Pharmacogenetics of HIV therapy: challenges for tailoring treatment in genetically complex populations

Tweetable abstract Pharmacogenetic tests are a promising strategy to improve safety and effectiveness of HIV therapy. However, implementation can be challenging in populations with complex genetic structure.

Unravelling the Proteomics of HLA-B*57:01+ Antigen Presenting Cells during Abacavir Medication

Type B adverse drug reactions (ADRs) are unpredictable based on the drug’s pharmacology and represent a key challenge in pharmacovigilance. For human leukocyte antigen (HLA)-mediated type B ADRs, it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells. Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication. The severe ADR in HLA-B*57:01+ patients treated with the antiretroviral drug abacavir (ABC) in anti-HIV therapy is an example of HLA-drug-T cell cooperation. However, the long-term damages of the HLA-B*57:01-expressing immune cells following ABC treatment remain unexplained. Utilizing full proteome sequencing following ABC treatment of HLA-B*57:01+ cells, we demonstrate stringent proteomic alteration of the HLA/drug presenting cells. The proteomic content indisputably reflects the cellular condition; this knowledge directs towards individual pharmacovigilance for the development of personalized and safe medication.

HIV Proviral Burden, Genetic Diversity, and Dynamics in Viremic Controllers Who Subsequently Initiated Suppressive Antiretroviral Therapy

HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure.

829. Incidence of Low BMD and Barriers to Routine Screening for Osteoporosis in HIV Patients in Eastern North Carolina

Background With HIV therapy, the life expectancy of persons with HIV (PWH) has improved and complications associated with long-standing HIV and antiretroviral drugs have become more apparent. Low bone mineral density (BMD) (defined by T score < -1) and osteoporosis (defined by T-score < -2.5) are common in PWH. In a meta-analysis of 884 HIV-infected patients, 67% had reduced BMD, of whom 15% had osteoporosis which is 3 times greater than HIV uninfected controls. IDSA guidelines recommend routine screening for osteoporosis in PWH aged ≥ 50 years, yet the rate of screening for osteoporosis in these patients remains low (7.4%-17%). This QI project aimed to estimate the frequency of and identify the barriers to screening for osteoporosis in eligible HIV patients. Methods This prospective observational study was conducted in the HIV clinic at East Carolina University from 2018-2019. A sample of 104 HIV patients, ≥ 50 years were selected randomly. Data regarding referral for DXA (dual X-ray absorptiometry) scan, its results, and their insurance provider was collected. The plan was to analyze the barriers associated with guideline-recommended BMD screening and implement it in eligible patients. Results From a total of 104, 89 patients (85.6%) were referred for a DXA scan. The reasons for lack of referral were obesity, insurance barrier, wheelchair-bound, and test ordered by another provider. Of the 89 patients referred for DXA, only 49 (47% of total) underwent the scan. In terms of barriers, insurance limitation was the most common reason. Out of the patients that had DXA scans, 19 (39%) were found to have low bone density and 1 had osteoporosis. Low BMD was more common in men (63%) as compared to women (37%) in this group. Percentage of patients who underwent a DXA scan and the barriers in those who didn’t Frequency of BMD screening Incidence of Low BMD BMD results Conclusion In our study, 47% of patients had a BMD assessment. This is better than what has been reported in other single-center studies, however, it is not ideal. About 34% of the patients had insurance coverage as the major barrier for routine screening, as has been mentioned in other similar studies. Of the patients who underwent the DXA scan, 41 % had a low BMD. Other studies have reported variable prevalence of abnormal BMD, from 47-93%. Interestingly, the prevalence of low BMD in our cohort was close to the national average in non-HIV patients. Disclosures All Authors: No reported disclosures

Small Molecule/HLA Complexes Alter the Cellular Proteomic Content

A medical product usually undergoes several clinical trials, including the testing of volunteers. Nevertheless, genomic variances in the patients cannot be considered comprehensively and adverse drug reactions (ADRs) are missed or misinterpreted during trials. Despite the relation between ADRs and human leukocyte antigen (HLA) molecules being known for several years, the fundamental molecular mechanisms leading to the development of such an ADR often remains only vaguely solved. The analysis of the peptidome can reveal changes in peptide presentation post-drug treatment and explain, for example, the severe cutaneous ADR in HLA-B*57:01-positive patients treated with the antiretroviral drug abacavir in anti-HIV therapy. However, as seen in the biophysical features of HLA-A*31:01-presented peptides, treatment with the anticonvulsant carbamazepine only induces minor changes. Since the binding of a drug to a certain HLA allelic variant is extremely distinct, the influence of the small molecule/protein complex on the proteomic content of a cell becomes clear. A sophisticated methodology elucidating the impact of drug treatment on cells is a full proteome analysis. The principal component analysis of abacavir, carbamazepine or carbamazepine-10,11-epoxid treated cells reveals clear clustering of the drug-treated and the untreated samples that express the respective HLA molecule. Following drug treatment, several proteins were shown to be significantly up- or downregulated. Proteomics and peptidomics are valuable tools to differential clinical outcomes of patients with the same HLA phenotype.

Characteristics of HIV-related stigma among health facility staff in Shenzhen, China

Background: HIV-related stigma poses a crucial barrier to HIV therapy and prevention worldwide. Stigma taking place in healthcare settings has also been a global challenge for years. Objective: To measure HIV-related stigma among health care facilities in Baoan, Shenzhen to inform decision making regarding stigma-reduction intervention. Methods: We conducted a cross-sectional survey in Baoan Maternal and Child Health Hospital, Shenzhen, China in February 2019. We collected data on HIV-related stigma from 207 hospital staff randomly selected for anonymous survey online by a standardized questionnaire. We analyzed the influence factors on HIV-related stigma taking place in health facilities using the statistical method. Results: The percentages of worry expressed when touching clothing, dressing wound, and drawing blood for PLWH were 60.9%, 84.5% and 82.6%, respectively. 76.3% of respondents reported at least one form of extra precautions taken during service provision to PLWH. Younger hospital employees with less working experience were more likely concerned about occupation risk of HIV infection (P<0.05). Single workers with lower education and none experience of training on HIV-related stigma were prone to discriminatory opinions against PLWH (P<0.05). Conclusion: HIV-related stigma in health facilities remains a significant challenge, and evidence-based interventions at both systematic and individual level are needed for improvements.

Expanding the use of dolutegravir-based antiretroviral therapy in multidrug-resistant TB

The wider availability of dolutegravir (DTG) containing HIV therapy for patients living with multidrug-resistant TB (MDR-TB) presents several advantages. DTG-based antiretroviral therapy (ART) has superior potency, reduces pill burden, and may reduce overall treatment-related toxicity, giving it the potential to improve outcomes in both diseases. While the uptake of DTG-based ART in programs where drug-resistant TB is treated remains unknown, there is early evidence from three programs that uptake is increasing. The use of DTG-based ART should be scaled-up, beginning with antiretroviral-naïve or virologically suppressed patients initiating MDR-TB treatment.