HIV resistance, phenotypic drug susceptibility and viral fitness
Paul Blanchard, HIV i-Base
In a second presentation Steve Deeks presented data from an observational study of patients remaining on protease inhibitor based therapy despite experiencing viral loads greater that 500 copies/mL.
It has already been observed by Deeks and others that such continued therapy despite the emergence of drug resistant virus may be associated with durable immunological and virological benefit. However, the natural history of viral evolution in the face of continued therapy has not been well described.
A series of individual patient plots were presented showing evolution over time of viral load, CD4 count, PI phenotype, replicative capacity and zidovudine phenotype. Over a median of 28.9 months there was a median change of +28 CD4 cells/mm3, +0.61 log copies/mL HIV RNA, 44 fold change in PI susceptibility, 2.3 fold change in NRTI susceptibility and a -1.5% change in replicative capacity (compared to wild type).
It was observed that all viral samples had evidence of impaired replicative capacity and that large changes in PI resistance were temporally associated with the emergence of both primary drug resistance mutations and decreased replicative capacity. Interestingly, more gradual increases in PI resistance were associated with stable or increasing replicative capacity and the emergence of secondary mutations.
Deeks concluded that long term virologic failure of a PI-based regimen is associated with:
- Progressive increases in viral load
- Variable CD4 changes
- Progressive loss of drug susceptibility
- Stable and often decreasing replicative capacity
A significant minority of patients were observed to maintain stable levels of viraemia over the study period despite continued viral evolution (and increasing resistance).
These observations (and those by Deeks on anti-HIV responses) were in PI-based therapy only. There is no data in 3NA’s or NNRTI based therapy and reasons to believe that similar observations would not be likely in non-PI regimens. It is also unknown if increasing time may eventually lead to full recovery of replicative capacity and pathogenicity.
Overall it should be remembered that the principles behind the treatment of HIV is unlikely to differ fundamentally from other infectious diseases where drug resistance is never seen as good news.
These observations do, however, give short term encouragement to patients with no other treatment options and low reserves of immune capacity to persevere with antiretroviral combinations containing PI’s.
Deeks SG, Wrin T, Barbour J et al. Evolution of phenotypic drug susceptibility and viral replication capacity during stable protease inhibitor-based therapy despite incomplete viral suppression. Antiviral Therapy 2001; 6 (Supplement 1):62. (Abstract 79)