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  12th International Workshop on Clinical Pharmacology of HIV Therapy
Miami, FL April 13-15, 2011
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HIV Infection Affects Cellular Pharmacology
of Zidovudine and Lamivudine: 3TC for prevention

  12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Intracellular concentrations of zidovudine (ZDV) and lamivudine (3TC) were significantly different in people with HIV than in people without HIV, according to results of a 43-person study [1]. ZDV monophosphate (ZDV-MP) levels were significantly higher in people with HIV, which could portend a higher risk of ZDV side effects. But 3TC monophosphate, diphosphate (DP), and triphosphate (TP) levels were significantly lower in people with HIV than in HIV-negative people, a result that could have implications for prophylactic use of 3TC in HIV-negative people. Gender did not affect intracellular accumulation of ZDV or 3TC in this study.
Both ZDV and 3TC require intracellular phosphorylation to reach their active triphosphate (TP) state inside cells. Because earlier studies suggested intracellular concentrations of these reverse transcriptase inhibitors may vary by HIV status and gender [2], researchers at the University of Colorado planned this comparison of intracellular ZDV and 3TC levels in volunteers with and without HIV infection.
Study participants took ZDV/3TC at a dose of 300/150 mg twice daily for 12 days and had blood collected 2, 5, and 8 hours after the first dose and on days 3, 7, and 12. HIV-positive people took ZDV/3TC as part of their regular antiretroviral regimen and had blood samples collected at the same times. The investigators measured plasma and TP levels of ZDV and 3TC in all samples, and MP and DP levels in 30% of samples.
The study enrolled 20 HIV-negative volunteers. Eight women and 8 men completed the study, and 4 men completed fewer than 12 days. In the 23-person HIV group, 16 men and 5 women completed 12 days, and 1 man and 1 woman completed fewer than 12 days. The investigators analyzed ZDV and 3TC levels in all participants, regardless of whether they completed the study. The HIV group had a median CD4 count of 266 (interquartile range 154 to 405) and a median viral load of about 65,000 copies.
Median ZDV levels in peripheral blood mononuclear cells (PMBCs) of HIV-negative volunteers were 243 fmol/million PBMCs (interquartile range [IQR] 142 to 418) for ZDV-MP, 30.9 fmol/million PBMCs (IQR 25.2 to 51.7) for ZDV-DP, and 37.2 fmol/million PBMCs (IQR 27.2 to 46.4) for ZDV-TP. ZDV-MP levels were 1.8-fold higher in HIV-positive people than in the HIV-negative group, a significant difference (P = 0.004). Median ZDV-DP and ZDV-TP levels differed less than 20% (nonsignificantly) between groups. ZDV plasma concentrations were associated with intracellular ZDV-MP (P = 0.01) in HIV-negative volunteers, but not with ZDV-DP or ZDV-TP.
ZDV-TP levels were similar in men (37.6 fmol/million PBMCs, IQR 25.1 to 42.1) and women (35.2 fmol/million PBMCs, IQR 24.8 to 43.3) (P = 0.9). Between-gender comparisons did not change when the investigators analyzed only the HIV-negative group or the HIV-positive group, or when they evaluated ZDV-MP, ZDV-DP, or ZDV-TP separately. Over the 12-day dosing period, ZDV-TP accumulated 1.3-fold.
Median 3TC concentrations in HIV-negative volunteers were 3.0 pmol/million PBMCs (IQR 2.3 to 4.7) for 3TC-MP, 2.9 pmol/million PBMCs (IQR 2.3 to 4.2) for 3TC-DP, and 5.3 pmol/million PBMCs (IQR 4.7 to 6.1) for 3TC-TP. Levels of all 3TC phosphates were significantly lower in HIV-positive volunteers. For 3TC-TP, median intracellular concentration in HIV-positive people was 3.9 pmol/million PBMCs (IQR 2.2 to 5.4) (P = 0.01 versus HIV-negative people). Higher 3TC-TP concentrations in HIV-negative people than in positive people "may confer high activity for prevention," the researchers suggested.
In contrast, plasma 3TC concentrations were significantly higher in people with HIV (P = 0.02). Plasma concentrations of 3TC were significantly associated with PBMC concentrations in HIV-positive people, but not in HIV-negative volunteers. Intracellular levels of 3TC-TP were similar in men (median 4.5 pmol/million PBMCs, IQR 3.4 to 5.6) and women (median 4.9 pmol/million PBMCs, IQR 3.9 to 6.2) (P= 0.24). (Another study presented at this workshop [3], reviewed separately by NATAP, also found no difference in 3TC-TP between men and women.) Through the 12-day dosing period, 3TC-TP accumulated approximately 3-fold.
Peter Anderson and colleagues believe their findings "suggest enhanced risk of adverse events linked to ZDV-MP in HIV-positive versus HIV-negative patients." They noted that "intracellular 3TC differences may have relevance for understanding PK-response for treatment (HIV-positive) versus prevention (HIV-negative)."
1. Anderson PI, Rower JE, Meditz A et al. The cellular pharmacology of zidovudine and lamivudine according to HIV-status and gender. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_06.
2. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS. 2003;17:2159-2168.
3. Else L, Jackson A, Puls R, et al. Pharmacokinetics of plasma lamivudine (3TC), and its active intracellular anabolite 3TC-triphosphate (3TC-TP) over a 24 hour dosing interval following administration of 3TC 300 mg and 150 mg once daily to HIV-negative healthy volunteers. The ENCORE2 study. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_05.