Search

Background Limited data is available on raltegravir (RAL) pharmacokinetics during pregnancy and the value of therapeutic drug monitoring (TDM) in pregnancy is unknown. This study aims to describe RAL trough plasma concentrations (Ctrough) during pregnancy and review the impact of RAL TDM on outcomes. Methods Women from the prospective mother-infant HIV cohort of Mother and Children’s Infectious Diseases Center who received RAL during their pregnancy between 2011-2020 were included. TDM reports were reviewed and Ctrough values estimated when possible, using historical RAL half-lives. Results We included 76 pregnant women of which 47 underwent TDM. We observed a significant association between virological response and Ctrough ( p-value .034) with an increase of 0.1 mg/L corresponding to a 2.96 reduction in the risk of having a detectable viral load. The results indicated that in pregnant women a RAL Ctrough threshold of 0.04 mg/L has a higher specificity (75%) as compared to our current Ctrough target value of 0.02 mg/L (25%) and an acceptable sensitivity (77%). No significant differences were observed between Ctrough at each trimester. When comparing pregnancies with and without TDM, no statistically significant differences were observed in the virologic response during pregnancy and at delivery, or with the need for triple antiretroviral prophylaxis in newborns. Conclusions An association between RAL Ctrough and viral load was observed and achieving a RAL Ctrough of 0.04 mg/L or greater is a predictor of virologic response in pregnant women. The impact of TDM in pregnancy, however, could not be demonstrated.

Despite availability of effective antiretroviral therapy (ART), many HIV patients still have a detectable viral load (VL). Predictive factors of detectable VL are not well documented. This study was done at two large multidisciplinary HIV outpatient clinics at the Centre hospitalier de l'Université de Montréal (CHUM) and the McGill University Health Centre (MUHC). This is a retrospective case-control study of patients treated between 2016 and 2018. Cases had a VL ≥50 copies/mL in 2018. Controls had an undetectable VL from 2016 to 2018. Matching was based on gender and year of HIV diagnosis. Primary objective was to identify predictive factors of detectable VL. Secondary objectives included to identify predictive factors of virologic failure, low persistent viremia, and viral blip. A forward stepwise model selection by the Akaike Information Criterion of the conditional logistic regression was used to identify predictive factors. Two hundred cases were identified and matched with 200 controls. The cohort was mostly male (68.0%) with a median age of 54 years (21-83 years). Among cases, viral blip was the most common type of detectable VL (43.0%). The strong predictive factors for a detectable VL were adherence to ART and seeking health care services. Asylum seekers were less at risk of detectable VL. Adherence to ART was the only strong predictive factor for virologic failure. Three main predictive factors of detectable VL were identified in two ambulatory clinic hospitals in Montreal. Ascertaining these factors will allow for identification of patients more at risk of detectable VL.

Appearance- and performance-enhancing supplements (APES) may be associated with liver and renal toxicity, but use is often under-reported. This study describes the use and safety of APES among gay, bisexual, and other men-who-have-sex with men (gbMSM) attending an urban HIV pre-exposure prophylaxis (PrEP) clinic. A cross-sectional study was conducted between February 2018 to September 2018 to assess APES usage in gbMSM taking daily tenofovir disoproxil fumarate/emtricitabine for PrEP. Renal and liver function were assessed from electronic medical records. Among 50 participants (98% male, median 32 years, 52% White, on PrEP for a median 4.4 years), 72% reported lifetime APES use, with 52% currently using APES (median 1.5 products/person) and 28% never used APES. The most common products included whey protein, creatine supplements and anabolic steroids. The primary reason for APES use was to increase muscle mass. Three (12%) current APES users had elevated serum creatinine (stage 1) versus zero (0%) in the non-APES group. Two (8%) current APES users experienced grade 3-4 ALT/AST elevations versus zero (0%) in the non-APES group. APES usage among gbMSM taking PrEP was high and may be associated with liver/renal lab abnormalities. Increased awareness of APES use and potential toxicity is encouraged to enhance safety.

We wished to evaluate the efficacy, safety, and acceptability of cabergoline for lactation inhibition in women who live with HIV. In this multicenter prospective observational study, cabergoline was offered as a single oral dose of 1 mg within the first 48 h postpartum. Women were recruited if they delivered a live infant after 35 weeks of gestational age. Participants filled out a questionnaire regarding symptoms of lactation and cabergoline adverse effects on day 2 and day 14 postpartum. On day 14, they also completed a questionnaire about their satisfaction with cabergoline treatment. Prolactin serum level was measured on both visits. Among 68 participants, all but one received cabergoline. The overall effectiveness defined by partial or complete success at day 14 was 98.3% (confidence intervals: 89.5–99.9). At day 14, 67.4% of women who received cabergoline had prolactin serum levels

We report the cases of two treatment-experienced HIV-infected patients with complex antiretroviral regimens that showed significant drug–drug interactions with etravirine. Unexpectedly high etravirine concentrations likely caused subtherapeutic levels of darunavir, elvitegravir and dolutegravir through concentration-dependent metabolic induction. Therapeutic drug monitoring allowed safe etravirine dose decreases to manage these interactions.

Therapeutic drug monitoring (TDM) constitutes a compelling approach for the optimization of antiretroviral therapy in treatment-experienced HIV-1 patients. While various inhibitory indices have been proposed to predict virologic outcome, there is a lack of consensus on the clinical value of TDM. Here, we report the comparative results of TDM in 14 HIV-1-infected patients who had previously received at least two different PI-based regimens and who initiated darunavir (DRV)-based salvage therapy. Pharmacokinetic/pharmacodynamics (PK/PD) parameters were calculated for each subject. Seventy-nine percent of subjects had a viral load50 copies/mL at 48 weeks. The only subject with two consecutive viral loads50 copies/mL at the end of the study period was the patient with the lowest instantaneous inhibitory potential (IIP). The sample size was insufficient to show an association between any of the PK/PD parameters and virologic response. Based on our observations, we suggest that the utility of IIP for antiretroviral combinations for the prediction of virologic outcome in HIV-1 drug-experienced patients should be studied further.

The role of pharmacists in HIV outpatient clinics has greatly increased in the past decades. Given the limited resources of the health system, the prioritization of pharmacist consults is now a main concern. This study aimed to create a scoring system allowing for standardized prioritization of pharmacist consults for patients living with HIV. Data was retrospectively collected from 200 HIV patients attending the Chronic Viral Illness Service at the McGill University Health Center. An expert panel consisting of four pharmacists working in the field of HIV prioritized each patient individually, after which a consensus was established and was considered as the gold standard. In order to create a scoring system, two different methods (Delphi, statistical) were used to assign a weight to each characteristic considered to be important in patient prioritization. A third method (equal weight to each characteristic) was also evaluated. The total score per patient for each method was then compared to the expert consensus in order to establish the score cut-offs to indicate the appropriate categories of delay in which to see the patient. All three systems failed to accurately prioritize patients into urgency categories ("less than 48 h", "less than 1 month", "less than 3 months", "no consult required") according to expert pharmacist consensus. The presence of high level interactions between patient characteristics, the limited number of patients and the low prevalence of some characteristics were hypothesized as the main causes for the results. Creating a prioritization tool for pharmacy consults in HIV outpatient clinics is a complex task and developing a decision tree algorithm may be a more appropriate approach in the future to take into account the importance of combinations of patient characteristic.

Background Men-who-have-sex-with-men (MSM) may experience more body image dissatisfaction compared to heterosexual men. The desire to be muscular has been linked with use of appearance- and performance-enhancing supplements (APES), including muscle-building supplements, steroids, and fat-burning products. APES use has been associated with potential health risks including serious liver and renal abnormalities. The purpose of this study was to describe the use and safety of APES among people attending an ambulatory pre-exposure prophylaxis (PrEP) clinic. Methods All participants ≥18 years on tenofovir disoproxil fumarate/emtricitabine were included; pregnant subjects were excluded. Prospective cross-sectional survey was conducted between February 1, 2018 and September 30, 2018 to assess APES usage, and retrospective chart reviews were done to determine the rates of liver and renal abnormalities from January 1, 2016 to September 30, 2018. RUCAM and Naranjo scales were used to assess causality with liver and renal abnormalities, respectively. Results Among 50 participants (median 32 years, 52% Caucasian, 86% MSM), 72% reported lifetime APES use and 52% with recent (within the past 6 months) use (APES group). Only 28% had never used APES (non-APES group). APES and non-APES groups had similar rates of liver abnormalities (mostly Grade 1), but 2 (8%) APES participants experienced Grade 3-4 elevations compared to none in the non-APES group. Liver enzyme elevations were possibly associated with creatine (n=4), whey protein (n=3), steroids (n=2), and weight-loss supplements (n=2). In the APES group, 12% had elevated serum creatinine (all stage 1) compared to none in the non-APES group. Whey protein (n=2), creatine (n=1), steroids (n=1), and tenofovir disoproxil fumarate (n=1) were possibly associated with renal abnormalities. Conclusion APES usage among people on PrEP was high and possibly associated with liver and/or renal abnormalities. Increasing provider and consumer awareness of potential health risks of APES is encouraged to enhance safety. Disclosure No significant relationships.

We report a case of therapeutic drug monitoring guided raltegravir use for the prevention of vertical HIV transmission in a premature neonate born to a woman living with perinatally acquired HIV and documented resistance to multiple HIV drugs. Maternal viral load was above 1,000 copies/ml at delivery. This case demonstrates delayed raltegravir elimination in a neonate born at 33 weeks gestational age and a need for less frequent raltegravir dosing than is used in older infants and children.

OBJECTIVES The testes are a potential viral sanctuary site for HIV-1 infection. Our study aims to provide insight into the expression and localization of key drug transporters and metabolic enzymes relevant to ART in this tissue compartment. METHODS We characterized gene and protein expression of 12 representative drug transporters and two metabolic enzymes in testicular tissue samples obtained from uninfected (n = 8) and virally suppressed HIV-1-infected subjects on ART (n = 5) and quantified antiretroviral drug concentrations in plasma and testicular tissues using LC/MS/MS from HIV-1-infected subjects. RESULTS Our data demonstrate that key ABC drug transporters (permeability glycoprotein, multidrug-resistance protein 1, 2 and 4, and breast cancer resistance protein), solute carrier transporters (organic anion transporting polypeptides 1B1 and 2B1, organic anion transporter 1, concentrative nucleoside transporter 1, equilibrative nucleoside transporter 2) and cytochrome P450 metabolic enzymes (CYP3A4 and CYP2D6) previously shown to interact with many commonly used antiretroviral drugs are expressed at the mRNA and protein level in the testes of both subject groups and localize primarily at the blood-testis barrier, with no significant differences between the two groups. Furthermore, we observed that PIs known to be substrates for ATP-binding cassette membrane transporters, displayed variable testicular tissue penetration, with darunavir concentrations falling below therapeutic values. In contrast, the NRTIs emtricitabine, lamivudine and tenofovir displayed favourable tissue penetration, reaching concentrations comparable to plasma levels. We also demonstrated that nuclear receptors, peroxisome proliferator-activated receptors α and γ exhibited higher gene expression in the testicular tissue compared with pregnane X receptor and constitutive androstane receptor, suggesting a potential regulatory pathway governing drug transporter and metabolic enzyme expression in this tissue compartment. CONCLUSIONS Our data suggest the testes are a complex pharmacological compartment that can restrict the distribution of certain antiretroviral drugs and potentially contribute to HIV-1 persistence.

Most HIV-infected patients who initiate combination antiretroviral therapy experience a viral load decline in several phases. These phases are characterized by different rates of viral load decay that decrease when transitioning from one phase to the next. There is no consensus as to the origin of these phases. One hypothesis put forward is that short- and long-lived infected cells are responsible for the first and second phases of decay, respectively. However, significant differences in drug concentrations are observed in monocytes from various tissues, suggesting the first two phases of decay in viral loads could instead be attributed to short-lived cells being differently exposed to drugs. Compared to a well-exposed compartment, new cell infection can be expected in a compartment with limited drug exposure, thus leading to a slower viral load decay with potential virologic failure and drug resistance. In the current study, the latter hypothesis was investigated using a model of viral kinetics. Empirical datasets were involved in model elaboration and parameter estimation. In particular, susceptibility assay data was used for an in vitro to in vivo extrapolation based on the expected drug concentrations inside physiological compartments. Results from numerical experiments of the short-term evolution of viral loads can reproduce the first two phases of viral decay when allowing new short-lived cell infections in an unidentified drug-limited compartment. Model long-term predictions are however less consistent with clinical observations. For the hypothesis to hold, efavirenz, tenofovir and emtricitabine drug exposure in the drug-limited compartment would have to be very low compared to exposure in peripheral blood. This would lead to significant long-term viral growth and the frequent development of resistant strains, a prediction not supported by clinical observations. This suggests that the existence of a drug-limited anatomical compartment is unlikely, by itself, to explain the second phase of viral load decay.

Concomitant administration of multiple drugs can lead to unanticipated drug interactions and resultant adverse drug events with their associated costs. A more thorough understanding of the different cytochrome P450 isoenzymes and drug transporters has led to new methods to try to predict and prevent clinically relevant drug interactions. There is also an increased recognition of the need to identify the impact of pharmacogenetic polymorphisms on drug interactions. More stringent regulatory requirements have evolved for industry to classify cytochrome inhibitors and inducers, test the effect of drug interactions in the presence of polymorphic enzymes, and evaluate multiple potentially interacting drugs simultaneously. In clinical practice, drug alert software programs have been developed. This review discusses drug interaction mechanisms and strategies for screening and minimizing exposure to drug interactions. We also provide future perspectives for reducing the risk of clinically significant drug interactions.

Background: Given their expertise in pharmacotherapy, pharmacists are well positioned to play a leading role in the implementation of pharmacogenomics in clinical practice. However, little is known about the opinions of pharmacists towards pharmacogenomics or their willingness to integrate this new field in their practice. Methods: We conducted a survey of 284 pharmacists practicing in the province of Québec (Canada) to describe the opinions, expectations and concerns of pharmacists toward pharmacogenomics. Results: Pharmacists were very hopeful regarding the potential role of pharmacogenomics. Moreover, more than 95% of responders would be willing to recommend pharmacogenomic testing. Nevertheless, only 7.7% of pharmacists currently felt comfortable advising patients based on pharmacogenomic test results. Accordingly, the majority of responders (96.6%) indicated that they would like to undertake continuing education related to pharmacogenomics. Conclusion: Pharmacists are extremely hopeful towards pharmacogenomic testing. Furthermore, a vast majority is willing to integrate these tests as part of their clinical practice. Proper education will be required if the integration of pharmacogenomics in patient care is to be optimal. Original submitted 21 September 2012; Revision submitted 16 November 2012

Amid numerous complications that plague the health and quality of life of people living with HIV, neurocognitive and psychiatric illnesses pose unique challenges. While there remains uncertainty with respect to the pathophysiology surrounding these disorders, their adverse implications are increasingly recognized. Left undetected, they have the potential to significantly impact patient well being, adherence to antiretroviral treatment and overall health outcomes. As such, early identification of HIV-associated neurocognitive disorders (HAND) and psychiatric illnesses will be paramount in the proactive management of affected patients. The present review focuses on strategies to ensure optimal screening and detection of HAND, depression and substance abuse in routine practice. For each topic, currently available screening methods are discussed. These include identification of risk factors, recognition of relevant symptomatology and an update on validated screening tools that can be efficiently implemented in the clinical setting. Specifically addressed in the present review are the International HIV Dementia Scale, a novel screening equation and algorithm for HAND, as well as brief, validated, verbal questionnaires for detection of depression and substance abuse. Adequate understanding and usage of these screening mechanisms can ensure effective use of resources by distinguishing patients who require referral for more extensive diagnostic procedures from those who likely do not.Parmi les multiples complications qui compromettent la santé et la qualité de vie des personnes qui vivent avec le VIH, les maladies neurocognitives et psychiatriques comportent des défis uniques. Il reste de l’incertitude quant à la physiopathologie de ces troubles, mais leurs conséquences négatives sont de plus en plus établies. Non décelées, elles peuvent nuire considérablement au bien-être du patient, à sa compliance à l’antivirothérapie et à son issue de santé globale. C’est pourquoi il est capital de dépister rapidement les troubles neurocognitifs associés au VIH (TNAV) et les maladies psychiatriques dans la prise en charge proactive des patients atteints. La présente analyse porte sur des stratégies pour garantir le dépistage et la détection optimales des TNAV, de la dépression et de la consommation abusive d’alcool et de drogues dans la pratique habituelle. Pour chaque sujet, les méthodes de dépistage existantes sont exposées,soitladéterminationdesfacteursderisqueetdelasymptomatologie pertinente ainsi qu’une mise à jour des outils de dépistage validés qui peuvent être mis en œuvre avec efficacité en milieu clinique. L’échelle de démence du VIH, un nouvel outil et algorithme de dépistage des TNAV et de brefs questionnaires verbaux validés pour déceler la dépression et la consommation excessive d’alcool et de drogues. Si on comprend et qu’on utilise bien ces mécanismes de dépistage, on peut s’assurer d’une utilisation efficace des ressources en séparant les patients qui ont besoin d’être aiguillés vers des interventions diagnostiques plus poussées de ceux qui n’en ont probablement pas besoin.

Background: Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefi t from prevention of depression. Objective: The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-α/ribavirin therapy. Methods: This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-α2b/ ribavirin, stratifi ed by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDIII) score greater than 15, confi rmed 2 weeks apart. Results: Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ signifi cantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. Conclusions: A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it signifi cantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV. Key words: citalopram, coinfection, depression, hepatitis C virus, HIV, interferon-alpha

BACKGROUND It is recommended to boost atazanavir with ritonavir (ATV/r) when it is combined with tenofovir disoproxil fumarate (TDF) because of drug interactions. For tolerability, unboosted atazanavir (ATV) is sometimes coadministered with TDF. The objective of this study was to evaluate the impact of this interaction on the proportion of patients achieving target ATV C troughs and genotypic inhibitory quotients (GIQ). MATERIALS AND METHODS A therapeutic drug monitoring database was screened to evaluate ATV concentrations. Differences in C trough and GIQ values among 4 antiretroviral drug combinations were evaluated. RESULTS Three hundred eight C troughs, 91 GIQs, and 92 viral loads were evaluated for 238, 68, and 69 patients, respectively. Patients receiving ATV/r and TDF compared with ATV and TDF were more likely to have a therapeutic C trough (odds ratio, 2.27; 95% confidence interval: 1.46-3.52; P < 0.001). Among patients on unboosted ATV, the odds of having a therapeutic ATV C trough did not differ between groups with TDF versus without TDF. Although ritonavir increased the GIQ in patients receiving TDF (odds ratio, 3.38; 95% confidence interval: 1.30-8.81; P = 0.013), a similar proportion of patients on TDF and either ATV/r or ATV achieved a therapeutic GIQ. CONCLUSIONS In patients receiving TDF, ritonavir increased the ATV C trough and GIQ and patients on ATV/r were more likely to have therapeutic C troughs. However, among subjects without ritonavir boosting, TDF compared with other nucleosides did not influence the odds of achieving a therapeutic ATV C trough. These data suggest that ritonavir boosting of ATV is prudent, particularly in patients with resistance mutations.

Background Use of combination antiretroviral therapy (cART) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with or without rituximab for treatment of diffuse large B-cell lymphoma (DLBCL) in HIV substantially increases response rates but may also increase toxicity, possibly due to antiretroviral– antineoplastic drug interactions. The objective of this study was to evaluate the frequency of complete remission (CR) of DLBCL in patients treated with CHOP while receiving a protease inhibitor (PI) versus a non-PI-based cART. Methods A retrospective multicentre pilot study was conducted in HIV-infected patients on cART treated for DLBCL with CHOP between 2002–2010 in three academic hospitals. Results A total of 34 patients were included with 65% and 35% of patients receiving a PI and non-PI-based cART, respectively. Baseline characteristics between groups were similar; overall 85% were male, median age was 43 years, 50% had an International Prognostic Index (IPI) of 2–3 and median CD4+ T-cell count was 225 cells/mm3. CR was achieved in 77% and 58% of patients in the PI and non-PI groups, respectively ( P=0.21), with 65% and 63% of patients achieving 2-year overall survival ( P=1.00). A multivariate analysis showed that lower IPI score alone was significantly associated with higher CR rates ( P=0.05). Toxicity was similar between both groups. Conclusions Similar efficacy and toxicity of CHOP was observed in patients receiving a PI and non-PI-based cART.

Over the past decade, there have been numerous advances in HIV therapy, with 6 drug classes comprising 24 indivi dual antiretroviral agents now available. For patients who are adherent with therapy and who have an undetectable viral load, HIV has become a chronic, manageable disease in an aging and genetically diverse population. The core goals of management remain maximal suppression of viral replication and promotion of immune reconstitution through combination antiretroviral therapy. Secondary goals of therapy include promoting long-term adherence, avoiding drug interactions, minimizing toxic effects, simplifying treatment regimens, decreasing drug costs, managing comorbid conditions, and preventing transmission of HIV by achieving undetectable viral load. Consequently, the pharmacist’s role has evolved and expanded to help patients and other health care providers to achieve these goals. Pharmacists are recognized as established and integral members of HIV health care teams across Canada and the United States. Pharmacists’ involvement in the care of HIVpositive patients has been associated with improved patient outcomes, including enhanced adherence, reduced pill burden and dosing frequency, greater increases in CD4 cell counts, higher rates of viral suppression, and decreases in medication errors. Guidelines and position statements on the role of the pharmacist in caring for patients with HIV/AIDS have been published by various national and international organizations, but there have been no updates since combination antiretro viral therapy came into use, about a dozen years ago. This paper provides current guidelines for a pharmacist’s role in the many aspects of caring for patients with HIV/AIDS, including selecting and reviewing therapy, tailoring treatment for specific populations, counselling patients, monitoring response to therapy, guiding transitions of care, and undertaking scholarly and professional activities. The target audience for these guidelines includes new HIV pharmacy practitioners, pharmacists with an interest in HIV but limited experience or therapeutic knowledge in this area, and pharmacy students. This paper may also serve as a model of pharmacy practice for ambulatory care in other therapeutic areas. A literature search was conducted using the electronic databases MEDLINE and PubMed from 2000 to March 2012. The following search terms were used: HIV, antiretrovirals, adverse drug reactions, drug interactions, adherence, pediatric, perinatal transmission, therapeutic drug monitoring, pharmacist, hepatitis B, hepatitis C, seamless care, and medication reconciliation. In addition, conference abstracts were searched for relevant studies. Updated guidelines for treatment of HIV and related conditions, landmark studies, and comprehensive review articles were selected for inclusion.

Contains fulltext : 109786.pdf (Publisher’s version ) (Open Access) beta-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results from in vitro studies suggest that beta-carotene may inhibit or induce cytochrome P450 enzymes and transporters. The study objective was to investigate the effect of beta-carotene on the steady-state pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1 infected individuals. Twelve hour nelfinavir pharmacokinetic analysis was conducted at baseline and after 28 days of beta-carotene supplementation (25,000 IU twice daily). Nelfinavir and M8 concentrations were measured with validated assays. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Geometric mean ratios comparing day 28 to day 1 area under the plasma concentration-time curve (AUC(0-12 h)), maximum (C(max)) and minimum (C(min)) concentrations of nelfinavir and M8 are presented with 90% confidence intervals. Eleven subjects completed the study and were included in the analysis. There were no significant differences in nelfinavir AUC(0-12 h) and C(min) (-10%, +4%) after beta-carotene supplementation. The M8 C(min) was increased by 31% while the M8 AUC(0-12 h) and C(max) were unchanged. During the 28 day period, mean CD4+ % and CD4+:CD8+ ratio increased significantly (p < 0.01). beta-carotene supplementation increased serum carotene levels but did not cause any clinically significant difference in the nelfinavir and M8 exposure.

Therapeutic drug monitoring (TDM) is a strategy whereby the plasma concentration of one or more drugs is measured and drug doses are adjusted accordingly to achieve concentrations within an acceptable therapeutic range. The goal of TDM is to maximize pharmacologic efficacy and minimize the drug’s toxic effects, and hence to contribute to optimizing the patient’s outcomes. In general, TDM is indicated if the following conditions are present: there is a direct relationship between drug exposure and pharmacologic response, the drug has a narrow therapeutic index and is used to treat a condition for which drug failure or toxicity is associated with substantial morbidity or mortality, and there is limited intrapatient but wide interpatient pharmaco kinetic variation. Differences in pharmacokinetic factors among patients are multifactorial and may include age, sex, ethnic background, pregnancy, and body weight, as well as comorbid conditions causing variations in hepatic function, renal function, drug absorption, and drug disposition. In some cases, genetic polymorphisms in the cytochrome P450 enzymes may explain the large interpatient variability for certain antiretroviral agents. For example, certain CYP2B6 and CYP2A6 polymorphisms are independent predictors of plasma concentrations of efavirenz. Moreover, the potential for complex or unpredictable drug–drug or drug–food interactions can significantly affect plasma drug concentrations. Finally, TDM depends on the availability of an accurate and feasible analytical method for a given drug. Among antiretroviral agents, the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered suitable candidates for TDM. Evidence exists of a relation between exposure to antiretrovirals and virologic response and, in more limited instances, between exposure to the drug and toxic effects. Recent data have suggested that intraindividual variation is limited (19.0% for NNRTIs and 38.1% for protease inhibitors). Preliminary data have also suggested that trough levels of maraviroc, a chemokine (C–C motif) receptor 5 (CCR5) antagonist, are predictive of virologic outcome, although TDM experience with this agent is extremely limited. In retrospective and prospective studies, observed interindividual variability in drug concentrations has been 45% to 112% for protease inhibitors and 75% for NNRTIs. Thus, a given dose of a particular antiretroviral agent may result in unacceptable toxic effects in some patients while yielding subtherapeutic concentrations in others. TDM represents a tool by which the effectiveness of these agents in clinical practice can be optimized through dosage adjustments tailored to patient-specific pharmacokinetic and pharmaco dynamic parameters. The current article reviews the literature on antiretroviral TDM, describes the development of an antiretroviral TDM program in Canada, and illustrates the role of the pharmacist in the clinical application of TDM. Given current evidence and personal experience, the authors support the use of antiretro viral TDM as a clinical tool in special patient populations and for specific clinical situations.

Hepatitis C (HCV)-related end stage liver disease is a primary cause of morbidity and mortality in people with HIV. Despite this, co-infected patients have low rates of HCV treatment initiation and completion. This is in large part due to the risk of pegylated-interferon alpha (PEG-IFN-alpha)-related neuropsychiatric complications. We describe the design of a multicentre randomized, placebo-controlled trial that evaluates whether antidepressant prophylaxis is superior to early detection and treatment of depression in increasing the successful completion of HCV therapy. Seventy-six HIV+ adults with chronic HCV infection requiring therapy and with no contraindications to PEG-IFN-alpha/ribavirin will be randomized in a 1:1 ratio to receive citalopram or placebo starting three weeks prior to HCV treatment. A novel aspect of the trial design is the built-in management of emergent depression while maintaining the blinded treatment assignment. This will permit the comparison of prophylactic versus therapeutic use of citalopram. The primary outcome is the average proportion of prescribed PEG-IFN-alpha and ribavirin doses taken per month at weeks 12 and 24, and will be compared between treatment arms. The study will also compare the development of moderate-to-severe depression between treatment arms. A unique feature of this trial will be the use of Telepsychiatry to standardize observer-administered neuropsychiatric evaluations. Assessments of anxiety, quality of life, and adherence to therapy, as well as pathogenetic studies of neuropsychiatric side effects, will be conducted. Intention-to-treat analyses using random regression modeling will be employed to analyze longitudinal data on prescribed PEG-IFN-alpha and ribavirin doses. Survival analyses will be used to compare the time to the development of depression between the two arms. Effective prevention of a broad range of neuropsychiatric symptoms by citalopram has the potential to diminish PEG-IFN-alpha associated morbidity and consequently, allow a greater number of patients to complete full therapy.

Lopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children6 months in the US and2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2 twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective.HIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cmin was1.0 mg/l LPV/r dose was increased by 33%. Plasma trough levels were drawn subsequently. HIV-1 RNA was followed-up until week 48.A total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4-13.2) years. Mean (+/-SD) AUC0-12h, Cmax and Cmin of LPV were 75.3 (+/-33.7) mg/l.h, 9.33 (+/-3.27) mg/l and 3.68 (+/-2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cmin was inadequate in 7/23 children. Significantly more children2 years had inadequate Cmin compared with children2 years. Dose increase to +/-300/75 mg/m2 LPV/r led to Cmin1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients.Mean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children2 years. Prospective pharmacokinetic studies using 300/75 mg/m2 LPV/r in this age population are urgently warranted.

BackgroundLopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children >6 months in the US and >2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective.MethodsHIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cminwas ResultsA total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4–13.2) years. Mean (±SD) AUC0–12h, Cmaxand Cminof LPV were 75.3 (±33.7) mg/l.h, 9.33 (±3.27) mg/l and 3.68 (±2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cminwas inadequate in 7/23 children. Significantly more children mincompared with children >2 years. Dose increase to ±300/75 mg/m2LPV/r led to Cmin>1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients.ConclusionsMean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children 2LPV/r in this age population are urgently warranted.

Objective: To describe a case of exacerbated mania potentially related to an interaction between lopinavir/ritonavir and valproic acid (VPA) and propose a mechanism of action for this interaction. Case Summary: A 30-year-old man with bipolar disorder and HIV initiated treatment with lopinavir/ritonavir, zidovudine, and lamivudine. Prior to beginning therapy with these antiretrovirals, he was receiving VPA 250 mg 3 times daily, with his most recent VPA concentration measured at 495 μmol/L. Twenty-one days after starting antiretroviral treatment, he became increasingly manic. His VPA concentration at admission was 238 μmol/L, a 48% decrease. The daily VPA dose was increased to 1500 mg, and olanzapine was introduced. The VPA concentration following this dose escalation was 392 μmol/L, and the patient improved clinically. Discussion: Fifty percent of VPA is metabolized by glucuronidation, 40% undergoes mitochondrial β-oxidation, and less than 10% is eliminated by the cytochrome P450 isoenzymes. Ritonavir can induce glucuronidation of several medications including ethinyl estradiol, levothyroxine, and lamotrigine. We believe that ritonavir-mediated induction of VPA glucuronidation resulted in a decrease in VPA concentrations and efficacy. An objective causality assessment suggested that the increased mania was probably related to the decrease in VPA concentration and that a possible interaction exists between lopinavir/ritonavir and VPA. Conclusions: A potential interaction exists between VPA and all ritonavir-boosted antiretroviral regimens. Clinicians should monitor patients closely for a decreased VPA effect when these medications are given concomitantly.

BACKGROUND: Clinicians frequently consult HIV drug interaction Web sites of unknown quality. OBJECTIVE: To systematically review and identify HIV drug interaction Web sites of high quality and usefulness for healthcare professionals. METHODS: Relevant Web sites were identified through a structured search on commonly used search engines. An assessment tool containing 4 domains (content, reliability, access restrictions, ease of navigation) was developed. English and French Web sites were selected for review if they included HIV drug interaction information directed to healthcare professionals. Web sites were excluded if antiretroviral interaction data were not available or were out of date. Commercial online databases and sites that required payment were not included. Seventeen HIV pharmacists from across Canada participated in the review. The Web sites were ranked with total mean scores. Mean scores for each domain were then analyzed. Interrater agreement and ANOVA using the rater as a covariate were determined. RESULTS: Nine Web sites met the criteria for review. Web sites from Toronto General Hospital (Canada), HIVinSite (beta version) (US), and the University of Liverpool (UK) ranked highest for total mean scores and for content. Other Web sites were found to be reliable, accessible, and easy to navigate; however, they did not consistently include unpublished data or data on herbal preparations, recreational drugs, or multiple interactions. CONCLUSIONS: Three HIV interaction Web sites of high quality were identified that can be valuable tools for HIV and non-HIV healthcare professionals. Regular reviews are necessary in order to keep pace with the growing body of HIV interaction data and the constant evolution of Web sites.