Challenges for the clinical development of new nucleoside reverse transcriptase inhibitors for HIV infection.


There is a need for new antiretroviral drugs with activity against HIV isolates resistant to currently available agents and improved short and long-term tolerability profiles. Clinical trial designs for nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs) are restricted by the characteristics of these agents (for example, their cross-resistance, resistance threshold and interaction profiles), the ethical need to ensure that patients are not maintained on suboptimal regimens, and regulatory requirements (for example, with regards to trial designs and patient populations). For example, consideration of cross-resistance profiles must influence the way in which an NRTI in development is sequenced to minimize any impact on future treatment options. The resistance threshold is determined by the number of mutations required to diminish sensitivity to a given drug. Pharmacokinetic or pharmacodynamic interactions restrict how NRTIs may be combined during clinical development. Doses may be selected on the basis of results from short-term monotherapy studies in treatment-naive patients, but such studies cannot establish the long-term efficacy or tolerability of new agents used in combination regimens. Confirmatory studies in treatment-naive populations do not meet the medical and regulatory needs for clinical data in treatment-experienced populations, while studies in treatment-experienced populations are subject to numerous clinical and logistical difficulties. Intensification, switch and hybrid study designs all offer suitable approaches to the evaluation of NRTIs with novel resistance profiles. Switch studies are particularly useful for agents with resistance profiles that suggest a specific sequencing approach in treatment and for those with the potential, based on pharmacokinetic data, for interactions with other agents. The successful development of new NRTIs will depend upon a thorough appreciation of these many and complex issues, not only among those involved in the design of clinical studies, but also those contributing to their review and conduct.




new topics/pols set partial results complete validated


No results available for this paper.

Entry validated by:

Log in to edit reference All References

Using Polbase tables:


Tables may be sorted by clicking on any of the column titles. A second click reverses the sort order. <Ctrl> + click on the column titles to sort by more than one column (e.g. family then name).


It is also possible to filter the table by typing into the search box above the table. This will instantly hide lines from the table that do not contain your search text.