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Background Persistent inflammation and immune activation are associated with lymph node fibrosis and end-organ diseases in treatment-suppressed people living with HIV (PLWH). We investigated the effect of switching to raltegravir and/or adding losartan on lymphoid tissue fibrosis and on the inflammatory/immune-activation mediators in treated HIV patients. Methods Chronic HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors (2NRTI) and one non-NRTI (NNRTI) or protease inhibitor (PI) during at least 48 weeks were randomized to four groups (n = 48): 2NRTI + efavirenz (EFV), 2NRTI + EFV + losartan, 2NRTI + raltegravir and 2NRTI + raltegravir + losartan for 48 weeks. Tonsillar biopsy and peripheral blood markers of CD4 and CD8 T-lymphocyte activation and senescence, monocyte activation and soluble markers of inflammation were determined at baseline and at week 48 and compared between groups. Results No changes in lymphoid tissue architecture were observed. Adding losartan had no impact on lymphocyte subsets. Conversely, patients who switched to raltegravir showed a higher decrease in all activated [CD4+CD38+HLA-DR+, -0.3 vs. 0.48 (P = 0.033); CD8+CD38+ HLA-DR+, -1.6 vs. 1.3 (P = 0.02)] and senescent [CD4+CD28-CD57+, -0.3 vs. 0.26 (P = 0.04); CD8+CD28-CD57+, -6.1 vs. 3.8 (P = 0.002)] T lymphocytes. In addition, the median CD4/CD8 ratio increased by 0.35 in patients in the raltegravir group vs. 0.03 in the other arms (P = 0.002). Differences between groups in monocyte subpopulations or soluble inflammation markers were not observed. Conclusions Losartan had no effect on lymphoid fibrosis or immune activation/inflammation. Conversely, switching to a regimen with raltegravir significantly decreased activated and senescent T-lymphocyte subpopulations and increased CD4/CD8 ratio in successfully treated PLWH.

Background Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy. Methods DOLAM is a phase 4, randomised, open-label, non-inferiority trial, done at six HIV clinics in Catalonia, Spain. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per ILL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible. Participants underwent computer-generated randomisation, stratified by the class of the third drug, and were assigned (1:1) to switch to oral dolutegravir 50 mg and lamivudine 300 mg once daily or to continue triple ART for 48 weeks. The primary endpoint was the proportion of people with an HIV RNA value of at least 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm, 8% non-inferiority margin). Both the primary and safety outcomes were evaluated in the intention-to-treat exposed population. The study is completed and was registered with EudraCT 201500027435. Findings Between July 7, 2015, and Oct 31, 2018, 265 participants were randomly assigned to switch to dolutegravir plus lamivudine (n=131) or to maintain triple ART (n=134) and all received at least one dose. Nine (7%) participants in the dual therapy group and ten (7%) in the triple therapy group were excluded before 48 weeks, mostly due to treatment discontinuations or virological failure. Participants were predominantly male (116 [87%] of 134 in the triple ART group and 111 [85%] of 131 in the dolutegravir plus lamivudine group). The difference in the proportion of participants with HIV RNA values of at least 50 copies per mL at 48 weeks between the dual therapy group (three [2%] of 131) and triple therapy group (two [1%] of 134) was 0middot8 percentage points (95% CI -3middot3 to 5middot2), showing non-inferiority of dolutegravir plus lamivudine dual therapy compared with triple ART. 73 (56%) of 131 participants allocated to dual therapy had 150 adverse effects, compared with 78 (58%) of 134 participants allocated to triple therapy who also had 150 adverse events (p=0middot68). Drug discontinuation due to adverse effects occurred in four people in the triple therapy group and three people in the dual therapy group. Interpretation Our findings show the efficacy and safety of dolutegravir plus lamivudine as a simplified therapy switch option for selected people with HIV with virological suppression on triple ART.

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 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 mu m) and Left (-6.1 versus +1.6 mu m) 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.

OBJECTIVES The aim of the study was to assess changes in and factors associated with anatomical [carotid artery intima-media thickness (CIMT)] and functional (arterial stiffness) markers of subclinical cardiovascular disease progression in antiretroviral-naive patients starting triple combination antiretroviral therapy containing contemporary protease inhibitors. METHODS This was a planned substudy of the ATADAR (Metabolic Effects of Atazanavir/Ritonavir Versus Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine in naive HIV-1 Infected Patients) clinical trial (ClinicalTrials.gov identifier NCT01274780). ATADAR is a multicentre, randomized, open-label clinical trial comparing the effects of ritonavir-boosted atazanavir and darunavir, both with tenofovir/emtricitabine, in antiretroviral-naive HIV-infected patients. Common CIMT and aortic augmentation index (AIx@75) were measured at baseline and after 12 months of follow-up. Antiretroviral treatment, traditional cardiovascular risk factors and HIV-related factors were assessed as potential predictors of CIMT and Aix@75 changes using linear regression analysis. RESULTS Thirty-three patients were included in this pilot study. While CIMT significantly increased in the pooled population [median (interquartile range (IQR)) 68 (-13, 128) μm; P = 0.0511], AIx@75 did not [median (IQR) 1 (-6, 5)%; P = 0.8964]. Patients on darunavir showed a trend to faster CIMT progression than those on atazanavir [median change (IQR) 117 (-2, 143) vs. -6 (-58, 89) μm, respectively; P = 0.0917]. However, after adjustment in the multivariate analysis, a higher baseline Framingham score was the only factor associated with CIMT progression (coefficient 16.02; 95% confidence interval -1.04, 33.08; P = 0.064). AIx@75 change was not associated with any baseline factor. CONCLUSIONS CIMT was a more sensitive marker of subclinical vascular disease progression than arterial stiffness in antiretroviral-naive patients starting antiretroviral therapy with contemporary protease inhibitors. Classical risk factors but not antiretroviral therapy were associated with faster CIMT progression.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL

This study using the Catalan PISCIS cohort explores risk factors of migrants' late presentation and the impact of late presentation on their health outcomes. We analyse 9590 new HIV diagnoses enrolled in the cohort between 2004 and 2016. Univariate and multivariate logistic regression models are used to identify risk factors associated with late presentation among migrants, giving crude and adjusted odds ratios and their 95% confidence intervals. Cox regression models are estimated to identify risk factors associated with AIDS/death, and crude and adjusted hazard ratios and 95% confidence intervals are reported. Late presentation is higher in migrants than non-migrants. Among migrants, region of origin is associated with late presentation and AIDS/death during follow-up. The results highlight persisting inequalities in HIV diagnosis and care among migrants in Catalonia. Targeted interventions addressed to specific subgroups in the migrant population are needed.

This update to the document on antiretroviral therapy (ART) in adults, which has been prepared jointly by GeSIDA and the Spanish National AIDS Plan for the last two decades, supersedes the document published in 2017.(1) The update provides physicians treating HIV-1-infected adults with evidence-based recommendations to guide their therapeutic decisions. The main difference with respect to the previous document concerns recommended initial ART regimens, only three of which are maintained as preferential. All three include dolutegravir or raltegravir, together with emtricitabine/tenofovir alafenamide or abacavir/lamivudine. Other differences concern the section on switching ART in patients with suppressed viral replication, which now includes new two- and three-drug regimens, and the antiretroviral drugs recommended for pregnant women and patients with tuberculosis. A recommendation has also been added for patients who present with acute HIV infection after pre-exposure prophylaxis. (C) 2018 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

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 years old or with a Framingham score >= 10% was highly efficacious and well tolerated, and improved the lipid profile.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL

Objective: The efficacy of therapeutic vaccines against HIV-1 infection has been modest, New inerts to redirect responses to vulnerable sites are urgently needed to improve these results. Design: We performed the first-in-human clinical trial with naked mRNA (IFIIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen). Methods: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4) as follow: TriMix-100g, TriMix-300g, TriMix-300g with HTI 300g, TriMix-300 g with HTI-600g, TriMix-300g with HTI-900g. Primary end-point was safety and secondary exploratory end-points were immunogenicity, changes in viral reservoir and transcriptome. Results: Overall, the vaccine was secure and well tolerated. There were 31 grade 1/2 and 1 grade 3 adverse events, mostly unrelated to the vaccination. Patients who received the highest dose showed a moderate increase in T-cell responses spanning HTI sequence at week 8, In addition, the proportion of responders receiving any dose of HTI increased from 31% at w0 to 80% postvaccination. The intervention had no impact on caHIV-DNA levels, however, cal-IIV-RNA expression and usVL were transiently increased at weeks 5 and 6 in the highest dose of iHIVARNA, and these changes were positively correlated with HIV-1-specific-induced immune responses. Conclusion: This phase I dose-escalating trial showed that iHIVARNA administration was safe and well tolerated, induced moderate HIV-specific T-cell responses and transiently increased different viral replication readouts. These data support further exploration of iHIVARNA in a phase II study. Copyright (C) 2018 The Authon(s). Published by Wolters Kluwer Health, Inc.

Background and aims: To investigate the uptake of hepatitisCvirus (HCV) therapy among HIV/HCV-coinfectedpatients inthepan-EuropeanEuroSIDAstudybetween2011and2016. Methods: All HCV-RNA patients were included. Baseline was defined as latest of anti-HCV , January 2011 or enrolment in EuroSIDA. The incidence of starting first interferon-free direct-Acting antiviral (DAA) therapy was calculated. Factors associated with starting interferon-free DAA were determined by Poisson regression. Results: Among 4308HCV-RNA patients (1255, 970, 663, 633, 787 fromSouth,West, North, Central East and East Europe, respectively) with 11 863 person-years of follow-up, 1113(25.8%)started anyHCVtherapy.Among patients with at least F3 fibrosis,more than 50% in all regions remained untreated. The incidence (per 1000 person-years of followup, 95% confidence interval) of starting DAA increased from 7.8 (5.9 9.8) in 2014 to 135.2 (122.0 148.5) in 2015 and 128.9 (113.5 144.3) in 2016. The increase was highest in North and West and intermediate in South, but remained modest in Central East and Eastern Europe. After adjustment, women, individuals fromCentral East or East, genotype 3, antiretroviral therapy nai ve and those with detectable HIV-RNAwere less likely to start DAA. Older persons, those withHCV-RNAmore than 500 000 IU/ml and those withmore advanced liver fibrosis were more likely to start DAA. Conclusion: Uptake of DAA therapy among HIV/HCV-coinfected patients increased considerably in Western Europe between 2014 and 2016, but was modest in Central East and East. In all regions more than 50% with at least F3 fibrosis remained untreated. Women were less likely to start DAA. © 2018 Lippincott Williams and Wilkins. All rights reserved.

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 >= 12months, no prior viral failure or resistance mutations to study drugs, nadir CD4.200 cells/mm(3), 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.

OBJECTIVES: The long-term side effects of stavudine (d4T) led to recommendations in 2009 to phase out use of this drug. We aimed to describe temporal patterns of d4T use across Europe. METHODS: Patients taking combination antiretroviral therapy (cART) in EuroSIDA with follow-up after 1 January 2006 were included in the study. cART was defined as d4T-containing [d4T plus at least two other antiretrovirals (ARVs) from any class] or non-d4T-containing (at least three ARVs from any class, excluding d4T). Poisson regression was used to describe temporal changes in the prevalence of d4T use and factors associated with initiating d4T. RESULTS: A total of 5850 patients receiving cART on 1 January 2006 were included in the current analysis, rising to 7768 patients on January 1 2013. During this time, the prevalence of d4T use fell from 11.2% to 0.7%, with an overall decline of 19% per 6 months [95% confidence interval (CI) 19-20%]. d4T use declined fastest in Northern Europe [26% (95% CI 23-29%) per 6 months], and slowest in Eastern Europe [17% (95% CI 16-19%) per 6 months]. In multivariable Poisson regression models, new d4T initiations decreased by 14% per 6 months [adjusted incidence rate ratio (aIRR) 0.86; 95% CI 0.80-0.91]. Factors associated with initiating d4T were residence in Eastern Europe (aIRR 4.31; 95% CI 2.17-9.98) versus other European regions and HIV RNA > 400 copies/mL (aIRR 3.11; 95% CI 1.60-6.02) versus HIV RNA < 400 copies/mL. CONCLUSIONS: d4T use has declined sharply since 2006 to low levels in most regions; however, a low but persistent level of d4T use remains in Eastern Europe, where new d4T initiations post 2006 are also more common. The reasons for the regional differences may be multifactorial, but it is important to ensure that all clinicians treating HIV-positive patients are aware of the potential harmful effects associated with d4T.

Summary Background Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation. Methods In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than −10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233. Findings Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI −4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported. Interpretation A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy. Funding Merck & Co, Inc.

Simplified regimens with reduced pill burden and fewer side-effects are desirable for people living with HIV. We investigated the efficacy and safety of switching to a single-tablet regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide versus continuing a regimen of boosted protease inhibitor, emtricitabine, and tenofovir disoproxil fumarate.EMERALD was a phase-3, randomised, active-controlled, open-label, international, multicentre trial, done at 106 sites across nine countries in North America and Europe. HIV-1-infected adults were eligible to participate if they were treatment-experienced and virologically suppressed (viral load50 copies per mL for ≥2 months; one viral load of 50-200 copies per mL was allowed within 12 months before screening), and patients with a history of virological failure on non-darunavir regimens were allowed. Randomisation was by computer-generated interactive web-response system and stratified by boosted protease inhibitor use at baseline. Patients were randomly assigned (2:1) to switch to the open-label study regimen or continue the control regimen. The study regimen consisted of a fixed-dose tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, which was taken once per day for 48 weeks. The primary outcome was the proportion of participants with virological rebound (confirmed viral load ≥50 copies per mL or premature discontinuations, with last viral load ≥50 copies per mL) cumulative through week 48; we tested non-inferiority (4% margin) of the study regimen versus the control regimen in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02269917.The study began on April 1, 2015, and the cutoff date for the week 48 primary analysis was Feb 24, 2017. Of 1141 patients (763 in the study group and 378 in the control group), 664 (58%) had previously received five or more antiretrovirals, including screening antiretrovirals, and 169 (15%) had previous virological failure on a non-darunavir regimen. The study regimen was non-inferior to the control for virological rebound cumulative through week 48 (19 [2·5%] of 763 patients in the study group vs eight (2·1%) of 378 patients in the control group; difference 0·4%, 95% CI -1·5 to 2·2; p0·0001). No resistance to any study drug was observed. Numbers of discontinuations related to adverse events (11 [1%] of 763 patients in the study group vs four [1%] of 378 patients in the control group) and grade 3-4 adverse events (52 [7%] patients vs 31 [8%] patients) were similar between the two groups. There was a small non-clinically relevant but statistically significant (0·2 [SD 1·1] vs 0·1 [1·1], p=0.010) difference between the two groups in change from baseline in total cholesterol to HDL-cholesterol ratio. Only one serious adverse event (pancreatitis in the study group) was deemed as possibly related to the study regimen.Our findings show the safety and efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide as a potential switch option for the treatment of HIV-1 infection in adults with viral suppression.Janssen.

Background HIV infection and HAART trigger genetic and functional mitochondrial alterations leading to cell death and adverse clinical manifestations. Mitochondrial dynamics enable mitochondrial turnover and degradation of damaged mitochondria, which may lead to apoptosis. Objectives To evaluate markers of mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART and determine their potential association with obstetric complications. Methods This controlled, single-site, observational study without intervention included 26 HIV-infected pregnant women on HAART and 18 control pregnancies and their newborns. Maternal PBMCs and neonatal cord blood mononuclear cells (CBMCs) were isolated at the first trimester of gestation and at delivery. The placenta was homogenized at 5% w/v. Mitochondrial dynamics, fusion events [mitofusin 2 (Mfn2)/β-actin] and fission events [dynamin-related protein 1 (Drp1/β-actin)] and apoptosis (caspase 3/β-actin) were assessed by western blot analysis. Results Obstetric complications were significantly more frequent in pregnancies among HIV-infected women [OR 5.00 (95% CI 1.21-20.70)]. Mfn2/β-actin levels in PBMCs from controls significantly decreased during pregnancy (202.13 ± 57.45%), whereas cases maintained reduced levels from the first trimester of pregnancy and no differences were observed in CBMCs. Mfn2/β-actin and Drp1/β-actin contents significantly decreased in the placenta of cases. Caspase 3/β-actin levels significantly increased during pregnancy in PBMCs of cases (50.00 ± 7.89%), remaining significantly higher than in controls. No significant differences in caspase 3/β-actin content of neonatal CBMCs were observed, but there was a slight increased trend in placenta from cases. Conclusions HIV- and HAART-mediated mitochondrial damage may be enhanced by decreased mitochondrial dynamics and increased apoptosis in maternal and placental compartments but not in the uninfected fetus. However, direct effects on mitochondrial dynamics and implication of apoptosis were not demonstrated in adverse obstetric outcomes.

We have previously shown that an HIV vaccine regimen including three doses of HIV-modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B) was safe and elicited moderate and durable (1 year) T-cell and antibody responses in 75% and 95% of HIV-negative volunteers (n = 24), respectively (RISVAC02 study). Here, we describe the long-term durability of vaccine-induced responses and the safety and immunogenicity of an additional MVA-B boost.

BACKGROUND: HIV infection and HAART trigger genetic and functional mitochondrial alterations leading to cell death and adverse clinical manifestations. Mitochondrial dynamics enable mitochondrial turnover and degradation of damaged mitochondria, which may lead to apoptosis. OBJECTIVES: To evaluate markers of mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART and determine their potential association with obstetric complications. METHODS: This controlled, single-site, observational study without intervention included 26 HIV-infected pregnant women on HAART and 18 control pregnancies and their newborns. Maternal PBMCs and neonatal cord blood mononuclear cells (CBMCs) were isolated at the first trimester of gestation and at delivery. The placenta was homogenized at 5% w/v. Mitochondrial dynamics, fusion events [mitofusin 2 (Mfn2)/ß-actin] and fission events [dynamin-related protein 1 (Drp1/ß-actin)] and apoptosis (caspase 3/ß-actin) were assessed by western blot analysis. RESULTS: Obstetric complications were significantly more frequent in pregnancies among HIV-infected women [OR 5.00 (95% CI 1.21-20.70)]. Mfn2/ß-actin levels in PBMCs from controls significantly decreased during pregnancy (202.13?±?57.45%), whereas cases maintained reduced levels from the first trimester of pregnancy and no differences were observed in CBMCs. Mfn2/ß-actin and Drp1/ß-actin contents significantly decreased in the placenta of cases. Caspase 3/ß-actin levels significantly increased during pregnancy in PBMCs of cases (50.00?±?7.89%), remaining significantly higher than in controls. No significant differences in caspase 3/ß-actin content of neonatal CBMCs were observed, but there was a slight increased trend in placenta from cases. CONCLUSIONS: HIV- and HAART-mediated mitochondrial damage may be enhanced by decreased mitochondrial dynamics and increased apoptosis in maternal and placental compartments but not in the uninfected fetus. However, direct effects on mitochondrial dynamics and implication of apoptosis were not demonstrated in adverse obstetric outcomes.

Objectives Ritonavir-boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir-boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir-induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved. Methods A 96-week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA

Objectives The aim of the study was to compare prospectively indicator-condition (IC)-guided testing versus testing of those with non-indicator conditions (NICs) in four primary care centres (PCCs) in Barcelona, Spain. Methods From October 2009 to February 2011, patients aged from 18 to 65 years old who attended a PCC for a new herpes zoster infection, seborrhoeic eczema, mononucleosis syndrome or leucopenia/thrombopenia were included in the IC group, and one in every 10 randomly selected patients consulting for other reasons were included in the NIC group. A proportion of patients in each group were offered an HIV test; those who agreed to be tested were given a rapid finger-stick HIV test (€6 per test). Epidemiological and clinical data were collected and analysed. Results During the study period, 775 patients attended with one of the four selected ICs, while 66 043 patients presented with an NIC. HIV screening was offered to 89 patients with ICs (offer rate 11.5%), of whom 85 agreed to and completed testing (94.4 and 100% acceptance and completion rates, respectively). In the NIC group, an HIV test was offered to 344 persons (offer rate 5.2%), of whom 313 accepted (90.9%) and 304 completed (97.1%) testing. HIV tests were positive in four persons [prevalence 4.7%; 95% confidence interval (CI) 1.3–11.6%] in the IC group and in one person in the NIC group (prevalence 0.3%; 95% CI 0.01–1.82%; P

Introduction HIV seropositivity is considered a risk factor for complications in hepatitis A virus (HAV) infection. HAV vaccination schedules are widely implemented in HIV-infected patients, but the immune response remains impaired. Methods We analysed the response to vaccination (antiHAV titres ≥20 IU/l) in 282 HIV-infected patients included in a standard (1440 Elisa Units (EU) at 0, 6 months) or rapidly accelerated schedule (720 EU at 0, 7, 21 days and 6 months) between 1997 and 2009. Factors associated with the response to vaccination were analysed using logistic regression. Results The overall response rate was 73.4%. Male sex (OR: 0.16, 95% CI 0.05–0.51) and hepatitis C virus co-infection (OR: 0.30, 95% CI 0.14–0.74) were associated with a lower probability of response. Protective antibody response was associated with a higher CD4/CD8 ratio (OR: 3.69, 95% CI 1.3–10.5) and having received two doses of standard schedule (compared with patients receiving only one dose of the same schedule) (OR: 2.51, 95% CI 1.22–5.15). Three doses of the rapidly accelerated schedule were not more effective than a single dose of 1440 EU (OR: 1.32, 95% CI 0.48–3.63). Conclusion The low responses observed in patients receiving a single dose suggest the need to emphasize adhesion to vaccination protocols to avoid failure. The CD4/CD8 ratio may be considered as an immune status marker which could help to better choose the moment of vaccination. Our findings underscore the importance of identifying strategies that optimize the timing and effectiveness of hepatitis A vaccination in HIV-infected patients and of the need for further studies on individual factors such as sex and hepatitis C co-infection that may affect the response to vaccination. Likewise, the sub-optimal effectiveness of three doses of 720 EU in the rapidly accelerated schedule, if confirmed in future studies, might lead to a revision of the current schedule recommended for HIV-infected travellers.

OBJECTIVE: To evaluate the trend in incidence of Pseudomonas aeruginosa bacteremia, underlying conditions of patients, mortality rate, and factors associated with poor outcome. PATIENTS AND METHODS: Medical charts of 189 consecutive episodes of P aeruginosa bacteremia, detected between January 1, 1991, and December 31, 1994, were prospectively evaluated. Associated risk factors, treatment, and outcome were recorded. RESULTS: Pseudomonas aeruginosa bacteremia represented 5.7% of the total number of bacteremias, 6.9% of nosocomial bacteremias, and 23.6% of nosocomial gram-negative bacteremias. There were 1.5 episodes per 1000 discharges. These numbers were slightly lower than those recorded at our hospital 10 years earlier. Human immunodeficiency virus infection was the most frequent underlying disease (28/189 [15%]). Overall mortality was 18% (34/189). The presence of fatal underlying disease (P < .001), surgery (P = .001), pneumonia (P = .02), and severe sepsis (P < .001) were associated with poor prognosis, the mortality of the patients with these variables being 28%, 28%, 47%, and 62%, respectively. The presence of inappropriate definitive antimicrobial treatment became an independent factor predictive of death (P = .04) only when the subset of patients with intravenous catheter-associated bacteremia was excluded from the analysis. The survival rate was no greater in patients who received 2 or more antibiotics active in vitro against P aeruginosa than in those who received only 1. Neutropenia was not associated with increased mortality. The use of colony-stimulating factors did not affect the outcome of the neutropenic patients. CONCLUSIONS: The rate of P aeruginosa bacteremia is falling slightly at our hospital. The emergence of the human immunodeficiency virus epidemic has had a considerable impact on both epidemiology and mortality. The presence of severe underlying disease, surgery, pneumonia, and, especially, severe sepsis are associated with a poor outcome. With the exclusion of patients with intravenous catheter-associated P aeruginosa bacteremia, the administration of an appropriate antimicrobial therapy is essential to a good outcome. Treatment with 1 active antibiotic seems to be sufficient.

OBJECTIVES The most recent guidelines suggest using integrase strand-transfer inhibitors (InSTIs) as the preferred antiretroviral regimens for naive HIV-infected individuals. However, resistance to InSTIs is not monitored in many centres at baseline. This study aimed to evaluate the prevalence of InSTI resistance substitutions in newly diagnosed patients with acute/recent HIV infection. METHODS Genotypic drug resistance tests were performed in all consecutive patients prospectively enrolled with a documented infection of

BACKGROUND: Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR).METHODS: In this prospective international cohort study, HIV-positive adult participants (aged ≥16 years) from the D:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1·73 m(2) were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6 months (whichever occurred first). Chronic kidney disease was defined as confirmed (>3 months apart) eGFR lower than 60 mL/min per 1·73 m(2). The primary outcome was the occurrence of chronic kidney disease. Poisson regression was used to estimate the incidence rate of chronic kidney disease associated with cumulative exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, other ritonavir-boosted protease inhibitors, or abacavir.FINDINGS: Between Jan 1, 2004, and July 26, 2013, 23,905 eligible individuals from the D:A:D study were included. Participants had a median baseline eGFR of 110 mL/min per 1·73 m(2) (IQR 100-125), a median age of 39 years (33-45), and median CD4 cell count of 441 cells per mm(3) (294-628). During a median follow-up of 7·2 years (IQR 5·1-8·9), 285 (1%) of 23,905 people developed chronic kidney disease (incidence 1·76 per 1000 person-years of follow-up [95% CI 1·56-1·97]). After adjustment, we recorded a significant increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate (adjusted incidence rate ratio 1·14 [95% CI 1·10-1·19], pINTERPRETATION: In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored.FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee.

Cardiovascular diseases have become a significant cause of morbidity in patients with human immunodeficiency virus (HIV) infection. Heart transplantation (HT) is a well-established treatment of end-stage heart failure (ESHF) and is performed in selected HIV-infected patients in developed countries. Few data are available on the prognosis of HIV-infected patients undergoing HT in the era of combined antiretroviral therapy (cART) because current evidence is limited to small retrospective cohorts, case series, and case reports. Many HT centers consider HIV infection to be a contraindication for HT; however, in the era of cART, HT recipients with HIV infection seem to achieve satisfactory outcomes without developing HIV-related events. Consequently, selected HIV-infected patients with ESHF who are taking effective cART should be considered candidates for HT. The present review provides epidemiological data on ESHF in HIV-infected patients from all published experience on HT in HIV-infected patients since the beginning of the epidemic. The practical management of these patients is discussed, with emphasis on the challenging issues that must be addressed in the pretransplant (including HIV criteria) and posttransplant periods. Finally, proposals are made for future management and research priorities.

A fraction of HIV-1 patients are able to generate broadly neutralizing antibodies (bNAbs) after 2 to 4 years of infection. In rare occasions such antibodies are observed close to the first year of HIV-1 infection but never within the first 6 months. In this study, we analyzed the neutralization breadth of sera from 157 antiretroviral-naive individuals who were infected for less than 1 year. A range of neutralizing activities was observed with a previously described panel of six recombinant viruses from five different subtypes (M. Medina-Ramirez et al., J Virol 85: 5804–5813, 2011, http://dx.doi.org/10.1128/JVI.02482-10 ). Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The neutralization breadth was positively associated with time postinfection ( P = 0.0001), but contrary to what has been reported for chronic infections, no association with the viral load was observed. Notably, five individuals within the first 6 months of infection (two as early as 77 and 96 days postinfection) showed substantial cross-neutralization. This was confirmed with an extended panel of 20 Env pseudoviruses from four different subtypes (two in tier 3, 14 in tier 2, and four in tier 1). Sera from these individuals were capable of neutralizing viruses from four different subtypes with a geometric mean 50% infective dose (ID 50 ) between 100 and 800. These results indicate that induction of cross-neutralizing responses, albeit rare, is achievable even within 6 months of HIV-1 infection. These observations encourage the search for immunogens able to elicit this kind of response in preventive HIV-1 vaccine approaches. IMPORTANCE There are very few individuals able to mount broadly neutralizing activity (bNA) close to the first year postinfection. It is not known how early in the infection cross-neutralizing responses can be induced. In the present study, we show that bNAbs, despite being rare, can be induced much earlier than previously thought. The identification of HIV-1-infected patients with these activities within the first months of infection and characterization of these responses will help in defining new immunogen designs and neutralization targets for vaccine-mediated induction of bNAbs.

Background: The proportion of HIV controllers developing virologic, immunological or clinical progression and the baseline predictors of these outcomes have not been assessed in large cohorts. Methods: A multicenter cohort of HIV controllers was followed from baseline (the first of the three HIV-1 RNA levels

Objective: To compare 48-week changes in bone mineral density (BMD) and body fat distribution between patients continuing lopinavir/ritonavir and two NRTIs and those switching to lopinavir/ritonavir and lamivudine. Methods: Substudy of a randomized, open-label, multicenter OLE study was carried out. Adult HIV-infected patients with = 6 months were randomized (1:1) to continue lopinavir/ritonavir and two NRTIs or switching to lopinavir/ritonavir and lamivudine. Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 48 weeks to measure bone composition and body fat distribution in both the groups. Results: Forty-one patients (dual-therapy, n = 23; triple-therapy, n = 18) of 239, who received at least one dose of study medication, completed the study: median age, 42 years, 71% male, 73% Caucasian. At week 48, total BMD increased by 1.04% (95% CI, 0.06 to 2.01%) among patients switching to dual-therapy, whereas no significant changes occurred in patients maintaining triple-therapy. Dual-therapy and older age were independently associated with total BMD increase. Among patients discontinuing tenofovir-DF, a significant increase was seen in total BMD (1.43; 95% CI, -0.04 to 2.91) and total hip (1.33%; 95% CI, 0.44 to 2.22%). A non-statistically significant decrease in femoral and spinal BMD was observed in patients who discontinued abacavir and in those continuing triple-therapy. Regarding fat distribution, no significant changes were seen in both the treatment groups. Discussion: BMD increased following switching to lopinavir/ritonavir plus lamivudine in HIV-infected patients on suppressive triple-therapy with lopinavir/ritonavir and two NRTIs including tenofovir-DF.

In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should comprise 3 drugs, namely, 2 nucleoside reverse transcriptase inhibitors (NRTI), and I drug from another family. Four of the recommended regimens, all of which have an integrase strand transfer inhibitor (INSTI) as the third drug, are considered a preferred regimen; a further 6 regimens, which are based on an INSTI, a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor boosted with cobicistat or ritonavir (PI/COBI, PI/r), are considered alternatives. The reasons and criteria for switching ART are presented both for patients with an undetectable PVL and for patients who experience virological failure, in which case the rescue regimen should include 3 (or at least 2) drugs that are fully active against HIV. The specific criteria for ART in special situations (acute infection, HIV-2 infection, pregnancy) and comorbid conditions (tuberculosis and other opportunistic infections, kidney disease, liver disease, and cancer) are updated. (C) 2016 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

Background Several potential immunological benefits have been observed during treatment with the CC chemokine receptor 5 (CCR5) antagonist maraviroc, in addition to its antiviral effect. Our objective was to analyse the in vitro effects of CCR5 blockade on T lymphocyte function and homeostasis. Methods Peripheral blood mononuclear cells (PBMCs) from both HIV-negative (n=28) and treated HIV-positive (n=27) individuals were exposed in vitro to different concentrations of maraviroc (0.1-100 μM). Effects on T cell activation were analysed by measuring the expression of the CD69, CD38, HLA-DR and CD25 receptors as well as CCR5 density using flow cytometry. Spontaneous and chemokine-induced chemotaxis were measured by transwell migration assays, and polyclonal-induced proliferation was assessed by a lymphoproliferation assay and carboxyfluorescein succinimidyl ester staining. Results Maraviroc increases CCR5 surface expression on activated T cells, even at low doses (0.1 μM). Slight differences were detected in the frequency and mean fluorescence intensity of activation markers at high concentrations of maraviroc. Expression of CD25, CD38 and HLA-DR tended to decrease in both CD4+ and CD8+ T lymphocytes, whereas expression of CD69 tended to increase. Maraviroc clearly inhibits T cell migration induced by chemokines in a dose-dependent manner. Moreover, at 100 μM, maraviroc tends to inhibit T cell proliferation. Conclusions These data showed that in vitro exposure to maraviroc decreases some activation expression markers on T lymphocytes and also migration towards chemoattractants. These results support the additional immunological effects of CCR5 blockade and suggest that maraviroc might have potential capacity to inhibit HIV-associated chronic inflammation and activation, both by directly affecting T cell activation and by reducing entrapment of lymphocytes in lymph nodes.

Objectives The aim of the study was to assess the separate contributions of smoking, diabetes and hypertension to acute coronary syndrome (ACS) in HIV-infected adults relative to uninfected adults. Methods Two parallel case–control studies were carried out. In the first study, HIV-positive adults diagnosed with ACS between 1997 and 2009 (HIV+/ACS) were matched for age, gender and known duration of HIV infection with HIV-positive adults without ACS (HIV+/noACS), each individual in the HIV+/ACS group being matched with three individuals in the HIV+/noACS group. In the second study, each individual in the HIV+/ACS group in the first study was matched for age, gender and calendar date of ACS diagnosis with three HIV-negative individuals diagnosed with ACS between 1997 and 2009 (HIV–/ACS). Each individual in the HIV–/ACS group was then matched for age and gender with an HIV-negative adult without ACS (HIV–/noACS). After matching, the ratio of numbers of individuals in the HIV+/ACS, HIV+/noACS, HIV–/ACS and HIV–/noACS groups was therefore 1 : 3 : 3 : 3, respectively. We performed logistic regression analyses to identify risk factors for ACS in each case–control study and calculated population attributable risks (PARs) for smoking, diabetes and hypertension in HIV-positive and HIV-negative individuals. Results There were 57 subjects in the HIV+/ACS group, 173 in the HIV+/noACS group, 168 in the HIV–/ACS group, and 171 in the HIV–/noACS group. Independent risk factors for ACS were smoking [odds ratio (OR) 4.091; 95% confidence interval (CI) 2.086–8.438; P

INTRODUCTION The GESIDA and National AIDS Plan panel of experts propose «preferred regimens» of antiretroviral treatment (ART) as initial therapy in HIV infected patients for 2012. The objective of this study is to evaluate the costs and the efficiency of initiating treatment with these «preferred regimens». METHODS Economic assessment of costs and efficiency (cost/efficacy) using decision tree analysis model. Efficacy was defined as the probability of having a viral load

Background Although HIV-infected patients are at greater risk of presenting with ischaemic necrosis of the femoral head, there have been concerns about whether total hip arthroplasty (THA) may have worse outcomes than expected. Methods From the Orthopedic and Trauma Surgery database we identified all patients who had undergone THA because of ischaemic necrosis of the femoral head from January 2001 until March 2010. Patient's diagnosis of HIV infection was confirmed at the time of arthroplasty by cross-matching with the HIV unit database. For every THA in HIV-infected patients, two THAs in patients not known to be HIV-infected, with the same diagnosis of ischaemic necrosis of the femoral head and having undergone surgery over the same period, were randomly selected. THAs were compared in HIV- and non-HIV-infected patients for surgical procedure, in-patient stay and long-term prognosis. Results There were 18 THAs in 13 HIV-infected patients and 36 THAs in 27 non-HIV-infected patients. No significant differences were observed in the mean time spent in surgery (106 vs. 109 minutes, respectively; P = 0.66), the need for red cell transfusion (1 vs. 4, respectively; P = 0.48) or the mean duration of hospitalization (7.8 vs. 9.4 days, respectively; P = 0.48). The two groups showed similar postoperative functional results, which were maintained until the end of the follow-up period (median 3.3 years in the HIV-positive group and 5.8 years in the HIV-negative group). Conclusion Our study suggests that the outcome of THA in HIV-positive patients is not worse than that of HIV-negative patients, although future research on larger numbers of patients is required to confirm this.

Results The prescriptions for 247 admissions (189 patients) were reviewed. Sixty antiretroviral-related problems were identified in 41 patients (21.7%). The most common problem was contraindicated combinations (n 5 20; 33.3%), followed by incorrect dose (n 5 10; 16.7%), dose omission (n 5 9; 15%), lack of dosage reduction in patients with renal or hepatic impairment (n 5 6; 10% and n 5 1; 1.7%, respectively), omission of an antiretroviral (n 5 6; 10%), addition of an alternative antiretroviral (n 5 5; 8.3%) and incorrect schedule according to outpatient treatment (n 5 3; 5%). Fifteen out of 20 errors were made during admission. A multivariate analysis showed that factors associated with an increased risk of antiretroviral-related problems included renal impairment [odds ratio (OR) 3.95; 95% confidence interval (CI) 1.39–11.23], treatment with atazanavir (OR 3.53; 95% CI 1.61–7.76) and admission to a unit other than an infectious diseases unit (OR 2.50; 95% CI 1.28– 4.88). Use of a nonnucleoside reverse transcriptase inhibitor was a protective factor (OR 0.33; 95% CI 0.13–0.81). Ninety-two per cent of the pharmacist’s interventions were accepted. Conclusion Antiretroviral-related errors affected more than one-in-five patients. The most common causes of error were contraindicated or not recommended drug–drug combinations and dose-related errors. A clinical pharmacist trained in HIV pharmacotherapy could help to detect errors and reduce the duration of their effect.

Objectives HIV-infected adults are considered to be at higher risk for influenza A H1N1 complications but data supporting this belief are lacking. We aimed to compare epidemiological data, clinical characteristics, and outcomes of influenza A H1N1 infection between HIV-infected and -uninfected adults. Methods From 26 April to 6 December 2009, each adult presenting with acute respiratory illness at the emergency department of our institution was considered for an influenza A H1N1 diagnosis by specific multiplex real-time polymerase chain reaction. For every HIV-infected adult diagnosed, three consecutive adults not known to be HIV-infected diagnosed in the same calendar week were randomly chosen as controls. Results Among 2106 adults tested, 623 (30%) had influenza A H1N1 infection confirmed. Fifty-six (9%) were HIV-positive and were compared with 168 HIV-negative controls. Relative to HIV-negative controls, HIV-positive patients were older, more frequently male, and more frequently smokers (P≤0.02). In the HIV-positive group, prior or current AIDS-defining events were reported for 30% of patients, 9% and 30% had CD4 counts of 0.05). Conclusions HIV infection did not increase the severity of influenza A H1N1 infection, and influenza A H1N1 infection did not have a major effect on HIV infection.