Pharmacokinetics and Safety of the Integrase Inhibitors Elvitegravir and Dolutegravir in Pregnant Women With HIV.

Objective: To synthesize data on the pharmacokinetics and safety of dolutegravir and elvitegravir in pregnant women living with HIV. Data Sources: A PubMed, EMBASE, Web of Science, and Google Scholar literature search (January 2010 to December 2018) was performed using the search terms dolutegravir, elvitegravir, women, pregnant*, and HIV. Additional reports were identified from conference abstracts and review of reference lists. Study Selection and Data Extraction: English-language studies reporting pharmacokinetic and/or safety data in pregnant women receiving dolutegravir or elvitegravir/cobicistat were included. Data Synthesis: A total of 17 studies were selected. Studies demonstrated a modest decrease in dolutegravir concentrations in pregnancy. Preliminary data suggest an increased risk of neural tube defects when dolutegravir is used at the time of conception. Available pharmacokinetic data in pregnant women showed significantly reduced plasma concentrations of elvitegravir/cobicistat which may increase the risk of virological failure. Current guidelines recommend that dolutegravir should not be initiated in women who have the potential to become pregnant or women in their first trimester of pregnancy and elvitegravir/cobicistat should be avoided during pregnancy. Relevance to Patient Care and Clinical Practice: This review highlights pharmacokinetic and safety data for dolutegravir and elvitegravir/cobicistat in pregnant women. Clinicians need to be aware of these data to convey the risks and benefits of using these agents in women of child-bearing potential. Conclusions: Changes in guideline recommendations reflect emerging data regarding the use of dolutegravir and elvitegravir/cobicistat in pregnancy. Until further information is available, raltegravir or other first-line agents are recommended for women with HIV planning to become pregnant.

Dolutegravir Dual Therapy as Maintenance Treatment in HIV-Infected Patients: A Review.

OBJECTIVE: To review available evidence for dolutegravir-based dual therapy as maintenance treatment in HIV-1 infected patients. DATA SOURCES: A literature search was conducted using PubMed, MEDLINE, and Google Scholar to the end of January 2018. Conference abstracts and article bibliographies were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language, randomized, and observational studies were included. DATA SYNTHESIS: In all, 12 studies were identified: 10 were observational, and 2 were randomized trials. Rilpivirine or lamivudine were the most common second agent used in combination with dolutegravir. Virological suppression seen in observational studies appear promising; however, the most compelling evidence to date is the 48-week results from 2 large open-label randomized trials (SWORD 1 and 2). These studies found that dual therapy with rilpivirine and dolutegravir was noninferior to 3- or 4-drug combination antiretroviral therapy (cART). The long-term efficacy, safety, and tolerability of dual therapy, as compared with usual cART, are less clear and require further data. CONCLUSIONS: Regimen switching in virally suppressed HIV-1-infected patients may be considered to reduce pill burden or dosing frequency, decrease short- or long-term toxicity, prevent or manage drug-drug interactions, and/or decrease cost. Based on available evidence, a switch to dual therapy with dolutegravir and rilpivirine appears viable for virologically suppressed patients without prior resistance mutations to these agents. Randomized studies of other dual-therapy regimens that include dolutegravir and longer-term follow-up as well as cost-effectiveness analyses are needed to provide confirmation that this strategy offers advantages to traditional cART regimens.

Probable interaction between levothyroxine and ritonavir: Case report and literature review.

PURPOSE: A case of probable interaction of levothyroxine and ritonavir is presented along with a review of the relevant literature and recommendations on clinical management. SUMMARY: A 37-year-old woman with human immunodeficiency virus infection who had recently undergone thyroidectomy for a benign multinodular goiter presented to a clinic with hypothyroidism (she was also found to be pregnant), and treatment with levothyroxine 75 µg daily was initiated. While receiving antiretroviral therapy (abacavir-lamivudine and lopinavir-ritonavir) during pregnancy, the patient had persistently elevated serum thyroid-stimulating hormone (TSH) concentrations (up to 125.89 µIU/mL) despite gradual escalation of the levothyroxine dosage to 175 µg daily. An interaction between ritonavir and levothyroxine was suspected, and dolutegravir was substituted for lopinavir-ritonavir. Within 4 months, the TSH concentration had normalized. The daily levothyroxine dose was tapered over a 5-month period and stabilized at 125 µg, and TSH concentrations remained within the normal range over an 18-month follow-up period. Scoring of the case using the Drug Interaction Probability Scale yielded a score of 6 out of 11, indicating a probable interaction between levothyroxine and ritonavir. A literature search identified 4 reported cases of interactions involving levothyroxine and ritonavir. CONCLUSION: A potentially serious and underrecognized drug interaction between ritonavir and levothyroxine was observed in a pregnant woman with postthyroidectomy-related hypothyroidism. This case and a review of other cases reported in the literature indicate that higher-than-usual doses of levothyroxine may be required in patients who are taking ritonavir concurrently.

HIV outcomes at a Canadian remand centre.

Purpose The purpose of this paper is to assess the impact of short-term incarceration on antiretroviral therapy (ART) adherence, virologic suppression, and engagement and retention in community care post-release. Design/methodology/approach A retrospective chart review of patients who attended the human immunodeficiency virus (HIV) Outreach Clinic at a Canadian remand center between September 2007 and December 2011 was carried out. Data extraction included CD4 lymphocyte count, HIV viral load, ART prescription refills, and community engagement and retention during and one-year pre- and post-incarceration. Findings Outpatient engagement increased by 23 percent ( p=0.01), as did ART adherence (55.2-70.7 percent, p=0.01), following incarceration. Retention into community care did not significantly improve following incarceration (22.4 percent pre-incarceration to 25.9 percent post-release, p=0.8). There was a trend toward improved virologic suppression (less than 40 copies/ml; 50-77.8 percent ( p=0.08)) during incarceration and 70. 4 percent sustained this one-year post-incarceration ( p=0.70). Originality/value The impact of short-term incarceration in a Canadian context of universal health coverage has not been previously reported and could have significant implications in optimizing HIV patient outcomes given the large number of HIV-positive patients cycling through short-term remand centers.

What Works and What's Safe in Pediatric Emergency Procedural Sedation: An Overview of Reviews.

BACKGROUND: Sedation is increasingly used to facilitate procedures on children in emergency departments (EDs). This overview of systematic reviews (SRs) examines the safety and efficacy of sedative agents commonly used for procedural sedation in children in the ED or similar settings. METHODS: We followed standard SR methods: comprehensive search; dual study selection, quality assessment, data extraction. We included SRs of children (1 month to 18 years) where the indication for sedation was procedure-related and performed in the ED. RESULTS: Fourteen SRs were included (210 primary studies). The most data were available for propofol (six reviews/50,472 sedations) followed by ketamine (7/8,238), nitrous oxide (5/8,220), and midazolam (4/4,978). Inconsistent conclusions for propofol were reported across six reviews. Half concluded that propofol was sufficiently safe; three reviews noted a higher occurrence of adverse events, particularly respiratory depression (upper estimate 1.1%; 5.4% for hypotension requiring intervention). Efficacy of propofol was considered in four reviews and found adequate in three. Five reviews found ketamine to be efficacious and seven reviews showed it to be safe. All five reviews of nitrous oxide concluded it is safe (0.1% incidence of respiratory events); most found it effective in cooperative children. Four reviews of midazolam made varying recommendations. To be effective, midazolam should be combined with another agent that increases the risk of adverse events (upper estimate 9.1% for desaturation, 0.1% for hypotension requiring intervention). CONCLUSIONS: This comprehensive examination of an extensive body of literature shows consistent safety and efficacy for nitrous oxide and ketamine, with very rare significant adverse events for propofol. There was considerable heterogeneity in outcomes and reporting across studies and previous reviews. Standardized outcome sets and reporting should be encouraged to facilitate evidence-based recommendations for care.

Twelve recommendations for integrating existing systematic reviews into new reviews: EPC guidance.

OBJECTIVES: As time and cost constraints in the conduct of systematic reviews increase, the need to consider the use of existing systematic reviews also increases. We developed guidance on the integration of systematic reviews into new reviews. METHODS: A workgroup of methodologists from Evidence-based Practice Centers developed consensus-based recommendations. Discussions were informed by a literature scan and by interviews with organizations that conduct systematic reviews. RESULTS: Twelve recommendations were developed addressing selecting reviews, assessing risk of bias, qualitative and quantitative synthesis, and summarizing and assessing body of evidence. CONCLUSIONS: We provide preliminary guidance for an efficient and unbiased approach to integrating existing systematic reviews with primary studies in a new review.

Discontinuing Pneumocystis jirovecii Pneumonia Prophylaxis in HIV-Infected Patients With a CD4 Cell Count <200 cells/mm3.

OBJECTIVE: To review the evidence for discontinuing primary and secondary Pneumocystis jirovecii pneumonia (PJP) prophylaxis in HIV-infected patients with a CD4 count <200 cells/mm(3). DATA SOURCES: We conducted a literature search in MEDLINE, EMBASE, Cochrane Library, Google Scholar, and the International Aids Society Library (up to August 2015) using the following key search terms: Pneumocystis jirovecii, pneumonia, human immunodeficiency virus, primary prophylaxis, secondary prophylaxis, and discontinuation. STUDY SELECTION AND DATA EXTRACTION: All English-language studies that evaluated discontinuation of primary and/or secondary PJP prophylaxis in HIV-infected patients with CD4 count <200 cells/mm(3) were included. DATA SYNTHESIS: Five studies were identified, which varied in design, sample size, outcomes, and duration of follow-up. Three studies examined discontinuation of primary and secondary PJP prophylaxis; 1 study evaluated discontinuing primary PJP prophylaxis; and 1 study evaluated stopping secondary PJP prophylaxis. Two out of the 5 studies pooled data for all opportunistic infections. Overall, there was a low incidence of PJP among HIV-infected patients who discontinued primary PJP prophylaxis and were well controlled on antiretroviral therapy (ART). CONCLUSIONS: Discontinuation of primary PJP prophylaxis appears to be safe in patients on combination ART with a suppressed HIV viral load and a CD4 count >100 cells/mm(3). Additional data are needed to support the safety of discontinuing secondary PJP prophylaxis. Decisions to discontinue PJP prophylaxis in patients with a CD4 count <200 cells/mm(3) should be done on an individual patient basis, taking into consideration clinical factors, including ongoing adherence to ART.

Advancing knowledge of rapid reviews: an analysis of results, conclusions and recommendations from published review articles examining rapid reviews.

BACKGROUND: Rapid review (RR) products are inherently appealing as they are intended to be less time-consuming and resource-intensive than traditional systematic reviews (SRs); however, there is concern about the rigor of methods and reliability of results. In 2013 to 2014, a workgroup comprising representatives from the Agency for Healthcare Research and Quality's Evidence-based Practice Center Program conducted a formal evaluation of RRs. This paper summarizes results, conclusions, and recommendations from published review articles examining RRs. METHODS: A systematic literature search was conducted and publications were screened independently by two reviewers. Twelve review articles about RRs were identified. One investigator extracted data about RR methods and how they compared with standard SRs. A narrative summary is presented. RESULTS: A cross-comparison of review articles revealed the following: 1) ambiguous definitions of RRs, 2) varying timeframes to complete RRs ranging from 1 to 12 months, 3) limited scope of RR questions, and 4) significant heterogeneity between RR methods. CONCLUSIONS: RR definitions, methods, and applications vary substantially. Published review articles suggest that RRs should not be viewed as a substitute for a standard SR, although they have unique value for decision-makers. Recommendations for RR producers include transparency of methods used and the development of reporting standards.

The Use of Therapeutic Drug Monitoring in Complex Antituberculous and Antiretroviral Drug Dosing in HIV/Tuberculosis-Coinfected Patients.

UNLABELLED: We report 2 cases coinfected with HIV and tuberculosis (HIV/TB), requiring drug dose adjustments guided by therapeutic drug monitoring (TDM) and/or serum drug concentrations. CASE 1: Over the course of the 9-months of TB treatment, drugs that required increased doses due to low concentrations included efavirenz (800 mg), rifampin (900 mg), and isoniazid (450 mg). Higher drug doses were well tolerated until the end of treatment. CASE 2: Over the 12-month course of TB therapy, drugs that required increased doses due to incomplete and/or delayed absorption were rifampin (1500 mg), moxifloxacin (800 mg), and ethambutol (1600 mg). Higher drug doses were well tolerated until the end of treatment. Due to delayed/incomplete drug absorption and weight gain during therapy, higher antituberculous doses may be required in patients coinfected with HIV/TB. A daily dose of efavirenz 800 mg was well tolerated in both patients (weight over 70 kg). Managing patients coinfected with HIV/TB is complex, and, therefore, TDM of drug concentrations can help guide clinical decision making.

Antiretroviral-Related Alopecia in HIV-Infected Patients.

Objective: To review the literature evaluating antiretroviral-related alopecia and to provide guidance on the differential diagnosis and management of this condition. DATA SOURCES: A literature search was performed using PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health (CINAHL), and the Cochrane database (through May 2014). Relevant conference abstracts and product monographs were reviewed. Search terms included antiretroviral, individual antiretroviral classes and names, highly active antiretroviral therapy, HIV, AIDS, alopecia, hair, hair loss and drug. STUDY SELECTION AND DATA EXTRACTION: English-language studies and case reports were included. A total of 16 articles and 1 conference abstract were retrieved, with a total of 46 patients with hair loss. DATA SYNTHESIS: The protease inhibitor class, in particular indinavir, was most commonly reported to cause hair loss, followed by the NRTI, lamivudine. The majority of cases presented with alopecia of the scalp alone, with a median time of onset of 2.5 months. Management involved discontinuing the drug in most cases, with at least partial reversal in half the cases. CONCLUSIONS: In antiretroviral-induced alopecia, discontinuation of the suspected agent is the optimal management, and hair regrowth should occur within 1 to 3 months. Management may also include replacing the offending medication with an antiretroviral less likely to cause hair loss. It is essential to rule out other causes of alopecia with a complete patient history, including characterization of the hair loss and assessment of the patient's medical history, medication use, and family history of alopecia.

Antiretroviral and Medication Errors in Hospitalized HIV-Positive Patients.

OBJECTIVE: To summarize the literature regarding antiretroviral and other medication errors in hospitalized HIV-positive patients and to discuss potential interventions and solutions that have been studied to minimize drug error. DATA SOURCES: A systematic search of MEDLINE, PubMed, and EMBASE (2000-April 2014) was conducted. Search terms included HIV/AIDS, HAART, hospitalization, patient admission, inpatient, patient transfer, medication error, inappropriate prescribing, drug interaction, drug omission, drug toxicity, and contraindication. STUDY SELECTION AND DATA EXTRACTION: English-language research articles, case reports, conference abstracts, and letters to the editor were reviewed. DATA SYNTHESIS: A high overall medication error rate was reported in HIV-positive inpatients. Errors occurred mainly at the time of prescribing on admission but were also detected throughout hospitalization and at discharge. Errors in the antiretroviral regimen, dosing, scheduling, and drug-drug and drug-food interactions were the most common. The most successful interventions involved a clinical pharmacist, who specializes in infectious diseases and/or HIV, completing medication reconciliation on admission, reviewing orders daily, and screening for errors at discharge. CONCLUSIONS: Although studies varied greatly in methodology, overall, a large number of medication errors occurred in this patient population. This underscores the important role the pharmacist has in optimizing care to hospitalized HIV-positive patients and provides further insights into the types of medication errors that occur and proposed solutions to reduce these errors. Because medication errors are multifactorial, ongoing initiatives to improve the quality of medication reconciliation processes, educate the health care team on antiretroviral medications, and improve the drug distribution system are required.

Treatment beliefs, illness perceptions, and non-adherence to antiretroviral therapy in an ethnically diverse patient population.

BACKGROUND: Ethnic diversity is increasingly encountered in the HIV-infected population in North America, and it is unknown if beliefs surrounding illness and treatment vary among different ethnic groups. OBJECTIVE: Our objectives were to determine whether self-reported adherence, illness perceptions and treatment beliefs regarding HIV differ based on ethnicity. SETTING: This study was conducted during outpatient HIV clinic visits between March 1, 2010 and April 30, 2010 at two hospital-based clinics in Edmonton, AB, Canada. METHODS: A cross-sectional sample of 65 patients on antiretroviral therapy (34 Caucasian, 23 Aboriginal, and 8 from other ethnic groups) attending hospital-based clinics completed a self-administered survey; medical records were reviewed for demographic and treatment information. MAIN OUTCOME MEASURE: An ANOVA with covariates was performed to measure variation of beliefs and adherence between ethnic groups. RESULTS: Mean self-reported adherence in the past week and past month was high (96 %) and the majority of patients (78.5 %) had a viral load <40 copies/mL. Patients had high perceived necessity scores and a low degree of perceived concern with antiretroviral therapy. In our study, treatment beliefs, illness perceptions, and self-reported adherence did not vary between ethnicities (p > 0.05). CONCLUSION: Treatment beliefs, illness perceptions, and adherence appear to be largely similar in English-speaking patients with diverse ethnic backgrounds who have been on treatment for at least 3 months. Strong supports may overcome any cultural differences in treatment beliefs that were expected at the outset.

Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir.

Drug interactions involving human immunodeficiency virus protease inhibitors are common due to their inhibition of the cytochrome P450 3A4 isoenzyme. We describe the case of an HIV-infected patient treated with ritonavir-boosted darunavir who developed cushingoid features following an intra-articular injection of triamcinolone acetate. We review the probable mechanism for this interaction and describe similar cases of Cushing syndrome in patients receiving concomitant ritonavir and triamcinolone.

Overview of reviews in child health: evidence synthesis and the knowledge base for a specific population.

BACKGROUND: Overviews of reviews are an evolving form of evidence synthesis. The Cochrane Child Health Field has been producing overviews since 2006, during which time the methods that have been used have changed, both due to the development of guidance within The Cochrane Collaboration and to the decisions made by individual author teams. This paper studies the first 29 overviews published in EBCH. OBJECTIVES: To describe some aspects of the approaches taken in EBCH overviews to producing evidence syntheses relevant to the healthcare needs of children; to highlight the contribution that overviews can make to the knowledge base for treatment for a particular population. METHODS: Data was extracted on: whether the overview included systematic review (SR) data only, or also data from individual trials not present in the included SRs; name(s) of the Cochrane Review Group (CRG) that prepared the included SRs; topics of the overviews as compared to the topics of the included reviews; age-subgroup analyses presented in the overviews. RESULTS: In 23 overviews, all published in 2012, the authors included trial data as well as SR data; two overviews addressed conditions not explicitly addressed by the included reviews; three overviews included pre-specified age-subgroup analyses. DISCUSSION: The aim of clinical relevance has been achieved by means such as: drawing from reviews produced by multiple CRGs; using SR evidence to explore clinically relevant topics that may not match exactly with the topics covered by the SRs; ensuring that the evidence in overviews is as up to date as possible by redoing searches and including trials not incorporated in the included SRs; and, where permitted by the data, using age-subgroup analyses to present the data in a way which matches the stages of childhood development. CONCLUSION: Overview authors are dependent on the nature of the data and methods reported in the included SRs. This suggests a need for further study about how SRs could be conducted in order to facilitate the conduct of overviews.

Factors associated with reduced antituberculous serum drug concentrations in patients with HIV-TB coinfection.

We describe correlates of reduced antituberculous serum drug concentrations (SDCs) in HIV-infected patients receiving treatment for active tuberculosis (TB). Cross-sectional analysis of individuals diagnosed with HIV and active TB in Northern Alberta, Canada, was performed. Of the 30 HIV-TB cases, 27 underwent measurement of SDCs. Rates of low SDCs were 9 of 26 (34%) for isoniazid (INH) and 16 of 25 (64%) for rifamycins. Increased weight and elevated body mass index (BMI) correlated with low SDCs for rifampin (P < .05) and increased weight also correlated with reduced SDCs for INH (P < .05). This suggests that conventional antituberculous dosing may be too low and consideration should be given to increase the maximum initial weight-based doses in HIV-infected patients.