Selection of PI mutations during slow decay of VL and resistance after PI failure
16 July 2000. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 4 Sitges 2000.
Development of resistance to treatment during the initial period of viral load decline has always been recognised as a possible risk, lending weight to the argument for maximally suppressive initial combinations with 4 or 5 drugs to increase the initial clearance rate. [1, 2, 3]
Several studies have also indicated that virological response at 8 or 12 weeks may be more useful markers for predicting later treatment success. .
This study, by Herve Fleury and colleagues from the APROCO study group, looked for evidence of the selection of mutations associated with drug resistance in a sub-study of patients (APROVIR), whose viral load remained detectable (>500 copies/ml) after 4 months of treatment. 10/243 patients (4%) from the larger study had this delayed response, with a median viral load at month 4 of 3.46 log10 copies/ml (range 2.85-4.73 log). 
Results in Table 1 show five patients with mutations at month 4 that were not detected at baseline.
|Pt No.||Time||PI used||Viral load||PR mutations||RT mutations|
|m 4||4371||PCR –||E44E/G, V75V/A, Y215Y|
|m 4||725||M46M/L. A71T, V77V/I||PCR –|
Although baseline viral load was higher in these patients than in the whole study group (280,000 against 5.04 log) the analysis of this relationship has still to be performed. Longer follow-up is needed to see whether mutations persist at month 8 and whether there is ultimately an association with later virological rebound.
These data support the case for a rapid induction of suppression of viral replication by the use of multiple agents (>3) when starting therapy. This should particularly be observed when viral load is at higher levels at baseline (> 100,000 copies?).
Additional factors might also be predictive of a slow decline on initiation of treatment and should be further defined. We may then be able to predict who might need more intensive induction.
- J. Lange et al – Alternative Multi-drug Regimen Provides Improved Suppression of HIV-1 Replication over Triple Therapy. AIDS (fast track) Vol:12. 1998
- P. Blanchard – Reports from SPICE, ADAM and other studies, DrFax 50, July 1998.
- J.Mellors et al – Patterns of Plasma HIV RNA Responses in Antiretroviral Treatment Success and Failure. 7th Conference Retroviruses and Opportunistic Infections, 2000. Abstract 451.
- H. Fleury et al – Selection of HIV-1 Resistant Mutants in Patients with Delayed Virological Response to PI-containing HAART. 4th Workshop on Drug Resistance & Treatment Strategies. June 2000, Sitges. Abstract 123.
- Martinez-Picado et al, Selection of Antiretroviral Resistance in the Latent Reservoir of Human Immunodeficiency Virus Type 1 during Successful Therapy. 7th Conference Retroviruses and Opportunistic Infections, 2000. Abstract 238.