High Need for more effective Antiviral Drugs

In recent years, the threat of a viral epidemic or even a pandemic has become more of a reality than ever before. The appearance and spreading of HIV has alerted the general public to the evils of pathogenic viruses and caught the attention of the media throughout the world. The HIV outbreak continues, new virus epidemics have emerged (e.g. the SARS virus) and, more recently, the world has become aware of a potential pandemic of avian influenza variants. Besides these new threats, even the known virus infections are becoming more difficult to treat due to the occurence of resistant virus strains. It is obvious that there is an urgent need for more effective antiviral drugs from new compound classes, directed not only against what now can be termed the "classical" viral targets, but also against novel targets and with novel mechanisms of action.

HIV

The AIDS epidemic emerged in the early 1980s as a highly lethal disease among men who have sexual intercourse with other men (practicing homosexual men) and among frequent recipients of blood product transfusions. Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The pharmaceutical industry has supported research and development of antiretroviral therapies that have prolonged the lives of individuals infected with HIV. Combination anti-HIV chemotherapy, commonly referred to as highly-active anti-retroviral therapy (HAART), has led to a remarkable reduction in mortality and morbidity in HIV-infected patients. Thus far, over 20 anti-HIV drugs have been approved for the treatment of HIV infection. Advances in the treatment of HIV infection have resulted in a fundamental shift in its epidemiology, making the disease a potentially chronic and manageable condition. However, as a consequence of the progressive evolution of viral resistance, the medical need for new antiretroviral agents remains high. This is particularly true since increasing evidence suggests that the transmission of drug-resistant viruses is becoming more common. In addition, there is still a need for new anti-retroviral drugs with reduced side effects and improved convenience. Moreover, any new antiretroviral therapy must be primed not only to work against future resistant strains but to work well with other agents as part of combination therapies.

HBV

Chronic hepatitis B virus (HBV) infection affects approximately 400 million people worldwide. Because of the slow kinetics of viral clearance and the spontaneous genetic variability of HBV, antiviral therapy of chronic hepatitis B is a clinical challenge. The efficacy of current treatment options is moderate at best and is limited by the poor tolerability of IFN and the development of resistance, coupled with concerns regarding the long-term safety. The development of nucleoside analogs that inhibit HBV polymerase has provided an important approach for treating HBV infection. However, the challenges that spring from the resistance and the off-therapy viral rebound are still unmet, and there is a need for development of new therapeutic agents.

HSV

Human herpes simplex virus (HSV) infection is a contagious infection with a large reservoir in the general population. It has a potential for significant complications in the immunocompromised host. In addition, psychological distress caused by the negative stigma associated with genital herpes and visible facial lesions in those experiencing frequent outbreaks renders it a challenging clinical dilemma. Genital herpes is the main cause of genital ulcers worldwide; the prevalence of HSV type 2 infections in the general population ranges from 10% to 60%. Most genital herpes is caused by HSV-2, although HSV-1 accounts for about half of all new cases in developed countries. The risk of acquiring HIV is three times higher in people with HSV-2. Neonatal herpes is an uncommon but serious complication of genital herpes. Most genital HSV-2 infections remain unrecognized and undiagnosed; infected individuals, even with mild symptoms, shed HSV and can infect sexual partners. Antiviral treatment of the infected partners can markedly reduce the risk of sexual transmission of HSV-2.

CMV

Human herpesviruses are found worldwide and are among the most frequent causes of viral infections in immunocompromised patients. Human cytomegalovirus (HCMV), a betaherpesvirus, represents an important pathogen for immunocompromised individuals, as well as the major infectious cause of birth defects. HCMV is a significant post-allograft pathogen and contributes to graft loss independently from graft rejection. Clinical manifestations can be observed following primary infection, re-infection, or re-activation. About 10% of infants are infected by the age of 6 months following transmission from their mothers via the placenta, during delivery, or by breastfeeding. However, total HCMV clearance is rarely achieved, and the viral genome remains at selected sites in a latent state. Treatment of HCMV infections is difficult because there are few options. The drugs available at present achieved significant clinical improvement, but suffer partially from poor oral bioavailability, development of resistance in clinical practice, and dose-limiting toxicities. All the currently approved treatments target the viral DNA polymerase. It is obvious that new drugs that are nontoxic, target a different viral function and are generally more efficacious than the present ones would be of great use especially for immunocompromised patients.

HCV

Infections with the hepatitis C virus (HCV), which was discovered in 1989, represent an important health-care problem worldwide. The prevalence of HCV-related diseases is increasing, and no vaccine is yet available. Since the identification of HCV as the causative agent of non-A, non-B hepatitis, treatment has progressed rapidly, but morbidity and mortality rates are still predicted to rise. Novel, more efficacious and tolerable therapies are urgently needed.

Hepatitis C virus (HCV) infection affects 3 percent of the world's population (180 million people) with the predominant prevalence being infection with genotype 1, followed by genotypes 2 and 3. Of the people infected today, less than 2 percent receive adequate therapy. Standard anti-HCV therapy consists of pegylated interferon administered by injection in combination with ribavirin. The current standard therapy aims at enhancing natural immune responses to the virus and achieves a sustained virological response (SVR) of 42%-46% in patients infected with genotype 1. In contrast, new therapeutic concepts target HCV directly. Novel treatment options under development focus on inhibitors of HCV-specific enzymes, NS3 protease and NS5B polymerase. These agents acting in concert represent the concept of specifically targeted antiviral therapy for HCV (STAT-C). STAT-C is an attractive strategy with the main goal of increasing the effectiveness of antiviral responses across all genotypes, with shorter treatment duration and better tolerability. However, the emergence of resistant mutations that limit the use of these compounds in monotherapy complicates the regimens. Thus, a predictable scenario for HCV treatment in the future will be based on combinations of drugs with distinct mechanisms of action that are analogous to those currently used for HIV.