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.

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.

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.

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.

[Acute outbreak of hepatitis C in human immunodeficiency virus-infected patients]. / Brote epidémico de hepatitis aguda C en pacientes infectados por el virus de la inmunodeficiencia humana.

BACKGROUND: Recent studies suggest an increased incidence of acute infection with hepatitisC virus (AHC) in men who have sex with men (MSM) co-infected with HIV. Early treatment with interferon-alpha, alone or in combination with ribavirin, significantly reduces the risk of chronic evolution. METHODS: This retrospective study includes all HIV patients with AHC in our centre from 2003 to March 2013. AHC was defined by seroconversion of HCV antibodies and detection of serum HCV RNA. RESULTS: 93 episodes of AHC were diagnosed in 89 patients. All but three were MSM with a history of unprotected sex. Thirty-seven (40%) patients had other associated sexually transmitted disease. The 29% (27) had any symptoms suggestive of AHC. HCV genotype 4 was the most common (41%), followed by genotype1. Seventy patients started treatment with interferon-alfa and weight-adjusted ribavirin. Currently 46 have completed treatment and follow-up, reaching 26 of them (56.5%) sustained viral response. CONCLUSIONS: The incidence of AHC in HIV MSM patients from our centre has increased exponentially in recent years; sexual transmission remains the main route of infection. Early treatment with interferon-alpha and ribavirin achieved a moderate response in these patients.

Executive summary of the GESIDA/National AIDS Plan Consensus Document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2015).

In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The strength and grade of the recommendation vary depending on the CD4+ T-lymphocyte count, the presence of opportunistic infections or comorbid conditions, age, and the efforts to prevent the transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should comprise three drugs, namely, two nucleoside reverse transcriptase inhibitors (NRTI) and one drug from another family. Three 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 seven regimens, which are based on an INSTI, an non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor boosted with ritonavir (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 three (or at least two) 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.

Executive summary of the GeSIDA/National AIDS Plan consensus document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2014).

In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The strength and grade of the recommendation varies with clinical circumstances, number of CD4 cells, comorbid conditions and prevention of transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load. Initial ART should always comprise a combination of 3 drugs, including 2 nucleoside reverse transcriptase inhibitors and a third drug from a different family (non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor). This update presents the causes and criteria for switching ART in patients with undetectable plasma viral load and in cases of virological failure. An update is also provided for the specific criteria for ART in special situations (acute infection, HIV-2 infection, and pregnancy) and with comorbid conditions (tuberculosis or other opportunistic infections, kidney disease, liver disease, and cancer).

Creatine kinase elevation in HIV-1-infected patients receiving raltegravir-containing antiretroviral therapy: a cohort study.

OBJECTIVES: To evaluate the incidence and risk factors for significant creatine kinase elevation in HIV-1-infected patients who were prescribed a raltegravir-containing antiretroviral therapy. DESIGN: A retrospective analysis of a prospectively collected cohort involving all consecutive patients who were prescribed a raltegravir-containing antiretroviral regimen between June 2005 and December 2010. METHODS: Significant creatine kinase elevation was defined as an elevation of at least 3-fold from the upper limit of normal (ULN) (grade 2, WHO classification) while receiving raltegravir. Blood analysis at each visit included at least creatine kinase, as well as plasma HIV-1 RNA and CD4 cell count. RESULTS: There were 475 patients who had been exposed to raltegravir for a median of 11.5 (IQR 8.2-15.2) months. An increase of creatine kinase ≥ 3-fold ULN was detected in 53 (11.2%) patients, representing an incidence of 3.8/100 person-years. Symptoms were reported by seven patients (1.5%), they showed either grade 1 (n = 3) or 2 (n = 4) creatine kinase increases. The median duration of raltegravir therapy before creatine kinase elevation was 5.9 (IQR 3.3-9.3) months. Evidence of creatine kinase elevation prior to raltegravir therapy [hazard ratio (HR) 3.30; 95% CI 1.59 ± 6.86; P = 0.001], abnormal baseline creatine kinase (HR 3.24; 95% CI 1.63 ± 6.45; P = 0.001) and male gender (HR 4.17; 95% CI 1.33 ± 1.27; P = 0.001) were identified as independent risk factors for creatine kinase elevation during raltegravir treatment. CONCLUSIONS: Although ≈ 1 in 10 patients on raltegravir therapy developed significant creatine kinase elevation as defined in this study, symptoms were uncommon, not severe and occurred in patients with easily identifiable risk factors.

Pharmacokinetic study of dual therapy with raltegravir 400 mg twice daily and Darunavir/Ritonavir 800/100 mg once daily in HIV-1-infected patients.

BACKGROUND: Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients. METHODS: This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits. RESULTS: Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients. CONCLUSIONS: Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.

Highly Efficient Autologous HIV-1 Isolation by Coculturing Macrophage With Enriched CD4+ T Cells From HIV-1 Patients.

We described a novel HIV autologous isolation method based in coculturing macrophages and CD4+T-cell-enriched fractions from peripheral blood collected from antiretroviral-treated (ART) HIV patients. This method allows the isolation of high viral titers of autologous viruses, over 1010HIV RNA copies/ml, and reduces the time required to produce necessary amounts for virus for use as antigens presented by monocyte-derived myeloid cells in HIV therapeutic vaccine approaches. By applying these high titer and autologous virus produced in the patient-derived cells, we intended to elicit a boost of the immunological system response in HIV therapeutic vaccines in clinical trials.

Effect of Intranodally Administered Dendritic Cell-Based HIV Vaccine in Combination With Pegylated Interferon α-2a on Viral Control Following ART Discontinuation: A Phase 2A Randomized Clinical Trial.

Introduction: Functional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches. Materials and Methods: We conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1. Results: Twenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4-6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients' viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-Æ´ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration. Discussion: Results from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants. Clinical Trial Registration: (www.ClinicalTrials.gov), identifier NCT02767193.

The HIV-1 Nucleocapsid Regulates Its Own Condensation by Phase-Separated Activity-Enhancing Sequestration of the Viral Protease during Maturation.

A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular 'sponges', stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of ∼2400 Gag and ∼120 GagPol by the viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak-strong-moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules.

Pilot study assessing HIV vaccine trial readiness among female sex workers, injection and non-injection drug users, and men who have sex with men in Spain.

The purpose of this study was to assess HIV risk and willingness to participate in HIV vaccine trials in three high risk populations in Spain. Eight hundred and forty-four participants, comprising female sex workers, injection and non-injection drug users (IDUs and NIDUs, respectively), and men who have sex with men were tested for HIV and surveyed for risk and willingness to participate in future preventive HIV vaccine trials. HIV seroprevalence was 3.8% (95% CI: 2-11). HIV infection was associated with transgender identification, IDU in the past year, and sex with an IDU or other drug-using partner. The majority (82%) expressed their willingness to participate in HIV vaccine trials. Substantial sexual and parenteral risk in all groups and concomitant willingness to participate in vaccine trials was found, particularly among women and IDUs. Additional longitudinal cohort studies in Spain are needed to plan future vaccine efficacy trials.

Short-term effect of ritonavir-boosted atazanavir in hepatitis B and/or C co-infected, treatment-experienced HIV patients.

OBJECTIVE: To describe the short-term, liver safety, immunological, and virological outcome in HIV subjects according to their hepatitis co-infection status after switching to ritonavir-boosted atazanavir (ATV/r)-based therapy. METHODS: Rates of treatment discontinuation, changes in liver enzyme values, viral load, and CD4+ T-cell counts responses from patients included in the Bristol-Myers Squibb Atazanavir Early Access Program (BMS ATV EAP) were evaluated in hepatitis C and/or B co-infected patients (co-infected) and non-co-infected. RESULTS: A total of 304 subjects with known HCV and/or HBV status from 55 centers were included in the analysis: 180 co-infected and 124 HIV non-co-infected. Accumulated follow-up until study closure was 762 and 551 person-months in the co-infected and non-co-infected subjects, respectively. The proportion of discontinuations through Month 6 was 9.4% (co-infected) and 5.6% (non-co-infected). Discontinuations due to elevated liver enzymes [1.7% (co-infected) and 0% (non-co-infected)] and due to scleral icterus/jaundice [4.4% (co-infected) and 3.2% (non-co-infected)] were low and similar between groups. Only three subjects (1%) discontinued due to virological failure. Successful virological outcome (viral load <500 copies/mL or a decrease >1 log(10)) was observed in 74% of subjects in each group. CD4+ T-cell count changes were +51 (co-infected) and +53 cells/mm3 (non-co-infected). CONCLUSIONS: Short-term effectiveness and liver safety in HCV and or HBV co-infected patients changing to an ATV/r-based regimen was similar to that observed in non-co-infected patients.

Improving the evidence for indicator condition guided HIV testing in Europe: Results from the HIDES II Study - 2012 - 2015.

BACKGROUND: It is cost-effective to perform an HIV test in people with specific indicator conditions (IC) with an undiagnosed HIV prevalence of at least 0.1%. Our aim was to determine the HIV prevalence for 14 different conditions across 20 European countries. METHODS: Individuals aged 18-65 years presenting for care with one of 14 ICs between January 2012 and June 2014 were included and routinely offered an HIV test. Logistic regression assessed factors associated with testing HIV positive. Patients presenting with infectious mononucleosis-like syndrome (IMS) were recruited up until September 2015. RESULTS: Of 10,877 patients presenting with an IC and included in the analysis, 303 tested positive (2.8%; 95% CI 2.5-3.1%). People presenting with an IC in Southern and Eastern Europe were more likely to test HIV positive as were people presenting with IMS, lymphadenopathy and leukocytopenia/ thrombocytopenia. One third of people diagnosed with HIV after presenting with IMS reported a negative HIV test in the preceding 12 months. Of patients newly diagnosed with HIV where data was available, 92.6% were promptly linked to care; of these 10.4% were reported lost to follow up or dead 12 months after diagnosis. CONCLUSION: The study showed that 10 conditions had HIV prevalences > 0.1%. These 10 ICs should be adopted into HIV testing and IC specialty guidelines. As IMS presentation can mimic acute HIV sero-conversion and has the highest positivity rate, this IC in particular affords opportunities for earlier diagnosis and public health benefit.

Abacavir does not influence the rate of virological response in HIV-HCV-coinfected patients treated with pegylated interferon and weight-adjusted ribavirin.

BACKGROUND: The combination of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is the standard of care for hepatitis C virus (HCV) treatment in HIV-coinfected individuals. In 2007, abacavir (ABC)-based antiretroviral therapy was, for the first time, reported to be associated with early virological failure during HCV treatment. The aim of our study was to evaluate the effect of ABC on the response rate to HCV therapy. METHODS: A retrospective analysis of HIV-HCV-coinfected patients treated with PEG-IFN and weight-adjusted RBV in four hospitals in Spain was performed. An analysis of baseline descriptive variables was conducted. Logistic regression models were used to test possible associations between non-response and pretreatment characteristics, including antiretroviral drugs. RESULTS: A total of 244 HIV-HCV-coinfected patients treated with PEG-IFN and RBV were included. Overall, 85% of patients were on highly active antiretroviral therapy; of these patients, 24% received ABC-based regimens. The most frequent genotypes were 1 and 3. RBV dosing was 213.2 mg/kg/day in 97% of the patients. In the global intent-to-treat analyses, 46.3% of patients reached a sustained virological response (SVR; 46.2% in ABC group versus 46.7% in non-ABC group, P=1). The only two factors in the multivariate analysis that were statistically associated with an increased risk of failure to achieve SVR were HCV genotypes 1 or 4 and older age. The use of ABC was not associated with failure to achieve SVR at any of the other time points evaluated. CONCLUSIONS: Our data suggest that the use of ABC-based regimens in the context of HCV therapy does not negatively affect the outcome of this treatment.

[Efficacy of atazanavir in simplification regimens]. / Atazanavir en el tratamiento de simplificación.

Atazanavir is a new azapeptide protease inhibitor with a remarkable pharmacokinetic profile, which means it can be administered in only two capsules once per day in combination with other antiretrovirals. Its strong antiviral efficacy is also accompanied by an excellent tolerance profile and no significant increase in cholesterol and triglyceride levels. The immunological and virological response obtained with atazanavir or atazanavir/ritonavir, in naive patients as well as in patients with previous virological failure with other protease inhibitors, is excellent. Atazanavir is an attractive drug for therapeutic simplification. Besides maintaining virological suppression, patients who change from other PI to atazanavir experience reductions in total cholesterol, HDL cholesterol and triglycerides. Preliminary data suggest that simplified maintenance treatment with atazanavir/ritonavir in monotherapy, can effectively maintain virological suppression in selected patients.

Changes in Cognitive Function Over 96 Weeks in Naive Patients Randomized to Darunavir-Ritonavir Plus Either Raltegravir or Tenofovir-Emtricitabine: A Substudy of the NEAT001/ANRS143 Trial.

BACKGROUND: Improvements in cognitive function are described after initiation of combination antiretroviral therapy (cART), with sparse data on differences between cART strategies. METHODS: We assessed changes in cognition, over 96 weeks, in therapy-naive HIV-positive adults randomized to darunavir/ritonavir (800/100 mg once daily) with either raltegravir (400 mg twice daily, Arm1) or tenofovir/emtricitabine (245/200 mg once daily, Arm2). Seven cognitive tests were administered at baseline and week (W) 96. Changes from baseline in individual cognitive test scores and composite score (NPZ) were assessed. Comparisons between treatment arms were by intention to treat and associations with immunological and virological parameters by regression models. FINDINGS: Of 343 subjects enrolled, 208 completed the W96 cognitive assessment. Baseline median (interquartile range) CD4 count and plasma HIV RNA were 348 (282-398) cells per microliter and 4.7 (4.2-5.1) log10 copies per milliliter, respectively. At W96, numbers with plasma HIV RNA undetectable and remaining on randomized cART were 85 (92%) and 110 (96%), and 84 (90%) and 107 (93%) in Arm1 and Arm2, respectively. Overall performance significantly improved by W96 in 5 of 7 individual tests and in NPZ. Mean changes in NPZ were 0.28 versus 0.21 for Arm1 and 2, respectively (P = 0.37). No statistically significant differences between study treatment arms were observed in individual cognitive domains apart from attention (greater improvement in Arm1, P = 0.0499). At W96, NPZ score increase was associated with increase in CD4 (P = 0.001) but not HIV RNA area under curve (P = 0.60). INTERPRETATION: Subsequent to the initiation of cART, immunological recovery rather than type of antiretroviral therapy is the major driver of changes in cognitive function.

Decreased pregnancy rate after in-vitro fertilization in HIV-infected women receiving HAART.

A study on in-vitro fertilization (IVF) was conducted among HIV-infected women. In these patients, a reduced pregnancy rate after IVF was observed if the patient's own oocytes were used. However, no significant reduction in the pregnancy rate was found if donated oocytes were used. The CD4 lymphocyte count was independently associated with ovarian resistance to hyperstimulation. Subclinical hypogonadism mediated by immunosuppression may explain these observations, suggesting the need to optimize the immunological status of the patient before considering assisted reproduction treatments.

Group A streptococcal infections in injection drug users in Barcelona, Spain: epidemiologic, clinical, and microbiologic analysis of 3 clusters of cases from 2000 to 2003.

An unexplained resurgence of Group A streptococci (GAS) infections has been observed since the mid-1980s in the United States and Europe, particularly among intravenous drug users (IDUs). Several risk factors have been identified. Mutations in the capsule synthesis regulator genes (csrRS) have been associated with an increase in virulence. From January 1998 to December 2003, we conducted a prospective and retrospective descriptive analysis of invasive GAS soft-tissue infections in IDUs in Barcelona, Spain. Clinical features were collected, and we conducted a surveillance study to identify risk factors associated with GAS soft-tissue infections. We analyzed chromosomal DNA by low cleavage restriction enzymes and used pulsed-field gel electrophoresis (PFGE) and variable gene sequence typing (VGST) of the emm gene to disclose the epidemiologic relationship between the strains. We analyzed the influence of clonality (M-type) and mutations in csrRS genes of these strains on clinical features. We identified 44 cases, all of which were grouped in 3 clusters: fall 2000, fall 2002, and fall 2003. Cellulitis with or without abscesses (75%) and fever (90.9%) were the most common clinical manifestations. Distant septic complications were infrequent (18.2%). Although all patients had severe infections (mainly bacteremic needle abscesses), their outcome with antibiotic therapy, usually beta-lactam, was successful in all cases. However, surgery was needed in 40.9% of patients. Through the surveillance study we found that infected patients had a higher number of drug injections per day (odds ratio [OR], 18.84; 95% confidence interval [CI], 4.83-79.4; p<0.00001), shared paraphernalia for drug use more frequently (OR, 11.11; 95% CI, 3.24-39.04; p<0.0001), were in a higher proportion both currently unemployed and homeless (OR, 4.22; 95% CI, 1.5-12.15; p<0.0001), were not in a methadone maintenance program (OR, 0.03; 95% CI, 0-0.19; p<0.00001), and more often bought drugs at a specific site (OR, 33.92; 95% CI, 7.44-174.93; p<0.00001) and from a specific dealer (OR, 72; 95% CI, 8-3090; p<0.00001), compared with patients not infected. The fall 2000 cluster was polyclonal, whereas the other 2 clusters were mainly due to the same strain of GAS (emm 25.2), and were defined as epidemic outbreaks. Clinically, the cases due to the clonal strain presented abscesses and needed surgery more frequently (p<0.001 and p=0.005, respectively). On the other hand, mutations in the csrRS genes were not associated with invasive GAS soft-tissue infection. There has been an increase in the number of cases of invasive GAS soft-tissue infections in IDUs in Barcelona, which seems to be related to drug users' habits and their socioeconomic status. Clonality (emm 25.2) but not mutations in the csrRS genes was associated with more severe GAS soft-tissue infections.