Rapporteur report
Track B: Clinical Research, Treatment and Care report by Sean Emery
This conference does indeed provide an incredible opportunity for bridging between technical streams. This is also true for bridging between disease settings and this session summarised important issues confronting the processes of drug development and developing clinical practice in hepatitis B and C infections. While clearly different diseases from HIV there are enormous parallels with both current themes in HIV and some aspects of history relating to product development.
Marian Peters provided a comprehensive overview of preclinical and early phase human studies used to characterise the potential use of exciting new drugs for the management of hepatitis C infection. Many component parts of the defined virus life cycle are potential targets for the development of therapeutic interventions. At present some 15-20 agents targeting 7-8 parts of the virus life cycle are under investigation. Notwithstanding this impressive progress the challenge is significant. Untreated HCV infection generates a billion/billion new particles/day through an error prone replicative machine. Drugs will have to be potent and possess a high genetic barrier to resistance. From early studies of lead candidates that target HCV protease (BILN2061 and VX950 - telaprivir), and the HCV RNA polymerase (NM283 nad R1626) have shown acivity consistent with the proof of concept. No drug has moved beyond late phase II studies because of insufficient potency evolution of resistance or safety concerns. Addditional drugs are based on inhibition of the RNA polymerase with non-nucleoside moelcules and host directed inhibitors targeting cyclophilin.
Professor Vicente Soriano highlighted to the consdiderable advances in clinical management of HIV-HBV coinfected patients arising from new drugs, viral genotype assays, monitoring of drug resistance and new non-invasive techniques for monitoring liver fibrosis.
Perhaps the most edifying public health message was presented by Professor Stephen Locarnini who summarised the current status of HBV drug resistance from a number of perspectives. It is clear from surveillance activities that there is a growing prevalence of clinically relevant drug resistance to increasing numbers of agents when they are used as monotherapeutic interventions in naive patients or as part of salvage therapy in patients who have prior exposure to the available anti-HBV agents (eg up to 80% resistance after 5 years for 3TC). In part, this is a problem arising from only one target in the virus life cycle being identified against which drugs can be developed but it is clearly also a problem of clinical practice including current guidelines that are yet to formally recommend initiation of these drugs must always be in the setting of combination therapy. Sophisticated monitoring and in vitro analysis has revealed some potentially treatment limiting aspects of how drug resistance evolves in HBV exposed to anti-HBV drugs. On the basis of chemistry, the drugs (all active against the hep B RNA-dependent DNA-polymerase) can be sub-classified into three categories (l-nucleosides, acyclic phosphonates and cyclopentene ring). Each drug supports a different evolutionary pathway for the development of resistance when employed as monotherapy. Unfortunately there are intersections in these pathways where sequential monotherapeutic intervention creates HBV with increasing mutations against the available drugs from more than one of the subcategories. One pathway promotes the acquisition of sufficient point mutations to create a virus that is fully resistant to all available anti-HBV drugs. More disturbingly this same virus has been characterised in primary isolates taken from patients in at least one clinical centre and probably in several others. More concerning still is that the increasing prevalence of resistance (through any of the defined pathways) is already linked to transmission of drug resistant HBV. The reluctance to generate evidence to support initiation with combination anti-HBV drugs does resonate with issues that prevailed several years ago in HIV infection. The impetus to evaluate combination therapy in that setting was helped through the generation of new drugs and particularly those with sufficiently different mechanisms of action. Clearly, such an advance would also assist with this issue in hepatitis B infection.
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