Managing Pharmacotherapy in People Living With HIV and Concomitant Malignancy.

Objective: To describe data with selected malignancies in people living with HIV (PLWH) and HIV in individuals affected by both conditions and to summarize drug-drug interactions (DDIs) with clinical recommendations for point-of-care review of combination therapies. Data Sources: Literature searches were performed (2005 to December 2018) in MEDLINE and EMBASE to identify studies of malignancies in PLWH in the modern era. Study Selection and Data Extraction: Article bibliographies and drug interaction databases were reviewed. Search terms included HIV, antiretroviral therapy, antineoplastic agents, malignancies, and drug interactions. Data Synthesis: In the pre-antiretroviral therapy (ART) era, malignancies in PLWH were AIDS-defining illnesses, and life expectancy was shorter. Nowadays, PLWH are living longer and developing malignancies, including lung, anal, and prostate cancers. Concurrently, the oncology landscape has evolved, with novel oral targeted agents and immunotherapies becoming routine elements of care. The increased need for and complexity with antineoplastics in PLWH has led to recommendations for multidisciplinary care of this unique population. Evaluation of DDIs requires review of metabolic pathways, absorption mechanisms, and various drug transporters associated with antineoplastics and ART. Relevance to Patient Care and Clinical Practice: This review summarizes available data of non-AIDS-defining malignancies, principles of HIV care in the patient with malignancy, and guidance for assessing DDIs between antineoplastics and ART. Summary DDI tables provide point-of-care recommendations. Conclusions: The availability of ART has transformed AIDS into a chronic medical condition, and PLWH are experiencing age-related malignancies. Pharmacists play an important role in the management of this patient population

Survey of physician knowledge regarding antiretroviral medications in hospitalized HIV-infected patients

<p>Abstract</p> <p>Background</p> <p>Antiretroviral prescribing errors are common among hospitalized patients. Inadequate medical knowledge is likely one of the factors leading to these errors. Our objective was to determine the proportion of hospital physicians with knowledge gaps about prescribing antiretroviral medications for hospitalized HIV-infected patients and to correlate knowledge with length and type of medical training and experience.</p> <p>Methods</p> <p>We conducted an electronic survey comprising of ten clinical scenarios based on antiretroviral-prescribing errors seen at two community teaching hospitals. It also contained demographic questions regarding length and type of medical training and antiretroviral prescribing experience. Three hundred and forty three physicians at both hospitals were asked to anonymously complete the survey between February 2007 and April 2007.</p> <p>Results</p> <p>One hundred and fifty-seven physicians (46%) completed at least one question. The mean percentage of correct responses was 33% for resident physicians, 37% for attending physicians, and 93% for Infectious Diseases or HIV (ID/HIV) specialist physicians. Higher scores were independently associated with ID/HIV specialty, number of outpatients seen per month and physician reported comfort level in managing HIV patients (P < .001).</p> <p>Conclusion</p> <p>Non-ID/HIV physicians had uniformly poor knowledge of common antiretroviral medication regimens. Involvement of ID/HIV specialists in the prescribing of antiretrovirals in hospitalized patients might mitigate prescribing errors stemming from knowledge deficits.</p

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead