HIV drug resistance can develop under HAART at low levels of viraemia

2 November 2001. Related: Conference reports, Drug resistance, EACS 8th Athens 2001.

Paul Blanchard, HIV i-Base

It is thought that HIV develops drug resistance by continued replication of virus during administration of antiretrovirals. In the clinic, replication of virus is monitored by measurement of plasma HIV-RNA levels (viral load). However, the level of plasma viral load which may allow the development of drug resistant HIV remains unclear.

Soo Aleman from the Karolinska Institute, Stockholm presented data from 14 patients who, after an initial decrease of viral load to less than 500 copies/mL, either experienced rebound to persistent low grade viraemia (<1000 copies/mL), or a slow rise to less than 4000 copies within one year. HAART was first line in 5 patients, second line in seven and third line in two. The majority were receiving a standard regimen of 2 nucleoside analogues (NA) and a PI, one was on a 2 NA + NNRTI combination and one received 1 PI + 1NNRTI. A total of 71 determinations of plasma viral load and 56 genotype tests were made during up to 30 months of antiretroviral therapy.

Virologic failure occurred a mean 9.1 months after treatment initiation at which time the median viral load was 650 copies/mL with a mean increase in CD4+ T cells of 92 cells/mm3. The last sampling point occurred 16.6 months after treatment initiation with viral load 1450 copies/mL and CD4 count +110 cells/mm3. Baseline primary drug resistance mutations were present in none of the 5 drug naïve patients, in 6 of the 9 treatment experienced patients (RT gene) and in the protease gene in one treatment experienced subject (V82A).

Appearance of new primary mutations

The following table shows the time and viral load at which new primary RT mutations appeared:

*Naïve vs. experienced = NS

And new primary protease mutations:

In one patient new primary RT and protease mutations were detected despite viral load being less than 50 copies/mL. Serial accumulation of drug resistance mutations were also seen even when increases in viral load were modest (median 1450 copies/mL) and with CD4+ cell counts continuing to rise.

Aleman concluded that selection of viruses with pre-existing and/or new drug resistance mutations can occur at low levels of viraemia even if CD4 counts continue to rise. Further, that the serial accumulation of primary mutations at such low levels of viraemia may threaten future drug treatment options.

Comment

This data may influence decisions as to what level of viraemia necessitates a switch in therapy, and the frequency of VL monitoring used once VL is below the level of detection. Serial accumulation of mutations seem to occur rapidly (over a few months) and are not necessarily associated with a cumulative rise in VL – development of alternate strategies to plasma viral load monitoring would appear to be required to detect and prevent this.

Reference:

Aleman S et al. Drug resistance at low viremia in treated HIV-1 infected patients with CD4+ T cell response. 8th ECCATH, Athens 2001. AbsO24.