Intracellular phosphorylation of stavudine (d4T) and 3TC correlates with their antiviral activity in naïve and zidovudine experienced patients.
Originally Published on January 1, 1998
Sommadossi J-P , Valantin MA, Zhou X-J, Xie M-Y, Moore J, Calvez V, Desa M, Katlama C.
5th Conference on Retroviruses and Opportunistic Infections, February 1-5, 1998, Chicago, Illinois. Abstract 362 page 146.
ABSTRACT:
ALTIS has shown a difference of 1 log10 in viral load decline with a combination of d4T/3TC between naïve and ZDV-experienced patients which could not be explained by phenotype and genotype analysis. ALTIPHAR was designed to investigate the pharmacological mechanisms which may be responsible for this difference among the following 3 groups treated with d4T/3TC: group 1-NRTi naïve patients (n=10) and responders (R)(> -1.0 log_{10}); group 2-long-term ZDV experienced patients (n=6) and non-responders (NR) (< -00-3 log_{10}); group 3-long-term ddI pretreated (n=1) and short-term (< 3 months) or non-compliant to ZDV treatment (n=2) and R. Intracellular concentrations of 3TC-TP and d4T-TP were measured in peripheral blood mononuclear cells.
Metabolites
Group 1
Group 2
Group 3
Wilcoxon test
D4T-TP
1 vs 2, p=0.01
(pmol/10^{6} cells)
0.22
0.06
0.15
2 vs 3, p=0.03
Mean(SD)
(0.18)
(0.03)
(0.04)
1 vs 3, p=1
3TC-TP
1 vs 2, p=0.03
(pmol/10^{6} cells)
3.45(1.37)
2.86(1.86)
4.24(1.41)
2 vs 3, p=0.004
Mean(SD)
1 vs 3, p=0.1
NRTi phosphorylation correlates significantly with R and NR in each group. Following long term ZDV treatment, NR was associated with a significant decrease in d4T and 3TC phosphorylation. The underlying molecular basis is being investigated. This data demonstrates that NRTi phosphorylation plays an important role in their antiviral activity in HIV-infected patients and partly explains decreased virological effects of d4T/3TC after ZDV exposure.
