The Medication Possession Ratio as a Predictor of Longitudinal HIV-1 Viral Suppression.

BACKGROUND: Antiretroviral adherence is essential to achieve viral suppression and limit HIV-related morbidity and mortality; however, antiretroviral adherence thresholds to achieve viral suppression in clinical practice have not been fully characterized using administrative claims data. OBJECTIVE: The purpose of this study was to assess the relationship between medication adherence and viral suppression among adult persons with HIV/AIDS (PWH) receiving antiretroviral therapy (ART) for ≥6 months. METHODS: This historical cohort, real-world investigation assessed maintenance of viral load suppression and viral load area-under-the-curve (vAUC) in PWH ≥18 years of age based on ART adherence. A marginal effects model was used to determine the predicted probabilities of final plasma HIV-1 RNA <50 copies/mL or vAUC <1,000 copy-days/mL according to the medication possession ratio (MPR), estimated using a Jackknife model variance estimator and a delta-method for marginal effects standard error. Tests for statistical significance used a Sidák method to correct for multiple comparisons. RESULTS: The mean MPR for ART was 86.7% (95% CI: 85.0%-88.4%) for the 372 PWH included in the study. The marginal effects analysis indicated that an MPR ≥82% was associated with a predicted probability of viral suppression <50 copies/mL (P < 0.05). Significant predicted probabilities for vAUC <1,000 copy-days/mL were observed with an MPR ≥90% (P < 0.05). CONCLUSION AND RELEVANCE: Medication possession ratio as a proxy for drug exposure was significantly and consistently associated with viral suppression using a longitudinal measure of HIV viremia. These findings can aid clinicians in the clinical management of PWH and inform future studies of adherence-viral suppression relationships with contemporary antiretroviral regimens.

Evaluation of human immunodeficiency virus curricular content in schools of pharmacy in the United States.

INTRODUCTION: Human immunodeficiency virus (HIV) is an important educational topic for student pharmacists given extended patient life expectancy and expanding pharmacist roles in HIV treatment and prevention. Data are lacking in regard to curricular content and type of training received by faculty to provide didactic and experiential HIV training. METHODS: A cross-sectional, population-based survey of United States (US) pharmacy schools was conducted using a 15-item questionnaire. HIV content experts were surveyed at 135 four-year, accredited programs. RESULTS: Thirty-seven responses were received from schools in the Midwestern (34%), Northeastern (26%), Southern (26%), and Western (14%) regions. Time devoted to didactic HIV education ranged from 0.5 to 60 hours. The majority of respondents (78%, n = 29) reported 10 or fewer hours of HIV-related content, with 41% (n = 15) reporting five or less hours of content. Experiential practice sites for HIV training were variable, with a majority (80%) including an outpatient infectious diseases/HIV clinic. Eighty percent of respondents also reported students receiving fewer than 25 encounters with people living with HIV (PLWH) throughout their entire experiential training. Over half (54%) of respondents reported that the primary HIV instructor devoted four hours per week or less to HIV care. CONCLUSIONS: Diversity in the amount of time devoted to HIV didactic education existed among reporting US pharmacy schools. Few schools have dedicated faculty spending a substantial amount of time in direct care of PLWH. Minimum standards for HIV education in schools of pharmacy should be established.

National estimates of case-mix, mortality, and economic outcomes among inpatient HIV/AIDS mono-infection and hepatitis C co-infection cases in the US.

RATIONALE, AIMS, AND OBJECTIVES: To assess inpatient clinical and economic outcomes for AIDS/HIV and Hepatitis C (HCV) co-infection in the United States from 2003 to 2014. METHOD: This historical cohort study utilized nationally representative hospital discharge data to investigate inpatient mortality, length of stay (LoS), and inflation-adjusted charges among adults (≥18 years). Outcomes were analysed via multivariable generalized linear models according to demographics, hospital and clinical characteristics, and AIDS/HIV or HCV sequelae. RESULTS: Overall, 17.8% of the 2.75 million estimated AIDS/HIV inpatient cases involved HCV from 2003 to 2014, averaging 48.5 ± 9.0 years of age and 68.0% being male. Advanced sequalae of AIDS and HCV incurred a LoS of 10.3 ± 11.9 days, charges of $88 789 ± 131 787, and a 16.9% mortality. Many cases involved noncompliance, tobacco use disorders, and substance abuse. Although mortality decreased over time, multivariable analyses indicated that poorer outcomes were generally associated with more advanced clinical conditions and AIDS-associated sequalae, although mixed results were observed for specific manifestations of HCV. Rural residence was independently associated with a 3.26 times higher adjusted odds of mortality from 2009 to 2014 for HIV/HCV co-infection (P < 0.001), although not for AIDS/HCV (OR = 1.38, P = 0.166). CONCLUSION: Given the systemic nature and modifiable risks inherent within coinfection, more proactive screening and intervention appear warranted, particularly within rural areas.

Sustained Virologic Response and Costs Associated with Direct-Acting Antivirals for Chronic Hepatitis C Infection in Oklahoma Medicaid.

BACKGROUND: Outcomes involving newer direct-acting antiviral (DAA) hepatitis C virus (HCV) regimens have not been studied extensively among the Medicaid population. OBJECTIVE: To assess clinical (treatment failure) and economic outcomes for chronic HCV-infected Oklahoma Medicaid members following treatment with DAAs and to measure associations with patient, treatment, and clinical characteristics. METHODS: This cross-sectional study used Oklahoma Medicaid pharmacy and medical claims data for adult members who used a newer DAA agent and had reported a successful or failed sustained virological response rate 12 weeks after therapy completion (SVR12) from January 1, 2014, to June 30, 2016. Multivariable logistic and gamma regressions assessed predictors of SVR12 failure and costs controlling for member demographics (i.e., age, sex, race, rural residence); type of DAA and adherence; clinical characteristics (e.g., comorbid conditions, advanced liver disease); and the implementation of changes to a prior authorization program. RESULTS: Of 934 Medicaid members eligible for treatment with DAAs between January 1, 2014, and June 30, 2016, 906 received DAA treatment, 40.6% (368/906) had reported SVR12 outcomes, and 59.4% (n = 538) did not have a reported SVR recorded. Of those with reported SVR12 outcomes, patients were 53.1 ± 9.7 years of age, 51.1% were male, 8.4% had SVR12 failure, and each member had mean costs of $140,283 ± $52,779. Multivariable analyses indicated higher odds of SVR12 failure was independently associated with cirrhosis (OR [decompensated] = 6.69 and OR [compensated] = 3.52, P < 0.001), while males had higher odds of failure than females (OR = 3.34, P < 0.010). No significant difference in SVR12 failure was noted, according to DAA type or a medication adherence threshold of > 95%. Ledipasvir/sofosbuvir was independently associated with lower costs (exp[b] = 0.81; P < 0.001) compared with sofosbuvir, while higher costs were associated with decompensated cirrhosis (exp[b] = 1.22; P < 0.001) and treatment failure (exp[b] = 1.18, P < 0.010). In an analysis including members without reported SVR12 outcomes, decompensated and compensated cirrhosis had lower odds (P < 0.001) of no reported SVR12 from ambulatory clinic settings. CONCLUSIONS: Almost 60% of Medicaid members receiving DAA treatment did not have a final reported SVR12 outcome. Among those with viral load measurements, treatment success was high and both decompensated and compensated cirrhosis were independently associated with significantly higher odds of treatment failure. Addressing a loss to follow-up among HCV patients and curtailing the development of cirrhosis to improve treatment success may warrant interventions that improve access to care and remove barriers that impede treatment initiation and completion. DISCLOSURES: No outside funding supported this study. Pham, Keast, Holderread, Nesser, and Skrepnek disclose either employment by the Oklahoma Health Care Authority or contractual work for this employer. Pham discloses fellowship funding from Purdue Pharma unrelated to this study. Keast and Skrepnek disclose research grant funding from Gilead Sciences and Abbvie. Holderread also reports grant funding from Gilead Sciences and fees from PRIME Education. Thompson, Farmer, and Rathbun have nothing to disclose.

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.

Propofol-associated QTc prolongation.

OBJECTIVES: Propofol is a preferred agent for sedation in patients in the intensive care unit (ICU) due, in part, to its established safety profile. Despite this, recent case reports have suggested a potential for prolongation of the corrected QT interval (QTc) in ICU patients receiving propofol, though limited empirical work has been conducted to evaluate this association. As such, the purpose of this study was to assess the relationship between propofol infusion and QTc prolongation in a historical cohort of ICU patients. METHODS: A single-center, historical, observational, pre-post cohort analysis of medical records from admitted patients ⩾18 years old with cardiovascular disease was conducted, involving cases who received propofol infusion for ⩾3 hours with sequential electrocardiogram monitoring from 2006 to 2012. A multivariable, generalized linear model regression was employed to assess the primary outcome of on-propofol QTc interval (QTc2), controlling for various demographic and clinical factors. RESULTS: A total of 96 patients met inclusion criteria, averaging 56.1 ± 14.1 years of age and 86.1 ± 25.0 kg, with 37.5% being female. A mean prolongation in QTc interval of 30.4 ± 55.5 ms (p < 0.001) was observed during the propofol infusion, with 43.8% of cases exhibiting an on-infusion QTc2 of ⩾ 500 ms. Regression analyses suggested that prolongation in on-propofol QTc was independently associated with baseline QTc interval and amiodarone use, while weight as inversely associated with QTc2 (p < 0.05). CONCLUSION: This historical cohort analysis of adult ICU patients receiving propofol suggests that on-infusion QTc prolongation was associated with increasing baseline QTc interval and with amiodarone use. Further research is needed to evaluate the clinical significance and cause-and-effect relationship between potential QTc changes and propofol use in the ICU.

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.

Collaborative practice model between cardiologists and clinical pharmacists for management of patients with cardiovascular disease in an outpatient clinic.

The increasing prevalence of cardiovascular disease (CVD) has prompted leading cardiovascular organizations to advocate utilization of a team approach to patient care that includes nonphysician providers. In spite of that, the American College of Cardiology reported that nonphysician providers are underutilized in the management of patients with CVD. A survey of cardiologists revealed that the underutilization is a result of lack of understanding of how best to involve nonphysician providers in the health care team. Clinical pharmacists are one category of nonphysician providers that have recognized effectiveness in managing patients with CVD. No example of a comprehensive model of collaboration between cardiologists and clinical pharmacists is described in the literature that could serve to close this gap in understanding. The objective of this report is to describe a model of cardiologist-clinical pharmacist collaboration in the longitudinal management of patients with CVD that has been successfully implemented in 2 diverse settings. The implementation, evolution, scope of practice, required pharmacist training, logistical elements needed for success, and implementation barriers are reviewed. A summary of the patients referred to the clinic are examined as well.

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.

Importance of direct patient care in advanced pharmacy practice experiences.

The Accreditation Council for Pharmacy Education issued revised standards (Standards 2007) for professional programs leading to the Doctor of Pharmacy degree in July 2007. The new standards require colleges and schools of pharmacy to provide pharmacy practice experiences that include direct interaction with diverse patient populations. These experiences are to take place in multiple practice environments (e.g., community, ambulatory care, acute care medicine, specialized practice areas) and must include face-to-face interactions between students and patients, and students and health care providers. In 2009, the American College of Clinical Pharmacy (ACCP) identified concerns among their members that training for some students during the fourth year of pharmacy curriculums are essentially observational experiences rather than encounters where students actively participate in direct patient care activities. These ACCP members also stated that there is a need to identify effective mechanisms for preceptors to balance patient care responsibilities with students' educational needs in order to fully prepare graduates for contemporary, patient-centered practice. The 2010 ACCP Educational Affairs Committee was charged to provide recommendations to more effectively foster the integration of pharmacy students into direct patient care activities during advanced pharmacy practice experiences (APPEs). In this commentary, the benefits to key stakeholders (pharmacy students, APPE preceptors, clerkship sites, health care institutions, academic pharmacy programs) of this approach are reviewed. Recommendations for implementation of direct patient care experiences are also provided, together with discussion of the practical issues associated with delivery of effective APPE. Examples of ambulatory care and acute care APPE models that successfully integrate pharmacy students into the delivery of direct patient care are described. Enabling students to engage in high-quality patient care experiences and to assume responsibility for drug therapy outcomes is achievable in a variety of practice settings. In our opinion, such an approach is mandatory if contemporary pharmacy education is to be successful in producing a skilled workforce capable of affecting drug therapy outcomes.

Impact of a clinical pharmacist on a cardiovascular surrogate endpoint: a pilot study.

UNLABELLED: Utilizing a multidisciplinary approach to management of patients with certain chronic cardiovascular diseases (CVD) has been shown to improve treatment outcomes. The role of clinical pharmacists in comprehensive outpatient CVD management has not been evaluated. OBJECTIVE: The objective of this pilot study was to evaluate the impact of a clinical pharmacist added to cardiologist care on blood pressure (BP), a key surrogate marker of CVD, in outpatients with CVD compared to cardiologist care alone. METHODS: A retrospective, matched-control study was conducted in patients established in a cardiovascular clinic. The intervention was referral to a pharmacist clinic; control was usual care from the cardiologist. The surrogate marker evaluated was the change in BP. RESULTS: Patients in the pharmacist-intervention (n=57) experienced significant reductions in diastolic BP (-2.6 mmHg, p=0.05) and non-significant reductions in systolic BP (-4.3 mmHg, p=0.16) compared to baseline, whereas patients in the control group experienced non-significant increases in both systolic and diastolic BP (+1.6/+0.7 mmHg, p=NS). Similarly, there were significant reductions in diastolic BP and non-significant reductions in systolic BP for the intervention group when compared to controls (difference 3.3 mmHg, p=0.04 and 5.9 mmHg, p=0.1, respectively). Lastly, the proportion of patients categorized as having Stage 2 BP was significantly reduced in the intervention group (p=0.02), but not in the controls (p=0.5). CONCLUSIONS: The multidisciplinary model of care that included a clinical pharmacist reduced BP more than usual care by a cardiologist alone. This benefit was demonstrated in complex patients with CVD who were already receiving specialized care. The impact of this model on clinical outcomes requires further evaluation and should be a high priority given the burden of CVD in the population.

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.

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.

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.

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.