Jomy M. George

Antiepileptic drug selection for people with HIV/AIDS: Evidence-based guidelines from the ILAE and AAN

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED–ARV interactions. Key findings from this literature search included the following: AED–ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme‐inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

Virologic outcomes of HAART with concurrent use of cytochrome P450 enzyme-inducing antiepileptics: a retrospective case control study

BackgroundTo evaluate the efficacy of highly-active antiretroviral therapy (HAART) in individuals taking cytochrome P450 enzyme-inducing antiepileptics (EI-EADs), we evaluated the virologic response to HAART with or without concurrent antiepileptic use.MethodsParticipants in the US Military HIV Natural History Study were included if taking HAART for ≥6 months with concurrent use of EI-AEDs phenytoin, carbamazepine, or phenobarbital for ≥28 days. Virologic outcomes were compared to HAART-treated participants taking AEDs that are not CYP450 enzyme-inducing (NEI-AED group) as well as to a matched group of individuals not taking AEDs (non-AED group). For participants with multiple HAART regimens with AED overlap, the first 3 overlaps were studied.ResultsEI-AED participants (n = 19) had greater virologic failure (62.5%) compared to NEI-AED participants (n = 85; 26.7%) for the first HAART/AED overlap period (OR 4.58 [1.47-14.25]; P = 0.009). Analysis of multiple overlap periods yielded consistent results (OR 4.29 [1.51-12.21]; P = 0.006). Virologic failure was also greater in the EI-AED versus NEI-AED group with multiple HAART/AED overlaps when adjusted for both year of and viral load at HAART initiation (OR 4.19 [1.54-11.44]; P = 0.005). Compared to the non-AED group (n = 190), EI-AED participants had greater virologic failure (62.5% vs. 42.5%; P = 0.134), however this result was only significant when adjusted for viral load at HAART initiation (OR 4.30 [1.02-18.07]; P = 0.046).ConclusionsConsistent with data from pharmacokinetic studies demonstrating that EI-AED use may result in subtherapeutic levels of HAART, EI-AED use is associated with greater risk of virologic failure compared to NEI-AEDs when co-administered with HAART. Concurrent use of EI-AEDs and HAART should be avoided when possible.

The impact of enzyme-inducing antiepileptic drugs on antiretroviral drug levels: A case-control study

PURPOSE To evaluate the impact of enzyme-inducing antiepileptic drugs (EI-AEDs) on serum antiretroviral (ARV) levels in patients with HIV. METHODS Data from the U.S. Military HIV Natural History Study were screened to identify participants taking ARVs with EI-AEDs and controls taking ARVs with non enzyme-inducing AEDs (NEI-AEDs). The proportion of serum ARV levels below the recommended minimum concentrations (C(min)) was compared between these groups. RESULTS ARV levels were available for 10 individuals exposed to 16 intervals on combined ARVs/EI-AEDs (phenytoin and carbamazepine) and for 25 controls exposed to 30 overlap intervals on combined ARVs/NEI-AEDs. The percentage of overlap intervals with ≥1 ARV levels below C(min) was higher in the EI-AED group than in controls (37.5% vs. 23.3%; p=0.124). After excluding intervals associated with serum levels of EI-AEDs below the reference range (n=6), the proportion of intervals with ≥1 ARV level below C(min) was significantly greater among EI-AED recipients (60%) compared to controls (23.3%; p=0.008). CONCLUSIONS ARV levels below C(min) were more common in participants receiving EI-AEDs, the difference being statistically significant for intervals associated with EI-AED levels within the reference range. These data suggest that, in agreement with current guidelines, EI-AEDs should be avoided in patients receiving ARV therapy.

Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers

Drug interactions between antiretroviral therapy and anticoagulant medications are of particular concern given that ≈50% of the current HIV population is >50 years of age. Moreover, HIV infection is characterized by a hypercoaguable state and premature immunologic aging, in which thromboembolic events may be as much as 10 times more prevalent than in the general population across all age spectra.1 Dabigatran was the first direct oral anticoagulant approved by the US Food & Drug Administration and is the only direct oral anticoagulant with a US Food & Drug Administration -approved specific reversal agent, idarucizumab. Unlike warfarin and many other direct oral anticoagulants, dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 metabolic enzymes. However, dabigatran is a substrate of Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 transporters. Cobicistat is a US Food & Drug Administration -approved antiretroviral-boosting agent that is coformulated with numerous fixed-dose combination antiretroviral products because of its inhibitory effects on cytochrome P450 3A4. Currently, ≈40% of all treatment-naive patients with HIV in the United States are initiated on a cobicistat-boosted antiretroviral regimen. In addition to cytochrome P450 3A4, cobicistat is also an inhibitor of both P-gp and multidrug and toxin extrusion-1 transporters.2 Thus, this study aimed to determine whether the …

Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug–Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine

Background Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. Methods This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. Results The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. Conclusions The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. Clinical Trials Registration NCT02771249.

Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran

ABSTRACT Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.)

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV-Infected Patient Following Oral and Jejunostomy-Tube Administration

The use of enteral feeding tubes to administer antiretroviral medications is necessary in certain patients with human immunodeficiency virus (HIV) infection. However, adequacy of drug exposures after these administration routes are largely unknown, making dosing recommendations and the attainment of viral suppression challenging in this patient population. This report describes a patient with advanced HIV infection and a complicated medical history including long‐term intractable nausea/vomiting necessitating antiretroviral medication administration via a Roux‐en‐Y jejunostomy (J)‐tube. Pharmacokinetic assessments were performed to compare differences in antiretroviral drug absorption and plasma exposure following oral and J‐tube administration of dolutegravir, tenofovir disoproxil fumarate, and emtricitabine. Results were also compared with published pharmacokinetic data in HIV‐infected individuals. Exposure to dolutegravir and tenofovir were similar between J‐tube and oral administration routes, whereas emtricitabine exposure was 38% lower when administered via J‐tube. However, in comparison with reference data in HIV‐infected individuals taking these medications orally, exposure to dolutegravir and tenofovir was 75–76% and 55–61% lower, respectively, following both routes of administration. Emtricitabine exposure was similar to and 71% higher than reference data following J‐tube and oral administration, respectively. This report highlights the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral treatment success.

Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products

ABSTRACT Introduction: Use of complementary and alternative medicines (CAMs) and over-the-counter (OTC) medications are very common among HIV-infected patients. These products can cause clinically significant drug-drug interactions (DDIs) with antiretroviral (ARV) medications, thereby increasing risk for negative outcomes such as toxicity or loss of virologic control. Areas covered: This article provides an updated review of the different mechanisms by which CAM and OTC products are implicated in DDIs with ARV medications. Expert commentary: Much of the literature published to date involves studies of CAMs interacting with older ARV agents via the cytochrome P450 (CYP450) system. However, the HIV treatment and prevention arsenal is continually evolving. Furthermore, our elucidation of the role of non-CYP450 mediated DDIs with ARV medications is greatly increasing. Therefore, clinicians are well served to understand the various mechanisms and extent by which new ARV therapies may be involved in drug interactions with CAMs and OTC medications.

Infectious Diseases Physicians' Approach to Antiretroviral Therapy in HIV/AIDS Patients Admitted to an Intensive Care Unit An Emerging Infections Network Survey

PurposeLittle is known regarding administration of antiretroviral therapy (ART) regimens in the setting of critical illness. We developed a survey to better understand how infectious disease experts use ART in critically ill HIV/AIDS patients admitted to an intensive care unit (ICU). MethodsWeb-based surveys were distributed in October 2010 to the 1080 adult infectious disease physician members of the Emerging Infections Network. Responses were stratified by region, practice type, years of HIV experience, and by a cumulative HIV medicine score developed to measure expertise in managing HIV. ResultsA total of 501 members (46%) responded. In both ART-naive and -experienced patients, respondents were more likely to initiate or continue ART during treatment of an opportunistic infection (OI) (69% and 87%, respectively) than for low CD4 count/high viral load (25% and 79%, respectively). The OI for which respondents would most likely start ART was Pneumocystis jiroveci pneumonia. Reported barriers for use of ART in the ICU included immune reconstitution syndrome (71%), drug interactions (72%), and variable drug absorption (65%). ConclusionsThere is a lack of consensus of how to manage ART in the critically ill HIV patient. Infectious disease specialists were most likely to initiate or continue ART in the setting of an OI. Among OIs, respondents would most likely initiate ART for P. jiroveci pneumonia. Immune reconstitution syndrome, drug interactions, and outpatient follow-up were the most common reported barriers to use of ART in the ICU. Further studies are needed to provide better guidance on ART use in critically ill patients.

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

Intravenous (IV) busulfan test dose pharmacokinetics (PK) has been shown to accurately predict once‐daily dose requirements and improve outcomes in adult transplant patients, but there are limited data to support this approach in children. Test doses of busulfan ∼0.8 mg/kg were infused over 2 to 3 hours, followed by serial sampling to 4‐6 hours postinfusion in pediatric hematopoietic stem cell transplant recipients (n = 5). Once‐daily busulfan doses were calculated based on a myelosuppressive area under the concentration‐time curve (AUC) target of ∼3700 to 4000 μmol·min/L and assumed dose‐proportionality to the test dose. PK analysis was then repeated at full daily doses within 6‐8 days of test dose administration. Plasma PK samples collected under test and full‐dose conditions were analyzed using validated commercial assays and noncompartmental methods. In 4 out of 5 patients, PK estimates after once‐daily IV busulfan administration differed in comparison to test dose estimates (AUC range –38.2% to +49.7%, clearance range –34.3% to +61.8%). Patients 1, 2, and 3 required increases in remaining daily busulfan doses to achieve AUC targets, and no adjustment was required in patient 4. Patient 5s AUC was 49.7% higher than expected, and he subsequently developed fatal sinusoidal obstruction syndrome. In our experience with pediatric patients, test dose PK failed to reliably predict daily dosing requirements with large discrepancies from predicted AUC targets. This article highlights the necessity for therapeutic drug monitoring of IV busulfan and inadvisability of relying solely on test‐dose busulfan PK in pediatric patients. Furthermore, clinicians should consider strategies to expedite dose adjustments in real time.