Effects of switching to dolutegravir/lamivudine from tenofovir alafenamide fumarate/emtricitabine/dolutegravir or abacavir/lamivudine/dolutegravir on body weight and lipid profile in Japanese people living with HIV.

BACKGROUND: The two-drug regimen of dolutegravir/lamivudine (DTG/3TC) is currently an optional antiretroviral therapy (ART). Despite its reported advantages on body weight and lipid profile, the same effects have not yet been reported for Asian population. METHODS: We conducted a single-center retrospective study involving Japanese people living with HIV (PLWH). They were divided into four groups: those who had received abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) and continued the same (ABC-ON group) or switched to DTG/3TC (ABC-OFF group), those who had received tenofovir alafenamide fumarate/emtricitabine/dolutegravir (TAF/FTC/DTG) and continued the same (TAF-ON group) or switched to DTG/3TC (TAF-OFF group). We compared changes in viral load, CD4⁺ cell count, CD4⁺/CD8⁺ ratio, body weight, BMI, lipid profiles, estimated glomerular filtration rate (eGFR), and fibrosis index based on four factors (FIB4-index) between the pre-switch and post-switch period. RESULTS: Of the 541 PLWH on DTG-based ART, 165, 94, 264 and 18 constituted the ABC-ON, ABC-OFF, TAF-ON, and TAF-OFF groups, respectively. Neither viral rebound nor CD4+decline was observed in the post-switch period in all groups. Multivariate analysis showed significant reduction in total cholesterol, LDL-C and HDL-C in the ABC-OFF group (-6.280, -6.957 and -2.268, p = 0.040, 0.012 and 0.022, respectively), but not in the TAF-OFF group (-3.000, 6.708 and 0.046, p = 0.607, 0.276 and 0.983, respectively). No significant changes were observed in body weight, eGFR, or FIB4-index at 72 weeks after the discontinuation of ABC or TAF. CONCLUSIONS: Switching from ABC/3TC/DTG to DTG/3TC lowered lipids significantly, but not with TAF/FTC/DTG. Neither switch affected body weight or other markers.

Comparison between the impact of tenofovir alafenamide and that of abacavir on rapid kidney function decline: A retrospective observational study.

OBJECTIVES: To compare the impact of tenofovir alafenamide (TAF) on the slope of the estimated glomerular filtration rate (eGFR) with that of abacavir in Japanese patients living with HIV infection. METHODS: The participants in this single-centre, retrospective, observational study were Japanese patients with HIV infection who started antiretroviral therapy with TAF/emtricitabine or abacavir/lamivudine or were switched from tenofovir disoproxil fumarate/emtricitabine to TAF/emtricitabine or abacavir/lamivudine (anchor drugs remained constant) between January 2012 and December 2020. The eGFR slope was defined as the regression coefficient between eGFR and time. The study outcome was rapid kidney function decline (RKFD; eGFR slope < -5 mL/min/1.73 m2 /year). The adjusted effect of TAF on the eGFR slope was compared with that of abacavir using multivariate logistic regression analysis. RESULTS: The study included 184 patients (with 2835 eGFR data points). The median duration of exposure to TAF or abacavir was 2.6 years [interquartile range (IQR): 1.7-3.3], and the median eGFR slope was -4.1 mL/min/1.73 m2 /year (IQR: -6.4 to -1.2). In all, 72 patients (39%) experienced RKFD. Patients receiving TAF were more likely to experience RKFD (adjusted odds ratio = 3.74) than those receiving abacavir. There was a significant independent association between baseline eGFR and RKFD. CONCLUSIONS: These findings suggest that renal function should be monitored carefully after the initiation of TAF in Japanese patients with HIV infection.

Increased human immunodeficiency virus viral load with cerebral infarction due to varicella zoster virus vasculopathy on treatment with bictegravir/emtricitabine/tenofovir alafenamide suspension: a case report and literature review.

BACKGROUND: Varicella-Zoster virus (VZV) vasculopathy occasionally occurs in immunocompromised patients and is difficult to treat. The risk factor and optimal therapy remain unclear. Patients with human immunodeficiency virus (HIV) and dysphagia or difficulty in oral intake receive antiretroviral therapy (ART) suspension. However, there remains little evidence regarding ART suspension. CASE PRESENTATION: We experienced a case of a 55-year-old man diagnosed with HIV and severe multiple cerebral infarctions due to VZV vasculopathy. We started on bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) and acyclovir (ACV), and prednisone. He was started on BIC/TAF/FTC suspension because of deteriorated swallowing. The HIV viral load was increased; however, no drug-resistance genes were detected. We successfully treated him with doltegravir/abacavir/lamibudine suspension. We performed two literature reviews of the administration of BIC/TAF/3TC suspension and VZV vasculopathy in patients with HIV. Three cases of BIC/TAF/3TC suspension were considered treatment failures. Recent history of VZV infection and a CD4 count under 200 µL may be risk factors for VZV vasculopathy. The effective treatment may be using steroid and ACV; however, treatment duration could differ. CONCLUSIONS: BIC/TAF/FTC suspension administration may be unstable, and treating ACV and steroid may be optimal therapy for VZV vasculopathy; however, the evidence level is low.

Comparison of Chemical and Electrochemical Approaches to Abacavir Oxidative Stability Testing.

A novel electrochemical approach using two different electrode materials, platinum and boron-doped diamond (BDD), was employed to study the oxidative stability of the drug abacavir. Abacavir samples were subjected to oxidation and subsequently analysed using chromatography with mass detection. The type and amount of degradation products were evaluated, and results were compared with traditional chemical oxidation using 3% hydrogen peroxide. The effect of pH on the rate of degradation and the formation of degradation products were also investigated. In general, both approaches led to the same two degradation products, identified using mass spectrometry, and characterised by 319.20 and m/z 247.19. Similar results were obtained on a large-surface platinum electrode at a potential of +1.15 V and a BDD disc electrode at +4.0 V. Degradation of 20% of abacavir, the rate required for pharmaceutical stability studies, took only a few minutes compared to hours required for oxidation with hydrogen peroxide. Measurements further showed that electrochemical oxidation in ammonium acetate on both types of electrodes is strongly pHdependent. The fastest oxidation was achieved at pH 9. The pH also affects the composition of the products, which are formed in different proportions depending on the pH of the electrolyte.

AOP-Based Transformation of Abacavir in Different Environments: Evolution Profile of Descyclopropyl-Abacavir and In Silico Toxicity Assessment of the Main Transformation Products.

This study explores the photocatalytic transformation of the antiviral drug abacavir employing different advanced oxidation processes (AOPs) such as UV/TiO2, UV/MOF/H2O2, UV/MOF/S2O82-, UV/Fe2+/H2O2, and UV/Fe2+/S2O82-. All processes appear to be effective in eliminating abacavir within a few minutes, while the evolution profile of the basic transformation product, descyclopropyl-abacavir (TP-247) was also monitored. Moreover, the implementation of the most efficient technologies towards the removal of abacavir in different matrices such as wastewater effluent and leachate was also assessed, revealing that the organic matter present or the inorganic constituents can retard the whole process. Four major transformation products were detected, and their time-evolution profiles were recorded in all studied matrices, revealing that different transformation pathways dominate in each matrix. Finally, the prediction of the toxicity of the major TPs employing ECOSAR software was conducted and showed that only hydroxylation can play a detoxification role in the treated solution.

HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk.

RATIONALE: People living with HIV on effective antiretroviral therapy are at increased risk of cardiovascular complications, possibly due to off-target drug effects. Some studies have associated antiretroviral therapy with increased risk of myocardial infarction and endothelial dysfunction, but a link between endothelial function and antiretrovirals has not been established. OBJECTIVE: To determine the effects of antiretrovirals in common clinical use upon in vitro endothelial function to better understand cardiovascular risk in people living with HIV. METHODS AND RESULTS: Human umbilical cord vein endothelial cells or human coronary artery endothelial cells were pretreated with the antiretrovirals abacavir sulphate (ABC), tenofovir disoproxil fumarate, or tenofovir alafenamide. Expression of adhesion molecules, ectonucleotidases (CD39 and CD73), tissue factor (TF), endothelial-derived microparticle (EMP) numbers and phenotype, and platelet activation were evaluated by flow cytometry. TF and ectonucleotidase activities were measured using colourimetric plate-based assays. ABC-treated endothelial cells had higher levels of ICAM (intercellular adhesion molecule)-1 and TF expression following TNF (tumor necrosis factor)-α stimulation. In contrast, tenofovir disoproxil fumarate and tenofovir alafenamide treatment gave rise to greater populations of CD39+CD73+ cells. These cell surface differences were also observed within EMP repertoires. ABC-treated cells and EMP had greater TF activity, while tenofovir disoproxil fumarate- and tenofovir alafenamide-treated cells and EMP displayed higher ectonucleotidase activity. Finally, EMP isolated from ABC-treated cells enhanced collagen-evoked platelet integrin activation and α-granule release. CONCLUSIONS: We report differential effects of antiretrovirals used in the treatment of HIV upon endothelial function. ABC treatment led to an inflammatory, prothrombotic endothelial phenotype that promoted platelet activation. In contrast, tenofovir disoproxil fumarate and tenofovir alafenamide conferred potentially cardioprotective properties associated with ectonucleotidase activity. These observations establish a link between antiretrovirals and specific functional effects that provide insight into cardiovascular disease in people living with HIV.

Abacavir pharmacokinetics in African children living with HIV: A pooled analysis describing the effects of age, malnutrition and common concomitant medications.

AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

TARC/CCL17 Expression Is Associated with CD8+ T Cell Recruitment in Abacavir-Induced Skin Hypersensitivity in HLA-Transgenic Mice.

Abacavir (ABC)-induced hypersensitivity (AHS) is strongly associated with human leukocyte antigen (HLA)-B*57 : 01 expression. Previous studies have demonstrated the feasibility of applying the HLA-transgenic mouse model in this context. ABC-induced adverse reactions were observed in HLA-B*57 : 01 transgenic (B*57 : 01-Tg) mice. Moreover, regulating immune tolerance could result in severe AHS that mimics symptoms observed in the clinical setting, which were modeled in CD4+ T cell-depleted programmed death-1 receptor (PD-1) knockout B*57 : 01-Tg (B*57 : 01-Tg/PD-1-/-) mice. Here, we aimed to examine whether thymus and activation-regulated chemokine (TARC)/CCL17 level can be used as a biomarker for AHS. Serum TARC levels increased in HLA-B*57 : 01-transgenic mice following oral administration of ABC; this increase was associated with the severity of skin toxicity. In ABC-fed CD4+ T cell-depleted B*57 : 01-Tg/PD-1-/- mice, TARC was detected in the epidermal keratinocytes of the ear. Skin toxicity was characterized by the infiltration of CD8+ T cells partially expressing C-C chemokine receptor type 4, which is the primary receptor for TARC. In vivo TARC neutralization effectively alleviated the symptoms of ear skin redness and blood vessel dilatation. Moreover, TARC neutralization suppressed the infiltration of CD8+ T cells to the ear skin but did not affect the ABC-induced adaptive immune response. Therefore, TARC was involved in ABC-induced skin toxicity and contributed to the recruitment of CD8+ T cells to skin. This evidence suggests that serum TARC level may be a functional biomarker for AHS.

Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir.

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradiation (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell invasion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic.

[Determination of abacavir in biological objects for the purpose of chemical and toxicological analysis]. / Opredelenie abakavira v biologicheskikh ob"ektakh dlya tselei khimiko-toksikologicheskogo analiza.

Purpose - to develop a technique for isolating abacavir, as well as its detection and quantification in biological objects. Extraction of abacavir from centrifuges was carried out with chloroform at pH 8 in the presence of an electrolyte saturated solution of (NH4)2SO4 once for 3 minutes. The determination of abacavir in extracts from urine, saliva and liver was carried out by thin-layer chromatography in the system of ethyl acetate: trichloromethane: ammonia, a concentrated solution of 25% (17:4:1) ascending method, UV spectrophotometry in a medium of hydrochloric acid 0.1 M, where the absorption spectrum abacavir is characterized by an absorption maximum at a wavelength of 297±1 nm, high performance liquid chromatography, during which one peak with a retention time of 9.5 min was observed on the chromatogram of a standard sample, which coincided with the retention time of abacavir obtained after extraction from biological objects.

Single Dose Abacavir Pharmacokinetics and Safety in Neonates Exposed to Human Immunodeficiency Virus (HIV).

Abacavir is a potential option for prophylaxis and early treatment of human immunodeficiency virus (HIV), but no data are available in neonates. Ten neonates administered a single abacavir dose of 8 mg/kg before 15 days of life had substantially higher exposures than those reported in infants and children, with no reported adverse events.

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

BACKGROUND: The 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. METHODS: A 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. RESULTS: A 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. CONCLUSIONS: HLA-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.

Safety and effectiveness of switching to Abacavir/Lamivudine plus rilpivirine for maintenance therapy in virologically suppressed HIV-1 individuals in Singapore (SEALS).

BACKGROUND: The efficacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC + RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed individuals. This study evaluated the effectiveness and safety of switching to ABC/3TC + RPV as maintenance therapy in virologically suppressed HIV-1 infected individuals in Singapore. METHODS: In this retrospective, single-centre study, we included individuals who were prescribed ABC/3TC + RPV, had HIV-1 viral load (VL) < 50 copies/ml immediately pre-switch, and had no documented history of resistance mutations or virologic failure to any of the components. The follow-up period was 48 ± 12 weeks. The primary outcome was the proportion of individuals who maintained virologic suppression of HIV-1 VL < 50 copies/ml at the end of follow-up period based on on-treatment analysis. The secondary outcomes were the resistance profiles associated with virologic failure, changes in immunologic and metabolic parameters, and the safety profile of ABC/3TC + RPV. RESULTS: A total of 222 individuals were included in the study. The primary outcome was achieved in 197 individuals [88.8%, 95% confidence interval: 83.7-92.4%]. There were 21 individuals (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 individuals experienced virologic failure, of whom, 3 of these individuals had developed emergent antiretroviral resistance and had HIV-1 VL > 500 copies/ml at the end of the 48 ± 12 weeks follow-up period. The remaining individual experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 individuals (14.0%), which led to 13 individuals discontinuing therapy. Neuropsychiatric adverse events were most commonly observed (53.1%). A statistically significant increase in CD4 was observed (p < 0.01), with a median absolute change of 31 cells/uL (interquartile range: - 31.50 to 140.75). No significant changes in lipid profiles were detected. CONCLUSION: ABC/3TC + RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 individuals with in Singapore.

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

WHAT IS KNOWN AND OBJECTIVE: 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). COMMENT: 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. WHAT IS NEW AND CONCLUSION: Despite small numbers, the long-term use of ABC/3TC IDCC was feasible, safe, and effective in the treatment of HIV-infected children.

Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir.

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

In silico, in ovo and in vitro antiviral efficacy of phosphorylated derivatives of abacavir: an experimental approach.

Outstanding increase of oral absorption, bioavailability, and antiviral efficacy of phosphorylated nucleosides and basic antiviral influence of abacavir is the central idea for the development of new series of phosphorylated abacavir (ABC) derivatives. The designed compounds were primarily screened for antiviral nature against HN protein of NDV and VP7 protein of BTV using the molecular environment approach. Out of all the designed compounds, the compounds which are having higher binding energies against these two viral strains were prompted for the synthesis of the target compounds (5A-K). Among the synthesized title compounds (5A-K), the compounds which have exhibited higher dock scores akin to the rest of the compounds were then selected and screened for the antiviral activity against NDV and BTV infected embryonated eggs and BHK 21 cell lines through the in ovo and in vitro approaches. The results revealed that all the designed compounds have formed higher binding energies against both the targets. Among all, the compounds which are selected based on their dock scores such as 5A, 5F, 5G, 5H, 5I, and 5K against NDV and 5J, 5E, 5I, 5C, 5A, and 5K against BTV have shown significant antiviral activity against HN protein of NDV, VP7 protein of Bluetongue virus in both NDV- and BTV-treated embryonated eggs and BHK 21 cell lines. Hence, it is concluded that, the best lead compounds will stand as the potential antiviral agents and prompted them as virtuous therapeutics against NDV and BTV in future.

Comparison of abacavir-specific effector and proliferating functions of CD8 T cells in abacavir-treated HIV-1 patients.

Susceptibility to abacavir hypersensitivity (ABH) in HIV-1-positive patients is strongly linked to the carriage of HLA-B*57:01 and the potential mechanism includes drug-specific activation of cytokine producing CD8 T cells exclusively in individuals carrying HLA-B*57:01. Here, we report a detailed characterization of abacavir-induced functional response of CD8 T cells in HLA-B*57:01pos individuals. Peripheral blood mononuclear cells (PBMNCs) from HLA-B*57:01pos ABHpos and HLA-B*57:01neg ABHneg individuals were stimulated with abacavir. Multicolor flow cytometry was performed to assess the cytokine (IFNγ) production and degranulation (CD107a expression) after 6-18 hr culture and to enumerate proliferating CD4/CD8 T cells by culturing carboxyfluorescein diacetate succinimidyl ester-loaded PBMNCs for 7 days. CD8 T cells from HLA-B*57:01pos ABHpos individuals were multifunctional: proliferating, IFNγ producing, degranulating (CD107apos ), and both degranulating and IFNγ producing (CD107apos IFNγpos ). Degranulating CD8 T cells in general and both degranulating and IFNγ producing CD8 T cells in particular dominated abacavir-specific immune response. All functional responses were partially blocked by addition of HLA-B*57:01-reactive Bw4 mAb, but not by non-HLA-B*57:01-reactive Bw6 mAb. In conclusion, the study demonstrates that abacavir-specific CD8 T-cell-restricted immune response in HLA-B*57:01pos ABHpos HIV-1 patients has multiple effector and proliferating functions, where the primary effector response appears to be the release of cytolytic granules. The findings have implications for immunotherapy of HLA-related drug hypersensitivities.

Efficacy and safety of abacavir/lamivudine plus rilpivirine as a first-line regimen in treatment-naïve HIV-1 infected adults.

BACKGROUND: The anti-retroviral combination of abacavir/lamivudine plus rilpivirine (ABC/3TC/RPV) is not recommended by international guidelines as the first-line regimen. However, it is potent, well-tolerated, and affordable, especially in resource-limited settings. This study evaluates the efficacy and safety of ABC/3TC/RPV as an initial regimen for treatment-naïve HIV-1 infected patients. METHODS: A retrospective study was conducted in the largest HIV care centre in Singapore, with data collected June 2011 to September 2017. All treatment-naïve HIV-1 infected adults prescribed ABC/3TC as part of their initial anti-retroviral therapy regimen were included. The third drug was a non-nucleoside reverse-transcriptase inhibitor (NNRTI) such as RPV or efavirenz (EFV), or boosted protease-inhibitor (PI). Patients were followed up for 48 weeks. The primary end-point was the percentage of patients achieving virologic suppression, analysed using on-treatment analysis. Secondary outcomes included CD4-count change, treatment discontinuation and treatment-related adverse events. RESULTS: 170 patients were included in the study, 66 patients in the RPV group, 104 patients in the comparator group (EFV or boosted PI). 96% (n = 24) in the RPV group and 87% (n = 26) in the comparator group achieved viral suppression at 48 weeks (p = 0.28). Median (interquartile range) time to viral suppression was similar: 17 (14-24) weeks in the RPV group, and 21 (13-26) weeks in the comparator group. There were no statistically significant differences in the CD4 count between the two groups. 14% (n = 9) of patients on RPV discontinued treatment before 48 weeks, compared to 30% (n = 31) from the comparator group (p = 0.053). Of these, 23 discontinuations were due to drug adverse effects, and only 1 attributed to RPV (p < 0.01). One patient in each group had virologic failure. CONCLUSION: RPV is effective, safe and considerably more tolerable than compared to NNRTI or boosted PI in ABC/3TC-containing regimens for treatment-naïve patients. It offers an affordable and attractive option, especially in resource-limited settings.

Abacavir versus Zidovudine-based regimens for treatment of HIV-infected children in resource limited settings: a retrospective cohort study.

BACKGROUND: Abacavir (ABC) and Zidovudine (AZT) based regimens are the preferred first line nucleoside reverse transcriptase (NRTIs) backbones being widely utilized for managing HIV infection in children. However, there is a dearth of data regarding the clinical outcomes and associated risk factors in Ethiopia. We compared the proportion of mortality and the rate of occurrence of Opportunistic Infections (OIs) with ABC versus AZT -based regimens in a cohort of HIV-infected children. METHODS: A 42 months retrospective cohort study was conducted. A total of 179 records were reviewed by including data from October 2014 to April 2017. Data were collected on socio-demographic, clinical characteristics of patients and drug related variables. Data were analyzed using STATA13.1. Kaplan-Meier and Cox regression were used to compare survival experience and identify independent predictors. Propensity score matching analysis was conducted to elucidate the average treatment effects of each regimen over OIs. RESULT: Of 179 patients, 98 (54.7%) were females. The mean (+SD) age of the study subjects was 6.53 ± 2.83 years. Through 42 months analysis, a total of 4 patients (1 (1.14%) from ABC group and 3 (3.3%) from AZT group (p = 0.339)) were died. The incidence of opportunistic infections attributed to ABC group was 8.77/100,000 person years (py) and that of AZT was 6.9/100,000py. The incidence rate ratio (IRR) for OIs was (IRR = 0.87, 95% CI [0.49-1.53] (p = 0.304). Baseline CD4 count (AHR = 0.99, 95% CI [0.98-0.99]), Severe acute malnutrition (AHR = 15.92, 95% CI [5.34-47.50]), and exposure to tuberculosis treatment (AHR = 2.93, 95% CI [1.39-6.17]) were the independent predictors for the development of OIs. CONCLUSION: ABC and AZT based ART regimens seem to have comparable survival benefit among HIV-infected children in Ethiopia. Therefore, both regimens might be used as an alternative in resource limited settings.

HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood-brain barrier integrity.

Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood-brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat- mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.