Staci M. Lockhart

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.

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.

Validity of a Stage of Change Instrument in Assessing Medication Adherence in Indigent Patients with HIV Infection

Background: Adherence to antiretroviral therapy (ART) is vital to achieve durable suppression of viral replication. Effective mechanisms to predict adherence can be difficult to implement in clinical practice settings. Self-administered questionnaires are a practical option for assessing patient adherence but may lack validation with objective measures of adherence. Objective: To examine the ability of a 2 item stage of change (SOC) questionnaire to predict medication adherence in indigent patients receiving ART. Methods: Patients participating in an ongoing study to examine adherence interventions were administered a 2 item SOC instrument to assess readiness for adherence behavior. The SOC instrument was given to patients prior to beginning ART and readministered after they had received 16 weeks of treatment. Electronic monitoring was used to examine the validity of the SOC instrument to predict patient readiness for adherence behavior. Results: Thirty-one patients completed the SOC questionnaire prior to beginning a new ART regimen. Most (87%) patients were male, had previously received antiretroviral therapy (77%). and had an AIDS diagnosis (77%). The SOC category determined at baseline was a poor predictor of adherence at 4 and 16 weeks; however, the SOC category determined after treatment onset (week 16) was a strong predictor of adherence at both time points (p < 0.001 for 4 and 16 weeks; one way ANOVA). Conclusions: The SOC category determined at baseline correlated poorly with subsequent medication adherence in our indigent, HIV-infected patient population. Prediction of adherence based on SOC after treatment initiation may provide a better estimate of adherence behavior. Recognition of this limitation may help clinicians more accurately interpret predicted adherence behavior from self-report instruments.

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.

Implications for Hepatitis C Treatment and Disease Progression in an HIV/HCV Co- Infected Population

Implications for Hepatitis C Treatment and Disease Progression in an HIV/HCV Co-Infected Population Morbidity and mortality rates from chronic liver disease secondary to hepatitis C virus (HCV) have become a significant issue for HIV infected patients. U.S. Department of Health and Human Service guidelines recommend HCV treatment for all coinfected patients without decompensated liver disease. Telaprevir and boceprevir are direct-acting agents (DAAs) recently approved for HCV genotype-1 mono-infection and have demonstrated marked improvements in viral suppression when combined with peg-interferon/ribavirin as triple therapy. Identification of co-infected patients who could benefit from HCV treatment is a necessary component of quality HIV care.