R Chris Rathbun

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.

Low-Dose Ritonavir for Protease Inhibitor Pharmacokinetic Enhancement

OBJECTIVE: To examine the use of low-dose ritonavir as a pharmacokinetic enhancer for HIV protease inhibitors. DATA SOURCES: Primary articles, review articles, and conference abstracts identified by MEDLINE search (1995–May 2001) and secondary sources. DATA SYNTHESIS: Low-dose ritonavir (100–200 mg) is increasingly being combined with HIV protease inhibitors to improve their effectiveness and allow less frequent dosing. An evaluation of the clinical evidence supporting this practice was conducted. CONCLUSIONS: Limited outcome data exist for low-dose ritonavir-based regimens in general. Although preliminary data appear promising, more clinical evidence is needed to determine the optimal dosing, long-term safety, and relative effectiveness of this approach. The role of these regimens in early therapy remains to be defined.

Management Protocol for Abacavir-Related Hypersensitivity Reaction

OBJECTIVE: To develop an abacavir hypersensitivity reaction management protocol for the University of Oklahoma Health Sciences Center. DATA SYNTHESIS: Conference abstracts, published literature, and manufacturer-provided materials were reviewed to define the syndrome and manifestations and to recommend steps to take when a patient develops abacavir-related reactions. RESULTS: Initial education, formalized contact and response mechanism, and intervention levels were incorporated into a protocol for clinicians. CONCLUSIONS: Abacavir, a newly approved agent for the treatment of HIV, has been associated with a fatal hypersensitivity reaction. Our protocol provides a mechanism to minimize progression of abacavir hypersensitivity reaction by providing a formalized management procedure

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.

Symptomatic Orthostasis with Extended‐Release Nifedipine and Protease Inhibitors

Human immunodeficiency virus (HIV) protease inhibitors are prone to drug interactions with other agents. As individuals with HIV infection live longer, the clinical significance of many interactions is becoming recognized. A 51‐year‐old man with HIV infection who was receiving extended‐release nifedipine developed symptomatic orthostasis and heart block after starting antiretroviral therapy that included nelfinavir. He experienced dizziness, fatigue, and hypotension and developed complete heart block with a junctional escape rhythm. Electrocardiogram abnormalities abated within 24 hours of discontinuing antiretroviral therapy. The patient developed orthostatic symptoms after restarting nelfinavir. He was switched successfully to an efavirenz‐based regimen. Subsequent administration of antiretroviral therapy containing ritonavir and indinavir with extended‐release nifedipine resulted in recurrence of his orthostatic symptoms. Discontinuation of atenolol, and nifedipine dosage reduction by 50% were effective in managing his orthostatic changes. Careful monitoring by clinicians is necessary when concomitant administration of HIV protease inhibitors are prescribed with other agents that are metabolized through the cytochrome P450 system.

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.

Cutaneous reactions with tenofovir disoproxil fumarate : a report of nine cases

Adverse drug reactions causing the early discontinuation of therapy are common in patients with HIV infection. Hypersensitivity consisting mainly of a maculopapular rash on the face, extremities and trunk has been observed at a rate higher than expected in patients treated with tenofovir at our clinics. We therefore examined nine patients with suspected tenofovir hypersensitivity reactions in two indigent care HIV clinics. Type I and type IV hypersensitivity may be involved as immunological mechanisms.

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.