Each year this distinguished workshop reports on the progress in basic science in HIV drug resistance including profiles of new agents, illuminating mechanisms of resistance and viral kinetics and considers the clinical relevance of these developments for those engaged with direct patient care.
An interesting feature of this meeting is the introduction of new discoveries in the field and the new terminology devised to explain these advances in science. Whilst many of these become common parlance in the description of drug resistance, hypersusceptibility and replication capacity being two commonly used terminologies, some become redundant soon after they are introduced. For example, the concept of resistant-repellent compounds much touted a few years ago has been rejected as a premature conclusion.
At this year’s workshop, a number of developments from previous workshops were consolidated into some distinct take-home messages. Most notably:
- A moratorium on companies who report not being able to find resistance to their compounds. Experience later in the clinic constantly refutes this supposition. The message is a resounding, ‘they should look harder’ and report signature mutations with the associated viral impact earlier so that they can be included in interpretation algorithms and pre-empted in the clinic.
- Severely restrict use of the term ‘second-generation’ only to those agents that have unique properties and target sites. Agents in existing classes which have structural differences from current compounds should not be considered ‘second-generation’, experts agreed.
- Standardise resistance profiles and assay techniques to level the playing field amongst emerging competitor agents.
- Admit that size does matter – conclusions drawn from studies can only be meaningful if cohorts and databases include a substantial number of patients.
- Rethink strategies for prevention of mother to child transmission (PMTCT) to incorporate not only prevention of transmission but ensuring that options for future treatment for both mother and child are not restricted by the occurrence of resistance.
- Agree meaningful definitions and cut-off values for terms such as hypersusceptibility (HS) and consensus values for replicative capacity (RC), and clinical implications for these cut-off measures.
- Caution against deferral of therapy on the basis that nadir CD4 is a strong prognostic marker for immune recovery and that sustaining the T-cell repertoire may be a crucial determinant in the durability and success of treatment outcomes.
- Looking for resistance only in the protease (PR) and reverse transcriptase (RT) regions is actually of limited use as changes in the gag domain have been correlated with the capacity of the virus to replicate. Changes at gag also serve as a pre-emptive indicator for future resistance evolution and alert to potential treatment failure.
- Investigators should be mindful of including in all new studies analysis of replicative capacity (RC), impact of drug levels on resistance pathways and activity against non-B viruses. Whilst it is not yet clear what the significance of some of these values may be, there is a compelling body of data now emerging suggesting that these values do correlate with response to treatment.
- A more sophisticated approach to selecting treatments is needed, not only on the basis of numbers or type of mutations that emerge, but to consider the fragility of some compounds due to their genetic barrier and the subsequent durability of the chosen regimen.
Read related reports from the XIII International HIV Drug Resistance Workshop, June 8-12, Tenerife, Spain
Entry and attachment inhibitors
As researchers learn more about the ways in which HIV develops resistance to entry and attachment inhibitors, the future shape of therapy with these new classes of drugs becomes clearer.
New concepts for the clinician
This year's workshop heard more about the clinical relevance of replication capacity and hypersusceptibility, and began to debate the potential therapeutic exploitation of interactions between resistance mutations.
Population surveys of resistance
What sort of resistance is occurring in clinic populations, and what does this tell us about clinical practice today?
Prevention of mother to child transmission
The threat of nevirapine resistance is forcing a rethink of strategies to prevent mother to child transmission. The workshop learnt more about resistance patterns, and why differences in HIV-1 subtype may need to be taken into account when thinking about preventing mother to child transmission.
Non-B HIV subtypes
As treatment access expands and the proportion of patients in Europe with non-B subtypes grows, understanding differences in resistance patterns between B and non-B HIV subtypes becomes more and more important.