Search

ObjectivesTo develop a population pharmacokinetic model for romidepsin given as an HIV latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity.MethodsA population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m2) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time–concentration curves on each occasion. The relationship between romidepsin AUC0–∞ and its in vivo effects was assessed.ResultsRomidepsin pharmacokinetics were best described by a three-compartment model with linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC0–∞ and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng·h/mL in romidepsin AUC0–∞, CD4+ counts decreased by a mean (95% CI) of 74 (42–94) cells/mm3 after dosing.ConclusionsA population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure.

Background: Severe cases of primary HIV infection have been described in patients presenting with neurological involvement, AIDS defining events or other life-threatening events. These severe forms have not been fully studied. Objectives: To determine the prevalence and characteristics of severe PHI in a hospital-based cohort of primary HIV infection, and the response to the early initiation of antiretroviral therapy (ART) at 12 months. Methods: Every patient with PHI attending Hospital Clínic of Barcelona (1997–2015) was evaluated. Severe PHI was defined using clinical, analytical and immunological criteria. Chi-squared test was used for categorical variables and Student’s t-test for quantitative variables. Results: 33% of 224 PHI patients (95% CI: 26.84%–39.16%) had a severe PHI. These patients had more symptoms, abnormal analytical parameters and hospital admissions. The severe PHI group had a significantly higher viral load although no differences were observed at 12 months in terms of viral suppression or CD4 count recovery. None died during PHI. Conclusions: Up to one third of patients in our cohort presented with a severe PHI, which was associated with higher hospitalization rates and higher plasma HIV RNA viral load. However, severe forms were not associated to a worse clinical, immunological or virological outcome at 12 months. Keywords: Primary HIV Infection, Acute HIV Infection, Recent HIV Infection, Severity, Early antiretroviral therapy

Objectives Antiretroviral treatment (ART) during acute/recent HIV infection decreases transmission and optimizes immune recovery but the optimal ART-regimen in this setting is unknown. The objectives were to analyze the virological efficacy, immunological reconstitution and tolerability of different ART-regimens at 3 years after starting ART during acute/recent HIV infection. Design Retrospective cohort study of consecutive acutely/recently infected patients who started ART within 6 months postinfection. Methods We compared regimens based on protease-inhibitors (N = 28), integrase-strand-transfer-inhibitors (InSTI, N = 87) and nonnucleoside-reverse-transcriptase-inhibitors (N = 22). Virological suppression (viral load 900 cells/μl and CD4/CD8 ratio >1) and adverse events leading to ART discontinuation at 1 and 3 years were compared. Results Baseline characteristics were comparable among groups. Overall viral suppression at 1 (96%) and 3 years (99%) was comparable in all ART regimens and, InSTI group, comparable for dolutegravir and elvitegravir within InSTIs. CD4 T-cell counts at 1 year were comparable in all ART regimens. Overall proportion of patients reaching CD4 cell count more than 900 cells/μl and CD4/CD8 ratio more than 1 was 36% and 40% and 46% and 63% at 1 and 3 years, respectively with no differences among ART regimens. Starting ART during the earliest Fiebig stages (I-V vs. VI) was associated with higher rates of CD4 cell count more than 900 cells/μl at 3 years (P = 0.027). Discontinuation due to adverse events was more frequent with nonnucleoside-reverse-transcriptase-inhibitors compared with other ART classes. Conclusion Viral suppression and immunological recovery were excellent, with no differences between ART regimens. Earlier ART initiation was associated with a higher proportion of long-term immunological recovery.

Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo,Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group.This is an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forumsis permitted, provided the original author(s) and the copyright owner(s) are creditedand that the original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction ispermitted which does notcomply with these terms. Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4+ T cells from HIV-1+ individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1+ individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8+ T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure. Peer Reviewed Article signat per 13 autors/es i un grup de recerca: Miriam Rosás-Umbert,Marta Ruiz-Riol, Marco A. Fernández, Marta Marszalek, Pep Coll, Christian Manzardo, Samandhy Cedeño, José M. Miró, Bonaventura Clotet, Tomáš Hanke, José Moltó, Beatriz Mothe, Christian Brander, and the BCN02 study group

Background: In people living with HIV, much is known about chronic kidney disease, defined as a glomerular filtration rate under 60 mL/min. However, there is scarce data about prevalence and risk factors for milder impairment (60–89 mL/min). Objective: The present study aims to assess the influence of sex, antiretroviral therapy, and classical risk factors on the occurrence of mild decreased renal function in a large Spanish cohort of HIV-infected patients. Methods: Cross-sectional, single center study, including all adult HIV-1-infected patients under antiretroviral treatment with at least two serum creatinine measures during 2014, describing the occurrence of and the risk factors for mildly decreased renal function (eGFR by CKD-EPI creatinine equation of 60–89 mL/min). Results: Among the 4337 patients included, the prevalence rate of mildly reduced renal function was 25%. Independent risk factors for this outcome were age older than 50 years (OR 3.03, 95% CI 2.58–3.55), female sex (OR 1.23, 95% CI 1.02–1.48), baseline hypertension (OR 1.57, 95% CI 1.25–1.97) or dyslipidemia (OR 1.48, 95% CI 1.17–1.87), virologic suppression (OR 1.88, 95% CI 1.39–2.53), and exposure to tenofovir disoproxil-fumarate (OR 1.67, 95% CI 1.33–2.08) or ritonavir-boosted protease-inhibitors (OR 1.19, 95% CI 1.03–1.39). Conclusions: Females and patients over 50 seem to be more vulnerable to renal impairment. Potentially modifiable risk factors and exposure to tenofovir disoproxil-fumarate or ritonavir-boosted protease-inhibitors are present even in earlier stages of chronic kidney dysfunction. It remains to be determined whether early interventions including antiretroviral therapy changes (tenofovir alafenamide, cobicistat) or improving comorbidities management will improve the course of chronic kidney disease. Keywords: HIV-infection, Antiretroviral drugs, Chronic kidney disease, Glomerular filtration rate estimates

Background The study aimed to investigate whether the clinical presentations and outcomes (length of stay, ICU admission, and 30-day mortality) of pneumococcal pneumonia in virologically suppressed patients who were HIV-infected on ART with a CD4+ T-cell count > 350 cells/mm3 are comparable to those seen in patients with HIV, using a case-control design. Methods A case-control study was carried out in Hospital Clinic, Barcelona, Spain (2001-2016). Control patients were matched by age (±10 years), sex, comorbidities, and pneumonia diagnosis in the same calendar period. Clinical presentation and outcomes of pneumococcal pneumonia in patients who were and were not infected with HIV were compared. Results Pneumococcal pneumonia was studied in 50 cases (HIV infection) and 100 control patients (non-HIV infection). Compared with the control patients, case patients had higher rates of influenza (14% vs 2%, P = .007) and pneumococcal vaccination (10% vs 1%, P = .016). The group of cases also presented a higher rate of coinfection with hepatitis B virus (6% vs 0%, P = .036). Both groups presented similar ICU admission (18% vs 27%, P = .22), need for mechanical ventilation (12% vs 8%; P = .43), length of stay (7 days vs 7 days, P = .76), and 0% of 30-day mortality. No evidence was found of a more severe presentation or a worse clinical outcome in cases than in control patients. Conclusions Pneumococcal pneumonia episodes requiring hospitalization in virologically suppressed patients with HIV with > 350 CD4+ T-cell count/mm3 were neither more severe nor had worse prognosis compared with uninfected patients. These results support the fact that such patients do not need treatment, admission, or care sites different to the general population. Trial Registry ClinicalTrials.gov; No. 2009/5451; URL: www.clinicaltrials.gov.

Primary HIV-1 infection is a relevant period for its virological and epidemiological consequences. Most patients present a symptomatic disease that can be potentially serious, but neurological involvement during primary HIV-1 infection has been poorly studied. The aim of this study was to describe the characteristics and outcomes of primary HIV-1 infection patients presenting neurological symptoms and to compare them with primary HIV-1 infection patients without neurological involvement. Retrospective case-control study (1:3) comparing primary HIV-1 infection patients with and without neurological involvement enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016. Matching criteria included age (±10 years), gender, year of diagnosis (±4 years), and Fiebig stage. The conditional logit model was used for comparisons. Fourteen out of 463 patients (3.02%) enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016 presented neurological symptoms. 28.5% of cases presented as meningitis and 71.5% as meningoencephalitis. Cerebrospinal fluid showed non-specific findings, including pleocytosis with lymphocyte predominance and increased protein levels. All cases required hospitalisation, whereas only 19% of the controls did. No other pathogen was identified in any case, but five patients initiated empirically antimicrobial treatment for other aetiologies until diagnosis was confirmed. CD4/CD8 ratio was significantly lower (p = 0.039) and plasmatic viral load significantly higher in the case group, compared to controls (p = 0.028). Risk factors, HIV-1 tropism, subtype distribution, and prescribed ART regimens were comparable between cases and controls. After 6 months on ART, 92% of cases had undetectable viral load, similar to controls, and CD4/CD8 ratio became also comparable between groups. All cases recovered rapidly with ART and were discharged without sequels. Neurological involvement during primary HIV-1 infection is unusual but serious, always requiring hospitalisation. Diagnosis is difficult because of the wide range of symptoms and similarities with other viral aetiologies. Neurological manifestations during primary HIV-1 infection are associated with a lower CD4/CD8 ratio and with a higher viral load than controls. Immediate ART initiation and rapid viral load decrease are required, allowing complete clinical recovery.

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control.

OBJECTIVES IFN-based therapy against hepatitis C recurrence after liver transplantation (LT) has poor effectiveness and tolerability. In HIV/HCV-coinfected liver transplant recipients, the results are even poorer. Here, we report our experience using direct antiviral agents (DAAs) in 11 consecutive coinfected patients within the LT setting. METHODS Four patients with compensated cirrhosis and hepatocellular carcinoma were treated while awaiting LT and seven patients received antiviral therapy due to severe hepatitis C recurrence after LT [fibrosing cholestatic hepatitis (n = 1), fibrosis stage ≥F3 (n = 2) and decompensated cirrhosis (n = 4)]. Patients were treated with different sofosbuvir-based regimens with or without ribavirin for 12 or 24 weeks. RESULTS Sustained virological response (SVR) was achieved in all patients. Two of the four patients treated while awaiting LT reached the time of transplant with undetectable HCV-RNA that remained undetectable 12 weeks after LT, one patient had detectable HCV-RNA at the time of transplant but achieved SVR after completing 12 weeks of therapy after LT and the last patient is still on the waiting list. Seven patients with severe post-LT hepatitis C recurrence were treated within 11-120 months after LT. In these patients, viral eradication was associated with an improvement in liver function and clinical decompensation. Tolerance to antiviral therapy was good and only four patients reported mild adverse events. CONCLUSIONS IFN-free regimens are effective and well tolerated in HIV/HCV-coinfected patients within the LT setting, but more data are needed to confirm our promising results and to establish the best treatment option in this population.

Background: Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods: BCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week)between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T-cells associated HIV-1 DNA. (NCT01712425). Findings: No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range)of 938 (73-6,805)IFN-γ SFU/106 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms. Interpretation: Heterologous prime-boost vaccination with ChAdV63-MVA/HIVconsv was well-tolerated and refocused pre-cART T-cell responses towards more protective epitopes, in which immune escape is frequently associated with reduced HIV-1 replicative fitness and which are common to most global HIV-1 variants. Funding: HIVACAT Catalan research program for an HIV vaccine and Fundació Gloria Soler. Vaccine manufacture was jointly funded by the Medical Research Council (MRC)UK and the UK Department for International Development (DFID)under the MRC/DFID Concordat agreements (G0701669. Research in Context: Evidence Before this Study: T cells play an important role in the control of HIV infection and may be particularly useful for HIV-1 cure by killing cells with reactivated HIV-1. Evidence is emerging that not all T-cell responses are protective and mainly only those targeting conserved regions of HIV-1 proteins are effective, but typically immunologically subdominant, while those recognizing hypervariable, easy-to-escape immunodominant ‘decoys’ do not control viremia and do not protect from a loss of CD4 T cells. We pioneered a vaccine strategy focusing T-cell responses on the most conserved regions of the HIV-1 proteome using an immunogen designated HIVconsv. T cells elicited by the HIVconsv vaccines in HIV-uninfected UK and Kenyan adults inhibited in vitro replication of HIV-1 isolates from 4 major global clades A, B, C and D. Added Value of this Study: The present study demonstrated the concept that epitopes subdominant in natural infection, when taken out of the context of the whole HIV-1 proteome and presented to the immune system by a potent simian adenovirus prime-poxvirus MVA boost regimen, can induce strong responses in patients on antiretroviral treatment and efficiently refocus HIV-1-specific T-cells to the protective epitopes delivered by the vaccine. Implications of all the Available Evidence: Nearly all HIV-1 vaccine strategies currently emphasize induction of broadly neutralizing Abs. The HIVconsv vaccine is one of a very few approaches focussing exclusively on elicitation of T cells and, therefore, can complement antibody induction for better prevention and cure. Given the cross-clade reach on the HIVconsv immunogen design, if efficient, the HIVconsv vaccines could be deployed globally. Effective vaccines will likely be a necessary component in combination with other available preventive measures for halting the HIV-1/AIDS epidemic.

We investigate whether the clinical presentations and outcomes of Legionella pneumonia in human immunodeficiency virus (HIV)-infected patients were comparable to those seen in non-HIV-infected patients (case-control design). HIV-infected individuals presented neither a more severe disease nor a worse clinical outcome than matched HIV-negative control patients.

Despite the availability of effective combined antiretroviral treatment, many patients still present with advanced HIV infection, often accompanied by an AIDS-defining disease. A subgroup of patients starting antiretroviral treatment under these clinical conditions may experience paradoxical worsening of their disease as a result of an exaggerated immune response towards an active (but also subclinical) infectious agent, despite an appropriate virological and immunological response to the treatment. This clinical condition, known as immune reconstitution inflammatory syndrome, may cause significant morbidity and even mortality if it is not promptly recognized and treated. This review updates current knowledge about the incidence, diagnostic criteria, risk factors, clinical manifestations, and management of opportunistic infections and immune reconstitution inflammatory syndrome in the combined antiretroviral treatment era.

Background: Despite recent data suggest similar postoperative survival after cardiac surgery for HIV-infected patients and general cardiac surgical population, no studies have comprehensively addressed the impact of epidemiological changes observed during the last three decades affecting the profile of these patients. Methods: Retrospective analysis of the baseline characteristics, immune status and HIV treatment, surgical aspects and prognosis of consecutive HIV-infected patients undergoing cardiac surgery at our institution. Findings: Between 1985 and 2014, 72 patients underwent 87 operations. Median follow-up was 1650 days (IQR 357-3600). Most common indication for surgery was infective endocarditis (left-sided/mixed in 86%), with 40·2% of operations. Epidemiological changing pattern along the study periods was observed: from young (median age 27 years), intravenous drug users (100%) with infective endocarditis (88·2%), untreated and recent HIV diagnosis (

Primary HIV-1 infection covers a period of around 12 weeks in which the virus disseminates from the initial site of infection into different tissues and organs. In this phase, viremia is very high and transmission of HIV is an important issue. Most guidelines recommend antiretroviral treatment in patients who are symptomatic, although the indication for treatment remains inconclusive in asymptomatic patients. In this article the authors review the main virological and immunological events during this early phase of infection, and discuss the arguments for and against antiretroviral treatment. Recommendations of different guidelines, the issue of the HIV transmission and transmission of resistance to antiretroviral drugs, as well as recently available information opening perspectives for functional cure in patients treated in very early steps of HIV infection are also discussed.

The access to antiretroviral treatment has been largely enlarged in Europe and North America in recent years, due to treatment guidelines that recommend earlier initiation of therapy. However, there are differences and heterogeneities in the health systems and in access and retention to care between different countries and regions, and for different subpopulations among the same country that impact in the final goal, that patients remain undetectable and in good health.

BACKGROUND Latent HIV-1-infected cells generated early in the infection are responsible for viral persistence, and we hypothesized that addition of maraviroc to triple therapy in patients recently infected with HIV-1 could accelerate decay of the viral reservoir. METHODS Patients recently infected (

BACKGROUND In the developed world, kidney transplantation (KT) in patients with human immunodeficiency virus (HIV) infection is well established. Developing countries concentrate 90% of the people living with HIV, but their experience is underreported. Regional differences may affect outcomes. OBJECTIVES We compared the 3-year outcomes of patients with HIV infection receiving a KT in two different countries, in terms of incomes and development. METHODS This was an observational, retrospective, double-center study, including all HIV-infected patients >18 years old undergoing KT. RESULTS Between 2005 and 2015, 54 KTs were performed (39 in a Brazilian center, and 15 in a Spanish center). Brazilians had less hepatitis C virus co-infection (5% vs 27%, P=.024). Median cold ischemia time was higher in Brazil (25 vs 18 hours, P=.001). Biopsy-proven acute rejection (AR) was higher in Brazil (33% vs 13%, P=.187), as were the number of AR episodes (22 vs 4, P=.063). Patient survival at 3 years was 91.3% in Brazil and 100% in Spain; P=.663. All three cases of death in Brazil were a result of bacterial infections within the first year post transplant. At 3 years, survival free from immunosuppressive changes was lower in Brazil (56% vs 90.9%, P=.036). Raltegravir-based treatment to avoid interaction with calcineurin inhibitor was more prevalent in Spain (80% vs 3%; P

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

Antiretroviral therapy has been immensely successful in reducing the incidence of opportunistic infections and death after HIV infection. This has resulted in heightened interest in noninfectious comorbidities including kidney disease. Although HIV-associated nephropathy, the most ominous kidney disease related to the direct effects of HIV, may be prevented and treated with antiretrovirals, kidney disease remains an important issue in this population. In addition to the common risk factors for kidney disease of diabetes mellitus and hypertension, HIV-infected individuals have a high prevalence of other risk factors, including hepatitis C and exposure to antiretrovirals and other medications. Therefore, the differential diagnosis is vast. Early identification (through efficient screening) and prompt treatment of kidney disease in HIV-infected individuals are critical to lead to better outcomes. This review focuses on clinical and epidemiological issues, treatment strategies (including dialysis and kidney transplantation), and recent advances among kidney disease in the HIV population.

Since the introduction of combined antiretroviral therapy (cART), solid organ transplantation (SOT) has become a therapeutic option for the HIV-positive population. In contrast with liver and kidney transplantation, only three simultaneous pancreas-kidney transplants (SPKT) have been reported among HIV-infected patients. Herein we have reported the first SPKT in an HIV-infected patient in Spain. The pancreas graft failed at 2 weeks and the patient died at 9 months because of a Pseudomonas aeruginosa infection. The three recipients reported in the literature lived, despite the failure of both the pancreas and kidney grafts in one subject. Despite the poor outcome of our case, HIV-1 infection was controlled after transplantation (stable CD4(+) cells and no AIDS-related events), and the kidney graft functioned with no episodes of rejection. The cART regimen used in the pretransplant period was switched at the time of transplantation to raltegravir and two nucleoside reverse transcriptase inhibitors (NRTI). Raltegravir has no interactions with immunosuppressive drugs. Target plasma levels of tacrolimus were achieved at a dose similar to that used in HIV-negative transplant recipients. The most adequate antiretroviral regimen for HIV-infected SOT recipients has not yet been established; however, one may consider switching protease inhibitors or non-NRTI-based regimens for a raltegravir-based regimen at the time of transplantation.

Introduction While the growing knowledge on HIV among solid organ transplant recipients (SOT) is limited to either pretransplant infection or allograft transmission, there are only sparse reports describing HIV-infection after transplantation through sexual route, the primary mode of transmission in the general population. Methods From two different centers, we report nine new cases of HIV infection in SOT recipients attributed to sexual acquisition: eight cases of kidney-transplant recipients and one heart-transplant recipient. Findings There were nine cases of post-transplant HIV-infection detected among 14 526 transplants performed 1998 to 2015. In 6/9 cases, infection was contracted 5 years after SOT. All but one patient had stable allograft function under immunosuppressive therapy. The main trigger to diagnosis was late CMV disease and sexually transmitted diseases; five patients had CDC-stage 3 HIV infection. In 7/9 patients, virologic response and CD4 recovery were achieved within 3 months after starting antiretroviral therapy (ART). After an average of 3.6 years post diagnosis, 5/9 patients remained alive with well-controlled infection and functioning allograft. Conclusion Sexual acquisition of HIV infection after SOT represents a difficult challenge, as it may occur in any kind of transplant and at any time. The course of infection resembles that of the general population, with life-threatening infectious complications, but good response to ART. Assessment of lifestyle and risk behavior is paramount, as indications may be not disclosed without direct questioning.

Summary For geographical and historical reasons, Spain is receiving an increasing number of immigrants. The aim of this study was to evaluate some epidemiological aspects and the main public health issues of communicable diseases in Barcelona's immigrant population. From 2001 to 2004, a population of immigrants from tropical, subtropical regions and Eastern Europe was attended to in our centre. Each patient was offered a complete screening for tropical and common diseases. The prevalence and demographical characteristics of eight diseases with a potential risk of transmission in our setting were studied: latent and active tuberculosis, syphilis, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), Chagas disease, Giardia intestinalis and Entamoeba histolytica/Entamoeba dispar. In all, 2464 immigrants mainly from sub-Saharan Africa were seen. Among the patients who underwent the screening, 46.5% had a positive tuberculin skin test (⩾10 mm), incidence of active tuberculosis was 324.7/100,000 immigrants in the period of the study, 6.4% had a positive syphilis serology, 7.7% had a positive HBsAg, 3.1% had a positive serology for HCV and 2.8% were HIV positive, 41 patients from Latin America with risk factors for American Trypanosomiasis were screened for Chagas disease by immunofluorescence assay and 34% had a positive result; 5.4% of stools parasitological tests were positive for G. intestinalis ; 4.2% for E. histolytica/E. dispar. Communicable diseases in immigrant population could lead to emerging and re-emerging infections in the European Union with important issues for public health. European countries may have to establish guidelines for screening of infectious diseases in immigrants from low-income countries.

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.

The introduction of highly active antiretroviral therapy (HAART) in developed countries has achieved a good control of HIV infection. Despite this, a delayed HIV diagnosis makes it necessary to start antiretroviral treatment in individuals with severe impairment of their immunological function. Very often, this is accompanied by an opportunistic infection that needs to be treated, with a consequent complication of management because of overlapping toxicities and pharmacokinetic interactions with antiretroviral drugs, and a greater pill burden. All this could impair adherence and reconstitution of the immune function with a paradoxical clinical worsening in some patients, especially if the CD4 cell count is below 50 cells/microl. The best antiretroviral regimen and the best timing for starting antiretroviral therapy in treatment-naive patients with advanced infection have not yet been established. Recommendations for the clinical management of advanced HIV disease come from panels of experts in the therapy of opportunistic infections and antiretroviral treatment, and they advise starting combined antiretroviral therapy 2-4 weeks after initiating treatment of the opportunistic infection. Many patients have been successfully treated with a pharmacologically enhanced (boosted) protease inhibitor (mainly lopinavir/ritonavir)-based regimens. The efficacy of non-nucleoside reverse transcriptase inhibitor-based regimens for the treatment of very immunosuppressed patients has been tested in few clinical trials during the HAART era. Some cohort studies and randomized clinical trials support the use of efavirenz-based antiretroviral therapy for the treatment of advanced HIV-1-infected patients; however, recent randomized controlled data suggest, in a moderately advanced HIV population, a better CD4 cell recovery for lopinavir-ritonavir than for efavirenz-treated patients, but a greater virological suppression in the efavirenz arm. Further randomized clinical trials are needed in order to determine whether the efficacy, tolerability and the immunological reconstitution of efavirenz-based therapy can match that achieved with lopinavir/ritonavir or other current boosted protease inhibitor regimens in advanced patients.

It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts300 cell/μL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression.The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation.A total of 8695 patients were included. CD4 cell counts fell to200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts350 cells/µL maintained counts ≥200 cells/µL.From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts300 cells/µL and HIV/HCV-coinfected patients with counts350 cells/µL.

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.

We report the first case of a pregnancy in a renal transplant recipient with HIV infection. She underwent renal transplantation in 2005 and became pregnant in 2009. The patient underwent vaginal delivery and a healthy full-term, female baby was born. Almost 6 years after delivery, both mother and child were doing well. The management of concurrent renal transplantation, HIV infection and pregnancy was extremely challenging. Women with HIV infection who have undergone renal transplantation should be accurately informed of the potential health risks for them and their offspring. Multidisciplinary teams are mandatory in order to properly manage these patients.

Objective: This article aims to investigate if the detection of preexisting drug-resistant minority variant (DRMV) and/or X4 HIV-1 variants could improve the efficacy of first-line combined antiretroviral therapy (ART) in late presenters. Design: Post-hoc, combined analysis of two open-label, prospective, randomized clinical trials comparing first-line ART with efavirenz (EFV) vs. ritonavir-boosted protease inhibitor (PI/r)-based regimens in ART-naive, HIV-1-infected patients, with CD4(+) T-cell counts less than 100 cells/mu l and wild-type HIV-1 by bulk sequencing. Methods: Pre-ART samples were reanalyzed for the presence of DRMVs and X4 HIV-1 using 454 sequencing. Kaplan-Meier curves and Cox regression were used to evaluate the association between X4 HIV and DRMVs and risk of virological failure. Results: From 141 evaluable patients, 57 received EFV, and 84 received PI/r, including first-line ART. Median pre-ART CD4(+) T-cell counts and HIV-1 RNA levels were 39 cells/mu l and 257-424 copies/ml, respectively; 35.5% of patients had X4 HIV variants. Detection of DRMVs leading to an ART-specific cumulative HIVdb score of at least 10 increased the risk of virological failure in patients initiating EFV [log-rank P = 0.048, hazard ratio = 4.3 (95% confidence interval: 0.8, 25.0), P = 0.074], but not in those starting PI/r. Presence of X4 HIV did not affect virological outcomes, but was associated with impaired CD4(+) T-cell count recovery over 2 years (214 vs. 315 cells/mu l with X4 vs. R5 HIV-1 tropism, respectively, P = 0.017). Conclusion: Accounting for preexisting DRMVs may improve the outcomes of first-line nonnucleoside reverse transcriptase inhibitor-based ART in late presenters with advanced immune suppression. Presence of X4 HIV-1 at diagnosis predicts impaired immune restoration under ART. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

HIV-1 is the most prevalent retrovirus, with over 30 million people infected worldwide. Nevertheless, infection caused by other human retroviruses like HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4 is gaining importance. Initially confined to specific geographical areas, HIV-2, HTLV-1 and HTLV-2 are becoming a major concern in non-endemic countries due to international migration flows. Clinical manifestations of retroviruses range from asymptomatic carriers to life-threatening conditions, such as AIDS in HIV-2 infection or adult T-cell lymphoma/leukemia or tropical spastic paraparesis in HTLV-1 infection. HIV-2 is naturally resistant to some antiretrovirals frequently used to treat HIV-1 infection, but it does have effective antiretroviral therapy options. Unfortunately, HTLV still has limited therapeutic options. In this article, we will review the epidemiological, clinical, diagnostic, pathogenic and therapeutic aspects of infections caused by these human retroviruses.

Background: Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naive, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens. Methods: Randomized, controlled, open-label, multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naive patients with

A marked decrease in incidence has been observed for most central nervous system (CNS) opportunistic infections (OIs) after the use of highly active antiretroviral therapy (HAART) in developed countries. However, the spectrum of these OIs in acquired immunodeficiency syndrome (AIDS) patients has remained almost unchanged. CNS toxoplasmosis, cryptococcosis, tuberculosis, and progressive multifocal leukoencephalopathy (PML) remain the most frequent ones. Primary CNS lymphoma should be included in the differential diagnosis of all cases with focal lesions. Final diagnosis is currently made by combining neuroimaging techniques (single-photon emission computed tomography [SPECT], positron emission tomography [PET], magnetic resonance imaging [MRI] and/or computed tomography [CT] scan) and molecular studies of cerebrospinal fluid (CSF) and therapeutical response. Stereotactic biopsy should only be performed in the case of atypical lesions or nonresponse to recommended treatments. After treatment of the acute phase, lifelong maintenance therapy is necessary to prevent OI recurrences. Once HAART is initiated, some patients can develop a clinical worsening of some CNS OIs with or without atypical neuroimaging manifestations. This paradoxical worsening is known as the immune reconstitution inflammatory syndrome (IRIS) and it results from reconstitution of the immune system's ability to recognize pathogens/antigens in patients with prior OIs and low CD4+ T-cell counts. In this context, IRIS can be seen in patients with CNS cryptococcosis, tuberculosis, or PML. On the other hand, HAART-induced immune reconstitution can improve the prognosis of some untreatable diseases such as PML, and can allow maintenance therapy of some CNS OI to be safely discontinued in patients with high and sustained CD4+ T-cell response.

OBJECTIVES: To evaluate the prevalence of transmitted drug resistance (TDR) and non-B subtypes in patients with acute/recent HIV-1 infection in Barcelona during the period 1997-2012. METHODS: Patients from the "Hospital Clinic Primary HIV-1 Infection Cohort" with a genotyping test performed within 180 days of infection were included. The 2009 WHO List of Mutations for Surveillance of Transmitted HIV-1 Drug Resistance was used for estimating the prevalence of TDR and phylogenetic analysis for subtype determination. RESULTS: 189 patients with acute/recent HIV-1 infection were analyzed in 4 time periods (1997-2000, n=28; 2001-4, n=42; 2005-8, n=55 and 2009-12, n=64). The proportion of patients with acute/recent HIV-1 infection with respect to the total of newly HIV-diagnosed patients in our center increased over the time and was 2.18%, 3.82%, 4.15% and 4.55% for the 4 periods, respectively (p=0.005). The global prevalence of TDR was 9%, or 17.9%, 9.5%, 3.6% and 9.4% by study period (p=0.2). The increase in the last period was driven by protease-inhibitor and nucleoside-reverse-transcriptase-inhibitor resistance mutations while non-nucleoside-reverse-transcriptase inhibitor TDR and TDR of more than one family decreased. The overall prevalence of non-B subtypes was 11.1%, or 0%, 4.8%, 9.1% and 20.3 by study period (p=0.01). B/F recombinants, B/G recombinants and subtype F emerged in the last period. We also noticed an increase in the number of immigrant patients (p=0.052). The proportion of men-who-have-sex-with-men (MSM) among patients with acute/recent HIV-1 infection increased over the time (p=0.04). CONCLUSIONS: The overall prevalence of TDR in patients with acute/recent HIV-1 infection in Barcelona was 9%, and it has stayed relatively stable in recent years. Non-B subtypes and immigrants proportions progressively increased.

Recent infection testing algorithms (RITAs) are used in public health surveillance to estimate the incidence of recently acquired HIV-1 infection.Our aims were (i) to evaluate the precision of the VITROS® Anti-HIV 1+2 automated antibody avidity assay for qualitative detection of antibodies to HIV 1+2 virus; (ii) to validate the accuracy of an automated guanidine-based antibody avidity assay to discriminate between recent and long standing infections using the VITROS 3600 platform; (iii) to compare this method with BED-CEIA assay; and (iv) to evaluate the occurrence of false recent misclassifications by the VITROS antibody avidity assay in patients with a CD4 count200 cells/μL and in patients on combination antiretroviral therapy (cART).The VITROS® antibody avidity assay is highly reproducible. The ROC curve analysis of the accuracy of this assay, optimized for sensitivity and specificity, had an AI cut off of ≤0.51, with sensitivity and specificity values of 86.67% (95% CI: 72.51-94.46) and 86.24% (95% CI: 78.00-91.84), respectively. The agreement between VITROS antibody avidity and BED-CEIA assays was good. Misclassifications of long standing infections as recent infection occurred in 8.2% of patients with CD4200 cell/μL and 8.7% in patients on combination antiretroviral therapy.The VITROS antibody avidity assay is a reliable serological method to detect recent HIV-1 infections and it could be incorporated into a RITA to estimate HIV incidence.

Background The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown. Methods Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation). Results Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8+ T cells were indistinguishable between the two arms and did not change over time between the groups. Conclusions Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.

Objectives To estimate the incidence of and risk factors for modifications to first antiretroviral therapy (ART) regimen, treatment interruption and death. Methods A total of 21 801 patients from 18 cohorts in Europe and North America starting ART on regimens including at least two nucleoside reverse transcriptase inhibitors and boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor during 2002-2009 were included. Incidence of modifications (change of drug class, substitution/addition within class, or switch to nonstandard regimen), interruption or death and associations with patient characteristics were estimated using competing-risks methods. Results During median 28 months follow-up, 8786 (40.3%) patients modified first ART, 2346 (10.8%) interrupted and 427 (2.0%) died before changing regimen. Three-year cumulative percentages of modification, interruption and death were 47, 12 and 2%, respectively. After adjustment, rates of interruption were highest for IDUs and lowest for MSM, and higher for patients starting ART with CD4 cell count above 350 cells/μl than other patients. Compared to efavirenz, patients on lopinavir and other protease inhibitors had higher rates of modification and interruption, on atazanavir had lower rates of class change, and on nevirapine higher rates of interruption. Those on tenofovir/emtricitabine backbone had lowest rates of substitutions and switches to nonstandard regimen, and on abacavir/lamivudine lowest rates of interruption. Rates of substitution and switches to nonstandard regimen were lower in 2006-2009. Conclusion Rates of modification and interruption were high, particularly in the first year of ART. Decreased rates of substitutions or switches to nonstandard regimen in recent years may be linked to greater use of well tolerated once-daily drugs.

Lluis Castells, Antoni Rimola, Christian Manzardo, Andres Valdivieso, Jose Luis Montero, Rafael Barcena, Manuel Abradelo, Xavier Xiol, Victoria Aguilera, Magdalena Salcedo, Manuel Rodriguez, Carmen Bernal, Francisco Suarez, Antonio Antela, Sergio Olivares, Santos del Campo, Montserrat Laguno, Jose R. Fernandez, Gloria de la Rosa, Fernando Aguero, Inaki Perez3,y, Juan Gonzalez-Garcia, Juan I. Esteban-Mur, Jose M. Miro3,⇑, on behalf of the FIPSE LT-HIV investigators

The prognosis of human immunodeficiency virus (HIV) infection has improved in recent years with the introduction of antiretroviral treatment. While the frequency of AIDS-defining events has decreased as a cause of death, mortality from non-AIDS-related events including end-stage renal diseases has increased. The etiology of chronic kidney disease is multifactorial: immune-mediated glomerulonephritis, HIV-associated nephropathy, thrombotic microangiopathies, and so on. HIV infection is no longer a contraindication to transplantation and is becoming standard therapy in most developed countries. The HIV criteria used to select patients for renal transplantation are similar in Europe and North America. Current criteria state that prior opportunistic infections are not a strict exclusion criterion, but patients must have a CD4+ count above 200 cells/mm(3) and a HIV-1 RNA viral load suppressible with treatment. In recent years, more than 200 renal transplants have been performed in HIV-infected patients worldwide, and mid-term patient and graft survival rates have been similar to that of HIV-negative patients. The main issues in post-transplant period are pharmacokinetic interactions between antiretrovirals and immunosuppressants, a high rate of acute rejection, the management of hepatitis C virus coinfection, and the high cardiovascular risk after transplantation. More studies are needed to determine the most appropriate antiretroviral and immunosuppressive regimens and the long-term outcome of HIV infection and kidney graft.

Objectives: We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART). Methods: Retrospective, European and Canadian multicohort study.. Patients were diagnosed with HIV from 1997-2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression (new AIDS event, death) was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (

Late diagnosis of HIV-1 infection is quite frequent in Western countries. Very few randomized clinical trials to determine the best antiretroviral treatment in patients with advanced HIV-1 infection have been performed. To compare immune reconstitution in two groups of very immunosuppressed (less than 100 CD4(+) cells/microl), antiretroviral-naive HIV-1-infected adults, 65 patients were randomly assigned in a 1:1 ratio to receive zidovudine + lamivudine + efavirenz (group A, 34 patients) or zidovudine + lamivudine + ritonavir-boosted indinavir (group B, 31 patients). The median (interquartile range) CD4(+) cell increase after 12 and 36 months was +199 (101, 258) and +299 (170, 464) cells/microl in the efavirenz arm and +136 (57, 235) and +228 (119, 465) cells/microl in the ritonavir-boosted indinavir arm (p0.05 for all time points). The proportion (95% confidence interval) of patients achieving HIV-1 RNA levels under 50 copies/ml was significantly greater in the efavirenz arm at 3 years by the intention-to-treat analysis [59% (41%, 75%) vs. 23% (10%, 41%)], whereas no differences were found in the on-treatment analysis. Immune activation (CD8(+)CD38(+) and CD8(+)CD38DR(+) T cells) was significantly lower for the efavirenz arm from month 6 to month 24. Adverse events were more frequent in the ritonavir-boosted indinavir arm. Almost all cases of disease progression and death were observed in the first year of treatment, with no significant differences between the two arms (p = 0.79 by the log-rank test). At 1 and 3 years, the immune reconstitution induced by an efavirenz-based regimen in very immunosuppressed patients was at least as potent as that induced by a ritonavir-boosted protease inhibitor-based antiretroviral regimen.

to projected growth in prevalence based on empirical evidence of trends in risk factors such as obesity and diabetes, the primary drivers of NAFLD incidence. Results: The projected cumulative number of LTs averted for ESLD patients due to highly effective HCV treatment is estimated to be 10,490 over the period 2015–2035 (see Figure). Of this total, 7,320 livers would accrue to patients without HCV, accounting for 9% of livers used for all non-HCV liver transplants over this time period and approximately 123,700 life-years gained by non-HCV patients. Conclusions: More systematic use of highly effective treatments for HCV in the US may have substantial public health benefits for patients suffering from ESLD due to decreased liver transplantation in the HCV population. Most of these benefits accrue to patients without HCV.

Background: Cidofovir (CDV) is a nucleotide analogue with broad antiviral activity. This drug has a very favorable pharmacokinetic profile that enables intermittent dosing, but the potential for nephrotoxicity has hitherto restricted its use in stem cell transplant recipients. Data on pediatric patients are limited. Objectives: To report the efficacy and toxicity of CDV in a group of pediatric patients with cytomegalovirus (CMV) reactivation after allogeneic stem cell transplantation. Study design: Prospective evaluation of safety and efficacy of CDV used pre-emptively for CMV reactivation in 10 out of 30 children who underwent allogeneic hematopoietic stem cell transplantation from January 2000 to December 2001. In all the patients but one, CDV was used as second-line therapy (after foscarnet or ganciclovir) of CMV reactivation. Results: Overall, 12 courses of CDV were administered with a median 5 doses per course, range 1–6 (two patients were treated twice). Considering the first CDV treatment episode, 8 out of 10 patients had positive CMV antigenemia assay when they started CDV. Five of eight antigenemic patients responded completely while three were switched to foscarnet or ganciclovir, respectively, due to increasing (one) or persistent CMV antigenemia (two). Overall, the therapy with CDV was well tolerated, but it was withdrawn in one patient due to a two-fold increase in the baseline creatinine level. This patient concurrently had a high tacrolimus blood level. Conclusion: Safety is the major concern regarding the use of CDV but the adoption of probenicid, intravenous hydration and anti-emetic therapy improved its tolerability profile. Our data suggest that CDV has an acceptable toxicity and would deserve further controlled studies in the setting of pre-emptive therapy for CMV.