Search

Abstract Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have previously demonstrated that a patient's antibody reaction pattern in a confirmatory line immunoassay (INNO-LIA™ HIV I/II Score) provides information on the duration of infection, which is unaffected by clinical, immunological and viral variables. In this report we have set out to determine the diagnostic performance of Inno-Lia algorithms for identifying incident infections in patients with known duration of infection and evaluated the algorithms in annual cohorts of HIV notifications. Methods Diagnostic sensitivity was determined in 527 treatment-naive patients infected for up to 12 months. Specificity was determined in 740 patients infected for longer than 12 months. Plasma was tested by Inno-Lia and classified as either incident (< = 12 m) or older infection by 26 different algorithms. Incident infection rates (IIR) were calculated based on diagnostic sensitivity and specificity of each algorithm and the rule that the total of incident results is the sum of true-incident and false-incident results, which can be calculated by means of the pre-determined sensitivity and specificity. Results The 10 best algorithms had a mean raw sensitivity of 59.4% and a mean specificity of 95.1%. Adjustment for overrepresentation of patients in the first quarter year of infection further reduced the sensitivity. In the preferred model, the mean adjusted sensitivity was 37.4%. Application of the 10 best algorithms to four annual cohorts of HIV-1 notifications totalling 2'595 patients yielded a mean IIR of 0.35 in 2005/6 (baseline) and of 0.45, 0.42 and 0.35 in 2008, 2009 and 2010, respectively. The increase between baseline and 2008 and the ensuing decreases were highly significant. Other adjustment models yielded different absolute IIR, although the relative changes between the cohorts were identical for all models. Conclusions The method can be used for comparing IIR in annual cohorts of HIV notifications. The use of several different algorithms in combination, each with its own sensitivity and specificity to detect incident infection, is advisable as this reduces the impact of individual imperfections stemming primarily from relatively low sensitivities and sampling bias.

Abstract Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have shown that a patient's antibody reaction in a confirmatory line immunoassay (INNO-LIATM HIV I/II Score, Innogenetics) provides information on the duration of infection. Here, we sought to further investigate the diagnostic specificity of various Inno-Lia algorithms and to identify factors affecting it. Methods Plasma samples of 714 selected patients of the Swiss HIV Cohort Study infected for longer than 12 months and representing all viral clades and stages of chronic HIV-1 infection were tested blindly by Inno-Lia and classified as either incident (up to 12 m) or older infection by 24 different algorithms. Of the total, 524 patients received HAART, 308 had HIV-1 RNA below 50 copies/mL, and 620 were infected by a HIV-1 non-B clade. Using logistic regression analysis we evaluated factors that might affect the specificity of these algorithms. Results HIV-1 RNA Conclusions The specificity of most Inno-Lia algorithms was high and not affected by HIV-1 variability, advanced disease and other factors promoting false-recent results in other STARHS. Specificity should be good in any group of untreated HIV-1 patients.

Abstract Background Replicative phenotypic HIV resistance testing (rPRT) uses recombinant infectious virus to measure viral replication in the presence of antiretroviral drugs. Due to its high sensitivity of detection of viral minorities and its dissecting power for complex viral resistance patterns and mixed virus populations rPRT might help to improve HIV resistance diagnostics, particularly for patients with multiple drug failures. The aim was to investigate whether the addition of rPRT to genotypic resistance testing (GRT) compared to GRT alone is beneficial for obtaining a virological response in heavily pre-treated HIV-infected patients. Methods Patients with resistance tests between 2002 and 2006 were followed within the Swiss HIV Cohort Study (SHCS). We assessed patients' virological success after their antiretroviral therapy was switched following resistance testing. Multilevel logistic regression models with SHCS centre as a random effect were used to investigate the association between the type of resistance test and virological response (HIV-1 RNA Results Of 1158 individuals with resistance tests 221 with GRT+rPRT and 937 with GRT were eligible for analysis. Overall virological response rates were 85.1% for GRT+rPRT and 81.4% for GRT. In the subgroup of patients with >2 previous failures, the odds ratio (OR) for virological response of GRT+rPRT compared to GRT was 1.45 (95% CI 1.00-2.09). Multivariate analyses indicate a significant improvement with GRT+rPRT compared to GRT alone (OR 1.68, 95% CI 1.31-2.15). Conclusions In heavily pre-treated patients rPRT-based resistance information adds benefit, contributing to a higher rate of treatment success.

Abstract Introduction Timely diagnosis of primary HIV infection is important to prevent further transmission of HIV. Primary HIV infection may take place without symptoms or may be associated with fever, pharyngitis or headache. Sometimes, the clinical presentation includes aseptic meningitis or cutaneous lesions. Intestinal ulceration due to opportunistic pathogens (cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii) has been described in patients with AIDS. However, although invasion of intestinal lymphoid tissue is a prominent feature of human and simian lentivirus infections, colonic ulceration has not been reported in acute HIV infection. Case description A 42-year-old Caucasian man was treated with amoxicillin-clavulanate for pharyngitis. He did not improve, and a rash developed. History taking revealed a negative HIV antibody test five months previously and unprotected sex with a male partner the month before admission. Repeated tests revealed primary HIV infection with an exceptionally high HIV-1 RNA plasma concentration (3.6 × 107 copies/mL) and a low CD4 count (101 cells/mm3, seven percent of total lymphocytes). While being investigated, the patient had a life-threatening hematochezia. After angiographic occlusion of a branch of the ileocaecal artery and initiation of antiretroviral therapy, the patient became rapidly asymptomatic and could be discharged. Colonoscopy revealed a bleeding colonic ulcer. We were unable to identify an etiology other than HIV for this ulcer. Conclusion This case adds to the known protean manifestation of primary HIV infection. The lack of an alternative etiology, despite extensive investigations, suggests that this ulcer was directly caused by primary HIV infection. This conclusion is supported by the well-described extensive loss of intestinal mucosal CD4+ T cells associated with primary HIV infection, the extremely high HIV viral load observed in our patient, and the rapid improvement of the ulcer after initiation of highly active antiretroviral therapy. This case also adds to the debate on treatment for primary HIV infection, especially in the context of severe symptoms and an extremely high viral load.

Abstract Background The prevalence and the origin of HIV-1 subtype B, the most prevalent circulating clade among the long-term residents in Europe, have been studied extensively. However the spatial diffusion of the epidemic from the perspective of the virus has not previously been traced. Results In the current study we inferred the migration history of HIV-1 subtype B by way of a phylogeography of viral sequences sampled from 16 European countries and Israel. Migration events were inferred from viral phylogenies by character reconstruction using parsimony. With regard to the spatial dispersal of the HIV subtype B sequences across viral phylogenies, in most of the countries in Europe the epidemic was introduced by multiple sources and subsequently spread within local networks. Poland provides an exception where most of the infections were the result of a single point introduction. According to the significant migratory pathways, we show that there are considerable differences across Europe. Specifically, Greece, Portugal, Serbia and Spain, provide sources shedding HIV-1; Austria, Belgium and Luxembourg, on the other hand, are migratory targets, while for Denmark, Germany, Italy, Israel, Norway, the Netherlands, Sweden, Switzerland and the UK we inferred significant bidirectional migration. For Poland no significant migratory pathways were inferred. Conclusion Subtype B phylogeographies provide a new insight about the geographical distribution of viral lineages, as well as the significant pathways of virus dispersal across Europe, suggesting that intervention strategies should also address tourists, travellers and migrants.

Background: Treatment with anti‐CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA‐based COVID‐19 vaccines in children aged 5–18 years undergoing rituximab treatment compared to healthy matched children. Methods: Between 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5–18 years under rituximab treatment who had received two mRNA‐based SARS‐CoV‐2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS‐CoV‐2 infection. Blood samples were collected at day 60 (±30) and day 270 (±90) after the second vaccination. Results: The rituximab‐treated group exhibited significantly lower levels of antibodies specific to the anti‐receptor binding domain (RBD) of the SARS‐CoV‐2 spike (S) protein than healthy controls at 60 (±30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p =.008). However, patients with a rituximab‐to‐vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti‐N antibody levels) had a high level of anti‐RBD antibodies. Conclusion: A past infection with SARS‐CoV‐2 may induce anti‐RBD‐specific memory B cells that can be re‐activated by SARS‐CoV‐2 vaccination, even after rituximab‐induced B‐cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Background Allogeneic hematopoietic cell transplant recipients (allo-HCTRs) with positive cytomegalovirus (CMV) serology may have false-positive results due to blood product transfusion–associated passive immunity. Methods This single-center cohort study included allo-HCTRs with negative baseline (at malignancy diagnosis) CMV serology and indeterminate/low-positive (CMV IgG titer, ≥0.6–<50 U/mL) pretransplant CMV serology with negative pretransplant plasma CMV DNAemia. The CMV status of those patients was reclassified from R+ to R− (CMVR− reclassification group). We compared those patients to allo-HCTRs with negative (CMV IgG titer <0.6 U/mL) pretransplant CMV IgG (CMVR− group). We describe the number and type of patients whose pretransplant CMV status was reclassified from indeterminate/positive to negative. We reviewed all plasma CMV DNAemia tests performed during the first 6 months posttransplant in both groups to assess the safety of this approach. Results Among 246 (84.5%) of 291 transplanted patients identified as CMVR+ pretransplant, 60 (24.4%) were reclassified from CMV serology indeterminate (N:10)/low-positive (N:50) to R−. Only 1 of 60 patients (1.67%) in the CMVR− reclassification group versus 3 of 44 (6.8%; P =.30) in the CMVR− group developed CMV DNAemia during the follow-up period. There were no significant differences in the number of CMV DNAemia tests performed, CMV DNAemia range, and time posttransplant between the 2 groups. Conclusions One of 4 allo-HCT CMVR+ may be falsely flagged as R+, with significant impact on donor selection and prophylaxis administration. A 2-step approach including CMV serology testing at hematologic malignancy diagnosis in allo-HCT candidates and careful review of pretransplant CMV IgG titers may help correctly classify CMV serology status. [ABSTRACT FROM AUTHOR]

Among 292 recipients of allogeneic hematopoietic cell transplant (2018–2022), 64 (21.9%) tested positive for anti–hepatitis E virus (HEV) immunoglobulin G. Among 208 recipients tested by plasma/serum HEV polymerase chain reaction (2012–2022), 3 (1.4%) primary HEV infections were diagnosed; in 1 patient, plasma HEV polymerase chain reaction relapsed positive for 100 days. HEV infection remains rare albeit associated with persistent viral replication. [ABSTRACT FROM AUTHOR]

Immunocompromised patients (ICPs) have a higher risk of developing severe forms of COVID-19 and experience a higher burden of complications and mortality than the general population. However, recent studies have suggested that the antibody response to SARS-CoV-2 mRNA vaccines could be highly variable among different ICPs. Using a collaborative, monocentric, prospective cohort study, we assessed anti-SARS-CoV-2 spike protein antibody titers following two and three doses of mRNA vaccines in four groups of ICPs (cancer [n = 232]: hematopoietic stem cell transplant [HSCT; n = 126] patients; people living with HIV [PLWH; n = 131]; and lung transplant [LT; n = 39] recipients) treated at Geneva University Hospitals; and healthy individuals (n = 49). After primo-vaccination, the highest anti-S antibody geometric mean titer (IU/mL) was observed in healthy individuals (2417 IU/mL [95% CI: 2327–2500]), the PLWH group (2024 IU/mL [95% CI:1854–2209]) and patients with cancer (840 IU/mL [95% CI: 625–1129]), whereas patients in the HSCT and LT groups had weaker antibody responses (198 IU/mL [95% CI: 108–361] and 7.3 IU/mL [95% CI: 2.5–22]). The booster dose conferred a high antibody response after 1 month in both PLWH (2500 IU/mL) and cancer patients (2386 IU/mL [95% CI: 2182–2500]), a moderate response in HSCT patients (521 IU/mL [95% CI: 306–885]) and a poor response in LT recipients (84 IU/mL [95% CI: 18–389]). Contemporary treatment with immunosuppressive drugs used in transplantation or chemotherapy was associated with a poor response to vaccination. Our findings confirmed the heterogeneity of the humoral response after mRNA vaccines among different ICPs and the need for personalized recommendations for each of these different groups. [ABSTRACT FROM AUTHOR]

Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen--viral load, length of untreated infection and viral diversity--independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 x 10[sup.-5]). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design., Author(s): Peter Rusert [1]; Roger D Kouyos [1, 2]; Claus Kadelka [1, 2]; Hanna Ebner [1]; Merle Schanz [1]; Michael Huber [1]; Dominique L Braun [1, 2]; Nathanael Hozé [3]; [...]

Background and Aims: Hepatitis C (HCV) programs face challenges, especially linked to key populations to achieve World Health Organization (WHO) goals of eliminating hepatitis. Médecins Sans Frontières and Mozambique's Ministry of Health first implemented HCV treatment in Maputo, in 2016 and harm reduction activities in 2017. Methods: We retrospectively analyzed routine data of patients enrolled between December 2016 and July 2021. Genotyping was systematically requested up to 2018 and subsequently in cases of treatment failure. Sustainable virological response was assessed 12 weeks after the end of treatment by sofosbuvir‐daclatasvir or sofosbuvir‐velpatasvir. Results: Two hundred and two patients were enrolled, with 159 (78.71%) males (median age: 41 years [interquartile range (IQR): 37.10, 47.00]). Risk factors included drug use (142/202; 70.29%). One hundred and eleven genotyping results indicated genotype 1 predominant (87/111; 78.37%). Sixteen patients presented genotype 4, with various subtypes. The people who used drugs and HIV coinfected patients were found more likely to present a genotype 1. Intention‐to‐treat analysis showed 68.99% (89/129) cure rate among the patients initiated and per‐protocol analysis, 88.12% (89/101) cure rate. Nineteen patients received treatment integrated with opioid substitution therapy, with a 100% cure rate versus 59.37% (38/64) for initiated ones without substitution therapy (p < 0.001). Among the resistance testing performed, NS5A resistance‐associated substitutions were found in seven patients among the nine tested patients and NS5B ones in one patient. Conclusion: We found varied genotypes, including some identified as difficult‐to‐treat subtypes. People who used drugs were more likely to present genotype 1. In addition, opioid substitution therapy was key for these patients to achieve cure. Access to second‐generation direct‐acting antivirals (DAAs) and integration of HCV care with harm reduction are crucial to program effectiveness. [ABSTRACT FROM AUTHOR]

Background Next-generation sequencing (NGS) is gradually replacing Sanger sequencing (SS) as the primary method for HIV genotypic resistance testing. However, there are limited systematic data on comparability of these methods in a clinical setting for the presence of low-abundance drug resistance mutations (DRMs) and their dependency on the variant-calling thresholds. Methods To compare the HIV-DRMs detected by SS and NGS, we included participants enrolled in the Swiss HIV Cohort Study (SHCS) with SS and NGS sequences available with sample collection dates ≤7 days apart. We tested for the presence of HIV-DRMs and compared the agreement between SS and NGS at different variant-calling thresholds. Results We included 594 pairs of SS and NGS from 527 SHCS participants. Males accounted for 80.5% of the participants, 76.3% were ART naive at sample collection and 78.1% of the sequences were subtype B. Overall, we observed a good agreement (Cohen's kappa >0.80) for HIV-DRMs for variant-calling thresholds ≥5%. We observed an increase in low-abundance HIV-DRMs detected at lower thresholds [28/417 (6.7%) at 10%–25% to 293/812 (36.1%) at 1%–2% threshold]. However, such low-abundance HIV-DRMs were overrepresented in ART-naive participants and were in most cases not detected in previously sampled sequences suggesting high sequencing error for thresholds <3%. Conclusions We found high concordance between SS and NGS but also a substantial number of low-abundance HIV-DRMs detected only by NGS at lower variant-calling thresholds. Our findings suggest that a substantial fraction of the low-abundance HIV-DRMs detected at thresholds <3% may represent sequencing errors and hence should not be overinterpreted in clinical practice. [ABSTRACT FROM AUTHOR]