Table E-2: Systematic Review of the Global Potential Co-Usage of Aeds and Arvs

E-Tables

Table e-1: Antiepileptic drugs and antiretroviral drugs in the review[1]

Drug / Class / Comments
Antiepileptic drugs
Phenobarbital/phenobarbitone (PB) / Barbiturate / *Metabolized by oxidative hydroxylation.
*A potent enzyme inducer.
Primidone (PRM) / Barbiturate / *Metabolized by liver and excreted in urine.
*Unknown if this is an enzyme inducer but similar in structure to PB (which is).
Clobazam (CLB)
Clonazepam (CNZ)
Diazepam (DZP)
Lorazepam (LZP) / Benzodiazepines (BZD) / *Hepatically metabolized.
*Are often affected by other inducers.
Phenytoin (PHT) / Hydantoin / *Metabolized by liver via oxidation.
*95% protein bound.
*Potent enzyme inducer.
Carbamazepine (CBZ) / Iminostilbene / *Metabolized by P450 system via CYP3A4 as well as other, unknown mechanisms.
*Is a CYP3A4, CYP2C9, CYP1A2, CYP2B6 and UGT inducer.
Oxcarbazepine (OXC) / Iminostilbene / *Metabolized by P450 system.
*Induces CYP3A4 and CYP3A5.
*Inhibits CYP2C19.
Ethosuximide (EXM) / Succinimide derivative / *Excreted in urine unchanged + hydroxylated + glucuronidated.
*Not protein bound.
Valproic acid (VPA) / Carboxylic acid derivative / *Metabolized by liver via oxidation and excreted in the urine.
*90% protein bound.
*Inhibits P450 system as well as UGTs.
Felbamate (FBM) / Dicarbonate / *Metabolized by hydroxylation and conjugation, then excreted in urine.
*Complex interactions with P450 system.
Gabapentin (GBP)
Pregabalin (PGB) / GABA-related structure / *Renally cleared unchanged.
*Not protein bound.
*Do not induce hepatic metabolism.
Vigabatrin (VGB) / GABA-related structure / *Renally excreted.
Levetiracetam (LEV) / Pyrrolidine derivative / *Renally excreted unchanged.
*No enzyme induction.
Lamotrigine (LTG) / Phenyltriazine derivative / *Hepatically metabolized by glucuronidation and excreted in the urine.
Zonisamide (ZNS) / Sulfonamide / *Metabolized by P450 system and excreted in urine.
*No known effects on hepatic enzymes.
Topiramate (TPM) / Sulfonamate-substituted derivative of D-fructose / *Not extensively metabolized before urinary excretion, but levels affected by other drugs (complex).
Tiagabine (TGB) / Nipecotic acid derivative / *Hepatic metabolism by CYP3A4 and excreted in urine and feces.
*96% protein bound.
*No known effects on hepatic metabolism.
Antiretrovirals
Abacavir (ABC)
Didanosine (DDI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Zidovudine (AZT) / Nucleoside reverse transcriptase inhibitors (NRTI) / *Renally eliminated except ABC, which undergoes hepatic metabolism.
Tenofovir (TDF) / Nucleotide reverse transcriptase inhibitors / *Renally eliminated.
Delavirdine (DLV)
Efavirenz (EFV)
Etravirine (ETR)
Nevirapine (NVP) / Nonnucleoside reverse transcriptase inhibitors (NNRTI) / *Metabolized by P450 system (CYP3A4 and CYP2B6).
*Requires a single point mutation for resistance to develop.
Amprenavir (APV)
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir (LPV)
Ritonavir (RTV)
Nelfinavir (NFV)
Saquinavir (SQV)
Tipranavir (TPV) / Protease inhibitor (PI) / *Metabolized by P450 system via CYP3A4 except NFV, which is by CYP3A4 and CYP2C19.
*RTV inhibits CYP3A4 and is used to “boost” levels of other PIs.
Maraviroc (MVC) / Fusion/Entry inhibitor / *Metabolized by P450 via CYP3A4. Levels increased with renal insufficiency. *76% protein bound.
Enfuvirtide (ENF) / Fusion inhibitor / *Elimination poorly described.
*92% protein bound.
Raltegravir (RAL) / Integrase inhibitor / *Metabolized by glucuronidation.
*83% protein bound.

Table e-2: Systematic review of the global potential co-usage of AEDs and ARVs

Publication / Study design / Population / Diagnosis / Findings
e15 / Analysis of subjects within an RCT[2] / Patents enrolled in the Delta trial. Excluded people with PN[3] at enrollment. / Clinical diagnosis by local physician / 177/3195 (5.5%) developed peripheral neuropathy symptoms during follow-up, with early onset seen in patients receiving NRTIs.
15 / Retrospective cohort study / Adults initiating ARVs in three large rural HIV clinics in Zambia / Single Question Neuropathy Screen / Prior to starting ARVs, 82/255 (32.2%) of patients had PN symptoms. During the first 2 years of treatment, 30/173 (17.3%) of patients without PN symptoms at ARV initiation developed PN symptoms.
18 / Cross-sectional study / Subset of ACTG study subjects / Brief Peripheral Neuropathy Screen positive plus 2 of 4 exam findings abnormal. / 53/101 (52.5%) had PN symptoms at enrollment.
16 / Retrospective case series / Patients from a single clinic in the UK on INH plus ARVs / PN clinically defined. Evaluator not blinded to exposure. / 2/30 (6.7%) had PN symptoms prior to initiating ARVs. 12/22 (55%) developed PN while on ARV + INH. Median onset of PN was 5 months after starting ARVs.
1 / Retrospective and prospective cohort study / Men from three US cities in hepatitis B study / Patients documented to have seizures after seroconversion for HIV. / 13/434 (3.0%) HIV+ men experienced 26 seizure episodes
13 / Retrospective chart review / HIV+ people enrolled in RCT with new-onset seizure / Patients documented to have seizures. / New-onset seizure occurred in 100/3920 (2.6%).
12/87 (14%) receiving PHT developed hypersensitivity and rash.
1/9 (11%) on CBZ developed leucopenia.
17 / Prospective cohort study / 272 patients with advanced HIV receiving care from three large urban US HIV clinics / Clinical diagnosis of PN / At baseline 95/272 (34%) had symptomatic PN. Among those without PN symptoms at enrollment, 32% developed PN in the first year of observation.
14 / Prospective cohort study / 550 consecutive HIV+ inpatients admitted to a single inpatient care unit in Barcelona / Admitted with new-onset seizure / 17/550 (3.1%) of HIV patients were admitted with new-onset seizure.
2 / Retrospective chart review / 831 consecutive HIV+ inpatients admitted to a single neurology unit / Admission with new-onset seizure. / 51/831 (6.1%) had new-onset seizure. Among these, 90% were on ARVs, and 53% received AEDs. No information on interactions reported.
19 / Prospective cohort study / 929 people with HIV, largely men / A least one abnormal exam findings for PN / 881/929 (57%) had PN.

Table e-3: Evidence table regarding potential interactions between AEDs and ARVs

Study / Study design/methods / Study population / Interaction assessed / Findings / Summary / Level of evidence
24 / Retrospective, matched cohort study / US Department of Defense HIV Natural History Study / EI-AED + ARV compared with non–EI-AED + ARV / Patients on EI-AED + ARV at increased risk of virologic failure. / EI-AED + ARV with PI or NNRTI had higher virologic failure rates (10/16) during first period of EI-AED/HAART as compared with 20/75 on non–EI-AEDs.
OR 4.58 [1.47-14.25]; p=0.009 / II
e16 / Case report / 44-year-old man with HIV/AIDS / VPA and AZT / VPA inhibited AZT glucuronidation resulting in plasma and CSF levels of AZT increasing to 2–3 times above baseline. / VPA ↑ AZT / IV
e17 / Case report / Adult / Addition of VPA to stable AZT-containing ARV regimen / Significant decline in hemoglobin (Hb) attributed to VPA inhibition of AZT glucuronidation. Hb recovered with discontinuation of AZT. / VPA ↑ AZT / IV
25 / Case report / 50-year-old man with HIV/AIDS on stable CBZ dose / CBZ levels after addition of TDF, 3TC, LPV/RTV and NFV / Patient experienced 50% increase in CBZ levels and clinical toxicity with addition of ARVs on two occasions that remitted with drug discontinuation. Attributed to LPV/RTV and NFV (though other ARVs present). / LPV/RTV ↑ CBZ
NFV ↑ CBZ / IV
30 / Case report / HIV+ patient on stable AED regimen (CBZ + PHT) / CBZ levels after addition of RTV + SQV to 3TC + DDI. / Developed clinical toxicity with CBZ level increase from 6.5 to 18 mcg/ml. Proposed mechanism is CYP34A inhibition by Pis. / RTV + SQV ↑ CBZ / IV
26 / Case report / Adult on stable PB dose / TPV/RTV effect on PB / PB level decreased from 16 to 8.1 mcg/ml after 4 weeks on TPV/RTV. Proposed mechanism is RTV induction of CYP2C9 and CYP2C19. / RTV ↓ PB / IV
20 / Prospective pharmacokinetic study / 17 healthy male volunteers (out of 21 enrolled) / LTG + ATV +/- RTV / ATV did not influence LTG AUC. ATV/RTV reduced LTG AUC by ~30%. / RTV ↓ LTG / II
e11 / Combination retrospective and prospective study / 21 HIV+ people on PHT and 557 historical controls on PHT without HIV / PHT and AZT / No difference in total PHT Css/dose ratio between groups / No clear influence of AZT on PHT levels was apparent. / III
e8 / Prospective pharmacokinetic study / 68 HIV+ patients on AZT. 25 were also on BZD. / AZT + BZD / No change in AZT clearance / No clear influence of BZD on AZT levels was apparent. / III
27 / Case report / Adult on stable CBZ / CBZ + RTV, SQV, EFV / Clinical toxicity and 2-fold increase in CBZ level after change in ARVs. Mechanism proposed CYP3A inhibition by RTV. / RTV ↑ CBZ / IV
29 / Prospective study of ARV +/- VPA / 34 HIV+ adult subjects / HIV+ subjects treated with (EVR (n=11) and LPV/RTV (n=11, 8 evaluable) were assessed before and after VPA 500 mg/day for 7 days. A third group not well matched for comedications received VPA without EFV or LPV / 1. EFV + VPA showed no change.
2. LPV was increased by 38% with VPA. / VPA and EFV do not interact
VPA ↑ LPN
LPV/RTV had no effect on VPA / II for assessment of impact of VPA on EFV
III for other assessments
31 / Case report / Adult on stable PB + PHT / NFV + stavudine added to PB + PHT / Breakthrough seizure with associated decline in PHT levels. This was attributed to NFV. / NFV ↓ PHT / IV
32 / Case report / Adult on IND, AZT, 3TC / CBZ added / IDV levels declined, HIV-RNA levels increased, and 3TC resistance developed. / CBZ ↓ IDV
CBZ ↓ 3TC
with clinical failure and resistance developing / IV
22 / Prospective, open-label, 2-period fixed sequence / 10 healthy volunteers / RAL on midazolam / Coadministration did not have any effect on a single dose of midazolam, a sensitive CYP3A4 probe. / No effect of RAL on midazolam / II
e9 / Prospective, randomized (but sequence of treatments not randomized), open-label, 2-period crossover, multiple-dose study / A total of 36 healthy volunteers (18–45 years old), 18 for each of two studies (27 evaluable overall) / EFV and CBZ / CBZ reduced EFV AUC by 36%; EFV reduced CBZ AUC by 27%. / EFV ↓ CBZ
CBZ ↓ EFV / III
33 / Case report / Adult on stable doses of CBZ and ZNS / Measures serial levels of CBZ and ZNS after 600-mg dose of RTV / Clinical toxicity with rise in serum levels of CBZ. / RTV ↑ CBZ / IV
e10 / Prospective, open-label, 2-period parallel group / 26 healthy female volunteers but small subgroups in each evaluation and short duration of treatment (only single doses for CBZ and PB) / PHT, CBZ, PB + NVP / NVP half-life reduced by CBZ and PHT, no effect on NVP half-life by single-dose PB. / CBZ ↓NVP
PHT ↓NVP
PB no effect on NVP / III
36 / Case report / Patient on PHT / IDV + PHT / PHT level increased after addition of IDV / IDV ↑PHT / IV
23 / Prospective, open-label / 6 HIV+ males on AZT for at least 6 weeks / VPA and AZT / AZT AUC almost doubled and AZT excretion decreased by 60%, suggesting glucuronidation of AZT is inhibited by VPA. / VPA ↑AZT / II
39 / Prospective, open-label, randomized (but no randomized treatment sequence ), 2-period parallel-armed study / 24 healthy volunteers (12 in each arm) / LPV/RTV + PHT / PHT decreased LPV and RTV AUC.
LPN/RTV decreased PHT AUC. / PHT ↓ LPV
PHT ↓ RTV
LPV/RTV ↓ PHT / II for arm A, assessing effect of PHT on LPV/RTV
III for arm B (assessing reverse interaction)
35 / Case report / Patient on stable PB, PHT, CBZ started on RTV/SQV/NVP / PB/PHT/CBZ + RTV/SQV/NVP / Clinical toxicity developed with associated increased CBZ levels. / RTV/SQV/NVP ↑ CBZ / IV
e13 / Case report / Patient with advanced HIV / EFV + PHT / PHT induced metabolism of EFV resulting in EFV levels that correlate with treatment failure.
Over time, EFV gradually increased PHT levels. / PHT ↓EFV
EFV ↑PHT / IV
e14 / Case report / HIV+ on stable VPA with / 3TC/DDI/EFV added / VPA levels decreased by >50% / EFV ↓ VPA / IV
37 / Case report / HIV+ bipolar patient on VPA started on LPV/RTV / LPV/RTV + VPA / Clinical mania and decreased VPA levels when LPV/RTV added. / LPV/RTV ↓ VPA / IV
e18 / Case report / HIV+ patient on PHT / EFV added / PHT levels dropped, and EFV levels were subtherapeutic with clinical failure until PHT replaced with non–EI-AED. / PHT ↓ EFV
EFV ↓ PHT / IV
38 / Open-label, sequential, 3-period, multidose PK study / 18 healthy volunteers completed out of 24 enrolled / LTG + LPV/RTV / LTG levels decreased by 50%. No effect of LTG on LPV/RTV on the basis of comparison with historical controls. / LPV/RTV ↓ LTG
LTG has no effect on LPV/RTV / III
21 / Random crossover
single dose PK / 24 healthy volunteers / LTG +RAL / LTG levels not affected by RAL / RAL has no effect on LTG / II
28 / Placebo-controlled, randomized crossover / 12 health male volunteers / Stiripentol (multiple dose) + SQV (single dose) / The mean SQV AUC in stiripentol + SQV was not different from placebo group. / Stiripentol has no effect on SQV, but confidence limits were wide / III
Retrospective chart review in a preexisting database / 169 HIV positive patients from a single clinic in Alberta, Canada who were on AED + ARV therapy (total database was 1245 patients) / Any AED and ARV / Mean blood CD8+ T cell levels remained unchanged during the 12 follow-up months in both patient groups with all AED therapies. / Difficult to interpret, as the impact of AEDs was not stratified by enzyme induction. All AED exposures were included in a single analytic group. / IV
e7 / Prospective open-label PK study / 12 HIV positive adults on a stable ARV regimen that included ATV/RTV / VPA + ATV/RTV / Serum concentrations of VPA, ATV and RTV. / Low-dose VPA had no effect on RTV or ATV. / III

Table e-4: Summary table

AEDs that impact ARVs
Antiepileptic drug / Effect / Level of Evidence
EI-AEDs / Virologic failure for patients on PIs and NNRTIs / Level II
PHT / Decreases NVP
Decreases LVP
Decreases RTV
Decreases EFV / Level III
Level II
Level II
Level IV
CBZ / Decreases IDV
Decreases 3TC
Decreases EFV
Decreases NVP / Level IV
Level IV
Level III
Level III
VPA / Increases AZT
Increases LPV
No effect on RTV
No effect on ATV / Level II
Level II
Level III
Level III
ARVs that impact AEDs
Antiretroviral / Effect / Level of Evidence
LPV/RTV / Increases CBZ
Decreases LTG
Decreases PHT
Decreases VPA / Level IV
Level III
Level II
Level IV
RTV / Increases CBZ
Decreases PB
Decreases LTG / Level III
Level IV
Level II
NFV / Increases CBZ
Decreases PHT / Level IV
Level IV
RTV+SQV / Increases CBZ / Level IV
EFV / Decreases CBZ
Increases PHT
Decreases PHT
Decreases VPA / Level III
Level IV
Level IV
Level IV
IDV / Increases PHT / Level IV
RTV+SQV+NVP / Increases CBZ / Level IV

[1] AHFS Drug Information  (2009)

[2] RCT=randomized, controlled trial

[3] PN=peripheral neuropathy