Proteomic Profile Associated With Loss of Spontaneous Human Immunodeficiency Virus Type 1 Elite Control.

BACKGROUND: Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers. METHODS: Plasma samples from ECs who spontaneously lost virological control (transient controllers [TCs]), at 2 years and 1 year before the loss of control, were compared with a control group of ECs who persistently maintained virological control during the same follow-up period (persistent controllers [PCs]). Comparative plasma shotgun proteomics was performed with tandem mass tag (TMT) isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry. RESULTS: Eighteen proteins exhibited differences comparing PC and preloss TC timepoints. These proteins were involved in proinflammatory mechanisms, and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, α-1-antichymotrypsin, ficolin-2, 14-3-3 protein, and galectin-3-binding protein were considered potential biomarkers. CONCLUSIONS: The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration, and coagulation. Galectin-3 binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in ECs.

Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection.

HIV-1 elite controllers (EC) maintain undetectable viral loads (VL) in the absence of antiretroviral treatment. However, these subjects have heterogeneous clinical outcomes, including a proportion that loses HIV-1 control over time. In this work, we compared, in a longitudinal design, transient EC, analyzed before and after the loss of virological control, with persistent EC. The aim was to identify factors leading to the loss of natural virological control of HIV-1 infection with a longitudinal retrospective study design. Gag-specific T-cell responses were assessed by in vitro intracellular polycytokine production quantified by flow cytometry. Viral diversity determinations and sequence dating were performed in proviral DNA by PCR amplification at limiting dilution of env and gag genes. The expression profile of 70 serum cytokines and chemokines was assessed by multiplex immunoassays. We identified transient EC as subjects with low Gag-specific T-cell polyfunctionality, high viral diversity, and high proinflammatory cytokine levels before the loss of control. Gag-specific T-cell polyfunctionality was inversely associated with viral diversity in transient controllers before the loss of control (r = -0.8; P = 0.02). RANTES was a potential biomarker of transient control. This study identified virological and immunological factors, including inflammatory biomarkers associated with two different phenotypes within EC. These results may allow a more accurate definition of EC, which could help in better clinical management of these individuals and in the development of future curative approaches.IMPORTANCE There is a rare group of HIV-infected patients who have the extraordinary capacity to maintain undetectable viral load levels in the absence of antiretroviral treatment, the so-called HIV-1 elite controllers (EC). However, there is a proportion within these subjects that eventually loses this capability. In this work, we found differences in virological and immune factors, including soluble inflammatory biomarkers, between subjects with persistent control of viral replication and EC that will lose virological control. The identification of these factors could be a key point for a right medical care of those EC who are going to lose natural control of viral replication and for the design of future immunotherapeutic strategies using as a model the natural persistent control of HIV infection.

Brief Report: Patients' Experiences and Opinions After Desimplification of Their Single-Tablet Regimens for the Treatment of HIV Infection: A Survey in a Multicentre Cohort.

OBJECTIVES: The aims of this study were to describe patients' experiences after single-tablet regimen (STR) desimplification and its impact on self-reported treatment adherence and quality of life. METHODS: We performed a survey among all patients from the multicenter cohort of the Spanish HIV/AIDS Network who had desimplified the STRs dolutegravir/abacavir/lamivudine (DGT/ABC/3TC) or rilpivirine/tenofovir disoproxil fumarate/emtricitabine to their separate components (DTG + generic ABC/3TC or RPV + generic TDF/FTC) between December 2016 and November 2018. RESULTS: Among 216 patients who fulfilled inclusion criteria, 138 (63.9%) completed the questionnaire. Most of the patients (78.3%) knew what generic drugs are, only 8.7% believed that treatment with 2 pills is less effective than treatment with an STR, and 67.4% agreed that it is reasonable to take 2 pills instead of 1 for HIV treatment to decrease costs for the health care system. After desimplification, 13.0% of the patients stated they had more secondary effects, 8.0% had forgotten one or more doses more frequently than before, and 10.9% had sometimes forgotten to take 1 pill, but not the other. A proportion of 30.4% reported not being happy to take more pills a day, and 10.1% experienced a worse quality of life after the treatment desimplification. CONCLUSIONS: After STR desimplification, most of the patients had a fair knowledge about generic antiretrovirals, and they agreed to desimplify their STR to decrease costs. Although almost a third of the respondents were not happy to take 2 pills a day, only a minority reported worse adherence or quality of life.

[Pancreatic tuberculosis with duodenal fistula]. / Tuberculosis pancreática con fistulización a duodeno.

Tuberculosis is a common infection worldwide. In developed countries, the incidence of this disease was low until a few years ago. However, due to the rise in immigration and HIV infection, the frequency of tuberculosis has recently shown a marked increase. Although the most frequent location of tuberculosis infection continues to be respiratory, infection in other sites, such as musculoskeletal, genitourinary, neurological and abdominal areas, has recently become more common. Abdominal infection, the most frequently described extrapulmonary localization, commonly affects the spleen, liver, ileocecal region, peritoneum, and regional lymph nodes. Tuberculosis of the pancreas is considered a rare entity.

Quadruple-2 protease inhibitors (PI)-therapy does not accelerate viral decay and suppression in PI-naive HIV-1 infected patients with severe immunosuppression and high viral load as compared with standard triple therapy.

To analyse if a four-drug combination including two protease inhibitors (PIs) accelerates viral decay and suppression as compared with standard triple therapy in heavily immunosuppressed HIV-1 infected patients, an open label clinical trial was designed. PIs naive patients receiving their first highly active antiretroviral therapy were included if their CD4 cell count was lower than 200/mm3 and their HIV viral load (VL) >100,000 RNA copies/mL. Every patient received two analogues and was randomized in two groups receiving either one PI (saquinavir soft gel capsule) or two PIs (saquinavir + nelfinavir). Viral efficacy (VL <50), time to reach VL <50, viral clearance rate constant and plasmatic elimination half-life were determined. In all, 30 patients were enrolled. No viral variable was significatively improved by the four-drug combination in the short term. No clinical benefit should be expected with a four-drug (two PIs) regimen in patients with low CD4+ cell count and high VL.

Efficacy and tolerability after 24 weeks of treatment with telaprevir, pegylated interferon and ribavirin in cirrhotic HIV-HCV coinfected subjects.

Efficacy and tolerability of telaprevir, pegylated interferon and ribavirin combination was assessed in 32 cirrhotic genotype 1 hepatitis C (HCV)-HIV coinfected patients. Undetectability of HCV-RNA was observed in 23/32 (71.9%) patients after 24 weeks. Treatment failure was observed in 9/32 subjects: four of them (45.5%) failed triple therapy due to virological rebound, while 5 patients (55.5%) experienced drug-related side effects driving to treatment interruption. These data suggest that telaprevir-containing triple therapy should be considered for treatment of genotype 1 HCV in HIV coinfected patients with liver cirrhosis, although a close vigilance is required because of potential drug-related side effects.

Dual therapy with darunavir/r plus etravirine is safe and effective as switching therapy in antiretroviral experienced HIV-patients. The BITER Study.

INTRODUCTION: Switching therapy studies are usually designed as second-line antiretroviral treatment (ART) in patients without previous virologic failures. Combined ART (cART) with DRV/r and ETR has a good pharmacokinetic profile, high genetic barrier and has been proved as rescue therapy. The aim of our study was to analyze efficacy and safety of therapy with DRV/r plus ETR in treatment experienced HIV-patients with previous therapeutic failures that need to switch ART. We present results at first 24 weeks. METHODS: Multicentre retrospective observational study. INCLUSION CRITERIA: adult HIV-patients on ART with HIV-VL <1000 cop/mL who started their ART with DRV/r (600/100 bid or 800/100 qd)+ETR by adverse events, non-adherence, tolerability or prevention of future complications. Patients with acute AIDS events, HBV, pregnancy, drug addiction or previous selected mutations to DRV or ETR were excluded. RESULTS: Ninety-nine patients were included, mean age: 47 years (r: 22-79); 70% men, 40.4% previous AIDS event and 39.3% HCV. Ninety-one patients had received ≥3 cART regimens and 45≥5, 75 patients had HIV-VL <50 cop/mL and 24 low-level viremia (LLV): 297.5±261.4 cop/mL, CD4+ 568±279 cells/µL. ART before switching: NRTI+PI/r (33%), NNRTI (17%), PI/r+NNRTI (23%), PI/r+INI (13%), other (14%). Main reason to switching was: toxicity/intolerance 50 patients (renal 32%, gastrointestinal: 14%, hyperlipidaemia 10%; osteopenia/osteoporosis: 6%); improving adherence 26 patients; prevention of complications 19 patients. Nine subjects withdrew ART during follow-up because: intolerance or new toxicity three; non-adherence two; simplification to DRV/r monotherapy two; persistence of previous toxicity one; virologic failure one. At week 24, among patients who continued with DRV/r+ETR (n=90): 81 (89%) had VL<50 cop/mL, in those with with HIV-VL<50 at baseline (67/90), 94% persisted with <50 cop., and in those with LLV (24/90), 61% (n=14) achieved a VL<50 cop. We didn't observe any significant difference in lab parameters between baseline and week 24. Estimated glomerular filtrate rate increased from 83.4±24.7 to 88.5±56.8 mL/min, p=NS. Regarding reason to switching, it improved in 42 cases, no changes: 20 cases; worsened: 4 cases, and non-applicable or unknown: 24 cases. CONCLUSIONS: Switching to dual therapy with DRV/r+ETR is an effective strategy in selected heavily experienced ART patients, even in those with LLV (<1000 cop/mL). This cART is safe and well tolerated, can reduce number of pills and improve adherence.

Genotypic tropism testing in proviral DNA to guide maraviroc initiation in aviremic subjects: 48-week analysis of the PROTEST study.

INTRODUCTION: In a previous interim 24-week virological safety analysis of the PROTEST study (1), initiation of Maraviroc (MVC) plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs) in aviremic subjects based on genotypic tropism testing of proviral HIV-1 DNA was associated with low rates of virological failure. Here we present the final 48-week analysis of the study. METHODS: PROTEST was a phase 4, prospective, single-arm clinical trial (ID: NCT01378910) carried on in 24 HIV care centres in Spain. Maraviroc-naïve HIV-1-positive adults with HIV-1 RNA (VL) <50 c/mL on stable ART during the previous 6 months, requiring an ART change due to toxicity, with no antiretroviral resistance to the ART started, and R5 HIV by proviral DNA genotypic tropism testing (defined as a G2P FPR >10% in a singleton), initiated MVC with 2 NRTIs and were followed for 48 weeks. Virological failure was defined as two consecutive VL>50 c/mL. Recent adherence was calculated as: (# pills taken/# pills prescribed during the previous week)*100. RESULTS: Tropism results were available from 141/175 (80.6%) subjects screened: 87/141 (60%) were R5 and 74/87 (85%) were finally included in the study. Their median age was 48 years, 16% were women, 31% were MSM, 36% had CDC category C at study entry, 62% were HCV+ and 10% were HBV+. Median CD4+ counts were 616 cells/mm(3) at screening, and median nadir CD4+ counts were 143 cells/mm(3). Previous ART included PIs in 46 (62%) subjects, NNRTIs in 27 (36%) and integrase inhibitors (INIs) in 1 (2%). The main reasons for treatment change were dyslipidemia (42%), gastrointestinal symptoms (22%), and liver toxicity (15%). MVC was given alongside TDF/FTC in 40 (54%) subjects, ABC/3TC in 30 (40%), AZT/3TC in 2 (3%) and ABC/TDF in 2 (3%). Sixty-two (84%) subjects maintained VL<50 c/mL through week 48, whereas 12 (16%) discontinued treatment: two (3%) withdrew informed consent, one (1%) had a R5→X4 shift in HIV tropism between the screening and baseline visits, one (1%) was lost to follow-up, one (1%) developed an ART-related adverse event (rash), two (3%) died due to non-study-related causes (1 myocardial infarction at week 0 and 1 lung cancer at week 36), and five (7%) developed protocol-defined virological failure, although two of them regained VL<50 c/mL with the same MVC regimen (Table 1). CONCLUSIONS: Initiation of MVC plus 2 NRTIs in aviremic subjects based on genotypic tropism testing of proviral HIV-1 DNA is associated with low rates of virological failure up to one year.

[Predictors of progression and death in patients with advanced HIV infection in the era of highly active antiretroviral therapy]. / Predictores de progresión y muerte en pacientes con infección avanzada por el VIH en la era de los tratamientos antirretrovirales de gran actividad.

INTRODUCTION: To assess the factors associated with progression of infection and death in HIV-positive patients with severe immunodepression in the era of highly active antiretroviral therapy (HAART). METHODS: We studied 146 HIV-infected patients with < 100 x 10(6)/L CD4+ lymphocytes and positive cytomegalovirus (CMV) serology enrolled between December 1997 and October 1998 and prospectively followed a median of 12.1 months. The main outcome measures were progression of HIV infection, defined as the appearance of a new AIDS-defining disease (CDC category C) or death. HIV viral load, lymphocyte count (CD4+ and CD8+), HAART administration and other clinical variables were evaluated at baseline. CMV viremia (determined by PCR) and HAART efficacy were recorded during follow-up. RESULTS: Progression was observed in 40% of patients and 17% died. Factors associated with progression or death were CD4+ lymphocyte count less than 50 x 10(6)/L, CD8+ lymphocyte count less than 500 x 10(6)/L, HIV viral load more than 300,000 copies RNA/mL, CMV viremia, and absence or inefficacy of HAART. In the multivariate model, absence of HAART and low CD4+ and CD8+ counts remained statistically associated with progression, but the only variable associated with death was CMV viremia. CONCLUSIONS: In patients with advanced HIV infection, CD4+ and CD8+ cell count and HAART were the most important factors related to progression, and CMV viremia was the strongest predictor of death.

Tuberculosis pancreática con fistulización a duodeno / Pancreatic tuberculosis with duodenal fistula

La tuberculosis es una entidad frecuente en todo el mundo. En los países desarrollados se describía hasta hace unos años un descenso en su incidencia, pero debido al aumento de flujos migratorios y a la aparición del sida, se ha detectado un notable aumento en su frecuencia en los últimos tiempos. A pesar de que la localización clásica con afectación pulmonar continúa siendo la forma de presentación más comunicada, se ha descrito un incremento en el diagnóstico en otras localizaciones. La afectación de otros órganos y aparatos, como el sistema muscular esquelético, el genitourinario, el neurológico o el abdominal, ha dejado de ser infrecuente. La abdominal es una localización extrapulmonar cada vez más frecuente, zona en la que se ha descrito una afectación de diversas estructuras: cadenas linfáticas mesentéricas, intestino delgado, peritoneo, hígado y bazo. La afectación pancreática es una entidad muy infrecuente

Tuberculosis is a common infection worldwide. In developed countries, the incidence of this disease was low until a few years ago. However, due to the rise in immigration and HIV infection, the frequency of tuberculosis has recently shown a marked increase. Although the most frequent location of tuberculosis infection continues to be respiratory, infection in other sites, such as musculoskeletal, genitourinary, neurological and abdominal areas, has recently become more common. Abdominal infection, the most frequently described extrapulmonary localization, commonly affects the spleen, liver, ileocecal region, peritoneum, and regional lymph nodes. Tuberculosis of the pancreas is considered a rare entity (AU)