Presentations

Summary and closing remarks

Abstract

At the risk of re-iterating the obvious, the most pressing need in HIV clinical care at present is the optimization of therapy and the introduction of novel agents. As has been clearly demonstrated by the preceding expert presentations, such approaches are required not only to improve the benefits of HAART for a substantial proportion of those currently on therapy, but also to extend those benefits into a situation of decades-long chronic disease management.

Of all the emerging data arguing for such optimization, and providing ways in which it can be approached, perhaps the most well-known and convincing example is the 48-week data from the Viradapt trial of genotype-assisted therapy, and its 24-week pharmacological sub-study (see figures 1�3).

Figure 1

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In this set of 108 individuals with viral loads >10,000 after at least 3 months of PI-based therapy, those 65 whose next regimen was individually selected on the basis of genotype testing experienced almost twice the reduction in viral load at 6 months than the 43 whose next regimen was based on standard of care alone. The introduction of open-label testing at month 6 extended this improvement to the control arm and resulted in a similar response at month 12 � a benefit that also extended to the percentage of participants below the 200 RNA copies/ml detection limit of the study (see figures 1�3).

Those in the genotyped arm who did not exhibit more than a single monthly plasma PI measurement below the wild-type IC 50 ('Optimal Concentrations' group) had markedly better viral load reductions over 6 months than those from the same arm who showed two or more PI measurements below this level (�Sub-Optimal Concentrations' group). In fact, the genotyped sub-optimal concentration group showed a very similar reduction to the control optimal concentration group. The implications of this are as sobering as they are surprising: that without adequate drug exposure there is no benefit to resistance testing beyond what can be obtained without it.

The Viradapt data demonstrate the importance of assessing cross-resistance and optimizing pharmacological exposure for maintaining and extending therapeutic efficacy. Moreover it emphasizes the importance of taking an integrated approach in which neither of these two factors, nor any other strategic element, is considered independently.

While resistance testing and pharmacological enhancement are two promising ways of preserving current therapy, a truly long-term solution to HIV management will require the introduction of entirely new drugs and drug classes against novel targets. Effective integrase inhibitors are still some way off despite ongoing pre-clinical research. Tat inhibitors are even further away. However, HIV entry inhibitors, both binding- and fusion-directed, are much closer to becoming a part of the antiretroviral armamentarium. Of these inhibitors, the most promising and furthest along the path of clinical development is T-20. As described by Drs Lange and Pozniak, T-20 has shown potent antiviral activity in its clinical trials and looks set to become the first member of the first new class of antiretroviral drug since the licensing of nevirapine introduced the non-nucleoside RT inhibitors. The incorporation of this and other new drugs into a framework of optimized strategies for continuing therapy can be expected to prolong significantly the wellbeing of those on HAART.

The importance of all these approaches to therapeutic optimization is reflected in the acknowledgement by the European Committee for Proprietary Medicinal Products that new agents and formulations addressing this need � such as formulations displaying improved pharmacokinetics and candidate drugs with activity against resistant virus � should be considered for expedited approval (see figures 4 & 5). The incorporation of the fundamental tenets of optimized therapy into the approvals procedure will assuredly lay the foundation for an extended and improved approach to HIV management that encompasses both the use of the current agents and of those yet to come.

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Biography

Dr Johnson is currently Consultant Physician in General Medicine, HIV/AIDS, Thoracic Medicine at the Royal Free Hospital NHS Trust, London and Honorary Senior Lecturer in Virology, Royal Free Hospital School of Medicine, University of London and Clinical Director HIV/AIDS, Royal Free NHS Trust.

Dr Johnson is currently Consultant Physician in General Medicine, HIV/AIDS, Thoracic Medicine at the Royal Free Hospital NHS Trust, London and Honorary Senior Lecturer in Virology, Royal Free Hospital School of Medicine, University of London and Clinical Director HIV/AIDS, Royal Free NHS Trust.and takes part in the majority of large European trials of new antiviral strategies, thus enabling patients to have a wide choice in therapy.

As well as co-ordinating a large number of research projects, Dr Johnson is involved in 25 ongoing clinical trials of antiviral therapies and treatments for opportunistic infections.

Dr Johnson has served or is serving on numerous national and international committees, has served on organising and scientific committees for national and international conferences including the World AIDS Conference (Geneva and Durban) and the 5th International Congress in Glasgow, and has published over 150 papers in the field of HIV and AIDS.

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