European HIV Drug Resistance Workshop: clinical implications of resistance

Coming so soon after the Thirteenth Conference on Retroviruses and Opportunistic Infections (CROI, Denver, February 2006), there was a distinct paucity of new data on the emerging therapies or novel classes presented at this workshop. However, two issues were clear from the discussions and limited presentations on new classes of drugs.

Firstly, the optimism about CCR5 inhibitors may be tempered by the limited diagnostic technology available at present to phenotype viral tropism. Without other surrogate markers, this is a prerequisite to commencing CCR5 inhibitor therapy. Only one commercial assay (Monogram, USA) is currently available and may serve as a limiting factor in the initial clinical uptake of CCR5 inhibitors of which the Pfizer compound, maraviroc (MVC) is furthest in development. However, much time and resources are being invested by other diagnostic laboratories as well as commitment by Pfizer to accelerate research in this field.

Enfuvirtide resistance and immune response

Sustaining a strong immunologic response for patients on consecutive failing regimens remains critically important. Any data that suggest correlates of immune recovery may prove to be valuable in constructing creative and sustainable regimens. Valentina Svicher from the University of Rome demonstrated some preliminary evidence of immunologic response in 54 patients receiving long-term ENF treatment. Contrary to popular advice, or perhaps because these patients had severely constrained options, ENF had been added as the single active agent on a background of failing drugs.

During a follow-up of 36 weeks, the researchers found evidence of rapid response at four weeks after introducing ENF to the regimen and an increase in CD4 cell count from a previous trend of decreasing CD4, a rise from 48 cells to 106 cells/mm³ in the first four weeks. They observed that viral load increased marginally during this time, but CD4 also continued to increase to a total of 136 cells at 36 weeks. The mutational profile was as follows: G36D, V38A/E, Q40H, N42S (previously reported to confer hyper-susceptibility) and L45M. Notably, this resistance profile differs to those commonly reported in the same genome sequence.

Correlations were found between a specific mutation, V38A/E and immunologic response. Patients harbouring this mutation reported an increase in CD4 count of 4.5-fold and 6-fold at weeks 24 and 36 respectively, compared with a 0.02 increase in patients who did not have the V38A/E mutation. No significant correlations in viral load were attributed to the resistance profile. A further mutation, N126K was linked to increase in CD4 response at 24 weeks in six ENF treated patients.

However, a negative association was confirmed with the combination mutations Q40H plus L45M present in 12% of patients at 36 weeks resulting in a loss of CD4 from 71 to 26 cells/mm³, but still with no link to changes in viral load. The authors conclude that ENF may have a markedly different impact by either reducing the cytopathic effect of HIV or by enhancing the immune response.

When asked whether they would be in favour of a maintaining ENF in a failing background regimen, Dr Svicher responded that this would depend on the profile of baseline mutations and in any case, should involve the close monitoring of emerging resistance related to ENF. Despite the observed improvements in CD4 count up to 36 weeks, a cautionary note was raised by Professor Jonathan Schapiro of Stanford University who questioned the durability of this response.

His query raises the interesting issue of whether it may be possible to maintain the V38A/E mutation with continued treatment and therefore, specific drug pressure. Information from studies such as this will enable clinical virologists, physicians and patients to make informed and perhaps even prognostic decisions about the value of ENF treatment based on genotypic profiling.