抗病毒治疗：技术・市场・企业

Abstract

Summary

This report reviews the current state-of-art of antiviral approaches including vaccines, pharmaceuticals and innovative technologies for delivery of therapeutics. The introduction starts with a practical classification of viral diseases according to their commercial importance. Various antiviral approaches are described including pharmaceuticals and molecular biological therapies such as gene therapy and RNA interference (RNAi) as well as vaccines for virus infections. Expert opinion is given about the current problems and needs in antiviral therapy. SWOT (strengths, weaknesses, opportunities and threats) analysis of antiviral approaches is presented against the background of concept of an ideal antiviral agent.

A novel feature of this report is the use of nanotechnology in virology and its potential for antiviral therapeutics. Interaction of nanoparticles with viruses are described. NanoViricides are polymeric micelles, which act as nanomedicines to destroy viruses. Various methods for local as well as systemic delivery of antiviral agents and vaccines are described. Nanobiotechnology plays an important role in improving delivery of antivirals. Advantages and limitations of delivery of gene-based, antisense and RNAi antiviral therapeutics are discussed.

Anti-influenza measures applicable to human as well as avian forms are described. Resistance can develop against neuraminidase inhibitors although it is less than that with adamantanes. Considering these problems, there is need for a more effective agent. Investigations into alternative anti-influenza target will probably expand in the coming years. These include the development of mechanisms to inhibit fusion between the virus envelope and the cell membrane.

After a discussion of current therapies of AIDS/HIV and their limitations, new strategies in development of antiviral agents are described. Drug resistance and toxicities are emerging as major treatment challenges. Based on a review of technologies and drugs in development, it can be stated that there are good prospects are of finding a cure for HIV/AIDS in the next decade.

Hepatitis viruses are described with focus on hepatitis C virus (HCV) and hepatitis B virus (HBV). Despite the presence of numerous drug candidates in the anti-HCV pipeline, and the commitment of major R&D resources by many pharmaceutical companies, it might still take several years for any new anti-HCV drugs to reach the market. Although many companies are focusing their efforts on developing viral inhibitors, cellular targets in the host are beginning to emerge as attractive possibilities because they might enable the development of broad-spectrum antiviral drugs with less chance for developing viral resistance.

Various commercially important viruses include herpes simplex (HSV) and human papilloma virus (HPV). There a number of treatments but HSV is not destroyed completely and remains dormant and activates from time to time to cause various clinical manifestations. There is discussion about the role of HPV in cervical cancer and vaccines available now seem to be adequate in preventing HSV-induced cervical cancer. There is no effective vaccine for respiratory syncytial virus (RSV) although monoclonal antibody (MAb) treatment is useful for prophylaxis and reducing the clinical manifestations. There is a need for an agent to eliminate this virus.

Various viruses that either occur in epidemics or in tropics and some naturally emerging infectious diseases are described, e.g. viral hemorrhagic fevers such as dengue and West Nile virus infection. These are a constant threat and impossible to anticipate. Some of these lack antiviral agents or vaccines for prevention. Although these include some of the most serious viral disorders, the development of antiviral agents for these is not commercially attractive. Current research and approaches to these virus infections are discussed.

Markets for antivirals are considered according to viruses and diseases caused by them and also according to management approaches: antiviral drugs, vaccines, MAbs and innovative approaches that include immunological and use of other technologies such as gene therapy, antisense, RNAi and nanobiotechnology. Antiviral markets are estimated starting with 2007 with projections up to the year 2017.

Profiles of 166 companies that are involved in developing various technologies and products are profiled and with 142 collaborations. These include major pharmaceutical companies (13), those developing antiviral therapeutics (100) as well as viral vaccine companies (53). The report is supplemented with 45 tables, 8 figures and 310 references from the literature.

Table of Contents

0. Executive Summary 15

1. Introduction to Virology 17

• Introduction 17
• Virus databases 17
• A practical classification of viruses 17
• Pathomechanism of viral diseases relevant to therapy 18
• Intrinsic host defense against retroviruses 19
• Life cycle of virus as basis for antiviral approaches 20
• Genetic switch in virus infections 20
• Prophylaxis versus therapy 21
• Economic impact of viral diseases 21
• Historical landmarks in the development of antiviral therapies 21

2. Antiviral Approaches 23

• Classification 23
• Antiviral drug discovery and development 23
• Viral versus cellular targets for antiviral therapy 23
• Antimicrobial peptides 25
• Immunological approaches 25
• Basics of immune regulation in relation to viruses 25
• Effect of viruses on the immune system 26
• Immunomodulating agents 26
• Amplification of innate immunity 26
• Enhancers of immune system 27
• Promoting immune-mediated clearance of a chronic viral infections 27
• Immunoglobulins 27
• Bovine lactoferrin 28
• Quercetin 28
• Monoclonal antibodies 28
• Bavituximab 29
• Treatment of viral infection with radiolabeled MAbs 29
• Limitations of MAbs and measures to overcome these 30
• Interferon-based approaches 30
• Novel antiviral approaches 30
• Synthetic modified hypericin compounds 30
• Targeting Toll-like receptors 31
• Potential and drawbacks of TLR-ligands in viral diseases 32
• Inhibition of viral transport from cytoplasm into the cell nucleus 32
• Nitric Oxide based antiviral therapeutics 32
• Gene therapy for viral infections 33
• Antisense approaches to viral infections 33
• Antisense oligonucleotides 33
• Limitations of antisense oligonucleotides as antivirals 34
• NEUGENE antisense 34
• RNAi 35
• RNAi screens of viral genomes 35
• RNAi for treatment of viral infections 36
• Promise and pitfalls of RNAi gene therapy 37
• Management of rapidly evolving pathogens 37
• Personalized medicine and viral diseases 37
• An integrated approach to viral diseases 37
• Expert opinion: current problems and needs in antiviral therapy 38

3. Vaccines for Virus Infections 39

• Introduction 39
• Types of vaccines 40
• Live attenuated virus vaccines 40
• DNA vaccines 40
• Nanotechnology-based vaccines 41
• Recombinant viral vaccines 42
• Synthetic peptides as vaccines 42
• Virosomes 43
• Vaccines based on reverse genetics 43
• Routine vaccination in children against viral infections 43
• Personalized vaccines 44
• Limitations of vaccines 44
• Neurological complications of vaccination 44
• Expert opinion on antiviral vaccines 45

4. Role of Nanotechnology in Developing Antiviral Agents 47

• Introduction 47
• Study of interaction of nanoparticles with viruses 47
• Nanoparticle antiviral agents 48
• Fullerenes 48
• Nanoviricides 48
• Role of micelles in nanopharmaceuticals 49
• Some physicochemical characteristics common to polymeric micelles 49
• Structure and function of nanoviricides 50
• Mechanism of action of NanoViricides 50
• Advantages of NanoViricides 51

5. Delivery of Antivirals 53

• Introduction 53
• Methods of delivery of antiviral agents 53
• Local application of antivirals 53
• Controlled delivery of antivirals 54
• Targeted delivery of antivirals 54
• Delivery of antivirals to the brain across the blood-brain barrier 54
• Antiviral vaccine delivery systems 55
• Minicell vaccine delivery 55
• Transnasal delivery of vaccines by Newcastle disease virus as vector 55
• Transdermal delivery of vaccines 55
• Transdermal vaccines for influenza 56
• HIV/AIDS vaccination by topical application 56
• CELLECTRAR electroporation device 56
• Use of nanotechnology for improving delivery of antivirals 57
• Macrophage-based nanoformulated antiretroviral therapy 57
• Improvement of antiviral vaccine delivery by nanotechnology 58
• Bacterial spores for delivery of vaccines 58
• Liposomal antiviral vaccine preparations 58
• Nanoparticles for DNA vaccines 59
• Chitosan-derived nanoparticles for vaccine delivery 59
• Proteosomes"! as vaccine delivery vehicles 59
• Polymeric micellae for delivery of DNA vaccine 59
• "Smart" nanoparticles for delivery of vaccines 60
• Nanospheres for controlled release of viral antigens 60
• Nanocoating for local viricidal effect 60
• Delivery of gene-based antiviral drugs 61
• Limitations of delivery of gene, RNAi and antisense therapies 61
• Systemic delivery of NanoViricides 61
• Concluding remarks on delivery of antiviral agents 62

6. Competitive Assessment of Antiviral Approaches 63

• Introduction 63
• An ideal antiviral agent 63
• SWOT analysis 63
• Concluding remarks 66

7. Influenza Viruses 67

• Introduction 67
• Colds due to rhinovirus 67
• Epidemiology 68
• Supermap of avian influenza 68
• Influenza A 68
• Avian influenza affecting humans 69
• Human influenza versus avian influenza 69
• Immune system and influenza 70
• Immune Epitope Database and Analysis Resources 70
• Anti-influenza approaches 71
• Pharmaceuticals 71
• Neuraminidase inhibitors 72
• Mechanism of action 72
• Tamiflu 72
• Zanamivir 72
• Resistance to neuraminidase inhibitors 73
• Adverse effects of neuraminidase inhibitors 73
• Other drugs for influenza 73
• Adamantanes 73
• Probenecid 73
• Vaccines 74
• Live attenuated influenza vaccine vs. inactivated vaccine 74
• Vaccines in development 75
• M2e-based human influenza A vaccine 75
• Recombinant hemagglutinin influenza vaccine 75
• Cell culture-derived influenza vaccines 76
• MF-59 as adjuvant for influenza vaccine 76
• Pre-pandemic split antigen H5N1 vaccine 77
• H5N1 avian flu vaccine based on virus-like particles 77
• Consensus hemagglutinin-based DNA vaccine for avian influenza 78
• Synthetic avian influenza vaccine 78
• Epitope-based vaccines for influenza 78
• Human trial of a DNA vaccine for avian influenza 79
• MAbs for passive immunization against avian influenza 79
• Current status of influenza vaccines and limitations 80
• Needs of influenza vaccines 80
• Problems with demand and supply of influenza vaccines 81
• Problems with access to virus samples 82
• FluVac project for development of pandemic influenza vaccine 82
• Influenza vaccines for multiple strains of the disease 83
• Current status of vaccine preparedness against H5N1 83
• RNAi-based approaches 83
• Inhibition of influenza virus by siRNAs 83
• Limitations of RNAi approach to influenza 84
• Challenges and future prospects of siRNAs for influenza 84
• Antisense approaches 85
• NEUGENER antisense for inhibition of multiple strains of influenza A 85
• Nanoviricides against influenza 85
• Other innovative approaches 86
• Polymeric coatings to inactivate influenza virus 86
• Cytotoxic therapy 86
• Cyanovirin 86
• MultiferonR 86
• Peramivir 87
• Pyrrolidine dithiocarbamate 87
• T-705 88
• Value of antivirals in preventing spread of influenza after exposure 88
• Resistance to influenza therapy and efforts to overcome it 88
• NIAID Centers of Excellence for research on pandemic influenza viruses 89
• Concluding remarks and future prospects 89

8. AIDS/HIV 91

• Introduction 91
• Epidemiology 91
• Current concepts of pathomechanisms 91
• Host-pathogen interactions that regulate HIV-1 replication 92
• Genentic basis of resistance against HIV 93
• Complications of AIDS 93
• AIDS and the nervous system 93
• Opportunistic infections in AIDS 94
• Coexistent HIV-1 and HSV-2 94
• Coexistent hepatitis virus infections with HIV 95
• HIV and HBV 95
• HIV and HCV 95
• AIDS wasting syndrome 96
• Current therapies 96
• Aim of anti-HIV drugs 98
• Efavirenz 98
• Tipranavir 99
• Enfuvirtide 99
• Darunavir 99
• Limitations of current therapies 100
• Adverse effects of antiretroviral therapy 100
• Drug resistance in AIDS 101
• Effect of interruption of HIV treatment 102
• Reservoirs of HIV Infection 102
• Persistance of low-level viremia in HIV-1 patients on retroviral therapy 102
• Reconsideration of abandoned therapies for AIDS 102
• Therapies in development 103
• Drugs in development for HIV/AIDS 103
• Nucleoside reverse transcriptase inhibitors 104
• Apricitabine 104
• Non-nucleoside reverse transcriptase inhibitors 104
• Etravirine 104
• IDX899 104
• Novel protease inhibitors 105
• Overcoming HIV-1 resistance to PIs 105
• PPL-100 106
• Entry inhibitors targeting CCR5 receptor 106
• Maraviroc 106
• SP-01A 107
• MAbs targeting CCR5 receptor 107
• PRO 140 108
• Integrase inhibitors 108
• Raltegravir (Isentress) 108
• Elvitegravir (GS 9137) 109
• Design of fusion inhibitor peptides against enfuvirtide-resistant HIV-1 109
• Maturation inhibitors 110
• Blocking of pre-integration complex translocation 110
• Immune enhancers 111
• Pyrimidinediones 111
• T-cell therapy for HIV infection 111
• Novel combinations of drugs for prevention of AIDS 112
• Truvada 112
• Combination of raltegravir, enfuvirtide, and darunavir 112
• Other innovative antiviral approaches against HIV/AIDS 112
• In vitro evaluation of antiviral drug activity 112
• Methods for sustaining antiviral activity 113
• Selective targeting of ITK to block multiple steps of HIV replication 113
• Drugs from natural sources 113
• Anti-HIV activity of drugs that stimulate cholesterol efflux 114
• Blocking of HIV budding by DC-SIGN protein 114
• ATR kinase as a target for anti-HIV drug discovery 114
• Nanoviricides for HIV/AIDS 115
• Prophylactic measures to prevent HIV infection 115
• Microbicidal agents for local application in HIV/AIDS 115
• Currently investigated microbicidals against HIV and their limitations 115
• CCR5 receptor blockers 116
• PSC-Rantes and recombinant chemokine analogs 117
• Next generation microbicides for HIV 117
• Intracellular immunization in HIV 117
• Engineered cellular proteins such as soluble CD4s 118
• Intracellular antibodies 118
• Selection of T-cell vaccine antigens 118
• Glycoprotein 120 as target for neutralizing HIV-1 antibodies 118
• Anti-rev single chain antibody fragment 119
• Gene therapy strategies in HIV/AIDS 119
• Inhibition of HIV-1 replication by lentiviral vectors 119
• VRX496 120
• Insertion of protective genes into target cells 120
• Use of genes to chemosensitize HIV-1 infected cells 120
• Autocrine interferon-b・ production by somatic cell gene therapy 121
• HIV/AIDS vaccines 121
• T-Cell vaccines 122
• Gene transfer for HIV vaccination 122
• Delivery of HIV vaccine by an adenoviral vector 122
• Vaccination after discontinuation of antiretroviral treatment 123
• Recombinant HIV proteins 123
• DNA vaccines for HIV/AIDS 124
• Epitope-based DNA vaccines against HIV 124
• Limitations and needs of HIV vaccines 125
• Innovations in HIV/AIDS vaccine 125
• Attenuated rabies virus-based vaccine for HIV 125
• Dendritic-cell targeted DNA vaccine for HIV 126
• MVA nef vaccine 126
• Peptide-based vaccine for HIV 126
• Transdermal nanoparticles for immune enhancement in HIV 126
• Vaccine to prevent HIV entry at the mucosal level 127
• Cell therapy for HIV/AIDS 127
• Dendritic cell-based vaccine for HIV 127
• Transplantation of genetically modified T cells 128
• Overlapping Peptide-pulsed Autologous Cells 128
• Transplantation of genetically modified hematopoietic cells 128
• Antisense approaches to AIDS 129
• Antisense oligodeoxynucleotides 129
• Antisense efforts with PNA constructs 129
• RNA decoys 129
• Ribozymes 130
• RNAi applications in HIV/AIDS 130
• A multiple shRNA approach for silencing of HIV-1 131
• Aptamer-mediated delivery of anti-HIV siRNAs 131
• Bispecific siRNA constructs 131
• Role of the nef gene during HIV-1 infection and RNAi 132
• siRNA-directed inhibition of HIV-1 infection 132
• Synergistic effect of snRNA and siRNA 133
• Targeting CXCR4 with siRNAs 133
• Targeting CCR5 with siRNAs 133
• Concluding remarks on RNAi approach to HIV/AIDS 134
• Companies involved in developing gene therapy for HIV/AIDS 134
• Conclusions regarding gene therapy of HIV/AIDS 135
• Testing for new anti-HIV therapies 135
• Personalized approach to management of HIV 136
• Differences in response of the body to HIV 136
• Variations in action of drugs on HIV 136
• Drug-resistance in HIV 136
• Replication Capacity measurement 137
• Role of biomarkers in management of HIV/AIDS 137
• Prevention of adverse reactions to antiviral drugs 137
• Nanoviricides as a personalized approach to HIV 138
• Concluding remarks and future prospects 138

9. Hepatitis Viruses 141

• Introduction 141
• Hepatitis A virus infection 141
• Hepatitis E virus infection 141
• HEV vaccines 142
• Epidemiology of HBV 142
• Pathogenesis of HBV-induced liver disease 142
• Current approaches to management of HBV 142
• Entecavir 143
• Adefovir dipivoxil 143
• Telbivudine 143
• Pegylated interferon-alpha 144
• Limitations of current therapies and needs of HBV 144
• Innovations in the management of HBV 144
• Tenofovir disoproxil fumarate 144
• Hepatitis B immune globulins 145
• Nabi-HB 145
• HepaGam B 145
• Hepatitis B vaccine composed in a novel nanoemulsion adjuvant 145
• Innovative pharmaceuticals for HBV 146
• Clevudine 146
• HepDirect prodrugs 146
• Monoclonal antibodies for HBV 146
• RNAi-based therapy of HBV 147
• Future prospects of management of hepatitis B 148
• Epidemiology of HCV 148
• HCV characteristics 148
• Pathomechanism of HCV infection 149
• Mechanism of HCV entry 149
• HCV and the immune system 149
• Mechanism of HCV replication and response to interferon 149
• Current approaches to management of HCV 150
• Interferon therapy for HCV 150
• Limitations of current HCV therapies 150
• Targeted delivery of hemoglobin-ribavirin conjugate for HCV 151
• Novel approaches to HCV 151
• HCV protease inhibitors 152
• Telaprevir (VX-950) 152
• Small molecule HCV protease inhibitors 152
• Nucleoside polymerase inhibitor 153
• Valopicitabine 153
• Host cell targets for hepatitis C therapy 153
• SP-10 154
• Innovations in interferon therapy for HCV 154
• Omega DUROS 154
• GEA007.1 155
• Personalizing interferon therapy of HCV 155
• Directed evolution of gene-shuffled IFN-a・ for treatment of HCV 155
• NS5a inhibitors 156
• Cyclophilin inhibitors 156
• Methylene blue 157
• Naringenin 157
• Nitazoxanide 157
• Cyclosporine and HCV 157
• RNAi-based approaches to HCV 158
• siRNAs for HCV 158
• Limitations and drawbacks of siRNA therapy for HCV 159
• Role of miRNA in viral infections 159
• miR-122 antagonists 159
• Therapeutic vaccine for HCV 160
• Clinical trials of HCV therapeutics 160
• Limitations to the development of effective anti-HCV therapeutics 161
• Causes of treatment failure in chronic hepatitis C 161
• HCV drug resistance 161
• Personalized management of HCV infection 162
• Future needs in HCV therapy 162
• Summary and concluding remarks 162

10. Miscellaneous Commercially Important Virus Infections 165

• Introduction 165
• Herpes viruses 165
• Herpes simplex virus 165
• Treatment of HSV-1 165
• Acyclovir 165
• Vaccine for HSV 166
• Antisense therapy for HSV-1 166
• Herpes simplex virus 2 and genital herpes 166
• Famciclovir 167
• Intravaginal microbicidal agents for HSV-2 167
• Vaccine for HSV-2 167
• Herpes simplex keratitis 167
• Herpes simplex encephalitis 168
• Limitations of current HSV therapies 168
• Herpes zoster virus 169
• Herpes zoster and chicken pox 169
• Epidemiology of herpes zoster 169
• Treatment of herpes zoster 169
• Herpes zoster vaccine 169
• Cytomegalovirus 170
• T-cell therapy for CMV 170
• Vaccine for CMV 171
• Gene therapy of CMV 171
• Antisense approach to CMV 171
• siRNA treatment of CMV 172
• Epstein-Barr virus 172
• Human papilloma virus 172
• Epidemiology 172
• Vaccines for HPV 173
• Gardasil 173
• Cervarix 173
• Vaccine based on fusion proteins of HPV envelope 174
• DNA vaccine VGX-3100 174
• Limitations of HPV vaccines 174
• Antivirals for HPV 175
• Imiquimod 175
• Novel approaches against HPV 175
• Intrabody strategies for the treatment of HPV 175
• A novel peptide to inhibit HPV 176
• Heat shock protein-based antivirals 176
• Respiratory syncytial virus 177
• Epidemiology 177
• Current management of RSV 177
• Palivizumab 177
• Innovative products in development 177
• RSV604 177
• RNAi approach to RSV 178
• Oral DNA vaccine for RSV 178
• Other respiratory viruses 178
• Parainfluenzavirus type 3 179
• Human metapneumovirus 179
• Gastrointestinal viruses 179
• Noroviruses 179
• Concluding remarks 180

11. Viruses with High Impact but Low Commercial Significance 181

• Introduction 181
• Chikungunya fever 181
• Coxsackie virus 181
• Japanese encephalitis 182
• Vaccines for JE 182
• Parvovirus 182
• Rabies 183
• Rabies vaccines 183
• Recombinant viral vaccines for rabies 184
• DNA vaccine against rabies 184
• Rabies immune globulin 184
• Monoclonal antibodies for rabies 184
• NanoViricides approach for rabies 185
• The Milwaukee protocol for rabies 185
• Rotavirus 185
• Epidemiology 185
• Vaccine against rotavirus 186
• Viral hemorrhagic fevers 186
• Dengue 187
• Antivirals in development 187
• Dengue vaccines 188
• Ebola virus 189
• DNA vaccine for Ebola 189
• Lassa fever 189
• Marburg hemorrhagic fever 190
• Yellow fever 190
• Sequencing of Aedes aegypti genome and control of yellow fever 191
• Crimean-Congo hemorrhagic fever 191
• West Nile virus 192
• Epidemiology 192
• Treatment of West Nile neuroinvasive disease 192
• Vaccines against WNV 192
• Innovative treatments for WNV 193
• Western equine encephalitis 193
• Sporadic virus epidemics 193
• Coronavirus/severe acute respiratory syndrome 193
• Therapeutic approaches to SARS 194
• MAbs for SARS 194
• siRNA treatment of SARS 195
• Zoonotic viral infections 195
• Vaccines for zoonotic viral diseases 195
• Virus bioterrorism and biowarfare 196
• Small pox as a biological weapon 196
• Status of small pox vaccination 196
• Strategies against virus bioterrorism and biowarfare 197
• Increasing resistance by stimulating innate immune mechanisms 197
• Nanoviricides for combating viral bioterrorism 198
• Concluding remarks 198

12. Markets for Antivirals 199

• Introduction 199
• Markets according to disease 199
• Influenza market 199
• HIV/AIDS market 200
• Hepatitis B and C markets 201
• Markets according to products and approaches 201
• Market values of monoclonal antibodies for viral diseases 201
• Market values of vaccines for viral diseases 201
• Markets for vaccines against HPV 202
• Markets for other antiviral vaccines 202
• Markets according to geographical areas 203
• Geographical distribution of HIV/AIDS market 203
• Unmet needs in antivirals 203
• Policies regarding conquered viral diseases 204
• Future of polio vaccine 204
• Policies concerning HPV vaccine for prevention of cervical cancer 205
• HPV vaccine in developing countries 205
• Future prospects of innovative approaches 206
• US Government support of antiviral efforts 207
• US Government support for R & D in avian influenza vaccines 207
• US Government support for developing anti-bioterrorism agents 207
• The European Union support of antiviral research 208
• European Commission' s research support for anti-HIV/AIDS programs 208
• European Commission' s support anti-influenza programs 209
• Collaboration of biotechnology companies with big pharma 210
• Strategies for marketing 210

13. Companies 211

• Introduction 211
• Top companies 211
• Profiles of pharmaceutical companies 212
• Profiles of antiviral companies 228
• Profiles of viral vaccine companies 335
• Collaborations 398

14. References 403

Tables

• Table 1 1: A practical classification of viruses 17
• Table 1 2: Vaccines vs therapeutics for viral diseases 21
• Table 1 3: Historical landmarks in the development of antiviral therapies 22
• Table 2 1: Classification of antiviral strategies 23
• Table 2 2: Viral vs cellular targets for discovery of antivirals 24
• Table 2 3: Viruses amenable to antisense oligonucleotides 34
• Table 2 4: Inhibition of viral replication by RNAi 36
• Table 3 1: Types of vaccines for viral diseases 40
• Table 4 1: Role of nanobiotechnology in virology 47
• Table 5 1: Methods of delivery of antiviral agents 53
• Table 5 2: Role of nanotechnology for improving delivery of antivirals 57
• Table 5 3: Commercially available liposomal antiviral vaccines 58
• Table 6 1: SWOT of monoclonal antibodies 63
• Table 6 2: SWOT of agents that prevention viral entry into cells 64
• Table 6 3: SWOT of drugs interfering with intracellular replication 64
• Table 6 4: SWOT of protease inhibitors 64
• Table 6 5: SWOT of integrase inhibitors 64
• Table 6 6: SWOT of maturation inhibitors 64
• Table 6 7: SWOT of neuraminidase inhibitors 65
• Table 6 8: SWOT of targeting Toll-like receptors (TLRs) 65
• Table 6 9: SWOT of topical antivirals agents against viral infections 65
• Table 6 10: SWOT of gene therapy, antisense oligonucleotides, RNAi 65
• Table 6 11: SWOT of vaccines 65
• Table 6 12: SWOT of NanoViricides 66
• Table 7 1: Anti-influenza approaches 71
• Table 7 2: Pharmaceutical products for influenza 72
• Table 8 1: Drugs in clinical development for HIV/AIDS 103
• Table 8 2: Strategies for gene therapy of AIDS 119
• Table 8 3: Classification of HIV/AIDS vaccines in clinical trials 121
• Table 8 4: Companies involved in developing gene therapy for HIV/AIDS 134
• Table 9 1: Innovations in the treatment of HBV 144
• Table 9 2: Innovations for management of HCV 151
• Table 9 3: Antiviral agents for HCV targeting host cells 153
• Table 9 4: HCV drugs in clinical trials 160
• Table 10 1: Methods of delivery of acyclovir 165
• Table 11 1: Strategies against virus bioterrorism and biowarfare 197
• Table 12 1: Worldwide market for all antiviral approaches 2007-2017 199
• Table 12 2: Markets for antivirals according to virus infections 2007-2017 199
• Table 12 3: Markets values of all drugs for HIV/AIDS 2007-2017 200
• Table 12 4: Market values of monoclonal antibodies for viral diseases 2007-2017 201
• Table 12 5: Market values of vaccines for viral diseases 2007-2017 202
• Table 12 6: Markets for antivirals according to geographical areas 2007-2017 203
• Table 12 7: Markets for vaccines according to geographical areas 2007-2017 203
• Table 13 1: Top five antiviral companies 211
• Table 13 2: Roche antiviral products in development 218
• Table 13 3: Collaborations of antiviral companies 398

Figures

• Figure 1 1: Varieties of host and cell responses to viral infections 19
• Figure 1 2: Cycle of infection and replication of a retrovirus 20
• Figure 2 1: An integrated approach to viral disea-ses 37
• Figure 4 1: Schematic representation of NanoViricide attacking a virus particle 51
• Figure 7 1: Evolution of mutations associated with virulence/drug resistance in H5N1 70
• Figure 8 1: Mode of action of some current anti-HIV drugs 97
• Figure 9 1: Omega DUROS device for interferon delivery in chronic hepatitis C 154
• Figure 12 1: Unmet needs in antivirals 204