Lorna Leal

Association of microbial translocation biomarkers with clinical outcome in controllers HIV-infected patients.

Background:A proportion of patients who spontaneously control viral load (controllers) experienced clinical progression. We hypothesized that microbial translocation would independently determine the rate of disease progression in controllers. Methods:sCD14, lipopolysaccharide-binding protein (LBP) and EndoCab levels were assessed in 114 antiretroviral-naive patients with CD4+ T cells above 500 cells/&mgr;l (including 63 controllers and 51 noncontrollers). The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, non-AIDS event, initiation of combination antiretroviral therapy (cART) or CD4+ cell count less than 500 cells/&mgr;l was assessed using a Cox regression model. Results:Most of the patients progressed to a combined endpoint (60%). Clinical progression in controllers was significantly lower than in noncontrollers (P = 0.02). Controllers with lower than the median baseline CD4+ T-cell count and higher than the median baseline viral load, sCD14 and EndoCab levels had a worse prognosis (P < 0.0001, P = 0.007, P = 0.05 and P = 0.012), while noncontrollers with higher than the median baseline LBP level also had a worse prognosis (P = 0.019). sCD14 and LBP increased and EndoCab decreased over time [from baseline (median values: 1486, 17604 ng/ml and 68 MMU/ml, respectively, to the date of event or the last determination (median values: 1663, 20230 ng/ml and 49 MMU/ml), respectively] in controllers (P = 0.04, 0.08 and 0.0006, respectively). Conclusion:Microbial translocation seems to be an important determinant of clinical progression in HIV-infected controllers independently of viremia. Measures to improve the intestinal mucosa damage or decrease translocation could influence the outcome in these patients.

Protease inhibitor monotherapy is associated with a higher level of monocyte activation, bacterial translocation and inflammation

Monotherapy with protease‐inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation.

New challenges in therapeutic vaccines against HIV infection

ABSTRACT Introduction: There is a growing interest in developing curative strategies for HIV infection. Therapeutic vaccines are one of the most promising approaches. We will review the current knowledge and the new challenges in this research field. Areas covered: PubMed and ClinicalTrial.gov databases were searched to review the progress and prospects for clinical development of immunotherapies aimed to cure HIV infection. Dendritic cells (DC)-based vaccines have yielded the best results in the field. However, major immune-virologic barriers may hamper current vaccine strategies. We will focus on some new challenges as the antigen presentation by DCs, CTL escape mutations, B cell follicle sanctuary, host immune environment (inflammation, immune activation, tolerance), latent reservoir and the lack of surrogate markers of response. Finally, we will review the rationale for designing new therapeutic vaccine candidates to be used alone or in combination with other strategies to improve their effectiveness. Expert commentary: In the next future, the combination of DCs targeting candidates, inserts to redirect responses to unmutated parts of the virus, adjuvants to redirect responses to sanctuaries or improve the balance between activation/tolerance (IL-15, anti-PD1 antibodies) and latency reversing agents could be necessary to finally achieve the remission of HIV-1 infection.

A randomized clinical trial comparing ritonavir-boosted lopinavir versus maraviroc each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection

OBJECTIVES The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus maraviroc, both with tenofovir disoproxil/emtricitabine as the backbone. METHODS We conducted a prospective, open, randomized clinical trial. Individuals attending the emergency room because of potential sexual exposure to HIV and who met criteria for receiving PEP were randomized to one of two groups: tenofovir disoproxil/emtricitabine (245/200 mg) once daily plus either ritonavir-boosted lopinavir (400/100 mg) or maraviroc (300 mg) twice daily. Five follow-up visits were scheduled for days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01533272. RESULTS One-hundred-and-seventeen individuals were randomized to receive ritonavir-boosted lopinavir and 120 to maraviroc (n = 237). PEP non-completion at day 28 was 38% (n = 89), with significant differences between arms [ritonavir-boosted lopinavir 44% (n = 51) versus maraviroc 32% (n = 38), P = 0.05]. We performed a modified ITT analysis including only those patients who attended on day 1 (n = 182). PEP non-completion in this subgroup was also significantly higher in the ritonavir-boosted lopinavir arm (27% versus 13%, P = 0.004). The proportion of patients with low adherence was similar between arms (52% versus 47%, P = 0.56). Adverse events were reported by 111 patients and were significantly more common in the ritonavir-boosted lopinavir arm (72% versus 51%, P = 0.003). No seroconversions were observed during the study. CONCLUSIONS PEP non-completion and adverse events were both significantly higher in patients allocated to ritonavir-boosted lopinavir. These data suggest that maraviroc is a well-tolerated antiretroviral that can be used in this setting.

Monocytes Phenotype and Cytokine Production in Human Immunodeficiency Virus-1 Infected Patients Receiving a Modified Vaccinia Ankara-Based HIV-1 Vaccine: Relationship to CD300 Molecules Expression

A modified vaccinia Ankara-based HIV-1 vaccine clade B (MVA-B) has been tested for safety and immunogenicity in low-risk human immunodeficiency virus (HIV)-uninfected individuals and as a therapeutic vaccine in HIV-1-infected individuals on combined antiretroviral therapy (cART). As a therapeutic vaccine, MVA-B was safe and broadly immunogenic; however, patients still showed a viral rebound upon treatment interruption. Monocytes are an important part of the viral reservoir and several studies suggest that they are partly responsible for the chronic inflammation observed in cART-treated HIV-infected people. The CD300 family of receptors has an important role in several diseases, including viral infections. Monocytes express CD300a, c, e, and f molecules and lipopolysaccharide (LPS) and other stimuli regulate their expression. However, the expression and function of CD300 receptors on monocytes in HIV infection is still unknown. In this work, we investigated for the first time the expression of CD300 molecules and the cytokine production in response to LPS on monocytes from HIV-1-infected patients before and after vaccination with MVA-B. Our results showed that CD300 receptors expression on monocytes from HIV-1-infected patients correlates with markers of HIV infection progression and immune inflammation. Specifically, we observed a positive correlation between the expression of CD300e and CD300f receptors on monocytes with the number of CD4+ T cells of HIV-1-infected patients before vaccination. We also saw a positive correlation between the expression of the inhibitory receptor CD300f and the expression of CD163 on monocytes from HIV-1-infected individuals before and after vaccination. In addition, monocytes exhibited a higher cytokine production in response to LPS after vaccination, almost at the same levels of monocytes from healthy donors. Furthermore, we also described a correlation in the expression of CD300e and CD300f receptors with TNF-α production in response to LPS, only in monocytes of HIV-1-infected patients before vaccination. Altogether, our results describe the impact of HIV-1 and of the MVA-B vaccine in cytokine production and monocytes phenotype.

Impact of long-term antiretroviral therapy interruption and resumption on viral reservoir in HIV-1 infected patients

&NA; We assessed if the increase on viral reservoir after long-term antiretroviral therapy (ART) interruption (ATI) is reversible upon ART resumption in chronic HIV-1 infected patients. Total HIV-1 DNA increased to pre-ART levels after 48 weeks of ATI to return to pre-ATI levels after 104 weeks of ART resumption. Conversely, integrated HIV-1 DNA remained elevated after ART reinitiation. These data suggest that the increase in reservoir after long-term ART discontinuation might not be reversible at midterm.

Tenofovir disoproxil fumarate/emtricitabine plus ritonavir-boosted lopinavir or cobicistat-boosted elvitegravir as a single-tablet regimen for HIV post-exposure prophylaxis

Objectives To assess HIV-1 post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus cobicistat-boosted elvitegravir as a single-tablet regimen (STR), using tenofovir disoproxil fumarate/emtricitabine with both of these therapies. Methods A prospective, open, randomized clinical trial was performed. Individuals attending the emergency room due to potential sexual exposure to HIV and who met criteria for PEP were randomized 1:3 into two groups receiving either 400/100 mg of lopinavir/ritonavir (n = 38) or 150/150 mg of elvitegravir/cobicistat (n = 119), with both groups also receiving 245/200 mg of tenofovir disoproxil fumarate/emtricitabine. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse effects and rate of seroconversions. Clinical trials.gov number: NCT08431173. Results Median age was 32 years and 95% were males. PEP non-completion at day 28 was 36% (n = 57), with a trend to be higher in the lopinavir/ritonavir arm [lopinavir/ritonavir 47% (n = 18) versus elvitegravir/cobicistat 33% (n = 39), P = 0.10]. We performed a modified ITT analysis including only those patients who attended on day 1. PEP non-completion in this subgroup was higher in the lopinavir/ritonavir arm than in the elvitegravir/cobicistat arm (33% versus 15%, respectively, P = 0.04). Poor adherence was significantly higher in the lopinavir/ritonavir arm versus the elvitegravir/cobicistat arm (47% versus 9%, respectively, P < 0.0001). Adverse events were reported by 73 patients (59%), and were significantly more common in the lopinavir/ritonavir arm (90% versus 49%, P = 0.0001). A seroconversion was observed in the elvitegravir/cobicistat arm in a patient with multiple exposures before and after PEP. Conclusions A higher PEP non-completion, poor adherence and adverse events were observed in patients allocated to the lopinavir/ritonavir arm, suggesting that STR elvitegravir/cobicistat is a well-tolerated antiretroviral for PEP.

HIVR4P 2016, Partnering for Prevention: Conference Summary and Highlights

Abstract HIV Research for Prevention: AIDS Vaccine, Microbicide, and ARV-based Prevention Science (HIVR4P) was built on a growing consensus that effective HIV prevention requires a combination of approaches and that understanding, analyzing, and debating the cross-cutting issues that impact prevention research are all essential to combat the global HIV/AIDS epidemic. To that end, the biennial HIVR4P conference is dedicated to all biomedical HIV prevention research approaches, including HIV vaccines, microbicides, pre-exposure prophylaxis, and treatment as prevention. The HIVR4P 2016 conference was held in Chicago, Illinois (USA), on October 17–21, and included more than 700 scientific presentations and 21 satellite sessions covering the latest and most promising advances across the HIV prevention research field. The theme “Partnering for Prevention” represented the conferences commitment to breaking down silos between research disciplines as well as between researchers, program developers, care providers, advocates, communities, and funders. Delegates spanning 42 countries attended the conference. One-third of those in attendance were early career investigators, which reflects a firm commitment to emerging researchers and ultimately to the goal of developing a sustainable scientific enterprise well into the future. This article presents a concise summary of highlights from the conference. For a more detailed account, one may find full abstracts, daily summaries, and webcasts on the conference website at hivr4p.org.

Shared Care Unit: a new model of coordinating HIV care between Primary Settings and Hospital

Introduction : Antiretroviral therapy (cART) has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. In addition, the profile of HIV infected patients is changing to an elderly population with increasing morbidities. This clinical scenario requires a new approach to coordinate the care between health teams responsible for the care of patients. To promote communication, cooperation and optimize the control of HIV infected patients, a multidisciplinary unit called Shared Care Unit (UCC) was created in 2008 among the Hospital Clinic of Barcelona and four primary care centers (CAP). In this unit, doctors and nurses from Primary Care settings and The Infectious Diseases Department from the Hospital, meet each two months to coordinate activities involving teaching, research and assistance in the field of HIV infection. We present now the results of a pilot study undertaken in 2013 for evaluating the shared care unit for HIV stable patients. Objectives : To compare the HIV standard of care (controls) with the care in UCC (cases). Methods: A pilot prospective case-control study with duration of 1.5 years was performed in the Hospital Clinic and three CAPs of the same health district. Inclusion criteria for cases were stable patients (Chronic HIV infection with CD4 above 350 cells/mm3 during the last 6 months and if on ART with an undetectable viral load). Exclusion criteria were HIV-infected adults with current therapeutic failure (defined by detectable viral load on cART or CD4 cell count below 250 cells/mm3), tumours, opportunistic infections, or pregnant women. Control patients were HIV infected patients matched for age, sex, primary care center, use of cART and undetectable viral load at the date of inclusion in the study. HIV care during the 18 months of follow-up was performed in control patients as usual in hospital (3 visits), whilst cases made two visits in CAP and the last one in the Hospital. Variables regarding clinical performance [HIV clinical parameters (CD4 cell count, viral load, opportunistic infections, death] and cART-compliance were evaluated throughout the study follow-up. Adherence was estimated at each clinical consultation by monitoring pharmacy refills and through self-reports and was considered high if the patients take more than 90% of the scheduled medication. Quality of life was evaluated through a questionnaire that has been validated in HIV patients (Mini International Neuropsychiatric Interview (MINI). Psychological and emotional Impact was evaluated using several validated screening questionnaires: the Hospital Anxiety and Depression (HAD) Scale to measure anxiety and depression. A qualitative statement about health services utilization in the study population was registered as well as acceptability and satisfaction with the type or care. Results: 93 patients (31 cases and 62 control patients) were included. The mean age of patients was 42 years, 86% were men, 81% men who have sex with men (MSM) and 29% were foreigners. The CD4 count, viral load and adherence to ART showed no significant differences in both groups. Quality of life, psychosocial assessment, the number of emergency room visits and other specialists was similar in cases and controls. 85% liked UCC and 93% considered in the future continue to use the UCC. Conclusions : A Shared Care Unit of HIV infection between Hospital and Primary Care Centers is possible and in this pilot study has been a safe tool for the clinical management of stable HIV infected patients. Sharing clinical management of stable HIV infection between Hospitals and Primary care centers might be an additional model of care.