**Meet the editor**

Patrick Arbuthnot is Personal Professor and Director of the Antiviral Gene Therapy Research Unit of the University of the Witwatersrand (Wits) in South Africa. After graduating with a medical degree from Wits, Patrick Arbuthnot completed a PhD in 1992. From 1993 to 1994, he worked as a post-doctoral researcher at Necker Hospital in Paris, and investigated the development of gene

therapy for treating liver cancer and hepatitis B virus (HBV) infection. On returning to South Africa, Patrick Arbuthnot established the Antiviral Gene Therapy Research Unit. This unit is now a Centre of Excellence of the African Network for Drug and Diagnostic Innovation (ANDI). The unit has a research interest in HBV infection, liver cancer, HIV-1 infection and developing new methods of treating these diseases.

Contents

**Preface IX** 

**Part 1 Clinical Management of Viral Infection 1** 

**Decompensated Cirrhotics 3** 

Chapter 2 **Virus Diagnostics and Antiviral Therapy** 

**in Acute Retinal Necrosis (ARN) 17** 

Chapter 3 **Leflunomide an Immunosuppressive Drug for** 

Chapter 4 **Modeling Virologic Response in HIV-1 Infected** 

Chapter 6 **Discovery of Novel Antiviral Agents Directed** 

Peter Rautenberg, Jost Hillenkamp, Livia Grančičova, Bernhard Nölle, Johann Roider and Helmut Fickenscher

**Patients to Assess Medication Adherence 51** 

Chapter 5 **Use of Animal Models for Anti-HIV Drug Development 71** 

**Against the Influenza A Virus Nucleoprotein 99**  Yoko Aida, Yutaka Sasaki and Kyoji Hagiwara

**for the Discovery of New Antiviral Drugs 121**  Joana Rocha-Pereira and Maria São José Nascimento

**Antiviral Purpose in Treatment for BK Virus-Associated Nephropathy After Kidney Transplantation 35** 

Chapter 1 **Antiviral Therapy in HCV-Infected** 

Fazal-I-Akbar Danish

Christophe Bazin

Yangxin Huang

Zandrea Ambrose

Chapter 7 **Targeting Norovirus: Strategies** 

**Part 2 Developing New Antivirals 69** 

### Contents

#### **Preface XI**

	- **Part 2 Developing New Antivirals 69**

X Contents

#### Chapter 8 **Single Domain Camelid Antibodies that Neutralize Negative Strand Viruses 151**  Francisco Miguel Lopez Cardoso, Lorena Itatí Ibañez, Bert Schepens and Xavier Saelens

#### Chapter 9 **Treatment of Herpes Simplex Virus with Lignin-Carbohydrate Complex Tablet, an Alternative Therapeutic Formula 171**  Blanca Silvia González López, Masaji Yamamoto and Hiroshi Sakagami

### Preface

Viral infections remain common causes of serious public health problems throughout the world. Viruses have highly varied mechanisms of propagation and the diseases that they cause are consequently very different. Approaches to countering virus infection therefore need to be tailored according to specific viral characteristics. Understanding the fundamentals of virus-related disease pathogenesis is critically important to improving treatment. The articles that appear in *Antiviral Drugs – Aspects of Clinical Use and Recent Advances* cover a broad collection of topics that reflect the fascinating range of viral characteristics and the measures that are being employed to counter the diseases that viruses cause.

Clinical management and new developments in the treatment of virus-related diseases are the two main topics covered in the book. The first section reviews the treatment of hepatitis C virus (HCV) infection in cirrhotic patients, the management of virusrelated acute retinal necrosis, the use of leflunomide therapy for BK virus-related nephropathy in renal transplant patients ,and the mathematical modeling of HIV-1 responses to antiviral therapies. Useful general concepts are provided in each chapter and will be helpful to physicians with general and specialized expertise. Chapters dealing with commonly occurring infections, such as those caused by HCV and HIV, are of wide interest. HCV infection occurs in approximately 170 million people in the world and ensuring that available licensed drugs are used in optimal treatment regimens is critical to minimizing risks associated with the virus infection. A complex, often misunderstood, topic is whether decompensation resulting from complicating cirrhosis is a contraindication to HCV treatment. In the chapter entitled *Antiviral Therapy in HCV-infected Decompensated Cirrhotics*, comprehensive and valuable treatment guidelines are provided. Another topic of global significance is the understanding of variable responses that HIV-infected individuals have to treatment. Adherence to the treatment regimens and also virus drug susceptibility are some of the important factors that influence patients' treatment responses. Measurement of patient adherence to therapy may be difficult. Evaluation is typically based on patient questionnaires and data derived from electronic medication monitoring caps or Medication Event Monitoring Systems (MEMS). The chapter entitled *Modeling Virologic Response in HIV-1 Infected Patients to Assess Medication Adherence* proposes a mechanismbased dynamic model to assess how adherence data based on questionnaires and the MEMS can be used to predict virologic responses. The modeling offers a means of

#### X Preface

assessing the effect of adherence on antiviral responses. Analysis was carried out in different situations and provides clinicians with a tool that will assist with making patient treatment decisions.

Basic applied research topics are dealt with in the second half of the book. Many interesting and promising new developments are covered and these include advances in the treatment of the influenza virus, animal models for the study of HIV-1 drug development, the use of single chain camelid antibodies to counter negative strand RNA viruses, new strategies for inhibition of norovirus infection, as well as the use of plant extracts to treat herpes simplex virus infection. The importance of structural insights for drug development is reinforced in the chapters dealing with advancing new norovirus and influenza virus treatments. Widening the range of drugs available for the treatment of HIV infection is a highly active and critically important field of research. The preclinical steps of drug development require careful planning to yield results that mitigate risks of testing in clinical trial settings. The chapter entitled *Use of Animal Models for Anti-HIV Drug Development* addresses many of these considerations and provides useful information on the appropriate selection of animal models for testing new HIV drugs. In another chapter, the antiviral utility of engineered protein derivatives of single domain binding camelid antibodies (HCAbs) is explored. Interestingly the epitope-binding domain of HCAbs, called single variable domain or VHH, retain their specificity when produced alone. These so-called nanobodies (Nbs) may be conveniently engineered and expressed in large numbers using standard recombinant procedures. The potential for neutralizing negative strand viruses, particularly influenza, respiratory syncytial and rabies viruses, is explored in the chapter entitled *Single domain camelid antibodies that neutralize negative strand viruses*.

The wide-ranging topics covered in *Antiviral Drugs – Aspects of Clinical Use and Recent Advances* provide a useful cross section within the field of antiviral drug development. Topics of general and specialized interest have been covered. The content of the book is not intended to be comprehensive, but aims to provide the reader with insights into selected aspects of established and new viral therapies. Students, clinicians, teachers, and basic scientists who have interests in advances in antiviral therapies will no doubt find the book helpful.

> **Patrick Arbuthnot**  Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, South Africa

X Preface

patient treatment decisions.

find the book helpful.

assessing the effect of adherence on antiviral responses. Analysis was carried out in different situations and provides clinicians with a tool that will assist with making

Basic applied research topics are dealt with in the second half of the book. Many interesting and promising new developments are covered and these include advances in the treatment of the influenza virus, animal models for the study of HIV-1 drug development, the use of single chain camelid antibodies to counter negative strand RNA viruses, new strategies for inhibition of norovirus infection, as well as the use of plant extracts to treat herpes simplex virus infection. The importance of structural insights for drug development is reinforced in the chapters dealing with advancing new norovirus and influenza virus treatments. Widening the range of drugs available for the treatment of HIV infection is a highly active and critically important field of research. The preclinical steps of drug development require careful planning to yield results that mitigate risks of testing in clinical trial settings. The chapter entitled *Use of Animal Models for Anti-HIV Drug Development* addresses many of these considerations and provides useful information on the appropriate selection of animal models for testing new HIV drugs. In another chapter, the antiviral utility of engineered protein derivatives of single domain binding camelid antibodies (HCAbs) is explored. Interestingly the epitope-binding domain of HCAbs, called single variable domain or VHH, retain their specificity when produced alone. These so-called nanobodies (Nbs) may be conveniently engineered and expressed in large numbers using standard recombinant procedures. The potential for neutralizing negative strand viruses, particularly influenza, respiratory syncytial and rabies viruses, is explored in the chapter entitled *Single domain camelid antibodies that neutralize negative strand viruses*.

The wide-ranging topics covered in *Antiviral Drugs – Aspects of Clinical Use and Recent Advances* provide a useful cross section within the field of antiviral drug development. Topics of general and specialized interest have been covered. The content of the book is not intended to be comprehensive, but aims to provide the reader with insights into selected aspects of established and new viral therapies. Students, clinicians, teachers, and basic scientists who have interests in advances in antiviral therapies will no doubt

Antiviral Gene Therapy Research Unit, School of Pathology,

**Patrick Arbuthnot** 

South Africa

Faculty of Health Sciences, University of the Witwatersrand,

**Part 1** 

**Clinical Management of Viral Infection** 
