The Addition of Mycophenolate Mofetil to Antiretroviral Therapy Including Abacavir Is Associated With Depletion of Intracellular Deoxyguanosine Triphosphate and a Decrease in Plasma HIV-1 RNA

Abstract

Mycophenolic acid (MPA) enhances the in vitro activity of abacavir (ABC) and other nucleoside analog reverse transcriptase inhibitors (NRTIs) against sensitive and NRTI-resistant HIV-1. This may occur via depletion of intracellular deoxyguanosine triphosphate (dGTP). Mycophenolate mofetil (MMF) 500 mg twice daily was added as a single agent to the antiretroviral regimens of five patients failing maximal available therapy. Therapy included ABC, and in most cases didanosine (DDI) and tenofovir (TDF). At entry, mean plasma HIV-1 RNA (VL) was 5.02 log copies/mL (median 4.78, range 4.71-5.63) and mean CD4 count was 106/microL (median 117, range 11-174). MMF was well tolerated. CD4 cell counts did not change significantly from baseline for up to 60 weeks of follow-up. Three of five subjects had VL declines of >0.5 log copies/mL immediately after adding MMF; a fourth subject had a sustained decline of >0.5 log copies/mL after week 8. Declines of >0.5 log copies/mL were lost in two patients at 6 and 8 weeks, and persisted in two patients at 36 and 60 weeks of follow-up, respectively. An increase in the ratio of carbovir triphosphate (CBV-TP), the active antiviral metabolite of ABC, to dGTP was documented in 3 of 4 subjects in temporal association with decreased VL. Trough plasma MPA levels ranged from 0.26-1.67 microg/mL; peak levels 90 minutes after dosing from 1.20-7.77 microg/mL. AUC of MPA appeared little changed when measured over 28 weeks of therapy. Declines in VL were observed in association with measurable changes in the CBV-TP/dGTP ratio in some patients, whereas MPA AUC was below the 30-60 microg*hr/mL range targeted in organ transplantation. The possibility that MMF may enhance the effect of selected NRTIs and be tolerated in late stage HIV disease deserves careful randomized study.

Hepatitis C and Renal Transplantation in the Era of Modern Immunosuppression

“…However, Fasola et al (33) showed that manifestations of hepatitis C disease recurrence after steroidresistant allograft rejection following orthotopic liver transplantation seems to be less severe in patients who use mycophenolate. Mycophenolate has also been used as adjunctive therapy in the treatment of HIV infection (34,35). However, some of the benefit of mycophenolate use may also be due to lowered rates of acute rejection after transplantation (36).…”

In Vitro Combination of Amdoxovir and the Inosine Monophosphate Dehydrogenase Inhibitors Mycophenolic Acid and Ribavirin Demonstrates Potent Activity against Wild-Type and Drug-Resistant Variants of Human Immunodeficiency Virus Type 1

“…MPA has been shown to increase the in vitro anti-HIV activity of ABC when used in combination (21). Several pilot clinical studies have been conducted to evaluate the effect of MPA (given as the prodrug MMF) in combination with HAART (8,9,22). Overall, therapy with MMF resulted in a transient decrease in HIV viral load in the majority of patients.…”

Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine

“…Potential clinical implications need to be evaluated in the future, including assessment of the analog/dNTP ratio over time, which influences the pharmacological efficacy of TDF/FTC (3,4,12).…”

“…Participants' age, weight, sex, race, and body mass index (BMI) were recorded upon enrollment in the study. Peripheral blood mononuclear cell (PBMC) samples were taken at baseline and at 8 h postdose on days 1,3,7,20,30, and 60 in all participants. The HIV-negative group had two additional visits on days 35 and 45 during the washout period.…”

“…Once incorporated, they terminate the elongation of the HIV DNA chain due to the lack of a 3= hydroxyl group to incorporate the next component (2). The ratio between drug concentration and the corresponding deoxynucleoside triphosphate (dNTP) affects the pharmacologic efficacy of TDF/FTC as a high ratio has been associated with greater antiviral activity (3,4).…”