initially developing antineuraminidase inhibitors. After two consecutive years of mild influenza, two of the companies ceased their development of the drugs, and the fact that only two remaining companies were producing them raised concern regarding the market’s capacity to support continued production. This situation could have catastrophic results during the next emergence of pandemic influenza. Stockpiling of these drugs is critical, and strategies that have been proven effective in maintaining an adequate supply of them must be implemented.

The development of new, improved therapies for influenza and other viruses is essential. However, incentives may be necessary to foster the development of antivirals for those viruses that do not represent large market opportunities but have high morbidity and mortality. The threat of certain viruses being used as agents of biological terrorism emphasizes the increased need for the development of new antivirals, as well as broadspectrum antivirals and immunomodulators, especially for those agents for which there are no vaccines, such as Ebola and Marburg. The possible targets for antiviral development include each step in the replication cycle, from virus attachment to release (see Table 4-3).

Antivirals to Human Immunodeficiency Virus (HIV)

An effective vaccine to prevent HIV infection has not yet been developed. The remarkable advances in the treatment of HIV have resulted largely from advances in antiviral chemotherapy. Combination chemotherapy that suppresses the replication of HIV results in a pronounced reduction in illness and death. Multidrug treatment of patients with indinavir, zidovudine, and lamivudine can reduce the serum levels of HIV to less than 50 copies per ml (see Figure 4-2). Although these treatments reduce replication, however, they do not completely suppress viral replication, and it is probable that a smoldering virus replication is present and difficult to detect. Nonetheless, the immune function of both CD4 and CD8 cells is regenerated, and persistent opportunistic infections are often resolved. It is this restoration of the immune function that has transformed the natural history of AIDS (Richman, 2001). The dramatic restoration of immune function comes at a cost, however—the expense, inconvenience, and toxicity of antiretroviral therapy.

Approximately 10 billion (1010) HIV virus particles are generated daily in an infected host (Perelson et al., 1996). With a mutation rate of about 10–5 nucleotides per replication cycle and no proofreading mechanism for reverse transcription, approximately one mutation is generated for each new genome of 92,000 nucleotides (Mansky and Temin, 1995). Thus, genomes with a mutation in any gene, as well as many with double mutations, could be generated daily. As a result, drug-resistant mutants can develop



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