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Antiviral Research (v.85, #1)

Notes to Authors (pp. co3).

Editorial Board (pp. ii).

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic by Samuel Broder (pp. 1-18).

In the last 25 years, HIV-1, the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), has gone from being an “inherently untreatable” infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir^® (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. These drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely if ever been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time in certain regions may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including (1) the life-long duration of therapy; (2) the ultimate role of pre-exposure prophylaxis (PrEP); (3) the cardiometabolic side-effects or other toxicities of long-term therapy; (4) the emergence of drug-resistance and viral genetic diversity (non-B subtypes); (5) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and (6) the continued pace of new HIV-1 infections in many parts of the world. All of these factors make refining current therapies and developing new therapeutic paradigms essential priorities, topics covered in articles within this special issue of Antiviral Research. Fortunately, there are exciting new insights into the biology of HIV-1, its interaction with cellular resistance factors, and novel points of attack for future therapies. Moreover, it is a short journey from basic research to public health benefit around the world. The current science will lead to new therapeutic strategies with far-reaching implications in the HIV-1/AIDS pandemic. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol. 85, issue 1, 2010.

Keywords: HIV-1; AIDS; Antiretroviral therapy; Zidovudine; Nucleoside reverse transcriptase inhibitors

In search of a selective therapy of viral infections by Erik De Clercq (pp. 19-24).

This article is meant as an introductory chapter to the special issue of Antiviral Research on “Twenty-five years of antiretroviral drug development: progress and prospects”, commemorating the first description of azidothymidine (AZT) as an antiretroviral agent. This has prompted me to highlight some of the hallmarks that played an important role in my own search of a selective therapy of viral infections: i.e., the induction of interferon by double-stranded RNA [such as poly(I)·poly(C)], allowing the cloning and expression of β-interferon; the discovery of the reverse transcriptase (RT) (and HIV as a retrovirus depending for its replication on RT), allowing the identification and development of a wide variety of RT inhibitors, nowadays used for the treatment of AIDS; the specificity of herpesvirus inhibitors such as acyclovir and BVDU, in the treatment of HSV and VZV infections; the role of acyclic nucleoside phosphonates (tenofovir, adefovir and cidofovir) in the treatment of HIV, HBV and DNA virus infections; and that of the NNRTIs (leading from TIBO to rilpivirine) as an essential part of the current anti-HIV drug cocktails. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: Double-stranded RNA; β-Interferon; Reverse transcriptase; NRTIs; NtRTIs; NNRTIs; Acyclovir; BVDU

Current status and challenges of antiretroviral research and therapy by José A. Esté; Tomas Cihlar (pp. 25-33).

Twenty-five years after the discovery of the therapeutic activity of azidothymidine (AZT), the first antiretroviral drug used in the clinic, infection with the human immunodeficiency virus (HIV) has become, at least in the industrialized world, a manageable chronic disease with a significant improvement in life expectancy and quality. Nevertheless, the number of new infections worldwide continues to rise, particularly in women, and effective drug treatments have not yet reached the vast majority of infected individuals in resource-limited countries. The current status of antiretroviral therapy is therefore encouraging, but significant challenges remain. Although highly active antiretroviral therapy (HAART) provides durable control of virus replication in many patients, it is not devoid of unwanted secondary effects, some of which are now surfacing in aging populations under long-term treatment. The emergence of multidrug resistance and transmission of drug-resistant HIV strains limit the clinical efficacy of current therapy. Further simplification of treatment and identification of more effective drug combinations are needed to improve patient adherence, the most significant cause of treatment failure. Finding new drugs and novel drug targets may lead to redefining the goals of antiretroviral therapy, with an attempt to achieve the ultimate objective: the eradication of infection. Preclinical and clinical biomedical research, rational drug design and a close collaboration with regulatory agencies to set standards for the transition of new treatment concepts into the clinic will be the cornerstones of future progress. This special issue of Antiviral Research [85(1), 2010] highlights the principal milestones of antiretroviral research over 25 years of drug discovery and development and offers a comprehensive analysis by leading experts of the efforts being made to meet the challenges of effective control of HIV infection.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: HIV; Antiretrovirals; Special issue

Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosides by John C. Martin; Michael J.M. Hitchcock; Erik De Clercq; William H. Prusoff (pp. 34-38).

The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogues for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A number of previously synthesized nucleoside analogues were comparatively evaluated, and stavudine (D4T) emerged as a promising candidate for development. Following clinical evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: Antiretroviral therapy; Nucleoside analogues; AZT; ddI; ddC; D4T; D4C; FLT

Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine by Tomas Cihlar; Adrian S. Ray (pp. 39-58).

Twenty-five years ago, nucleoside analog 3′-azidothymidine (AZT) was shown to efficiently block the replication of HIV in cell culture. Subsequent studies demonstrated that AZT acts via the selective inhibition of HIV reverse transcriptase (RT) by its triphosphate metabolite. These discoveries have established the first class of antiretroviral agents: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs). Over the years that followed, NRTIs evolved into the main component of antiretroviral drug combinations that are now used for the treatment of all populations of HIV infected patients. A total of thirteen NRTI drug products are now available for clinical application: eight individual NRTIs, four fixed-dose combinations of two or three NRTIs, and one complete fixed-dose regimen containing two NRTIs and one non-nucleoside RT inhibitor. Multiple NRTIs or their prodrugs are in various stages of clinical development and new potent NRTIs are still being identified through drug discovery efforts. This article will review basic principles of the in vitro and in vivo pharmacology of NRTIs, discuss their clinical use including limitations associated with long-term NRTI therapy, and describe newly identified NRTIs with promising pharmacological profiles highlighting those in the development pipeline.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, volume 85, issue 1, 2010.

Keywords: NRTI; HIV reverse transcriptase; Nucleoside; Nucleotide; NRTI resistance

Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance by Annemarie M.J. Wensing; Noortje M. van Maarseveen; Monique Nijhuis (pp. 59-74).

HIV protease plays a crucial role in the viral life cycle and is essential for the generation of mature infectious virus particles. Detailed knowledge of the structure of HIV protease and its substrate has led to the design of specific HIV protease inhibitors. Unfortunately, resistance to all protease inhibitors (PIs) has been observed and the genetic basis of resistance has been well documented over the past 15 years.The arrival of the early PIs was a pivotal moment in the development of antiretroviral therapy. They made possible the dual class triple combination therapy that became known as HAART. However, the clinical utility of the first generation of PIs was limited by low bioavailability and high pill burdens, which ultimately reduced adherence and limited long-term viral inhibition. When therapy failure occurred multiple protease resistance mutations were observed, often resulting in broad class resistance.To combat PI-resistance development, second-generation approaches have been developed. The first advance was to increase the level of existing PIs in the plasma by boosting with ritonavir. The second was to develop novel PIs with high potency against the known PI-resistant HIV protease variants. Both approaches increased the number of protease mutations required for clinical resistance, thereby raising the genetic barrier.This review provides an overview of the history of protease inhibitor therapy, its current status and future perspectives. It forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: HIV; Protease; Inhibitor; Drug resistance; Therapy

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989–2009) by Marie-Pierre de Béthune (pp. 75-90).

It is almost 20 years since NNRTIs were identified as a new class of antiretroviral drugs for the treatment of HIV-1 infection. Although they belong to different and diverse chemical families, they share a common and unique mechanism of action: their interaction with HIV-1 reverse transcriptase induces conformational changes that inhibit the catalytic activities of the enzyme. They are characterized by their specificity for HIV-1, which makes them very selective inhibitors of the virus. First generation NNRTIs nevirapine and efavirenz, in combination with other antiretroviral drugs, have become a cornerstone for the treatment of HIV-1 infection, in patients initiating antiretroviral therapy. Further research has led to the discovery and development of next generation NNRTIs with an increased genetic barrier to the development of resistance. Etravirine is the first NNRTI to show sustained virologic efficacy in patients with NNRTI resistant HIV-1. This review covers the NNRTI class of anti-HIV-1 drugs, from the initial discovery of the class in 1990 to the current compounds in clinical development, i.e. around 20 years of research and development efforts. It describes the characteristics of the NNRTIs, their mechanisms of action, HIV-1 resistance to the inhibitors, and the drugs that have been approved for the treatment of HIV-1 infection, or are currently in clinical development. The role of NNRTIs in prevention of HIV transmission is also addressed. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: NNRTI; Efavirenz; Nevirapine; Etravirine; Rilpivirine; Next generation NNRTI

Entry inhibitors in the treatment of HIV-1 infection by John C. Tilton; Robert W. Doms (pp. 91-100).

Infection of target cells by HIV is a complex, multi-stage process involving attachment to host cells and CD4 binding, coreceptor binding, and membrane fusion. Drugs that block HIV entry are collectively known as entry inhibitors, but comprise a complex group of drugs with multiple mechanisms of action depending on the stage of the entry process at which they act. Two entry inhibitors, maraviroc and enfuvirtide, have been approved for the treatment of HIV-1 infection, and a number of agents are in development. This review covers the entry inhibitors and their use in the management of HIV-1 infection.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: HIV; Entry inhibitors; Maraviroc; Enfuvirtide; Highly active antiretroviral therapy (HAART)

Strand transfer inhibitors of HIV-1 integrase: Bringing IN a new era of antiretroviral therapy by Damian J. McColl; Xiaowu Chen (pp. 101-118).

HIV-1 integrase (IN) is one of three essential enzymes (along with reverse transcriptase and protease) encoded by the viral pol gene. IN mediates two critical reactions during viral replication; firstly 3′-end processing (3′EP) of the double-stranded viral DNA ends and then strand transfer (STF) which joins the viral DNA to the host chromosomal DNA forming a functional integrated proviral DNA. IN is a 288 amino acid protein containing three functional domains, the N-terminal domain (NTD), catalytic core domain (CCD) and the C-terminal domain (CTD). The CCD contains three conserved catalytic residues, Asp64, Asp116 and Glu152, which coordinate divalent metal ions essential for the STF reaction. Intensive research over the last two decades has led to the discovery and development of small molecule inhibitors of the IN STF reaction (INSTIs). INSTIs are catalytic inhibitors of IN, and act to chelate the divalent metal ions in the CCD. One INSTI, raltegravir (RAL, Merck Inc.) was approved in late 2007 for the treatment of HIV-1 infection in patients with prior antiretroviral (ARV) treatment experience and was recently approved also for first line therapy. A second INSTI, elvitegravir (EVG, Gilead Sciences, Inc.) is currently undergoing phase 3 studies in ARV treatment-experienced patients and phase 2 studies in ARV naïve patients as part of a novel fixed dose combination. Several additional INSTIs are in early stage clinical development. This review will discuss the discovery and development of this novel class of antiretrovirals. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: HIV-1; Integrase (IN); Integrase strand transfer inhibitor (INSTI); Raltegravir (RAL); Elvitegravir (EVG); Drug resistance

Novel approaches to inhibiting HIV-1 replication by Catherine S. Adamson; Eric O. Freed (pp. 119-141).

Considerable success has been achieved in the treatment of HIV-1 infection, and more than two-dozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug–drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, we highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activity of the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. We discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: Virus entry; Virus assembly; Retrovirus; Drug resistance; HIV-1 drug therapy

Development of topical microbicides to prevent the sexual transmission of HIV by Robert W. Buckheit Jr.; Karen M. Watson; Kathleen M. Morrow; Anthony S. Ham (pp. 142-158).

Women comprise almost 50% of the population of people living with HIV and the majority of these women contracted the virus through sexual transmission in monogamous relationships in the developing world. In these environments, where women are not empowered to protect themselves through the negotiation of condom use, effective means of preventing HIV transmission are urgently needed. In the absence of an approved and effective vaccine, microbicides have become the strategy of choice to provide women with the ability to prevent HIV transmission from their infected partners. Topical microbicides are agents specifically developed and formulated for use in either the vaginal or rectal environment that prevent infection by sexually transmitted infectious organisms, including pathogenic viruses, bacteria and fungi. Although a microbicidal product will have many of the same properties as other anti-infective agents and would be similarly developed through human clinical trials, microbicide development bears its own challenges related to formulation and delivery and the unique environment in which the product must act, as well as the requirement to develop a product that is acceptable to the user. Herein, perspectives based on preclinical and clinical microbicide development experience, which have led to an evolving microbicide development algorithm, will be discussed. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of anti-retroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: HIV transmission; Microbicide; Prevention; Formulation; Acceptability; Development algorithm

Evaluation of antiretrovirals in animal models of HIV infection by Koen K.A. Van Rompay (pp. 159-175).

Animal models of HIV infection have played an important role in the development of antiretroviral drugs. Although each animal model has its limitations and never completely mimics HIV infection of humans, a carefully designed study allows experimental approaches that are not feasible in humans, but that can help to better understand disease pathogenesis and to provide proof-of-concept of novel intervention strategies. While rodent and feline models are useful for initial screening, further testing is best done in non-human primate models, such as simian immunodeficiency virus (SIV) infection of macaques, because they share more similarities with HIV infection of humans. In the early years of the HIV pandemic, non-human primate models played a relatively minor role in the antiretroviral drug development process. Since then, a better understanding of the disease and the development of better drugs and assays to monitor antiviral efficacy have increased the usefulness of the animal models. In particular, non-human primate models have provided proof-of-concept for (i) the benefits of chemoprophylaxis and early treatment, (ii) the preclinical efficacy of novel drugs such as tenofovir, (iii) the virulence and clinical significance of drug-resistant viral mutants, and (iv) the role of antiviral immune responses during drug therapy. Ongoing comparison of results obtained in animal models with those observed in human studies will further validate and improve these animal models so they can continue to help advance our scientific knowledge and to guide clinical trials.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: Macaque; Primate; Drug; SIV; FIV; Murine; Animal model; Chemoprophylaxis; Chemotherapy

Pharmacokinetics and drug–drug interactions of antiretrovirals: An update by Laura Dickinson; Saye Khoo; David Back (pp. 176-189).

Current antiretroviral treatment has allowed HIV infection to become a chronic manageable condition with many HIV patients living longer. However, available antiretrovirals are not without limitations, for example the development of resistance and adverse effects. Consequently, new drugs in existing and novel classes are urgently required to provide viable treatment options to patients with few remaining choices. Darunavir, etravirine, maraviroc and raltegravir have been recently approved for treatment-experienced patients and other agents such as rilpivirine, vicriviroc and elvitegravir are currently under phase III study. Clinical studies are necessary to optimise potential treatment combinations and to manage drug–drug interactions to help avoid toxicity or therapy failure. This review aims to summarise the pharmacokinetics and key drug–drug interaction studies for newly available antiretrovirals and those in development. Further information regarding drug–drug interactions of well established antiretrovirals and those recently approved are readily available online at sites such ashttp://www.hiv-druginteractions.org,http://www.clinicaloptions.com/hiv,http://hivinsite.ucsf.edu.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: Antiretrovirals; Pharmacokinetics; Drug–drug interactions; Protease inhibitors; Non-nucleoside reverse transcriptase inhibitors; CCR5 antagonists; Integrase inhibitors

Pharmacogenetics of antiretrovirals by Valerio Tozzi (pp. 190-200).

The introduction of highly active antiretroviral therapy (HAART) as standard of care has changed the natural history of HIV infection into a manageable chronic disease requiring long-term antiretroviral (ARV) treatment. However, response to HAART is often limited by the occurrence of toxicity or by the emergence of drug resistance. Antiretroviral treatment is characterized by differing rates of adverse events and responses. Genetic variations between human beings account for a relevant proportion of this variability. A relevant number of associations between human genetic variants and predisposition to adverse events have been described and for some antiretroviral drugs a clear and casual genotype–phenotype correlation has already been established. The strong association between abacavir hypersensitivity reaction and HLA-B*5701 has been demonstrated in both observational and blinded randomized clinical trials in racially diverse populations and represents the best example of the clinical utility of pharmacogenetic screening in HIV medicine. Genotyping for HLA-B*5701 before prescribing an abacavir containing regimen has been introduced into routine clinical practice as the standard of care for all patients. Other well-established associations include CYP2B6 alleles and efavirenz central nervous system side effects, UGT1A1 alleles and atazanavir-associated hyperbilirubinemia and HLA class II allele HLA-DRB*0101 and nevirapine-associated hypersensitivity. Despite genetic associations having been described for peripheral neuropathy, lipodystrophy, hyperlipidaemia, pancreatitis and renal proximal tubulopathy, numerous barriers exist to the successful introduction of widespread genetic testing to the clinic. Future prospects point in the direction of individualization of antiretroviral therapy through insights from host genetics. The present paper is aimed to provide a comprehensive review of the published literature and to summarize the state of research in this area.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: Pharmacogenetics; HIV; HAART; Antiretroviral therapy; Hypersensitivity reactions; Pharmacokinetics; Pharmacodynamics

Understanding and managing the adverse effects of antiretroviral therapy by Trevor Hawkins (pp. 201-209).

Highly active antiretroviral therapy (HAART) has changed the landscape of HIV disease in a way that seemed unthinkable a decade ago; from an almost uniformly fatal disease to a chronic manageable one. The first HAART regimens worked in suppressing virus, but were encumbered by a variety of short term and long term side effects. More recent regimens became simpler, easier to take, and with fewer adverse events. As we look to people living perhaps a normal life span with HIV, the increasing number of antiretroviral agents available means that individualizing treatment has become more feasible and the longer downstream adverse events related to HAART, such as its effect on cardiovascular disease and diabetes, renal and hepatic disease, have begun to dominate our choice of drugs. A knowledge of both the short and long term adverse events associated with HAART is essential for providers and for patients. For new drugs to be acceptable in the current field, they will have to pass a litmus test of tolerability. Since adverse events are often remarkably idiosyncratic, pharmacogenomics may offer a way of predicting side effects and their severity from a particular drug or drug class in individual patients. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol. 85, issue 1, 2010.

Keywords: HIV; HAART; Tolerability; Adverse events; Aging; Pharmacogenomics

Molecular basis of human immunodeficiency virus drug resistance: An update by Luis Menéndez-Arias (pp. 210-231).

Antiretroviral therapy has led to a significant decrease in human immunodeficiency virus (HIV)-related mortality. Approved antiretroviral drugs target different steps of the viral life cycle including viral entry (coreceptor antagonists and fusion inhibitors), reverse transcription (nucleoside and non-nucleoside inhibitors of the viral reverse transcriptase), integration (integrase inhibitors) and viral maturation (protease inhibitors). Despite the success of combination therapies, the emergence of drug resistance is still a major factor contributing to therapy failure. Viral resistance is caused by mutations in the HIV genome coding for structural changes in the target proteins that can affect the binding or activity of the antiretroviral drugs. This review provides an overview of the molecular mechanisms involved in the acquisition of resistance to currently used and promising investigational drugs, emphasizing the structural role of drug resistance mutations. The optimization of current antiretroviral drug regimens and the development of new drugs are still challenging issues in HIV chemotherapy.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: HIV; Reverse transcriptase; Drug resistance; Thymidine analogues; Phosphorolysis; DNA polymerase

Running a tightrope: Regulatory challenges in the development of antiretrovirals by Lisa K. Naeger; Kimberly A. Struble; Jeffrey S. Murray; Debra B. Birnkrant (pp. 232-240).

Since the approval of Retrovir, (zidovudine, AZT) in 1987 by the Food and Drug Administration, a number of regulatory initiatives were codified into regulation which contributed to the rapid development of new treatments for HIV-1 infection. These initiatives are a testament to the efforts of AIDS activists and regulators to improve access to drugs for serious and life-threatening diseases. Currently, 28 antiretroviral drugs and combinations of antiretrovirals are available to treat HIV-1 infection. The broadening armamentarium of approved antiretroviral drugs provides new options and more choices for physicians and HIV patients. Importantly, the introduction of these newly approved HIV drugs has shown that the majority of HIV-1-infected treatment-naïve and treatment-experienced patients can achieve maximal virologic suppression (less than 50copies/mL HIV-1 RNA). This article describes the past and current regulatory challenges in the development of new HIV treatments and provides an overview of the drug regulations that were required for the approval of HIV drugs.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: HIV-1; Drug regulations; Accelerated approval; Surrogate endpoint; Fast track; Clinical trial designs; Resistance; PEPFAR; Expanded access

The evolution of HIV treatment guidelines: Current state-of-the-art of ART by Andrew R. Zolopa (pp. 241-244).

Expert panels have provided guidelines for the treatment of HIV infection for more than a decade. The guidelines have evolved rapidly reflecting the remarkable improvements in HIV therapeutics over this time. From guidelines based mostly on expert opinion – the current guidelines are now primarily evidence-based recommendations – which the vast majority of treating clinicians accept and follow. We will highlight the major guideline recommendations for initiation of antiretroviral therapy – focusing on new data for the asymptomatic patient and those presenting with acute AIDS-related opportunistic infections. Given the number of new drugs available, we are currently able to offer virtually all patients in practice – a fully suppressive regimen, even in patients with substantial multi-drug resistant HIV. A remarkable achievement since AZT was first introduced for the treatment of HIV. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: Keyword; HIV treatment guidelines

Clinical management of HIV-1 resistance by Roger Paredes; Bonaventura Clotet (pp. 245-265).

Antiretroviral drug resistance is a fundamental survival strategy for the virus that stems from its vast capacity to generate diversity. With the recent availability of new ARV drugs and classes, it is now possible to prescribe fully active ART to most HIV-infected subjects and achieve viral suppression even in those with multidrug-resistant HIV. It is uncertain, however, if this scenario will endure. Given that ART must be given for life, and new compounds other than second-generation integrase inhibitors may not reach the clinic soon, all efforts must be done to avoid the development of resistance to the new agents. Here, we discuss relevant aspects for the clinical management of antiretroviral drug resistance, leaving detailed explanations of mechanisms and mutation patterns to other articles in this issue.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: Human Immunodeficiency Virus; Antiretroviral resistance; Antiretroviral treatment; Genotype; Phenotype; Ultrasensitive resistance testing; Allele-specific PCR; Ultradeep sequencing

Update on antiretroviral therapy in paediatrics by Martina Penazzato; Daniele Donà; Pia-Sophie Wool; Osvalda Rampon; Carlo Giaquinto (pp. 266-275).

This review provides an update on the most relevant issues concerning the current management of HIV infection in infants and children.Tremendous progress has been made over the last few years to diagnose and treat infants and children with HIV infection, yet much remains to be done. Every day there are nearly 1150 new infections in children under 15 years of age, more than 90% of them occurring in the developing world and most being the result of transmission from mother-to-child (WHO 2008).The comprehensive approach to preventing mother-to-child transmission (MTCT) has clearly reduced the number of children acquiring the infection in Western countries; while a further reduction of mother-to-child transmission should be aimed for personalized setting, specific intervention needs to be put in place and new efforts are now required in order to optimise treatment and care in HIV-infected children. The prompt initiation of treatment and a careful selection of first-line regimen, which considers potency as well as tolerability remain central. In addition, occurrence and prevention of opportunistic infections, adherence as well as long-term psychosocial consequences are becoming more and more relevant in the era of effective antiretroviral therapy. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of Antiretroviral Drug Discovery and Development, vol. 85, issue 1, 2010.

Keywords: HIV-infected children; Antiretroviral therapy in children; HAART in children; Paediatric HIV

Sexual transmission of HIV-1 by Julie Fox; Sarah Fidler (pp. 276-285).

HIV-1 transmission occurs in a limited number of ways all of which are preventable. Overall, the risk of HIV-1 transmission following a single sexual exposure is low especially in comparison with other sexually transmitted infections (STIs); with estimates of the average probability of male to female HIV-1 transmission only 0.0005–0.0026 per coital act. The risk of acquiring HIV-1 from a single contact varies enormously and is dependant upon the infectiousness of the HIV-1 positive individual and the susceptibility to HIV-1 of their sexual partner. An understanding of the determinants of HIV-1 transmission is important not only to assess the infection risk to an individual when exposed to the virus (e.g. to determine the provision of post exposure prophylaxis), but also to make accurate predictions on the potential spread of HIV-1 infection in a population and to direct appropriate targeted prevention strategies. In this review article we summarise the current literature on the major worldwide source of HIV-1 acquisition, sexual transmission. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: HIV-1; Sexual transmission; Risk behaviour; Prevention

HIV reservoirs, latency, and reactivation: Prospects for eradication by Viktor Dahl; Lina Josefsson; Sarah Palmer (pp. 286-294).

Current antiretroviral therapy effectively suppresses but does not eradicate HIV-1 infection. During therapy patients maintain a persistent low-level viremia requiring lifelong adherence to antiretroviral therapies. This viremia may arise from latently infected reservoirs such as resting memory CD4+ T-cells or sanctuary sites where drug penetration is suboptimal. Understanding the mechanisms of HIV latency will help efforts to eradicate the infection. This review examines the dynamics of persistent viremia, viral reservoirs, the mechanisms behind viral latency, and methods to purge the viral reservoirs. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

Keywords: HIV; HIV latency; HIV reservoirs; HIV eradication; Persistent HIV viremia; HIV cure

Effector mechanisms in HIV-1 infected elite controllers: Highly active immune responses? by Joel N. Blankson (pp. 295-302).

Elite controllers (EC) are HIV-1 infected patients control viral replication to a level of <50copies/ml without antiretroviral therapy. These patients are also known as elite suppressors, or HIV controllers, and they differ from traditional long-term non-progressors (LTNPs) who maintain stable CD4 counts and are asymptomatic without antiretroviral therapy. Recent studies suggest that many EC are infected with replication-competent virus. Thus it appears that host factors such as innate immunity, the humoral immune response, and the cellular immune response are involved in the suppression of viral replication in EC. This article will review the effector mechanisms that are thought to play a role in the remarkable control of viral replication seen in these patients.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: Elite controller; Elite suppressor; Long-term non-progressor; HLA-B*57; HLA-B*27; Escape mutations; Neutralizing antibody; CD8; CD4

Viral hepatitis and HIV co-infection by Vincent Soriano; Eugenia Vispo; Pablo Labarga; Jose Medrano; Pablo Barreiro (pp. 303-315).

Chronic hepatitis B virus (HBV) infection is overall recognised in 10% of HIV+ persons worldwide, with large differences according to geographical region. Chronic hepatitis C virus (HCV) infection affects 25% of HIV+ individuals, with greater rates (∼75%) in intravenous drug users and persons infected through contaminated blood or blood products. HIV-hepatitis co-infected individuals show an accelerated course of liver disease, with faster progression to cirrhosis. The number of anti-HBV drugs has increased in the last few years, and some agents (e.g. lamivudine, emtricitabine, tenofovir) also exert significant activity against HIV. Emergence of drug resistance challenges the long-term benefit of anti-HBV monotherapy, mainly with lamivudine. The results using new more potent anti-HBV drugs (e.g. tenofovir) are very promising, with prospects for stopping or even revert HBV-related liver damage in most cases. With respect to chronic hepatitis C, the combination of pegylated interferon plus ribavirin given for 1 year permits to achieve sustained HCV clearance in no more than 40% of HIV–HCV co-infected patients. Thus, new direct anti-HCV drugs are eagerly awaited for this population. Although being a minority, HIV+ patients with delta hepatitis and those with multiple hepatitis show the worst prognosis. Appropriate diagnosis and monitoring of chronic viral hepatitis, including the use of non-invasive tools for assessing liver fibrosis and measurement of viral load, may allow to confront adequately chronic viral hepatitis in HIV+ patients, preventing the development of end-stage liver disease, for which the only option available is liver transplantation. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Keywords: Hepatitis B; Hepatitis C; Hepatitis delta; HIV; Co-infection; Liver; Interferon; Ribavirin; Entecavir; Adefovir; Lamivudine; Tenofovir; Antiviral drugs

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