Pharmacokinetics and safety of twice-daily ritonavir-boosted atazanavir with rifampicin.

BACKGROUND: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

Atazanavir Resensitizes Candida auris to Azoles.

Candida auris represents an urgent health threat. Here, we identified atazanavir as a potent drug capable of resensitizing C. auris clinical isolates to the activity of azole antifungals. Atazanavir was able to significantly inhibit the efflux pumps, glucose transport, and ATP synthesis of all tested isolates of C. auris. In addition, the combination of itraconazole with atazanavir-ritonavir significantly reduced the burden of azole-resistant C. auris in murine kidneys by 1.3 log10 (95%), compared to itraconazole alone.

Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study.

Candida albicans is the chief etiological agent of candidiasis, a mycosis prevalent in individuals with acquired immunodeficiency syndrome (AIDS). In recent years, the introduction of human immunodeficiency virus (HIV) protease inhibitors (HIV-PI) has reduced the prevalence of candidiasis in these patients. Seeking new therapeutic strategies based on the perspective of drug repositioning, we evaluated the effects of two second-generation HIV-PIs, atazanavir (ATV) and darunavir (DRV), on virulence factors of C. albicans and experimental candidiasis. For this, clinical strains of C. albicans were subjected to in vitro and in vivo treatments with ATV or DRV. As a result, ATV and DRV exhibited antifungal activity against fungal cells at 512 µg/mL, reduced the viability and biomass of biofilms, and inhibited filamentation of C. albicans. In addition, these HIV-PIs downregulated the expression of SAP2 and BRC1 genes of C. albicans. In an in vivo study, prophylactic use of ATV and DRV prolonged the survival rate of Galleria mellonella larvae infected with C. albicans. Therefore, ATV and DRV showed activity against C. albicans by reducing cell growth, biofilm formation, filamentation, and expression of virulence genes. Furthermore, ATV and DRV decreased experimental candidiasis, suggesting the repurposing of HIV-PIs as antifungal treatments for C. albicans infections.

Atazanavir-Concentrate Loaded Soft Gelatin Capsule for Enhanced Concentration in Plasma, Brain, Spleen, and Lymphatics.

This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain, spleen, and lymphatics beneficial in the significant reduction of viral load in HIV infection. For this purpose, ATV-concentrate in the presence and absence of Soluplus with corn oil, oleic acid, tween 80, and propylene glycol was developed. The developed ATV-concentrate was found to have enhanced dispersibility with no signs of precipitation after dilution with simulated G.I fluid as evident from particle size (16.49±0.32 nm) and PDI (0.217±0.02) analysis. The rheological and molecular docking studies explainedthe reduction of viscosity of SuATV-C due to the intermolecular H-bond between ATV and Soluplus that helps to retard crystallization. The shell of the soft gelatin capsule retains its integrity when subjected to a folding endurance test on a texture analyzer depicting that the concentrate did not affect the integrity of the soft gelatin capsule shell. An ex vivo and in vivo pharmacokinetic study in rats revealed that the SuATV-C soft gelatin capsule (SuATV-C SGC) indicated 2.9 fold improvement in rate and extent of permeation and absorption than that of ATV-suspension. The tissue distribution study also exhibited higher drug concentration in the brain (2.5 fold), lymph nodes (2.7 fold), and spleen (1.2 fold) administered with SuATV-C SGC, revealing the overwhelming influence of Soluplus and corn oil. In a nutshell, these studies demonstrated that SuATV-C SGC seems to have the potential to deliver an anti-retroviral drug to the viral sanctuaries for the better management of HIV.

Evaluation of cardiotoxicity and other adverse effects associated with concomitant administration of artemether/lumefantrine and atazanavir/ritonavir-based antiretroviral regimen in patients living with HIV.

The interplay of artemether-lumefantrine (AL) and atazanavir-ritonavir (ATVr) with Cytochrome P (CYP) 3A4 isoenzyme and QTc-interval may spawn clinically significant drug interactions when administered concomitantly. Cardiotoxicity and other adverse effects associated with interaction between AL and ATVr were evaluated in patients with HIV infection and malaria comorbidity. In a two-arm parallel study design, six doses of AL 80/480 mg were administered to 20 participants [control-arm (n = 10) and ATVr-arm (n = 10)], having uncomplicated Falciparum malaria, at intervals of 0, 8, 24, 36, 48 and 60 h respectively. Participants in the control arm took only AL while those in ATVr-arm took both AL and ATVr-based ART regimen. Electrocardiography, adverse events monitoring and blood tests were carried out for each of them at pre and post doses of AL. Data obtained were analyzed. QTc-interval was significantly increased in the ATVr-arm (0.4079 ± 0.008 to 0.4215 ± 0.007 s, p = 0.008) but not in the control-arm (0.4016 ± 0.018 to 0.4024 ± 0.014 s, p = 0.962). All values were, however, within normal range [0.36 - 0.44 / 0.46 s (male/female)]. General body weakness and chest pain were new adverse events reported, at post-dose of AL, in the ATVr-arm but not in the control-arm. There was no significant change (p > 0.05) in the plasma levels of creatinine, alanine aminotransferase, aspartate aminotransferase and hemoglobin at post-dose compared to pre-dose of AL in both arms of study. Concomitant administration of artemether-lumefantrine with atazanavir-ritonavir-based regimen is potentially cardiotoxic but not associated with clinically significant renal, blood nor liver toxicities. They must be used with caution.

Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients.

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.

Evaluation of the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine in patients living with HIV in Lagos University Teaching Hospital, South-Western Nigeria.

PURPOSE: Atazanavir-ritonavir (ATVr)-based antiretroviral therapy and artemether-lumefantrine (AL) are commonly used drugs for the treatment of human immune deficiency virus (HIV) infection and malaria respectively. However, interaction of both drugs, with Cytochrome P 3A4 (CYP 3A4) isoenzyme, may spawn clinically significant pharmacokinetic interactions. This study evaluated the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine. METHOD: In a case-control study, twenty participants having Plasmodium falciparum malaria were recruited and divided into two groups (ATVr-arm, n=10; and control-arm, n= 10). All the participants were administered six oral doses of AL 80-480 mg (Coartem). Thereafter, their blood samples were collected at different time intervals over seven days. The concentration of lumefantrine in each sample was quantified with high-performance liquid chromatography (HPLC) and used to determine its pharmacokinetic parameters which were compared between the test and control groups. RESULTS: ATVr increased the mean day 7 concentration of lumefantrine (ATVr 3847.09 ± 893.35 ng/mL, control 1374.53 ± 265.55 ng/mL, p = 0.016) and the area under its plasma concentration-time curve (ATVr 670529.57 ± 157172.93 ng.h/mL, control 447976.28 ± 80886.99 ng.h/mL, p = 0.224) by 179.88 % and 49.68 %, respectively, but decreased its mean maximum plasma drug concentration (Cmax) (ATVr 13725.70 ± 2658.44 ng/mL, control 15380.48 ± 2332.62 ng/mL, p = 0.645) by 10.76 %. CONCLUSION: ATVr increased drug exposure and day 7 plasma concentration of lumefantrine. AL is therefore considered effective for the treatment of malaria in patients taking ATVr-based regimen. However, the safety associated with the interaction requires further elucidation. TRIAL REGISTRATION: Clin ClinicalTrials.gov Identifier: NCT04531072, August 27, 2020. "Retrospectively registered".

DFT investigation of atazanavir as potential inhibitor for 2019-nCoV coronavirus M protease.

Atazanavir (ATZ) is an antiviral drug synthesized.ATZ is being investigated for potential application against the Coronavirus 2019-nCoV. To find candidate drugs for 2019-nCoV, we have carried out a computational study to screen for effective available drug ATZ which may work as an inhibitor for the Mpro of 2019-nCoV. In the present work, the first time the molecular structure of ATZ molecule has been studied using Density Functional Theory (CAMB3LYP/6-31G*) in solvent water. The electronic properties, atomic charges, MEP, NBO analysis, and excitation energies of ATZ have also been studied. The interaction of ATZ compound with the Coronavirus was performed by molecular docking studies.

Is the Risk of Myocardial Infarction in People With Human Immunodeficiency Virus (HIV) Associated With Atazanavir or Darunavir? A Nested Case-Control Study Within the French Hospital Database on HIV.

BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study has reported an increased risk of cardiovascular diseases in people with human immunodeficiency virus who were exposed to darunavir (DRV) but not to atazanavir (ATV). Our objective was to evaluate associations between ATV or DRV exposures and the risk of myocardial infarction (MI) in a nested case-control study within ANRS-CO4 French Hospital Database on HIV (FHDH). METHODS: Cases were individuals who had a first validated MI between 2006 and 2012. Up to 5 controls were selected at random with replacement among individuals with no history of MI, followed at the time of MI diagnosis, and matched for age and sex. Conditional logistic regression models were used to adjust for potential confounders (MI risk factors and HIV-related parameters) and for cumulative exposure to each antiretroviral drug (ARV). RESULTS: Overall, 408 MI cases and 1250 controls were included: 109 (27%) cases and 288 (23%) controls had been exposed to ATV, and 41 (10%) cases and 107 (9%) controls had been exposed to DRV. There was no significant association between exposure to ATV (adjusted odds ratio [OR] = 1.54; 95% confidence interval [CI], .87-2.73) or DRV (adjusted OR = 0.51; 95% CI, .11-2.32) and the risk of MI. CONCLUSIONS: In FHDH, exposures to ATV or to DRV were not significantly associated with the risk of MI, adjusting for complete ARV history, contrary to the analysis in DAD.

Lipid profile levels in HIV-AIDS patients on treatment with efavirenz and atazanavir. Cohort study.

INTRODUCTION: Antiretroviral treatment for HIV generates dyslipidemia, which is associated with cardiovascular risk and atherosclerosis. OBJECTIVE: To compare antiretroviral agents effects on lipids in patients with HIV-AIDS. METHODS: Retrospective cohort. The lipid profiles of patients receiving efavirenz (EFV) vs. atazanavir (ATV) with a zidovudine + lamivudine backbone for 36 months were compared. RESULTS: 212 patients were included in the study. From baseline to month 36, HDL increase in the group of patients treated with ATV was higher in comparison with that of patients on EFV (8.33 vs. 4.26; p < 0.01); a difference in triglycerides was observed between groups, with a decrease of 19.06 mg/dL in patients on ATV and an increase of 40.62 mg/dL in those who received EFV (p < 0.001). Mean difference in total and LDL-cholesterol change between both treatments was not significant (p = 0.32 and p = 0.951, respectively). CONCLUSIONS: ATV-containing regimens were associated with more favorable changes in triglyceride and HDL levels than EFV regimens. This benefit could be associated with a reduction in long-term cardiovascular risk; this relationship requires further study.

INTRODUCCIÓN: El tratamiento antirretroviral para VIH genera dislipidemia asociada a riesgo cardiovascular y aterosclerosis. OBJETIVO: Comparar los efectos lipídicos de los antirretrovirales en pacientes con VIH-sida. MÉTODOS: Cohorte retrospectiva. Se comparó el perfil lipídico de los pacientes que recibieron efavirenz (EFV) versus atazanavir (ATV) con una backbone de zidovudina + lamivudina durante 36 meses. RESULTADOS: Se incluyeron 212 pacientes. Desde el inicio hasta los 36 meses, el aumento del HDL del grupo de pacientes en tratamiento con ATV fue mayor en comparación con el que presentaron los pacientes con EFV (8.33 versus 4.26, respectivamente; p < 0.01); se observó una diferencia de triglicéridos entre los grupos, con disminución de 19.06 mg/dL en los pacientes con ATV y aumento de 40.62 mg/dL en los que recibieron EFV (p < 0.001). La diferencia de medias en el cambio de colesterol total y LDL entre ambos tratamientos no fue significativa (p = 0.32 y p = 0.951, respectivamente). CONCLUSIONES: Los regímenes con ATV se asociaron a cambios más favorables en los niveles de triglicéridos y HDL que los regímenes con EFV, relación que podría asociarse a reducción del riesgo cardiovascular a largo plazo, la cuál requiere estudios adicionales.

Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.

Targeting of endoplasmic reticulum (ER) stress in gliomas.

Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past decade, extracellular stress and intracellular DNA damage have been shown to disturb proteostasis leading to Endoplasmic Reticulum (ER) stress that is implicated in the regulation of gene expression and the pathogenesis of several tumor types, including gliomas. Upon ER stress induction, neoplastic cells activate the adaptive mechanism of unfolded protein response (UPR), an integrated signaling system that either restores ER homeostasis or induces cell apoptosis. Recently, the manipulation of the UPR has emerged as a new therapeutic target in glioma treatment. General UPR activators or selective GRP78, ATF6 and PERK inducers have been detected to modulate cell proliferation and induce apoptosis of glioma cells. At the same time, target-specific UPR inhibitors and small molecule proteostasis disruptors, work in reverse to increase misfolded proteins and cause a dysregulation in protein maturation and sorting, thus preventing the growth of neoplastic cells. Herein, we discuss the pathogenic implication of ER stress in gliomas onset and progression, providing an update on the current UPR modifying agents that can be potentially used in glioma treatment.

Alteration of liver immunity by increasing inflammatory response during co-administration of methamphetamine and atazanavir.

Objective: Use of methamphetamine (METH) is prevalent among HIV-infected individuals. Previous research has shown that both METH and HIV protease inhibitors exert influences on mitochondrial respiratory metabolism and hepatic nervous system. This study aims to study the joint effect of METH and HIV protease inhibitors on hepatic immune function.Materials and methods: Based on the differentially expressed genes obtained from RNA-seq of the liver from mouse model, the expression levels of CD48 and Macrophage Receptor with Collagenous Structure (MARCO) were examined using qRT-PCR and flow cytometry, and the expression and secretion of cytokines IL-1ß, IL-6, IL-8, IL-10, IFN-γ, IFN-ß, and TNF-α were determined using qRT-PCR and ELISA in THP-1-derived macrophages.Results: Our results indicated that compared with the control group, CD48 molecules were significantly down-regulated by METH-atazanavir co-treatment, and the expression level of CD48 decreased as METH concentration increases. MARCO molecules were increased, especially at larger doses of METH and atazanavir treatment. In addition, in the presence of METH-atazanavir, the expression and secretion of a series of pro-inflammatory cytokines TNF-α, IL-1ß, IL-6, and IL-8 increased while the expression and secretion of anti-inflammatory cytokine IL-10 decreased.Conclusion: These results demonstrated that METH and atazanavir had a combined impact on the liver immunity, suggesting that the co-treatment could enhance inflammatory response and suppress NK cell activation via CD48.

Use of Contemporary Protease Inhibitors and Risk of Incident Chronic Kidney Disease in Persons With Human Immunodeficiency Virus: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study.

BACKGROUND: It is unclear whether use of contemporary protease inhibitors pose a similar risk of chronic kidney disease (CKD) as use of older protease inhibitors. METHODS: Participants in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were followed up until the earliest occurrence of CKD, the last visit plus 6 months, or 1 February 2016. Adjusted Poisson regression was used to assess associations between CKD and the use of ritonavir-boosted atazanavir (ATV/r) or ritonavir-boosted darunavir (DRV/r). RESULTS: The incidence of CKD (10.0/1000 person-years of follow-up; 95% confidence interval, 9.5-10.4/1000 person-years of follow-up) increased gradually with increasing exposure to ATV/r, but the relation was less clear for DRV/r. After adjustment, only exposure to ATV/r (adjusted incidence rate ratio, 1.4; 95% confidence interval, 1.2-1.6), but not exposure to DRV/r (1.0; .8-1.3), remained significantly associated with CKD. CONCLUSION: While DRV/r use was not significantly associated with CKD an increasing incidence with longer ATV/r use was confirmed.

Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.

Malaria and babesiosis are bloodborne protozoan infections for which the emergence of drug-resistant strains poses a threat. Our previous phage display cDNA screens established the essentiality of Plasmodium falciparum signal peptide peptidase (SPP) in asexual development at the blood stage of malaria infection. Given the structural similarities between SPP inhibitors and HIV protease inhibitors, we screened ten HIV protease inhibitors and selected Lopinavir and Atazanavir for their ability to inhibit PfSPP activity. Using a transcription-based assay, we observed that Lopinavir inhibits both parasite-and host-derived SPP activities whereas Atazanavir inhibited only parasite derived SPP activity. Consistent with their inhibitory effect on Plasmodium growth, both Lopinavir and Atazanavir strongly inhibited intraerythrocytic Babesia microti growth ex vivo. Moreover, Lopinavir prevented the steep rise in Babesia microti parasitemia typically observed in rag1-deficient mice. Our data provide first evidence that inhibition of parasite-derived SPPs by HIV protease inhibitors offers a promising therapeutic avenue for the treatment of severe babesiosis and infections caused by other Apicomplexa parasites.

An observational study in an urban Ugandan clinic comparing virological outcomes of patients switched from first-line antiretroviral regimens to second-line regimens containing ritonavir-boosted atazanavir or ritonavir-boosted lopinavir.

BACKGROUND: The World Health Organisation approved boosted atazanavir as a preferred second line protease inhibitor in 2010. This is as an alternative to the current boosted lopinavir. Atazanavir has a lower genetic barrier than lopinavir. We compared the virological outcomes of patients during the roll out of routine viral load monitoring, who had switched to boosted second- line regimens of either atazanavir or lopinavir. METHODS: This was a cross-sectional study involving adult patients at the Infectious Diseases Institute Kampala, Uganda started on a standard WHO recommended second-line regimen containing either boosted atazanavir or boosted lopinavir between 1 Dec 2014 and 31 July 2015.. Mantel -Haenszel chi square was used to test for the statistical significance of the odds of being suppressed (VL < 400 copies/ml) when on boosted atazanavir compared to boosted lopinavir after stratifying by duration on antiretroviral therapy (ART). Multivariate logistic regression analysis used to determine if the type of boosted protease inhibitor (bPI) was associated with virological outcome. RESULTS: Ninety (90) % on ATV/r and 83% on LPV/r had a VL less than 1000 copies/ml. The odds of being suppressed using the same viral load cut-off while on boosted atazanavir compared to boosted lopinavir was not statistically significant after stratifying for duration on ART (p = 0.09). In a multivariate analysis the type of bPI used was not a predictor of virological outcome (p = 0.60). CONCLUSIONS: Patients using the WHO recommended second-line of boosted atazanavir have comparable virological suppression to those on boosted lopinavir.

Efficacy and tolerability of lamivudine plus dolutegravir compared with lamivudine plus boosted PIs in HIV-1 positive individuals with virologic suppression: a retrospective study from the clinical practice.

BACKGROUND: Direct comparisons between lamivudine plus bPIs and lamivudine plus dolutegravir as maintenance strategies in virologically-suppressed HIV positive patients are lacking. METHODS: Time to treatment discontinuation (TD) and virological failure (VF) were compared in a cohort of HIV+ patients on a virologically-effective ART starting lamivudine with either darunavir/r, atazanavir/r or dolutegravir. Changes in laboratory parameters were also evaluated. RESULTS: Four-hundred-ninety-four patients were analyzed (170 switching to darunavir/r, 141 to atazanavir/r, 183 to dolutegravir): median age was 49 years, with 8 years since ART start. Groups differed for age, HIV-risk factor, time since HIV-diagnosis and on ART, previous therapy and reasons for switching. Estimated proportions free from TD at week 48 and 96 were 79.8 and 48.3% of patients with darunavir/r, 87.0 and 70.9% with atazanavir/r, and 88.2 and 82.6% with dolutegravir, respectively (p < 0.001). Calendar years, HIV-risk factor, higher baseline cholesterol and an InSTI-based previous regimen predicted TD, whereas lamivudine+dolutegravir therapy and previous tenofovir use were protective. VF was the cause of TD in 6/123 cases with darunavir/r, 4/97 with atazanavir/r and 3/21 with dolutegravir. Other main reasons for TD were: toxicity (43.1% with darunavir/r, 39.2% with atazanavir/r, 52.4% with dolutegravir), further simplification (36.6% with darunavir/r, 30.9% with atazanavir/r, 14.3% with dolutegravir). Incidence of VF did not differ among study groups (p = 0.747). No factor could predict VF. Lipid profile improved in the dolutegravir group, whereas renal function improved in the bPIs groups. CONCLUSIONS: In real practice, a switch to lamivudine+dolutegravir showed similar efficacy but longer durability than a switch to lamivudine+bPIs.

Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study.

OBJECTIVES: Dyslipidaemia is common in perinatally HIV-infected (PHIV) youth receiving protease inhibitors (PIs). Few studies have evaluated longitudinal lipid changes in PHIV youth after switch to newer PIs. METHODS: We compared longitudinal changes in fasting lipids [total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and TC:HDL-C ratio] in PHIV youth enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) study who switched to atazanavir/ritonavir (ATV/r)- or darunavir/ritonavir (DRV/r)-based antiretroviral therapy (ART) from an older PI-based ART and those remaining on an older PI. Generalized estimating equation models were fitted to assess the association of a switch to ATV/r- or DRV/r-based ART with the rate of change in lipids, adjusted for potential confounders. RESULTS: From 2007 to 2014, 47 PHIV children/adolescents switched to ATV/r or DRV/r, while 120 remained on an older PI [primarily lopinavir/r (72%) and nelfinavir (24%)]. Baseline age ranged from 7 to 21 years. After adjustment for age, Tanner stage, race/ethnicity, and HIV RNA level, a switch to ATV/r or DRV/r was associated with a more rapid annual rate of decline in the ratio of TC:HDL-C. (ß = -0.12; P = 0.039) than remaining on an older PI. On average, TC declined by 4.57 mg/dL/year (P = 0.057) more in the switch group. A switch to ATV/r or DRV/r was not associated with the rate of HDL-C, LDL-C, or TG change. CONCLUSIONS: A switch to ATV/r or DRV/r may result in more rapid reduction in TC and the TC:HDL-C ratio in PHIV youth, potentially impacting long-term cardiovascular disease risk.

Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe.

OBJECTIVES: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. METHODS: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. RESULTS: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. CONCLUSIONS: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.