Viral resistance, development using

In this chapter we describe the current insights into the evolution of viruses under pressure of antiviral therapy and the potential impact on viral fimess. As most recent work in this field has been done in the field of human immunodeficiency virus (HIV), we use the evolution of this virus as the basis for the chapter. Subsequently, we describe resistance evolution for Hepatitis B virus (HBV), where large progress has been made in recent years. Furthermore, we describe the resistance development for Hepatitis C virus (HCV), for which a very active drug development program is undertaken by several pharmaceutical companies. Finally, we discuss resistance evolution for Influenza. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

The pharmacokinetic interactions with efavirenz and rifampicin are likely to be clinically important. The reduction in maraviroc plasma levels seen could result in decreased efficacy and the development of viral resistance. Doubling the dose of maraviroc overcame this interaction, and this is the suggested approach of the manufacturer when maraviroc is used in the absence of protease inhibitors. Efavirenz appears to halve the increase in maraviroc levels seen with ritonavir-boosted protease inhibitors. 

A number of peptidic protease inhibitors are currently used in clinical practice. Although these inhibitors represent a major advance in HIV chemotherapy, adverse side effects and viral resistance is a cause of constant concern. A further limitation of current protease inhibitors is their complexity and difficult synthetic pathway with high cost of production, hi order to overcome all these difficulties, it is desirable to identify new inhibitors of simpler structure. Up to now, only one non-peptide compound (Tipranavir, 7) has been approved for HIV treatment. Some reached chnical trials but could not be developed further, signifying the urgent need for development of new inhibitors. 

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

---