Stopping protease inhibitor therapy whilst maintaining nucleoside analogue treatment may preserve crippled viruses for up to 36 weeks whilst sparing PI-related toxicity, and prevent both viral rebound and CD4 decline in highly treatment experienced patients, according to a study presented to the Tenth Conference on Retroviruses and Opportunistic Infections this week in Boston.
The study, carried out by Dr Steve Deeks of San Francisco General Hospital, is the latest in a series of studies designed to investigate the effects of staying on failing regimens in the light of evidence that many patients continue to have a good CD4 cell response to therapy despite moderate viral rebound and drug resistance.
Dr Deeks reported on the effects of removing one class of drug in twenty patients with viral load above 400 copies/ml who had experienced viral rebound despite good adherence. The patients had a median viral load –1.26 log below their viral set point (the level at which viral load stabilises after seroconversion), and a median CD4 cell count 245 cells above the pre-treatment level at the time of interruption. The median baseline viral load was 3.9 log copies/ml (approximately 8,000 copies/ml) and the median CD4 T-cell count was 336 cells/mm3.
Patients experiencing toxicities stopped protease inhibitor treatment but continued with their nucleoside analogues, and after 24 weeks only two had experienced a significant viral load rebound. No evidence of increased susceptibility to protease inhibitors was evident in any of the 15 patients to week 24, despite the lack of selective drug pressure. However, in the two patients who had experienced rebound, drug sensitivity began to return after week 24, PI-related mutations began to disappear and replicative capacity improved.
In contrast, five patients who stopped nucleoside analogues but maintained PI treatment experienced prompt rebounds in viral load, in three cases associated with a loss of the 3TC-associated M184V mutation and an increase in replicative capacity.
Dr Deeks speculates that the M184V mutation, amongst others, reduces the replicative capacity of viruses, and that NRTI therapy maintains that state of reduced fitness whilst also exerting a moderate antiviral effect.
“Complete resistance to nucleoside analogues was uncommon in this cohort”, he told the conference.
Patients who stopped PI therapy also experienced significant falls in triglycerides and cholesterol over 24 weeks.
Dr Deeks argues that this approach requires further study, and that it may be useful for patients who have extensive treatment experience and who cannot assemble a potent regimen from newly available drugs such as T-20 due to high-level protease inhibitor resistance. Rather than waste T-20 by adding it as a single agent to failing therapy, it may be better to explore such approaches until more agents of new classes become available, especially for patients with low CD4 counts at risk of disease progression if they attempt treatment interruption to purge drug-resistant virus.
Deeks S et al. Continued Reverse Transcriptase Inhibitor Therapy is Sufficient to Maintain Short-Term Partial Suppression of Multi-drug Resistant Viremia. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 640, 2003.