Emergence and Apparent Transmission of Rimantadine-Resistant Influenza A Virus in Families

Abstract

To determine whether rimantadine can protect family members from acquiring influenza A viral illness and to assess the possible selection of drug-resistant strains of virus, we conducted a randomized, double-blind, placebo-controlled study in three communities during two influenza seasons. When influenza A occurred in a family, the members (including the index patient) were given either rimantadine (adult oral dose, 200 mg per day) or placebo for 10 days. The presence of illness was monitored by daily recording of symptoms and temperature measurements; infection was determined by isolation of the virus and by serologic studies. Among households with documented influenza A infections, symptomatic illness occurred in one or more contacts in 10 of 28 families treated with rimantadine and in 10 of 209 families treated with placebo. Asymptomatic secondary influenza A infections were found in five families assigned to receive rimantadine and in four families assigned to receive placebo. Rimantadine-resistant strains of influenza A virus (H3N2 subtype) with mutations consisting of single amino acid changes in the M2 protein (residue 27, 30, or 31) were recovered from eight index patients and five contacts treated with rimantadine. There was apparent transmission of drug-resistant strains of virus in six contacts with secondary illnesses in five families. We conclude that when index patients are treated concurrently, rimantadine is ineffective in protecting household members from influenza A infection. If rimantadine is used for both treatment and postexposure prophylaxis in families, rapid selection and apparent transmission of drug-resistant influenza A viruses can occur.

Specific structural alteration of the influenza haemagglutinin by amantadine.

“…The characterization of drug resistant mutants isolated either following passage of virus in tissue culture in the presence of drug or from humans or birds treated with either rimantadine (amethyl-1-adamantane methylamine) or amantadine, respectively (Belshe et al, 1988;Bean et al, 1989;Hayden et al, 1989) has indicated that the target of drug action is the membrane-spanning domain of the M2 protein. The similarities in the single amino acid substitutions which confer drug resistance demonstrates the correspondence between the mechanisms of action in vivo and in vitro.…”

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

“…O desenvolvimento de vacinas tem sido apenas parcialmente eficiente no controle da gripe, devido à alta capacidade de mutação que o vírus apresenta 24 . Atualmente estão disponíveis na Europa e Estados Unidos quatro fármacos antivirais específicos para a influenza: os fármacos clássicos, amantadina (4) e rimantadina (5), e os antivirais de segunda geração, zanamivir (6) e oseltamivir (7) (Figura 9).…”

“…Atualmente estão disponíveis na Europa e Estados Unidos quatro fármacos antivirais específicos para a influenza: os fármacos clássicos, amantadina (4) e rimantadina (5), e os antivirais de segunda geração, zanamivir (6) e oseltamivir (7) (Figura 9). Os antivirais 6 e 7 foram licenciados pelas autoridades sanitárias brasileiras, encontrando-se disponíveis no mercado desde o ano de 2000 24 …”

Influenza: vaccination and treatment

“…Administration of a drug as prophylaxis and treatment to nursing home residents during outbreaks of influenza within the facility may interrupt transmission but has led to the emergence and transmission of drug-resistant strains. Postexposure prophylaxis of household contacts prevents influenza A illness by y70%, but drug resistance may emerge rapidly and render prophylaxis ineffective if the index case is also treated simultaneously [79]. The genetic basis for resistance appears to be single amino acid substitutions at positions 26, 27, 30, 31 or 34 in the transmembrane portion of the M2 ion channel [80].…”