Abacavir Research Articles

FORMULATION AND IN-VITRO CHARACTERIZATION OF ABACAVIR SULPHATE EFFERVESCENT FLOATING TABLETS

fter oral administration of Abacavir, rapid absorption occurs from upper part of gastro intestinal tract with peak concentrations occurring at 0.63 - 1 hr after dosing. Conventional drug therapy with tablets produce relatively rapid and high peak blood levels that requires frequent administration to maintain effective range of plasma drug levels. This conventional therapy leads to reduced effectiveness with poor therapeutic management. To overcome the inadequacy of conventional therapy with tablets, floating sustained release Abacavir tablets were developed. Floating sustained release Abacavir Sulphate tablets were prepared by using direct compression method. Tablet were formulated using Ethyl Cellulose with hydrocolloids like Hydroxypropyl Methylcellulose (HPMC K4M) and Carbopol 974P as release retarding polymers, Sodium bicarbonate (NaHCO3) and Citric acid as effervescent agents. Tablets were then evaluated for various physical parameters including hardness, thickness, weight variation, friability, drug content, in-vitro buoyancy, Swelling index and Invitro gastro retentive drug release were conducted. Drug and excipient compatibility studies show that they are compatible with each other. The optimized formulation (F9) shows the hardness of 5.7kg/cm2, tablet thickness of 2.74mm, 0.45% of friability, in-vitro buoyancy was up to 6 hours and % drug release was 90.56% in 6 hours. Drug release kinetics was found to follow non-fickian diffusion. Hence, F9 is considered as optimized formulation based on invitro buoyancy and % drug release.

An up-to-date evaluation of dolutegravir/abacavir/lamivudine for the treatment of HIV

ABSTRACT Introduction There are more than 30 agents available for the treatment of HIV with guidelines shifting toward integrase strand transfer inhibitors (INSTIs) as part of first line therapy. The fixed dose combination of dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) is a convenient, well tolerated, and highly effective option for treating HIV infection and remains a first line therapy across several prominent guidelines. Areas covered In this drug evaluation, the authors provide a comprehensive overview of DTG/ABC/3TC for the treatment of HIV including the pharmacokinetics, pharmacodynamics, efficacy, safety, and tolerability. The authors also provide the reader with their expert perspectives on this particular treatment strategy. Expert opinion While DTG/ABC/3TC remains a valuable HIV treatment option, newer combination regimens have entered the market. Bictegravir with tenofovir alafenamide and emtricitabine offers the benefit of same day initiation and efficacy in hepatitis B co-infection, while new two-drug regimens enhance the simplicity of HIV treatment. Continued study is required into the mechanisms and optimal management strategies for weight gain for many regimens, including DTG/ABC/3TC.

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.

Pharmacokinetic Study of Abacavir Sulphate Loaded Niosomes and Proniosomes in Rats

The plasma pharmacokinetic study of abacavir sulphate was investigated after oral administration of free abacavir sulphate solution, freshly prepared niosomal and proniosomal abacavir sulphate dispersions. The abacavir sulphate loaded niosome vesicles were prepared by the thin-film hydration method and proniosomes were prepared by the slurry method using tween 60 as surfactant cholesterol as a membrane stabilizer and dicetyl phosphate as a negative charge inducer. Maltodextrin was used as a carrier in the proniosome formulations. The formulations were evaluated for various evaluation parameters such as drug-polymer interaction, phase identification analysis and in vivo pharmacokinetic study. The comparative pharmacokinetics of free, niosome encapsulated and proniosome encapsulated abacavir sulphate was evaluated in rats at a dose of 8.57 mg/kg of abacavir sulphate. The results of niosome and proniosome encapsulated abacavir sulphate showed a significant increase in bioavailability and prolonged release characteristics. Increased half-life of 3.40 h in the case of niosomes and 4.88 h in the case of proniosomes were observed. Based on the results, it can be concluded that niosomal and proniosomal formulation could be a promising delivery system for abacavir sulphate with improved oral bioavailability and prolonged drug release profiles.

Toxicity estimation using QSAR methodology and analytical approach for the accurate determination of two potential genotoxic impurities in Abacavir Sulfate antiviral drug at TTC level by liquid chromatography-mass spectrometry (LC-MS/MS)

Toxicity estimation using QSAR methodology and analytical approach for the accurate determination of two potential genotoxic impurities in Abacavir Sulfate antiviral drug at TTC level by liquid chromatography-mass spectrometry (LC-MS/MS)

822. Tenofovir Alafenamide (TAF) is an Independent Risk Factor for Hyperlipidemia in Persons with Human Immunodeficiency Virus (HIV) on Antiretroviral Therapy (ART)

Abstract Background ART-associated weight gain, metabolic disorders, and co-morbidities such as cardiovascular disease are challenges in long-term human immunodeficiency virus (HIV) care. We explore the effects of different ART classes on lipids at The Ohio State University Medical Center Infectious Diseases Clinic. Methods This was a retrospective, cohort study of adult PWH on ART for ≥ 3 months seen at our clinic from 1/1/2015 to 1/1/2017. Patients with CD4+ count < 200 cells/mm3 and viral load >200 copies/mL, history of malignancy, or pregnancy were excluded. Lipid values were collected over the study period. The primary outcome was change in total cholesterol (TC), high density lipoprotein (HDL) cholesterol, and non-HDL cholesterol over the study period. Multivariable regression was used to model these outcomes. Results Among 411 PWH who met criteria, 87.4% were male, and 43.3% had a baseline diagnosis of hyperlipidemia. 21.1% were on a protease inhibitor (PI), 45% were on a non-nucleoside reverse transcriptase inhibitor (NNRTI), and 37% were on an integrase strand transfer inhibitor (INSTI). 70.1% were on tenofovir disoproxil fumarate (TDF)/ emtricitabine (FTC), 20.7% were on abacavir (ABC)/ lamivudine (3TC), and 4.4% were on TAF/FTC. The mean population (MP) difference in TC was -1.54 ± 1.34 mg/dL (p=0.25), the MP difference in non-HDL cholesterol was -1.78 ± 1.26 mg/dL (p=0.16), and the MP difference in HDL cholesterol was 0.24 ± 0.43 mg/dL (p=0.6). In multivariable linear regression models (Table 1), TAF/FTC was associated with a change of TC of 18.2 ± 6.4 mg/dL (P= 0.005), a change of non-HDL cholesterol of 12.0 ± 6.0 mg/dL (p=0.046), and a change of HDL cholesterol of 6.2 ± 2.1 mg/dL (p=0.003). These models included terms for months of follow up, male gender and baseline hyperlipidemia. Though race, diabetes mellitus, and ethnicity were not significant in the model, after adjustments for them, PWH on TAF/FTC showed a change of TC of 18.0 ± 6.4 mg/dL (p=0.005), a change of non-HDL cholesterol of 11.8 ± 6.0 mg/dL (P=0.051), and a change of HDL of 6.2 ± 2.1 (p=0.03). Multivariable Linear Regression Models for Change in Total Cholesterol and Non-HDL Cholesterol Conclusion Prior studies have shown an increase in lipid levels associated with TAF compared to TDF. This study shows that TAF is an independent risk factor for increased TC, non-HDL cholesterol, and HDL cholesterol in the PWH population as a whole. Disclosures Carlos Malvestutto, M.D., Lilly (Scientific Research Study Investigator)Regeneron Inc. (Scientific Research Study Investigator)ViiV Healthcare (Advisor or Review Panel member)

Rapid Near Point-of-Care Assay for HLA-B*57:01 Genotype Associated with Severe Hypersensitivity Reaction to Abacavir.

The nucleoside reverse transcriptase inhibitor abacavir (ABC) is used commonly to treat young children with HIV infection and is a component of the fixed-dose-combination Triumeq®. ABC can trigger a severe hypersensitivity reaction in people who are homozygous or heterozygous for HLA-B*57:01. Testing for HLA-B*57:01 before ABC initiation is standard-of-care in high-resource settings, but current tests are costly or difficult to access in resource-limited settings. To address these gaps, we developed an inexpensive simple-to-use rapid assay to detect HLA-B*57:01. We designed and optimized a multiplexed polymerase chain reaction (PCR) to amplify HLA-B*57 subtypes and the human beta-globin gene; employed probes and ligation to specifically tag the HLA-B*57:01 allele with biotin. Tagged-ligated products were detected by immunocapture in an enzyme-linked immunosorbent assay plate or lateral flow strip. Cell lines with known HLA genotypes were used to optimize the assay. The optimized assay was then compared with genotypes of clinical specimens (n = 60) determined by sequencing, with specimens enriched for individuals with HLA-B*57:01. The optimized assay utilizes 40-min 35-cycle multiplex PCR for B*57 and beta-globin; 20-min ligation reaction; and 15-min detection. Evaluation of the HLA-B*57:01 oligonucleotide ligation assay using clinical specimens had a sensitivity of 100% (n = 27/27 typed as B*57:01) and specificity of 100% (n = 33/33 typed as non-B*57:01) by visual interpretation of lateral flow strips. The cost is US$5.96/specimen. This rapid and economical assay accurately detects HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping and facilitate safe same-day initiation of ABC-based treatment.

SPECTROPHOTOMETRIC METHOD DEVELOPMENT AND VALIDATION FOR SIMULTANEOUS ESTIMATION OF ABACAVIR AND LAMIVUDINE IN COMBINED DOSAGE FORM

Antiretroviral therapy [ART] has been developed remarkably within last three decades, since the first NRTI (nucleoside reverse transcriptase inhibitor) developed. For the mostly patients the challenge of complete and sustain suppression of viral has been clarify, since the triple therapy arrived. Convenient pill burden and tolerability are the main limiting factor for enhancing the long term benefit of ART. ABACAVIR (ABA) and LAMIVUDINE (LAM) are synthetic nucleotide analog (SNA) that showing a synergistic and potent inhibitory effect on human immunodeficiency virus-I (HIV-I), causative agent of AIDS. ABA and LAM belongs to nucleoside reverse transcriptase inhibitor (NRTI) class. As per new therapeutic strategy these two antiretroviral (ARV) drugs are required for the treatment of AIDS. When ARV regimens changed due to lack to virologic response ABA should be avoided. ABA is getting converted in to the active metabolite (carbovir triphosphate) which is an deoxyguanosine-5’ triphosphate analog by intracellular enzymes. LAM gets converted in its active 5’-triphosphate metabolite through phosphorylation. Chemically, ABA is (1S, cis)-4-[2-amino-6-(cyclopropyl amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulphate and LAM is (2R, cis)-4-amino-1-(2-hydroxymethyl-1, 3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Fig. 1 and 2 show ABA and LAM’s structure respectively.

Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity

Idiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype is a rare and unpredictable life-threatening adverse drug reaction for which prospective mechanistic studies in humans are difficult. Here, we show the importance of immune tolerance for IDT onset and determine whether it is susceptible to a common IDT, HLA-B*57:01-mediated abacavir (ABC)-induced hypersensitivity (AHS), using CD4+ T cell-depleted programmed death-1 receptor (PD-1)-deficient HLA-B*57:01 transgenic mice (B*57:01-Tg/PD-1−/−). Although AHS is not observed in B*57:01-Tg mice, ABC treatment increases the proportion of cytokine- and cytolytic granule-secreting effector memory CD8+ T cells in CD4+ T cell-depleted B*57:01-Tg/PD-1−/− mice, thereby inducing skin toxicity with CD8+ T cell infiltration, mimicking AHS. Our results demonstrate that individual differences in the immune tolerance system, including PD-1highCD8+ T cells and regulatory CD4+ T cells, may affect the susceptibility of humans to HLA-mediated IDT in humans.

Bone Deleterious Effects of Different NRTIs in Treatment-naïve HIV Patients After 12 and 48 Weeks of Treatment.

BackgroundBone alterations have been observed in the course of HIV infection, characterized by a marked decrease in bone mineral density (BMD) and an increase in the frequency of fractures as a result of fragility. We aim to evaluate early changes in bone metabolic profile and the possible association with tenofovir and other nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-naïve HIV patients.MethodsWe conducted a prospective study in naïve HIV-infected adults (under 50 years), separated into three groups according to NRTI therapy: tenofovir disoproxil fumarate (TDF); tenofovir alafenamide (TAF) and abacavir (ABC). BMD and epidemiological, immunological and metabolic bone parameters were evaluated. Bone markers were analyzed in plasma at baseline, 12 and 48 weeks after initiating treatment.ResultsAverage age of patients was 34.8 years (± 9.6). 92.4% of them with CD4 count > 200 cel/μL. At week 12 after starting treatment, both TDF [increase in PN1P (31.7%, p = 0.004), TRAP (11.1%, p = 0.003), OPN (19.3%, p = 0.045) and OC (38.6%, p = 0.001); decrease in OPG (-23.4%, p = 0.003)] and TAF [increase in 42.6% for CTX (p = 0.011), 27.3% for OC (p = 0.001) and 21% for TRAP (p = 0.008); decrease in OPG (-28.8%, p = 0.049)] presented a deep resorption profile compared to ABC, these differences in bone molecular markers, a tendency to equalize at week 48, where no significant differences were observed. Patients treated with TDF showed the greatest decrease in Z-score in both lumbar spine (LS) and femoral neck (FN) at week 48 without statistically significant differences.ConclusionTreatment-naïve HIV patients have a high prevalence of low bone density. Treatment with TDF is associated with greater bone deterioration at 12 and 48 weeks. TAF seems to present similar early bone deterioration at 12 weeks which disappears at 48 weeks.

Analysis of the ternary antiretroviral therapy dolutegravir, lamivudine and abacavir using UV spectrophotometry and chemometric tools

Herein, a simple spectrophotometric method coupled with chemometric techniques i.e. partial least square (PLS) and genetic algorithm (GA) were utilized for the simultaneous determination of the vital ternary antiretroviral therapy dolutegravir (DTG), lamivudine (LMV), and abacavir (ACV) in their combined dosage form. Calibration (25 samples) and validation (13 samples) sets were prepared for these drugs at different concentrations via implementing partial factorial experimental designs. The zero order UV spectra of calibration and validation sets were measured and then subjected for further chemometric analysis. Partial least squares with/without variable selection procedures i.e. genetic algorithm (GA) were utilized to untangle the UV spectral overlapping of these mixtures. Cross-validation and external validation methods were applied to compare the performance of these chemometric techniques in terms of accuracy and predictive abilities. It was found that six latent variables were optimum for modelling DTG, four latent variables for modelling LMV and three latent variables for modelling ACV. Although, good recoveries with prompt predictive ability were attained by these PLS, GA-PLS showed better analytical performance owing to its capability to remove redundant variables i.e. the number of absorbance variables have been reduced to about 21–29%. The proposed chemometric methods can be reliably applied for simultaneous determination of DTG, LMV, and ACV in their laboratory prepared mixtures and pharmaceutical preparation posing these chemometric methods as worthy and substantial analytical tools in in-process testing and quality control analysis of many antiretroviral pharmaceutical preparations.

Bone outcomes in virally suppressed youth with HIV switching to tenofovir disoproxil fumarate.

BackgroundTenofovir disoproxil fumarate (TDF) is included in first-line antiretroviral treatment (ART) for adolescents living with HIV (ALWH). Associated toxicities remain a concern.ObjectiveWe evaluated bone and renal safety outcomes in virologically suppressed South African ALWH after switching to TDF.MethodWe recruited virally suppressed (< 100 copies/mL) adolescents, aged 15–20 years, who switched from an abacavir (ABC)-based to a TDF-based efavirenz regimen. Bone mass and renal function were assessed at Week 0 and at Week 24 after the switch to TDF using dual-energy X-ray absorptiometry (DXA) and serum renal markers. A change in the lumbar spine (LS) and the whole-body less head (WBLH) bone mineral density (BMD) Z-scores and the estimated glomerular filtration rate (eGFR) between the two measures were compared (paired t-tests) and stratified by sex.ResultsFifty participants (48% male), with a median duration of prior ART of 11.4 years, were enrolled. Among 47 participants with 24-week DXA results, 15 (32%) had either no change or a decreased LS-BMD after the switch, with a mean change of –1.6%. Overall, more female participants experienced this outcome: 58% versus 4%, P < 0.0001. The mean change (standard deviation) in the LS-Z-score was –0.03 (0.25) and in the WBLH-Z-score was 0.02 (0.24). A decrease in the eGFR from 132.2 to 120.4 was observed (P = 0.0003); however, the levels remained clinically acceptable.ConclusionSouth African ALWH switching from abacavir to TDF-based ART experienced statistically significant decreases in eGFR but not in LS and WBLH BMD. Female ALWH were more likely to experience a decrease in LS-BMD and may require closer monitoring.

Prevalence of human leukocyte antigen HLA-B*57:01 in individuals with HIV in West and Central Africa

BackgroundThe presence of the human leukocyte antigen HLA-B*57:01 is associated with the development of a hypersensitivity reaction to abacavir (ABC). Limited data exist on HLA-B*57:01 prevalence in individuals with HIV-1 in Africa. This study aimed to estimate HLA-B*57:01 prevalence in individuals with HIV-1 in West and Central Africa.MethodsA cross-sectional study was conducted in four countries in West and central Africa (Burkina-Faso, Côte d’Ivoire, Gabon, and Togo) from January 2016 to February 2020 to determine the status of HLA-B*57:01 in adults with HIV-1. The presence of HLA-B*57:01 was determined by using Single Specific Primer-Polymerase Chain Reaction (SSP-PCR) in blood samples. Prevalence rates were stratified based on country.ResultsA total of 4016 (69.8% women) individuals with HIV were enrolled. Their median age was 45, and the interquartile range was 38–52. We included 500 (12.4%) patients in Burkina-Faso, 1453 (36.2%) in Côte d’Ivoire, 951 (23.7%) in Gabon, and 1112 (27.7%) in Togo. The overall HLA-B*57:01 prevalence was 0.1% [95% CI: 0.0–0.2%]. The prevalence of HLA-B*57:01 was similar according to the four countries. Only one case was reported in each country except Togo, with no cases.ConclusionsHLA-B*57:01 prevalence is low in individuals with HIV in West and central Africa, and there is no difference among countries. This study does not confirm the utility of HLA-B*57:01 allele testing for abacavir use in this region.

Associations between plasma nucleoside reverse transcriptase inhibitors concentrations and cognitive function in people with HIV.

To investigate the associations of plasma lamivudine (3TC), abacavir (ABC), emtricitabine (FTC) and tenofovir (TFV) concentrations with cognitive function in a cohort of treated people with HIV (PWH). Pharmacokinetics (PK) and cognitive function (Cogstate, six domains) data were obtained from PWH recruited in the POPPY study on either 3TC/ABC or FTC/tenofovir disoproxil fumarate (TDF)-containing regimens. Association between PK parameters (AUC0-24: area under the concentration-time curve over 24 hours, Cmax: maximum concentration and Ctrough: trough concentration) and cognitive scores (standardized into z-scores) were evaluated using rank regression adjusting for potential confounders. Median (IQR) global cognitive z-scores in the 83 PWH on 3TC/ABC and 471 PWH on FTC/TDF were 0.14 (-0.27, 0.38) and 0.09 (-0.28, 0.42), respectively. Higher 3TC AUC0-24 and Ctrough were associated with better global z-scores [rho = 0.29 (p = 0.02) and 0.27 (p = 0.04), respectively], whereas higher 3TC Cmax was associated with poorer z-scores [rho = -0.31 (p<0.01)], independently of ABC concentrations. Associations of ABC PK parameters with global and domain z-scores were non-significant after adjustment for confounders and 3TC concentrations (all p's>0.05). None of the FTC and TFV PK parameters were associated with global or domain cognitive scores. Whilst we found no evidence of either detrimental or beneficial effects of ABC, FTC and TFV plasma exposure on cognitive function of PWH, higher plasma 3TC exposures were generally associated with better cognitive performance although higher peak concentrations were associated with poorer performance.

Effectiveness and tolerability of dolutegravir and abacavir/lamivudine administered as two separate pills compared to their equivalent single-tablet regimen in a multicentre cohort in Spain.

IntroductionWe aimed to assess the effectiveness and tolerability of dolutegravir (DTG), abacavir (ABC) and lamivudine (3TC) administered as branded STR (DTG/ABC/3TC) or as two separate pills (DTG and either branded ABC/3TC [DTG+(ABC/3TC)b] or generic ABC/3TC [DTG+(ABC/3TC)g]).MethodsWe included individuals from the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) who received DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g during 2015 to 2018. We used multivariable logistic regression to compare the proportion of antiretroviral‐naïve individuals who achieved viral suppression (VS) (viral load ≤50 copies/mL) at 24 weeks of initiating with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g versus DTG/ABC/3TC. We also calculated the proportion of virologically suppressed individuals who maintained VS at 24 weeks after switching from DTG/ABC/3TC to DTG+(ABC/3TC)g.ResultsDuring the study period, 829, 68 and 47 treatment‐naïve individuals started treatment with DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g respectively. The proportions of individuals who changed their regimens due to side effects during the first 24 weeks were 3.7%, 4.4% and 6.4% respectively (p = 0.646). We did not find significant differences in VS at 24 weeks among individuals starting with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g compared to those initiating with DTG/ABC/3TC. Among 177 virologically suppressed individuals who switched from DTG/ABC/3TC to DTG+(ABC/3TC)g, 170 (96.0%) maintained VS at 24 weeks.ConclusionsIn naïve individuals, the effectiveness and tolerability at 24 weeks of DTG plus ABC/3TC administered as two separate pills, either as branded or generic ABC/3TC, was similar to the STR DTG/ABC/3TC. Switching the STR DTG/ABC/3TC to its separate components DTG+(ABC/3TC)g in virologically suppressed individuals did not seem to impair its effectiveness.

Abacavir Dosing in Neonates from Birth to 3 Months of Life

Background: No evidence-based dosing guidance is available for abacavir (ABC) liquid formulation use from birth. Newly available ABC pharmacokinetic (PK) data from neonates and immature infants were used to determine the optimal ABC dosing strategy (mg/kg) for infants 0-3 months and propose dosing per World Health Organization (WHO) weight-bands for neonates. Methods: Abacavir PK and safety data were pooled from three studies: (1) PACTG 321 (2) the Tygerberg Cohort and (3) IMPAACT P1106. Studies 1 and 2 were performed in neonates exposed to HIV receiving a single dose of ABC. Study 3 included predominantly low birth weight (LBW; <2500g) infants on antiretroviral therapy enrolled <3 months of life. We developed a population PK model and performed simulations to achieve ABC exposures (AUC 0-12 ) within the range 3·2-25·2 mcg.hr/mL reported in children. Findings: Forty-five infants contributed 308 ABC concentrations; 21 neonates were <15 days of life. At first PK assessment, median post-natal age was 1·0, 9·5 and 73 days, and median weight was 3·1, 3·3 and 3·8 kg for each study, respectively. ABC clearance was ~5-fold lower than adults at birth but rapid increased in early life. Therapeutic targets were achieved with exact ABC doses of 2·0 mg/kg BID from 0-4 weeks and 4·0 mg/kg BID from 4-12 weeks. A fixed weight-band dosing strategy of 8 mg (2-3 kg), 10 mg (3-4 kg) and 12 mg (4-5 kg) ABC BID achieved target exposures throughout the first 4 weeks of life without dose adjustment for weight changes were necessary. No Grade 3 or more adverse event was ABC related. Interpretation: We propose the first evidence-based ABC dosing strategy from birth using both exact and weight-band dosing for the liquid formulation. Integration of these new ABC dosing recommendations into National and International guidelines will provide an additional antiretroviral option from birth that is easily implementable. Trial Registration: Clinical trial.gov Identifier: NCT02383849 (P1106), NC0864 (PACTG 321) Funding: For PACTG321 and IMPAACT P1106, overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Tygerberg Cohort study was supported by the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) - Growing the Leaders of Tomorrow Fellowship Programme. Declaration of Interest: AB, EVC, AV, MFC, RM, HR and MM received funding from the IMPAACT Network. MM received funding from Gilead Sciences, Merck & Co, and ViiV Healthcare. HR received funding from Abbvie. INCOMPLETE Ethical Approval: All studies were approved by the institutional review board responsible for study oversight. Written informed consent was obtained from all infants’ mothers/legal caregivers prior to entry.

Cardiovascular Diseases Associated Inflammatory Biomarker Levels in a Small Cohort of HIV-1 Infected Patients Deintensificated from Abacavir/Lamivudine/ Dolutegravir to Lamivudine Plus Dolutegravir Running Head: Risk of Cardiovascular Diseases and Abacavir Use

Following the successful introduction of combined Antiretroviral Therapy (cART), a dramatic decrease in viral burden and opportunistic infections along with a consistent increase in life expectancy has been observed in Human Immunodeficiency Virus (HIV) infected patients [1]. This deep change in the HIV disease evolution has determined that HIV positive subjects were effectively monitored for several alterations of many tissue and organs due to HIV chronic disease and antiretroviral treatment for example, cardiovascular system, bone, adipose tissues, kidney and central nervous system represent the major target of these structural and functional damages during HIV infection. In particular, Cardiovascular Diseases (CVD) were considered important clinical complications in the HIV patient and represent a leading cause of death among HIV-positive patients, accounting for approximately 11% of the total deaths in this population [2]; the risk of CVD is higher in HIV positive individuals compared with HIV negative people, and particularly the reported Myocardial Infarction (MI) incidence in cohort study ranges from 3 to 11 cases per 1000 patients a year in HIV- positive individuals against 2 to 7 cases per 1000 patients-years in HIV-negative population [3,4]. Although initial studies indicated a higher prevalence of traditional CVD risk factors in HIV infected population [5,6] as a possible cause, the molecular mechanisms of increased CVD risk in HIV still remain incompletely defined and should be probably attributable to a combination of multiple factors, including both direct and indirect effects of HIV infection on metabolism. Evidence from experimental and observational studies [7,8] in recent years suggested a more important role of HIV itself in contributing to CVD. Endothelial dysfunction due to gp120, Tat and Nef proteins have been identified as a critical link between infection, inflammation, immune activation, atherosclerosis and cardiovascular system. Moreover, ART may play a role in the exacerbation of risk factors for CVD [9]; since the presentation of findings from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study in 2008 demonstrating a 90% increased risk of MI in HIV- positive individuals receiving ART regimens including Abacavir (ABC), subsequent studies, conducted by FDA [10], GlaxoSmithKline [11] and independent researchers [12], to investigate this risk have yielded conflicting results. Although more recent studies have shown an effective increased risk of CVD associated with use of ABC, many results did not reach statistical significance [13-17]. The absence of a demonstrated underlying biological mechanism for such a risk added interest and confusion about the question, as well as the higher prevalence of risk factors for CVD, such as renal impairment and substance abuse among abacavir recipients; in addition, a recent meta analysis suggests that Relative Risk (RR) for MI is increased within a 6 months exposure to ABC (RR=1.61; 95% confidence interval: 1.48–1.75) and in cART-naive population [18]. While the published evidence remains conflicting and a plausible biological mechanism for this potential association has not yet been identified, in the following study we have tried to verify whether, after introduction of ABC and its discontinuation in the contest of HAART deintensification, common metabolic markers CVD related such as glucose, LDL, HDL, total cholesterol and triglycerides and inflammatory biomarkers such as IL-6 and D-dimer could change in a small cohort of HIV-1 infected patients.

Weight-adapted fixed-dose combined adult antiretroviral tablets for HIV-infected children.

Therapeutic alternatives to simplify antiretroviral therapy (ART) in HIV-infected children are needed. We report our experience with abacavir(ABC)/lamivudine(3TC) individualized dose compounded capsules (IDCC). We present a prospective case series of HIV-infected children who did not weigh enough to receive the adult fixed-dose combination including ABC/3TC 600mg/300mg, and were treated with weight-adapted ABC/3TC IDCC in Barcelona, Spain. Thirteen patients (12 girls) received ABC/3TC IDCC for a median(IQR) time of 30(17-54) months. No significant changes were observed in CD4 cell counts, weight or height z-scores over time. Suppression of viral replication was maintained in 7 patients with undetectable viremia at baseline. Another 5 patients achieved viral suppression with ABC/3TC IDCC-based ART, while one non-adherent girl did not. No adverse events related to ABC/3TC IDCC were observed. Despite small numbers, the long-term use of ABC/3TC IDCC was feasible, safe, and effective in the treatment of HIV-infected children.

LB-7. Weight Change in Suppressed People with HIV (PWH) Switched from Either Tenofovir Disoproxil Fumarate (TDF) or Abacavir (ABC) to Tenofovir Alafenamide (TAF)

BackgroundWeight gain in PWH occurred in both naïve and switch studies and is linked to use of integrase inhibitors (INSTIs) with varying associations with nucleoside reverse transcriptase inhibitors (NRTIs). One hypothesis is that gain associated with TAF when switching from TDF is a result of cessation of TDF-induced weight suppression.MethodsThe study evaluated weight change in suppressed PWH on INSTI+NRTIs switched from ABC or TDF to TAF. Eligible pts had HIV, were ≥ 18 yrs at index (date of switch), treatment-experienced with known prior regimen, suppressed at index (-12 to +1 mo) and 1 yr, ≥ 6 mo pre-index history, with weight measures at index and 1 yr, no current or pre-index use of protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Univariate comparisons were performed using Χ2 for categorical and t-test for continuous variables; negative binomial model with log link function evaluated risk of gain ≥ 3% of body weight between groups accounting for age, gender, race, body mass index (BMI), CD4. Linear mixed effects model was used to estimate mean weight at index and 1 yr post switch.ResultsOf 970 pts, 828 (85%) switched from TDF to TAF and 142 (15%) from ABC to TAF. Groups were balanced by race, gender, index BMI [Table 1]. Figures 1a-b describe pre- and post-switch INSTI use. At 1 yr, mean unadjusted weight change was 1.4 kg in TDF and 0.2 in ABC group p=0.039. TDF to TAF had higher proportion of PWH with gain ≥ 3% vs ABC to TAF (40% vs 27% p=0.003); differences in gain ≥ 5% and ≥ 10% were not statistically significant (26% vs 22% p=0.323 and 10% vs 6% p=0.220). Pts who gained ≥ 3% were younger, with greater proportion of females, non-obese, with 1 prior regimen, and prior elvitegravir (EVG) use. In adjusted analysis TDF to TAF had higher risk of gain ≥ 3% vs ABC to TAF [Figure 2]. In sensitivity analysis accounting for EVG or dolutegravir (DTG) use, TDF to TAF also had higher risk of ≥ 3% gain vs ABC to TAF: adjusted risk ratio (aRR)= 1.38 [1.01–1.89] and aRR= 1.42 [1.02–1.97].Table 1. Baseline (index) characteristics. Figures 1a-b. Distribution of pre switch and post switch INSTI use. Figure 2. Risk of weight gain ≥ 3% of body weight at 1 year post switch accounting for age, gender, race, index BMI, and CD4. ConclusionSwitching from TDF to TAF in INSTI-based regimens had a greater risk of weight gain vs ABC to TAF. This difference persisted when accounting for impact of the INSTI agent in the current regimen. These data suggest that differences in weight gain between TAF and TDF are driven by removal of TDF-associated weight suppression.Disclosures Paul Sax, MD, Gilead (Consultant, Research Grant or Support)Janssen (Consultant)Merck (Consultant, Research Grant or Support)ViiV Healthcare (Consultant, Research Grant or Support) Keri N. Althoff, PhD, MPH, Gilead (Advisor or Review Panel member) Keri N. Althoff, PhD, MPH, All of Us Study (NIH) (Individual(s) Involved: Self): Consultant; MedIQ (Individual(s) Involved: Self): Consultant; TrioHealth (Individual(s) Involved: Self): Advisor or Review Panel member Todd T. Brown, MD, PhD, Gilead (Consultant)Merck (Consultant)Theratechnologies (Consultant)ViiV Healthcare (Consultant) Janna Radtchenko, MBA, Trio Health (Employee) Helena Diaz Cuervo, PhD, Gilead Sciences (Employee) Steven Santiago, MD, Gilead (Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker's Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Karam Mounzer, MD, Epividian (Advisor or Review Panel member)Gilead (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)Janssen (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)Merck (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)ViiV Healthcare (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau) Richard Elion, MD, Gilead (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)Janssen (Speaker's Bureau)Proteus (Research Grant or Support)ViiV Healthcare (Advisor or Review Panel member, Research Grant or Support)

1028. Long-term Follow-up After a Switch to Bictegravir, Emtracitabine, Tenofovir Alafenamide from Dolutegravir, Abacavir, Lamivudine

BackgroundBictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) is a guidelines-recommended single-tablet regimen (STR) for people living with HIV-1 (PLWH). Week (W) 48 primary endpoint results of this phase 3 study switching to B/F/TAF from dolutegravir (DTG), abacavir (ABC) and lamivudine (3TC) established the safety and efficacy of B/F/TAF. Here we report outcomes from an open-label (OL) extension of B/F/TAF.MethodsAdults virologically suppressed on DTG, ABC, and 3TC were randomized 1:1 to switch to B/F/TAF once daily or continue their current regimen as a STR in a double blind (DB) manner. Unblinding occurred after the W48 primary endpoint, then participants received B/F/TAF in an OL extension while transitioning off the study. All participants who received B/F/TAF in the DB or OL phases are included in analyses. Efficacy was assessed as the proportion with HIV-1 RNA < 50 copies/mL at each study visit using missing=excluded (M=E) analysis, efficacy in in subgroups with pre-existing resistance was assessed using last observation carried forward. Safety was assessed by adverse events (AEs) and laboratory results.Results563 participants were randomized and treated (282 B/F/TAF, 281 ABC/DTG/3TC); 524 (93%) completed the DB phase and received OL B/F/TAF; a total of 547 participants received B/F/TAF in DB and/or OL phases: 11% women, 21% Black, median age 47 yrs (range 21, 71). The median duration of B/F/TAF was 96 weeks (IQR 49-119). HIV-1 RNA < 50 c/mL was maintained in 99-100% at all timepoints (M=E) through a maximum of 168 weeks, including high efficacy in those with archived resistance (Table 1). No participant developed resistance to B/F/TAF. Study drug-related AEs occurred in 7% on B/F/TAF; most were grade 1; the most common was headache (1.6%). 7 (1%) participants had an AE leading to premature study drug discontinuation, only 1, headache, occurred in the OL phase. Estimated GFR and lipids were mostly stable with slightly increased LDL at W96; weight changes are noted at W48 and W96. (Table 2).Table 1. Table 2. ConclusionExtended follow-up to the study of switching to B/F/TAF from DTG/ABC/3TC, demonstrates continued high rates of virologic suppression with no resistance and excellent safety and tolerability of B/F/TAF through a maximum of 168 weeks for treatment of PLWH.Disclosures Indira Brar, MD, Gilead (Speaker’s Bureau)janssen (Speaker’s Bureau)ViiV (Speaker’s Bureau) Peter Ruane, MD, AbbVie (Consultant, Grant/Research Support, Speaker’s Bureau)Bristol-Myers Squibb (Grant/Research Support)Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Shareholder, Speaker’s Bureau)Idenix (Consultant)Janssen (Grant/Research Support, Speaker’s Bureau)Viiv Healthcare (Grant/Research Support) Douglas Ward, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Merck (Advisor or Review Panel member)Viiv Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Jean-michel Molina, MD, PhD, Bristol-Myers Squibb (Advisor or Review Panel member)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Teva (Advisor or Review Panel member)Viiv Healthcare (Advisor or Review Panel member) Anthony Mills, MD, Gilead (Grant/Research Support, Advisor or Review Panel member)Janssen Pharmaceutica (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Shionogi (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Mezgebe Berhe, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator) Cynthia Brinson, MD, Gilead (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Moti Rampogal, MD, Gilead Sciences (Consultant, Research Grant or Support, Speaker’s Bureau)Janssen (Consultant, Research Grant or Support, Speaker’s Bureau)Merck (Consultant, Research Grant or Support)ViiV Healthcare (Consultant, Research Grant or Support, Speaker’s Bureau) Keith Henry, MD, Gilead (Research Grant or Support, Paid to institution)GSK/ViiV (Research Grant or Support, Paid to institution)Janssen (Research Grant or Support, Paid to institution)Merck (Research Grant or Support, Paid to institution) Hailin Huang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Kristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Hal Martin, MD, MPH, Gilead Sciences Inc. (Employee, Shareholder)