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Clinical outcomes and immune benefits of anti-epileptic drug therapy in HIV/AIDS.

Lee K, Vivithanaporn P, Siemieniuk RA, Krentz HB, Maingat F, Gill MJ, Power C - BMC Neurol (2010)

Bottom Line: Herein, AED usage, associated toxicities and immune consequences were investigated.The most frequently prescribed AEDs were calcium channel blockers (gabapentin/pregabalin), followed by sodium channel blockers (phenytoin, carbamazepine, lamotrigine) and valproate.AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Southern Alberta Clinic, Alberta Health Services, Calgary, AB, Canada.

ABSTRACT

Background: Anti-epileptic drugs (AEDs) are frequently prescribed to persons with HIV/AIDS receiving combination antiretroviral therapy (cART) although the extent of AED use and their interactions with cART are uncertain. Herein, AED usage, associated toxicities and immune consequences were investigated.

Methods: HIV replication was analysed in proliferating human T cells during AED exposure. Patients receiving AEDs in a geographically-based HIV care program were assessed using clinical and laboratory variables in addition to assessing AED indication, type, and cumulative exposures.

Results: Valproate suppressed proliferation in vitro of both HIV-infected and uninfected T cells (p <0.05) but AED exposures did not affect HIV production in vitro. Among 1345 HIV/AIDS persons in active care between 2001 and 2007, 169 individuals were exposed to AEDs for the following indications: peripheral neuropathy/neuropathic pain (60%), seizure/epilepsy (24%), mood disorder (13%) and movement disorder (2%). The most frequently prescribed AEDs were calcium channel blockers (gabapentin/pregabalin), followed by sodium channel blockers (phenytoin, carbamazepine, lamotrigine) and valproate. In a nested cohort of 55 AED-treated patients receiving cART and aviremic, chronic exposure to sodium and calcium channel blocking AEDs was associated with increased CD4+ T cell levels (p <0.05) with no change in CD8+ T cell levels over 12 months from the beginning of AED therapy.

Conclusions: AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved.

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Related in: MedlinePlus

In vitro effects of AEDs on T cell proliferation and viral replication. (A) and (B) FACS analysis of cultured CD3+ T cells following mock (HIV (-)) and HIV (HIV (+)) infection in the (i) absence or (ii) presence of valproate treatment (75 μg/ml) showing reduced proliferation in valproate-treated cultures at day 2 post-infection. (C) Valproate exerted a suppressive effect on T cell proliferation with and without HIV infection in contrast to the other AEDs. (D) None of the AEDs affected HIV replication in CD3+ T cells, measured as reverse transcriptase activity in culture supernatants collected at day 2 and 4 post-infection. Data represent mean ± SEM. (Tukey-Kramer post hoc test, **p < 0.01)
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Figure 1: In vitro effects of AEDs on T cell proliferation and viral replication. (A) and (B) FACS analysis of cultured CD3+ T cells following mock (HIV (-)) and HIV (HIV (+)) infection in the (i) absence or (ii) presence of valproate treatment (75 μg/ml) showing reduced proliferation in valproate-treated cultures at day 2 post-infection. (C) Valproate exerted a suppressive effect on T cell proliferation with and without HIV infection in contrast to the other AEDs. (D) None of the AEDs affected HIV replication in CD3+ T cells, measured as reverse transcriptase activity in culture supernatants collected at day 2 and 4 post-infection. Data represent mean ± SEM. (Tukey-Kramer post hoc test, **p < 0.01)

Mentions: Previous studies have reported that exposure to different AEDs influenced both HIV replication and leukocyte viability or proliferation [14,19-22]. To investigate the comparative effects of commonly used AEDs, human primary blood lymphocytes (PBLs) with and without concurrent HIV-1 infection were treated with gabapentin, valproate or phenytoin at therapeutic concentrations. These studies revealed that HIV infection suppressed T cell proliferation in vitro (Figure 1B and 1C) compared with uninfected (Figure 1A and 1C) cell cultures at day 2 post-infection in cells, as expected. However, valproate exposure to PBLs suppressed T cell proliferation in both HIV-infected and uninfected cultures in comparison with untreated cultures (Figure 1C). Conversely, gabapentin and phenytoin did not influence T cell proliferation in vitro (Figure 1C). None of the present AEDs exerted effects on viral production in terms of reverse transcriptase activity in supernatants from PBLs relative to untreated HIV-infected cultures (Figure 1D). A sub-analysis of valproate exposure on T cell proliferation at day 3 post infection showed that valproate not only reduced but also altered proliferation pattern (Figure 2A-C). In uninfected lymphocyte cultures, the valproate-treated cells displayed higher parent generation (P) and generation 1 (G1) and lower generation 3 (G3) levels than the untreated group. The majority of cells in HIV-infected PBLs with valproate exposure remained undivided (P generation) while HIV-infected PBLs divided two times in the absence of valproate (Figure 2B and 2D). Similar effects were observed at day 4 post-infections (data not shown). These studies highlighted the potential impact of valproate on T cell function while also indicating a relative lack of effect on viral replication mediated by any of the AEDs on proliferating T cells, prompting us to analyse the clinical effects of these same AEDs.


Clinical outcomes and immune benefits of anti-epileptic drug therapy in HIV/AIDS.

Lee K, Vivithanaporn P, Siemieniuk RA, Krentz HB, Maingat F, Gill MJ, Power C - BMC Neurol (2010)

In vitro effects of AEDs on T cell proliferation and viral replication. (A) and (B) FACS analysis of cultured CD3+ T cells following mock (HIV (-)) and HIV (HIV (+)) infection in the (i) absence or (ii) presence of valproate treatment (75 μg/ml) showing reduced proliferation in valproate-treated cultures at day 2 post-infection. (C) Valproate exerted a suppressive effect on T cell proliferation with and without HIV infection in contrast to the other AEDs. (D) None of the AEDs affected HIV replication in CD3+ T cells, measured as reverse transcriptase activity in culture supernatants collected at day 2 and 4 post-infection. Data represent mean ± SEM. (Tukey-Kramer post hoc test, **p < 0.01)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902446&req=5

Figure 1: In vitro effects of AEDs on T cell proliferation and viral replication. (A) and (B) FACS analysis of cultured CD3+ T cells following mock (HIV (-)) and HIV (HIV (+)) infection in the (i) absence or (ii) presence of valproate treatment (75 μg/ml) showing reduced proliferation in valproate-treated cultures at day 2 post-infection. (C) Valproate exerted a suppressive effect on T cell proliferation with and without HIV infection in contrast to the other AEDs. (D) None of the AEDs affected HIV replication in CD3+ T cells, measured as reverse transcriptase activity in culture supernatants collected at day 2 and 4 post-infection. Data represent mean ± SEM. (Tukey-Kramer post hoc test, **p < 0.01)
Mentions: Previous studies have reported that exposure to different AEDs influenced both HIV replication and leukocyte viability or proliferation [14,19-22]. To investigate the comparative effects of commonly used AEDs, human primary blood lymphocytes (PBLs) with and without concurrent HIV-1 infection were treated with gabapentin, valproate or phenytoin at therapeutic concentrations. These studies revealed that HIV infection suppressed T cell proliferation in vitro (Figure 1B and 1C) compared with uninfected (Figure 1A and 1C) cell cultures at day 2 post-infection in cells, as expected. However, valproate exposure to PBLs suppressed T cell proliferation in both HIV-infected and uninfected cultures in comparison with untreated cultures (Figure 1C). Conversely, gabapentin and phenytoin did not influence T cell proliferation in vitro (Figure 1C). None of the present AEDs exerted effects on viral production in terms of reverse transcriptase activity in supernatants from PBLs relative to untreated HIV-infected cultures (Figure 1D). A sub-analysis of valproate exposure on T cell proliferation at day 3 post infection showed that valproate not only reduced but also altered proliferation pattern (Figure 2A-C). In uninfected lymphocyte cultures, the valproate-treated cells displayed higher parent generation (P) and generation 1 (G1) and lower generation 3 (G3) levels than the untreated group. The majority of cells in HIV-infected PBLs with valproate exposure remained undivided (P generation) while HIV-infected PBLs divided two times in the absence of valproate (Figure 2B and 2D). Similar effects were observed at day 4 post-infections (data not shown). These studies highlighted the potential impact of valproate on T cell function while also indicating a relative lack of effect on viral replication mediated by any of the AEDs on proliferating T cells, prompting us to analyse the clinical effects of these same AEDs.

Bottom Line: Herein, AED usage, associated toxicities and immune consequences were investigated.The most frequently prescribed AEDs were calcium channel blockers (gabapentin/pregabalin), followed by sodium channel blockers (phenytoin, carbamazepine, lamotrigine) and valproate.AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Southern Alberta Clinic, Alberta Health Services, Calgary, AB, Canada.

ABSTRACT

Background: Anti-epileptic drugs (AEDs) are frequently prescribed to persons with HIV/AIDS receiving combination antiretroviral therapy (cART) although the extent of AED use and their interactions with cART are uncertain. Herein, AED usage, associated toxicities and immune consequences were investigated.

Methods: HIV replication was analysed in proliferating human T cells during AED exposure. Patients receiving AEDs in a geographically-based HIV care program were assessed using clinical and laboratory variables in addition to assessing AED indication, type, and cumulative exposures.

Results: Valproate suppressed proliferation in vitro of both HIV-infected and uninfected T cells (p <0.05) but AED exposures did not affect HIV production in vitro. Among 1345 HIV/AIDS persons in active care between 2001 and 2007, 169 individuals were exposed to AEDs for the following indications: peripheral neuropathy/neuropathic pain (60%), seizure/epilepsy (24%), mood disorder (13%) and movement disorder (2%). The most frequently prescribed AEDs were calcium channel blockers (gabapentin/pregabalin), followed by sodium channel blockers (phenytoin, carbamazepine, lamotrigine) and valproate. In a nested cohort of 55 AED-treated patients receiving cART and aviremic, chronic exposure to sodium and calcium channel blocking AEDs was associated with increased CD4+ T cell levels (p <0.05) with no change in CD8+ T cell levels over 12 months from the beginning of AED therapy.

Conclusions: AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved.

Show MeSH
Related in: MedlinePlus