Resistance still present after 3 months off treatment

Treatment breaks which are intended to drive down the levels of drug resistance prior to starting a salvage drug combination do not appear to eliminate resistant virus entirely, according to French researchers, and should be followed by the most suppressive treatment available.

Dr Jacques Izopet, reporting in the May 15 issue of the Journal of Infectious Diseases, described the impact of a three month treatment interruption on his group’s ability to detect the V82A and L90M protease mutations using a real-time PCR assay that could detect the mutations even when less than 20% of the virus population carried one of these mutations. Standard resistance tests cannot detect minority populations that make up less than 20% of the virus population.

Researchers have expressed concern that studies of the effects of treatment interruptions on drug resistance and the response to salvage regimens might over-state the degree to which treatment interruptions contribute to the clearance of resistant virus, creating the risk that patients with very low CD4 cell counts and high levels of resistance could be needlessly exposed to treatment interruptions that carry a risk of rapid CD4 cell declines and potential illness.

The French study sought to determine how much resistant virus is left below the limits of detection of standard resistance tests, and what impact this has on the response to a salvage regimen. The findings are particularly applicable to the analysis of the GIGHAART study, which has set a new trend in France for treatment interruptions to be taken before starting a salvage regimen.

In this study, viruses bearing one or both of these mutations could be detected in eight of 14 patients after a three month treatment interruption, compared to 13 out of 14 at the time of treatment interruption.

After the treatment interruption, patients were assigned to a new treatment regimen by a clinician who did not know the results of the ultrasensitive resistance test. Five patients with evidence of low-level resistance were assigned to a protease inhibitor-containing regimen, and the remainder received a regimen without a protease inhibitor (PI).

There was no difference in the rate of response between those who received a PI-containing regimen and those who received a PI-sparing regimen, and PI treatment did not lead to the more rapid selection of protease resistance mutations.

Mutations that re-emerged were not specific to the salvage regimen. In all four patients with low-level protease resistance who received NNRTI-based regimens, the selective pressure of protease inhibitor treatment was not needed for protease mutations to re-emerge, and the authors suggested that in these cases, the new regimen had not been strong enough to suppress viral replication from latently infected cells that had been infected prior to the treatment interruption.