secretion weight when volunteers were challenged with 10(4.1) EID50 of influenza virus A/Eng/40/83 (H3N2). Overall, prophylaxis with 200 mg/day and 100 mg/day gave 91% and 72% protection against illness relative to placebo, respectively. In addition, prophylaxis with both regimens for seven days also significantly reduced the number of volunteers who excreted virus. In a therapeutic study, volunteers were inoculated with the same dose of virus and those who developed symptoms which persisted for 6-15 h were treated with 200 mg/day of drug (20 volunteers) or placebo (19 volunteers) for four days. Generally, treatment reduced both the amount of virus excreted and the mean daily clinical score. However, these reductions were only statistically significant (P less than 0.05) on the third day of medication for the amount of virus excreted and on the fourth day of treatment for the mean clinical score. It was concluded that ICI 130,685 is effective in the prevention and treatment of influenza virus infection. An initial tolerance study in 16 volunteers who received either drug (200 mg/day) (8 volunteers) or placebo (8 volunteers) for seven days, indicated that the drug was generally well tolerated. Combining data from all studies, 43% of volunteers who received the drug at the 200 mg/day dosage and 21% who received placebo complained of one or more symptoms. However, symptoms were generally minor and of short duration. At the lower dosage (100 mg/day) the symptoms were qualitatively similar to those reported with placebo.

Impact of Emerging Antiviral Drug Resistance on Influenza Containment and Spread: Influence of Subclinical Infection and Strategic Use of a Stockpile Containing One or Two Drugs

“…Considerable uncertainty exists regarding the maximal infectiousness of individuals in relation to the symptomatic course of influenza, although viral shedding data has been related to infectious potential [16] [17]. We do not explicitly characterise symptom onset in our model, but assume a one-day latent period ( E ) between inoculation and the onset of three days' constant infectious duration ( I ), exponentially distributed over the period, of which at least part of one day is likely to be presymptomatic.…”

Minimum Infective Dose of the Major Human Respiratory and Enteric Viruses Transmitted Through Food and the Environment

“…The H 3 N 2 influenza strain A/England/42/72 infected and caused disease in just over half of the inoculated population when a 3.5 9 10 3 TCID 50 or a 1,000 times higher doses were used (Arroyo et al 1975;Douglas et al 1975). The infection rate with 1.2 9 10 4 TCID 50 of the A/England/40/ 83 strain was reported to be over 90% and this dose caused illness in 40% of the subjects (Al-Nakib et al 1986). The two H 3 N 2 influenza strains, A/University of Maryland/1/70 and A/University of Maryland/2/74, caused Illness in a majority ([86%) of volunteers inoculated with about 10 4 TCID 50 .…”

A modified dose-response model that describes the relationship between haemagglutination inhibition titre and protection against influenza infection

“…The model fits to the pooled data for H3N2 (A/Eng/40/83) from two studies summarized in Table 1 (Al‐Nakib et al . & Phillpotts et al . ): (a) Infection as the endpoint, (b) Morbidity (illness) as the endpoint.…”

“…; Al‐nakib et al . ) that used the same challenge strain and similar experimental protocols and the pooled data set for both infection and illness (Table , pooling 1 & 2, and Fig. ) met the criteria we established.…”

“…We performed a pooling analysis to evaluate if some of the data sets in Table 1 have similar patterns (Table 3). We pooled data from two studies (Phillpotts et al 1984;Al-nakib et al 1986) that used the same challenge strain and similar experimental protocols and the pooled data set for both infection and illness (Table 3, pooling 1 & 2, and Fig. 3) met the criteria we established.…”