Michelle D. Liedtke

Anticonvulsant and Antiretroviral Interactions

OBJECTIVE To evaluate the clinical significance of interactions between anticonvulsant and antiretroviral agents and provide recommendations regarding their concurrent use. DATA SOURCES A PubMed search (1966 to April 2003) was conducted using individual anticonvulsant and antiretroviral drug names and the following key search terms: anticonvulsant, antiepileptic, antiretroviral, protease inhibitor, and pharmacokinetic. Abstracts from scientific meetings that pertained to drug interactions were manually reviewed. STUDY SELECTION AND DATA EXTRACTION All articles identified by the PubMed search were examined. Articles and abstracts from scientific meetings with relevant information were included. DATA SYNTHESIS Six case reports were identified that describe interactions between anticonvulsant agents and protease inhibitors. In several reports, carbamazepine serum concentrations increased by approximately two- to threefold with concurrent ritonavir, resulting in carbamazepine-related toxicity. Carbamazepine was also associated with loss of viral suppression when combined with indinavir. Phenytoin serum concentrations were decreased with nelfinavir in a patient who developed recurrent seizures. The effect of ritonavir on phenytoin was variable; a 30% reduction in phenytoin serum concentration occurred in one patient, while no apparent change was observed in another. Interactions with nonnucleoside reverse-transcriptase inhibitors are poorly characterized because existing data involve concurrent protease inhibitor therapy. The utility of newer anticonvulsant agents is explored. Experience with newer anticonvulsant agents in 2 patients at our site is also described. CONCLUSION Limited data exist regarding interactions between anticonvulsant and antiretroviral agents. Valproic acid and newer anticonvulsant agents may provide useful alternatives to first-generation agents. Clinicians need to be diligent when monitoring for anticonvulsant–antiretroviral interactions because of the potential for toxicity, loss of seizure control, and incomplete viral suppression.

Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

Drug interactions with antiretrovirals and warfarin

Importance of the field: Antiretroviral therapy exhibits significant potential to alter the metabolism of other medications. Warfarin is widely used for the management of clotting disorders and is prone to drug–drug interactions that can result in subtherapeutic anticoagulation or over-anticoagulation. Areas covered in this review: The mechanism and clinical significance of drug–drug interactions between warfarin and individual antiretrovirals are discussed. Literature searches were conducted in August of 2009 using multiple databases including Medline (1950 – 2009), EMBASE (1980 – 2009), International Pharmaceutical Abstracts (1970 – 2009) and the Cochrane Database of Systematic Reviews. The following search terms were utilized: warfarin, HIV, antiretroviral, drug interaction, protease inhibitor (PI), non-nucleoside reverse-transcriptase inhibitor (NNRTI), cytochrome P450 (CYP450), CYP2C9 and individual antiretrovirals by name. The manufacturers of PIs and NNRTIs were also contacted regarding unpublished data. What the reader will gain: Clinicians will gain an understanding of the antiretrovirals that are prone to alter warfarin metabolism and the implications for warfarin dose modification. Take home message: Metabolic interaction between warfarin and antiretrovirals is likely, particularly if NNRTIs or PIs are included in the antiretroviral regimen. Titration of warfarin dose should be conducted on the basis of close monitoring of the international normalized ratio. Empiric warfarin dose modifications should be considered for individual antiretrovirals.

Dolutegravir, a Second-Generation Integrase Inhibitor for the Treatment of HIV-1 Infection

Objective: To review the pharmacology, safety, and efficacy of dolutegravir, an integrase strand-transfer inhibitor (INSTI), and to discuss its role in the treatment of HIV-1-infected patients. Data Sources: PubMed articles indexed through August 2013 were identified using the search terms S/GSK1349572, dolutegravir, and integrase inhibitor. Information was also identified from the package insert, cited publication references, professional meeting abstracts, and the ClinicalTrials.gov registry. Study Selection and Data Extraction: English language articleswere selected for evaluation, with preference given to safety, efficacy, and pharmacokinetic studies conducted in HIV-1-infected patients. Data Synthesis: Dolutegravir is a new INSTI approved for combination treatment in HIV-1-infected adults and adolescent children. Four phase 3 studies provide the basis for current labeling in antiretroviral-naïve and antiretroviral-experienced adults. Results from these studies demonstrate that dolutegravir is noninferior in efficacy to raltegravir in antiretroviral-naïve patients and superior in antiretroviral-experienced patients. Superiority to efavirenz and darunavir/ritonavir was also demonstrated in antiretroviral-naïve patients. Dolutegravir is well tolerated, exhibits low potential for drug-drug interactions, and has a long serum half-life, allowing it to be administered once-daily in patients without preexisting INSTI resistance. Twice-daily administration is recommended in patients with known or suspected resistance mutations to first-generation INSTIs. Mild elevations in serum creatinine occur following dolutegravir initiation from inhibition of renal organic cation transporter 2 but do not reflect changes in glomerular filtration. Conclusions: Dolutegravir is the first second-generation INSTI and exhibits several advantages over current integrase inhibitors and other preferred antiretrovirals. Long-term efficacy and safety are needed to define dolutegravirs role in treatment.

The role of dolutegravir in the management of HIV infection.

Dolutegravir is the most recent integrase strand transfer inhibitor approved for HIV-1 infection in both treatment-naïve and experienced patients. As a tricyclic carbamoyl pyridone analog, dolutegravir is rapidly absorbed and distributes through the cerebrospinal fluid. It is hepatically metabolized by uridine diphosphate glucuronosyl transferase 1A1; no inhibition or induction of cytochrome P450 enzymes is noted. As a substrate of CYP 3A4, dolutegravir is affected by rifampin, efavirenz, tipranavir/ritonavir, fosamprenavir/ritonavir, and dose increase is required. Dolutegravir inhibits the organic cation transporter 2, resulting in decreased creatinine clearance with no apparent decrease in renal function. Other adverse effects are minimal but include diarrhea, headache, and nausea. Clinical trials in treatment-naïve and experienced patients are ongoing and will be presented in this text.

Long-term efficacy and safety of raltegravir in the management of HIV infection

Raltegravir is an integrase strand-transfer inhibitor approved for the treatment of HIV infection. It was the first medication in a novel class of antiretroviral agents to be approved for use in the United States in 2007. Raltegravir exhibits potent activity against wild-type HIV-1, but resistance development has been noted through three different pathways. It is metabolized primarily through uridine diphosphate glucuronosyltransferase 1A1 and has a single inactive glucuronide metabolite. Raltegravir is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes and exhibits low potential for drug–drug interactions; however, strong uridine diphosphate glucuronosyltransferase 1A1 inhibitors or inducers can alter the pharmacokinetics of raltegravir. It is well tolerated, and the most commonly reported adverse effects include headache, nausea, and diarrhea. Serious adverse effects with raltegravir are rare but include rhabdomyolysis and severe skin and hypersensitivity reactions. It has been approved for use in both treatment-naïve and treatment-experienced patients and is a preferred first-line agent in both United States and European HIV treatment guidelines. Although initial approval was granted on 48-week data, 5-year clinical data have recently been published. This article reviews the data supporting long-term efficacy and safety of raltegravir in the treatment of HIV infection.

Incidence of Transmitted Antiretroviral Drug Resistance in Treatment-Naive HIV-1-Infected Persons in a Large South Central United States Clinic

Background: Transmitted drug resistance (TDR) can limit effective treatment options to antiretroviral-naive HIV-infected persons and increase the risk of treatment failure. Limited estimates of TDR have been reported from the South Central United States. Objective: To describe the incidence of TDR in Oklahoma and to examine whether TDR rates have increased with time. Methods: This was a retrospective observational study of antiretroviral-naive patients at the Infectious Diseases Institute, a large infectious diseases clinic in Oklahoma City, Oklahoma, who had received baseline antiretroviral resistance testing. Mutations were screened using the 2011 International Antiviral Society-USA Drug Resistance Mutation (DRM) update, and categorized using the 2009 World Health Organization (WHO) Surveillance Drug Resistance Mutation (SDRM) list. Results: Genotypic sequences from 428 patients revealed a 6.0% to 13.6% incidence of SDRMs between 2007 and 2011, though no progression in the frequency was apparent during the study period. Primary DRMs were detected in 12.6% of the sampled patients, most commonly involving nonnucleoside reverse transcriptase inhibitors (NNRTIs; 8.2%), followed by protease inhibitors (PIs; 3.5%) and nucleoside reverse transcriptase inhibitors (NRTIs; 3.3%). The K103N/S and E138A reverse transcriptase mutations were the most common DRMs identified, both present in 3.5% of patients. The L90M mutation was the most frequently observed PI SDRM (1.6%), while the T215C/D/I mutation was the most common NRTI SDRM identified (1.9%). This study was limited by the fact that the WHO SDRM list was last updated in 2009. Conclusions: The frequency of DRMs in central and western Oklahoma is similar to recently reported rates in the United States which lack data from this region. However, the frequency of second-generation NNRTI DRMs (4.4%) suggests the need to closely monitor epidemiologic trends for increasing resistance rates to individual classes of ARVs in order to predict the impact of TDR on therapeutic options.

Electrocardiogram abnormalities with atazanavir and lopinavir/ritonavir.

Abstract Purpose: Concurrent atazanavir (ATV) and lopinavir/ritonavir (LPV/r) may be useful for patients with extensive antiretroviral resistance; however, limited information exists concerning the pharmacokinetics and safety of this combination. Method: A parallel-arm pharmacokinetic study was conducted in HIV-infected patients (n = 10) using contemporary formulations of each agent. Intensive pharmacokinetics were conducted at Day 6 (ATV/r), Day 16 (ATV qd + LPV/r bid), and Day 20 (ATV + LPV/r qd) in Arm A and Day 6 (LPV/r) and Day 12 (LPV/r bid + ATV qd) in Arm B. Plasma ATV, LPV, and ritonavir concentrations were measured by HPLC-UV. Electrocardiograms (12-lead) and safety labs were conducted at each visit. Results: Prolonged PR and QRS intervals occurred in the majority of patients (mean increase: 16 ms and 5 ms, respectively; p ≤ .01). Two patients developed new-onset arrhythmias (bundle branch block, atrioventricular block), resulting in premature termination of the study. No change in ATV or LPV pharmacokinetics was evident. Conclusion: Concurrent ATV and LPV/r was associated with PR and QRS interval changes in this small study population. Electrocardiogram monitoring should be considered for patients receiving concurrent ATV and LPV/r shortly after their initiation, especially if other risk factors for altered conduction are present.

A Probable Interaction between Warfarin and the Antiretroviral TRIO Study Regimen

OBJECTIVE: To report a probable drug interaction between the antiretroviral TRIO regimen (ritonavir-boosted darunavir, etravirine, and raltegravir) and warfarin in an HIV-infected patient. CASE SUMMARY: In January 2010, a 50-year-old transgender female with HIV infection and recurrent deep vein thrombosis began treatment with the TRIO study regimen. Treatment had been maintained with warfarin for the past 5 years and emtricitabine monotherapy for the preceding 22 months. Emtricitabine was discontinued when the TRIO regimen was started. The mean weekly warfarin dose while the patient was receiving emtricitabine monotherapy was 13.3 mg (95% CI 12.7 to 13.8), with a mean international normalized ratio (INR) of 2.8 (95% CI 2.5 to 3.1). Following the initiation of the TRIO regimen, the mean weekly warfarin dose was increased to 19.3 mg (95% CI 18.5 to 20.1) and was maintained over the ensuing 71 weeks with a mean INR of 2.6 (95% CI 2.2 to 3.0). DISCUSSION: Information on the effect of newer antiretrovirals on warfarin metabolism, as well as the collective contribution of combination antiretroviral therapy including multiple agents that may alter warfarin metabolism, is limited. We predicted that warfarin dose requirements would change upon initiation of the TRIO regimen. Given the variability in INR that can occur with chronic warfarin treatment, weekly warfarin doses were averaged during emtricitabine monotherapy (90 weeks) and TRIO regimen (71 weeks) periods. Mean weekly warfarin doses increased by 45% (p < 0.001) following initiation of the TRIO regimen. Mean INR results for the 2 time periods were not significantly different, demonstrating that stable anticoagulation was maintained. The Horn drug interaction probability scale score to assess causation indicated a probable interaction. CONCLUSIONS: An increased weekly warfarin dose requirement is predicted when warfarin is used concurrently with the antiretroviral TRIO regimen. Increased INR monitoring is prudent when the combination is administered.

Acute Care Management of the HIV-Infected Patient: A Report from the HIV Practice and Research Network of the American College of Clinical Pharmacy

Patients infected with human immunodeficiency virus (HIV) admitted to the hospital have complex antiretroviral therapy (ART) regimens with an increased medication error rate upon admission. This report provides a resource for clinicians managing HIV‐infected patients and ART in the inpatient setting.