Evaluation of the concurrent use of dolutegravir and metformin in human immunodeficiency virus-infected patients.

An analysis of the interaction between dolutegravir and metformin was conducted in the HIV ambulatory clinic setting. This was a multicenter, retrospective case series evaluating adult, HIV-infected patients concurrently prescribed dolutegravir and metformin. Historical electronic medical records were utilized to collect case-specific data. Laboratory parameters including serum creatinine (SCr), hemoglobin A1c (HgbA1c), plasma HIV RNA, CD4 cell count, and lactate were reviewed. Adverse drug reactions were assessed using patient-reported gastrointestinal intolerance and hypoglycemic symptoms. Metformin dose reduction or discontinuation was also recorded. Nineteen patients identified as concurrently taking metformin and dolutegravir were included. Eighteen patients were on metformin prior to dolutegravir initiation, with 13 having received metformin for at least six months prior to dolutegravir. At the time of dolutegravir initiation, one patient had a preemptive metformin dose reduction. Seven patients were initiated on dolutegravir with a metformin dose greater than 1000 mg daily. Eleven patients had baseline and three- to six-month follow-up HgbA1c. Of those 11 patients, eight had stable or decreased values. Thirteen of the 19 patients had an increase in SCr, with a median increase of 0.3 mg/dl (0.03-0.43). Gastrointestinal distress (N = 3) and hypoglycemic symptoms (N = 3) were reported in a total of five patients. Adverse drug reactions resulted in metformin dose reduction (N = 2) and/or discontinuation (N = 2). There were no reported cases of lactic acidosis. Providers concurrently prescribing dolutegravir and metformin should be aware of potential consequences with this combination and may consider an empiric metformin dose reduction to prevent intolerable adverse drug reactions.

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

OBJECTIVE: 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. METHODS: A survey of the authors was conducted to evaluate common issues that arise during an acute hospitalization for HIV-infected patients. After a group consensus, a review of the medical literature was performed to determine the supporting evidence for the following HIV-associated hospital queries: admission/discharge orders, antiretroviral hospital formularies, laboratory monitoring, altered hepatic/renal function, drug-drug interactions (DDIs), enteral administration, and therapeutic drug monitoring. RESULTS: With any hospital admission for an HIV-infected patient, a specific set of procedures should be followed including a thorough admission medication history and communication with the ambulatory HIV provider to avoid omissions or substitutions in the ART regimen. DDIs are common and should be reviewed at all transitions of care during the hospital admission. ART may be continued if enteral nutrition with a feeding tube is deemed necessary, but the entire regimen should be discontinued if no oral access is available for a prolonged period. Therapeutic drug monitoring is not generally recommended but, if available, should be considered in unique clinical scenarios where antiretroviral pharmacokinetics are difficult to predict. ART may need adjustment if hepatic or renal insufficiency ensues. CONCLUSIONS: Treatment of hospitalized patients with HIV is highly complex. HIV-infected patients are at high risk for medication errors during various transitions of care. Baseline knowledge of the principles of antiretroviral pharmacotherapy is necessary for clinicians managing acutely ill HIV-infected patients to avoid medication errors, identify DDIs, and correctly dose medications if organ dysfunction arises. Timely ambulatory follow-up is essential to prevent readmissions and facilitate improved transitions of care.

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.

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 dolutegravir's role in treatment.

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.

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.

Electrocardiogram abnormalities with atazanavir and lopinavir/ritonavir.

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 < or = .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.

Warfarin-antiretroviral interactions.

OBJECTIVE: To review the literature for information regarding interactions between warfarin and antiretroviral agents and evaluate the clinical significance of these interactions. DATA SOURCES: Primary literature was identified through a search of MEDLINE (1950-July 2008) and International Pharmaceutical Abstracts (1970-July 2008) using individual antiretroviral drug names and the following key search terms: warfarin, antiretroviral, protease inhibitor, nonnucleoside reverse transcriptase inhibitor, cytochrome P450, 2C9, HIV, and drug interactions. Relevant abstracts from infectious disease and HIV conferences (2005-2008), reference citations from relevant articles, and manufacturers' product information were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified through the data search were examined. Studies and reports addressing warfarin interactions with antiretrovirals, CYP2C9 polymorphism, and antiretroviral CYP2C9 effects were evaluated. A total of 12 case reports were identified that described interactions between warfarin and either protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). DATA SYNTHESIS: The drugs used in the case reports were limited to 6 antiretroviral agents (efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, saquinavir, ritonavir). The mechanism of interaction between antiretroviral agents and warfarin appears to be mediated through alteration in CYP2C9 metabolism. Concurrent use of warfarin with efavirenz or saquinavir was associated with overanticoagulation, identified by increases in international normalized ratio (INR). Use of warfarin with lopinavir/ritonavir, nelfinavir, ritonavir, and nevirapine resulted in subtherapeutic INRs. Interactions with delavirdine, etravirine, and atazanavir are anticipated; however, no published cases have reported these interactions. Interactions between warfarin and nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and CCR5 antagonists are not anticipated. CONCLUSIONS: Interactions between warfarin and antiretrovirals are likely, especially when PIs or NNRTIs are used. Induction or inhibition of warfarin metabolism may occur, depending on the specific antiretroviral agent. When warfarin is used concurrently with antiretrovirals, close monitoring of INR response is recommended in lieu of empiric warfarin dosing adjustments, given the limited information available and the quality of evidence.

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. CONCLUSIONS: 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.