Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

INTRODUCTION: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. METHODS: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48 weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48 weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. RESULTS: Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. CONCLUSIONS: Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.

Limited Weight Impact After Switching From Boosted Protease Inhibitors to Dolutegravir in Persons With Human Immunodeficiency Virus With High Cardiovascular Risk: A Post Hoc Analysis of the 96-Week NEAT-022 Randomized Trial.

BACKGROUND: In the NEAT022 trial, virologically suppressed persons with human immunodeficiency virus (HIV) at high cardiovascular risk switching from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D) showed noninferior virological suppression and significant lipid and cardiovascular disease risk reductions on switching to dolutegravir relative to continuing protease inhibitors. METHODS: In post hoc analysis, major endpoints were 48-week and 96-week weight and body mass index (BMI) changes. Factors associated with weight/BMI changes within the first 48 weeks of DTG exposure, proportion of participants by category of percentage weight change, proportions of BMI categories over time, and impact on metabolic outcomes were also assessed. RESULTS: Between May 2014 and November 2015, 204 (DTG-I) and 208 (DTG-D) participants were included. Weight significantly increased (mean, +0.810 kg DTG-I arm, and +0.979 kg DTG-D arm) in the first 48 weeks postswitch, but remained stable from 48 to 96 weeks in DTG-I arm. Switching from darunavir, White race, total to high-density lipoprotein cholesterol ratio <3.7, and normal/underweight BMI were independently associated with higher weight/BMI gains. The proportion of participants with ≥5% weight change increased similarly in both arms over time. The proportions of BMI categories, use of lipid-lowering drugs, diabetes and/or use of antidiabetic agents, and hypertension and/or use of antihypertensive agents did not change within or between arms at 48 and 96 weeks. CONCLUSIONS: Switching from protease inhibitors to dolutegravir in persons with HIV with high cardiovascular risk led to modest weight gain limited to the first 48 weeks, which involved preferentially normal-weight or underweight persons and was not associated with negative metabolic outcomes. CLINICAL TRIALS REGISTRATION: NCT02098837 and EudraCT 2013-003704-39.

Incidence of Hypertension and Blood Pressure Changes in Persons With Human Immunodeficiency Virus at High Risk for Cardiovascular Disease Switching From Boosted Protease Inhibitors to Dolutegravir: A Post-hoc Analysis of the 96-week Randomised NEAT-022 Trial.

BACKGROUND: Integrase inhibitors have been recently linked to a higher risk for hypertension. In NEAT022 randomized trial, virologically suppressed persons with human immunodeficiency virus (HIV, PWH) with high cardiovascular risk switched from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D). METHODS: Primary endpoint was incident hypertension at 48 weeks. Secondary endpoints were changes in systolic (SBP) and diastolic (DBP) blood pressure; adverse events and discontinuations associated with high blood pressure; and factors associated with incident hypertension. RESULTS: At baseline, 191 (46.4%) participants had hypertension and 24 persons without hypertension were receiving antihypertensive medications for other reasons. In the 197 PWH (n = 98, DTG-I arm; n = 99, DTG-D arm) without hypertension or antihypertensive agents at baseline, incidence rates per 100 person-years were 40.3 and 36.3 (DTG-I) and 34.7 and 52.0 (DTG-D) at 48 (P = .5755) and 96 (P = .2347) weeks. SBP or DBP changes did not differed between arms. DBP (mean, 95% confidence interval) significantly increased in both DTG-I (+2.78 mmHg [1.07-4.50], P = .0016) and DTG-D (+2.29 mmHg [0.35-4.23], P = .0211) arms in the first 48 weeks of exposure to dolutegravir. Four (3 under dolutegravir, 1 under protease inhibitors) participants discontinued study drugs due to adverse events associated with high blood pressure. Classical factors, but not treatment arm, were independently associated with incident hypertension. CONCLUSIONS: PWH at high risk for cardiovascular disease showed high rates of hypertension at baseline and after 96 weeks. Switching to dolutegravir did not negatively impact on the incidence of hypertension or blood pressure changes relative to continuing protease inhibitors.

Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir.

BACKGROUND: In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. METHODS: PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. RESULTS: Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. DISCUSSION: After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.

Atherogenicity of low-density lipoproteins after switching from a protease inhibitor to dolutegravir: a substudy of the NEAT022 study.

BACKGROUND: The aim of this study was to investigate whether switching from a ritonavir-boosted PI-based regimen to a dolutegravir-based regimen improved the atherogenic properties of LDL particles in patients with HIV. METHODS: This was a substudy of the NEAT022 study (ClinicalTrials.gov NCT02098837). Adults with HIV with a Framingham score >10% or aged >50 years and being treated with a stable boosted PI-based regimen were randomized to either switch to dolutegravir or continue with boosted PI. At baseline and Week 48, we assessed atherogenic LDL properties: LDL particle size and phenotype (A, intermediate, B), oxidized LDL (ox-LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. RESULTS: Eighty-six participants (dolutegravir 44; PI 42) were included. Participants had a median (IQR) age of 54 (51-57) years and 79.1% were male. In the dolutegravir arm, after 48 weeks, we observed: (1) an increase in LDL size [median 1.65 Š(IQR -0.60 to 4.20); P = 0.007], correlated with the decrease in triglyceride concentration [Spearman correlation = -0.352 (P = 0.001)], with a corresponding decrease of subjects with atherogenic LDL phenotype B (36.4% to 20.5%; P = 0.039); (2) a decrease in Lp-PLA2 activity [median 1.39 µmol/min/mL (IQR -2.3 to 0.54); P = 0.002]; and (3) a decrease in ox-LDL [median 14 U/L (IQR -102 to 13); P = 0.006]. In the PI arm, none of these favourable lipid modifications was observed. CONCLUSIONS: Forty-eight weeks after switching from a PI-based to a dolutegravir-based regimen, patients with Framingham score >10% or aged >50 years showed improvement of several atherogenic lipid features, including LDL particle phenotype, ox-LDL and Lp-PLA2.

Switching from boosted PIs to dolutegravir decreases soluble CD14 and adiponectin in high cardiovascular risk people living with HIV.

BACKGROUND: Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown. METHODS: We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury. RESULTS: Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (-11%, P < 0.001) and adiponectin (-11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (-13%, P = 0.069) and oxidized LDL (-13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001). CONCLUSIONS: Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.

Switching from boosted PIs to dolutegravir in HIV-infected patients with high cardiovascular risk: 48 week effects on subclinical cardiovascular disease.

BACKGROUND: Switching from boosted PIs to dolutegravir in virologically suppressed HIV-infected patients with high cardiovascular risk significantly decreased total cholesterol and other proatherogenic lipid fractions at 48 weeks. The impact of this strategy on subclinical cardiovascular disease is unknown. METHODS: NEAT022 is a European, multicentre, open-label, randomized, non-inferiority trial. HIV-infected adults aged >50 years or with a Framingham score >10% were eligible if plasma HIV RNA was <50 copies/mL for >24 weeks on a boosted PI-based regimen. Patients were randomized 1:1 to switch from boosted PIs to dolutegravir or to continue on boosted PIs. Common carotid arteries intima-media thickness (CIMT) and pulse wave velocity (PWV) were measured following a standardized protocol in a subgroup of NEAT022 study participants at baseline and at Week 48. RESULTS: One hundred and fifty-six patients participated in the ultrasonography and arterial stiffness substudies, respectively. In each substudy, population characteristics did not differ between arms and matched those of the main study. At 48 weeks, patients who switched to dolutegravir had lower mean progression of both right (+4 versus +14.6 µm) and left (-6.1 versus +1.6 µm) CIMT and also a smaller increase in mean PWV (+0.18 versus +0.39 m/s) than patients continuing on boosted PIs, although differences were not statistically significant. CIMT trends were consistent across Framingham score, age and country. Inconsistent effects were seen in arterial stiffness. CONCLUSIONS: Relative to continuing on boosted PIs, switching to dolutegravir in virologically suppressed patients with high cardiovascular risk showed consistent favourable although non-significant trends on CIMT progression at 48 weeks.

Immediate Versus Deferred Switching From a Boosted Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen in Virologically Suppressed Patients With High Cardiovascular Risk or Age ≥50 Years: Final 96-Week Results of the NEAT022 Study.

Background: Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to a dolutegravir (DTG)-based regimen may improve lipid profile. Methods: European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)-infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results: Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, -.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile. Clinical Trials Registration: NCT02098837 and EudraCT: 2013-003704-39.

Cholesterol efflux responds to viral load and CD4 counts in HIV+ patients and is dampened in HIV exposed.

Cholesterol efflux (CE) capacity has been inversely associated with atherosclerosis and may provide an insight on inflammation occurring in human immunodeficiency virus (HIV) individuals. We address this by studying CE in HIV patients at different stages of HIV disease progression. In this cross-sectional study, CE from ApoB-depleted plasma, lipids levels, viral load (VL), CD4+/CD8+ T-cells, high-sensitive C-reactive protein (hsCRP), and lipoprotein (a) were evaluated in untreated HIV-infected patients (UHIVs; n = 43), elite controllers (ECs; n = 8), HIV-exposed seronegative individuals (HESNs; n = 32), and healthy controls (HCs; n = 14). Among UHIVs, those with CD4+ <500 cells/mm3 presented the lowest significant CE, HDL cholesterol (HDL-C), and ApoAI levels. ECs showed similar HDL-C, ApoAI, and CE compared with HCs. Among UHIVs, CE positively correlated with CD4+ T-cell counts (Beta: 1.05; 95% CI: 1.02; 1.07), and for VL higher than 3.8 log, CE was inversely associated with VL (Beta: 0.70; 95% CI: 0.51; 0.95). Remarkably, HESNs presented higher CE (0.78 ± 0.14) than UHIVs (0.65 ± 0.17; P = 0.0005), but lower than HCs (0.90 ± 0.13; P = 0.009). hsCRP levels were highest in the UHIV group (0.45 ± 0.49). CE was sensitive to HIV disease progression. Low CE in HIV patients was associated with lower CD4+ T-cells and higher VL and hsCRP. CE was also lower in HESNs compared with HCs. Our results suggest that immune status secondary to HIV progression and exposure influence plasma HDL-CE capacity.

Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial.

Background: No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART. Methods: We used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (≥5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load <50 copies/mL for ≥12 months, no prior viral failure or resistance mutations to study drugs, nadir CD4 >200 cells/mm3, and hepatitis B virus surface antigen negative were randomized 1:1:1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patient's wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435. Results: Ninety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm. Conclusions: In contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy.

Loading dendritic cells with gold nanoparticles (GNPs) bearing HIV-peptides and mannosides enhance HIV-specific T cell responses.

Gold nanoparticles (GNPs) decorated with glycans ameliorate dendritic cells (DC) uptake, antigen-presentation and T-cells cross-talk, which are important aspects in vaccine design. GNPs allow for high antigen loading, DC targeting, lack of toxicity and are straightforward prepared and easy to handle. The present study aimed to assess the capacity of DC to process and present HIV-1-peptides loaded onto GNPs bearing high-mannoside-type oligosaccharides (P1@HM) to autologous T-cells from HIV-1 patients. The results showed that P1@HM increased HIV-specific CD4+ and CD8+ T-cell proliferation and induced highly functional cytokine secretion compared with HIV-peptides alone. P1@HM elicits a highly efficient secretion of pro-TH1 cytokines and chemokines, a moderate production of pro-TH2 and significant higher secretion of pro-inflammatory cytokines such as TNF-α and IL-1ß. Thus, co-delivery of HIV-1 antigens and HM by GNPs is an excellent vaccine delivery system inducing HIV-specific cellular immune responses in HIV+ patients, being a promising approach to improve anti-HIV-1 vaccines.

The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity.

BACKGROUND: HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. RESULTS: Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4+ T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable. CONCLUSIONS: Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response against HIV-1 in animal models.

Tolerability of integrase inhibitors in a real-life setting.

Background: Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them. Aims: We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients. Methods: Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models. Results: Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P = 0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P = 0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P = 0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P = 0.0007) was the only independent risk factor for early discontinuation due to toxicity. Conclusions: Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir.

Cyclosporine A in addition to standard ART during primary HIV-1 infection: pilot randomized clinical trial.

Background: Initiating ART during acute/recent HIV-1 infection reduces viral reservoir formation. It has been proposed that, during this phase, the size of the viral reservoir could be further reduced by the association of immunomodulatory therapy with ART. Contradictory results have emerged, however, from two trials evaluating the impact on immune recovery and the viral reservoir of adding cyclosporine A to ART during primary HIV-1 infection. Patients and methods: Twenty patients with acute/recent HIV-1 infection were randomized to receive ART alone (tenofovir, emtricitabine and lopinavir/ritonavir) or associated with 8 weeks of cyclosporine A (0.3-0.6 mg/kg twice daily). The impact on viral load, immune response and integrated and non-integrated DNA viral reservoir at 0, 8 and 36 weeks of treatment was evaluated. Results: The estimated median time from HIV-1 infection to ART onset was 63 days (IQR 53; 79.5) with 90% of patients at Fiebig V stage. No significant differences were observed in viral load decay, CD4 T cell recovery, immune response markers or the evolution of integrated DNA at week 8 (end of cyclosporine A) and week 36 between groups. However, non-integrated DNA significantly increased in the cyclosporine A arm between weeks 0 and 36. Cyclosporine A was well tolerated. Conclusions: Adding cyclosporine A to ART during acute/recent infection did not improve immune recovery. However, unintegrated DNA increased in the cyclosporine A group, suggesting an anti-integration effect, a point warranting further research (ClinicalTrials.gov Identifier: NCT00979706).

Lipid raft-like liposomes used for targeted delivery of a chimeric entry-inhibitor peptide with anti-HIV-1 activity.

The work reports the design and synthesis of a chimeric peptide that is composed of the peptide sequences of two entry inhibitors which target different sites of HIV-1 gp41. The chimeric peptide offers the advantage of targeting two gp41 regions simultaneously: the fusion peptide and the loop both of which are membrane active and participate in the membrane fusion process. We therefore use lipid raft-like liposomes as a tool to specifically direct the chimeric inhibitor peptide to the membrane domains where the HIV-1 envelope protein is located. Moreover, the liposomes that mimic the viral membrane composition protect the chimeric peptide against proteolytic digestion thereby increasing the stability of the peptide. The described liposome preparations are suitable nanosystems for managing hydrophobic entry-inhibitor peptides as putative therapeutics.

Maraviroc, as a Switch Option, in HIV-1-infected Individuals With Stable, Well-controlled HIV Replication and R5-tropic Virus on Their First Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Plus Ritonavir-boosted Protease Inhibitor Regimen: Week 48 Results of the Randomized, Multicenter MARCH Study.

BACKGROUND: Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. METHODS: The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1:2:2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200 copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was < -12% in the intention-to-treat (ITT) population. RESULTS: The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t)RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. CONCLUSIONS: These data support MVC as a switch option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r. CLINICAL TRIALS REGISTRATION: NCT01384682.

Increased expression with differential subcellular location of cytidine deaminase APOBEC3G in human CD4(+) T-cell activation and dendritic cell maturation.

APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T cells are highly permissive for HIV-1 replication, whereas resting CD4(+) T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory. We investigated whether these differences could be related to a differential A3G expression and/or subcellular distribution. We found that A3G mRNA and protein expression is very low in resting CD4(+) T cells and immature DCs, but increases strongly following T-cell activation and DC maturation. The Apo-7 anti-A3G monoclonal antibody (mAb), which was specifically developed, confirmed these differences at the protein level and disclosed that A3G is mainly cytoplasmic in resting CD4(+) T cells and immature DCs. Nevertheless, A3G translocates to the nucleus in activated-proliferating CD4(+) T cells, yet remaining cytoplasmic in matured DCs, a finding confirmed by immunoblotting analysis of cytoplasmic and nuclear fractions. Apo-7 mAb was able to immunoprecipitate endogenous A3G allowing to detect complexes with numerous proteins in activated-proliferating but not in resting CD4(+) T cells. The results show for the first time the nuclear translocation of A3G in activated-proliferating CD4(+) T cells.

Beyond viral suppression of HIV - the new quality of life frontier.

BACKGROUND: In 2016, the World Health Organization (WHO) adopted a new Global Health Sector Strategy on HIV for 2016-2021. It establishes 15 ambitious targets, including the '90-90-90' target calling on health systems to reduce under-diagnosis of HIV, treat a greater number of those diagnosed, and ensure that those being treated achieve viral suppression. DISCUSSION: The WHO strategy calls for person-centered chronic care for people living with HIV (PLHIV), implicitly acknowledging that viral suppression is not the ultimate goal of treatment. However, it stops short of providing an explicit target for health-related quality of life. It thus fails to take into account the needs of PLHIV who have achieved viral suppression but still must contend with other intense challenges such as serious non-communicable diseases, depression, anxiety, financial stress, and experiences of or apprehension about HIV-related discrimination. We propose adding a 'fourth 90' to the testing and treatment target: ensure that 90 % of people with viral load suppression have good health-related quality of life. The new target would expand the continuum-of-services paradigm beyond the existing endpoint of viral suppression. Good health-related quality of life for PLHIV entails attention to two domains: comorbidities and self-perceived quality of life. CONCLUSIONS: Health systems everywhere need to become more integrated and more people-centered to successfully meet the needs of virally suppressed PLHIV. By doing so, these systems can better meet the needs of all of their constituents - regardless of HIV status - in an era when many populations worldwide are living much longer with multiple comorbidities.

Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression.

OBJECTIVES: We reviewed the 24 week outcomes of HIV-infected patients from our hospital who had their ART switched to dolutegravir monotherapy on an individual clinical basis. METHODS: Retrospective hospital database assessment of virally suppressed patients in whom the treating physician had switched to 50 mg of dolutegravir once daily due to one or more of the following reasons: antiretroviral-related adverse effects; comorbidities; risk of interactions; or archived resistance. Patients had ≥24 weeks of follow-up. Population, virological and immunological responses and safety and tolerability are described. RESULTS: Thirty-three (22 on PIs, of whom 18 had ritonavir-boosted PI monotherapy) patients were identified: median (IQR) age of 56 (50-62) years, 55% women, median (IQR) of 19 (17-23) years of known HIV infection, 39% prior AIDS events, median (IQR) of 8 (4-13) years with undetectable plasma HIV-1 RNA and median (IQR) CD4 cell count of 596 (420-843) cells/mm(3). Twenty-five (76%) patients had antiretroviral-related adverse effects, 32 (97%) patients had comorbidities, 28 (85%) patients had risk of interactions and 16 (48%) patients had archived resistance. One patient with suboptimal adherence had low-level virological failure through weeks 4-24. HIV RNA genotypic resistance tests detected no integrase mutations at weeks 4 and 24, but 118R was detected in 7% of the integrated HIV DNA at 24 weeks. Patients had significant median decreases in triglycerides (-117 mg/dL), total cholesterol (-36 mg/dL), the total cholesterol/HDL cholesterol ratio (-0.7) and high-sensitivity C-reactive protein (-0.05 mg/dL) (P ≤ 0.007), although the Chronic Kidney Disease Epidemiology Collaboration equation also decreased (-7.1 mL/min) (P < 0.0001). CONCLUSIONS: These data suggest the efficacy of dolutegravir monotherapy as a maintenance strategy to be further confirmed in randomized clinical trials.

Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical trial.

BACKGROUND: It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. METHODS: ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. RESULTS: At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. CONCLUSIONS: We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance. Clinical Trials Registration. NCT01274780.