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Background: This retrospective follow‐up study aims to investigate the dynamic longitudinal change of plasma neurofilament light (NfL) levels after antiretroviral therapy (ART) initiation in a cohort of people living with human immunodeficiency virus (HIV) (PWH). Methods: We tested a convenience sample of 116 patients from the NORTHIV study. Plasma NfL levels—measured using Single molecule array (Simoa) technology—as well as other laboratory parameters were collected at baseline, weeks 4, 48, 96, and 144. Linear mixed‐effects models were estimated to evaluate longitudinal change over time. Baseline CD4+ T‐cell levels, CDC classification, and HIV RNA levels were considered. Models were adjusted by age, sex, treatment regimen, and baseline serum creatinine levels. Results: Plasma NfL levels were higher at baseline and also declined faster during the follow‐up for participants with CD4+ count <100 cells/µl compared with >100 cells/µl. No significant difference was found between the CD4+ strata 100–199 and 200–499/µl. Participants with CDC classification stages B and C had higher levels of plasma NfL at baseline, as well as faster decline compared with participants with stage A. No significant main effects or change over time was found in baseline HIV RNA levels, treatment regimen, or sex. Conclusion: Plasma NfL is a sensitive biomarker to assess ongoing central nervous system injury in PWH. Plasma NfL concentrations decline relatively fast following ART initiation and then stabilize after 48 weeks. Plasma NfL concentrations are associated with CD4+ count and stage of HIV disease. No correlations were seen with different ART regimens. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) can develop resistance to all antiretroviral drugs. Multidrug resistance, however, is a rare event in modern HIV treatment, but can be life‐threatening, particular in patients with very long therapy histories and in areas with limited access to novel drugs. To understand the evolution of multidrug resistance, we analyzed the EuResist database to uncover the accumulation of mutations over time. We hypothesize that the accumulation of resistance mutations is not acquired simultaneously and randomly across viral genotypes but rather tends to follow a predetermined order. The knowledge of this order might help to elucidate potential mechanisms of multidrug resistance. Our evolutionary model shows an almost monotonic increase of resistance with each acquired mutation, including less well‐known nucleoside reverse transcriptase (RT) inhibitor‐related mutations like K223Q, L228H, and Q242H. Mutations within the integrase (IN) (T97A, E138A/K G140S, Q148H, N155H) indicate high probability of multidrug resistance. Hence, these IN mutations also tend to be observed together with mutations in the protease (PR) and RT. We followed up with an analysis of the mutation‐specific error rates of our model given the data. We identified several mutations with unusual rates (PR: M41L, L33F, IN: G140S). This could imply the existence of previously unknown virus variants in the viral quasispecies. In conclusion, our bioinformatics model supports the analysis and understanding of multidrug resistance. [ABSTRACT FROM AUTHOR]

Mucus is a self‐healing gel that lubricates the moist epithelium and provides protection against viruses by binding to viruses smaller than the gel's mesh size and removing them from the mucosal surface by active mucus turnover. As the primary nonaqueous components of mucus (≈0.2%–5%, wt/v), mucins are critical to this function because the dense arrangement of mucin glycans allows multivalence of binding. Following nature's example, bovine submaxillary mucins (BSMs) are assembled into "mucus‐like" gels (5%, wt/v) by dynamic covalent crosslinking reactions. The gels exhibit transient liquefaction under high shear strain and immediate self‐healing behavior. This study shows that these material properties are essential to provide lubricity. The gels efficiently reduce human immunodeficiency virus type 1 (HIV‐1) and genital herpes virus type 2 (HSV‐2) infectivity for various types of cells. In contrast, simple mucin solutions, which lack the structural makeup, inhibit HIV‐1 significantly less and do not inhibit HSV‐2. Mechanistically, the prophylaxis of HIV‐1 infection by BSM gels is found to be that the gels trap HIV‐1 by binding to the envelope glycoprotein gp120 and suppress cytokine production during viral exposure. Therefore, the authors believe the gels are promising for further development as personal lubricants that can limit viral transmission. [ABSTRACT FROM AUTHOR]

Objectives: To explore the effectiveness and durability of integrase strand transfer inhibitor (INSTI)‐based regimens in pre‐treated subjects. Methods: Treatment‐experienced individuals starting an INSTI‐based regimen during 2012–2019 were selected from the INTEGRATE collaborative study. The time to virological failure [VF: one measurement of viral load (VL) ≥ 1000 copies/mL or two ≥ 50 copies/ml or one VL measurement ≥ 50 copies/mL followed by treatment change] and to INSTI discontinuation were evaluated. Results: Of 13 560 treatments analysed, 4284 were from INSTI‐naïve, non‐viraemic (IN‐NV) individuals, 1465 were from INSTI‐naïve, viraemic (IN‐V) individuals, 6016 were from INSTI‐experienced, non‐viraemic (IE‐NV) individuals and 1795 were from INSTI‐experienced, viraemic (IE‐V) individuals. Major INSTI drug resistance mutations (DRMs) were previously detected in 4/519 (0.8%) IN‐NV, 3/394 (0.8%) IN‐V, 7/1510 (0.5%) IE‐NV and 25/935 (2.7%) IE‐V individuals. The 1‐year estimated probabilities of VF were 3.1% [95% confidence interval (CI): 2.5–3.8] in IN‐NV, 18.4% (95% CI: 15.8–21.2) in IN‐V, 4.2% (95% CI: 3.6–4.9) in IE‐NV and 23.9% (95% CI: 20.9–26.9) in IE‐V subjects. The 1‐year estimated probabilities of INSTI discontinuation were 12.1% (95% CI: 11.1–13.0) in IN‐NV, 19.6% (95% CI: 17.5–21.6) in IN‐V, 10.8% (95% CI: 10.0–11.6) in IE‐NV and 21.7% (95% CI: 19.7–23.5) in IE‐V subjects. Conclusions: Both VF and INSTI discontinuation occur at substantial rates in viraemic subjects. Detection of DRMs in a proportion of INSTI‐experienced individuals makes INSTI resistance testing mandatory after failure. [ABSTRACT FROM AUTHOR]

General consensus suggests that even singleton E138A mutations in HIV reverse transcriptase at baseline are associated with resistance to rilpivirine (RPV). We detected 11 pre‐existing E138A carriers treated with RPV in the pan European EuResist database. However, all 11 patients presented with full virological efficacy for first‐line RPV‐based ART regimens. [ABSTRACT FROM AUTHOR]

Objectives: Humoral and cellular immunity to SARS‐CoV‐2 following COVID‐19 will likely contribute to protection from reinfection or severe disease. It is therefore important to characterise the initiation and persistence of adaptive immunity to SARS‐CoV‐2 amidst the ongoing pandemic. Methods: Here, we conducted a longitudinal study on hospitalised moderate and severe COVID‐19 patients from the acute phase of disease into convalescence at 5 and 9 months post‐symptom onset. Utilising flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune responses during and after human SARS‐CoV‐2 infection. Results: During acute COVID‐19, we observed an increase in germinal centre activity, a substantial expansion of antibody‐secreting cells and the generation of SARS‐CoV‐2‐neutralising antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralising antibody titres as well as robust specific memory B cell responses and polyfunctional T cell responses at 5 and 9 months after symptom onset in both moderate and severe COVID‐19 patients. Conclusion: Our findings describe the initiation and, importantly, persistence of cellular and humoral SARS‐CoV‐2‐specific immunological memory in hospitalised COVID‐19 patients long after recovery, likely contributing towards protection against reinfection. [ABSTRACT FROM AUTHOR]

Objectives: The role of innate lymphoid cells (ILCs) in coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is unknown. Understanding the immune response in COVID‐19 could contribute to unravel the pathogenesis and identification of treatment targets. Here, we describe the phenotypic landscape of circulating ILCs in COVID‐19 patients and identified ILC phenotypes correlated to serum biomarkers, clinical markers and laboratory parameters relevant in COVID‐19. Methods: Blood samples collected from moderately (n = 11) and severely ill (n = 12) COVID‐19 patients, as well as healthy control donors (n = 16), were analysed with 18‐parameter flow cytometry. Using supervised and unsupervised approaches, we examined the ILC activation status and homing profile. Clinical and laboratory parameters were obtained from all COVID‐19 patients, and serum biomarkers were analysed with multiplex immunoassays. Results: Innate lymphoid cells were largely depleted from the circulation of COVID‐19 patients compared with healthy controls. Remaining circulating ILCs revealed decreased frequencies of ILC2 in severe COVID‐19, with a concomitant decrease of ILC precursors (ILCp) in all patients, compared with controls. ILC2 and ILCp showed an activated phenotype with increased CD69 expression, whereas expression levels of the chemokine receptors CXCR3 and CCR4 were significantly altered in ILC2 and ILCp, and ILC1, respectively. The activated ILC profile of COVID‐19 patients was associated with soluble inflammatory markers, while frequencies of ILC subsets were correlated with laboratory parameters that reflect the disease severity. Conclusion: This study provides insights into the potential role of ILCs in immune responses against SARS‐CoV‐2, particularly linked to the severity of COVID‐19. [ABSTRACT FROM AUTHOR]

Marginal structural Cox models have been used to estimate the causal effect of a time-varying treatment on a survival outcome in the presence of time-dependent confounders. These methods rely on the positivity assumption, which states that the propensity scores are bounded away from zero and one. Practical violations of this assumption are common in longitudinal studies, resulting in extreme weights that may yield erroneous inferences. Truncation, which consists of replacing outlying weights with less extreme ones, is the most common approach to control for extreme weights to date. While truncation reduces the variability in the weights and the consequent sampling variability of the estimator, it can also introduce bias. Instead of truncated weights, we propose using optimal probability weights, defined as those that have a specified variance and the smallest Euclidean distance from the original, untruncated weights. The set of optimal weights is obtained by solving a constrained quadratic optimization problem. The proposed weights are evaluated in a simulation study and applied to the assessment of the effect of treatment on time to death among people in Sweden who live with human immunodeficiency virus and inject drugs. [ABSTRACT FROM AUTHOR]

Background: A lower virulence of HIV-1 subtype C (HIV-1C) is suggested to be related to the global dominance of HIV-1C. In this observational study, combining in vivo (clinical monitoring) and in vitro (genotypic, biochemical, and phenotypic assays), we explored whether HIV-1C from East Africa (HIV-1CEA) is more pathogenic due to the evolution of a PYxE-insertion (CPYxEi) in the gag-p6 that also could affect the therapy response. Methods: HIV-1B (n = 112) and HIV-1CEA (n = 128)-infected individuals residing in Sweden were analyzed with regard to Gag-p6 genotype and clinically monitored. Based on the Gag-p6 characteristics, three HIV-1CEA and one HIV-1 B patient-derived p2-INT-recombinant virus (gag-p2/NCp7/p1/p6/pol-PR/RT/IN) were constructed to analyze viral growth kinetics (VGKs) and drug sensitivity assays. Reverse transcriptase (RT) from the same samples was cloned into the heterodimer expression plasmid (pRT6H-PROT) to analyze catalytic efficiency of RT. Results: A higher viral failure rate and lower pre-therapy CD4+ T-cell counts were observed in HIV-1CEA-infected patients compared to HIV-1B-infected patients. In Gag-p6, PTAP-duplication was more common in HIV-1C. HIV-1CEA-infected patients with signature CPYxEi, evidenced very low pre-therapy CD4+ T-cell counts and suboptimal gain in CD4+ T-cells following therapy, as compared to the non-CPYxEi-strains indicating higher virulence. VGKs showed a statistically significant higher replication capacity (RC) for the CPYxEi viruses than the other two non-CPYxEi strains. No statistically significant difference was observed in the catalytic efficiency among HIV-1C RTs. Conclusions: This is the first evidence of polymerase independent increased virulence and RC in HIV-1CEA following PYxE-insertion that is associated with suboptimal CD4+ T-cell gain following therapy initiation. J. Med. Virol. 89:106-111, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Little is known about the incidence and risk of cervical intraepithelial neoplasia (CIN) grade 3, adenocarcinoma in situ and invasive cervical cancer (CIN3+) among migrants living with HIV in a European setting. We assessed the cumulative incidence (CuI) and hazard ratio (HR) of CIN2+ and CIN3+ in a cohort of women living with HIV (WLWH) ( n = 893) identified from the Swedish national HIV register and HIV-negative women ( n = 205,842) identified from the Swedish Population Register, matched on region of birth and age. Data was collected between 1993 and 2011 by linking our cohort with the Swedish National Cervical Screening Registry, collecting all cytological and histological results since 1993. The CuI of CIN3+ was 13.1% [95% confidence interval (CI) 8.9-17.2] for WLWH and 2.1% (95% CI 2.0-2.2) for HIV-negative after 18 years of follow-up. WLWH had more than eight times higher, age and region of birth matched, risk of CIN3+ than HIV-negative (HR 8.8: 95% CI 6.9-11.3). WLWH born in the East region, dominated by Thai women, had a two times higher risk of CIN3+ compared with WLWH born in Sweden (HR 2.47: 95% CI 1.2-5.0), which remained after adjusting for immunosuppression. Our results showed a substantially increased risk of CIN3+ among WLWH, which differed depending on birth region. Early HIV diagnosis and attendance to cervical cancer screening, with focus on migrants, is of crucial importance to minimize the incidence of cervical intraepithelial neoplasia. [ABSTRACT FROM AUTHOR]

Introduction The role of microbial translocation (MT) in HIV patients living with HIV from low‐ and middle‐income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden. Methods Cross‐sectional samples were obtained from treatment‐naïve patients living with HIV‐1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti‐flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme‐linked immunosorbent assay. Results All three biomarkers were significantly increased in patients living with HIV‐1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti‐flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti‐flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection. Conclusions Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high‐income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome. [ABSTRACT FROM AUTHOR]

Drug resistance testing is an important tool in the management of HIV-1 infection. As access to genotypic resistance assays is limited in low- and middle-income settings, alternatives are warranted. The aim of the study was to adapt a phenotypic drug susceptibility assay, ExaVir Drug, for detection of resistance to the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR). Five NNRTI resistant mutant forms of RT were produced (L100I, K103N, L100I/K103N, Y181C, V179D) in order to validate the assay for ETR. Furthermore, HIV-1 RT was purified from plasma samples (n = 28) obtained from treatment naïve and experienced HIV-1 infected patients, and ETR drug susceptibility (IC50) was estimated. The direct sequencing of the pol gene was performed. The recombinant RT mutants had the expected changes in drug sensitivity patterns. The RTs isolated from plasma of therapy naïve individuals showed low IC50 for ETR. In the plasma virus from treatment experienced patients with Y181C, A98G, V108I, and/or K101E mutations in the pol gene, higher IC50 values were found in line with reduced susceptibility data for ETR. This study demonstrates that ExaVir® Drug, a simple enzymatic phenotypic assay, can be used for detection of ETR resistance, including cross-resistance to other NNRTIs, in clinical samples. A further evaluation is needed to define clinical cut-offs; however the assay is an alternative to more costly HIV drug resistance tests, especially in low-income countries. J. Med. Virol. 85:703-708, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Invariant CD1d-restricted NKT cells play important roles in regulating both innate and adaptive immunity. They are targeted by HIV-1 infection and severely reduced in number or even lost in many infected subjects. Here, we have investigated the characteristics of NKT cells retained by some patients despite chronic HIV-1 infection. NKT cells preserved under these circumstances displayed an impaired ability to proliferate and produce IFN-γ in response to CD1d-restricted lipid antigen as compared with cells from uninfected control subjects. HIV-1 infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor (CD279) on the CD4 subset of NKT cells. However, blocking experiments indicated that the functional defects in NKT cells were largely PD-1-independent. Furthermore, the elevated PD-1 expression and the functional defects were not restored by anti-retroviral treatment, and the NKT cell numbers in blood did not recover significantly in response to treatment. The functional phenotype of NKT cells in these patients suggests an irreversible immune exhaustion due to chronic activation in vivo. The data demonstrate a severe functional impairment in the remaining NKT-cell compartment in HIV-1-infected patients, which limits the prospects to mobilize these cells in immunotherapy approaches in patients. [ABSTRACT FROM AUTHOR]

Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n = 43), triple (n = 14) or dual (n = 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or four-drug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine + PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy. J. Med. Virol. 81:1-8, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT- Thirty-nine of 61 prospectively followed patients who had had acute non-A, non-B hepatitis in 1978 were clinically reexamined in 1991 and tested for antibodies to hepatitis C virus (anti-HCV) with a second generation ELISA and RIBA and for HCV RNA by PCR. Acute hepatitis C was diagnosed in stored sera from 1978 in 24 patients, who were found still to be anti-HCV positive in 1991, and 16 of them were also HCV RNA positive. The majority of anti-HCV positive patients with or without HCV RNA had elevated serum ALT levels 13 years after onset of their acute hepatitis C. After 13 years follow-up, 1.6% of the patients had died of end-stage liver disease, 8% of anti-HCV positive patients had histologically confirmed liver cirrhosis, 79% of anti-HCV positive patients were judged to have chronic infection, whereas 21% seemed to have recovered. To conclude, we found that a majority of our patients with acute symptomatic hepatitis C continued to be viraemic 13 years after onset of hepatitis C, and that all continued to be anti-HCV positive by second-generation ELISA. [ABSTRACT FROM AUTHOR]

Introduction The health condition of HIV-1 infected patients has improved during the last years, but lifelong antiretroviral treatment is still needed. However resistance, multiple side effects and drug to drug interactions of antiretrovirals challenge the establishment of a long lasting regimen. The average running time of each antiretroviral drug composing the therapy episodes combination antiretroviral therapy (cART) may be seen as an indicator of effectiveness and tolerability. Materials and Methods To evaluate the running time of each drug used in HIV-1 treatment, we extracted therapy episodes from the latest release of the EuResist database (). The evaluation period was from Oct 2006 to Oct 2012. Inclusion criteria for this analysis were continuous patient monitoring for at least two years (i.e. latest therapy start in Oct 2010), and the extraction of at least 100 cases per drug analyzed. Drug intake interruptions of less than a month were ignored. Results At the time of data extraction (Feb 2013), the EuResist database contained data from 61,953 patients of which 11,499 fulfilled the inclusion criteria. We obtained 37,035 drug treatment lines from 38,153 cARTs and the overall average length of drug intake was 18.7 months. For each single drug these average durations measured in months were: 18.3 (3TC); 20.8 (ABC); 12.3 (d4T); 14.3 (ddI); 23.2 (FTC); 23.0 (TDF); 13.4 (ZDV); 19.8 (EFV); 21.9 (ETR); 17.7 (NVP); 19.2 (ATV); 22.7 (DRV); 18.7 (FPV); 17.9 (LPV); 15.2 (SQV); 14.6 (TPV); 22.6 (RAL); 21.9 (MVC) and 8.9 (T20). Overall drug discontinuation rates at one, two and three years were 35.0, 48.8 and 95.8%, respectively. Average discontinuation rates for the different drug classes at two years these were: 46.2% for NRTIs; 49.7% for NNRTIs; 55.4% for PIs and 37.6% for Raltegravir/Maraviroc. Conclusions In this cohort the overall frequency of therapy changes is high. After two years of treatment, on average 49% of the patients change at least one drug in their cART. Thus, we have to expect numerous changes in the long term perspective of treatments. The observed differences in durations suggest that newer drugs might have advantages over older ones. However possible reasons and confounding factors (such as number of past treatment lines, co-medication, risk group, etc.) were not addressed at this time of the analysis. [ABSTRACT FROM AUTHOR]