IP-10 and MIG are sensitive markers of early virological response to HIV-1 integrase inhibitors.

Background: Interferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART). Methods: Persons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay. Results: IP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH≥ 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels. Conclusion: Plasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels.

Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.

BACKGROUND: There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. METHODS: We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression. RESULTS: Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs. CONCLUSIONS: Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.

Interleukin 18 (IL-18) and IL-3 in Extracellular Vesicles: Biomarkers for Durable Elite Control of HIV-1.

Plasma extracellular vesicle (EV)-associated cytokines were quantified in people with HIV (PWH) with different virological control status, including elite controllers (EC) who maintain persistent control (PC) or not (TC). Cytokine signatures and pathways were determined for each group. Median EV-associated cytokine levels were higher among PWH than HIV-uninfected. EC showed the highest levels of EV-associated cytokines among PWH with PC levels higher than TC levels. IL-18 levels best distinguished PWH from uninfected controls, and EC from ART-treated, and IL-3 distinguished PC from TC. The role of EV-cytokines in intercellular communication and endogenous control of HIV expression should be investigated further.

Determinants of long-term survival in late HIV presenters: The prospective PISCIS cohort study.

Background: Late HIV diagnosis (i.e CD4≤350 cells/µL) is associated with poorer outcomes. However, determinants of long-term mortality and factors influencing immune recovery within the first years after antiretroviral treatment (ART) initiation are poorly defined. Methods: From PISCIS cohort, we included all HIV-positive adults, two-year survivors after initiating ART between 2005-2019. The primary outcome was all-cause mortality according to the two-year CD4 count. We used Poisson regression. The secondary outcome was incomplete immune recovery (i.e., two-year CD4<500 cells/µL). We used logistic regression and propensity score matching. Findings: We included 2,719 participants (16593·1 person-years): 1441 (53%) late presenters (LP) and 1278 non-LP (1145 non-LP with two-year CD4 count >500 cells/µL, reference population). Overall, 113 patients (4·2%) died. Mortality was higher among LP with two-year CD4 count 200-500 cells/µL (aMRR 1·95[95%CI:1·06-3·61]) or <200 cells/µL (aMRR 4·59[2·25-9·37]).Conversely, no differences were observed in participants with two-year CD4 counts >500 cells/µL, regardless of being initially LP or non-LP (aMRR 1·05[0·50-2·21]). Mortality rates within each two-year CD4 strata were not affected by the initial CD4 count at ART initiation (test-interaction, p = 0·48). The stronger factor influencing immune recovery was the CD4 count at ART initiation. First-line integrase-inhibitor-(INSTI)-based regimens were associated with reduced mortality compared to other regimens (aMRR 0·54[0·31-0·93]) and reduced risk of incomplete immune recovery in LP (aOR 0·70[0·52-0·95]). Interpretation: Two-year immune recovery is a good early predictor of long-term mortality in LP after surviving the first high-risk 2 years. Nearly half experienced a favorable immune recovery with a life expectancy similar to non-LP. INSTI-based regimens were associated with higher rates of successful immune recovery and better survival compared to non-INSTI regimens. Funding: Southern-Denmark University, Danish AIDS-foundation, and Region of Southern Denmark.

Intracerebral Varicella Zoster Virus Vasculopathy in a Patient with Systemic Lupus Erythematosus and Imaging-Clinical Discordance.

BACKGROUND Varicella zoster virus (VZV) infection can increase the risk of cerebrovascular disease, involving small and large arteries, especially in immunosuppressed patients with ophthalmic division of the trigeminal nerve involvement. We present the case of a patient with intracerebral VZV vasculopathy without overt clinical manifestation but with abnormal imaging findings in the brain magnetic resonance (MR). CASE REPORT A 59-year-old woman with systemic lupus erythematosus (SLE), without other traditional cardiovascular risk factors, presented to the hospital due to headache, vertical diplopia, decreased of visual acuity of right eye, and disseminated varicella zoster virus (VZV) infection with predominant skin lesions distributed along the ophthalmic division of the right trigeminal nerve. Cerebrospinal fluid (CSF) testing revealed meningitis and positive polymerase chain reaction (PCR) for VZV, and a brain MRI scan showed a right occipital hemorrhagic lesion; thus, she was diagnosed with disseminated VZV infection with neurological involvement. She received intravenous acyclovir for 10 days. One month later, a physical examination was unremarkable and she was asymptomatic, but control brain MR angiography showed stenosis of the right internal carotid and the right middle cerebral artery, compatible with VZV vasculopathy. The PCR for VZV turned negative in CSF but the titers of anti-VZV IgG antibodies in CSF were high, and no increase of plasma autoimmune biomarkers were detected at any time in the course of the clinical evolution. CONCLUSIONS Discordance between imaging findings and clinical manifestations can appear in intracerebral VZV vasculopathy. A differential diagnosis is mandatory, especially if there is underlying immunosuppression.

Predictors of low-level HIV viraemia and virological failure in the era of integrase inhibitors: A Spanish nationwide cohort.

OBJECTIVES: To pinpoint factors associated with low-level viraemia (LLV) and virological failure (VF) in people living with HIV in the era of high-efficacy antiretroviral treatment (ART) and widespread use of integrase strand transfer inhibitor (INSTIs)-based ART. METHODS: We included adults aged > 18 years starting their first ART between 2015 and 2018 in the Spanish HIV/AIDS Research Network National Cohort (CoRIS). Low-level viraemia was defined as plasma viral load (pVL) of 50-199 copies/mL at weeks 48 and 72 and VF was defined as pVL ≥ 50 copies/mL at week 48 and pVL ≥ 200 copies/mL at week 72. Multivariable logistic regression models assessed the impact on LLV and VF of baseline CD4 T-cell count, CD4/CD8 T-cell ratio and pVL, initial ART classes, age at ART initiation, time between HIV diagnosis and ART initiation, gender and transmission route. RESULTS: Out of 4186 participants, 3120 (76.0%) started INSTIs, 455 (11.1%) started boosted protease inhibitors (bPIs) and 443 (10.8%) started nonnucleoside reverse transcriptase inhibitors (NNRTIs), either of them with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs). Low-level viraemia was met in 2.5% of participants and VF in 4.3%. There were no significant differences throughout the years for both virological outcomes. Baseline HIV-1 RNA > 5 log10 copies/mL was the only consistent predictor of higher risk of LLV [adjusted odds ratio (aOR) = 9.8, 95% confidence interval (CI): 2.0-48.3] and VF (aOR = 5.4, 95% CI: 1.9-15.1), even in participants treated with INSTIs. CONCLUSIONS: The rates of LLV and VF were low but remained steady throughout the years. Baseline HIV-1 RNA > 5 log10 copies/mL showed a persistent association with LLV and VF even in participants receiving INSTIs.

SARS-CoV-2 Evolution and Spike-Specific CD4+ T-Cell Response in Persistent COVID-19 with Severe HIV Immune Suppression.

Intra-host evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in cases with persistent coronavirus disease 2019 (COVID-19). In this study, we describe a severely immunosuppressed individual with HIV-1/SARS-CoV-2 coinfection with a long-term course of SARS-CoV-2 infection. A 28-year-old man was diagnosed with HIV-1 infection (CD4+ count: 3 cells/µL nd 563000 HIV-1 RNA copies/mL) and simultaneous Pneumocystis jirovecii pneumonia, disseminated Mycobacterium avium complex infection and SARS-CoV-2 infection. SARS-CoV-2 real-time reverse transcription polymerase chain reaction positivity from nasopharyngeal samples was prolonged for 15 weeks. SARS-CoV-2 was identified as variant Alpha (PANGO lineage B.1.1.7) with mutation S:E484K. Spike-specific T-cell response was similar to HIV-negative controls although enriched in IL-2, and showed disproportionately increased immunological exhaustion marker levels. Despite persistent SARS-CoV-2 infection, adaptive intra-host SARS-CoV-2 evolution, was not identified. Spike-specific T-cell response protected against a severe COVID-19 outcome and the increased immunological exhaustion marker levels might have favoured SARS-CoV-2 persistence.

Massive Release of CD9+ Microvesicles in Human Immunodeficiency Virus Infection, Regardless of Virologic Control.

BACKGROUND: The role of extracellular vesicles (EVs) in human immunodeficiency virus (HIV) pathogenesis is unknown. We examine the cellular origin of plasma microvesicles (MVs), a type of ectocytosis-derived EV, the presence of mitochondria in MVs, and their relationship to circulating cell-free mitochondrial deoxyribonucleic acid (ccf-mtDNA) in HIV-infected patients and controls. METHODS: Five participant groups were defined: 30 antiretroviral therapy (ART)-naive; 30 ART-treated with nondetectable viremia; 30 elite controllers; 30 viremic controllers; and 30 HIV-uninfected controls. Microvesicles were quantified and characterized from plasma samples by flow cytometry. MitoTrackerDeepRed identified MVs containing mitochondria and ccf-mtDNA was quantified by real-time polymerase chain reaction. RESULTS: Microvesicle numbers were expanded at least 10-fold in all HIV-infected groups compared with controls. More than 79% were platelet-derived MVs. Proportions of MVs containing mitochondria (22.3% vs 41.6%) and MV mitochondrial density (706 vs 1346) were significantly lower among HIV-infected subjects than controls, lowest levels for those on ART. Microvesicle numbers correlated with ccf-mtDNA levels that were higher among HIV-infected patients. CONCLUSIONS: A massive release of platelet-derived MVs occurs during HIV infection. Some MVs contain mitochondria, but their proportion and mitochondrial densities were lower in HIV infection than in controls. Platelet-derived MVs may be biomarkers of platelet activation, possibly reflecting pathogenesis even in absence of HIV replication.

Neonatal bilateral cerebral high flow fistulae leading to detection of a HHT-family carrier.

Cerebral and spinal cord high-flow arteriovenous fistulae (HFAVF) are part of the spectrum of lesions found in Hereditary Hemorrhagic Telangiectasia (HHT). HFAVF consist of communications between large arteries and veins without interposed nidi or capillary transitions. The association between HHT and cerebral or spinal HFAVF in children has been reported and suggested as a potential marker for HHT. We present a newborn with bilateral intracranial HFAVF tested positive for HHT1 and belonging to a family non known for carrying a HHT mutation. We also review reported cases of neonates and infants with cerebral and spinal HFAVF emphasizing their associations with genetic syndromes. Our aim is to add a new case to the pertinent literature and emphasize the need for molecular testing in children with spinal or brain HFAVF.

Overdose of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in an HIV-1-infected subject with attempted suicide.

INTRODUCTION: Data are lacking regarding overdose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF). MATERIAL AND METHODS: We present the first report of suicidal attempt with E/C/F/TAF in a Human Immunodeficiency Virus-infected subject. RESULTS: A reversible acute renal failure with no proximal tubulopathy and neuropsychiatric issues are discussed. E/C/F/TAF withdrawal resulted in favourable renal and neuropsychiatric outcomes. The suicide attempt seemed unrelated to the integrase strand transfer inhibitor, being evenly explained within the context of stressful personal conflicts. CONCLUSION: A suicidal attempt with an E/C/F/TAF overdose in an HIV-infected patient, resulted in a favourable outcome from a renal and neuropsychiatric standpoint.

Clinical Impact of Virological Failure and Resistance Analysis Definitions used in Pivotal Clinical Trials of Initial Antiretroviral Treatment: A Systematic Review

There are no standardized criteria to characterize confirmed protocol-defined virological failure (PDVF) nor the inclusion criteria for the resistance analysis population (RAP) in Phase III randomized clinical trials (RCTs) of initial antiretroviral therapy (ART). We assessed the clinical impact of mismatching between virological non-response (HIV-1 RNA ≥50 copies/mL), confirmed PDVF (48 weeks), and RAP definition in studies with the newest first-line ART. A systematic review of all Phase III RCTs was performed, including preferred once-daily ART (EACS European AIDS guidelines) or recently approved by the US Food and Drug Administration. We identified 16 treatment arms (14 RCTs) with 6175 participants treated with dolutegravir, bictegravir, elvitegravir/cobicistat, raltegravir, darunavir/cobicistat, rilpivirine, or doravirine. Plasma HIV-1 RNA thresholds for PDVF or RAP ranged from 40 to 50, 200, 400, and 500 copies/mL. This led to discrepancies between trials regarding the participants defined as virological non-responders, PDVF, or included in RAP. Overall, 85/296 (29%) patients with PDVF were not genotyped. There was a linear correlation between the threshold of HIV RNA chosen to perform genotyping and rates of participants with PDVF but not genotyped. Only eight treatment arms genotyped all participants with PDVF. Most of the remaining eight arms genotyped roughly < 50% of those with PDVF. In summary, the absence of standardized definitions of VF and criteria for resistance testing in pivotal Phase III RCTs of the first-line ART leads to the possibility of underreporting of resistance mutations when genotypes are only performed at higher viral load cutoffs. Stringent homogeneous criteria should be defined to ensure that all participants with PDVF (e.g., confirmed HIV RNA ≥ 50 copies/mL and the second > 200 copies/mL) undergo genotyping.

Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies.

The presence of resistance-associated substitutions (RASs) at NS5A region might compromise the efficacy of Direct Acting Antiviral agents (DAAs). HCV resistance at NS5A region is mainly focused on patients with hepatitis C virus (HCV) genotypes 1a (G1a) and 3 (G3) with other factors of poor treatment response (ie cirrhosis, prior treatment-exposure, or HCV-RNA >800 000 IU/mL). Herein, we evaluated in a cohort of HCV G1a and G3 infected patients the prevalence of RASs at domain I NS5A using population-based sequencing and the impact of RASs on the optimization of current therapeutic strategies. The RASs considered as clinically relevant were: M28A/G/T, Q30D/E/H/G/K/L/R, L31M/V/F, H58D, and Y93C/H/N/S for G1a and Y93H for G3. A total of 232 patients naïve to NS5A inhibitors were included (166 G1a, 66 G3). The overall prevalence of NS5A RASs for G1a and G3 patients was low (5.5%) or null, respectively. A high proportion of patients harbored, at least, one factor of poor response (78.9% for G1a, and 75.8% for G3). Overall, the rates of patients harboring NS5A RASs in combination with any of the other factors were low and the vast majority of patients (G1a> 94% and G3 100%) could be treated with standard treatments of 12 weeks without ribavirin. In conclusion, testing NS5A RASs in specific HCV-infected populations (ie G1a & G3, cirrhosis, prior treatment experienced, HCV-RNA >800 000 IU/mL) might be useful to optimize current NS5A-based therapies avoiding ribavirin-related toxicities, and shortening treatment duration in the majority of patients.

Cure of chronic hepatitis C virus infection in an HIV-coinfected patient with multiple comorbidities and drug interaction challenges.

Curing hepatitis C virus (HCV) infection in patients harbouring multiple severe comorbidities is a medical challenge. Evidence-based data are lacking regarding HCV treatment with direct-acting antiviral regimens in particular populations of HCV/HIV-coinfected patients with cirrhosis and chronic kidney disease on haemodialysis. Here, we present the HCV treatment challenges facing a patient with HIV coinfection, prior failure of both HIV-1 and HCV therapy, cirrhosis, end-stage renal failure on haemodialysis, as well as management of drug-drug interactions, especially given the need to receive long-term amiodarone therapy.

Inconsistency in classifying vascular anomalies: What's in a name?

BACKGROUND: Vascular anomalies are a heterogeneous group of disorders seen in children and adults. A standard nomenclature for classification has been offered by the International Society for the Study of Vascular Anomalies. Its application is important for communication among the multiple specialties involved in the care of patients and for planning treatment, as well as for research and billing. We hypothesized that terminology still is not uniformly applied, and that this could have an impact on treatment. METHODS: We retrospectively reviewed the medical records of patients with nonbrain lesions from our institutional vascular anomalies database seen during 2010-2016 for whom at least one clinic visit, radiologic imaging report, and pathology report were available to compare diagnoses among and within disciplines, and treatment recommendations. Diagnoses and referral patterns by community healthcare providers were also reviewed. RESULTS: Of 400 patients seen during the targeted time interval, 35 had clinical, imaging, and pathology reports. Agreement in terminology from initial clinic notes with imaging and pathology reports was noted in only three cases (9%). "Hemangioma" was often misused; "lymphangioma" and "cystic hygroma" persist as diagnostic labels. Community healthcare providers referred vascular malformations with a diagnosis of "mass" or "hemangioma" in 17 of 18 cases where that information was available. Incomplete or mislabeling of vascular anomalies sometimes delayed referrals to appropriate clinics, though it did not have a major impact on treatment. CONCLUSIONS: An understanding of vascular anomalies as tumors or malformations is not uniform. Ongoing education will be needed to promote consensus terminology and facilitate referrals.

Characterization of chronic HCV infection in Northwest Spain: Impact of the treatment strategic plan of the Spanish National Health Service on HCV cure.

The aim of the study was to characterize HCV infection in Northwest Spain and assess the impact of the Spanish Strategic Plan to cure HCV infection. Overall, 387 patients were included (60.9% HIV/HCV coinfected and 28.2% cirrhotic). Of these, 72.9% of patients that were recognized as priority for HCV treatment according to the Spanish Strategic Plan (≥F2, transplant or extrahepatic manifestations), initiated treatment during 2015. Globally, SVR12 was achieved in 96.5% of patients. The implementation of the Spanish Strategic Plan has been critical to advance in HCV cure, but 27.1% of priority patients still remain awaiting HCV treatment initiation.

Immune reconstitution inflammatory syndrome in an HIV-infected patient using subcutaneous silicone fillers.

The immune reconstitution inflammatory syndrome (IRIS) remains a concern in severely immunosuppressed HIV-infected patients after starting antiretroviral therapy. We present an HIV-infected transgender woman with subcutaneous silicone fillers, who simultaneously developed tuberculosis-associated and silicone-related IRIS. We propose a possible connection between IRIS and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA).