Three-year efficacy of switching to dolutegravir plus lamivudine: A real-world study.

BACKGROUND: Dolutegravir (DTG) plus lamivudine (3TC) has proven highly efficacious as a switching strategy in virologically suppressed people with HIV (PWH). As this strategy was introduced relatively recently, real-world, long-term durability studies are lacking. METHODS: We performed a retrospective review of treatment-experienced patients who started DTG + 3TC in a cohort of PWH. HIV-RNA <50 copies/mL was analysed at 144 weeks in an intention-to-treat (ITT) analysis (missing = failure) and a per-protocol (PP) analysis (patients with missing data or changes for reasons other than virological failure were excluded). RESULTS: The study population comprised 358 PWH (19% women). Median age and time with HIV infection were 51.7 and 13.4 years, respectively. The median number of previous antiretroviral combinations was three. Previous virological failure was reported in 27.1% of patients, and the M184V resistance mutation was detected in 17 patients. At 144 weeks, the percentage of individuals with HIV-RNA <50 copies/mL was 77.4% (277/358) in the ITT analysis and 95.5% (277/290) in the PP analysis. A total of 68 participants were excluded from the PP analysis (data missing, 25, discontinuation due to toxicity, 19; other, 16; death, 8). Two people with virological failure selected resistance-associated mutations (M184V and M184V + R263K). HIV-RNA remained undetectable in 17 patients with a previous history of the M184V mutation. CONCLUSION: Our results confirm the real-world, long-term efficacy, tolerability and high genetic barrier of DTG + 3TC in treatment-experienced PWH. Although scarce, mutations causing resistance to nucleosides and integrase can emerge.

Genetic variants associated with steatohepatitis and liver fibrosis in HIV-infected patients with NAFLD.

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver damage in people living with HIV (PLWHIV). Several studies have investigated candidate genes for susceptibility to NAFLD and to steatohepatitis. PNPLA3, TM6SF2, and MBOAT7-TMC4 have been reported to be associated with elevated ALT levels and the histologic parameters of nonalcoholic steatohepatitis and severity of fibrosis. Our objective was to analyze the relationship between PNPLA3, TM6SF2, and MBOAT7-TMC4 and steatosis, steatohepatitis, and liver fibrosis in PLWHIV with NAFLD. Method: A cohort of PLWHIV with persistently elevated aminotransferase levels and suspected NAFLD who underwent liver biopsy and determination of genetic variants was assessed at two large centers in Spain. All participants included in the current study were genotyped for rs738409 (PNPLA3), rs58542926 (TM6SF2), and rs641738 (MBOAT7-TMC4). Results: The study population comprised PLWHIV who were on stable antiretroviral therapy [7.7% women; median age, 49.3 years (44-53.4)]. The median CD4 count was 829 (650-980), 60% had metabolic syndrome, and 18.5% were diabetic. The median BMI was 28.9 (25.5-30.8). Patients with liver steatosis (any grade) vs. nonsteatosis tended to harbor the PNPLA3 G allele variant [57.6% vs. 16.7% (p = 0.09)], but not TM6SF2 or MBOAT7-TMC4 variants. However, those with steatohepatitis vs. nonsteatohepatitis significantly more frequently had the PNPLA3 G allele variant [69.4% vs. 39.1% (p < 0.05)] and the MBOAT7-TMC4 A allele variant [75% vs. 42% (p < 0.05)]. In our cohort, the TM6SF2 gene variant was not associated with steatosis or steatohepatitis. The PNPLA3 G allele variant was associated with steatohepatitis [OR 4.9 (1.3-18); p 0.02] and liver fibrosis [OR 4.3 (1.1-17.4); p 0.04], and the MBOAT7-TMC4 A allele variant was associated with steatohepatitis [OR 6.6 (1.6-27.6); p 0.01]. Conclusion: The PNPLA3 G allele variant and MBOAT7-TMC4 A allele variant were associated with steatohepatitis and liver fibrosis in PLWHIV with persistently elevated aminotransferases and NAFLD. We recommend routine genotyping for PNPLA3 and MBOAT7-TMC4 in PLWHIV with NAFLD to identify those at higher risk of progression.

Assessment of Noninvasive Markers of Steatosis and Liver Fibrosis in Human Immunodeficiency Virus-Monoinfected Patients on Stable Antiretroviral Regimens.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major nonacquired immune deficiency syndrome-defining condition for persons with human immunodeficiency virus (PWH). We aimed to validate noninvasive tests for the diagnosis of NAFLD in PWH. Methods: This is a cross-sectional study of PWH on stable antiretroviral therapy with persistently elevated transaminases and no known liver disease. The area under the receiver operating characteristic curve (AUROC) was calculated to compare the diagnostic accuracy of liver biopsy with abdominal ultrasound, transient elastography (TE) (including controlled attenuation parameter [CAP]), and noninvasive markers of steatosis (triglyceride and glucose index [TyG], hepatic steatosis index [HSI], fatty liver index [FLI]) and fibrosis ([FIB]-4, aminotransferase-to-platelet ratio index [APRI], NAFLD fibrosis score). We developed a diagnostic algorithm with serial combinations of markers. Results: Of 146 patients with increased transaminase levels, 69 underwent liver biopsy (90% steatosis, 61% steatohepatitis, and 4% F ≥3). The AUROC for steatosis was as follows: ultrasound, 0.90 (0.75-1); CAP, 0.94 (0.88-1); FLI, 0.81 (0.58-1); HSI, 0.74 (0.62-0.87); and TyG, 0.75 (0.49-1). For liver fibrosis ≥F3, the AUROC for TE, APRI, FIB-4, and NAFLD fibrosis score was 0.92 (0.82-1), 0.96 (0.90-1), 0.97 (0.93-1), and 0.85 (0.68-1). Optimal diagnostic performance for liver steatosis was for 2 noninvasive combined models of tests with TyG and FLI/HSI as the first tests and ultrasound or CAP as the second tests: AUROC = 0.99 (0.97-1, P < .001) and 0.92 (0.77-1, P < .001). Conclusions: Ultrasound and CAP performed best in diagnosing liver steatosis, and FLI, TyG, and HSI performed well. We propose an easy-to-implement algorithm with TyG or FLI as the first test and ultrasound or CAP as the second test to accurately diagnose or exclude NAFLD.

[Real-world efficacy of switching to bictegravir/ emtricitabine/tenofovir alafenamide in pretreated patients with triple therapy containing rilpivirine]. / Eficacia en vida real del cambio a bictegravir/ emtricitabina/tenofovir alafenamida en pacientes previamente tratados con pautas triples que contienen rilpivirina.

OBJECTIVE: To analyze the efficacy and tolerability of the strategy to change from rilpivirine (RPV) based regimens to bictegravir / emtricitabine / tenofovir alafenamide (B/F/TAF). METHODS: Single-center, observational and retrospective study. Patients who made the change to B/F/TAF before February 2020 were selected, analyzing the results after 24 and 48 weeks. The percentage that remained with an undetectable viral load was determined, as well as the changes in CD4 + lymphocytes, metabolic parameters and renal function. RESULTS: A total of 42 patients were included. Thirty-two of the 35 patients (91.4%) who completed the 48 weeks of follow-up had an undetectable viral load. The CD4 + lymphocyte count remained stable at 24 and 48 weeks. The response to B/F/TAF was not influenced by the two analogs previously received. CONCLUSIONS: Switching from triple therapy with RPV to B/F/TAF is a safe and effective strategy in real life.

Past and future of HIV infection. A document based on expert opinion.

HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection.

[Helicobacter pylori infection in the HIV + population: a comorbidity to think about]. / Infección por Helicobacter pylori en la población VIH+: una comorbilidad en la que pensar.

OBJECTIVE: Gastrointestinal disorders are frequent in HIV+. Helicobacter pylori may be an underdiagnosed cause. METHODS: Patients with HIV and H. pylori were described since January 1998 up to December 2017. RESULTS: A total de 132 patients were included. The most frequent symptom was dyspepsia. 88.5% had chronic atrophic gastritis. Eradication was achieved in 102 (77.3%). Healing was more frequent with quadruple regimen (p=0.004) and in the youngest (p=0.041). CONCLUSIONS: H. pylori infection could be responsible for nonspecific digestive manifestations in HIV + patients.

Determinants of blood telomere length in antiretroviral treatment-naïve HIV-positive participants enrolled in the NEAT 001/ANRS 143 clinical trial.

OBJECTIVES: Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults. METHODS: A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics. RESULTS: The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39 years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1 years, the mean HIV-1 RNA load was 4.7 log10 HIV-1 RNA copies/mL, the mean nadir and baseline CD4 counts were 301 and 324 cells/µL, respectively, and the mean CD4:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10 years) (P < 0.001), HIV-1 RNA ≥ 100 000 copies/mL (P = 0.001), CD4 count < 200 cells/µL (P = 0.037), lower CD4:CD8 ratio (P = 0.018), statin treatment (P = 0.004), and current alcohol consumption (P = 0.035). In the multivariable analysis, older age (P < 0.001) and HIV RNA ≥ 100 000 copies/mL (P = 0.054) were independently associated with shorter telomere length. CONCLUSIONS: Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.

Decreasing rates of acute myocardial infarction in people living with HIV: a nationwide cohort study in Spain, 2004-2015.

OBJECTIVES: Contemporary data from country-wide cohorts are needed to reveal trends in the occurrence of acute myocardial infarction (AMI) in people living with HIV (PLWH). We analysed time trends in the standardized incidence rate (sIR) of AMI in PLWH in Spain from 2004 to 2015, and compared them with trends in the general population. METHODS: A longitudinal study in a nationwide contemporary multicentre HIV-infected cohort was carried out. Data on all incident AMI events were collected, and age- and sex-standardized IRs calculated. To analyse the IR of AMI in the general population, the national rates of hospital discharges for AMI per 100 000 inhabitants stratified for age and sex from 2004 to 2015 were obtained using the morbidity report data from the National Statistics Institute. A Poisson regression model was fitted to assess the effect of covariates of interest on AMI occurrence. RESULTS: The sIRs of AMI in 2004-2015 were 237.92 [95% confidence interval (CI) 225.95-249.90] and 66.75 (95% CI: 23.49-110.01) per 100 000 patient-years in male and female PLWH, respectively. There was a decrease in the sIR of AMI in male PLWH from 279.02 (95% CI: 265.46-292.59) per 100 000 person-years in 2004-2009 to 222.13 (95% CI: 210.83-233.42) per 100 000 person-years in 2010-2015. Compared with the general population, the sIR ratio was 1.41 (95% CI: 1.26-1.55) in 2004-2009, and 1.28 (95% CI: 1.15-1.43) in 2010-2014. AMI occurrence was associated with older age (P < 0.066 for each 10-year age stratum ≥ 35-years compared with the 25-34 year stratum), higher plasma HIV RNA (P < 0.001), lower CD4 count (P < 0.04 for CD4 strata > 350 cells/µL compared with the 0-100 cells/µL stratum), and the period 2004-2009 (P < 0.001). CONCLUSIONS: There has been a decreasing incidence of AMI in PLWH in Spain, associated with improving immune and virological status, but the incidence of AMI has remained higher than in the general population.

Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: HIV infection is associated with a higher prevalence of low bone mineral density (BMD) and fractures than that found in the general population. There are limited data in HIV-positive adults, naïve to antiretroviral therapy (ART), with which to estimate the relative contribution of untreated HIV infection to bone loss. METHODS: The primary objective of the Strategic Timing of AntiRetroviral Treatment (START) Bone Mineral Density Substudy is to compare the effect of immediate versus deferred initial ART on bone. We evaluated traditional, demographic, HIV-related and immunological factors for their associations with baseline hip and lumbar spine BMD, measured by dual-energy X-ray absorptiometry, using multiple regression. RESULTS: A total of 424 ART-naïve participants were enrolled at 33 sites on six continents; the mean age was 34 years [standard deviation (SD) 10.1 years], 79.0% were nonwhite, 26.0% were women, and 12.5% had a body mass index (BMI) < 20 kg/m(2) . Mean (SD) Z-scores were -0.41 (0.94) at the spine and -0.36 (0.88) for total hip; 1.9% had osteoporosis and 35.1% had low BMD (hip or spine T-score < -1.0). Factors independently associated with lower BMD at the hip and spine were female sex, Latino/Hispanic ethnicity, lower BMI and higher estimated glomerular filtration rate. Longer time since HIV diagnosis was associated with lower hip BMD. Current or nadir CD4 cell count and HIV viral load were not associated with BMD. CONCLUSIONS: In this geographically and racially diverse population of ART-naïve adults with normal CD4 cell counts, low BMD was common, but osteoporosis was rare. Lower BMD was significantly associated with traditional risk factors but not with CD4 cell count or viral load.

Visceral leishmaniasis as an independent cause of high immune activation, T-cell senescence, and lack of immune recovery in virologically suppressed HIV-1-coinfected patients.

OBJECTIVES: Different immune alterations have been described in HIV-infected patients with visceral leishmaniasis (VL). We aimed to identify the immunological factors involved in the lack of immunological recovery and VL relapses in HIV-infected patients with VL, by comparison with other HIV-infected patients. METHODS: We carried out a cross-sectional study of 55 patients receiving suppressive combination antiretroviral therapy (cART) for at least 1 year: nine with previous relapsing VL, 20 with an immunodiscordant response (IDR) to cART (CD4 count < 200 cells/µL) and no previous VL, and 26 with a concordant response (CR) to cART (CD4 count > 350 cells/µL) without VL. Immunosenescence was investigated by analysing CD57(+) CD28(-) levels, immune activation by analysing CD38(+) HLA-DR(+) levels, inflammation by analysing interleukin (IL)-6 levels, and microbial translocation by analysing lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels. RESULTS: In VL patients, the median time since VL diagnosis was 42 months, and all patients had had at least one relapse despite suppressive cART for a median time of 43 months. Patients with previously diagnosed VL had a higher CD8 T-cell activation level (P < 0.001) than those with IDR. Also, levels of IL-6, LPS and especially sCD14, associated with bacterial translocation and additional monocyte activation, were significantly increased in patients with previous VL compared with patients with IDR (P = 0.048, P = 0.049 and P < 0.001, respectively). In addition, patients with previous VL had higher levels of CD8 T-cell senescence. Notably, the levels of immune activation and inflammation in patients with previous VL were not related to the time of VL diagnosis, the number of VL relapses, or hepatitis C virus (HCV) coinfection. CONCLUSIONS: Our data demonstrate that VL patients had an even worse immunological status than patients with IDR, which was probably associated with increased microbial translocation and additional monocyte/macrophage activation. These data explain the observed lack of immunological recovery and the occurrence of VL relapses in HIV-infected patients with previous VL.

Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir.

OBJECTIVES: Ritonavir-boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir-boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir-induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved. METHODS: A 96-week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA < 50 HIV-1 RNA copies/mL and study drug discontinuation because of adverse effects at 24 weeks. Analyses were intent-to-treat. RESULTS: One hundred and seventy-eight patients received once-daily treatment with either atazanavir/ritonavir (n = 90) or darunavir/ritonavir (n = 88) plus tenofovir/emtricitabine. At 24 weeks, mean total cholesterol had increased by 7.26 and 11.47 mg/dL in the atazanavir/ritonavir and darunavir/ritonavir arms, respectively [estimated difference -4.21 mg/dL; 95% confidence interval (CI) -12.11 to +3.69 mg/dL; P = 0.75]. However, the ratio of total to high-density lipoprotein (HDL) cholesterol tended to show a greater decrease with atazanavir/ritonavir compared with darunavir/ritonavir (estimated difference -1.02; 95% CI -2.35 to +0.13; P = 0.07). Total bilirubin significantly increased with atazanavir/ritonavir (estimated difference +1.87 mg/dL; 95% CI +1.58 to +2.16 mg/dL; P < 0.01), but bilirubin changes were not associated with lipid changes. Secondary endpoints other than total bilirubin were not significantly different between arms. CONCLUSIONS: Atazanavir/ritonavir and darunavir/ritonavir plus tenofovir/emtricitabine did not show significant differences in total cholesterol change or overall tolerability at 24 weeks. However, there was a trend towards a lower total to HDL cholesterol ratio with atazanavir/ritonavir and this effect was unrelated to bilirubin.

Switching to lopinavir/ritonavir with or without abacavir/lamivudine in lipoatrophic patients treated with zidovudine/abacavir/lamivudine.

BACKGROUND: Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery. METHODS: This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007). RESULTS: Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)]. CONCLUSIONS: In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

[HIV-1 neuropathogenesis: therapeutic strategies against neuronal loss induced by gp120/Tat glycoprotein in the central nervous system]. / Neuropatogenesis inducida por el virus del sida: estrategias terapeuticas frente a la neurodegeneracion inducida por la glucoproteina gp120/Tat en el sistema nervioso central.

Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors (CXCR4, CX3CR1 and CR5) produces proinflammatory cytokine release by infected cells, increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species (ROS) that eventually damage the neuron. Moreover, the neurotoxin Tat produces dendritic loss by interacting with the low-density lipoprotein receptor (LRP) and also overstimulates N-methyl D-aspartate receptors (NMDA). Furthermore, the aberrant interaction of glycoprotein gp120 with the CXCR4 chemokine receptor causes caspase-3-dependent apoptosis (ceramide is also released) activating apoptotic proteins (p53 and retinoblastoma), which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS. Similarly, gliosis/microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid (MCP-1 and fractalkine, among others) contribute to the neuropathogenesis of HIV-1. Alpha-synuclein and beta amyloid deposits have also been detected in post mortem brains of seropositives patients. In addition, there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system; such as osteopontin, CD163 and fractalkine, among others. Lastly, clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins (GSK-3 beta), microglial activation inhibitors (minocycline), antioxidants (selegiline) or trophic factors (IGF-1, growth hormone or erythropoietin). These trials have shown that their treatments are beneficial and complementary to treat complications of HIV/AIDS.

[Reproducibility of the glucose tolerance test in patients with impaired fasting glucose]. / Reproducibilidad de la prueba de sobrecarga oral de glucosa en pacientes con glucosa alterada en ayunas.

BACKGROUND AND OBJECTIVES: Impaired fasting glucose (IFG) is defined by a fasting glucose between 5.6 and 6.9 mmol/l in subjects with no known diabetes. The present study objectives were: a) to analyze the glucose tolerance test (GTT) reproducibility and b) to assess this test's diagnostic classification agreement. PATIENTS AND METHOD: Cross-sectional study in adult patients diagnosed with IFG. Study subjects underwent a 75 g GTT in two occasions. RESULTS: Fifty-nine patients were studied. The interval between GTT tests was 37 +/- 26 days. Fasting and post-GTT plasma glucose intra-individual variation coefficients were 6.9 and 31.0%, respectively. Diagnostic agreement between the two tests (normal tolerance vs. abnormal tolerance) was measured using the kappa index: 0.62 (95% CI 0.42-0.82). Agreement ranged from 80% (95% CI, 70-90%) to 83% (95% CI, 73-93%) depending on whether the first GGT results were abnormal or normal, respectively. CONCLUSIONS: GTT reproducibility is moderate in patients diagnosed with IFG. Considering this fact, perhaps this test should be repeated before therapeutic decisions are made.

Mujer de 23 años con crisis hipertensiva / A 23-year old woman with hypertensive episode

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Hombre con lesión cutánea 'en coliflor' / Male patient with a cauliflower-like cutaneous lesion

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